An Open-Label, Uncontrolled, Single-Arm Clinical Trial of Tofacitinib, an Oral JAK1 and JAK3 Kinase Inhibitor, in Chinese Patients with Keloid.

BACKGROUND: The keloid treatment is still a thorny and complicated clinical problem, especially in multiple keloids induced by wound, severe burn, ethnic background or cultural behaviors, or unexplained skin healing. Mainstream treatments have limited efficacy in treating multiple keloids. As no oral treatment with painlessness and convenience is available, oral treatment strategies should be formulated. OBJECTIVES: This study aimed to investigate the efficacy and therapeutic mechanism of oral tofacitinib in keloid patients. METHODS: We recruited the 7 patients with keloid scars and prescribed 5 mg of tofacitinib twice a day orally with a maximum follow-up of 12 weeks. The Patient and Observer Scar Assessment Scale (POSAS), the Vancouver scar scale (VSS), ANTERA 3D camera, and the DUB Skin Scanner 75 were used to assess the characteristics of the lesion. Immunohistochemistry was performed to evaluate collagen synthesis, proliferation, and relative molecular pathways. Moreover, the effects of tofacitinib were assessed on keloid fibroblast in vitro. RESULTS: After 12 weeks of oral tofacitinib, significant improvement in POSAS, VSS, and Dermatology Life Quality Index (DLQI) scores was observed (p < 0.05). The volume, lesion height, and dermis thickness of the keloid decreased (p < 0.05). Moreover, significant decreases in the expression of collagen I, Ki67, p-STAT 3, and p-SMAD2 were observed after 12 weeks of administration. In vitro experiments suggested that tofacitinib treatment inhibits fibroblast proliferation and collagen I synthesis via suppression of STAT3 and SMAD2 pathway. CONCLUSION: Tofacitinib, a new candidate oral drug for keloid, could reduce keloid lesion volume by inhibiting collagen synthesis and inhibiting fibroblast proliferation, and alleviate itch and pain to obtain a better life quality.

Isolation, Culture, and Characterization of Primary Dermal Fibroblasts from Human Keloid Tissue.

Fibroblasts, the major cell type in keloid tissue, play an essential role in the formation and development of keloids. The isolation and culture of primary fibroblasts derived from keloid tissue are the basis for further studies of the biological function and molecular mechanisms of keloids, as well as new therapeutic strategies for treating them. The traditional method of obtaining primary fibroblasts has limitations, such as poor cellular state, mixing with other types of cells, and susceptibility to contamination. This paper describes an optimized and easily reproducible protocol that could reduce the occurrence of possible issues when obtaining fibroblasts. In this protocol, fibroblasts can be observed 5 days after isolation and reach nearly 80% confluency after 10 days of culture. Then, the fibroblasts are passaged and verified using PDGFRα and vimentin antibodies for immunofluorescence assays and CD90 antibodies for flow cytometry. In conclusion, fibroblasts from keloid tissue can be easily acquired through this protocol, which can provide an abundant and stable source of cells in the laboratory for keloid research.

TSP1 promotes fibroblast proliferation and extracellular matrix deposition via the IL6/JAK2/STAT3 signalling pathway in keloids.

Keloids are benign fibroproliferative diseases with abnormally proliferated bulges beyond the edge of the skin lesions, and they are characterized by uncontrolled fibroblast proliferation and excessive extracellular matrix deposition in the dermis. However, the definite mechanisms that increase fibroblast proliferation and collagen deposition in keloids remain unclear. Thrombospondin 1 (TSP1) has been suggested to play an important role in wound healing and fibrotic disorders, but its role in keloids is unknown. In this study, we aimed to clarify the specific role of TSP1 in keloids and explore the potential mechanism. Our results demonstrated that TSP1 was highly expressed in keloid lesions compared to normal skin. Knockdown of TSP1 in keloid fibroblasts decreased cell proliferation and collagen I deposition. Exogenous TSP1 treatment increased cell proliferation and collagen I deposition in normal fibroblasts. We further investigated the underlying mechanism and found that TSP1 promoted fibroblast proliferation and extracellular matrix deposition by upregulating the IL6/JAK2/STAT3 pathway. Moreover, we verified that TSP1 expression was positively correlated with IL6/STAT3 signalling activity in keloids. Taken together, our findings indicate that TSP1 promotes keloid development via the IL6/JAK2/STAT3 signalling pathway and blocking TSP1 may represent a potential strategy for keloid therapy.

ResDNet: Efficient Dense Multi-Scale Representations With Residual Learning for High-Level Vision Tasks.

Deep feature fusion plays a significant role in the strong learning ability of convolutional neural networks (CNNs) for computer vision tasks. Recently, works continually demonstrate the advantages of efficient aggregation strategy and some of them refer to multiscale representations. In this article, we describe a novel network architecture for high-level computer vision tasks where densely connected feature fusion provides multiscale representations for the residual network. We term our method the ResDNet which is a simple and efficient backbone made up of sequential ResDNet modules containing the variants of dense blocks named sliding dense blocks (SDBs). Compared with DenseNet, ResDNet enhances the feature fusion and reduces the redundancy by shallower densely connected architectures. Experimental results on three classification benchmarks including CIFAR-10, CIFAR-100, and ImageNet demonstrate the effectiveness of ResDNet. ResDNet always outperforms DenseNet using much less computation on CIFAR-100. On ImageNet, ResDNet-B-129 achieves 1.94% and 0.89% top-1 accuracy improvement over ResNet-50 and DenseNet-201 with similar complexity. Besides, ResDNet with more than 1000 layers achieves remarkable accuracy on CIFAR compared with other state-of-the-art results. Based on MMdetection implementation of RetinaNet, ResDNet-B-129 improves mAP from 36.3 to 39.5 compared with ResNet-50 on COCO dataset.

Single-cell Raman-activated sorting and cultivation (scRACS-Culture) for assessing and mining in situ phosphate-solubilizing microbes from nature.

Due to the challenges in detecting in situ activity and cultivating the not-yet-cultured, functional assessment and mining of living microbes from nature has typically followed a 'culture-first' paradigm. Here, employing phosphate-solubilizing microbes (PSM) as model, we introduce a 'screen-first' strategy that is underpinned by a precisely one-cell-resolution, complete workflow of single-cell Raman-activated Sorting and Cultivation (scRACS-Culture). Directly from domestic sewage, individual cells were screened for in-situ organic-phosphate-solubilizing activity via D2O intake rate, sorted by the function via Raman-activated Gravity-driven Encapsulation (RAGE), and then cultivated from precisely one cell. By scRACS-Culture, pure cultures of strong organic PSM including Comamonas spp., Acinetobacter spp., Enterobacter spp. and Citrobacter spp., were derived, whose phosphate-solubilizing activities in situ are 90-200% higher than in pure culture, underscoring the importance of 'screen-first' strategy. Moreover, employing scRACS-Seq for post-RACS cells that remain uncultured, we discovered a previously unknown, low-abundance, strong organic-PSM of Cutibacterium spp. that employs secretary metallophosphoesterase (MPP), cell-wall-anchored 5'-nucleotidase (encoded by ushA) and periplasmic-membrane located PstSCAB-PhoU transporter system for efficient solubilization and scavenging of extracellular phosphate in sewage. Therefore, scRACS-Culture and scRACS-Seq provide an in situ function-based, 'screen-first' approach for assessing and mining microbes directly from the environment.

Event-Triggered Adaptive Asymptotic Tracking Control of Uncertain MIMO Nonlinear Systems With Actuator Faults.

In this article, an adaptive event-triggered fault-tolerant asymptotic tracking control problem guaranteeing prescribed performance is addressed for a class of block-triangular multi-input and multioutput uncertain nonlinear systems with unknown nonlinearities, unknown control directions, and actuator faults. Through a systematic co-design of the adaptive control law and the event-triggered mechanism, including fixed and relative threshold strategies, a control scheme with low structure and calculation complexity is designed to conserve system communication and computation resources. In this design, the output asymptotic tracking is achieved. The Nussbaum gain technique is incorporated to overcome unknown control directions with a new adaptive law, and a type of barrier Lyapunov function is adopted to handle the prescribed performance control problem, which contributes to a novel control law with strong robustness. The robust controller can address the uncertainties and couplings derived from the system structure, actuator faults, and event-triggered rules, without using approximating structures or compensators. Besides, the explosion of complexity is avoided. It is proved that all signals of the closed-loop system remain bounded, and system tracking errors asymptotically approach 0 with the prescribed performance, while the Zeno behavior is prevented. Finally, the effectiveness of the proposed control scheme is evaluated via an application example of the half-car active suspension system.

The Exploration of Poor Ovarian Response-Related Risk Factors: A Potential Role of Growth Differentiation Factor 8 in Predicting Ovarian Response in IVF-ET Patient.

Controlled ovarian hyperstimulation (COH) is the most common therapeutic protocol to obtain a considerable number of oocytes in IVF-ET cycles. To date, the risk factors affecting COH outcomes remain elusive. Growth differentiation factor 8 (GDF-8), a member of transforming growth factor ß (TGF-ß) superfamily, has been long discerned as a crucial growth factor in folliculogenesis, and the aberrant expression of GDF-8 is closely correlated with the reproductive diseases. However, less is known about the level of GDF-8 in IVF-ET patients with different ovarian response. In the present study, the potential risk factors correlated with ovarian response were explored using logistic regression analysis methods. Meanwhile, the expression changes of GDF-8 and its responsible cellular receptors in various ovarian response patients were determined. Our results showed that several factors were intensely related to poor ovarian response (POR), including aging, obesity, endometriosis, surgery history, and IVF treatment, while irregular menstrual cycles and PCOS contribute to hyperovarian response (HOR). Furthermore, POR patients exhibited a decrease in numbers of MII oocytes and available embryos, thereby manifesting a lower clinical pregnancy rate. The levels of GDF-8, ALK5, and ACVR2B in POR patients were higher compared with those in control groups, whereas the expression level of ACVR2A decreased in poor ovarian response patients. In addition, clinical correlation analysis results showed that the concentration of GDF-8 was negatively correlated with LH and estradiol concentration and antral follicle count. Collectively, our observations provide a novel insight of ovarian response-associated risk factors, highlighting the potential role of GDF-8 levels in ovarian response during COH process.

Molybdenum Carbide and Sulfide Nanoparticles as Selective Hydrotreating Catalysts for FCC Slurry Oil to Remove Olefins and Sulfur.

As the two types of major impurities in FCC slurry oil (SLO), olefins and sulfur seriously deteriorate the preparation and quality of mesophase pitch or needle coke. The development of a hydrotreatment for SLO to remove olefins and sulfur selectively becomes imperative. This work presents the potentiality of dispersed Mo2C and MoS2 nanoparticles as selective hydrotreating catalysts of SLO. Mo2C was synthesized by the carbonization of citric acid, ammonium molybdate and KCl mixtures while MoS2 was prepared from the decomposition of precursors. These catalysts were characterized by XRD, HRTEM, XPS, BJH, BET, and applied to the hydrotreating of an SLO surrogate with defined components and real SLO. The conversion of olefins, dibenzothiophene and anthracene in the surrogate was detected by GC-MS. Elemental analysis, bromine number, diene value, 1H-NMR and spot test were used to characterize the changes of the real SLO. The results show that hydrotreating the SLO surrogate with a very small amount of Mo-based nanoparticles could selectively remove olefins and sulfur without the overhydrogenation of polyaromatics. Mo2C exhibited much better activity than MoS2, with 95% of olefins and dibenzothiophene in the surrogate removed while only 15% anthracene was hydrogenated. The stability of the real SLO was significantly improved. Its structural parameters changed subtly, proving the aromatic macromolecules had been preserved.

YolTrack: Multitask Learning Based Real-Time Multiobject Tracking and Segmentation for Autonomous Vehicles.

Modern autonomous vehicles are required to perform various visual perception tasks for scene construction and motion decision. The multiobject tracking and instance segmentation (MOTS) are the main tasks since they directly influence the steering and braking of the car. Implementing both tasks using a multitask learning neural network presents significant challenges in performance and complexity. Current work on MOTS devotes to improve the precision of the network with a two-stage tracking by detection model, which is difficult to satisfy the real-time requirement of autonomous vehicles. In this article, a real-time multitask network named YolTrack based on one-stage instance segmentation model is proposed to perform the MOTS task, achieving an inference speed of 29.5 frames per second (fps) with slight accuracy and precision drop. The YolTrack uses ShuffleNet V2 with feature pyramid network (FPN) as a backbone, from which two decoders are extended to generate instance segments and embedding vectors. Segmentation masks are used to improve the tracking performance by performing logic AND operation with feature maps, proving that foreground segmentation plays an important role in object tracking. The different scales of multiple tasks are balanced by the optimized geometric mean loss during the training phase. Experimental results on the KITTI MOTS data set show that YolTrack outperforms other state-of-the-art MOTS architectures in real-time aspect and is appropriate for deployment in autonomous vehicles.

Growth differentiation factor 8 suppresses cell proliferation by up-regulating CTGF expression in human granulosa cells.

Connective tissue growth factor (CTGF) is a matricellular protein that plays a critical role in the development of ovarian follicles. Growth differentiation factor 8 (GDF8) is mainly, but not exclusively, expressed in the mammalian musculoskeletal system and is a potent negative regulator of skeletal muscle growth. The aim of this study was to investigate the effects of GDF8 and CTGF on the regulation of cell proliferation in human granulosa cells and to examine its underlying molecular determinants. Using dual inhibition approaches (inhibitors and small interfering RNAs), we have demonstrated that GDF8 induces the up-regulation of CTGF expression through the activin receptor-like kinase (ALK)4/5-mediated SMAD2/3-dependent signaling pathways. In addition, the increase in CTGF expression contributes to the GDF8-induced suppressive effect on granulosa cell proliferation. Our findings suggest that GDF8 and CTGF may play critical roles in the regulation of proliferative events in human granulosa cells.

[Distribution Characteristics of Sedimentary Pigments in the Changjiang Estuary and Zhe-Min Coast and its Implications].

Compositions and contents of sedimentary pigments were examined using high performance liquid chromatography in order to discuss the spatial distributions of phytoplankton primary production, phytoplankton functional type and the preservation efficiency of phytoplankton pigments and their influencing factors. The results showed that: chloropigments [Chlorins, including chlorophyll-a (Chl-a) and pheopigments (Pheo-a), such as pheophytin-a (PHtin-a), pheophorbide-a (PHide-a), pPheophytin-a (pPHtin-a), sterol chlorin esters (SCEs) and carotenol chlorin esters (CCEs)] were the major type of sedimentary pigments. The nutrients inputs from Changjiang Diluted Water and upwelling in the Zhe-Min coastal mud area were the major cause for the patchy distribution with high sedimentary chloropigment contents. Carotenoid contents showed no trending changes and exhibited high values in the Changjiang Estuary and Zhe-Min Coasts. Based on the relative proportions of each diagnostic carotenoid to the total diagnostic carotenoids in the sediments, the relative contributions of diatoms, dinoflagellates, prymnesiophytes, prasinophytes, cryptophytes and cyanobacterias in the phytoplankton fuctional types were 48.8% +/- 17.4%, 10.7% +/- 11.5%, 8.1% +/- 7.2%, 18.6% +/- 8.2%, 9.4% +/- 6.4% and 4.3% +/- 3.2%, respectively. The preference for external environmental conditions (e.g., nutrient level and water salinity) was the main cause for the decreasing trends of diatoms and dinoflagellates proportions and the increasing trends of prasinophytes, cryptophytes and cyanobacterias seawards. Based on the spatial distribution of Chl-a/Pheo-a ratios, the higher preservation efficiencies of sedimentary pigments in the coastal regions (e.g., outer edge of maximum turbidity zone in the Changjiang Estuary, mouth of the Hangzhou Bay and upwelling region in the Zhe-Min Coast) were mainly due to the higher sedimentation rate and seasonal occurrences of hypoxia in bottom water, and these regions with higher sedimentary pigment preservation efficiencies were probably ideal areas for the marine eco-environmental evolutions. The bad sedimentary environment caused by the water exchange inside and outside of Hangzhou Bay was the dominant reason for the low sedimentary pigment contents and preservation efficiencies in this region.

[Effect of Water and Sediment Regulation on the Transport of Particulate Organic Carbon in the Lower Yellow River].

Both natural processes and human activities in river basins have important impacts on the transport of riverine organic carbon (OC). Better understanding of the riverine OC transport processes is critical for the studies of global carbon cycling. Suspended particulate matters collected from the Lijin Station in the lower Yellow River during the water and sediment regulation ( WSR) period in 2012 (19 June-20 July) were analyzed for grain size, particulate OC (POC) and stable carbon isotopic ratios (delta13C) to investigate-the sources, composition, abundance of POC and the effect of WSR on the transport of POC. The results showed that the WSR in 2012 could be divided into two stages according to the variation of water and sediment discharges: the water-release stage (WRS) and the sediment-release stage (SRS). Variations of the water discharge, sediments, POC and delta13C in these two stages reflected the impacts of WSR on the sources of particulate matters and associated OC. The water discharge in the WRS stage was the highest (4270 m3 x s(-1)), and the sediments scoured from the riverbed in the lower reaches were the major source of suspended particulate matters in this stage, therefore the particles were characterized by relatively coarse grain size (13.9 microm in average of median grain size), low POC (avg. 0.38%) and relatively enriched and constant delta13C (-24.2% per hundred +/- 0.3% per hundred), probably because POC in the sediments scoured from the riverbed had old radiocarbon ages and high degradation. The suspended particulate matters in the SRS stage were mainly derived from the upstream reservoirs and flushed riverbanks due to local rainstorm, and the POC age was relatively young, thus this stage was characterized by high concentration of suspended particulate matters (up to 17.8 kg x m(-3)), fine particles (5.9 microm in average of median grain size), high POC (avg. 0.50%), and depleted and varied delta13C values (-24.8% per hundred +/- 0.6% per hundred). Variation of daily POC flux had similar pattern with sediment discharge, and the total POC flux during the water and sediment regulation period was 1.13 x 10(5) tons, accounting for 12% of the total POC flux in 2012. Compared with previous years, the total water discharge during the WSR period in 2012 has increased, while the total sediment flux and POC flux have reduced. In general, WSR played an important role on the transport of POC in the Yellow River. And furthermore, there was significant difference in the sources, composition and transport of POC in different stages of WSR.

TARANIS Functions with Cyclin A and Cdk1 in a Novel Arousal Center to Control Sleep in Drosophila.

Sleep is an essential and conserved behavior whose regulation at the molecular and anatomical level remains to be elucidated. Here, we identify TARANIS (TARA), a Drosophila homolog of the Trip-Br (SERTAD) family of transcriptional coregulators, as a molecule that is required for normal sleep patterns. Through a forward-genetic screen, we isolated tara as a novel sleep gene associated with a marked reduction in sleep amount. Targeted knockdown of tara suggests that it functions in cholinergic neurons to promote sleep. tara encodes a conserved cell-cycle protein that contains a Cyclin A (CycA)-binding homology domain. TARA regulates CycA protein levels and genetically and physically interacts with CycA to promote sleep. Furthermore, decreased levels of Cyclin-dependent kinase 1 (Cdk1), a kinase partner of CycA, rescue the short-sleeping phenotype of tara and CycA mutants, while increased Cdk1 activity mimics the tara and CycA phenotypes, suggesting that Cdk1 mediates the role of TARA and CycA in sleep regulation. Finally, we describe a novel wake-promoting role for a cluster of ∼14 CycA-expressing neurons in the pars lateralis (PL), previously proposed to be analogous to the mammalian hypothalamus. We propose that TARANIS controls sleep amount by regulating CycA protein levels and inhibiting Cdk1 activity in a novel arousal center.

Phononic and magnonic dispersions of surface waves on a permalloy/BARC nanostructured array.

Phononic and magnonic dispersions of a linear array of periodic alternating Ni80Fe20 and bottom anti-reflective coating nanostripes on a Si substrate have been measured using Brillouin light scattering. The observed phononic gaps are considerably larger than those of laterally patterned multi-component crystals previously reported, mainly a consequence of the high elastic and density contrasts between the stripe materials. Additionally, the phonon hybridization bandgap has an unusual origin in the hybridization and avoided crossing of the zone-folded Rayleigh and pseudo-Sezawa waves. The magnonic band structure features near-dispersionless branches, with unusual vortex-like dynamic magnetization profiles, some of which lie below the highly-dispersive fundamental mode branch. Finite element calculations of the phononic and magnonic dispersions of the magphonic crystal accord well with experimental data.

dyschronic, a Drosophila homolog of a deaf-blindness gene, regulates circadian output and Slowpoke channels.

Many aspects of behavior and physiology are under circadian control. In Drosophila, the molecular clock that regulates rhythmic patterns of behavior has been extensively characterized. In contrast, genetic loci involved in linking the clock to alterations in motor activity have remained elusive. In a forward-genetic screen, we uncovered a new component of the circadian output pathway, which we have termed dyschronic (dysc). dysc mutants exhibit arrhythmic locomotor behavior, yet their eclosion rhythms are normal and clock protein cycling remains intact. Intriguingly, dysc is the closest Drosophila homolog of whirlin, a gene linked to type II Usher syndrome, the leading cause of deaf-blindness in humans. Whirlin and other Usher proteins are expressed in the mammalian central nervous system, yet their function in the CNS has not been investigated. We show that DYSC is expressed in major neuronal tracts and regulates expression of the calcium-activated potassium channel SLOWPOKE (SLO), an ion channel also required in the circadian output pathway. SLO and DYSC are co-localized in the brain and control each other's expression post-transcriptionally. Co-immunoprecipitation experiments demonstrate they form a complex, suggesting they regulate each other through protein-protein interaction. Furthermore, electrophysiological recordings of neurons in the adult brain show that SLO-dependent currents are greatly reduced in dysc mutants. Our work identifies a Drosophila homolog of a deaf-blindness gene as a new component of the circadian output pathway and an important regulator of ion channel expression, and suggests novel roles for Usher proteins in the mammalian nervous system.

A molecular mechanism underlying ovarian dysfunction of polycystic ovary syndrome: hyperandrogenism induces epigenetic alterations in the granulosa cells.

The objective of this study was to explore whether hyperandrogenism induces epigenetic alterations of peroxisome proliferator-activated receptor gamma 1 (PPARG1), nuclear corepressor 1 (NCOR1), and histone deacetylase 3 (HDAC3) genes in granulosa cells (GCs) of polycystic ovary syndrome (PCOS) women and whether these alterations are involved in the ovarian dysfunction induced by hyperandrogenism. Thirty-two infertile PCOS women and 147 infertile women with tubal blockage were recruited. PCOS women were divided into the hyperandrogenism (HA) PCOS group (n = 13) and nonhyperandrogenism (N-HA) PCOS group (n = 19). Sixty female Sprague-Dawley rats were used for PCOS model establishment. In GCs of HA PCOS women, PPARG1 mRNA expression was lower, whereas NCOR1 and HDAC3 mRNA expression were higher than N-HA PCOS women and controls (P < 0.05). When all women were divided into successful and failed pregnancy subgroups according to the following clinical pregnancy outcome, we found lower PPARG1 mRNA levels and higher NCOR1 and HDAC3 mRNA levels in the failed subgroup of HA PCOS (P < 0.05). Two hypermethylated CpG sites in the PPARG1 promoter and five hypomethylated CpG sites in the NCOR1 promoter were observed only in HA PCOS women (P < 0.01 to P < 0.0005). The acetylation levels of histone H3 at lysine 9 and p21 mRNA expression were decreased in human GCs treated with dihydrotestosterone in vitro (P < 0.05). PCOS rat models also showed alterations of PPARG1, NCOR1, and HDAC3 mRNA expression and methylation changes of PPARG1 and NCOR1, consistent with the results from humans. Hyperandrogenism induces the epigenetic alterations of PPARG1, NCOR1, and HDAC3 in GCs, which are involved in the ovarian dysfunction of HA PCOS.