Re-epithelialization is a complex process during skin wound healing, and cell migration is an integral part of this phenomenon. Here we identified a role for LRG1 as a key regulator of epidermal keratinocyte migration where LRG1 acts via enhancement of HIF-1 alpha stability. We showed that LRG1 is upregulated at murine skin wound edges and that addition of recombinant human LRG1 accelerates keratinocyte migration and skin wound healing. Furthermore, we identified transcription factor ELK3 as a downstream effector of LRG1. We confirmed that elevated ELK3 levels manipulated by LRG1 can promote cell migration through upregulation of HIF-1 alpha stability. Because hyperglycemia complicatedly affects HIF-1 alpha stability and activation, our findings provide insights into the molecular controls of wound-associated cell migration and identify potential therapeutic targets for the treatment of chronic diabetic wounds. In conclusion, we demonstrated that LRG1 promotes wound repair through keratinocyte migration and is important for normalization of an abnormal process of diabetic wound healing where HIF-1 alpha stability is insufficient.

Many psoriasis patients treated with biologics do not achieve total skin clearance. These patients possess residual plaques despite ongoing biologic treatment. To elucidate mechanisms of plaque persistence despite overall good drug response, we studied 50 subjects: psoriasis patients with residual plaques treated with one of three different biologics, untreated patients, and healthy controls. Skin biopsies from all subjects were characterized using three methods: mRNA expression, histology, and FACS of hematopoietic skin cells. Although all three methods provided evidence of drug effect, gene expression analysis revealed the persistence of key psoriasis pathways in treated plaques, including granulocyte adhesion and diapedesis, T helper type17 activation pathway, and interferon signaling with no novel pathways emerging. Focal decreases in parakeratosis and keratinocyte proliferation and differential reduction in IL-17 producing CD103e T cells, but no change in CD103thorn tissue-resident memory T cells were observed. Of note, antitumor necrosis factor increased the interferon signaling pathway already present. Interestingly mast cells were the dominant source of IL-22 in all psoriasis subjects. These data suggest that while subtle differences can be observed in drug-treated plaques, underlying biologic mechanisms are similar to those present in untreated psoriatic lesions.

Background: The development of Chronic Obstructive Pulmonary Disease (COPD) has been assessed and divided into slow development (SD), normal development (ND) and quick development (QD). Little is known about the plasma proteome characters among these three phenotypes. Methods: We performed a comparative proteomic analysis in the plasma of normal control (NC), SD, ND and QD phenotype COPD patients using isobaric tags for relative and absolute quantitation (iTRAQ) technique. Results: A total of 683 proteins were successfully identified in the plasma samples, of which 394 were considered as high-quality proteins (95% confidential peptides >= 2). Further, a total of 25, 19 and 27 different abundant proteins (DAPs) were identified in SD, ND and QD groups, respectively. Gene ontology (GO) classification analysis of all DAPs showed that immune system process (GO:0002376) were the most significant. The pathway enrichment analysis showed that innate immune response (GO:0045087), receptor-mediated endocytosis (GO:0006898) and proteolysis (GO:0006508) were the branch-end terms. Notably, the 15 QD special DAPs were considered as potential markers for identify patient might have quick development COPD, and thus provided more aggressive treatment strategy for these patients. Conclusion: This work provides an insight into global plasma proteome profiles among the SD, ND and QD phenotypes of COPD patients. The most significant GO terms that the DAPs enriched in were immune system related terms. In addition, the 15 QD specific DPAs provided candidates of potential markers to predict the development types of COPD patients.

Activin/Smad3 signaling plays a pivotal role in follicle development and atresia. However, the precise mechanisms underlying this process are not yet fully understood. Herein, we identified miR-181a as a central component of activin/Smad3-mediated follicle atresia. miR-181a was strikingly upregulated in porcine atretic follicles, which induced the apoptosis of porcine granulosa cells (GCs) in vitro. Furthermore, the transforming growth factor-beta type 1 receptor (TGFBR1) was confirmed as a direct target of miR-181a by bioinformatics analysis and luciferase assays. Transfection with an miR-181a agomir repressed the TGFBR1 mRNA and protein levels. In addition, TGFBR1 overexpression repressed GC apoptosis, whereas TGFBR1 inhibition promoted GC apoptosis. miR-181a overexpression downregulated the phosphorylation of Smad3 and blocked the activation of TGF-beta signaling. Moreover, activin A downregulated miR-181a expression and upregulated the TGFBR1 and p-Smad3 protein levels. Collectively, these data suggest that miR-181a regulates porcine GC apoptosis by targeting TGFBR1 via the activin signaling pathway.

In tropical forests, leaf phenology-particularly the pronounced dry-season green-up-strongly regulates biogeochemical cycles of carbon and water fluxes. However, uncertainties remain in the understanding of tropical forest leaf phenology at different spatial scales. Phenocams accurately characterize leaf phenology at the crown and ecosystem scales but are limited to a few sites and time spans of a few years. Time-series satellite observations might fill this gap, but the commonly used satellites (e.g. MODIS, Landsat and Sentinel-2) have resolutions too coarse to characterize single crowns. To resolve this observational challenge, we used the PlanetScope constellation with a 3 m resolution and near daily nadir-view coverage. We first developed a rigorous method to cross-calibrate PlanetScope surface reflectance using daily BRDF-adjusted MODIS as the reference. We then used linear spectral unmixing of calibrated PlanetScope to obtain dry-season change in the fractional cover of green vegetation (GV) and non-photosynthetic vegetation (NPV) at the PlanetScope pixel level. We used the Central Amazon Tapajos National Forest k67 site, as all necessary data (from field to phenocam and satellite observations) was available. For this proof of concept, we chose a set of 22 dates of PlanetScope measurements in 2018 and 16 in 2019, all from the six drier months of the year to provide the highest possible cloud-free temporal resolution. Our results show that MODIS-calibrated dry-season PlanetScope data (1) accurately assessed seasonal changes in ecosystem-scale and crown-scale spectral reflectance; (2) detected an increase in ecosystem-scale GV fraction (and a decrease in NPV fraction) from June to November of both years, consistent with local phenocam observations with R-2 around 0.8; and (3) monitored large seasonal trend variability in crown-scale NPV fraction. Our results highlight the potential of integrating multi-scale satellite observations to extend fine-scale leaf phenology monitoring beyond the spatial limits of phenocams.

The goal of this study was to characterize the spectral characteristics and spatial topography of local field potential (LFP) activity in the internal segment of the globus pallidus (GPi) in patients with Parkinson's disease utilizing directional (segmented) deep brain stimulation (dDBS) leads. Data were collected from externalized dDBS leads of three patients with idiopathic Parkinson's disease after overnight withdrawal of parkinsonian medication at rest and during a cued reach-to-target task. Oscillatory activity across lead contacts/segments was examined in the context of lead locations and contact orientations determined using co-registered preoperative 7 Tesla (T) MRI and postoperative CT scans. Each of the three patients displayed a unique frequency spectrum of oscillatory activity in the pallidum, with prominent peaks ranging from 5 to 35 Hz, that modulated variably across subjects during volitional movement. Despite subject-specific spectral profiles, a consistent finding across patients was that oscillatory power was strongest and had the largest magnitude of modulation during movement in LFPs recorded from segments facing the postero-lateral sensorimotor region of GPi, whereas antero-medially-directed segmented contacts facing the internal capsule and/or anterior GPi, had relatively weaker LFP power and less modulation in the 5 to 35 Hz. In each subject, contact configurations chosen for clinically therapeutic stimulation (following data collection and blinded to physiology recordings), were in concordance with the contact pairs showing the largest amplitude of LFP oscillations in the 5-35 Hz range. Although limited to three subjects, these findings provide support for the hypothesis that the sensorimotor territory of the GPi corresponds to the site of maximal power of oscillatory activity in the 5 to 35 Hz and provides the greatest benefit in motor signs during stimulation in the GPi. Variability in oscillatory activity across patients is likely related to Parkinson's disease phenotype as well as small differences in recording location (i.e. lead location), highlighting the importance of lead location for optimizing stimulation efficacy. These data also provide compelling evidence for the use of LFP activity for the development of predictive stimulation models that may optimize patient benefits while reducing clinic time needed for programming.