High Levels of Oxidative Stress and Skin Microbiome are Critical for Initiation and Development of Chronic Wounds in Diabetic Mice.

A balanced redox state is critical for proper healing. Although human chronic wounds are characterized by high levels of oxidative stress (OS), whether OS levels are critical for chronic wound development is not known. For these studies, we used our chronic wound model in diabetic mice that has similar characteristics as human chronic wounds, including naturally developed biofilm. We hypothesize that OS levels in wound tissues are critical for chronic wound initiation and development. We show that increased OS levels in the wound correlate with increased chronicity. Moreover, without increased OS levels, biofilm taken from chronic wounds and placed in new excision wounds do not create chronic wounds. Similarly, high OS levels in the wound tissue in the absence of the skin microbiome do not lead to chronic wounds. These findings show that both high OS levels and bacteria are needed for chronic wound initiation and development. In conclusion, OS levels in the wound at time of injury are critical for biofilm formation and chronic wound development and may be a good predictor of the degree of wound chronicity. Treating such wounds might be accomplished by managing OS levels with antioxidants combined with manipulation of the skin microbiome after debridement

A Calibrated Method of Massage Therapy Decreases Systolic Blood Pressure Concomitant With Changes in Heart Rate Variability in Male Rats.

ObjectiveThe purpose of this study was to develop a method for applying calibrated manual massage pressures by using commonly available, inexpensive sphygmomanometer parts and validate the use of this approach as a quantitative method of applying massage therapy to rodents.MethodsMassage pressures were monitored by using a modified neonatal blood pressure (BP) cuff attached to an aneroid gauge. Lightly anesthetized rats were stroked on the ventral abdomen for 5 minutes at pressures of 20 mm Hg and 40 mm Hg. Blood pressure was monitored noninvasively for 20 minutes following massage therapy at 5-minute intervals. Interexaminer reliability was assessed by applying 20 mm Hg and 40 mm Hg pressures to a digital scale in the presence or absence of the pressure gauge.ResultsWith the use of this method, we observed good interexaminer reliability, with intraclass coefficients of 0.989 versus 0.624 in blinded controls. In Long-Evans rats, systolic BP dropped by an average of 9.86% ± 0.27% following application of 40 mm Hg massage pressure. Similar effects were seen following 20 mm Hg pressure (6.52% ± 1.7%), although latency to effect was greater than at 40 mm Hg. Sprague-Dawley rats behaved similarly to Long-Evans rats. Low-frequency/high-frequency ratio, a widely-used index of autonomic tone in cardiovascular regulation, showed a significant increase within 5 minutes after 40 mm Hg massage pressure was applied.ConclusionsThe calibrated massage method was shown to be a reproducible method for applying massage pressures in rodents and lowering BP

Epi-illumination SPIM for volumetric imaging with high spatial-temporal resolution.

We designed an epi-illumination SPIM system that uses a single objective and has a sample interface identical to that of an inverted fluorescence microscope with no additional reflection elements. It achieves subcellular resolution and single-molecule sensitivity, and is compatible with common biological sample holders, including multi-well plates. We demonstrated multicolor fast volumetric imaging, single-molecule localization microscopy, parallel imaging of 16 cell lines and parallel recording of cellular responses to perturbations

Identification of 34 Novel Proinflammatory Proteins in a Genome-Wide Macrophage Functional Screen

Signal transduction pathways activated by Toll-like Receptors and the IL-1 family of cytokines are fundamental to mounting an innate immune response and thus to clearing pathogens and promoting wound healing. Whilst mechanistic understanding of the regulation of innate signalling pathways has advanced considerably in recent years, there are still a number of critical controllers to be discovered. In order to characterise novel regulators of macrophage inflammation, we have carried out an extensive, cDNA-based forward genetic screen and identified 34 novel activators, based on their ability to induce the expression of cxcl2. Many are physiologically expressed in macrophages, although the majority of genes uncovered in our screen have not previously been linked to innate immunity. We show that expression of particular activators has profound but distinct impacts on LPS-induced inflammatory gene expression, including switch-type, amplifier and sensitiser behaviours. Furthermore, the novel genes identified here interact with the canonical inflammatory signalling network via specific mechanisms, as demonstrated by the use of dominant negative forms of IL1/TLR signalling mediators

From 2000 years of Ganoderma lucidum to recent developments in nutraceuticals

Medicinal mushrooms have been used for centuries as nutraceuticals to improve health and to treat numerous chronic and infectious diseases. One such mushroom is Ganoderma lucidum, commonly known as Lingzhi, a species revered as a medicinal mushroom for treating assorted diseases and prolonging life. The fungus is found in diverse locations, and this may have contributed to confusion regarding the correct taxonomic classification of the genus Ganoderma. G. lucidum was first used to name a specimen found in England and thereafter was naively applied to a different Ganoderma species found in Asia, commonly known as Chinese Lingzhi. Despite the taxonomic confusion, which has largely been uncorrected, the popularity of Lingzhi has escalated across the globe. The current taxonomic situation is now discussed accurately in this Special Issue on Ganoderma. Today it is a multi-billion dollar industry wherein Lingzhi is cultivated or collected from the wild and consumed as a tea, in alcoholic beverages, and as a nutraceutical to confer numerous health benefits. Consumption of nutraceuticals has grown in popularity, and it is becoming increasingly important that active ingredients be identified and that suppliers make substantiated health claims about their products. The objective of this article is to present a review of G. lucidum over the past 2000 years from prized ancient herbal remedy to its use in nutraceuticals and to the establishment of a 2.5 billion $ (US) industry.NZ Focus to BK, MPG and LRF is acknowledged. YX was funded by a Phyllis Paykel Memorial Scholarship, and KSB and LRF were supported by the Auckland Cancer Society Research Centre

Generic 3D Representation via Pose Estimation and Matching

Though a large body of computer vision research has investigated developing generic semantic representations, efforts towards developing a similar representation for 3D has been limited. In this paper, we learn a generic 3D representation through solving a set of foundational proxy 3D tasks: object-centric camera pose estimation and wide baseline feature matching. Our method is based upon the premise that by providing supervision over a set of carefully selected foundational tasks, generalization to novel tasks and abstraction capabilities can be achieved. We empirically show that the internal representation of a multi-task ConvNet trained to solve the above core problems generalizes to novel 3D tasks (e.g., scene layout estimation, object pose estimation, surface normal estimation) without the need for fine-tuning and shows traits of abstraction abilities (e.g., cross-modality pose estimation). In the context of the core supervised tasks, we demonstrate our representation achieves state-of-the-art wide baseline feature matching results without requiring apriori rectification (unlike SIFT and the majority of learned features). We also show 6DOF camera pose estimation given a pair local image patches. The accuracy of both supervised tasks come comparable to humans. Finally, we contribute a large-scale dataset composed of object-centric street view scenes along with point correspondences and camera pose information, and conclude with a discussion on the learned representation and open research questions.Comment: Published in ECCV16. See the project website http://3drepresentation.stanford.edu/ and dataset website https://github.com/amir32002/3D_Street_Vie

PDANet: Polarity-consistent Deep Attention Network for Fine-grained Visual Emotion Regression

Existing methods on visual emotion analysis mainly focus on coarse-grained emotion classification, i.e. assigning an image with a dominant discrete emotion category. However, these methods cannot well reflect the complexity and subtlety of emotions. In this paper, we study the fine-grained regression problem of visual emotions based on convolutional neural networks (CNNs). Specifically, we develop a Polarity-consistent Deep Attention Network (PDANet), a novel network architecture that integrates attention into a CNN with an emotion polarity constraint. First, we propose to incorporate both spatial and channel-wise attentions into a CNN for visual emotion regression, which jointly considers the local spatial connectivity patterns along each channel and the interdependency between different channels. Second, we design a novel regression loss, i.e. polarity-consistent regression (PCR) loss, based on the weakly supervised emotion polarity to guide the attention generation. By optimizing the PCR loss, PDANet can generate a polarity preserved attention map and thus improve the emotion regression performance. Extensive experiments are conducted on the IAPS, NAPS, and EMOTIC datasets, and the results demonstrate that the proposed PDANet outperforms the state-of-the-art approaches by a large margin for fine-grained visual emotion regression. Our source code is released at: https://github.com/ZizhouJia/PDANet.Comment: Accepted by ACM Multimedia 201

Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis.

The TAR DNA-binding protein 43 (TDP-43) has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP) were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V) were identified in the analysis of 92 familial ALS patients (3.3%), while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43-positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the approximately 25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis

Age-related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins

AbstractTransgenic FVB/N mice overexpressing human (Hu) or mouse (Mo) Alzheimer amyloid precursor protein (APP695) die early and develop a CNS disorder that includes neophobia and impaired spatial alternation, with diminished glucose utilization and astrogliosis mainly in the cerebrum. Age at onset of neophobia and age at death decrease with increasing levels of brain APP. HuAPP transgenes induce death much earlier than MoAPP transgenes expressed at similar levels. No extracellular amyloid was detected, indicating that some deleterious processes related to APP overexpression are dissociated from formation of amyloid. A similar clinical syndrome occurs spontaneously in ∼20% of nontransgenic mice when they reach mid-to late-adult life, suggesting that APP overexpression may accelerate a naturally occuring age-related CNS disorder in FVB/N mice