Although the clinical demand for bioengineered blood vessels continues to rise, current options for vascular conduits remain limited. The synergistic combination of emerging advances in tissue ...fabrication and stem cell engineering promises new strategies for engineering autologous blood vessels that recapitulate not only the mechanical properties of native vessels but also their biological function. Here we explore recent bioengineering advances in creating functional blood macro and microvessels, particularly featuring stem cells as a seed source. We also highlight progress in integrating engineered vascular tissues with the host after implantation as well as the exciting pre-clinical and clinical applications of this technology.
Song et al. explore recent bioengineering advances in creating functional blood macro- and microvessels, particularly featuring stem cells as a seed source. They highlight progress in integrating engineered vascular tissues with the host after implantation as well as the exciting pre-clinical and clinical applications of this technology.
The ability to simultaneously record from large numbers of neurons in behaving animals has ushered in a new era for the study of the neural circuit mechanisms underlying cognitive functions. One ...promising approach to uncovering the dynamical and computational principles governing population responses is to analyze model recurrent neural networks (RNNs) that have been optimized to perform the same tasks as behaving animals. Because the optimization of network parameters specifies the desired output but not the manner in which to achieve this output, "trained" networks serve as a source of mechanistic hypotheses and a testing ground for data analyses that link neural computation to behavior. Complete access to the activity and connectivity of the circuit, and the ability to manipulate them arbitrarily, make trained networks a convenient proxy for biological circuits and a valuable platform for theoretical investigation. However, existing RNNs lack basic biological features such as the distinction between excitatory and inhibitory units (Dale's principle), which are essential if RNNs are to provide insights into the operation of biological circuits. Moreover, trained networks can achieve the same behavioral performance but differ substantially in their structure and dynamics, highlighting the need for a simple and flexible framework for the exploratory training of RNNs. Here, we describe a framework for gradient descent-based training of excitatory-inhibitory RNNs that can incorporate a variety of biological knowledge. We provide an implementation based on the machine learning library Theano, whose automatic differentiation capabilities facilitate modifications and extensions. We validate this framework by applying it to well-known experimental paradigms such as perceptual decision-making, context-dependent integration, multisensory integration, parametric working memory, and motor sequence generation. Our results demonstrate the wide range of neural activity patterns and behavior that can be modeled, and suggest a unified setting in which diverse cognitive computations and mechanisms can be studied.
Summary
Background
Psoriasis is a chronic skin disorder that manifests as epidermal keratinocyte hyperplasia.
Objectives
We examined the effect of oxymatrine treatment on cell proliferation and ...apoptosis in skin lesions of psoriasis.
Patients and methods
Patients with severe plaque psoriasis were treated with oxymatrine or with acitretin. The skin lesions were stained with proliferating cell nuclear antigen (PCNA), Ki‐67 and Bcl‐2, as well as examined by terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labelling (TUNEL). We performed correlations of the Psoriasis Area and Severity Index (PASI) and the proliferation and apoptosis index.
Results
Oxymatrine significantly reduced the psoriasis lesions as demonstrated by the reduced PASI score after treatment 6·91; 95% confidence interval (CI) 5·00–8·81, P < 0·001. In the oxymatrine group, the mitotic index was 26·15 (95% CI 24·80–27·49) before oxymatrine treatment, decreasing to 14·52 (95% CI 13·82–15·25; P < 0·001) after treatment, but remained higher than the normal group (6·24; 95% CI 5·87–6·61, P < 0·001). Oxymatrine also inhibited the proliferation of epidermal cells in the skin lesion as indicated by the reduced proliferation index after treatment (P < 0·01). In addition, oxymatrine treatment reduced cellular apoptosis as shown by increased Bcl‐2 expression and a decrease in TUNEL‐positive cells. The PASI score was positively correlated with mitotic index, proliferation index and apoptotic index (TUNEL), but negatively correlated with Bcl‐2 expression.
Conclusions
Oxymatrine treatment reduced proliferation but inhibited apoptosis of cells in the skin lesion. The balance between cell proliferation and turnover may contribute to the significant alleviation of psoriasis by oxymatrine.
What's already known about this topic?
Psoriasis manifests as epidermal keratinocyte hyperplasia with proliferation, keratinocyte maturation and turnover rates.
Current drugs for psoriasis may inhibit cell proliferation but could not adjust the balance of cell division, differentiation and apoptosis.
What does this study add?
We studied the efficacy of oxymatrine in the treatment of psoriasis and analysed the correlation of skin lesions, proliferation and apoptosis index before and after oxymatrine treatment.
What is the translational message?
Our study has demonstrated that oxymatrine is effective in the treatment of severe plaque psoriasis.
It has comparable efficacy with acitretin.
Because acitretin treatment was sometimes associated with metabolic abnormalities, our study suggests oxymatrine therapy as an alternative treatment for psoriasis in the context of acitretin allergy or adverse reactions.
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Linked Comment: Groma. Br J Dermatol 2019; 181:891–892.
Recently it has been proposed that information in working memory (WM) may not always be stored in persistent neuronal activity but can be maintained in 'activity-silent' hidden states, such as ...synaptic efficacies endowed with short-term synaptic plasticity. To test this idea computationally, we investigated recurrent neural network models trained to perform several WM-dependent tasks, in which WM representation emerges from learning and is not a priori assumed to depend on self-sustained persistent activity. We found that short-term synaptic plasticity can support the short-term maintenance of information, provided that the memory delay period is sufficiently short. However, in tasks that require actively manipulating information, persistent activity naturally emerges from learning, and the amount of persistent activity scales with the degree of manipulation required. These results shed insight into the current debate on WM encoding and suggest that persistent activity can vary markedly between short-term memory tasks with different cognitive demands.
The current therapies to treat hepatitis B virus (HBV) infection are limited. Recently, clustered regularly interspaced short palindromic repeat (CRISPR) systems, originally identified in bacteria ...and archaea, have been found to consist of an RNA-based adaptive immune system that degrades complimentary sequences of invading plasmids and viruses. Here, we studied the effects of the CRISPR/CRISPR-associated Cas9 system that was targeted to the surface antigen (HBsAg)-encoding region of HBV, both in a cell culture system and in vivo. The HBsAg levels in the media of the cells and in the sera of mice were analyzed by a quantitative enzyme-linked immunosorbent assay. The HBV DNA levels were assessed by quantitative PCR and HBsAg expression in mouse livers was assessed by an immunohistochemical assay. The amount of HBsAg secreted in the cell culture and mouse serum was reduced by CRISPR/Cas9 treatment. Immunohistochemistry analyses showed almost no HBsAg-positive cells in the liver tissue of CRISPR/Cas9-S1+X3-treated mice. The CRISPR/Cas9 system efficiently produced mutations in HBV DNA. Thus, CRISPR/Cas9 inhibits HBV replication and expression in vitro and in vivo and may constitute a new therapeutic strategy for HBV infection.
Context. Various binary black hole formation channels have been proposed since the first gravitational event GW150914 was discovered by the Advanced Laser Interferometer Gravitational-Wave ...Observatory (AdLIGO). The immediate progenitor of the binary black hole is a close binary system composed of a black hole and a helium star, which can be the outcome of the classical isolated binary evolution through the common envelope, or alternatively of the massive close evolution through chemically homogeneous channel. Aims. We study the spin angular momentum evolution of the helium star in order to constrain the spin of the second-born black hole. This work focuses on the common envelope formation channel, however, some of our conclusions are also relevant for the chemically homogeneous evolution channel. Methods. We perform detailed stellar structure and binary evolution calculations that take into account, mass-loss, internal differential rotation, and tidal interactions between the helium star and the black hole companion, where we also calculate the strength of the tidal interactions from first principles based on the structure of the helium stars. We systematically explore the parameter space of initial binary properties, including initial black hole and helium star masses, initial rotation of the helium star as well as metallicity. Results. We argue that the natal spin of the first-born black hole through the common envelope scenario is negligible (≲0.1), and therefore the second-born black hole’s spin dominates the measured effective spin, χeff, from gravitational wave events of double black hole mergers. We find that tides can be only important when orbital periods are shorter than 2 days. Upon core collapse, the helium star produces a black hole (the second-born black hole in the system) with a spin that can span the entire range from zero to maximally spinning. We show that the bimodal distribution of the spin of the second-born black hole obtained in recent papers is mainly due to oversimplifying assumptions. We find an anti-correlation between the merging timescale of the two black holes, Tmerger, and the effective spin χeff. Finally, we provide new prescriptions for the tidal coefficient E2 for both H-rich and the He-rich stars. Conclusions. To understand the spin of the second-born black hole, careful treatment of both tides and stellar winds is needed. We predict that, with future improvements to AdLIGO’s sensitivity, the sample of merging binary black hole systems will show an overdensity of sources with positive but small χeff originating from lower-mass black hole mergers born at low redshift.
MicroRNAs (miRNAs) are believed to have fundamental roles in tumorigenesis and have great potential for the diagnosis and treatment of cancer. However, the roles of miRNAs in hepatocellular ...carcinogenesis are still not fully elucidated. We investigated the aberrantly expressed miRNAs involved in hepatoma by comparison of miRNA expression profiles in cancerous hepatocytes with normal primary human hepatocytes, and 37 dysregulated miRNAs were screened out by twofold change with a significant difference (P<0.05). Clustering analysis based on 13 miRNAs with changes over 15-folds showed that the miRNA expression patterns between the cancerous and normal hepatocytes were clearly different. Among the 13 miRNAs, we found that miR-375 was significantly downregulated in hepatocellular carcinoma (HCC) tissues and cell lines. Overexpression of miR-375 in liver cancer cells decreased cell proliferation, clonogenicity, migration/invasion and also induced G1 arrest and apoptosis. To unveil the molecular mechanism of miR-375-mediated phenotype in hepatoma cells described above, we examined the putative targets using bioinformatics tools and found that astrocyte elevated gene-1 (AEG-1) was a potential target of miR-375. Then we demonstrated that miR-375 bound directly to the 3'-untranslated region of AEG-1 and inhibited the expression of AEG-1. TaqMan quantitative reverse transcriptase-PCR and western blot analysis showed that miR-375 expression was inversely correlated with AEG-1 expression in HCC tissues. Knockdown of AEG-1 by RNAi in HCC cells, similar to miR-375 overexpression, suppressed tumor properties. Ectopic expression of AEG-1, conversely, could partially reverse the antitumor effects of miR-375. In a mouse model, therapeutic administration of cholesterol-conjugated 2'-O-methyl-modified miR-375 mimics (Chol-miR-375) could significantly suppress the growth of hepatoma xenografts in nude mice. In conclusion, our findings indicate that miR-375 targets AEG-1 in HCC and suppresses liver cancer cell growth in vitro and in vivo, and highlight the therapeutic potential of miR-375 in HCC treatment.
Summary
The incidence of atypical femoral fractures (AFFs) was 2.95% among 6644 hip and femoral fractures. Independent risk factors included the use of bisphosphonates (BPs), osteopenia or ...osteoporosis, rheumatoid arthritis, increased femoral curvatures, and thicker femoral cortices. Patients with AFFs and BP treatment were more likely to have problematic healing than those with typical femoral fractures (TFFs) and no BP treatment.
Introduction
To determine the incidence and risk factors of atypical femoral fractures (AFFs), we performed a multicenter case-control study. We also investigated the effects of bisphosphonates (BPs) on AFF healing.
Methods
We retrospectively reviewed the medical records and radiographs of 6644 hip and femoral fractures of patients from eight tertiary referral hospitals. All the radiographs were reviewed to distinguish AFFs from TFFs. Univariate and multivariate logistic regression analyses were performed to identify risk factors, and interaction analyses were used to investigate the effects of BPs on fracture healing.
Results
The incidence of AFFs among 6644 hip and femoral fractures was 2.95% (90 subtrochanter and 106 femoral shaft fractures). All patients were females with a mean age of 72 years, and 75.5% were exposed to BPs for an average duration of 5.2 years (range, 1–17 years). The use of BPs was significantly associated with AFFs (
p
< 0.001, odds ratio = 25.65; 95% confidence interval = 10.74–61.28). Other independent risk factors for AFFs included osteopenia or osteoporosis, rheumatoid arthritis, increased anterior and lateral femoral curvatures, and thicker lateral femoral cortex at the shaft level. Interaction analyses showed that patients with AFFs using BPs had a significantly higher risk of problematic fracture healing than those with TFFs and no BP treatment.
Conclusions
The incidence of AFFs among 6644 hip and femoral fractures was 2.95%. Osteopenia or osteoporosis, use of BPs, rheumatoid arthritis, increased anterior and lateral femoral curvatures, and thicker lateral femoral cortex were independent risk factors for the development of AFFs. Patients with AFFs and BP treatment were more likely to have problematic fracture healing than those with TFFs and no BP treatment.
Liver regeneration is a well-orchestrated process that is typically studied in animal models. Although previous animal studies have offered many insights into liver regeneration, human biology is ...less well understood. To this end, we developed a three-dimensional (3D) platform called structurally vascularized hepatic ensembles for analyzing regeneration (SHEAR) to model multiple aspects of human liver regeneration. SHEAR enables control over hemodynamic alterations to mimic those that occur during liver injury and regeneration and supports the administration of biochemical inputs such as cytokines and paracrine interactions with endothelial cells. We found that exposing the endothelium-lined channel to fluid flow led to increased secretion of regeneration-associated factors. Stimulation with relevant cytokines not only amplified the secretory response, but also induced cell-cycle entry of primary human hepatocytes (PHHs) embedded within the device. Further, we identified endothelial-derived mediators that are sufficient to initiate proliferation of PHHs in this context. Collectively, the data presented here underscore the importance of multicellular models that can recapitulate high-level tissue functions and demonstrate that the SHEAR device can be used to discover and validate conditions that promote human liver regeneration.
The hot ductility of a 1Cr–0.5Mo low alloy steel is investigated over a temperature range of 700–1050°C using a Gleeble thermomechanical simulator in conjunction with various characterization ...techniques. The steel samples undoped and doped with cerium are heated at 1300°C for 3min and then cooled with a rate of 5Ks−1 down to different test temperatures, followed by tensile deformation until fracture. The results show that the hot ductility of the steel, evaluated by the reduction in area, can be substantially enhanced by a minor addition of cerium, especially in the range 800–1000°C. In the austenite–ferrite dual-phase region, cerium may delay the formation of proeutectoid ferrite layers along austenite grain boundaries, thereby increasing the hot ductility of the steel. In the single austenite region, grain boundary segregation of cerium may increase the grain boundary cohesion, toughening the steel and thus raising the resistance to grain boundary sliding as well as promoting dynamic recrystallization. Consequently, the hot ductility of the steel is enhanced.
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