Abstract
Lowering of prion protein (PrP) expression in the brain is a genetically validated therapeutic hypothesis in prion disease. We recently showed that antisense oligonucleotide (ASO)-mediated ...PrP suppression extends survival and delays disease onset in intracerebrally prion-infected mice in both prophylactic and delayed dosing paradigms. Here, we examine the efficacy of this therapeutic approach across diverse paradigms, varying the dose and dosing regimen, prion strain, treatment timepoint, and examining symptomatic, survival, and biomarker readouts. We recapitulate our previous findings with additional PrP-targeting ASOs, and demonstrate therapeutic benefit against four additional prion strains. We demonstrate that <25% PrP suppression is sufficient to extend survival and delay symptoms in a prophylactic paradigm. Rise in both neuroinflammation and neuronal injury markers can be reversed by a single dose of PrP-lowering ASO administered after the detection of pathological change. Chronic ASO-mediated suppression of PrP beginning at any time up to early signs of neuropathology confers benefit similar to constitutive heterozygous PrP knockout. Remarkably, even after emergence of frank symptoms including weight loss, a single treatment prolongs survival by months in a subset of animals. These results support ASO-mediated PrP lowering, and PrP-lowering therapeutics in general, as a promising path forward against prion disease.
Bone Regeneration Is Regulated by Wnt Signaling Kim, Jae‐Beom; Leucht, Philipp; Lam, Kentson ...
Journal of bone and mineral research,
December 2007, Letnik:
22, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Tissue regeneration is increasingly viewed as reactivation of a developmental process that, when misappropriated, can lead to malignant growth. Therefore, understanding the molecular and cellular ...pathways that govern tissue regeneration provides a glimpse into normal development as well as insights into pathological conditions such as cancer. Herein, we studied the role of Wnt signaling in skeletal tissue regeneration.
Introduction: Some adult tissues have the ability to regenerate, and among these, bone is one of the most remarkable. Bone exhibits a persistent, lifelong capacity to reform after injury, and continual bone regeneration is a prerequisite to maintaining bone mass and density. Even slight perturbations in bone regeneration can have profound consequences, as exemplified by conditions such as osteoporosis and delayed skeletal repair. Here, our goal was to determine the role of Wnts in adult bone regeneration.
Materials and Methods: Using TOPgal reporter mice, we found that damage to the skeleton instigated Wnt reporter activity, specifically at the site of injury. We used a skeletal injury model to show that Wnt inhibition, achieved through adenoviral expression of Dkk1 in the adult skeleton, prevented the differentiation of osteoprogenitor cells.
Results: As a result, injury‐induced bone regeneration was reduced by 84% compared with controls. Constitutive activation of the Wnt pathway resulting from a mutation in the Lrp5 Wnt co‐receptor results in high bone mass, but our experiments showed that this same point mutation caused a delay in bone regeneration. In these transgenic mice, osteoprogenitor cells in the injury site were maintained in a proliferative state and differentiation into osteoblasts was delayed.
Conclusions: When considered together, these data provide a framework for understanding the roles of Wnt signaling in adult bone regeneration and suggest a feasible approach to treating clinical conditions where enhanced bone formation is desired.
The fetal skeleton arises from neural crest and from mesoderm. Here, we provide evidence that each lineage contributes a unique stem cell population to the regeneration of injured adult bones. Using ...Wnt1Cre::Z/EG mice we found that the neural crest-derived mandible heals with neural crest-derived skeletal stem cells, whereas the mesoderm-derived tibia heals with mesoderm-derived stem cells. We tested whether skeletal stem cells from each lineage were functionally interchangeable by grafting mesoderm-derived cells into mandibular defects, and vice versa. All of the grafting scenarios, except one, healed through the direct differentiation of skeletal stem cells into osteoblasts; when mesoderm-derived cells were transplanted into tibial defects they differentiated into osteoblasts but when transplanted into mandibular defects they differentiated into chondrocytes. A mismatch between the Hox gene expression status of the host and donor cells might be responsible for this aberration in bone repair. We found that initially, mandibular skeletal progenitor cells are Hox-negative but that they adopt a Hoxa11-positive profile when transplanted into a tibial defect. Conversely, tibial skeletal progenitor cells are Hox-positive and maintain this Hox status even when transplanted into a Hox-negative mandibular defect. Skeletal progenitor cells from the two lineages also show differences in osteogenic potential and proliferation, which translate into more robust in vivo bone regeneration by neural crest-derived cells. Thus, embryonic origin and Hox gene expression status distinguish neural crest-derived from mesoderm-derived skeletal progenitor cells, and both characteristics influence the process of adult bone regeneration.
Mechanical loading of bone is important for maintenance of bone mass and structural stability of the skeleton. When bone is mechanically loaded, movement of fluid within the spaces surrounding bone ...cells generates fluid shear stress (FSS) that stimulates osteoblasts, resulting in enhanced anabolic activity. The mechanisms by which osteoblasts convert the external stimulation of FSS into biochemical changes, a process known as mechanotransduction, remain poorly understood. Focal adhesions are prime candidates for transducing external stimuli. Focal adhesion kinase (FAK), a nonreceptor tyrosine kinase found in focal adhesions, may play a key role in mechanotransduction, although its function has not been directly examined in osteoblasts. We examined the role of FAK in osteoblast mechanotransduction using short interfering RNA (siRNA), overexpression of a dominant negative FAK, and FAK−/− osteoblasts to disrupt FAK function in calvarial osteoblasts. Osteoblasts were subjected to varying periods oscillatory fluid flow (OFF) from 5 min to 4 h, and several physiologically important readouts of mechanotransduction were analyzed including: extracellular signal‐related kinase 1/2 phosphorylation, upregulation of c‐fos, cyclooxygenase‐2, and osteopontin, and release of prostaglandin E2. Osteoblasts with disrupted FAK signaling exhibited severely impaired mechanical responses in all endpoints examined. These data indicate the importance of FAK for both short and long periods of FSS‐induced mechanotransduction in osteoblasts.
We report a facile and direct fabrication method for integrating functional optical microstructures on the top surface of an optical fiber. A programmable maskless fabrication system was developed by ...using digital micromirror device (DMD), which allows rapid prototyping and low-cost fabrication without physical photomask. This maskless UV exposure system has the spatial resolution of 2.2 μm for an exposed area of 245 μm x 185 μm. Diverse optical microstructures were photolithographically defined on multimode fibers and a single mode optical fiber serially spliced with a coreless silica fiber segment. This method provides a new route for developing compact functional fiber-optic applications such as laser scanning, biosensing, or laser endomicroscopy.
Basements are increasingly being used as living and working spaces, and the interest in the feasibility of using wireless devices in these environments is increasing. Therefore, it is very important ...to develop a propagation prediction model for basements. Especially, the isolated communication cell against the satellite or the other building will be promising due to the lack of available frequency resources. However, the propagation model for outdoor-to-basement has not been reported. Only the outdoor-to-indoor in the overground environment has been studied. Therefore, as far as our knowledge, this letter could be the first approach for the building entry loss (BEL) to analyze propagation paths to a basement from outside the building. Experiments were conducted on the basis of three different scenarios for the propagation paths between the exterior of the building and the basement. The BEL was measured at 61 and 71 dB at frequencies of 1.5 and 3 GHz, respectively; these values exceeded the value of about 30 dB of the over-the-ground model described in the International Telecommunications Union Radio-communication Sector P.2109. Further, BEL on the ground floor of the building and the penetration loss between the different floors were measured. Finally, BEL on the building side with parking lot entrance was evaluated.
This article reports the diffractive optical elements of rotational offset microlens arrays for generating highly efficient structured light patterns in active stereoscopic 3D imaging. The ...double‐side configuration of microlens arrays increases the uniformity of diffraction patterns by using two successive refractions on microlens surfaces. In addition, the rotational offsets between the frontside and the backside microlens arrays with rectangular or hexagonal arrangements control the contrast and the density of structured dot array patterns. Two layers of microlens arrays with high curvature and high fill‐factor are microfabricated on both sides of the glass wafer by using ultrathin fluorocarbon encapsulation, thermal reflow, and parylene gap filling. The rotational offset angles of 22.5°, 28°, and 37° in rectangular and 13.25°, 21.75°, and 27.75° in hexagonal arrangements efficiently provide diffractive dot arrays with high uniformity, contrast, and density by minimizing the overlapping of diffractive patterns. The active stereo imaging using rotational offset microlens arrays successfully acquire high‐resolution depth map for 3D plaster objects with smooth and curved surfaces. The structured light pattern projection using rotational offset microlens arrays will provide promising opportunities for compact advanced imaging systems in industrial, medical, or military applications.
This article reports the diffractive optical elements of rotational offset microlens arrays for generating highly efficient structured light patterns. Two layers of microlens arrays with high curvature and fill‐factor are microfabricated on both sides of the substrate with rotational offsets. The active stereo imaging using rotational offset microlens arrays successfully acquires high‐resolution depth map for objects with smooth surfaces.
OBJECTIVENon-variceal upper gastrointestinal bleeding (NVUGIB) in patients receiving oral anticoagulants (OACs) may be fatal; however, little is known about re-bleeding and all-cause mortality after ...successful hemostasis. We investigated the clinical characteristics and risk factors for re-bleeding and death after successful hemostasis. METHODSPatients receiving OACs and diagnosed with NVUGIB between 2007 and 2021 were enrolled. All NVUGIB incidents were confirmed if definite bleeding in the upper gastrointestinal tract was detected via esophagogastroduodenoscopy. RESULTSA total of 132 patients receiving OACs were diagnosed with NVUGIB. Males were the majority (72, 54.5%), and bleeding was detected mostly in the stomach (99, 75%) and was most often due to peptic ulcers (PU) (88, 66.7%). After successful hemostasis of index NVUGIB, 40 patients (30.3%) experienced re-bleeding. Among them, 15 (37.5%) died, and among those, 3 (2.3%) were related to re-bleeding. Multivariate analysis revealed that duodenal bleeding (odds ratio OR: 3.305; 95% confidence interval CI: 1.152-9.479, p = 0.026) and Charlson comorbidity index score (CCI) (OR: 1.22; 95% CI: 1.052-1.419, p = 0.009) were significant risk factors for re-bleeding. Index albumin levels (OR: 0.134; 95% CI: 0.035-0.506, p = 0.003), previous PU or upper gastrointestinal bleeding (UGIB) history (OR: 4.626; 95% CI: 1.375-15.567, p = 0.013), and CCI (OR: 1.293; 95% CI: 1.058-1.581, p = 0.012) were related all-cause mortality. CONCLUSIONCCI and duodenal bleeding are risk factors for re-bleeding in patients with NVUGIB who were receiving OACs, while low index albumin levels and previous PU and UGIB history are associated with all-cause mortality.
We conducted a 16-week double-blind randomized controlled single-center trial to evaluate the safety and efficacy of dermal rice bran supercritical CO2 extract (RB-SCE) in the treatment of androgenic ...alopecia. Fifty alopecia patients were randomly assigned to the experimental and placebo groups. The experimental group received a dermal application of 0.5% RB-SCE (8 mL/d) to the head skin for 16 weeks while the control group received a dermal application of placebo. Changes in hair count, diameter, and density were evaluated with a Folliscope®. Patient satisfaction was evaluated via questionnaire and clinical photographs were rated by dermatologists. The results showed that RB-SCE significantly increased hair density and hair diameter in male subjects. Patient satisfaction and the evaluation of photographs by dermatologists also confirmed the effectiveness of RB-SCE in the treatment of alopecia. No adverse reactions related to RB-SCE were reported. Therefore, RB-SCE shows promise for use in functional cosmetics and pharmaceuticals.
Pancreatic alpha amylase (P-AMY) is used as a biomarker of acute pancreatitis (AP) in human medicine. To our knowledge, there are no studies evaluating the usefulness of P-AMY in dogs with AP. In ...this study, we evaluated the diagnostic value of P-AMY, currently not verified in veterinary medicine. The AP group (
= 40) consisted of dogs with AP diagnosed using clinical signs and laboratory examinations, including abnormal canine pancreatic lipase (cPL) concentration, and compatible abdominal ultrasound examination at first presentation. Evaluation of the canine AP severity (CAPS) score was performed. The control group (
= 38) was composed of normal dogs without any abnormalities in clinical findings, blood exams or diagnostic imaging. The correlation of P-AMY with cPL was confirmed by Pearson's correlation analysis (
= 0.564,
< .001). The sensitivity and specificity for the most appropriate cut-off values of P-AMY were recorded similar to the values of DGGR. The dogs with AP and CAPS ≥11 had significantly higher serum P-AMY (
= .016) contrary to DGGR lipase and cPL. Furthermore, there was a significant difference in the median P-AMY dependent on the presence of systemic inflammatory response syndrome (
= .001). P-AMY showed similar level of diagnostic accuracy along with sensitivity and specificity compared to DGGR lipase. In addition, P-AMY showed a significant association with CAPS score, contrary to cPL and DGGR lipase. Along with other biomarkers associated with AP, P-AMY has the potential of usefulness as a supportive diagnostic and prognostic biomarker of AP in dogs.
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