Aging of human bone marrow – functional and epigenetic changes in senescent mesenchymal stromal cells

Aging is a complex process that is associated with changes in many parts of the body over the lifespan of an individual. In this work, various aspects of aging in the human bone marrow were investigated. As the regenerative power of a tissue is linked to the potential of its stem cells to replace the accumulated damages, the aging process in somatic stem cells was studied focusing on the influence of the niche in regulating stem cell aging. The hematopoietic stem cells (HSC) together with elements that constitute the bone marrow niche were investigated as a model for somatic stem cell aging as HSCs are accessible in healthy human individuals. The subjects ranged from 20 to 60 years with a median age of 33.2 years. From each bone marrow sample, the CD34+ population as HSCs and four other cell subpopulations, lymphocytes and precursors (LYM), monocytes/macrophages precursors (MON), granulocytic (GRA), and erythroid precursors (ERP) were isolated by flow cytometry. The mesenchymal stromal cells (MSC) were isolated by in vitro culture. We found that the relative proportions, cell size as well as cell granularity of the major bone marrow constituents did not correlate with the biological age of the donors. However, further downstream analysis indicated that age-associated changes were prominent on protein level in HSCs as well as in other cell types of the niche such as MSCs. The interactions between the HSCs and the niche were studied in vitro using a coculture system of CD34+ cells and mesenchymal stromal cells (MSC). As previous studies indicated that the supportive function of MSCs as well as their differentiation potentials towards adipocytes and osteocytes change significantly with age, we have examined the supportive ability of the undifferentiated MSCs versus adipogenically differentiated MSCs (ADI-MSCs) and osteogenically differentiated MSCs (OST-MSCs) for HSCs. We showed that MSCs, ADI-MSCs and OST-MSCs were able to support the proliferation of HSCs and maintain their primitive immunephenotype. Compared to undifferentiated MSCs and OST-MSCs, the co-culture with ADI-MSCs increased the proliferation of HSCs much stronger while still maintaining the HSCs at a high expression level of CD34. As the impact of the MSCs on HSCs might be caused by epigenetic changes, the aging-associated alterations in the marrow niche were studied at the chromatin level. To this end, changes in chromatin accessibility were studied in MSCs by ATAC-seq. After establishing the protocol for performing ATAC-seq using primary MSCs, we studied the MSC samples derived from 16 healthy human subjects of different ages between 21 and 59 years. A set of 122,884 ATAC-seq peaks was identified. We have demonstrated that donor age is associated with alterations in open chromatin profiles. Moreover, at a false discovery rate of 5%, we could identify 4,579 differential chromatin accessible sites upon aging. A functional analysis of these sites showed enrichment of cell development and differentiation processes. Additionally, genes of the hippo signaling pathway, TGF-beta signaling pathway, cancer pathways and cell adhesion pathways were also found to be enriched. A motif enrichment analysis suggested that TATA box motifs and binding sites for transcription factors TFAP2C, KLF16, HIC1.p2, WT1 and MTF.p2 were enriched in promoter regions of differential chromatin accessible sites upon aging. In conclusion, this study showed that the interplay with the stem cell niche controls HSC functions. The differentiation of MSCs affects the proliferation and stemness of HSCs in vitro. Furthermore, we have demonstrated that aging is associated with chromatin accessibility alterations in MSCs, which provides a foundation for further in-depth mechanistic analyses

A Contrastive Cross-Channel Data Augmentation Framework for Aspect-based Sentiment Analysis

Aspect-Based Sentiment Analysis is a fine-grained sentiment analysis task, which focuses on detecting the sentiment polarity towards the aspect in a sentence. However, it is always sensitive to the multi-aspect challenge, where features of multiple aspects in a sentence will affect each other. To mitigate this issue, we design a novel training framework, called Contrastive Cross-Channel Data Augmentation (C3DA). A source sentence will be fed a domain-specific generator to obtain some synthetic sentences and is concatenated with these generated sentences to conduct supervised training and proposed contrastive training. To be specific, considering the limited ABSA labeled data, we also introduce some parameter-efficient approaches to complete sentences generation. This novel generation method consists of an Aspect Augmentation Channel (AAC) to generate aspect-specific sentences and a Polarity Augmentation (PAC) to generate polarity-inverted sentences. According to our extensive experiments, our C3DA framework can outperform those baselines without any augmentations by about 1\% on accuracy and Macro-F1

Local application of silver nitrate as an adjuvant treatment before deep lamellar keratoplasty for fungal keratitis poorly responsive to medical treatment

ObjectiveThe purpose of this study is to evaluate the efficacy and safety of the local application of silver nitrate (LASN) as an adjuvant treatment before deep lamellar keratoplasty (DLKP) for fungal keratitis responding poorly to medical treatment.MethodsA total of 12 patients (12 eyes) with fungal keratitis responding poorly to medical treatment (for at least 2 weeks) were included. LASN was performed using 2% silver nitrate, the ulcer was cleaned and debrided, and then, the silver nitrate cotton stick was applied to the surface of the ulcer for a few seconds. The effect of LASN was recorded. The number of hyphae before and after treatment was determined by confocal microscope. After the condition of the ulcer improved, DLKP was performed. Fungal recurrence, best-corrected visual acuity (BCVA), loose sutures, and endothelial cell density (ECD) were recorded in detail.ResultsClinical resolution of corneal infiltration and edema was observed, and the ulcer boundary became clear in all 12 patients after 7–9 days of LASN. Confocal microscopy showed that the number of hyphae was significantly reduced. Ocular pain peaked on days 1 and 2 after treatment, and 9 patients (75%, day 1) and 1 patient (8.3%, day 2) required oral pain medication. During the follow-up period after DLKP, no fungal recurrence and loose sutures were observed. After the operation, the BCVA of all patients improved. The mean corneal ECD was 2,166.83 ± 119.75 cells/mm2.ConclusionThe LASN was safe and effective and can be well tolerated by patients. Eye pain can be relieved quickly. LASN as an adjuvant treatment before DLKP might be a promising therapeutic strategy

Joint Optimization of Beamforming, Phase-Shifting and Power Allocation in a Multi-cluster IRS-NOMA Network

The combination of non-orthogonal multiple access (NOMA) and intelligent reflecting surface (IRS) is an efficient solution to significantly enhance the energy efficiency of the wireless communication system. In this paper, we focus on a downlink multi-cluster NOMA network, where each cluster is supported by one IRS. We aim to minimize the transmit power by jointly optimizing the beamforming, the power allocation and the phase shift of each IRS. The formulated problem is non-convex and challenging to solve due to the coupled variables, i.e., the beamforming vector, the power allocation coefficient and the phase shift matrix. To address this non-convex problem, we propose an alternating optimization based algorithm. Specifically, we divide the primal problem into the two subproblems for beamforming optimization and phase shifting feasiblity, where the two subproblems are solved iteratively. Moreover, to guarantee the feasibility of the beamforming optimization problem, an iterative algorithm is proposed to search the feasible initial points. To reduce the complexity, we also propose a simplified algorithm based on partial exhaustive search for this system model. Simulation results demonstrate that the proposed alternating algorithm can yield a better performance gain than the partial exhaustive search algorithm, OMA-IRS, and NOMA with random IRS phase shift

Deep Reinforcement Learning Based Optimization for IRS Based UAV-NOMA Downlink Networks

This paper investigates the application of deep deterministic policy gradient (DDPG) to intelligent reflecting surface (IRS) based unmanned aerial vehicles (UAV) assisted non-orthogonal multiple access (NOMA) downlink networks. The deployment of the UAV equipped with an IRS is important, as the UAV increases the flexibility of the IRS significantly, especially for the case of users who have no line of sight (LoS) path to the base station (BS). Therefore, the aim of this letter is to maximize the sum rate by jointly optimizing the power allocation of the BS, the phase shifting of the IRS and the horizontal position of the UAV. Because the formulated problem is not convex, the DDPG algorithm is utilized to solve it. The computer simulation results are provided to show the superior performance of the proposed DDPG based algorithm