Objective
Increased protein phosphatase magnesium‐dependent 1A (PPM1A) levels in patients with ankylosing spondylitis regulate osteoblast differentiation in bony ankylosis; however, the potential ...mechanisms that regulate osteoclast differentiation in relation to abnormal bone formation remain unclear. This study was undertaken to investigate the relationship of PPM1A to osteoclast differentiation by generating conditional gene‐knockout (PPM1Afl/fl;LysM‐Cre) mice and evaluating their bone phenotype.
Methods
The bone phenotypes of LysM‐Cre mice (n = 6) and PPM1Afl/fl;LysM‐Cre mice (n = 6) were assessed by micro–computed tomography. Osteoclast differentiation was induced by culturing bone marrow–derived macrophages in the presence of RANKL and macrophage colony‐stimulating factor (M‐CSF), and was evaluated by counting tartrate‐resistant acid phosphatase–positive multinucleated cells. Levels of messenger RNA for PPM1A, RANK, and osteoclast‐specific genes were examined by real‐time quantitative polymerase chain reaction, and protein levels were determined by Western blotting. Surface RANK expression was analyzed by fluorescence flow cytometry.
Results
The PPM1Afl/fl;LysM‐Cre mice displayed reduced bone mass (P < 0.001) and increased osteoclast differentiation (P < 0.001) and osteoclast‐specific gene expression (P < 0.05) compared with their LysM‐Cre littermates. Mechanistically, reduced PPM1A function in osteoclast precursors in PPM1Afl/fl;LysM‐Cre mice induced osteoclast lineage commitment by up‐regulating RANK expression (P < 0.01) via p38 MAPK activation in response to M‐CSF. PPM1A expression in macrophages was decreased by Toll‐like receptor 4 activation (P < 0.05). The Ankylosing Spondylitis Disease Activity Score was negatively correlated with the expression of PPM1A in peripheral blood mononuclear cells from patients with axial spondyloarthritis (SpA) (γ = −0.7072, P < 0.0001).
Conclusion
The loss of PPM1A function in osteoclast precursors driven by inflammatory signals contributes to osteoclast lineage commitment and differentiation by elevating RANK expression, reflecting a potential role of PPM1A in dynamic bone metabolism in axial SpA.
Abstract
In the summer of 2020, South Korea experienced record-breaking rainfall due to 15 consecutive heavy rainfall events (HREs) from mid-June to early September. Among them, 11 HREs occurred in ...late June to mid-August with distinct synoptic characteristics depending on the occurrence period. All HREs from 29 June to 27 July (P1) were triggered by extratropical cyclones, while those from 28 July to 15 August (P2) mainly occurred along monsoon rainband. We argue that their transition is associated with atmospheric teleconnections. During P1, the western North Pacific subtropical high (WNPSH) anomalously extended westward, but its northward expansion was hindered by the meridional wave train from the suppressed convection over the South China Sea. This condition prevented a northward migration of the monsoon rainband but allowed more extratropical cyclones to pass over the Korean Peninsula, resulting in four HREs. During P2, the South China Sea convection was enhanced, and its circulation response prompted an abrupt northward expansion of the WNPSH with a large pressure gradient along its northern boundary. With intensified southwesterly moisture transport, a monsoon rainband was activated over the Korean Peninsula, producing six HREs. The opposite phases of the summer North Atlantic Oscillation, i.e., negative in P1 but positive in P2, further contributed to the anomalous monsoon circulation by modulating the mid-latitude circulation response to the South China Sea convection. This study demonstrates that the nature of summertime HREs in East Asia can be strongly modulated by remote forcings.
To analyze risk factors and the dose-effect relationship for osteoradionecrosis (ORN) of the mandible after radiotherapy of oral and oropharyngeal cancers.
One-hundred ninety-eight patients with oral ...(45%) and oropharyngeal cancer (55%) who had received external radiotherapy between 1990 and 2000 were retrospectively reviewed. All patients had a dental evaluation before radiotherapy. The median radiation dose was 60 Gy (range, 16-75 Gy), and the median biologically effective dose for late effects (BED(late)) in bone was 114 Gy(2) (range, 30-167 Gy(2)).
The frequency of ORN was 13 patients (6.6%). Among patients with mandibular surgery, eight had ORN at the surgical site. Among patients without mandibular surgery, five patients had ORN on the molar area of the mandible. The median time to ORN was 22 months (range, 1-69 months). Univariate analysis revealed that mandibular surgery and Co-60 were significant risk factors for ORN (p = 0.01 and 0.04, respectively). In multivariate analysis, mandibular surgery was the most important factor (p = 0.001). High radiation doses over BED 102.6 Gy(2) (conventional dose of 54 Gy at 1.8 Gy/fraction) were also a significant factor for ORN (p = 0.008) and showed a positive dose-effect relationship in logistic regression (p = 0.04) for patients who had undergone mandibular surgery.
Mandibular surgery was the most significant risk factor for ORN of mandible in oral and oropharyngeal cancers patients. A BED of 102.6 Gy(2) or higher to the mandible also significantly increases the risk of ORN.
This paper proposes ZenFS+, a new storage backend of RocksDB for small-zone ZNS SSD. RocksDB has complicated internal operations such as flush and compaction. Flush and compaction run in separate ...threads, and it is well known that they closely interact around the sstables. Due to the concurrent storage I/O between flush and compaction, ZenFS presents unsatisfactory performance for small-zone ZNS SSD. We believe that ZenFS+ presents how ZNS SSD can support the performance and isolation of modern key-value stores. Leveraging the ZNS SSD, ZenFS+ intelligently identifies the independent zones group (IZG), which reveals the device's internal parallelism. With the IZG information, ZenFS+ effectively isolates the flush workloads of RocksDB from compaction. Besides, ZenFS+ spreads the sstables to multiple IZGs so that the storage write can leverage the hardware parallelism. ZenFS+ presents up to 4.8x higher storage throughput for write-intensive microbenchmark and stabilizing 99.9P tail latency by 1/51 from existing ZenFS. Further, ZenFS+ implements proactive garbage collection, and presents sustainable performance over longer lifespan of the device.
Single-cell RNA-seq reveals the cellular heterogeneity inherent in the population of cells, which is very important in many clinical and research applications. Recent advances in droplet ...microfluidics have achieved the automatic isolation, lysis, and labeling of single cells in droplet compartments without complex instrumentation. However, barcoding errors occurring in the cell encapsulation process because of the multiple-beads-in-droplet and insufficient throughput because of the low concentration of beads for avoiding multiple-beads-in-a-droplet remain important challenges for precise and efficient expression profiling of single cells. In this study, we developed a new droplet-based microfluidic platform that significantly improved the throughput while reducing barcoding errors through deterministic encapsulation of inertially ordered beads. Highly concentrated beads containing oligonucleotide barcodes were spontaneously ordered in a spiral channel by an inertial effect, which were in turn encapsulated in droplets one-by-one, while cells were simultaneously encapsulated in the droplets. The deterministic encapsulation of beads resulted in a high fraction of single-bead-in-a-droplet and rare multiple-beads-in-a-droplet although the bead concentration increased to 1000 μl
, which diminished barcoding errors and enabled accurate high-throughput barcoding. We successfully validated our device with single-cell RNA-seq. In addition, we found that multiple-beads-in-a-droplet, generated using a normal Drop-Seq device with a high concentration of beads, underestimated transcript numbers and overestimated cell numbers. This accurate high-throughput platform can expand the capability and practicality of Drop-Seq in single-cell analysis.
Nicotine, an abundant molecule in tobacco, has immunomodulatory effects on inflammatory diseases, primarily due to the activation of alpha7 nicotinic acetylcholine receptor (α7 nAChR). We aim to ...evaluate the expression of the α7 nAChR+ cells in joint tissue and the effect of smoking on immune cells and peripheral arthritis in curdlan-administered SKG mice, a murine model of spondyloarthropathy (SpA). The SKG mice were injected with curdlan two times at 2-week intervals and were divided into two groups; one exposed to cigarette smoke and the other not exposed. We found that the α7 nAChR+ cells increased in the joint tissue of curdlan-administered SKG mice compared to in the wild type. Furthermore, the peripheral arthritis scores and histological scores for synovial inflammation were lower in smoke-exposed curdlan-administered SKG mice than in mice not exposed to smoke. Immunofluorescence staining of the α7 nAChR+ and IL-17A+ cells was lower in the synovia of smoke-exposed mice than the control mice. The proportions of α7 nAChR+IL-17A+ and α7 nAChR+IL-17A+FOXP3+ cells also decreased in the synovia of smoke-exposed mice compared with the controls. We observed an increase in the α7 nAChR+ cells within the joint tissue of curdlan-administered SKG mice and that cigarette smoke had an influence on both peripheral arthritis and immune cell population, especially α7 nAChR+ cells. Thus, exposure to cigarette smoke after arthritogenic stimuli may have an anti-arthritogenic effect in curdlan-administered SKG mice.
The development of gastrointestinal (GI) bleeding and end-stage renal disease (ESRD) can be a concern in the management of Henoch-Schönlein purpura (HSP). We aimed to evaluate whether the ...neutrophil-to-lymphocyte ratio (NLR) is associated with the prognosis of adult patients with HSP.
Clinical data including the NLR of adult patients with HSP were retrospectively analyzed. Patients were classified into three groups as follows: (a) simple recovery, (b) wax & wane without GI bleeding, and (c) development of GI bleeding. The optimal cut-off value was determined using a receiver operating characteristics curve and the Youden index.
A total of 66 adult patients were enrolled. The NLR was higher in the GI bleeding group than in the simple recovery or wax & wane group (simple recovery vs. wax & wane vs. GI bleeding; median IQR, 2.32 1.61-3.11 vs. 3.18 2.16-3.71 vs. 7.52 4.91-10.23, P<0.001). For the purpose of predicting simple recovery, the optimal cut-off value of NLR was 3.18, and the sensitivity and specificity were 74.1% and 75.0%, respectively. For predicting development of GI bleeding, the optimal cut-off value was 3.90 and the sensitivity and specificity were 87.5% and 88.6%, respectively.
The NLR is useful for predicting development of GI bleeding as well as simple recovery without symptom relapse. Two different cut-off values of NLR, 3.18 for predicting an easy recovery without symptom relapse and 3.90 for predicting GI bleeding can be used in adult patients with HSP.
Interleukin-32 gamma (IL-32γ) is a recently discovered cytokine that is elevated in inflamed tissues and contributes to pathogenic features of bone in human inflammatory rheumatic diseases. ...Nevertheless, the role of IL-32γ and its direct involvement in bone metabolism is unclear. We investigated the molecular mechanism of IL-32γ in bone remodeling and the hypothetical correlation between IL-32γ and disease activity in osteoporosis patients. Transgenic (TG) mice overexpressing human IL-32γ showed reduced bone loss with advancing age, increased bone formation, and high osteogenic capacity of osteoblast compared to wild-type (WT) mice through the upregulation of miR-29a, which caused a reduction of Dickkopf-1 (DKK1) expression. IL-32γ TG mice were protected against ovariectomy (OVX)induced osteoporosis compared with WT mice. Decreased plasma IL-32γ levels were associated with bone mineral density (BMD) in human patients linked to increased DKK1 levels. These results indicate that IL-32γ plays a protective role for bone loss, providing clinical evidence of a negative correlation between IL-32γ and DKK1 as bone metabolic markers.
Purpose Most patients with tongue cancer require surgical resection of the tongue to varying degrees. As a result, quality of life, which is strongly related to speech, chewing, and swallowing, can ...deteriorate severely from extensive surgical treatment of tongue cancer. In addition to surgery, adjuvant therapy may affect the severity of functional impairment. Therefore, the influence of postoperative radiotherapy on functional outcome after partial glossectomy with free flap reconstruction was evaluated in patients with early oral tongue cancer. Patients and Methods Functional outcome was measured and charts of 31 patients with oral tongue cancer who were surgically treated at Yonsei Head and Neck Cancer Clinic from 2003 through 2008 were reviewed. Only patients who underwent partial glossectomy and reconstruction with radial forearm free flap and did not develop recurrence were included. Speech integrity was evaluated with diadochokinetic testing by a professional speech therapist. Tongue mobility was checked by measurements of upward distance, protrusion distance, and lateral deviation distance. Swallowing capacity was evaluated with the M.D. Anderson Dysphagia Inventory. Results Diadochokinetic rates of the surgery-only and postoperative radiotherapy groups were 27.8 and 23.9, respectively, which was statistically different. Swallowing capacity was significantly superior in the surgery-only group. Tongue mobility was not statistically different between the 2 groups. Conclusions Functional outcome of speech and swallowing is negatively influenced by postoperative radiotherapy.
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