Identification and characterization of recent retrovirus in Rhinolophus ferrumequinum bats.

An investigation into retrovirus was conducted in six species of bats (Myotis aurascens, Myotis petax, Myotis macrodactylus, Miniopterus fuliginosus, Rhinolophus ferrumequinum, and Pipistrellus abramus) inhabiting South Korea. Exogenous retroviruses (XRVs) were detected in the tissue samples of R. ferrumequinum individuals by PCR assay. Proviruses were identified in all tissue samples through viral quantification using a digital PCR assay per organ (lung, intestine, heart, brain, wing, kidney, and liver), with viral loads varying greatly between each organ. In phylogenetic analysis based on the whole genome, the Korean bat retroviruses and the R. ferrumequinum retrovirus (RfRV) strain formed a new clade distinct from the Gammaretrovirus clade. The phylogenetic results determined these viruses to be RfRV-like viruses. In the Simplot comparison, Korean RfRV-like viruses exhibited relatively strong fluctuated patterns in the latter part of the envelope gene area compared to other gene areas. Several point mutations within this region (6,878-7,774 bp) of these viruses were observed compared to the RfRV sequence. One Korean RfRV-like virus (named Y4b strain) was successfully recovered in the Raw 264.7 cell line, and virus particles replicated in the cells were confirmed by transmission electron microscopy. RfRVs (or RfRV-like viruses) have been spreading since their first discovery in 2012, and the Korean RfRV-like viruses were assumed to be XRVs that evolved from RfRV.IMPORTANCER. ferrumequinum retrovirus (RfRV)-like viruses were identified in greater horseshoe bats in South Korea. These RfRV-like viruses were considered exogenous retroviruses (XRVs) that emerged from RfRV. Varying amounts of provirus detected in different organs suggest ongoing viral activity, replication, and de novo integration in certain organs. Additionally, the successful recovery of the virus in the Raw 264.7 cell line provides strong evidence supporting their status as XRVs. These viruses have now been identified in South Korea and, more recently, in Kenya since RfRV was discovered in China in 2012, indicating that RfRVs (or RfRV-like viruses) have spread worldwide.

Antioxidant Efficacy of Hwangryunhaedok-tang through Nrf2 and AMPK Signaling Pathway against Neurological Disorders In Vivo and In Vitro.

Alzheimer's disease (AD) is a representative cause of dementia and is caused by neuronal loss, leading to the accumulation of aberrant neuritic plaques and the formation of neurofibrillary tangles. Oxidative stress is involved in the impaired clearance of amyloid beta (Aß), and Aß-induced oxidative stress causes AD by inducing the formation of neurofibrillary tangles. Hwangryunhaedok-tang (HHT, Kracie K-09®), a traditional herbal medicine prescription, has shown therapeutic effects on various diseases. However, the studies of HHT as a potential treatment for AD are insufficient. Therefore, our study identified the neurological effects and mechanisms of HHT and its key bioactive compounds against Alzheimer's disease in vivo and in vitro. In a 5xFAD mouse model, our study confirmed that HHT attenuated cognitive impairments in the Morris water maze (MWM) test and passive avoidance (PA) test. In addition, the prevention of neuron impairment, reduction in the protein levels of Aß, and inhibition of cell apoptosis were confirmed with brain tissue staining. In HT-22 cells, HHT attenuates tBHP-induced cytotoxicity, ROS generation, and mitochondrial dysfunction. It was verified that HHT exerts a neuroprotective effect by activating signaling pathways interacting with Nrf2, such as MAPK/ERK, PI3K/Akt, and LKB1/AMPK. Among the components, baicalein, a bioavailable compound of HHT, exhibited neuroprotective properties and activated the Akt, AMPK, and Nrf2/HO-1 pathways. Our findings indicate a mechanism for HHT and its major bioavailable compounds to treat and prevent AD and suggest its potential.

Fermented Glutinous Rice Extract Mitigates DSS-Induced Ulcerative Colitis by Alleviating Intestinal Barrier Function and Improving Gut Microbiota and Inflammation.

Ulcerative colitis (UC) is an inflammatory bowel disease caused by various factors, including intestinal inflammation and barrier dysfunction. Herein, we determined the effects of fermented glutinous rice (FGR) on the expression of tight junction proteins and levels of inflammation and apoptosis in the dextran sodium sulfate (DSS)-induced acute colitis model. FGR was orally administered once per day to C57BL/6J mice with colitis induced by 5% DSS in drinking water. FGR administration recovered DSS-induced body weight loss and irregularly short colon lengths. FGR inhibited the DSS-induced decrease in FITC-dextran (FD)-4 permeability and myeloperoxidase activity. Moreover, FGR treatment repaired the reduction of zonula occluden-1 (ZO-1) and occludin expression and the increase in claudin-2 expression in colonic tissue relative to that following DSS administration. FGR treatment significantly recovered expression of cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1ß, in serum or respective mRNA expression in colonic tissue relative to that following DSS administration. FGR regulated levels of oxidative stress-related factors, such as malondialdehyde and glutathione, and the activity of catalase and superoxide dismutase in the colon tissue of the DSS-induced acute colitis mice model. Furthermore, FGR treatment inhibited apoptosis by reducing the activity of caspase-3 and the ratio of Bcl-2 associated X (Bax)/B-cell lymphoma 2 (Bcl-2). Collectively, FGR treatment protected the intestinal barrier from dysfunction and inhibited inflammation and apoptosis in DSS-induced colitis. Therefore, FGR may decrease the inflammatory response and be a candidate for treating and prevention inflammatory bowel disease by protecting the intestinal integrity.

TMED3 Complex Mediates ER Stress-Associated Secretion of CFTR, Pendrin, and SARS-CoV-2 Spike.

Under ER stress conditions, the ER form of transmembrane proteins can reach the plasma membrane via a Golgi-independent unconventional protein secretion (UPS) pathway. However, the targeting mechanisms of membrane proteins for UPS are unknown. Here, this study reports that TMED proteins play a critical role in the ER stress-associated UPS of transmembrane proteins. The gene silencing results reveal that TMED2, TMED3, TMED9 and TMED10 are involved in the UPS of transmembrane proteins, such as CFTR, pendrin and SARS-CoV-2 Spike. Subsequent mechanistic analyses indicate that TMED3 recognizes the ER core-glycosylated protein cargos and that the heteromeric TMED2/3/9/10 complex mediates their UPS. Co-expression of all four TMEDs improves, while each single expression reduces, the UPS and ion transport function of trafficking-deficient ΔF508-CFTR and p.H723R-pendrin, which cause cystic fibrosis and Pendred syndrome, respectively. In contrast, TMED2/3/9/10 silencing reduces SARS-CoV-2 viral release. These results provide evidence for a common role of TMED3 and related TMEDs in the ER stress-associated, Golgi-independent secretion of transmembrane proteins.

Hypermethylation of miR-205-5p by IR Governs Aggressiveness and Metastasis via Regulating Bcl-w and Src.

Although radiotherapy has been successfully applied to treat many cancer types, surviving cancer cells often acquire therapeutic resistance, leading to increased risk of local recurrence and distant metastases via modification of the tumor microenvironment. Previously, we reported that high expression of Bcl-w in cancer patients is significantly correlated with poor survival as well as malignant activity. However, the relationship between ionizing radiation (IR)-induced resistance and Bcl-w expression in cancer cells is currently unclear. We showed that IR-induced Bcl-w contributes to EMT (epithelial-mesenchymal transition), migration, angiogenesis, stemness maintenance, and metastasis by promoting the expression of factors related to these phenotypes, both in vitro and in vivo. Meanwhile, IR enhanced hypermethylation of miR-205-5p CpG islands through Src activation, leading to decreased miR-205-5p expression and, in turn, potentially stimulating Bcl-w-mediated malignant activity and metastasis. The clinical applicability of Bcl-w and miR-205-5p from cells or animal models was confirmed using tissues and plasma of breast carcinoma patients. Based on the collective findings, we propose that miR-205-5ps as important negative mediators of resistance in radiotherapy could serve as useful potential targets of concurrently applied genetic therapy aimed to inhibit tumor aggressiveness and enhance the efficiency of radiotherapy in cancer patients.

SRSF3-regulated miR-132/212 controls cell migration and invasion by targeting YAP1.

Although SRSF3 (Serine/arginine-rich splicing factor 3) plays a significant role in various biological processes, many of its functions still remain unclear. More particularly, little is known about SRSF3's involvement in the regulation of miRNA. In this report, we found that invasive and migratory abilities were inhibited in SRSF3-silenced U2OS and HeLa cells. We also found that a knockdown of SRSF3 results in a decreased expression level of REST (RE1-silencing transcription factor). The silencing of REST increased the expression of primary miR-132/212 as well as their mature forms. In particular, miR-132-3p and miR-212-3p possess an identical seed sequences and a common target gene. Overexpression of miR-132-3p and miR-212-3p suppressed the expression of YAP1 (Yes-associated protein 1) by directly binding to the 3՚UTR of its mRNA. CCND1 (Cyclin D1), which acts downstream of YAP1, was downregulated in both miR-132-3p and miR-212-3p-overexpressed cells, in correlation with diminished YAP1 levels. Taken together, our results reveal that SRSF3 controls the expression of the miR-132/212 cluster through regulating REST expression, and that the REST-elicited alteration of miRNA expression is implicated in enabling the migratory and invasive abilities of cancer cells.

IL-4, a direct target of miR-340/429, is involved in radiation-induced aggressive tumor behavior in human carcinoma cells.

Radiotherapy induces the production of cytokines, thereby increasing aggressive tumor behavior. This radiation effect results in the failure of radiotherapy and increases the mortality rate in patients. We found that interleukin-4 (IL-4) and IL-4Rα (IL-4 receptor) are highly expressed in various human cancer cells subsequent to radiation treatment. In addition, IL-4 is highly overexpressed in metastatic carcinoma tissues compared with infiltrating carcinoma tissues. High expression of IL-4 in patients with cancer is strongly correlated with poor survival. The results of this study suggest that radiation-induced IL-4 contributes to tumor progression and metastasis. Radiation-induced IL-4 was associated with tumorigenicity and metastasis. IL-4 expression was downregulated by miR-340 and miR-429, which were decreased by ionizing radiation (IR). Radiation-regulated miR-340/429-IL4 signaling increased tumorigenesis and metastasis by inducing the production of Sox2, Vimentin, VEGF, Ang2, and MMP-2/9 via activating JAK, JNK, ß-catenin, and Stat6 in vitro and in vivo. Our study presents a conceptual advance in our understanding of the modification of tumor microenvironment by radiation and suggests that combining radiotherapy with genetic therapy to inhibit IL-4 may be a promising strategy for preventing post-radiation recurrence and metastasis in patients.

Neurofibromatosis 2 (NF2) controls the invasiveness of glioblastoma through YAP-dependent expression of CYR61/CCN1 and miR-296-3p.

Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor derived from non-neuronal glial cells. Neurofibromatosis 2 (NF2) protein, also termed as merlin, is a well-known tumor suppressor; however, the molecular mechanism underlying this effect has not yet been fully defined. To investigate the role of NF2 in the invasiveness of GBM, we used two GBM cell lines: NF2-expressing T98G cells and NF2-deficient A172 cells. Knockdown of NF2 increased the invasiveness of T98G cells, whereas NF2-overexpressing A172 cells showed decreased invasive activity. Moreover, re-expression of NF2 reversed the high invasiveness of NF2-silenced T98G cells, indicating that NF2 negatively regulates GBM invasiveness. We further found that the NF2-mediated regulation of invasiveness was dependent on YAP and TEAD2 expression levels. NF2 also controlled the expression of YAP targets, including cysteine-rich angiogenic inducer 61 (CYR61/CCN1), by regulating the nuclear localization of YAP. Silencing of CYR61/CCN1 blocked the increased invasiveness of T98G cells, suggesting that CYR61/CCN1 is required for NF2-mediated invasiveness. Through microRNA microarray analysis, we found that NF2 negatively regulates the expression of miR-296-3p. Overexpression of miR-296-3p suppressed the expression of STAT5A, induced the phosphorylation of STAT3 by downregulating SOCS2, and increased the invasiveness of T98G cells. Taken together, we demonstrate that NF2 negatively controls the invasiveness of GBM through YAP-dependent induction of CYR61/CCN1 and miR-296-3p.

Ubiquitin-specific protease 4 controls metastatic potential through ß-catenin stabilization in brain metastatic lung adenocarcinoma.

Brain metastasis is the most common type of intracranial cancer and is the main cause of cancer-associated mortality. Brain metastasis mainly originates from lung cancer. Using a previously established in vitro brain metastatic model, we found that brain metastatic PC14PE6/LvBr4 cells exhibited higher expression of ß-catenin and increased migratory activity than parental PC14PE6 cells. Knockdown of ß-catenin dramatically suppressed the motility and invasiveness of PC14PE6/LvBr4 cells, indicating ß-catenin is involved in controlling metastatic potential. Since ß-catenin protein was increased without a significant change in its mRNA levels, the mechanism underlying increased ß-catenin stability was investigated. We found that ubiquitin-specific protease 4 (USP4), recently identified as a ß-catenin-specific deubiquitinylating enzyme, was highly expressed in PC14PE6/LvBr4 cells and involved in the increased stability of ß-catenin protein. Similar to ß-catenin knockdown, USP4-silenced PC14PE6/LvBr4 cells showed decreased migratory and invasive abilities. Moreover, knockdown of both USP4 and ß-catenin inhibited clonogenicity and induced mesenchymal-epithelial transition by downregulating ZEB1 in PC14PE6/LvBr4 cells. Using bioluminescence imaging, we found that knockdown of USP4 suppressed brain metastasis in vivo and significantly increased overall survival and brain metastasis-free survival. Taken together, our results indicate that USP4 is a promising therapeutic target for brain metastasis in patients with lung adenocarcinoma.

Overexpression of microRNA-95-3p suppresses brain metastasis of lung adenocarcinoma through downregulation of cyclin D1.

Despite great efforts to improve survival rates, the prognosis of lung cancer patients is still very poor, mainly due to high invasiveness. We developed brain metastatic PC14PE6/LvBr4 cells through intracardiac injection of lung adenocarcinoma PC14PE6 cells. Western blot and RT-qPCR analyses revealed that PC14PE6/LvBr4 cells had mesenchymal characteristics and higher invasiveness than PC14PE6 cells. We found that cyclin D1 was upregulated, miR-95-3p was inversely downregulated, and pri-miR-95 and its host gene, ABLIM2, were consistently decreased in PC14PE6/LvBr4 cells. MiR-95-3p suppressed cyclin D1 expression through direct binding to the 3' UTR of cyclin D1 mRNA and suppressed invasiveness, proliferation, and clonogenicity of PC14PE6/LvBr4 cells. Ectopic cyclin D1 reversed miR-95-3p-mediated inhibition of invasiveness and clonogenicity, demonstrating cyclin D1 downregulation is involved in function of miR-95-3p. Using bioluminescence imaging, we found that miR-95-3p suppressed orthotopic tumorigenicity and brain metastasis in vivo and increased overall survival and brain metastasis-free survival. Consistent with in vitro metastatic cells, the levels of miR-95-3p, pri-miR-95, and ABLIM2 mRNA were decreased in brain metastatic tissues compared with lung cancer tissues and higher cyclin D1 expression was involved in poor prognosis. Taken together, our results demonstrate that miR-95-3p is a potential therapeutic target for brain metastasis of lung adenocarcinoma cells.

Design of highly sensitive and selective Au@NiO yolk-shell nanoreactors for gas sensor applications.

Au@NiO yolk-shell nanoparticles (NPs) were synthesized by simple solution route and applied for efficient gas sensor towards H2S gas. Carbon encapsulated Au (Au@C core-shell) NPs were synthesized by glucose-assisted hydrothermal method, whereas Au@NiO yolk-shell NPs were synthesized by precipitation method using Au@C core-shell NPs as a template. Sub-micrometer Au@NiO yolk-shell NPs were formed having 50-70 nm Au NPs at the periphery of NiO shell (10-20 nm), which was composed of 6-12 nm primary NiO particles. Au@NiO yolk-shell NPs showed higher response for H2S compared to other interfering gases (ethanol, p-xylene, NH3, CO and H2). The maximum response was 108.92 for 5 ppm of H2S gas at 300 °C, which was approximately 19 times higher than that for the interfering gases. The response of Au@NiO yolk-shell NPs to H2S was approximately 4 times higher than that of bare NiO hollow nanospheres. Improved performance of Au@NiO yolk-shell NPs was attributed to hollow spaces that allowed the accessibility of Au NPs to gas molecules. It was suggested that adsorption of H2S on Au NPs resulted in the formation of sulfide layer, which possibly lowered its work function, and therefore tuned the electron transfer from Au to NiO rather NiO to Au, which leaded to increase in resistance and therefore response.

Cobalt chloride induces neuronal differentiation of human mesenchymal stem cells through upregulation of microRNA-124a.

Human mesenchymal stem cells (hMSCs) are known to have the capacity to differentiate into various cell types, including neurons. To examine our hypothesis that miRNA was involved in neuronal differentiation of hMSCs, CoCl2, a hypoxia-mimicking agent was used to induce neuronal differentiation, which was assessed by determining the expression of neuronal markers such as nestin and Tuj1. Treatment of hMSCs with CoCl2 led to increased expression of miR-124a, a neuron-specific miRNA. HIF-1α silencing and JNK inhibition abolished CoCl2-induced miR-124a expression, suggesting that JNK and HIF-1α signals were required for the miR-124a expression induced by CoCl2 in hMSCs. Overexpression of miR-124a or CoCl2 treatment suppressed the expression of anti-neural proteins such as SCP1 and SOX9. Silencing of both SCP1 and SOX9 induced neuronal differentiation of hMSCs, indicating that suppression of miR-124a targets is important for CoCl2-induced neuronal differentiation of hMSCs. Knockdown of HIF-1α or inhibition of JNK restored the expression of SCP1 and SOX9 in CoCl2-treated cells. Inhibition of miR-124a blocked CoCl2-induced suppression of SCP1 and SOX9 and abolished CoCl2-induced neuronal differentiation of hMSCs. Taken together, we demonstrate that miR-124a is critically regulates CoCl2-induced neuronal differentiation of hMSCs by suppressing the expression of SCP1 and SOX9.

MicroRNA-146a suppresses metastatic activity in brain metastasis.

Primary lung tumors, breast tumors, and melanoma metastasize mainly in the brain where therapy is limited to surgery and radiation. To investigate the molecular basis of brain metastases, we isolated brain-trophic metastatic MDA-MB-435-LvBr2 (LvBr2) cells via left ventricle (LV) injection of MDA-MB-435 cells into immunodeficiency (NOD/SCID) mice. Whereas parent MDA-MB-435 cells displayed an elongated morphology, LvBr2 cells were round and displayed an aggregated distribution. LvBr2 cells expressed lower ß-catenin levels and higher heterogeneous nuclear ribonucleoprotein C1/C2 (hnRNPC) levels than parental cells. Since microRNAs are known to play an important role in cancer progression including metastasis, we screened microRNAs expressed specifically in brain metastases. MicroRNA-146a was almost undetectable in LvBr2 cells and highly expressed in the parental cells. Overexpression of miR-146a increased ß-catenin expression and suppressed the migratory and invasive activity of LvBr2 cells. The miR-146a-elicited decrease in hnRNPC in turn lowered the expression of MMP-1, uPA, and uPAR and inhibited the migratory and invasive activity of LvBr2 cells. Taken together, our findings indicate that miR-146a is virtually absent from brain metastases and can suppress their metastatic potential including their migratory and invasive activities associated with upregulation of ß-catenin and downregulation of hnRNPC.

Heterogeneous nuclear ribonucleoprotein C1/C2 controls the metastatic potential of glioblastoma by regulating PDCD4.

MicroRNAs (miRNAs) have been implicated in the pathogenesis and progression of brain tumors. miR-21 is one of the most highly overexpressed miRNAs in glioblastoma multiforme (GBM), and its level of expression correlates with the tumor grade. Programmed cell death 4 (PDCD4) is a well-known miR-21 target and is frequently downregulated in glioblastomas in accordance with increased miR-21 expression. Downregulation of miR-21 or overexpression of PDCD4 can inhibit metastasis. Here, we investigate the role of heterogeneous nuclear ribonucleoprotein C1/C2 (hnRNPC) in the metastatic potential of the glioblastoma cell line T98G. hnRNPC bound directly to primary miR-21 (pri-miR-21) and promoted miR-21 expression in T98G cells. Silencing of hnRNPC lowered miR-21 levels, in turn increasing the expression of PDCD4, suppressing Akt and p70S6K activation, and inhibiting migratory and invasive activities. Silencing of hnRNPC reduced cell proliferation and enhanced etoposide-induced apoptosis. In support of a role for hnRNPC in the invasiveness of GBM, highly aggressive U87MG cells showed higher hnRNPC expression levels and hnRNPC abundance in tissue arrays and also showed elevated levels as a function of brain tumor grade. Taken together, our data indicate that hnRNPC controls the aggressiveness of GBM cells through the regulation of PDCD4, underscoring the potential usefulness of hnRNPC as a prognostic and therapeutic marker of GBM.

Peroxisome proliferator-activated receptor-gamma expression in the lung tissue of obese rats.

PURPOSE: Obesity is a risk factor for asthma and type II diabetes. Peroxisome proliferator- activated receptor (PPAR)-γ has been suggested to regulate inflammatory responses in diabetes and asthma. We investigated whether PPAR-α, PPAR-γ, adiponectin receptors (AdipoR1, AdipoR2), leptin, and tumor necrosis factor (TNF)-α are expressed in rat lung tissues and whether the expression differs between obese Otsuka Long-Evans Tokushima Fatty (OLETF) and lean Long Evans Tokushima Otsuka (LETO) rats. MATERIALS AND METHODS: Obese and lean rats were given with a high fat diet or a 30% restricted diet for 32 weeks, and their blood glucose levels and weights were monitored. After 32 weeks, mRNA levels of PPAR-α, PPAR-γ, AdipoR1, AdipoR2, leptin, and TNF-α in lung tissues were measured using real time PCR. RESULTS: PPAR-α, PPAR-γ, AdipoR1, AdipoR2, leptin, and TNF-α were expressed in both obese and lean rat lung tissues. Increased serum glucose levels on intraperitoneal glucose tolerance testing and a higher weight gain at 32 weeks were observed in OLETF control rats compared to OLETF diet restricted rats. PPAR-γ expression was markedly elevated in obese control and diet restricted rats compared to lean rats, although PPAR-γ expression in obese rats was not affected by diet restriction. Leptin was highly expressed in OLETF rats compared to LETO rats. TNF-α expression was enhanced in OLETF control rats compared LETO diet restricted rats, and decreased by diet restriction. PPAR-α, AdipoR1, and AdipoR2 expression were not significantly different between obese and lean rats. CONCLUSION: PPAR-γ was highly expressed in the lung tissues of obese rats and may be a novel treatment target for regulating lung inflammation associated with obesity.

Fas/Fas ligand-mediated apoptosis promotes hypersensitivity pneumonitis in mice by enhancing maturation of dendritic cells.

RATIONALE: Fas/Fas ligand (FasL)-mediated apoptosis has been implicated in various lung diseases, but whether Fas/FasL-mediated apoptosis in the lungs plays a critical role in the development of hypersensitivity pneumonitis (HP) is unclear. OBJECTIVES: To explore the functional roles of Fas/FasL-mediated apoptosis in HP. METHODS: Fas-deficient (lpr/lpr), FasL-deficient (gld/gld), and B6 mice were challenged with Saccharopolyspora rectivirgula (SR) antigen intranasally. MEASUREMENTS AND MAIN RESULTS: lpr/lpr and gld/gld mice exhibited attenuation of HP in terms of histological alterations, influx of immune cells in bronchoalveolar lavage fluid (BALF), and SR-specific immune responses compared with B6 mice, similar to the effects of SR in B6 mice given a caspase inhibitor. The lungs of lpr/lpr and gld/gld mice showed high IL-4 production and low IFN-gamma, IL-8, macrophage inflammatory protein-2, IL-1beta, and tumor necrosis factor-alpha production compared with those of B6 mice. Moreover, mice with chimeric B6 and lpr/lpr bone marrow revealed that apoptosis of nonhematopoietic and BALF immune cells of the lungs enhanced immune responses against SR antigen. Gr-1(+) granulocytes in BALF expressed annexin V and their depletion in B6 mice attenuated HP. Apoptosis of nonhematopoietic cells and Gr-1(+) granulocytes in the lungs enhanced the maturation of pulmonary CD11c(+) dendritic cells and their production of macrophage inflammatory protein-1alpha and monocyte chemoattractant protein-1, resulting in recruitment of immune cells into the lungs during HP. CONCLUSIONS: These results suggest that apoptosis in nonhematopoietic cells and Gr-1(+) granulocytes of the lungs promotes HP by enhancing maturation and chemokine production of CD11c(+) dendritic cells.

NEFL Pro22Arg mutation in Charcot-Marie-Tooth disease type 1.

Charcot-Marie-Tooth disease (CMT) is classified into demyelinating neuropathy (CMT1) and axonal neuropathy (CMT2). Mutations in the neurofilament light chain polypeptide (NEFL) gene are present in CMT2E and CMT1F neuropathies. Two types of Pro22 mutations have been previously reported: Pro22Ser in CMT2E with giant axons, and Pro22Thr in CMT1F. In this study, we identified another Pro22 mutation, Pro22Arg, in a Korean CMT1 family. An investigation to identify the clinical and pathological characteristics of the Pro22Arg revealed that it is associated with demyelinating neuropathy features in CMT1F. Histopathological findings showed onion bulb formations but no giant axons. It appears that the Pro22 mutations may influence not only the Thr-Pro phosphorylation site by proline-directed protein kinases but also other structural alteration of the NEFL protein in a different way.