DNA binding properties and cell viabilities of metal complexes derived from (E)-2-hydroxy-N'-((thiophen-2-yl)methylene)benzohydrazone and (E)-N'-((thiophen-2-yl)methylene)isonicotinylhydrazone.

OBJECTIVE: This study aims to investigate the CT-DNA (Calf thymus DNA) binding properties and HeLa cell viabilities of metal complexes derived from (E)-2-hydroxy-N'-((thiophen-2-yl)methylene)benzohydrazone (H2L1) and (E)-N'-((thiophen-2-yl)methylene)isonicotinylhydrazone (HL2). MATERIALS AND METHODS: A series of metal complexes derived from (E)-2-hydroxy-N'-((thiophen-2-yl)methylene)benzohydrazone (H2L1) and (E)-N'-((thiophen-2-yl)methylene)isonicotinylhydrazonewere (HL2) were synthesized, and their structures were characterized through FT-IR, ESI-MS, elemental analysis, molar conductivities and X-ray diffraction. DNA binding properties between CT-DNA and metal complexes were investigated by UV-Vis spectrophotometry and viscosity titration. The toxicological properties of compounds on HeLa cell were measured in vitro. RESULTS: Ligand H2L1 or HL2 exhibits a tridentate and anion ligand and uses oxygen anion, nitrogen atom and sulfur atom to coordinate with metal ions. When coordinated with metal ions, the unit O=C-NH- of each ligand has been enolized and deprotonated into -O-C=N-. The suggested chemical formulas of metal complexes are: [Co(HL1)2], [Ni(HL1)2], [Cu(HL1)2], [Co(L2)2], [Cu(L2)2], [Zn(L2)2], [ScL2(NO3)2(H2O)2], [Pr(L2)2(NO3)] and [Dy(L2)2(NO3)]. Both ligands and their metal complexes can bind strongly to CT-DNA through hydrogen bond and intercalation with Kb of 104~105 L mol-1 compared to ethidium bromide [classical DNA intercalator, Kb(EB-DNA) = 3.068 × 104 L mol-1]; however, the groove pattern cannot be excluded. The coexistence of multiple binding modes may be a common form of drug binding to DNA. HeLa cell shows lower viabilities in the presence of [Ni(HL1)2] and [Cu(HL1)2] (*p < 0.05) compared to the other compounds, with the LC50 of 2.6 µmol L-1 and 2.2 µmol L-1, respectively. CONCLUSIONS: These compounds, especially [Ni(HL1)2] and [Cu(HL1)2], will be promising for anti-tumor drugs, which should be further studied.

Ethical, legal and social issues raised by human brain banks.

Based on the research methods of literature review and philosophical reflection, this article points out the deficiencies and problems in the current research of brain banks: lack of nature analysis of brain banks and human brains; insufficient discussion of ethical, legal and social issues (ELSI) in the process of brain bank implementation - which has become the main research goal of this article. The article firstly clarifies the formation process of modern brain banks and briefly introduces the current development status of brain banks in the UK, the US and China, as well as the different types of modern brain banks. Next, the nature of brain banks and human brain samples are analyzed through an analogical model. Then, the ELSI issues at different stages are analyzed according to three stages: recruitment of donors, acquisition and storage of human brain tissue samples, and release and use of human brain tissue samples. Last, in the conclusion section, the main ideas of this paper are reiterated and questions for further reflection are presented.

Lithium Chloride-Substituted Methylammonium Lead Tribromide Perovskites for Dual γ/Neutron Sensing.

Dual γ/neutron radiation sensors are a critical component of the nuclear security mission to prevent the proliferation of a special nuclear material (SNM). While high-performing semiconductors such as high purity germanium (HPGe) and CdZnTe (CZT) already exist in the nuclear security enterprise, their high cost and/or logistical burdens make widespread deployment difficult to achieve. Metal lead halide perovskites (MHPs) have attracted interest in recent years to address this challenge. In particular, methylammonium lead tribromide (CH3NH3PbBr3, MAPbBr3, or MAPB) has been widely evaluated for its radiation sensing capabilities. While previous studies have demonstrated low-energy X-ray and α particle sensing of MAPB-based detectors and several studies discuss the potential for γ ray sensing, neutron sensing of this material has been rarely explored. Here, we explore the incorporation of lithium in the form of LiCl into the MAPB structure to add thermal neutron sensitivity. Characterizations of the lithium-doped MAPB crystals demonstrate that quality growths are achievable with single crystals that exhibit high crystallinity, no phase change, and high macroscopic bulk quality. Finally, we report on the first demonstrated γ ray and thermal neutron sensing based on lithium-doped MAPB single crystals, which is a significant milestone in the development of 3D dual γ/neutron MHP sensors.

[Analysis on off-label use of drugs in pediatric guidelines and consensus published by Chinese authors].

Objective: To understand the current situation regarding pediatric off-label use of drugs recommendations in Chinese clinical practice guidelines and to make recommendations for standardized reporting format regarding off-label use of drugs for children. Methods: This cross-sectional study was carried out by systematically searching the databases for Chinese guideline consensus articles published in journals between 2018 and 2020 and extracting recommendations regarding off-label use of drugs from those articles. The essential characteristics of the included guidelines, the ranking of off-label drug types, the order of drug information, the type of off-label drug use, and the percentage of citation studies on which the recommendations were based were analyzed. Results: Among 108 studies that included Chinese off-label guidelines and consensus, 364 recommendations on pediatric off-label use of drugs were included. The Chinese Medical Association published the most, 48 out of the 108 studies (44.4%), and of those 14 studies (13.0%) were on infectious and parasitic diseases. Of the 364 recommendations on off-label use of drugs, the most commonly addressed drugs were 16 recommendations (4.4%) for cyclosporine A, 11 recommendations (3.0%) for methotrexate , and 11 recommendations (3.0%) for fentanyl. The most commonly addressed drug categories were as follows: 68 recommendations (18.6%) were immune system drugs, 66 recommendations (18.1%) were anti-infectives, and 56 recommendations (15.4%) were oncology drugs. The most commonly addressed drug information accounts were as follows: 364 recommendations (100.0%) were indications, 204 recommendations (56.0%) were dosages, and 198 recommendations (54.4%) were the route of administration. Based on the instructions approved by the Chinese Food and Drug Administration, the main forms of the off-label drug were as follows: 175 recommendations (48.1%) were unapproved indications, 127 recommendations (34.9%) were unapproved populations, and 72 recommendations (19.8%) were unapproved ages. Only 129 recommendations (35.4%) were cited, mainly including clinical guidelines (48 studies, 23.4%), reviews (22 studies, 10.7%), and pediatric randomized controlled trials (22 studies, 10.7%). Conclusions: Off-label use of drugs is commonly recommended in pediatric guidelines and consensus documents written by Chinese authors. However, the reporting of the recommendations varies widely, and the quality of the supporting evidence is poor.

Identification of cis-regulatory modules for adeno-associated virus-based cell-type-specific targeting in the retina and brain.

Adeno-associated viruses (AAVs) targeting specific cell types are powerful tools for studying distinct cell types in the central nervous system (CNS). Cis-regulatory modules (CRMs), e.g., enhancers, are highly cell-type-specific and can be integrated into AAVs to render cell type specificity. Chromatin accessibility has been commonly used to nominate CRMs, which have then been incorporated into AAVs and tested for cell type specificity in the CNS. However, chromatin accessibility data alone cannot accurately annotate active CRMs, as many chromatin-accessible CRMs are not active and fail to drive gene expression in vivo. Using available large-scale datasets on chromatin accessibility, such as those published by the ENCODE project, here we explored strategies to increase efficiency in identifying active CRMs for AAV-based cell-type-specific labeling and manipulation. We found that prescreening of chromatin-accessible putative CRMs based on the density of cell-type-specific transcription factor binding sites (TFBSs) can significantly increase efficiency in identifying active CRMs. In addition, generation of synthetic CRMs by stitching chromatin-accessible regions flanking cell-type-specific genes can render cell type specificity in many cases. Using these straightforward strategies, we generated AAVs that can target the extensively studied interneuron and glial cell types in the retina and brain. Both strategies utilize available genomic datasets and can be employed to generate AAVs targeting specific cell types in CNS without conducting comprehensive screening and sequencing experiments, making a step forward in cell-type-specific research.

Quasi-2D Perovskite Crystalline Layers for Printable Direct Conversion X-Ray Imaging.

Polycrystalline perovskite film-based X-ray detector is an appealing technology for assembling large scale imager by printing methods. However, thick crystalline layer without trap and solvent residual is challenging to fabricate. Here, the authors report a solution method to produce high quality quasi-2D perovskite crystalline layers and detectors that are suitable for X-ray imaging. By introducing n-butylamine iodide into methylammonium lead iodide precursor and coating at elevated temperatures, compact and crystalline layers with exceptional uniformity are obtained on both rigid and flexible substrates. Photodiodes built with the quasi-2D layers exhibit a low dark current and stable operation under constant electrical field over 96 h in dark, and over 15 h under X-ray irradiation. The detector responds sensitively under X-ray, delivering a high sensitivity of 1214 µC Gyair -1  cm-2 and a sensitivity gain is observed when operated under higher fields. Finally, high resolution images are demonstrated using a single pixel device that can resolve 80-200 µm features. This work paves the path for printable direct conversion X-ray imager development.

Cutaneous small vessel vasculitis triggered by Fusobacterium infection.

We report the case of a 94-year-old woman presenting clinically with a cutaneous small vessel vasculitis. We hypothesize that this was triggered by Fusobacterium necrophorum.

Determination of X-ray detection limit and applications in perovskite X-ray detectors.

X-ray detection limit and sensitivity are important figure of merits for perovskite X-ray detectors, but literatures lack a valid mathematic expression for determining the lower limit of detection for a perovskite X-ray detector. In this work, we present a thorough analysis and new method for X-ray detection limit determination based on a statistical model that correlates the dark current and the X-ray induced photocurrent with the detection limit. The detection limit can be calculated through the measurement of dark current and sensitivity with an easy-to-follow practice. Alternatively, the detection limit may also be obtained by the measurement of dark current and photocurrent when repeatedly lowering the X-ray dose rate. While the material quality is critical, we show that the device architecture and working mode also have a significant influence on the sensitivity and the detection limit. Our work establishes a fair comparison metrics for material and detector development.

[Comparative analysis of the clinical application of two femtosecond laser-assisted cataract operation platforms].

Objective: To evaluate the operability and clinical application effects of femtosecond laser-assisted cataract surgery systems of LenSx and LenSAR. Methods: This was a randomized controlled study. A total of 86 patients (90 eyes) who underwent femtosecond laser-assisted cataract surgery in Wuhan Aier Eye Hospital from April 2018 to November 2018 were enrolled and divided into two groups randomly, including 44 patients (45 eyes) in the LenSx group and 42 patients (45 eyes) in the LenSAR group. During the operation, the following observation indexes were obtained. Operational indicators included the number of docking attempts, anterior capsulotomy time, nucleus pre-treatment time, total femtosecond laser emission time, and total vacuum suction duration. Clinical outcome indicators included changes in the patient's intraocular pressure during femtosecond laser surgery, the rate of subconjunctival hemorrhage, capsulotomy integrity (yes/no), roundness and centricity of the anterior capsule opening (yes/no), the rate of anterior capsule opening tear, and the rate of posterior capsule rupture. The t-test, rank-sum test or chi-square test were used for statistical analysis. Results: There were no significant differences between groups in the age and the lens density (both P>0.05). The number of docking attempts in the LenSx group was 1 (1 to 4) and in the LenSAR group was 1 (1 to 2); there was statistically significant difference (Z =-2.23, P<0.05). The difference in the anterior capsulotomy time between the two groups was statistically significant [13.00 (10.00 to 22.00) s compared with 3.00 (1.00 to 3.00) s, Z=-8.71, P<0.05]. The femtosecond laser pre-nucleation time and total femtosecond laser emission time of the LenSx group were (16.67±3.36) s and (30.49±3.53) s, and those of the LenSAR group were (12.38±4.36) s and (15.36±4.29) s, respectively; the differences between the two groups were statistically significant (t=-5.23, -18.26; both P<0.05). The total vacuum suction duration in the LenSx group was (97.23±19.96) s, shorter than that in the LenSAR group [(123.76±16.81) s] (t=6.82, P<0.05). The intraocular pressure after femtosecond laser surgery in both groups was higher than that before surgery. The increase of intraocular pressure in the LenSAR group was (5.64±5.42) mmHg (1 mmHg=0.133 kPa), higher than that in the LenSx group [(2.99±4.66) mmHg] (t=-2.49, P<0.05). The rate of subconjunctival hemorrhage in the LenSx group was 33.3% (15/45), while it was 8.9% (4/45) in the LenSAR group; the difference between the two groups was statistically significant (χ²=6.67, P<0.05). There were no significant differences between groups in capsulotomy integrity, roundness and centricity of the anterior capsule opening, the rate of anterior capsule opening tear, and the rate of posterior capsule rupture (all P>0.05). Conclusion: The docking process of the LenSAR system is convenient, and there is less subconjunctival hemorrhage; the total vacuum suction duration of LenSx is short, and the increase of intraocular pressure is low. (Chin J Ophthalmol, 2020, 56: 530-535).

Clinical features, outcomes and risk factors for posterior reversible encephalopathy syndrome in systemic lupus erythematosus: a case-control study.

OBJECTIVE: The objective of this paper is to investigate the clinical features, outcomes, and risk factors for posterior reversible encephalopathy syndrome (PRES) in systemic lupus erythematosus (SLE). METHODS: From 2011 to October 2017, SLE patients with PRES were identified from the First Affiliated Hospital of Zhengzhou University, China. Patients presenting with neuropsychiatric lupus hospitalized in the same period were included as controls. Additionally, survival status was acquired via telephone follow-up in March 2018. RESULTS: Thirty episodes of PRES were identified in 29 SLE patients from a total of 7059 SLE patients (prevalence 0.43%). Patients with PRES had a younger age at onset than controls, with seizures more commonly the initial clinical manifestation (80.00% vs 42.37%, p = 0.001). Multiple logistic regression yet again confirmed several known risk factors, including younger age (odds ratio (OR) 1.15 (95% confidence interval (CI) 1.13-1.16)), nephritis (OR 20.74 (18.10-23.75)), history of hypertension (OR 1.17 (1.05-1.31)), SLE Disease Activity Index without neurologic symptoms (SLEDAI-N) score >12 (OR 1.14 (1.11-1.18)) and eclampsia (OR 9.38 (7.84-11.23)). Furthermore, we identified two novel independent risk factors for PRES in SLE: white blood cells >9 × 109/l (OR 2.33 (2.05-2.64)) and heart failure (OR 2.10 (1.18-2.42)). At follow-up, SLE patients with PRES had higher mortality than controls (30.77% vs 8.33%, respectively, p = 0.012). CONCLUSIONS: PRES may be a reversible neurological deficit in patients with SLE other than neuropsychiatric lupus. Our results indicate two new risk factors for PRES and that PRES is associated with a higher mortality rate.

[A new simple scoring system to determine the timing and efficacy of entecavir therapy in hepatitis B-related acute-on-chronic liver failure].

Objective: To determine the timing and efficacy of entecavir (ETV) therapy in hepatitis B-related acute-on-chronic liver failure (HBV-ACLF) using a new simple scoring system. Methods: A total of 212 patients with HBV-ACLF were treated with ETV 0.5 mg daily besides the routine treatment. The severity of illness was scored by the HBV-ACLF prognostic scoring system. Hepatic failure severity scores, hepatitis B virus DNA (HBV DNA) load, and length of hospital stay were recorded at the time of initiation of treatment, and the time of survival to hospital discharge/end of life. Results: Patiens were divided into four groups by the admission severity scores according to the percentile table: low score group (score≤ 4), medium-low score group (score: 5-7), medium-high score group (score: 8-11), and high score group (score ≥12). As the scores increased, the mortality rate increased. There were significant differences among different groups (χ(2)=310.662, P<0.001). There were significant difference of the admission and discharge/death severity scores in the low score group (P=0.003). There were significant differences of the comparison of HBV DNA load at admission and death/discharge using ETV in low-, medium-low, and medium-high score groups (P<0.001). There were no significant differences of HBV DNA load at admission and death/discharge using ETV for dead and survival patients in the medium-low, and medium-high score groups. Conclusions: The efficacy of ETV in the rescue treatment of HBV-ACLF is related to the severity of ACLF when starting medication. The HBV-ACLF prognostic scoring system can clearly determine the timing and efficacy of ETV treatment of HBV-ACLF.

Homeostatic synaptic plasticity as a metaplasticity mechanism - a molecular and cellular perspective.

The molecular mechanisms underlying various types of synaptic plasticity are historically regarded as separate processes involved in independent cellular events. However, recent progress in our molecular understanding of Hebbian and homeostatic synaptic plasticity supports the observation that these two types of plasticity share common cellular events, and are often altered together in neurological diseases. Here, we discuss the emerging concept of homeostatic synaptic plasticity as a metaplasticity mechanism with a focus on cellular signaling processes that enable a direct interaction between Hebbian and homeostatic plasticity. We also identify distinct and shared molecular players involved in these cellular processes that may be explored experimentally in future studies to test the hypothesis that homeostatic synaptic plasticity serves as a metaplasticity mechanism to integrate changes in neuronal activity and support optimal Hebbian learning.

Retinoic Acid Receptor RARα-Dependent Synaptic Signaling Mediates Homeostatic Synaptic Plasticity at the Inhibitory Synapses of Mouse Visual Cortex.

Homeostatic synaptic plasticity is a synaptic mechanism through which the nervous system adjusts synaptic excitation and inhibition to maintain network stability. Retinoic acid (RA) and its receptor RARα have been established as critical mediators of homeostatic synaptic plasticity. In vitro studies reveal that RA signaling enhances excitatory synaptic strength and decreases inhibitory synaptic strength. However, it is unclear whether RA-mediated homeostatic synaptic plasticity occurs in vivo, and if so, whether it operates at specific types of synapses. Here, we examine the impact of RA/RARα signaling in the monocular zone of primary visual cortex (V1m) in mice of either sex. Exogenous RA treatment in acute cortical slices resulted in a reduction in mIPSCs of layer 2/3 pyramidal neurons, an effect mimicked by visual deprivation induced by binocular enucleation in postcritical period animals. Postnatal deletion of RARα blocked RA's effect on mIPSCs. Cell type-specific deletion of RARα revealed that RA acted specifically on parvalbumin (PV)-expressing interneurons. RARα deletion in PV+ interneurons blocked visual deprivation-induced changes in mIPSCs, demonstrating the critical involvement of RA signaling in PV+ interneurons in vivo Moreover, visual deprivation- or RA-induced downregulation of synaptic inhibition was absent in the visual cortical circuit of constitutive and PV-specific Fmr1 KO mice, strongly suggesting a functional interaction between fragile X mental retardation protein and RA signaling pathways. Together, our results demonstrate that RA/RARα signaling acts as a key component for homeostatic regulation of synaptic transmission at the inhibitory synapses of the visual cortex.SIGNIFICANCE STATEMENTIn vitro studies established that retinoic acid (RA) and its receptor RARα play key roles in homeostatic synaptic plasticity, a mechanism by which synaptic excitation/inhibition balance and network stability are maintained. However, whether synaptic RA signaling operates in vivo remains undetermined. Here, using a conditional RARα KO mouse and cell type-specific Cre-driver lines, we showed that RARα signaling in parvalbumin-expressing interneurons is crucial for visual deprivation-induced homeostatic synaptic plasticity at inhibitory synapses in visual cortical circuits. Importantly, this form of synaptic plasticity is absent when fragile X mental retardation protein is selectively deleted in parvalbumin-expressing interneurons, suggesting a functional connection between RARα and fragile X mental retardation protein signaling pathways in vivo Thus, dysfunction of RA-dependent homeostatic plasticity may contribute to cortical circuit abnormalities in fragile X syndrome.

The microRNA-182-PDK4 axis regulates lung tumorigenesis by modulating pyruvate dehydrogenase and lipogenesis.

Reprogrammed metabolism is one of the hallmarks of cancer. The dysregulation of glycolysis in cancer has been heavily studied. However, it remains largely unclear how other metabolic processes are regulated in cancer cells. Here we show that microRNA-182 (miR-182) suppresses pyruvate dehydrogenase (PDH) kinase 4 (PDK4) and promotes lung tumorigenesis. miR-182 is dysregulated and inversely correlated with PDK4 in human lung adenocarcinomas. The miR-182-PDK4 axis regulates lung cancer cell growth by modulating the activity of PDH, the gatekeeping enzyme of pyruvate flux into acetyl-CoA, and subsequently de novo lipogenesis of cancer cells. Suppression of lipogenesis by silencing ATP citrate lyase (ACLY) and fatty acid synthase (FASN) or by chemical inhibitors diminishes the effects of miR-182-PDK4 in tumor growth. Alteration of de novo lipogenesis also affects reactive oxygen species (ROS) production and the downstream JNK signaling pathway. Hence, our work suggests that the miR-182-PDK4 axis is a crucial regulator of cancer cell metabolism and a potential target for antitumor therapy.

Transferrin receptor facilitates TGF-ß and BMP signaling activation to control craniofacial morphogenesis.

The Pierre Robin Sequence (PRS), consisting of cleft palate, glossoptosis and micrognathia, is a common human birth defect. However, how this abnormality occurs remains largely unknown. Here we report that neural crest cell (NCC)-specific knockout of transferrin receptor (Tfrc), a well known transferrin transporter protein, caused micrognathia, cleft palate, severe respiratory distress and inability to suckle in mice, which highly resemble human PRS. Histological and anatomical analysis revealed that the cleft palate is due to the failure of palatal shelves elevation that resulted from a retarded extension of Meckel's cartilage. Interestingly, Tfrc deletion dramatically suppressed both transforming growth factor-ß (TGF-ß) and bone morphogenetic protein (BMP) signaling in cranial NCCs-derived mandibular tissues, suggesting that Tfrc may act as a facilitator of these two signaling pathways during craniofacial morphogenesis. Together, our study uncovers an unknown function of Tfrc in craniofacial development and provides novel insight into the etiology of PRS.

Acetic acid recovery from a hybrid biological-hydrothermal treatment process of sewage sludge - a pilot plant study.

A two-stage process consisting of anaerobic fermentation followed by sub-critical wet oxidation was used to generate acetic acid from sewage sludge at pilot scale. Volatile fatty acids, dominated by propionic acid, were produced over 4-6 days in the 2,000 L fermentation reactor, which also achieved 31% solids reduction. Approximately 96% of the carbon was retained in solution over the fermentation stage. Using a 200 L wet oxidation reactor operating in batch mode, the second stage achieved 98% volatile suspended solids (VSS) destruction and 67% total chemical oxygen demand (tCOD) destruction. Acetic acid produced in this stage was recalcitrant to further degradation and was retained in solution. The gross yield from VSS was 16% for acetic acid and 21% for volatile fatty acids across the process, higher than reported yields for wet oxidation alone. The pilot plant results showed that 72% of the incoming phosphorus was retained in the solids, 94% of the nitrogen became concentrated in solution and 41% of the carbon was converted to a soluble state, in a more degradable form. Acetic acid produced from the process has the potential to be used to offset ethanol requirements in biological nutrient removal plants.

In situ quantification and visualization of lithium transport with neutrons.

A real-time quantification of Li transport using a nondestructive neutron method to measure the Li distribution upon charge and discharge in a Li-ion cell is reported. By using in situ neutron depth profiling (NDP), we probed the onset of lithiation in a high-capacity Sn anode and visualized the enrichment of Li atoms on the surface followed by their propagation into the bulk. The delithiation process shows the removal of Li near the surface, which leads to a decreased coulombic efficiency, likely because of trapped Li within the intermetallic material. The developed in situ NDP provides exceptional sensitivity in the temporal and spatial measurement of Li transport within the battery material. This diagnostic tool opens up possibilities to understand rates of Li transport and their distribution to guide materials development for efficient storage mechanisms. Our observations provide important mechanistic insights for the design of advanced battery materials.

Comprehensive analysis of miRNA expression in T-cell subsets of rheumatoid arthritis patients reveals defined signatures of naive and memory Tregs.

Disturbed expression of microRNAs (miRNAs) in regulatory T cells (Tregs) leads to development of autoimmunity in experimental mouse models. However, the miRNA expression signature characterizing Tregs of autoimmune diseases, such as rheumatoid arthritis (RA) has not been determined yet. In this study, we have used a microarray approach to comprehensively analyze miRNA expression signatures of both naive Tregs (CD4+CD45RO-CD25++) and memory Tregs (CD4+CD45RO+CD25+++), as well as conventional naive (CD4+CD45RO-CD25-) and memory (CD4+CD45RO+CD25-) T cells (Tconvs) derived from peripheral blood of RA patients and matched healthy controls. Differential expression of selected miRNAs was validated by TaqMan-based quantitative reverse transcription-PCR. We found a positive correlation between increased expression of miR-451 in T cells of RA patients and disease activity score (DAS28), erythrocyte sedimentation rate levels and serum levels of interleukin-6. Moreover, we found characteristic, disease- and treatment-independent, global miRNA expression signatures defining naive Tregs, memory Tregs, naive Tconvs and memory Tconvs. The analysis allowed us to define miRNAs characteristic for a general naive phenotype (for example, miR-92a) and a general memory phenotype (for example, miR-21, miR-155). Importantly, the analysis allowed us to define miRNAs that are specifically expressed in both naive and memory Tregs, defining as such miRNA signature characterizing the Treg phenotype (that is, miR-146a, miR-3162, miR-1202, miR-1246 and miR-4281).

Suppression of MIM by microRNA-182 activates RhoA and promotes breast cancer metastasis.

Breast cancer is the most common type of cancer among women worldwide, and metastasis represents the most devastating stage of the disease. Recent studies have revealed that microRNAs (miRNA) have critical roles to regulate cancer cell invasion and metastasis. Here we present evidence to show the role of miR-182 in breast cancer metastasis. miR-182 is upregulated in the malignant cell line variants of both human MCF10 and mouse 4T1 series. Ectopic expression of miR-182 enhanced breast cancer cell motility and invasiveness, whereas miR-182 inhibition resulted in opposite changes. In nude mice, miR-182 led to increased pulmonary colonization of cancer cells. We further demonstrated that miR-182 directly targets MIM (Missing in Metastasis), which suppresses metastasis by inhibiting ras homolog family member A (RhoA) activity and stress fiber formation in breast cancer cells. Restoring MIM expression completely blocked the pro-metastasis function of miR-182, while RhoA inhibition reversed the phenotypes of both miR-182 overexpression and MIM knockdown. In breast tumor samples, miR-182 induction is linked to downregulation of MIM, RhoA activation and poor prognosis. Hence, our data delineates the molecular pathway by which miR-182 promotes breast cancer invasion and metastasis, and may have important implication for the treatment of metastatic cancers.