Family adaptation in families of individuals with Down syndrome from 12 countries.

Our current understanding of adaptation in families of individuals with Down syndrome (DS) is based primarily on findings from studies focused on participants from a single country. Guided by the Resiliency Model of Family Stress, Adjustment, and Adaptation, the purpose of this cross-country investigation, which is part of a larger, mixed methods study, was twofold: (1) to compare family adaptation in 12 countries, and (2) to examine the relationships between family variables and family adaptation. The focus of this study is data collected in the 12 countries where at least 30 parents completed the survey. Descriptive statistics were generated, and mean family adaptation was modeled in terms of each predictor independently, controlling for an effect on covariates. A parsimonious composite model for mean family adaptation was adaptively generated. While there were cross-country differences, standardized family adaptation mean scores fell within the average range for all 12 countries. Key components of the guiding framework (i.e., family demands, family appraisal, family resources, and family problem-solving communication) were important predictors of family adaptation. More cross-country studies, as well as longitudinal studies, are needed to fully understand how culture and social determinants of health influence family adaptation in families of individuals with DS.

A Single-Center Retrospective Analysis of Periprocedural Variables Affecting Local Tumor Progression after Radiofrequency Ablation of Colorectal Cancer Liver Metastases.

Background Local tumor progression (LTP) is associated with poorer survival in patients undergoing radiofrequency ablation (RFA) for colorectal liver metastasis (CLM). An algorithmic strategy to predict LTP may help in selection of patients who would benefit most from RFA for CLM. Purpose To estimate local tumor progression-free survival (LTPFS) following RFA of CLM and develop an algorithmic strategy based on clinical variables. Materials and Methods In this retrospective study, between March 2000 and December 2014, patients who underwent percutaneous RFA for CLM were randomly split into development (60%) and internal validation (40%) data sets. Kaplan-Meier method was used to estimate LTPFS and overall survival (OS) rates. Independent factors affecting LTPFS in the development data set were investigated by using multivariable Cox proportional hazard regression analysis. Risk scores were assigned to the risk factors and applied to the validation data set. Results A total of 365 patients (mean age, 60 years ± 11 [standard deviation]; 259 men) with 512 CLMs were evaluated. LTPFS and OS rates were 85% and 92% at 1 year, 73% and 41% at 5 years, 72% and 30% at 10 years, and 72% and 28% at 15 years, respectively. Independent risk factors for LTP included tumor size of 2 cm or greater (hazard ratio [HR], 3.8; 95% CI: 2.3, 6.2; P < .001), subcapsular tumor location (HR, 1.9; 95% CI: 1.1, 3.1; P = .02), and minimal ablative margin of 5 mm or less (HR, 11.7; 95% CI: 4.7, 29.2; P < .001). A prediction model that used the risk factors had areas under the curve of 0.89, 0.92, and 0.90 at 1, 5, and 10 years, respectively, and it showed significantly better areas under the curve when compared with the model using the minimal ablative margin of 5 mm or less alone. Conclusion Radiofrequency ablation provided long-term control of colorectal liver metastases. Although minimal ablative margin of 5 mm or less was the most dominant factor, the multifactorial approach including tumor size and subcapsular location better predicted local tumor progression-free survival. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Soulen and Sofocleous in this issue.

Measurement of Family Management in Families of Individuals With Down Syndrome: A Cross-Cultural Investigation.

Down syndrome (DS) is the most common genetic cause of intellectual disability worldwide. The purpose of this analysis was to determine the internal consistency reliability of eight language versions of the Family Management Measure (FaMM) and compare family management of DS across cultures. A total of 2,740 parents of individuals with DS from 11 countries completed the FaMM. The analysis provided evidence of internal consistency reliability exceeding .70 for four of six FaMM scales for the entire sample. Across countries, there was a pattern of positive family management. Cross-cultural comparisons revealed parents from Brazil, Spain, and the United States had the most positive family management and respondents from Ireland, Italy, Japan, and Korea had the least positive. The rankings were mixed for the four remaining countries. These findings provide evidence of overall strong internal consistency reliability of the FaMM. More cross-cultural research is needed to understand how social determinants of health influence family management in families of individuals with DS.

mHealth Family Adaptation Intervention for Families of Young Children with Down Syndrome: A Feasibility Study.

PURPOSE: The aim of this study was to explore the feasibility of using the mHealth Family Adaptation Intervention (FamilyAdapt-DS), with families of young children with Down syndrome (DS), and to assess the effect of participating in this mHealth intervention on family adaptation. DESIGN AND METHODS: A one-group pre-test post-test design was employed. Sixteen parents from eight families of young children with DS (under the age of three years) participated in this study between September 2015 and September 2016. A Wilcoxon signed rank test was used to identify the difference between the pre-test and post-test scores. RESULTS: All parents perceived that the program was feasible to use and they were willing to recommend the intervention to other families. Improvements were noted between pre-test and post-test scores. For fathers, views of their child's daily life became more positive, their child's condition became more manageable, their problem-solving communication became more affirming and their family functioning scores improved. Mothers reported less difficulty managing their child's condition. CONCLUSIONS: These findings suggest that FamilyAdapt-DS is a feasible m-Health intervention for families of young children with DS; however, scaling up of this program with larger and more diverse samples is needed to test its effectiveness. PRACTICE IMPLICATIONS: Nurses and other healthcare providers may find it helpful to use therapeutic conversations and mHealth interventions such as the one described in this paper to tailor the care they provide to families of young children with DS.

Discovery of Oxazol-2-amine Derivatives as Potent Novel FLT3 Inhibitors.

Internal tandem duplication (ITD) of FMS-like tyrosine kinase 3 (FLT3) is the most common mutation in patients with acute myeloid leukemia (AML). FLT3-ITD+ induces constitutive activation of FLT3, causing an abnormally rapid proliferation of cancer cells. In this study, we identified novel FLT3 inhibitors and investigated 5-(4-fluorophenyl)-N-phenyloxazol-2-amine (compound 7; 7c) as candidates for the treatment of AML. The results showed that 7c inhibited the activities of FLT3 and mutated FLT3 in a cell-free kinase assay and Molm-13 and MV4-11 cells, as well as the proliferation of FLT3-ITD+ AML cells, increasing apoptosis. The anti-leukemic activity of 7c was confirmed by in vivo tumor growth inhibition in MV4-11 xenograft mice. Besides, 7c suppressed the expression of DNA damage repair genes. Combination treatment with 7c and olaparib (a poly (ADP-ribose) polymerase [PARP] inhibitor) synergistically inhibited cell proliferation in Molm-13 and MV4-11 cells. Our findings demonstrated that 7c is a therapeutic candidate targeting FLT3 for AML treatment and suggested that combination treatment with 7c and a PARP inhibitor may be an effective therapy regimen for FLT3-mutated AML.

A Small Compound KJ-28d Enhances the Sensitivity of Non-Small Cell Lung Cancer to Radio- and Chemotherapy.

We previously reported on a poly (ADP-ribose) polymerase (PARP) 1/2 inhibitor N-(3-(hydroxycarbamoyl)phenyl)carboxamide (designated KJ-28d), which increased the death of human ovarian cancer BRCA1-deficient SNU-251 cells. In the present study, we further investigated the antitumor activities of KJ-28d in BRCA-proficient non-small cell lung cancer (NSCLC) cells to expand the use of PARP inhibitors. KJ-28d significantly inhibited the growth of NSCLC cells in vitro and in vivo, and induced DNA damage and reactive oxygen species in A549 and H1299 cells. Combined treatment with KJ-28d and ionizing radiation led to increased DNA damage responses in A549 and H1299 cells compared to KJ-28d or ionizing radiation alone, resulting in apoptotic cell death. Moreover, the combination of KJ-28d plus a DNA-damaging therapeutic agent (carboplatin, cisplatin, paclitaxel, or doxorubicin) synergistically inhibited cell proliferation, compared to either drug alone. Taken together, the findings demonstrate the potential of KJ-28d as an effective anti-cancer therapeutic agent for BRCA-deficient and -proficient cancer cells. KJ-28d might have potential as an adjuvant when used in combination with radiotherapy or DNA-damaging agents, pending further investigations.

Antitumor Activity of a Novel Tyrosine Kinase Inhibitor AIU2001 Due to Abrogation of the DNA Damage Repair in Non-Small Cell Lung Cancer Cells.

Class III receptor tyrosine kinase (RTK) inhibitors targeting mainly FLT3 or c-KIT have not been well studied in lung cancer. To identify a small molecule potentially targeting class III RTK, we synthesized novel small molecule compounds and identified 5-(4-bromophenyl)-N-(naphthalen-1-yl) oxazol-2-amine (AIU2001) as a novel class III RKT inhibitor. In an in vitro kinase profiling assay, AIU2001 inhibited the activities of FLT3, mutated FLT3, FLT4, and c-KIT of class III RTK, and the proliferation of NSCLC cells in vitro and in vivo. AIU2001 induced DNA damage, reactive oxygen species (ROS) generation, and cell cycle arrest in the G2/M phase. Furthermore, AIU2001 suppressed the DNA damage repair genes, resulting in the 'BRCAness'/'DNA-PKness' phenotype. The mRNA expression level of STAT5 was downregulated by AIU2001 treatment and knockdown of STAT5 inhibited the DNA repair genes. Our results show that compared to either drug alone, the combination of AIU2001 with a poly (ADP-ribose) polymerase (PARP) inhibitor olaparib or irradiation showed synergistic efficacy in H1299 and A549 cells. Hence, our findings demonstrate that AIU2001 is a candidate therapeutic agent for NSCLC and combination therapies with AIU2001 and a PARP inhibitor or radiotherapy may be used to increase the therapeutic efficacy of AIU2001 due to inhibition of DNA damage repair.

Adaptation in families of children with Down syndrome in East Asian countries: an integrative review.

AIM: The purpose of this integrative literature review was to understand the experiences of East Asian families of children with Down syndrome and identify factors affecting their adaptation in the Resiliency Model of Family Stress, Adjustment and Adaptation. BACKGROUND: Socio-cultural factors influence how well families adapt following the birth of a child with Down syndrome. Existing literature in this area has focused primarily on families from Western cultures. This is problematic because nurses care for families from all over the world. Therefore, the focus of this review is on families of children with Down syndrome living in East Asia, where Confucianism is dominant. DESIGN: Integrative literature review. DATA SOURCES: Online databases (i.e. PubMed, CINAHL and PsycINFO) and a public search engine (i.e. Google Scholar) were used along with manual searches of reference lists and major journals. Studies were limited to original publications written in English and published between 1990-2014. REVIEW METHODS: Two authors independently performed integrative review processes proposed by Whittemore and Knafl and a quality assessment using the Mixed Methods Appraisal Tool. RESULTS: Like families in Western cultures, some East Asian families of children with Down syndrome adapted well and even thrived while others struggled. Various socio-cultural factors, including some associated with Confucianism, played a role in how individuals, dyads and families adapted. CONCLUSION: An understanding of socio-cultural influences can help nurses implement culturally sensitive family-centred interventions with families of children with Down syndrome. It may also facilitate policy changes concerning resources for these families.

Delays and Disabilities: NP Screening and Care Management.

Neurodevelopmental Disorders (ND) impair functioning and are associated with increased physical and psychological health risks. ND care is increasingly being provided by NPs in primary care settings. To assess NP's knowledge and care management practices for pediatric patients with potential or existing ND, practicing NPs in North Carolina were invited to complete an online survey. NC NP's provide care to ND patients in a variety of settings and have varied levels of experience with ND. Differences in knowledge, screening, and management practices are identified. Methods for improving outcomes and supporting NPs providing care for this at-risk population are discussed.

Transarterial chemoembolization vs. radiofrequency ablation for the treatment of single hepatocellular carcinoma 2 cm or smaller.

OBJECTIVES: To compare the effectiveness of transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) for treating small (≤2 cm) hepatocellular carcinomas (HCCs). METHODS: This retrospective study consisted of 287 patients (mean age, 57.1 years; age range, 29-84 years; 221 men, 66 women; 73.5% with HBV; 100% with liver cirrhosis) with Barcelona Clinic Liver Cancer very early-stage HCC (≤2 cm single HCC) who were initially treated with TACE (n=122) or RFA (n=165). The primary study end point was overall patient survival. Secondary study end points were time to progression and tumor response. RESULTS: The RFA and TACE groups were well balanced in terms of baseline variables. The two groups did not differ significantly in overall survival (P=0.079) or major complication (P>0.999) rates. The respective cumulative survival rates at 1, 3, 5, and 8 years were 97.6, 86.7, 74.5, and 60.0% for RFA and 93.4, 75.4, 63.1, and 51.1% for TACE. Their objective tumor regression (complete or partial response) rates were 100% (165/165) and 95.9% (117/122), respectively (P=0.013). The median times to progression for RFA and TACE were 27.0±3.8 (95% confidence intervals (CIs): 19.6-34.4) and 18.0±2.9 (95% CIs: 12.2-23.8) months, respectively. RFA yielded a significantly longer time to progression (P=0.034). CONCLUSIONS: TACE may be a viable alternative treatment for ≤2 cm HCCs when RFA is not feasible.

Factors influencing maternal-fetal attachment in pregnant women during the COVID-19 pandemic: a cross-sectional study.

PURPOSE: Coronavirus disease 2019 (COVID-19) has spread widely throughout the world, causing psychological problems such as fear, anxiety, and stress. During the COVID-19 pandemic, pregnant women have been concerned about both their own health and the health of their fetuses, and these concerns could negatively affect maternal-fetal attachment. Thus, this study aimed to explore the level of COVID-19 stress, resilience, and maternal-fetal attachment among pregnant women during the COVID-19 pandemic, and to identify factors influencing maternal-fetal attachment. METHODS: In total, 118 pregnant women past 20 weeks gestation were recruited from two maternity clinics in Daegu, Korea, to participate in this descriptive correlational study during COVID-19. The factors influencing maternal-fetal attachment were analyzed using hierarchical multiple regression analysis. RESULTS: The mean scores for COVID-19 stress, resilience, and maternal-fetal attachment were 57.18±10.32 out of 84, 67.32±15.09 out of 100, and 77.23±9.00 out of 96, respectively. Nulliparous pregnant women reported greater maternal-fetal attachment than multiparous pregnant women (p=.003). Religious pregnant women also reported greater maternal-fetal attachment than non-religious pregnant women (p=.039). Resilience (ß=.29, p=.002), COVID-19 stress (ß=.20, p=.030) and parity (ß=-.17, p=.047) were factors influencing maternal-fetal attachment, and these factors explained 26.4% of the variance in maternal-fetal attachment (F=10.12, p<.001). CONCLUSION: Converse to common sense, COVID-19 stress exerted a positive influence on maternal-fetal attachment in pregnant women during the COVID-19 pandemic. Healthcare providers need to recognize the positive influence of COVID-19 stress and implement intervention strategies to strengthen resilience in pregnant women to improve maternal-fetal attachment.

Analysis of suicide statistics and trends between 2011 and 2021 among Korean women.

PURPOSE: This study aims to analyze the number of suicide deaths in women, trends in suicide mortality, characteristics of suicide by age, and outcomes of suicide means over the past decade (2011- 2021) in South Korea. METHODS: Using cause of death data from Statistics Korea, an in-depth analysis of Korean women's suicide trends was conducted for the period of 2011-2021. RESULTS: In 2021, women's suicide death in Korea was 4,159, a rate of 16.2 per 100,000 population. The rate increased by 1.4% from the previous year. Since 2011, women's suicide rate has been on a steady downward trend, but since 2018, it has been on the rise again. Suicide rates among women in their 20s and 30s have increased, especially since the coronavirus disease 2019 pandemic, and suicide rates among women over 70 years remain high. As compared to 2011, pesticide poisoning and hanging among the means of suicide have decreased significantly, while drug and carbon monoxide continue to increase. CONCLUSION: Suicide rates for Korean women in their 20s and 30s have increased significantly in recent years, and those for women over 70 years remain high. Therefore, it is necessary to investigate the causes and establish national policies for targeted management of these age groups, which contributes significantly to the rising suicide rate among Korean women.

Symmetry-Mismatched SBU Transformation in MOFs: Postsynthetic Metal Exchange from Zn to Fe and Its Effects on Gas Adsorption and Dye Selectivity.

This research explores the alteration of metal-organic frameworks (MOFs) using a method called postsynthetic metal exchange. We focus on the shift from a Zn-based MOF containing a [Zn4O(COO)6] secondary building unit (SBU) of octahedral site symmetry (ANT-1(Zn)) to a Fe-based one with a [Fe3IIIO(COO)6]+ SBU of trigonal prismatic site symmetry (ANT-1(Fe)). The symmetry-mismatched SBU transformation cleverly maintains the MOF's overall structure by adjusting the conformation of the flexible 1,3,5-benzenetribenzoate linker to alleviate the framework strain. The process triggers a decrease in the framework volume and pore size alongside a change in the framework's charge. These alterations influence the MOF's ability to adsorb gas and dye. During the transformation, core-shell MOFs (ANT-1(Zn@Fe)) are formed as intermediate products, demonstrating unique gas sorption traits and adjusted dye adsorption preferences due to the structural modifications at the core-shell interface. Heteronuclear clusters, located at the framework interfaces, enhance the heat of CO2 adsorption. Furthermore, they also influence the selectivity of the dye size. This research provides valuable insights into fabricating novel MOFs with unique properties by modifying the SBU of a MOF with flexible organic linkers from one site symmetry to another.

Informed choice of pregnant women regarding noninvasive prenatal testing in Korea: a cross-sectional study.

PURPOSE: This study explored the degree to which pregnant women in Korea made informed choices regarding noninvasive prenatal testing (NIPT) and investigated factors influencing whether they made informed choices. METHODS: In total, 129 pregnant women in Korea participated in a web-based survey. Multidimensional measures of informed choice regarding NIPT and decisional conflict were used to measure participants' levels of knowledge, attitudes, deliberation, uptake, and decisional conflict related to NIPT. Additional questions were asked about participants' NIPT experiences and opinions. RESULTS: All 129 pregnant women were recruited from an online community. Excluding those who expressed neutral attitudes toward NIPT, according to the definition of informed choice used in this study, only 91 made an informed choice (n=63, 69.2%) or an uninformed choice (n=28, 30.8%). Of the latter, 75.0% had insufficient knowledge, 39.3% made a value-inconsistent decision, and 14.3% did not deliberate sufficiently. No difference in decisional conflict was found between the two groups. A significant difference was found between the two groups in the reasons why NIPT was introduced or recommended (p=.021). Multiple logistic regression analysis showed that pregnant women who were knowledgeable (odds ratio [OR], 4.77; 95% confidence interval [CI], 2.17- 10.47) and deliberated (OR, 0.74; 95% CI, 0.57-0.98) were significantly more likely to make an informed choice. CONCLUSION: The results of this study help healthcare providers, including nurses in maternity units, understand pregnant women's experiences of NIPT. Counseling strategies are needed to improve pregnant women's knowledge of NIPT and create an environment that promotes deliberation regarding this decision.

An iron-chelating sulfonamide identified from Drosophila-based screening for antipathogenic discovery.

We exploited bacterial infection assays using the fruit fly Drosophila melanogaster to identify anti-infective compounds that abrogate the pathological consequences in the infected hosts. Here, we demonstrated that a pyridine-3-N-sulfonylpiperidine derivative (4a) protects Drosophila from the acute infections caused by bacterial pathogens including Pseudomonas aeruginosa. 4a did not inhibit the growth of P. aeruginosa in vitro, but inhibited the production of secreted toxins such as pyocyanin and hydrogen cyanide, while enhancing the production of pyoverdine and pyochelin, indicative of iron deprivation. Based on its catechol moiety, 4a displayed iron-chelating activity in vitro toward both iron (II) and iron (III), more efficiently than the approved iron-chelating drugs such as deferoxamine and deferiprone, concomitant with more potent antibacterial efficacy in Drosophila infections and unique transcriptome profile. Taken together, these results delineate a Drosophila-based strategy to screen for antipathogenic compounds, which interfere with iron uptake crucial for bacterial virulence and survival in host tissues.

Maternal, infant, and perinatal mortality statistics and trends in Korea between 2018 and 2020.

PURPOSE: This study aimed to identify maternal, infant, and perinatal mortality using the nationalpopulation data of South Korea between 2018 and 2020, and to analyze mortality rates according tocharacteristics such as age, date of death, and cause of death in each group. This study updates themost recent study using 2009 to 2017 data. METHODS: Analyses of maternal, infant, and perinatal mortality were done with data identifiedthrough the supplementary investigation system for cases of death from the Census of PopulationDynamics data provided by Statistics Korea from 2018 to 2020. RESULTS: Between 2018 and 2020, a total of 99 maternal deaths, 2,427 infant deaths, and 2,408 perinatal deaths were identified from 901,835 live births. The maternal mortality ratio was 11.3 deathsper 100,000 live births in 2018; it decreased to 9.9 in 2019 but increased again to 11.8 in 2020. Thematernal mortality ratio increased steeply in women over the age of 40 years. An increasing trend inthe maternal mortality ratio was found for complications related to the puerperium and hypertensive disorders. Both infant and perinatal mortality continued to decrease, from 2.8 deaths per 1,000live births in 2018 to 2.5 in 2020 and from 2.8 in 2018 to 2.5 in 2020, respectively. CONCLUSION: Overall, the maternal, infant, and perinatal mortality statistics showed improvements.However, more attention should be paid to women over 40 years of age and specific causes of maternal deaths, which should be taken into account in Korea's maternal and child health policies.

Effects of Silica Shell Encapsulated Nanocrystals on Active χ-Fe5C2 Phase and Fischer-Tropsch Synthesis.

Among various iron carbide phases, χ-Fe5C2, a highly active phase in Fischer-Tropsch synthesis, was directly synthesized using a wet-chemical route, which makes a pre-activation step unnecessary. In addition, χ-Fe5C2 nanoparticles were encapsulated with mesoporous silica for protection from deactivation. Further structural analysis showed that the protective silica shell had a partially ordered mesoporous structure with a short range. According to the XRD result, the sintering of χ-Fe5C2 crystals did not seem to be significant, which was believed to be the beneficial effect of the protective shell providing restrictive geometrical space for nanoparticles. More interestingly, the protective silica shell was also found to be effective in maintaining the phase of χ-Fe5C2 against re-oxidation and transformation to other iron carbide phases. Fischer-Tropsch activity of χ-Fe5C2 in this study was comparable to or higher than those from previous reports. In addition, CO2 selectivity was found to be very low after stabilization.

Cholesterol inhibits M-type K+ channels via protein kinase C-dependent phosphorylation in sympathetic neurons.

M-type (KCNQ) potassium channels play an important role in regulating the action potential firing in neurons. Here, we investigated the effect of cholesterol on M current in superior cervical ganglion (SCG) sympathetic neurons, using the patch clamp technique. M current was inhibited in a dose-dependent manner by cholesterol loading with a methyl-beta-cyclodextrin-cholesterol complex. This effect was prevented when membrane cholesterol level was restored by including empty methyl-beta-cyclodextrin in the pipette solution. Dialysis of cells with AMP-PNP instead of ATP prevented cholesterol action on M currents. Protein kinase C (PKC) inhibitor, calphostin C, abolished cholesterol-induced inhibition whereas the PKC activator, PDBu, mimicked the inhibition of M currents by cholesterol. The in vitro kinase assay showed that KCNQ2 subunits of M channel can be phosphorylated by PKC. A KCNQ2 mutant that is defective in phosphorylation by PKC failed to show current inhibition not only by PDBu but also by cholesterol. These results indicate that cholesterol-induced inhibition of M currents is mediated by PKC phosphorylation. The inhibition of M currents by PDBu and cholesterol was completely blocked by PIP(2) loading, indicating that the decrease in PIP(2)-channel interaction underlies M channel inhibition by PKC-mediated phosphorylation. We conclude that cholesterol specifically regulates M currents in SCG neurons via PKC activation.

The Chromatin Remodeling Complex CHD1 Regulates the Primitive State of Mesenchymal Stromal Cells to Control Their Stem Cell Supporting Activity.

The primitive state (stemness) of mesenchymal stromal cells (MSCs) is responsible for supporting the function of tissue-specific stem cells to regenerate damaged tissues. However, molecular mechanisms regulating the stemness of MSCs remain unknown. In this study, we found that the primitive state of MSCs is hierarchically regulated by the expression levels of the chromatin remodeling complex, CHD1, with CHD1 expression levels higher in the undifferentiated state, and decreasing upon MSC differentiation. Consistently, CHD1 expression levels decrease during progressive loss of clonogenic progenitors (CFU-F) induced by passage cultures. Moreover, knockdown (KD) of CHD1 decreased CFU-F frequency, whereas CHD1 overexpression increased it. In addition, the expression of stem cell-specific genes was down- or upregulated upon KD or overexpression of CHD1, respectively, accompanied by associated changes in chromatin condensation. Importantly, altering CHD1 expression levels affected the ability of MSCs to support the self-renewing expansion of hematopoietic stem cells (HSCs). Furthermore, CHD1 levels were significantly decreased in MSCs from acute myeloid leukemia or aplastic anemia patients, where CFU-F and HSC-supporting activities are lost. Altogether, these findings show that chromatin remodeling by CHD1 is a molecular parameter that influences the primitive state of MSCs and their stem cell-supporting activity, which controls tissue regeneration.

An antipathogenic compound that targets the OxyR peroxide sensor in Pseudomonas aeruginosa.

Introduction. Antipathogenic or antivirulence strategy is to target a virulence pathway that is dispensable for growth, in the hope to mitigate the selection for drug resistance.Hypothesis/Gap Statment. Peroxide stress responses are one of the conserved virulence pathways in bacterial pathogens and thus good targets for antipathogenic strategy.Aim. This study aims to identify a new chemical compound that targets OxyR, the peroxide sensor required for the full virulence of the opportunistic human pathogen, Pseudomonas aeruginosa.Methodology. Computer-based virtual screening under consideration of the 'eNTRy' rules and molecular docking were conducted on the reduced form of the OxyR regulatory domain (RD). Selected hits were validated by their ability to phenocopy the oxyR null mutant and modulate the redox cycle of OxyR.Results. We first isolated three robust chemical hits that inhibit OxyR without affecting prototrophic growth or viability. One (compound 1) of those affected the redox cycle of OxyR in response to H2O2 treatment, in a way to impair its function. Compound 1 displayed selective antibacterial efficacy against P. aeruginosa in Drosophila infection model, without antibacterial activity against Staphylococcus aureus.Conclusion. These results suggest that compound 1 could be an antipathogenic hit inhibiting the P. aeruginosa OxyR. More importantly, our study provides an insight into the computer-based discovery of new-paradigm selective antibacterials to treat Gram-negative bacterial infections presumably with few concerns of drug resistance.