DNA methylation-mediated Siglec-7 regulation in natural killer cells via two 5' promoter CpG sites.

First discovered on the natural killer (NK) cell, the cell surface inhibitory receptor sialic acid-binding immunoglobulin-like lectin-7 (Siglec-7) is known for regulating many important biological activities. However, the detail regulatory mechanism for Siglec-7 expression in NK cells currently remains unclear. In this study, we aimed to investigate how cell surface Siglec-7 expression is regulated and found that, in both NK cell lines and peripheral NK cells, transcription was the main regulatory step. Furthermore, when NK-92MI and peripheral NK cells were treated with DNA methyltransferase (DNMT) inhibitor, the CpG island, with 9 CpG sites, in 5' Siglec-7 promoter became noticeably hypomethylated, and Siglec-7 expression increased in both RNA transcript and surface protein. Within this CpG island, we identified both CpG 8 and CpG 9 as two key regulators responsible for Siglec-7 expression. Additionally, by using histone deacetylases (HDAC) inhibitor, butyric acid, we showed that Siglec-7 expression was also subjected to the histone modification. And a combined treatment with both 5-azacytidine and butyric acid showed an additive effect on Siglec-7 transcript expression in peripheral NK cells.

Co(II) and Ni(II) binding of the Escherichia coli transcriptional repressor RcnR orders its N terminus, alters helix dynamics, and reduces DNA affinity.

RcnR, a transcriptional regulator in Escherichia coli, derepresses the expression of the export proteins RcnAB upon binding Ni(II) or Co(II). Lack of structural information has precluded elucidation of the allosteric basis for the decreased DNA affinity in RcnR's metal-bound states. Here, using hydrogen-deuterium exchange coupled with MS (HDX-MS), we probed the RcnR structure in the presence of DNA, the cognate metal ions Ni(II) and Co(II), or the noncognate metal ion Zn(II). We found that cognate metal binding altered flexibility from the N terminus through helix 1 and modulated the RcnR-DNA interaction. Apo-RcnR and RcnR-DNA complexes and the Zn(II)-RcnR complex exhibited similar 2H uptake kinetics, with fast-exchanging segments located in the N terminus, in helix 1 (residues 14-24), and at the C terminus. The largest difference in 2H incorporation between apo- and Ni(II)- and Co(II)-bound RcnR was observed in helix 1, which contains the N terminus and His-3, and has been associated with cognate metal binding. 2H uptake in helix 1 was suppressed in the Ni(II)- and Co(II)-bound RcnR complexes, in particular in the peptide corresponding to residues 14-24, containing Arg-14 and Lys-17. Substitution of these two residues drastically affected DNA-binding affinity, resulting in rcnA expression in the absence of metal. Our results suggest that cognate metal binding to RcnR orders its N terminus, decreases helix 1 flexibility, and induces conformational changes that restrict DNA interactions with the positively charged residues Arg-14 and Lys-17. These metal-induced alterations decrease RcnR-DNA binding affinity, leading to rcnAB expression.

Ni(II) Sensing by RcnR Does Not Require an FrmR-Like Intersubunit Linkage.

E. coli RcnR (resistance to cobalt and nickel regulator) is a homotetrameric DNA binding protein that regulates the expression of a Ni(II) and Co(II) exporter (RcnAB) by derepressing expression of rcnA and rcnB in response to binding Co(II) or Ni(II). Prior studies have shown that the cognate metal ions, Ni(II) and Co(II), bind in six-coordinate sites at subunit interfaces and are distinguished from noncognate metals (Cu(I), Cu(II), and Zn(II)) by coordination number and ligand selection. In analogy with FrmR, a formaldehyde-responsive transcriptional regulator in the RcnR/CsoR family, the interfacial site allows the metal ions to "cross-link" the N-terminal domain of one subunit with the invariant Cys35 residue in another, which has been deemed to be key to mediating the allosteric response of the tetrameric protein to metal binding. Through the use of mutagenesis to disconnect one subunit from the metal-mediated cross-link, X-ray absorption spectroscopy (XAS) as a structural probe, LacZ reporter assays, and metal binding studies using isothermal titration calorimetry (ITC), the work presented here shows that neither the interfacial binding site nor the coordination number of Ni(II) is important to the allosteric response to binding of this cognate metal ion. The opposite is found for the other cognate metal ion, Co(II), with respect to the interfacial binding site, suggesting that the molecular mechanisms for transcriptional regulation by the two ions are distinct. The metal binding studies reveal that tight metal binding is maintained in the variant. XAS is further used to demonstrate that His33 is not a ligand for Co(II), Ni(II), or Zn(II) in WT-RcnR. The results are discussed in the context of the overall understanding of the molecular mechanisms of metallosensors.

The Helicobacter pylori HypA·UreE2 Complex Contains a Novel High-Affinity Ni(II)-Binding Site.

Helicobacter pylori is a human pathogen that colonizes the stomach, is the major cause of ulcers, and has been associated with stomach cancers. To survive in the acidic environment of the stomach, H. pylori uses urease, a nickel-dependent enzyme, to produce ammonia for maintenance of cellular pH. The bacteria produce apo-urease in large quantities and activate it by incorporating nickel under acid shock conditions. Urease nickel incorporation requires the urease-specific metallochaperone UreE and the (UreFGH)2 maturation complex. In addition, the H. pylori nickel urease maturation pathway recruits accessory proteins from the [NiFe] hydrogenase maturation pathway, namely, HypA and HypB. HypA and UreE dimers (UreE2) are known to form a protein complex, the role of which in urease maturation is largely unknown. Herein, we examine the nickel-binding properties and protein-protein interactions of HypA and UreE2 using isothermal titration calorimetry and fluorometric methods under neutral and acidic pH conditions to gain insight into the roles played by HypA in urease maturation. The results reveal that HypA and UreE2 form a stable complex with micromolar affinity that protects UreE from hydrolytic degradation. The HypA·UreE2 complex contains a unique high-affinity (nanomolar) Ni2+-binding site that is maintained under conditions designed to mimic acid shock (pH 6.3). The data are interpreted in terms of a proposed mechanism wherein HypA and UreE2 act as co-metallochaperones that target the delivery of Ni2+ to apo-urease with high fidelity.

Self-Perceived Health and Sleep Quality of Community Older Adults after Acupunch Exercises.

OBJECTIVES: To test the long-term effects of the 12-month Healthy Beat Acupunch (HBA) exercise program on the self-perceived health and sleep quality of older adults in community care centers, and to compare the effects of two delivery methods: instructor-led HBA for the first 6 months and DVD-guided HBA for another 6 months. DESIGN: Cluster-randomized controlled trial. SETTING: Eight community care centers. PARTICIPANTS: In total, 232 participants were recruited from eight community care centers, and cluster-randomized to the experimental (4 centers, N = 113) and control (4 centers, N = 119) groups. INTERVENTION: The experimental group received the instructor-led HBA program 3 times weekly for the first 6 months, followed by the DVD-guided HBA program for another 6 months. MEASUREMENTS: Self-perceived health and sleep quality were assessed using the Short Form Health Survey and the Pittsburgh Sleep Quality Index, respectively, at baseline and every 3 months for 1 year. RESULTS: The experimental group reported more favorable self-perceived physical and mental health, higher subjective sleep quality, and less daytime dysfunction than did the control group. Effect sizes of physical health and sleep quality increased from the instructor-led stage to the DVD-guided stage; the effect size of physical health showed the most significant change, increasing from 0.38 in the instructor-led stage to 0.55 in the DVD-guided stage. CONCLUSIONS: The exercise program consisting of the instructor-led class, followed by the DVD-guided class, was an effective and feasible longitudinal program for older adults in community care centers.

Chloride Supports O2 Activation in the D201G Facial Triad Variant of Factor-Inhibiting Hypoxia Inducible Factor, an α-Ketoglutarate Dependent Oxygenase.

α-Ketoglutarate (αKG) dependent oxygenases comprise a large superfamily of enzymes that activate O2 for varied reactions. While most of these enzymes contain a nonheme Fe bound by a His2(Asp/Glu) facial triad, a small number of αKG-dependent halogenases require only the two His ligands to bind Fe and activate O2. The enzyme "factor inhibiting HIF" (FIH) contains a His2Asp facial triad and selectively hydroxylates polypeptides; however, removal of the Asp ligand in the Asp201→Gly variant leads to a highly active enzyme, seemingly without a complete facial triad. Herein, we report on the formation of an Fe-Cl cofactor structure for the Asp201→Gly FIH variant using X-ray absorption spectroscopy (XAS), which provides insight into the structure of the His2Cl facial triad found in halogenases. The Asp201→Gly variant supports anion dependent peptide hydroxylation, demonstrating the requirement for a complete His2X facial triad to support O2 reactivity. Our results indicated that exogenous ligand binding to form a complete His2X facial triad was essential for O2 activation and provides a structural model for the His2Cl-bound nonheme Fe found in halogenases.

The Role of Mixed Amine/Amide Ligation in Nickel Superoxide Dismutase.

Superoxide dismutases (SODs) utilize a ping-pong mechanism in which a redox-active metal cycles between oxidized and reduced forms that differ by one electron to catalyze the disproportionation of superoxide to dioxygen and hydrogen peroxide. Nickel-dependent SOD (NiSOD) is a unique biological solution for controlling superoxide levels. This enzyme relies on the use of cysteinate ligands to bring the Ni(III/II) redox couple into the range required for catalysis (∼300 mV vs. NHE). The use of cysteine thiolates, which are not found in any other SOD, is a curious choice because of their well-known oxidation by peroxide and dioxygen. The NiSOD active site cysteinate ligands are resistant to oxidation, and prior studies of synthetic and computational models point to the backbone N-donors in the active site (the N-terminal amine and the amide N atom of Cys2) as being involved in stabilizing the cysteines to oxidation. To test the role of the backbone N-donors, we have constructed a variant of NiSOD wherein an alanine residue was added to the N-terminus (Ala0-NiSOD), effectively altering the amine ligand to an amide. X-ray absorption, electronic absorption, and magnetic circular dichroism (MCD) spectroscopic analyses of as-isolated Ala0-NiSOD coupled with density functional theory (DFT) geometry optimized models that were evaluated on the basis of the spectroscopic data within the framework of DFT and time-dependent DFT computations are consistent with a diamagnetic Ni(II) site with two cysteinate, one His1 amide, and one Cys2 amidate ligands. The variant protein is catalytically inactive, has an altered electronic absorption spectrum associated with the nickel site, and is sensitive to oxidation. Mass spectrometric analysis of the protein exposed to air shows the presence of a mixture of oxidation products, the principal ones being a disulfide, a bis-sulfenate, and a bis-sulfinate derived from the active site cysteine ligands. Details of the electronic structure of the Ni(III) site available from the DFT calculations point to subtle changes in the unpaired spin density on the S-donors as being responsible for the altered sensitivity of Ala0-NiSOD to O2.

Glutamate Ligation in the Ni(II)- and Co(II)-Responsive Escherichia coli Transcriptional Regulator, RcnR.

Escherichia coli RcnR (resistance to cobalt and nickel regulator, EcRcnR) is a metal-responsive repressor of the genes encoding the Ni(II) and Co(II) exporter proteins RcnAB by binding to PRcnAB. The DNA binding affinity is weakened when the cognate ions Ni(II) and Co(II) bind to EcRcnR in a six-coordinate site that features a (N/O)5S ligand donor-atom set in distinct sites: while both metal ions are bound by the N terminus, Cys35, and His64, Co(II) is additionally bound by His3. On the other hand, the noncognate Zn(II) and Cu(I) ions feature a lower coordination number, have a solvent-accessible binding site, and coordinate protein ligands that do not include the N-terminal amine. A molecular model of apo-EcRcnR suggested potential roles for Glu34 and Glu63 in binding Ni(II) and Co(II) to EcRcnR. The roles of Glu34 and Glu63 in metal binding, metal selectivity, and function were therefore investigated using a structure/function approach. X-ray absorption spectroscopy was used to assess the structural changes in the Ni(II), Co(II), and Zn(II) binding sites of Glu → Ala and Glu → Cys variants at both positions. The effect of these structural alterations on the regulation of PrcnA by EcRcnR in response to metal binding was explored using LacZ reporter assays. These combined studies indicate that while Glu63 is a ligand for both metal ions, Glu34 is a ligand for Co(II) but possibly not for Ni(II). The Glu34 variants affect the structure of the cognate metal sites, but they have no effect on the transcriptional response. In contrast, the Glu63 variants affect both the structure and transcriptional response, although they do not completely abolish the function of EcRcnR. The structure of the Zn(II) site is not significantly perturbed by any of the glutamic acid variations. The spectroscopic and functional data obtained on the mutants were used to calculate models of the metal-site structures of EcRcnR bound to Ni(II), Co(II), and Zn(II). The results are interpreted in terms of a switch mechanism, in which a subset of the metal-binding ligands is responsible for the allosteric response required for DNA release.

Applying the transtheoretical model to promote functional fitness of community older adults participating in elastic band exercises.

AIMS: The transtheoretical model was applied to promote behavioural change and test the effects of a group senior elastic band exercise programme on the functional fitness of community older adults in the contemplation and preparation stages of behavioural change. BACKGROUND: Forming regular exercise habits is challenging for older adults. The transtheoretical model emphasizes using different strategies in various stages to facilitate behavioural changes. DESIGN: Quasi-experimental design with pre-test and post-tests on two groups. METHODS: Six senior activity centres were randomly assigned to either the experimental or control group. The data were collected during 2011. A total of 199 participants were recruited and 169 participants completed the study (experimental group n = 84, control group n = 85). The elastic band exercises were performed for 40 minutes, three times per week for 6 months. The functional fitness of the participants was evaluated at baseline and at the third and sixth month of the intervention. Statistical analyses included a two-way mixed design analysis of variance, one-way repeated measures analysis of variance and an analysis of covariance. RESULTS: All of the functional fitness indicators had significant changes at post-tests from pre-test in the experimental group. The experimental group had better performances than the control group in all of the functional fitness indicators after three months and 6 months of the senior elastic band exercises. CONCLUSION: The exercise programme provided older adults with appropriate strategies for maintaining functional fitness, which improved significantly after the participants exercising regularly for 6 months.

Sleep quality and depression of nursing home older adults in wheelchairs after exercises.

BACKGROUND: Sleep disturbances and depression are costly and potentially disabling conditions that affect a considerable proportion of older adults. The purpose of this study was to test the effectiveness of 6 months of elastic band exercises on sleep quality and depression of wheelchair-bound older adults in nursing homes. METHODS: One hundred twenty-seven older adults from 10 nursing homes participated in this cluster randomized controlled trial, and 114 completed the study. Participants were randomly assigned to two groups: experimental group (five nursing homes, n = 59) and control group (five nursing homes, n = 55). A 40-minute wheelchair-bound senior elastic band exercise program was implemented 3 times per week for 6 months. Sleep quality and depression of the participants were examined at baseline, after 3 months, and at the end of the 6-month study. DISCUSSION: Participants in the experimental group had longer sleep durations, better habitual sleep efficiencies, and less depression than the control group at 3 months of the study and maintained them throughout the rest of the 6-month study. CONCLUSIONS: Nursing home directors could recruit volunteers to learn the program and lead the elderly residents in wheelchairs in practicing the wheelchair-bound senior elastic band exercises regularly in the facilities.

Social welfare utilization and needs of older adults in Taiwan: survey research.

BACKGROUND: The demand for long-term care for older adults has escalated sharply. A good policy dedicated to the welfare of older adults has improved their quality of life. The purpose of this study was to explore the social welfare utilization and needs of older adults and compare their differences among age groups, genders, and functional dependency levels. METHODS: Three hundred eighty-four stratified, random-sampled Taiwanese community-dwelling older adults were recruited for this survey research. Participants rated their utilization of and needs for the 30 social welfare services provided by the government on a Likert-type scale. RESULTS: The most widely used and needed social welfare services by the older adults were senior monetary stipend and a subsidy for the national health insurance premium. Young-old, male, and functionally independent older adults had more knowledge of the social welfare services than their counterparts. CONCLUSIONS: While designing a comprehensive social welfare system, differing needs of different age groups, genders, and functional dependency levels should be taken into consideration.

Development and feasibility of a senior elastic band exercise program for aged adults: a descriptive evaluation survey.

OBJECTIVE: This study aimed to develop a tailored elastic band exercise program for aged adults (persons 65 years and older), to evaluate the feasibility of a program, and to determine appropriate elastic band exercise frequencies and preferences of aged adults. METHODS: This study had 2 phases. In phase I, 11 professional experts were consulted to develop the Senior Elastic Band (SEB) exercise program. They responded to detailed description and demonstrations of the program contained on either a hard copy or a DVD. In phase II, 20 participants 65 years or older were interviewed for their feedback on the SEB after participating in 1 month of instructor-led SEB group practice. Both quantitative and qualitative strategies were included in the subject evaluation. The quantitative evaluation results were analyzed using descriptive statistics of mean and SD. The qualitative revision suggestions were critically analyzed and summarized using content analysis to revise the program. RESULTS: Both the experts in phase I and the senior participants in phase II rated the SEB highly and commented that the program was feasible, safe, suitable, and helpful. The participants further suggested practicing SEB 3 times per week for 60 minutes per session in a group of 20 to 29 people. CONCLUSIONS: Based on the feedback from the expert panel, the final SEB included 3 phases with 20 movements. The program took 40 minutes to complete. The SEB program was supported by the 11 experts with 5 professional backgrounds and was well accepted by a small group of community seniors. The participants expressed that the program was feasible, was manageable, and could be helpful to their health promotion.

Feasibility appraisal of an elastic band exercise program for older adults in wheelchairs.

This study appraised the feasibility of an elastic band exercise program for older adults in wheelchairs. A descriptive program review survey was used. A wheelchair-bound senior elastic band (WSEB) exercise program tailored to older adults in wheelchairs was initially developed by a group of 12 experts. A feasibility appraisal survey was administered to 10 older adults in wheelchairs through individual interviews after 4 weeks of the WSEB program. Study participants revealed that the WSEB program was feasible, safe, appropriate, and helpful to them. Participants further suggested practicing the WSEB program 3 times/week for 40 min/session in a group of 15-20 people. The finalized WSEB program has 2 levels: the basic and the advanced WSEB program. It is suggested that the basic level to be taught first with practice until participants are familiar with those exercises before proceeding to the advanced level.

Psychological and socioeconomic health of community-dwelling older adults.

Different dimensions of health are intertwined. The purposes of this study were: (1) to investigate the psychological and socioeconomic health status of community-dwelling older adults in Taiwan, and (2) to compare the psychological and socioeconomic health differences among people of different age groups, gender, marital status, and exercise habits. Using stratified random sampling, 384 Taiwanese community-dwelling older adults were recruited for this survey research. Based on the Health Model of Older Adults, seven constructs were measured: (1) psychological health: sleep quality, emotional health, cognitive functioning, and health promotion behaviors; (2) socioeconomic health: social engagement, social support, and financial status. Results showed that most participants were in a good state of psychological and socioeconomic health, except that 38.02% of them suffered from sleep disruptions, and the majority of them were not involved in any social group, nor engaged in any volunteer work. Young-old older adults had better psychological and socioeconomic health than middle-old and old-old older adults. Male older adults had better psychological health than female older adults; however, they had less social engagement and social support than female older adults. Married older adults and exercisers performed better in most of the psychological and socioeconomic health indicators than single/widowed older adults and non-exercisers.

Genetic surveillance and outcomes of pyrazinamide and fluoroquinolones-resistant tuberculosis in Taiwan.

BACKGROUND: Pyrazinamide (PZA) and fluoroquinolone (FQ), particularly moxifloxacin (MXF), are essential drugs in the World Health Organization (WHO) recommended short-course regimen to treat drug-susceptible tuberculosis (TB). METHODS: To understand the extent of PZA and MXF susceptibility in general TB cases in Taiwan, we conducted retrospective analyses of 385 conservative Mycobacterium tuberculosis complex (MTBC) isolates identified from 4 TB laboratories in different regions of Taiwan. The case information was obtained from the TB registry. Genotypic drug susceptibility testing (DST) was performed by sequencing drug-resistance associated genes, PZA (pncA) and FQ (gyrA, and gyrB). Phenotypic DST was determined using the Bactec MGIT 960 system or the agar proportion method. Genotyping was carried out using spacer oligonucleotide typing. RESULTS: In this study, 4.7% (18/385) cases' isolates harbored pncA mutations and 7.0% (27/385) cases' isolates harbored gyrA or gyrB mutation. Notably, pncA mutation was associated with Beijing family genotypes (P = 0.028), East African-Indian (EAI) genotypes (P = 0.047) and MDR-TB (P < 0.001). Whereas, gyrA or gyrB mutation was associated with EAI genotypes (P = 0.020) and MDR-TB (P = 0.006). In addition, a statistically significant difference was found between the favorable outcomes using active and inactive PZA (P = 0.009) in 38 case isolates with any pncA, gyrA, or gyrB mutation. CONCLUSION: We concluded that routine PZA and FQ susceptibility tests are recommended for guiding the treatment of TB.

A Multitarget Therapeutic Peptide Derived From Cytokine Receptors Based on in Silico Analysis Alleviates Cytokine-Stimulated Inflammation.

Septicemia is a severe inflammatory response caused by the invasion of foreign pathogens. Severe sepsis-induced shock and multiple organ failure are the two main causes of patient death. The overexpression of many proinflammatory cytokines, such as TNF-α, IL-1ß, and IL-6, is closely related to severe sepsis. Although the treatment of sepsis has been subject to many major breakthroughs of late, the treatment of patients with septic shock is still accompanied by a high mortality rate. In our previous research, we used computer simulations to design the multifunctional peptide KCF18 that can bind to TNF-α, IL-1ß, and IL-6 based on the binding regions of receptors and proinflammatory cytokines. In this study, proinflammatory cytokines were used to stimulate human monocytes to trigger an inflammatory response, and the anti-inflammatory ability of the multifunctional KCF18 peptide was further investigated. Cell experiments demonstrated that KCF18 significantly reduced the binding of proinflammatory cytokines to their cognate receptors and inhibited the mRNA and protein expressions of TNF-α, IL-1ß, and IL-6. It could also reduce the expression of reactive oxygen species induced by cytokines in human monocytes. KCF18 could effectively decrease the p65 nucleus translocation induced by cytokines, and a mice endotoxemia experiment demonstrated that KCF18 could reduce the expression of IL-6 and the increase of white blood cells in the blood stimulated by lipopolysaccharides. According to our study of tissue sections, KCF18 alleviated liver inflammation. By reducing the release of cytokines in plasma and directly affecting vascular cells, KCF18 is believed to significantly reduce the risk of vascular inflammation.

Ephrin A4-ephrin receptor A10 signaling promotes cell migration and spheroid formation by upregulating NANOG expression in oral squamous cell carcinoma cells.

Ephrin type-A receptor 10 (EPHA10) has been implicated as a potential target for breast and prostate cancer therapy. However, its involvement in oral squamous cell carcinoma (OSCC) remains unclear. We demonstrated that EPHA10 supports in vivo tumor growth and lymphatic metastasis of OSCC cells. OSCC cell migration, epithelial mesenchymal transition (EMT), and sphere formation were found to be regulated by EPHA10, and EPHA10 was found to drive expression of some EMT- and stemness-associated transcription factors. Among EPHA10 ligands, exogenous ephrin A4 (EFNA4) induced the most OSCC cell migration and sphere formation, as well as up-regulation of SNAIL, NANOG, and OCT4. These effects were abolished by extracellular signal-regulated kinase (ERK) inhibition and NANOG knockdown. Also, EPHA10 was required for EFNA4-induced cell migration, sphere formation, and expression of NANOG and OCT4 mRNA. Our microarray dataset revealed that EFNA4 mRNA expression was associated with expression of NANOG and OCT4 mRNA, and OSCC patients showing high co-expression of EFNA4 with NANOG or OCT4 mRNA demonstrated poor recurrence-free survival rates. Targeting forward signaling of the EFNA4-EPHA10 axis may be a promising therapeutic approach for oral malignancies, and the combination of EFNA4 mRNA and downstream gene expression may be a useful prognostic biomarker for OSCC.

Acupunch Exercise Program Development and Feasibility Evaluation for Older Adults.

PURPOSE: The aim of the study was to develop the Healthy Beat Acupunch (HBA) exercise program and evaluate its feasibility for community older adults. DESIGN: Stage I: The Delphi technique was used to consult 16 experts to develop the program. Stage II: A preexperimental, one-group, posttest-only design was used to pilot-test the program feasibility with 31 older adults. METHODS: After 4 weeks of interventions, participants evaluated the program based on four criteria (simplicity, safety, suitability, and helpfulness) and responded to five open-ended questions. FINDINGS: The developed HBA program from Stage I includes three phases with 24 motions and takes 40 minutes to complete. Program feasibility in Stage II showed average scores ranged from 8.84 ± 1.32 to 9.97 ± 0.18. CONCLUSION: Both experts and elderly participants confirmed that the HBA program was simple, safe, suitable, and helpful to older adults. CLINICAL RELEVANCE: The HBA program provides older adults with a new set of exercise options.

Complexation of the nickel and cobalt transcriptional regulator RcnR with DNA.

RcnR is a transcription factor that regulates the homeostasis of cobalt and nickel in bacterial cells. Escherichia coli RcnR was crystallized with DNA that encompasses the DNA-binding site. X-ray diffraction data were collected to 2.9 Šresolution. The crystal belonged to space group P6122 or P6522, with unit-cell parameters a = b = 73.59, c = 157.66 Å, α = ß = 90, γ = 120°.

TGF-ß regulated leukemia cell susceptibility against NK targeting through the down-regulation of the CD48 expression.

Transforming growth factor-ß (TGF-ß) is known to function as a dual role regulatory cytokine for being either a suppresser or promoter during tumor initiation and progression. In solid tumors, TGF-ß secreted from tumor microenvironment acts as a suppresser against host immunity, like natural killer (NK) cells, to favor tumor evasion. However, besides solid tumors, the underlying mechanism of how TGF-ß regulates leukemogenesis, tumor progression, immunoediting, and NK function is still not clear in detail. In this study, we found that TGF-ß induced leukemia MEG-01 and U937 cells to become less sensitive to NK-92MI targeting by down-regulating CD48, a ligand for NK activating receptor 2B4, but not down-regulating other tumor-associated carbohydrate antigens (TACAs). In CD48-knockdown cells, cells responding to NK-92MI targeting displayed a phenotype of less NK susceptibility and cell conjugation. On the other hand, when NK cells were treated with TGF-ß, TGF-ß suppressed NK recognition, degranulation, and killing activity in time-dependent manner by regulating ICAM-1 binding capacity instead of affecting expressions of activating and inhibitory receptors. Taken together, both leukemia cells and immune NK cells could be regulated by TGF-ß through suppressing leukemia cell surface CD48 to escape from host surveillance and down-regulating NK cell surface ICAM-1 binding activity to impair NK functions, respectively. Our results suggested that TGF-ß had effect in leukemia similar to that observed in solid tumors but through different regulatory mechanism.