In vivo switch to IL-10–secreting T regulatory cells in high dose allergen exposure

High dose bee venom exposure in beekeepers by natural bee stings represents a model to understand mechanisms of T cell tolerance to allergens in healthy individuals. Continuous exposure of nonallergic beekeepers to high doses of bee venom antigens induces diminished T cell–related cutaneous late-phase swelling to bee stings in parallel with suppressed allergen-specific T cell proliferation and T helper type 1 (Th1) and Th2 cytokine secretion. After multiple bee stings, venom antigen–specific Th1 and Th2 cells show a switch toward interleukin (IL) 10–secreting type 1 T regulatory (Tr1) cells. T cell regulation continues as long as antigen exposure persists and returns to initial levels within 2 to 3 mo after bee stings. Histamine receptor 2 up-regulated on specific Th2 cells displays a dual effect by directly suppressing allergen-stimulated T cells and increasing IL-10 production. In addition, cytotoxic T lymphocyte–associated antigen 4 and programmed death 1 play roles in allergen-specific T cell suppression. In contrast to its role in mucosal allergen tolerance, transforming growth factor β does not seem to be an essential player in skin-related allergen tolerance. Thus, rapid switch and expansion of IL-10–producing Tr1 cells and the use of multiple suppressive factors represent essential mechanisms in immune tolerance to a high dose of allergens in nonallergic individuals.     

A regulatory role for the cohesin loader NIPBL in nonhomologous end joining during immunoglobulin class switch recombination

DNA double strand breaks (DSBs) are mainly repaired via homologous recombination (HR) or nonhomologous end joining (NHEJ). These breaks pose severe threats to genome integrity but can also be necessary intermediates of normal cellular processes such as immunoglobulin class switch recombination (CSR). During CSR, DSBs are produced in the G1 phase of the cell cycle and are repaired by the classical NHEJ machinery. By studying B lymphocytes derived from patients with Cornelia de Lange Syndrome, we observed a strong correlation between heterozygous loss-of-function mutations in the gene encoding the cohesin loading protein NIPBL and a shift toward the use of an alternative, microhomology-based end joining during CSR. Furthermore, the early recruitment of 53BP1 to DSBs was reduced in the NIPBL-deficient patient cells. Association of NIPBL deficiency and impaired NHEJ was also observed in a plasmid-based end-joining assay and a yeast model system. Our results suggest that NIPBL plays an important and evolutionarily conserved role in NHEJ, in addition to its canonical function in sister chromatid cohesion and its recently suggested function in HR.DNA double strand breaks (DSBs) pose a severe threat to genome integrity, but can also be a necessary part of normal cellular processes, such as meiosis and Ig class switch recombination (CSR). Depending on cell cycle phase and DSB structure, different strategies are used for repair. Homologous recombination (HR) depends on a homologous DNA template for repair, preferentially the identical sister chromatid, and is therefore mainly active during the S and G2 phases. Nonhomologous end joining (NHEJ), however, is active throughout the cell cycle and is the principal pathway during the G1 phase, when there is no immediate close template for homologous repair. The classical NHEJ pathway requires not only the key components of the NHEJ machinery, i.e., Ku70/Ku80, DNA-PKcs, Artemis, XLF (Cernunnos), XRCC4, and DNA ligase IV, but also several DNA damage sensors or adaptors, such as ATM, γH2AX, 53BP1, MDC1, RNF168, and the Mre11–Rad50–NBS1 complex.Cohesin is an evolutionarily conserved multisubunit complex consisting of a heterodimer of two structural maintenance of chromosomes (SMC) proteins, SMC1A and SMC3, one kleisin protein RAD21 (MCD1 or SCC1) and SA (STAG1/2 or SCC3). The SMC proteins fold back on themselves in the hinge region to form long antiparallel coiled-coil arms, with the amino and carboxyl termini coming together to create head domains that contain ATPases. RAD21 bridges the two head domains to facilitate the formation of the proposed ring-like structure of the complex, and it also interacts with the SA subunit. The cohesin complex ensures correct chromosome segregation through cohesion between sister chromatids (Nasmyth and Haering, 2009). In addition to this canonical role, cohesin and its loading complex NIPBL/MAU2 have also been suggested to be important for regulation of gene expression and repair of DSBs through HR, presumably by facilitating proximity between the broken DNA ends and the repair template (Sjögren and Nasmyth, 2001; Vrouwe et al., 2007; Nasmyth and Haering, 2009). Smc1, the yeast SMC1A orthologue, has furthermore been suggested to coordinate the HR and NHEJ processes (Schär et al., 2004).Cornelia de Lange syndrome (CdLS) is a developmental disorder characterized by growth retardation, severe intellectual disability, gastrointestinal abnormalities, malformations, of the upper limbs and characteristic facial dysmorphisms. Heterozygous loss-of-function mutations in NIPBL, encoding the cohesin loader NIPBL, are the major cause of CdLS (Liu and Baynam, 2010). In addition, mutations in the SMC1A, SMC3, PDS5B, RAD21, and HDAC8 encoding genes, all being part of the cohesion pathway, have been found in selected CdLS patients. The multisystem dysfunctions connected to the syndrome implicate defective gene regulation during fetal development and current evidence suggests that CdLS may be caused by alterations in cohesin chromatin-binding dynamics (Liu et al., 2009). In addition, cell lines established from CdLS patients have an increased sensitivity to DNA damage that has been suggested to be caused by defective HR-mediated repair (Vrouwe et al., 2007).Here, we show an increased DNA damage sensitivity, especially after exposure to γ-rays, in B-lymphoblastoid (LCLs) and fibroblast cell lines (FBs) from NIPBL-deficient CdLS patients. However, we also observed that the majority of the patient and control cells studied were in the G1 phase of the cell cycle, where NHEJ is the principle DSB repair mechanism. We therefore investigated whether defective NHEJ could underlie the DNA damage sensitivity observed in the patient cells.     

The CD6/ALCAM pathway promotes lupus nephritis via T cell–mediated responses

T cells are central to the pathogenesis of lupus nephritis (LN), a common complication of systemic lupus erythematosus (SLE). CD6 and its ligand, activated leukocyte cell adhesion molecule (ALCAM), are involved in T cell activation and trafficking. Previously, we showed that soluble ALCAM is increased in urine (uALCAM) of patients with LN, suggesting that this pathway contributes to disease. To investigate, uALCAM was examined in 1038 patients with SLE and LN from 5 ethnically diverse cohorts; CD6 and ALCAM expression was assessed in LN kidney cells; and disease contribution was tested via antibody blockade of CD6 in murine models of SLE and acute glomerulonephritis. Extended cohort analysis offered resounding validation of uALCAM as a biomarker that distinguishes active renal involvement in SLE, irrespective of ethnicity. ALCAM was expressed by renal structural cells whereas CD6 expression was exclusive to T cells, with elevated numbers of CD6⁺ and ALCAM⁺ cells in patients with LN. CD6 blockade in models of spontaneous lupus and immune-complex glomerulonephritis revealed significant decreases in immune cells, inflammatory markers, and disease measures. Our data demonstrate the contribution of the CD6/ALCAM pathway to LN and SLE, supporting its use as a disease biomarker and therapeutic target.     

DNA polymerase beta is able to repair breaks in switch regions and plays an inhibitory role during immunoglobulin class switch recombination

Immunoglobulin (Ig) class switch recombination (CSR) is initiated by activation-induced cytidine deaminase (AID), which converts cytosines to uracils in switch (S) regions. Subsequent excision of dU by uracil DNA glycosylase (UNG) of the base excision repair (BER) pathway is required to obtain double-strand break (DSB) intermediates for CSR. Since UNG normally initiates faithful repair, it is unclear how the AID-instigated S region lesions are converted into DSBs rather than correctly repaired by BER. Normally, DNA polymerase beta (Polbeta) would replace the dC deaminated by AID, leading to correct repair of the single-strand break, thereby preventing CSR. We address the question of whether Polbeta might be specifically down-regulated during CSR or inhibited from accessing the AID-instigated lesions, or whether the numerous AID-initiated S region lesions might simply overwhelm the BER capacity. We find that nuclear Polbeta levels are induced upon activation of splenic B cells to undergo CSR. When Polbeta(-/-) B cells are activated to switch in culture, they switch slightly better to IgG2a, IgG2b, and IgG3 and have more S region DSBs and mutations than wild-type controls. We conclude that Polbeta attempts to faithfully repair S region lesions but fails to repair them all.     

Interligand communication in a metal mediated LL′CT system – a case study

A series of oxo-Mo(iv) complexes, [MoO(Dt²⁻)(Dt⁰)] (where Dt²⁻ = benzene-1,2-dithiol (bdt), toluene-3,4-dithiol (tdt), quinoxaline-2,3-dithiol (qdt), or 3,6-dichloro-benzene-1,2-dithiol (bdtCl₂); Dt⁰ = N,N′-dimethylpiperazine-2,3-dithione (Me₂Dt⁰) or N,N′-diisopropylpiperazine-2,3-dithione (ⁱPr₂Dt⁰)), possessing a fully oxidized and a fully reduced dithiolene ligand have been synthesized and characterized. The assigned oxidation states of coordinated dithiolene ligands are supported with spectral and crystallographic data. The molecular structure of [MoO(tdt)(ⁱPr₂Dt⁰)] (6) demonstrates a large ligand fold angle of 62.6° along the S⋯S vector of the Dt⁰ ligand. The electronic structure of this system is probed by density functional theory (DFT) calculations. The HOMO is largely localized on the Dt²⁻ ligand while virtual orbitals are mostly Mo and Dt⁰ in character. Modeling the electronic spectrum of 6 with time dependent (TD) DFT calculations attributes the intense low energy transition at ∼18 000 cm⁻¹ to a ligand-to-ligand charge transfer (LL′CT). The electron density difference map (EDDM) for the low energy transition depicts the electron rich Dt²⁻ ligand donating charge density to the redox-active orbitals of the electron deficient Dt⁰ ligand. Electronic communication between dithiolene ligands is facilitated by a Mo-monooxo center and distortion about its primary coordination sphere.

The interligand communication between non-innocent dithiolene ligands of different oxidation states has been described in a Mo system. The fully reduced ene-dithiolate (Dt²⁻) acts as a donor moiety to the oxidized dithione (Dt⁰) in an LL′CT process.     

Contrasting roles for all-trans retinoic acid in TGF-β–mediated induction of Foxp3 and Il10 genes in developing regulatory T cells

Extrathymic induction of regulatory T (T reg) cells is essential to the regulation of effector T cell responses in the periphery. In addition to Foxp3, T reg cell expression of suppressive cytokines, such as IL-10, is essential for peripheral tolerance, particularly in the intestines. TGF-β has been shown to induce expression of Foxp3 as well as IL10 and the vitamin A metabolite; all-trans retinoic acid (RA [at-RA]) has been found to enhance the former. We report that in contrast to its enhancement of TGF-β–mediated Foxp3 induction, at-RA potently inhibits the TGF-β–mediated induction of Il10 in naive CD4 T cells. Thus, mucosal DC subsets that are active producers of at-RA inhibit induction of Il10 in naive CD4 T cells while promoting induction of Foxp3. Accordingly, mice with vitamin A deficiency have increased numbers of IL-10–competent T reg cells. Activation of DCs by certain Toll-like receptors (TLRs), particularly TLR9, suppresses T cell induction of Foxp3 and enables induction of Il10. Collectively, our data indicate that at-RA has reciprocal effects on the induction of Foxp3 and Il10 in developing CD4⁺ T reg cells and suggest that TLR9-dependent inhibition of at-RA production by antigen-presenting cells might represent one mechanism to promote the development of IL-10–expressing T cells.     

Fanca deficiency reduces A/T transitions in somatic hypermutation and alters class switch recombination junctions in mouse B cells

Fanconi anemia is a rare genetic disorder that can lead to bone marrow failure, congenital abnormalities, and increased risk for leukemia and cancer. Cells with loss-of-function mutations in the FANC pathway are characterized by chromosome fragility, altered mutability, and abnormal regulation of the nonhomologous end-joining (NHEJ) pathway. Somatic hypermutation (SHM) and immunoglobulin (Ig) class switch recombination (CSR) enable B cells to produce high-affinity antibodies of various isotypes. Both processes are initiated after the generation of dG:dU mismatches by activation-induced cytidine deaminase. Whereas SHM involves an error-prone repair process that introduces novel point mutations into the Ig gene, the mismatches generated during CSR are processed to create double-stranded breaks (DSBs) in DNA, which are then repaired by the NHEJ pathway. As several lines of evidence suggest a possible role for the FANC pathway in SHM and CSR, we analyzed both processes in B cells derived from Fanca^−/− mice. Here we show that Fanca is required for the induction of transition mutations at A/T residues during SHM and that despite globally normal CSR function in splenic B cells, Fanca is required during CSR to stabilize duplexes between pairs of short microhomology regions, thereby impeding short-range recombination downstream of DSB formation.To respond to the enormous variety of pathogens they might encounter, B lymphocytes have evolved processes to alter their genetic material to assemble novel functional Ig genes through site-specific V(D)J recombination. Later, contact with antigens can induce two different activation-induced cytidine deaminase (AID)–dependent processes, which are known as somatic hypermutation (SHM) and class switch recombination (CSR). SHM is responsible for the targeted introduction of point mutations into the variable (V) region of the Ig gene, creating Ig variants with enhanced affinity for a particular antigen. CSR allows for exchange of the initial IgM constant region (Cμ) with a downstream constant region (Cδ, Cγ, Cε, or Cα) through deletional recombination to generate different classes of effector antibodies (Alt et al., 2013).AID, which converts cytosines into uracils, initiates both SHM and CSR by creating dU:dG mismatches (Alt et al., 2013). During SHM, mutations arise from these mismatches through several different mechanisms: (a) DNA replication across the uracil leads to transition mutations; (b) abasic sites generated by the base excision repair glycosylase UNG may be replicated in an error-prone manner by the translesional synthesis (TLS) polymerase REV1 to yield either transition or transversion mutations at the site of the C/G base pair; and (c) mismatch repair (MMR) proteins (MSH2/MSH6 and EXO1) can trigger excision and error-prone resynthesis of short stretches of DNA by the TLS polymerase Polη, thus spreading mutations to surrounding U/G base pairs (Liu and Schatz, 2009). In contrast, during CSR, both base excision repair and MMR proteins induce double-stranded breaks (DSBs) within the switch (S) regions situated upstream of each Ig C_H gene. These breaks are then repaired by either the classical nonhomologous end-joining (NHEJ) pathway, which directly rejoins DNA ends with minimal modification of the broken ends, or by the alternative NHEJ pathway, which makes use of sequence microhomologies (MHs) to associate and rejoin distal DSBs (Alt et al., 2013).Fanconi anemia (FA) is a rare, inherited chromosomal breakage disorder presenting bone marrow failure and cancer predisposition. FA is genetically heterogeneous, with 16 FANC genes (named A through Q) identified to date. After DNA damage or replicative stress, eight FANC proteins (FANCA, -B, -C, -E, -F, -G, -L, and -M) assemble into the FANCcore complex, which is necessary for the monoubiquitination and nuclear foci formation of both FANCD2 and FANCI. Monoubiquitinated FANCD2/FANCI heterodimer functionally or biochemically interacts with FANCD1/BRCA2, FANCN/PALB2, FANCJ/BRIP1, FANCO/RAD51C, FANCP/SXL4, and FANCQ/XPF to eliminate DNA lesions and rescue replication (Kottemann and Smogorzewska, 2013). FANC proteins promote homologous recombination and suppress NHEJ repair (Adamo et al., 2010; Pace et al., 2010). Moreover, FANC pathway disruption has been associated with abnormalities of several proteins involved in SHM or CSR, including the TLS polymerases REV1 and Polη (Kim et al., 2012; Fu et al., 2013; Renaud and Rosselli, 2013), the MMR protein MSH2 (Williams et al., 2011), the helicase BLM, and the DSB repair protein MRE11 (Pichierri et al., 2002, 2004; Naim and Rosselli, 2009). High levels of FANCD2 have been detected in germinal center (GC) cells in the spleen, tonsil, and reactive lymph nodes (Hölzel et al., 2003). Finally, expression of the Fanca mRNA, but not the Fancg mRNA, is specifically increased in GC B cells, which show high levels of SHM and CSR (Heng and Painter, 2008). In light of the above, we decided to analyze SHM and CSR in B cells derived from Fanca^−/− mice to determine a possible involvement of FANCA in the process of secondary Ig diversification.     

Not young but still immature: a HIF-1α–mediated maturation checkpoint in regenerating muscle

Muscle fibers express particular isoforms of contractile proteins, depending on the fiber’s function and the organism’s developmental stage. In the adult, after a muscle injury, newly generated fibers transition through embryonic and neonatal myosins, prior to selecting their distinctive adult myosin isoform. In this issue of the JCI, Wang et al. discover a checkpoint that regulates the neonatal-to-adult myosin isoform transition. They found that HIF-1α regulated this checkpoint, with elevated HIF-1α levels blocking progression, while HIF-1α knockout accelerated the transition. They further related these findings to centronuclear myopathy, a disease in which HIF-1α is similarly elevated and neonatal myosin expression is maintained. These findings highlight a maturation checkpoint that impacts the skeletal muscle regeneration following ischemic injury, providing a pharmacologically accessible pathway in injury and diseases such as centronuclear myopathy.     

Identification of heme oxygenase-1–specific regulatory CD8+ T cells in cancer patients

Treg deficiencies are associated with autoimmunity. Conversely, CD4⁺ and CD8⁺ Tregs accumulate in the tumor microenvironment and are associated with prevention of antitumor immunity and anticancer immunotherapy. Recently, CD4⁺ Tregs have been much studied, but little is known about CD8⁺ Tregs and the antigens they recognize. Here, we describe what we believe to be the first natural target for CD8⁺ Tregs. Naturally occurring HLA-A2–restricted CD8⁺ T cells specific for the antiinflammatory molecule heme oxygenase-1 (HO-1) were able to suppress cellular immune responses with outstanding efficacy. HO-1–specific CD8⁺ T cells were detected ex vivo and in situ among T cells from cancer patients. HO-1–specific T cells isolated from the peripheral blood of cancer patients inhibited cytokine release, proliferation, and cytotoxicity of other immune cells. Notably, the inhibitory effect of HO-1–specific T cells was far more pronounced than that of conventional CD4⁺CD25⁺CD127^– Tregs. The inhibitory activity of HO-1–specific T cells seemed at least partly to be mediated by soluble factors. Our data link the cellular stress response to the regulation of adaptive immunity, expand the role of HO-1 in T cell–mediated immunoregulation, and establish a role for peptide-specific CD8⁺ T cells in regulating cellular immune responses. Identification of potent antigen-specific CD8⁺ Tregs may open new avenues for therapeutic interventions in both autoimmune diseases and cancer.     

CD4+ T Cell–mediated Granulomatous Pathology in Schistosomiasis Is Downregulated by a B Cell–dependent Mechanism Requiring Fc Receptor Signaling

The effector functions of CD4⁺ T lymphocytes are generally thought to be controlled by distinct populations of regulatory T cells and their soluble products. The role of B cells in the regulation of CD4-dependent host responses is less well understood. Hepatic egg granuloma formation and fibrosis in murine schistosomiasis are dependent on CD4⁺ lymphocytes, and previous studies have implicated CD8⁺ T cells or cross-regulatory cytokines produced by T helper (Th) lymphocytes as controlling elements of this pathologic process. In this report, we demonstrate that B cell–deficient (μMT) mice exposed to Schistosoma mansoni develop augmented tissue pathology and, more importantly, fail to undergo the spontaneous downmodulation in disease normally observed during late stages of infection. Unexpectedly, B cell deficiency did not significantly alter T cell proliferative response or cause a shift in the Th1/Th2 balance. Since schistosome-infected Fc receptor–deficient (FcR γ chain knockout) mice display the same exacerbated egg pathology as that observed in infected μMT mice, the B cell– dependent regulatory mechanism revealed by these experiments appears to require receptor-mediated cell triggering. Together, the data demonstrate that humoral immune response/FcR interactions can play a major role in negatively controlling inflammatory disease induced by CD4⁺ T cells.     

Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues

A combination of anti–CTLA-4 plus anti–PD-1/PD-L1 is the most effective cancer immunotherapy but causes high incidence of immune-related adverse events (irAEs). Here we report that targeting of HIF-1α suppressed PD-L1 expression on tumor cells and tumor-infiltrating myeloid cells, but unexpectedly induced PD-L1 in normal tissues by an IFN-γ–dependent mechanism. Targeting the HIF-1α/PD-L1 axis in tumor cells reactivated tumor-infiltrating lymphocytes and caused tumor rejection. The HIF-1α inhibitor echinomycin potentiated the cancer immunotherapeutic effects of anti–CTLA-4 therapy, with efficacy comparable to that of anti–CTLA-4 plus anti–PD-1 antibodies. However, while anti–PD-1 exacerbated irAEs triggered by ipilimumab, echinomycin protected mice against irAEs by increasing PD-L1 levels in normal tissues. Our data suggest that targeting HIF-1α fortifies the immune tolerance function of the PD-1/PD-L1 checkpoint in normal tissues but abrogates its immune evasion function in the tumor microenvironment to achieve safer and more effective immunotherapy.     

Endothelin-1/endothelin-B receptor–mediated increases in NHE3 activity in chronic metabolic acidosis

Decreases in blood pH activate NHE3, the proximal tubular apical membrane Na/H antiporter. In cultured renal epithelial cells, activation of the endothelin-B (ET(B)) receptor increases NHE3 activity. To examine the role of the ET(B) receptor in the response to acidosis in vivo, the present studies examined ET(B) receptor-deficient mice, rescued from neonatal lethality by expression of a dopamine beta-hydroxylase promoter/ET(B) receptor transgene (Tg/Tg:ET(B)(-/-) mice). In proximal tubule suspensions from Tg/Tg:ET(B)(+/-) mice, 10(-8) M endothelin-1 (ET-1) increased NHE3 activity, but this treatment had no effect on tubules from Tg/Tg:ET(B)(-/-) mice. Acid ingestion for 7 days caused a greater decrease in blood HCO(3)(-) concentration in Tg/Tg:ET(B)(-/-) mice compared with Tg/Tg:ET(B)(+/+) and Tg/Tg:ET(B)(+/-) mice. Whereas acid ingestion increased apical membrane NHE3 by 42-46% in Tg/Tg:ET(B)(+/+) and Tg/Tg:ET(B)(+/-) mice, it had no effect on NHE3 in Tg/Tg:ET(B)(-/-) mice. In C57BL/6 mice, excess acid ingestion increased renal cortical preproET-1 mRNA expression 2.4-fold and decreased preproET-3 mRNA expression by 37%. On a control diet, Tg/Tg:ET(B)(-/-) mice had low rates of ammonium excretion, which could not be attributed to an inability to acidify the urine, as well as hypercitraturia, with increased titratable acid excretion. Acid ingestion increased ammonium excretion, citrate absorption, and titratable acid excretion to the same levels in Tg/Tg:ET(B)(-/-) and Tg/Tg:ET(B)(+/+) mice. In conclusion, metabolic acidosis increases ET-1 expression, which increases NHE3 activity via the ET(B) receptor.     

New spirobisnaphthalenes from an endolichenic fungus strain CGMCC 3.15192 and their anticancer effects through the P53–P21 pathway

Natural products from fungi have remained a rich resource for drug discovery. Here we report the isolation of three new spirobisnaphthalenes, namely sacrosomycin A-C (1–3), and three known analogues (4–6), from the ethyl acetate extract of a nonsporulating endolichenic fungus derived from Peltigera elisabethae var. mauritzii. The structures of these compounds were elucidated by IR, UV, MS, and NMR. Biological functions of these compounds were evaluated using cultured human cancer cell lines. Short-term cell growth and long-term cell survival assays show that compound 5 demonstrated the strongest cancer cell growth inhibition effect. We reveal that compound 5 induced both cell cycle arrest at the G2/M phase and cell death. Using western blotting, luciferase reporter assay and quantitative PCR (qPCR), we show that compound 5 induced up-regulation of the P53–P21 pathway, supporting the cell cycle arrest and growth inhibition effect of this compound. In contrast, these compounds did not induce cell death in a normal cell line. These results demonstrate a potential anticancer effect of this rare family of spirobisnaphthalene compounds isolated from endolichenic fungi.

New spirobisnaphthalenes from an endolichenic fungus strain and their anticancer effects mediated by the P53–P21 pathway.     

A new COF linked by an ether linkage (–O–): synthesis,characterization and application in supercapacitance

A new COF (NWNU-COF-4) linked by an aryl ether bond (Ar–O–Ar) was synthesized by the condensation reaction of 2,4,6-trihydroxypyrimidine and trinitrophenol under simple and easy reaction conditions. Fourier transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS), N₂ adsorption–desorption, thermogravimetric analysis (TGA), powder X-ray diffraction (XRD) and scanning electron microscopy (SEM) were utilized to characterize the product. The BET specific surface area of NWNU-COF-4 was 21.33 m² g⁻¹, and its pore size was about 1.351 nm. Additionally, this method of preparation was simple and cheap. The electrochemical measurements showed that the synthesized NWNU-COF-4 had excellent pseudocapacitive performance with maximum specific capacitance of 133.44 F g⁻¹ at 0.3 A g⁻¹ in 6 mol L⁻¹ KOH electrolyte. When the current density increased by 10 times (3.0 A g⁻¹), the specific capacitance was 114.12 F g⁻¹, and the retention rate was 82%. After 10 000 GCD cycles, the capacitance still kept 94% of its initial capacitance.

A new COF (NWNU-COF-4) linked by aryl ether bonds was readily synthesized by condensation of 2,4,6-trihydroxypyrimidine and trinitrophenol. It exhibited excellent pseudocapacitive performance and cycling stability, with promising application as a supercapacitor electrode.     

A client-centered approach in home care for older persons – an integrative review

Objective To describe and synthesize client-centered care and service in home care for older persons.Methods The study was an integrative review using the guidelines for literature reviews by the Joanna Briggs Institute. The research process followed the Whittemore and Knafl framework and PRISMA toolkit in the selection of eligible articles. The CINAHL, Medline, Scopus, Web of Science and Social Sciences abstracts were searched for articles published between January 2007 and May 2020 according to previously designed search strategies. In total, 24 articles were deemed relevant for an analysis using a thematic analysis.Results The analysis resulted in four themes with sub-themes which revealed that client-centered care and service in home care consist of: 1) Clients’ involvement in their own care; self-care, decision-making, satisfactory daily life, 2) Family members’ and care partners’ participation in care; family members’ and care partners’ commitment to care, family members’ and care partners’ competence in care, 3) Communication and co-operation; communication models, empowerment, partnership, and 4) Evidence-based service competence; delivery and organization of services, implementation of services, versatile clinical skills, quality outcomes and personnel wellbeing.Conclusions According to the results, achieving client-centered care and service in home care requires the realization of all of the above aspects. The practice of nursing must better identify all dimensions of client-centered care and take these into account in the delivery of home care services.

KEY POINTS

• Client-centeredness is a fundamental value and the basis of nursing and care in home care provided for older persons
• This paper:
• deepens and structures the concept of client-centered care in the context of home care.
• assists professionals to understand the factors behind client-centered care within the home care environment.
• provides deeper understanding of the roles of the older person, family members, and the service system in developing client-centered services in home care for older persons.

     

The role of biocatalysis in the asymmetric synthesis of alkaloids – an update

Alkaloids are a group of natural products with interesting pharmacological properties and a long history of medicinal application. Their complex molecular structures have fascinated chemists for decades, and their total synthesis still poses a considerable challenge. In a previous review, we have illustrated how biocatalysis can make valuable contributions to the asymmetric synthesis of alkaloids. The chemo-enzymatic strategies discussed therein have been further explored and improved in recent years, and advances in amine biocatalysis have vastly expanded the opportunities for incorporating enzymes into synthetic routes towards these important natural products. The present review summarises modern developments in chemo-enzymatic alkaloid synthesis since 2013, in which the biocatalytic transformations continue to take an increasingly ‘central’ role.

This review article discusses developments in the chemo-enzymatic synthesis of alkaloids since 2013, showcasing how modern methods of organic synthesis and biocatalysis are combined to establish novel routes towards these important natural products.