Nanotechnology for catalysis and solar energy conversion.

This roadmap on Nanotechnology for Catalysis and Solar Energy Conversion focuses on the application of nanotechnology in addressing the current challenges of energy conversion: 'high efficiency, stability, safety, and the potential for low-cost/scalable manufacturing' to quote from the contributed article by Nathan Lewis. This roadmap focuses on solar-to-fuel conversion, solar water splitting, solar photovoltaics and bio-catalysis. It includes dye-sensitized solar cells (DSSCs), perovskite solar cells, and organic photovoltaics. Smart engineering of colloidal quantum materials and nanostructured electrodes will improve solar-to-fuel conversion efficiency, as described in the articles by Waiskopf and Banin and Meyer. Semiconductor nanoparticles will also improve solar energy conversion efficiency, as discussed by Boschloo et al in their article on DSSCs. Perovskite solar cells have advanced rapidly in recent years, including new ideas on 2D and 3D hybrid halide perovskites, as described by Spanopoulos et al 'Next generation' solar cells using multiple exciton generation (MEG) from hot carriers, described in the article by Nozik and Beard, could lead to remarkable improvement in photovoltaic efficiency by using quantization effects in semiconductor nanostructures (quantum dots, wires or wells). These challenges will not be met without simultaneous improvement in nanoscale characterization methods. Terahertz spectroscopy, discussed in the article by Milot et al is one example of a method that is overcoming the difficulties associated with nanoscale materials characterization by avoiding electrical contacts to nanoparticles, allowing characterization during device operation, and enabling characterization of a single nanoparticle. Besides experimental advances, computational science is also meeting the challenges of nanomaterials synthesis. The article by Kohlstedt and Schatz discusses the computational frameworks being used to predict structure-property relationships in materials and devices, including machine learning methods, with an emphasis on organic photovoltaics. The contribution by Megarity and Armstrong presents the 'electrochemical leaf' for improvements in electrochemistry and beyond. In addition, biohybrid approaches can take advantage of efficient and specific enzyme catalysts. These articles present the nanoscience and technology at the forefront of renewable energy development that will have significant benefits to society.

Direct evidence of catalyst reduction on dye and catalyst co-sensitized NiO photocathodes by mid-infrared transient absorption spectroscopy.

Co-sensitization of molecular dyes and catalysts on semiconductor surfaces is a promising strategy to build photoelectrodes for solar fuel production. In such a photoelectrode, understanding the charge transfer reactions between the molecular dye, catalyst and semiconductor material is key to guide further improvement of their photocatalytic performance. Herein, femtosecond mid-infrared transient absorption spectroscopy is used, for the first time, to probe charge transfer reactions leading to catalyst reduction on co-sensitized nickel oxide (NiO) photocathodes. The NiO films were co-sensitized with a molecular dye and a proton reducing catalyst from the family of [FeFe](bdt)(CO)6 (bdt = benzene-1,2-dithiolate) complexes. Two dyes were used: an organic push-pull dye denoted E2 with a triarylamine-oligothiophene-dicyanovinyl structure and a coumarin 343 dye. Upon photo-excitation of the dye, a clear spectroscopic signature of the reduced catalyst is observed a few picoseconds after excitation in all co-sensitized NiO films. However, kinetic analysis of the transient absorption signals of the dye and reduced catalyst reveal important mechanistic differences in the first reduction of the catalyst depending on the co-sensitized molecular dye (E2 or C343). While catalyst reduction is preceded by hole injection in NiO in C343-sensitized NiO films, the singly reduced catalyst is formed by direct electron transfer from the excited dye E2* to the catalyst in E2-sensitized NiO films. This change in mechanism also impacts the lifetime of the reduced catalyst, which is only ca. 50 ps in E2-sensitized NiO films but is >5 ns in C343-sensitized NiO films. Finally, the implication of this mechanistic study for the development of better co-sensitized photocathodes is discussed.

The higher frequency of IgA deficiency among Swedish twins is not explained by HLA haplotypes.

Serum immunoglobulin A (IgA) concentrations were determined in 12 600 adult Swedish twins, applying a high-throughput reverse-phase protein microarray technique. The prevalence of IgA deficiency (IgAD) was found to be 1:241 in monozygotic (MZ) twins and 1:198 in dizygotic (DZ) twins. Hence, the prevalence in twins is markedly elevated as compared with the normal Swedish adult population (1:600). The twins did not show a difference in the frequency of HLA haplotypes in comparison with almost 40 000 healthy Swedish controls. As expected, the risk-conveying HLA alleles A*01, B*08 and DRB1*01 were overrepresented among the IgAD twins and were also associated with significantly lower mean serum IgA concentrations in the twin cohort. In contrast, significantly higher mean IgA concentrations were found among individuals carrying the protective HLA alleles B*07 and DRB1*15. Exome sequencing data from two MZ twin pairs discordant for the deficiency showed no differences between the siblings. Model fitting analyses derived a heritability of 35% and indicate that genetic influences are modestly important for IgAD. The probandwise concordance rates for IgAD were found to be 31% for MZ and 13% for DZ twins.

The autoimmune spectrum of myasthenia gravis: a Swedish population-based study.

OBJECTIVES: To determine the prevalence of myasthenia gravis (MG) and the rate of concurrent autoimmune diseases in patients with MG. DESIGN AND SETTING: Using the Swedish health and population registers, during the period 2005-2010, we conducted a nested case-control study of patients with MG (n = 2045) with five age- and sex-matched population-based controls per case. Register-based MG diagnosis was validated against the Stockholm MG Cohort. Similar nested case-control studies were conducted in patients with multiple sclerosis (MS), as a neuroinflammatory disease control, and siblings of patients with MG. MAIN OUTCOME MEASURE: Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated as a measure of the association between MG and other autoimmune diseases. RESULTS: The prevalence of MG was 24.8/100,000, and patients with MG had an increased risk of another autoimmune disease compared to controls (22.0% vs. 8.9%; OR: 2.82, 95% CI: 2.49-3.20); this risk was stronger amongst younger persons and women. Polymyositis/dermatomyositis, systemic lupus erythematosus and Addison's disease, three conditions regulated by the HLA-B8-DR3 haplotype, were most strongly associated with MG, especially early-onset disease. HLA typing in the Stockholm MG Cohort showed that early-onset MG was indeed dominated by HLA-B8-DR3. The risk of another autoimmune disease was increased in both patients with MS and siblings of patients with MG, compared to their respective controls, but to a lesser extent than in patients with MG. CONCLUSIONS: Our results suggest that MG shares risk factors with other autoimmune diseases, to a greater degree than MS, with a particular role of the HLA-B8-DR3 haplotype, especially amongst younger and female patients.

Genetic defects in B-cell development and their clinical consequences.

Expression of selected genes in hematopoietic stem cells has been identified as a regulator of differentiation of B cells in the liver and bone marrow. Moreover, naïve B cells expressing surface immunoglobulin need other types of genes for antigen-dependent development in secondary lymphoid organs. Many advanced molecular mechanisms underlying primary antibody deficiencies in humans have been described. We provide an overview of the mutations in genes known to be involved in B-cell development and their clinical consequences.

The case for mandatory newborn screening for severe combined immunodeficiency (SCID).

Severe combined immunodeficiency (SCID) is the most severe form of inherited primary immunodeficiency and is a paediatric emergency. Delay in recognising and detecting SCID can have fatal consequences and also reduces the chances of a successful haematopoietic stem cell transplant (HSCT). Screening for SCID at birth would prevent children from dying before HSCT can be attempted and would increase the success of HSCT. There is strong evidence to show that SCID fulfills the internationally-established criteria for a condition to be screened for at birth. There is also a test (the T-cell receptor excision circle (TREC) assay) that is now being successfully used in an increasing number of US states to screen for SCID in routine newborn Guthrie samples. Concerted lobbying efforts have highlighted the need for newborn screening (NBS) for SCID, and its implementation is being discussed in Europe both at EU and individual country level, but as yet there is no global mandate to screen for this rare and frequently lethal condition. This paper summarizes the current evidence for, and the success of SCID NBS, together with a review of the practical aspects of SCID testing and the arguments in favour of adding SCID to the conditions screened for at birth.

Health-related quality of life (HRQL) in immunodeficient adults with selective IgA deficiency compared with age- and gender-matched controls and identification of risk factors for poor HRQL.

PURPOSE: Selective IgA deficiency (SIgAD) is the most common primary immunodeficiency with a prevalence of 1/600 in the general population. Any targeted health-related quality of life (HRQL) study of adults with SIgAD has never been presented. The objectives of the study were to compare HRQL between SIgAD adults and randomly selected age- and gender-matched population controls, and to identify risk factors for poor HRQL. METHODS: Thirty-two SIgAD individuals and 63 controls answered three questionnaires (clinical data, Short Form-36 Health Survey (SF-36), infection-related HRQL) at baseline before undergoing medical/dental examinations and laboratory assessments. HRQL in SIgAD was re-evaluated after 6 and 12 months. RESULTS: Baseline: Selective IgA deficiency individuals reported significantly increased fear of contracting infections (p < 0.01). Those scoring high on fear also perceived significantly poorer physical health (p < 0.01). SF-36 results indicated that SIgAD individuals perceived poorer HRQL, although this was not statistically significant. FOLLOW-UP: Compared with SF-36 responses at baseline, SIgAD individuals reported significantly more pain (p < 0.01) at 6 months, poorer general health (p < 0.05) and summarised physical HRQL (p < 0.01) at 6 and 12 months and decreased vitality at 12 months. The summarised mental scale remained stable over time. Risk factors for poor HRQL: The number of antibiotic treatments during the previous year (p < 0.001), number of daily medications (p < 0.01), allergic rhinoconjunctivitis (p < 0.05), chronic musculoskeletal symptoms at least every week (p < 0.05) and anxiety and/or insomnia (p < 0.05) were identified as independent risk factors for poor HRQL. CONCLUSION: The study highlights the importance of identifying and thoroughly evaluating, educating and following up individuals with SIgAD, as their HRQL may be negatively affected due to health problems possible to prevent and treat.

IgA deficiency and mortality: a population-based cohort study.

IgA deficiency has been linked to increased morbidity but data on mortality is lacking. In this population-based prospective cohort study we examined mortality in patients with IgA deficiency compared with the general population. Through six university hospitals in Sweden we identified 2,495 individuals with IgA deficiency (IgA deficiency ≤0.07 mg/L) diagnosed between 1980 and 2012. Each patient with IgA deficiency was matched on age, sex, place of residence, and year of diagnosis with up to 10 general population controls (n = 24,509). Data on education level and emigration status were obtained from Statistics Sweden. Our main outcome measure was all-cause mortality retrieved from the nationwide Causes of Death Register, which includes >99 % of all deaths in Sweden. We used Cox regression to estimate mortality hazard ratios conditioned on the matching factors and adjusted for education level. During 25,367 person-years of follow-up (median 8.3), there were 260 deaths in the IgA deficiency group versus 1,599 deaths during 257,219 person-years (median 8.6) in the general population controls (102 versus 62 deaths per 10,000 person-years; incidence rate difference, 40, 95%CI 28­53, P < .001). This corresponded to a conditional mortality hazard ratio of 1.8 (95%CI 1.6­2.1, P < .001). Relative mortality varied by follow-up time (P < .001) from a hazard ratio of 3.6 (95%CI 2.5­5.3; P < .001) during the first year to 1.9 (95%CI 1.5­2.4; P < .001) year 1­4; 1.9 (95%CI 1.4­2.4; P < .001) year 5-9; 1.5 (1.0­2.2; P = .054) year 10­14.9; and 1.1 (0.7­1.6; P = .66) year 15­25. Effect modification was also seen by age in each stratum of follow-up time, with higher relative mortality in younger than older patients (P < .001). In conclusion, patients with IgA deficiency are at increased risk of death in the first 10 to 15 years after diagnosis.

Outcomes of splenectomy in patients with common variable immunodeficiency (CVID): a survey of 45 patients.

Splenectomy has been used in patients with common variable immunodeficiency disorders (CVID), mainly in the context of refractory autoimmune cytopenia and suspected lymphoma, but there are understandable concerns about the potential of compounding an existing immunodeficiency. With increasing use of rituximab as an alternative treatment for refractory autoimmune cytopenia, the role of splenectomy in CVID needs to be re-examined. This retrospective study provides the largest cohesive data set to date describing the outcome of splenectomy in 45 CVID patients in the past 40 years. Splenectomy proved to be an effective long-term treatment in 75% of CVID patients with autoimmune cytopenia, even in some cases when rituximab had failed. Splenectomy does not worsen mortality in CVID and adequate immunoglobulin replacement therapy appears to play a protective role in overwhelming post-splenectomy infections. Future trials comparing the effectiveness and safety of rituximab and splenectomy are needed to provide clearer guidance on the second-line management of autoimmune cytopenia in CVID.

Clinical symptoms in adults with selective IgA deficiency: a case-control study.

Selective IgA deficiency (SIgAD) is the most common primary immunodeficiency in Caucasians with a prevalence of 1/600 and is generally considered a mild disorder. In this study, the clinical status of 32 adults with SIgAD was investigated and compared to 63 age- and gender matched controls, randomly selected from a population database. The SIgAD individuals reported significantly more often contracting various upper and lower respiratory infections, with 8 (25.0 %) having been diagnosed with ≥1 pneumonia in the preceding two years, compared to one (1.6 %) control (p < 0.001). Furthermore, the SIgAD individuals were found to have increased proneness to infections and increased prevalence of allergic diseases and autoimmunity, with a total of 84.4 % being affected by any of these diseases, compared to 47.6 % of the controls (p < 0.01). This study challenges the common statement of SIgAD being a mild form of immunodeficiency. It also highlights the importance of using matched controls in PID clinical research to better detect clinically important manifestations.

Rare mutations in TNFRSF13B increase the risk of asthma symptoms in Swedish children.

TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) mutations seem to be associated with autoimmunity and common variable immunodeficiency in humans. Because of its role in immune responses, we investigated the association between TACI mutations and infection proneness/asthma symptoms in children. A total of 2372 children were genotyped for TACI mutations (I87N, C104R, S144X, A181E, R202H and ins204A). Serum IgA, IgG and specific IgE levels were determined in children with mutations. Data on parentally reported allergic diseases and infections were collected. In all, 55 individuals with TACI mutations were identified. Children with TACI mutations had a 2-fold increased risk of wheeze at 2 and 4 years of age and a 2.5-fold increased risk of asthma was seen at 4 years of age. None of the children with mutations suffered from IgA deficiency (<0.07 g l(-1)). No significant differences in serum IgG levels or specific IgE were found. Common variants in asthma susceptibility genes may account for up to 40% of cases of childhood-onset asthma, indicating a high contribution, compared with other common disorders. The role of rare variants/mutations in the pathogenesis of asthma is less clear. We conclude that mutations in TACI are the contributing factors for asthma symptoms in Swedish children, although the mechanisms still remain elusive.

Safety and persistence of orally administered human Lactobacillus sp. strains in healthy adults.

The aim of the study was to evaluate the safety and persistence of selected Lactobacillus strains in the gastrointestinal tract (GIT) of healthy adult volunteers after oral consumption of high doses of lactobacilli to identify potential candidates for probiotic and biotechnological applications. In the first phase of the study, nine individuals consumed capsules containing Lactobacillus gasseri 177 and E16B7, Lactobacillus acidophilus 821-3, Lactobacillus paracasei 317 and Lactobacillus fermentum 338-1-1 (each daily dose 1×1010 cfu) for 5 consecutive days. Data on gut health, blood parameters, and liver and kidney function were collected. The persistence of Lactobacillus strains was assessed by culturing combined with arbitrarily primed polymerase chain reaction (AP-PCR) and PCR-denaturing gradient gel electrophoresis (PCR-DGGE) on days 0, 5, 8, 10 and 20 from faecal samples. All strains survived gastrointestinal passage and were detected on the 5th day. L. acidophilus 821-3 was detected in four volunteers on the 8th day (4.3 to 7.0 log10 cfu/g) and in two on the 10th day (8.3 and 3.9 log10 cfu/g, respectively). In the second phase of the study, five additional volunteers consumed L. acidophilus 821-3 (daily 1×1010 cfu) for 5 consecutive days. The strain was subsequently detected in faeces of all individuals using real-time PCR on the 10th day (range 4.6-6.7; median 6.0 log10 cell/g) in both phases of the study for at least 5 days after discontinuation of consumption. The administration of high doses of different Lactobacillus strains did not result in any severe adverse effects in GIT and/or abnormal values of blood indices. Thus, the strain L. acidophilus 821-3 is a promising candidate for probiotic and biotechnological applications. Further studies will be performed to confirm the strain persistence and safety in a larger number of individuals.

Isolated growth hormone deficiency in a patient with immunoglobulin class switch recombination deficiency.

Growth hormone deficiency (GHD) may be associated with a number of immunodeficiency diseases, but its association with immunoglobulin class switch recombination (Ig CSR) deficiencies is very rare. We report the case of a patient with a history of recurrent diarrhea and respiratory infections diagnosed with hyper IgM syndrome on the basis of immunological findings (low serum levels of IgG and IgA and an elevated serum level of IgM). In view of the patient's short stature, growth hormone evaluation was performed and growth hormone deficiency confirmed. The patient received growth hormone therapy in addition to Ig replacement therapy and antibiotics and responded well. As the coding regions of the genes known to be responsible for Ig CSR (CD40L, CD40, AICDA, and UNG) were intact in our patient, this might be a new form of Ig CSR deficiency.

The shared CTLA4-ICOS risk locus in celiac disease, IgA deficiency and common variable immunodeficiency.

IgA deficiency (IgAD) and common variable immunodeficiency (CVID) often co-occur in families, associating with chronic inflammatory diseases such as celiac disease (CD). ICOS (inducible co-stimulator) and CTLA4 (cytotoxic T-lymphocyte-associated protein-4) may be important in both disorders, as ICOS is necessary for Ig class-switching and CTLA4 negatively regulates T-cell activation. Linkage and association of CD with CTLA4-ICOS is well documented, we thus aimed to further pinpoint CD susceptibility by haplotype-tagging analysis. We genotyped 663 CD families from Finland and Hungary, 575 additional CD patients from Finland, Hungary and Italy; 275 Swedish and Finnish IgAD individuals and 87 CVID individuals for 14-18 genetic markers in CTLA4-ICOS. Association was found between CTLA4-ICOS and both IgAD (P=0.0015) and CVID (P=0.0064). We confirmed linkage of CTLA4-ICOS with CD (LOD 2.38, P=0.0005) and found association of CTLA4-ICOS with CD (P=0.0009). Meta-analysis of the IgAD, CVID and CD materials revealed intergenic association (P=0.0005). Disease-associated markers were associated with lower ICOS and higher CTLA4 expression, indicating that the risk haplotypes contain functional variants. In summary, we identified a novel shared risk locus for IgAD, CVID and CD, the first report of association between CTLA4-ICOS and IgAD. Association between CD and CTLA4-ICOS was also confirmed in a large European data set.

Rapid subcutaneous immunoglobulin administration every second week results in high and stable serum immunoglobulin G levels in patients with primary antibody deficiencies.

Subcutaneous immunoglobulin G (SCIG) infusions as life-long replacement therapy in patients with primary antibody deficiences (PAD) is being applied increasingly. However, only a few published pharmacokinetic studies are available for this route of administration. Therefore, the pharmacokinetics of a 16% immunoglobulin G (IgG) preparation intended for subcutaneous use were investigated in patients with common variable immunodeficiency and X-linked agammaglobulinaemia. SCIG infusions (200 mg/kg body weight) were administered to 12 adult patients every 14 days for 24 weeks (total of 144 infusions). Pharmacokinetic parameters were determined based on serum IgG trough levels and antibody levels against tetanus. The median half-life of the total serum IgG and for the tetanus antibodies was 40.6 and 23.3 days respectively. Median in vivo recovery of serum IgG and tetanus immunoglobulins were 36% and 46% respectively. Median, preinfusion serum IgG trough levels per patient were high without major variations between infusions and ranged from 7.24 to 7.86 g/l. Safety, in terms of adverse events including systemic adverse reactions and local tissue reactions at infusions sites, was monitored throughout the study. Six mild, local tissue reactions were observed during the study in one patient. No systemic adverse reactions related to the study drug were observed and no serious other adverse event occurred during the study. It is concluded that the bi-weekly SCIG therapy was well tolerated in the study and that it results in high and stable serum IgG levels, offering an alternative therapy regimen to patients suffering from PAD.

Characterization of oral lactobacilli as potential probiotics for oral health.

INTRODUCTION: Intestinal lactobacilli have been successfully used as probiotics to treat gastrointestinal disorders, but only limited data are available for the probiotic properties of oral lactobacilli to combat oral diseases. We aimed to characterize oral lactobacilli for their potential probiotic properties according to the international guidelines for the evaluation of probiotics, and to select potential probiotic strains for oral health. METHODS: The study included 67 salivary and subgingival lactobacilli of 10 species, isolated from healthy humans. All strains were identified using amplified ribosomal DNA restriction analysis, tested for antimicrobial activity against oral pathogens, tolerance of low pH and bile content. Thereafter, the lysozyme tolerance and antibiotic susceptibility of 22 potential probiotic strains were assessed. RESULTS: The majority of strains suppressed the growth of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, and Streptococcus mutans, but none inhibited Candida albicans. The lowest pH tolerated by lactobacilli following 4 h of incubation was pH 2.5, but none of the strains grew at this pH. All strains tolerated a high concentration of lysozyme (10 mg/ml) and half of the strains tolerated a high concentration of human bile [5% volume/volume (V/V)]. Four Lactobacillus plantarum and two Lactobacillus oris strains expressed resistance to tetracycline and/or doxycycline. CONCLUSIONS: Strains of L. plantarum, Lactobacillus paracasei, Lactobacillus salivarius, and Lactobacillus rhamnosus expressed both high antimicrobial activity and high tolerance of environmental stress. The absence of transferable antibiotic-resistance genes in L. plantarum strains remains to be confirmed. These results suggest a potential for oral lactobacilli to be used as probiotics for oral health.

Intravenous polyclonal IgM-enriched immunoglobulin therapy in sepsis: a review of clinical efficacy in relation to microbiological aetiology and severity of sepsis.

The efficacy of intravenous polyclonal immunoglobulin (IVIG) as adjunct therapy in sepsis has long been debated. Clinical trials have yielded contradicting results, in part due to the varying study design and varying microbiological aetiologies. In most trials, the study drug has been IVIG containing polyclonal IgG. However, in recent reports, the efficacy of IgM-enriched IVIG as adjunct therapy in sepsis has been highlighted. Here we review studies on IgM-enriched IVIG therapy in sepsis and we discuss the clinical efficacy in relation to microbiological aetiology and severity of sepsis. The results suggest that patients most likely to benefit from IgM-enriched IVIG therapy are those with Gram-negative septic shock.