Molecular evolution of far-red light-acclimated photosystem II

Cyanobacteria are major contributors to global carbon fixation and primarily use visible light (400−700 nm) to drive oxygenic photosynthesis. When shifted into environments where visible light is attenuated, a small, but highly diverse and widespread number of cyanobacteria can express modified pigments and paralogous versions of photosystem subunits and phycobiliproteins that confer far-red light (FRL) absorbance (700−800 nm), a process termed far-red light photoacclimation, or FaRLiP. During FaRLiP, alternate photosystem II (PSII) subunits enable the complex to bind chlorophylls d and f, which absorb at lower energy than chlorophyll a but still support water oxidation. How the FaRLiP response arose remains poorly studied. Here, we report ancestral sequence reconstruction and structure-based molecular evolutionary studies of the FRL-specific subunits of FRL-PSII. We show that the duplications leading to the origin of two PsbA (D1) paralogs required to make chlorophyll f and to bind chlorophyll d in water-splitting FRL-PSII are likely the first to have occurred prior to the diversification of extant cyanobacteria. These duplications were followed by those leading to alternative PsbC (CP43) and PsbD (D2) subunits, occurring early during the diversification of cyanobacteria, and culminating with those leading to PsbB (CP47) and PsbH paralogs coincident with the radiation of the major groups. We show that the origin of FRL-PSII required the accumulation of a relatively small number of amino acid changes and that the ancestral FRL-PSII likely contained a chlorophyll d molecule in the electron transfer chain, two chlorophyll f molecules in the antenna subunits at equivalent positions, and three chlorophyll a molecules whose site energies were altered. The results suggest a minimal model for engineering far-red light absorbance into plant PSII for biotechnological applications

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS).

The inclusion of a chapter on pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (or PANDAS) is essential to provide a history of the disease and provide current information about its association with Streptococcus pyogenes (group A streptococci), tics, obsessive compulsive disorder (OCD) and its relationship to Sydenham chorea (SC), which is the neurologic manifestation of acute rheumatic fever. PANDAS has been misunderstood and confusing to doctors since its discovery, but the original group of the first 50 cases as described by Dr Susan Swedo (Swedo, et al., 1998) has a similarity to Sydenham chorea that distinguishes this initial group from tic and OCD cases. As this chapter will examine, the acute onset is an important feature of these disorders, as are their piano-playing choreiform movements, enuresis, night-time fears, separation anxiety, learning regression, and handwriting disabilities. The most current literature, which has been recently published in the Journal of Child and Adolescent Psychopharmacology (Murphy, et al., 2015b; Murphy, Parker-Athill, Lewin, Storch, & Mutch, 2015a; Toufexis, et al., 2015; Gerardi, Casadonte, Patel, & Murphy, 2015; Chang, et al., 2015), provides new insight into the clinical phenotype of PANDAS; namely, a subgroup of pediatric acute-onset neuropsychiatric syndrome (PANS), which has been proposed to have multiple etiologies, including those that are genetic and immunologic, and that present either with or without preceding infections, such as with Streptococcus pyogenes (Toufexis, et al., 2015). PANS is a subtype of obsessive compulsive disorder (OCD) that presents with an abrupt onset or exacerbation of neuropsychiatric symptoms (Murphy, et al., 2015b), including moderate or severe OCD. Elevated anti-streptococcal antibody titers tended to have higher OCD severity and the symptoms tended to lead to sudden and severe impairment, due to comorbidities, such as anxiety, behavioral regression, depression, and suicidality. Comorbid tics in PANS were associated with decline in school performance, visuomotor impairment, eating disorders, deterioration of handwriting skills, and lower quality of life, as compared to children without tics (Murphy, et al., 2015b). In addition, clinical evaluation of youth with PANS and PANDAS and recommendations for diagnosis were reported from the 2013 PANS conference held at Stanford University where a group of clinicians and researchers who were academicians with clinical and research interest in PANDAS and PANS (Chang, et al., 2015). PANDAS is clearly a subtype of PANS (Murphy, et al., 2015b; Murphy, Parker-Athill, Lewin, Storch, & Mutch, 2015a; Chang, et al., 2015) and not all PANS cases have an underlying streptococcal infection—but all PANDAS cases are associated with streptococcal infections, at least temporally. When these diseases appear, treatment with antibiotics can be successful, and a treatment trial of cefdinir by Murphy and colleagues indicated that therapy with cefdinir, a β lactam antibiotic, provided notable improvements in tic symptoms rated by the Yale Global Tic Severity Scale (YGTSS) and OCD symptoms rated by the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS). However, the differences within the groups as a whole were not significant. β-lactam antibiotics have been proposed to be neuroprotective above and beyond their antibiotic efficacy (Murphy, Parker-Athill, Lewin, Storch, & Mutch, 2015a). Anti-neuronal autoantibodies against the brain in SC and PANDAS react with brain antigens including dopamine receptors (Cox, et al., 2013; Brimberg, et al., 2012), lysoganglioside (Kirvan, Swedo, Heuser, & Cunningham, 2003; Kirvan, Swedo, Snider, & Cunningham, 2006a), and tubulin (Kirvan, Cox, Swedo, & Cunningham, 2007), as well as the activation of the calcium calmodulin-dependent protein kinase II (CaM KII) in human neuronal cells (Kirvan, Swedo, Heuser, & Cunningham, 2003). Human anti-brain antibodies expressed in Tg mice targeted dopaminergic neurons and signaled the dopamine D2 receptor (D2R) (Cox, et al., 2013). Evidence strongly suggests that human anti-brain autoantibodies induced by Streptococcus pyogenes infections target the dopamine receptors (Cox, et al., 2013; Brimberg, et al., 2012) and that animal models immunized with the S. pyogenes antigen develop obsessive behaviors and movement problems, along with antibodies that react with the dopamine receptors and signal the CaMKII, similar to antibodies found in humans with SC and PANDAS (Brimberg, et al., 2012; Lotan, et al., 2014a)

Highly Pathogenic Avian Influenza Virus among Wild Birds in Mongolia

Mongolia combines a near absence of domestic poultry, with an abundance of migratory waterbirds, to create an ideal location to study the epidemiology of highly pathogenic avian influenza virus (HPAIV) in a purely wild bird system. Here we present the findings of active and passive surveillance for HPAIV subtype H5N1 in Mongolia from 2005-2011, together with the results of five outbreak investigations. In total eight HPAIV outbreaks were confirmed in Mongolia during this period. Of these, one was detected during active surveillance employed by this project, three by active surveillance performed by Mongolian government agencies, and four through passive surveillance. A further three outbreaks were recorded in the neighbouring Tyva Republic of Russia on a lake that bisects the international border. No HPAIV was isolated (cultured) from 7,855 environmental fecal samples (primarily from ducks), or from 2,765 live, clinically healthy birds captured during active surveillance (primarily shelducks, geese and swans), while four HPAIVs were isolated from 141 clinically ill or dead birds located through active surveillance. Two low pathogenic avian influenza viruses (LPAIV) were cultured from ill or dead birds during active surveillance, while environmental feces and live healthy birds yielded 56 and 1 LPAIV respectively. All Mongolian outbreaks occurred in 2005 and 2006 (clade 2.2), or 2009 and 2010 (clade 2.3.2.1); all years in which spring HPAIV outbreaks were reported in Tibet and/or Qinghai provinces in China. The occurrence of outbreaks in areas deficient in domestic poultry is strong evidence that wild birds can carry HPAIV over at least moderate distances. However, failure to detect further outbreaks of clade 2.2 after June 2006, and clade 2.3.2.1 after June 2010 suggests that wild birds migrating to and from Mongolia may not be competent as indefinite reservoirs of HPAIV, or that HPAIV did not reach susceptible populations during our study.published_or_final_versio

The Effects of Governmental Protected Areas and Social Initiatives for Land Protection on the Conservation of Mexican Amphibians

Traditionally, biodiversity conservation gap analyses have been focused on governmental protected areas (PAs). However, an increasing number of social initiatives in conservation (SICs) are promoting a new perspective for analysis. SICs include all of the efforts that society implements to conserve biodiversity, such as land protection, from private reserves to community zoning plans some of which have generated community-protected areas. This is the first attempt to analyze the status of conservation in Latin America when some of these social initiatives are included. The analyses were focused on amphibians because they are one of the most threatened groups worldwide. Mexico is not an exception, where more than 60% of its amphibians are endemic. We used a niche model approach to map the potential and real geographical distribution (extracting the transformed areas) of the endemic amphibians. Based on remnant distribution, all the species have suffered some degree of loss, but 36 species have lost more than 50% of their potential distribution. For 50 micro-endemic species we could not model their potential distribution range due to the small number of records per species, therefore the analyses were performed using these records directly. We then evaluated the efficiency of the existing set of governmental protected areas and established the contribution of social initiatives (private and community) for land protection for amphibian conservation. We found that most of the species have some proportion of their potential ecological niche distribution protected, but 20% are not protected at all within governmental PAs. 73% of endemic and 26% of micro-endemic amphibians are represented within SICs. However, 30 micro-endemic species are not represented within either governmental PAs or SICs. This study shows how the role of land conservation through social initiatives is therefore becoming a crucial element for an important number of species not protected by governmental PAs

Two Major Medicinal Honeys Have Different Mechanisms of Bactericidal Activity

Honey is increasingly valued for its antibacterial activity, but knowledge regarding the mechanism of action is still incomplete. We assessed the bactericidal activity and mechanism of action of Revamil® source (RS) honey and manuka honey, the sources of two major medical-grade honeys. RS honey killed Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa within 2 hours, whereas manuka honey had such rapid activity only against B. subtilis. After 24 hours of incubation, both honeys killed all tested bacteria, including methicillin-resistant Staphylococcus aureus, but manuka honey retained activity up to higher dilutions than RS honey. Bee defensin-1 and H2O2 were the major factors involved in rapid bactericidal activity of RS honey. These factors were absent in manuka honey, but this honey contained 44-fold higher concentrations of methylglyoxal than RS honey. Methylglyoxal was a major bactericidal factor in manuka honey, but after neutralization of this compound manuka honey retained bactericidal activity due to several unknown factors. RS and manuka honey have highly distinct compositions of bactericidal factors, resulting in large differences in bactericidal activity

Search for CP violation in D+→ϕπ+ and D+s→K0Sπ+ decays

A search for CP violation in D + → ϕπ + decays is performed using data collected in 2011 by the LHCb experiment corresponding to an integrated luminosity of 1.0 fb−1 at a centre of mass energy of 7 TeV. The CP -violating asymmetry is measured to be (−0.04 ± 0.14 ± 0.14)% for candidates with K − K + mass within 20 MeV/c 2 of the ϕ meson mass. A search for a CP -violating asymmetry that varies across the ϕ mass region of the D + → K − K + π + Dalitz plot is also performed, and no evidence for CP violation is found. In addition, the CP asymmetry in the D+s→K0Sπ+ decay is measured to be (0.61 ± 0.83 ± 0.14)%

Pig-to-Nonhuman Primates Pancreatic Islet Xenotransplantation: An Overview

The therapy of type 1 diabetes is an open challenging problem. The restoration of normoglycemia and insulin independence in immunosuppressed type 1 diabetic recipients of islet allotransplantation has shown the potential of a cell-based diabetes therapy. Even if successful, this approach poses a problem of scarce tissue supply. Xenotransplantation can be the answer to this limited donor availability and, among possible candidate tissues for xenotransplantation, porcine islets are the closest to a future clinical application. Xenotransplantation, with pigs as donors, offers the possibility of using healthy, living, and genetically modified islets from pathogen-free animals available in unlimited number of islets. Several studies in the pig-to-nonhuman primate model demonstrated the feasibility of successful preclinical islet xenotransplantation and have provided insights into the critical events and possible mechanisms of immune recognition and rejection of xenogeneic islet grafts. Particularly promising results in the achievement of prolonged insulin independence were obtained with newly developed, genetically modified pigs islets able to produce immunoregulatory products, using different implantation sites, and new immunotherapeutic strategies. Nonetheless, further efforts are needed to generate additional safety and efficacy data in nonhuman primate models to safely translate these findings into the clinic

Boolean analysis reveals systematic interactions among low-abundance species in the human gut microbiome

The analysis of microbiome compositions in the human gut has gained increasing interest due to the broader availability of data and functional databases and substantial progress in data analysis methods, but also due to the high relevance of the microbiome in human health and disease. While most analyses infer interactions among highly abundant species, the large number of low-abundance species has received less attention. Here we present a novel analysis method based on Boolean operations applied to microbial co-occurrence patterns. We calibrate our approach with simulated data based on a dynamical Boolean network model from which we interpret the statistics of attractor states as a theoretical proxy for microbiome composition. We show that for given fractions of synergistic and competitive interactions in the model our Boolean abundance analysis can reliably detect these interactions. Analyzing a novel data set of 822 microbiome compositions of the human gut, we find a large number of highly significant synergistic interactions among these low-abundance species, forming a connected network, and a few isolated competitive interactions

CLEC5A Regulates Japanese Encephalitis Virus-Induced Neuroinflammation and Lethality

CLEC5A/MDL-1, a member of the myeloid C-type lectin family expressed on macrophages and neutrophils, is critical for dengue virus (DV)-induced hemorrhagic fever and shock syndrome in Stat1−/− mice and ConA-treated wild type mice. However, whether CLEC5A is involved in the pathogenesis of viral encephalitis has not yet been investigated. To investigate the role of CLEC5A to regulate JEV-induced neuroinflammation, antagonistic anti-CLEC5A mAb and CLEC5A-deficient mice were generated. We find that Japanese encephalitis virus (JEV) directly interacts with CLEC5A and induces DAP12 phosphorylation in macrophages. In addition, JEV activates macrophages to secrete proinflammatory cytokines and chemokines, which are dramatically reduced in JEV-infected Clec5a−/− macrophages. Although blockade of CLEC5A cannot inhibit JEV infection of neurons and astrocytes, anti-CLEC5A mAb inhibits JEV-induced proinflammatory cytokine release from microglia and prevents bystander damage to neuronal cells. Moreover, JEV causes blood-brain barrier (BBB) disintegrity and lethality in STAT1-deficient (Stat1−/−) mice, whereas peripheral administration of anti-CLEC5A mAb reduces infiltration of virus-harboring leukocytes into the central nervous system (CNS), restores BBB integrity, attenuates neuroinflammation, and protects mice from JEV-induced lethality. Moreover, all surviving mice develop protective humoral and cellular immunity against JEV infection. These observations demonstrate the critical role of CLEC5A in the pathogenesis of Japanese encephalitis, and identify CLEC5A as a target for the development of new treatments to reduce virus-induced brain damage