Wetness severity increases abrupt shifts in ecosystem functioning in arid savannas.

The accelerating pace of climate change has led to unprecedented shifts in surface temperature and precipitation patterns worldwide, with African savannas being among the most vulnerable regions. Understanding the impacts of these extreme changes on ecosystem health, functioning and stability is crucial. This paper focuses on the detection of breakpoints, indicative of shifts in ecosystem functioning, while also determining relevant ecosystem characteristics and climatic drivers that increase susceptibility to these shifts within the semi-arid to arid savanna biome. Utilising a remote sensing change detection approach and rain use efficiency (RaUE) as a proxy for ecosystem functioning, spatial and temporal patterns of breakpoints in the savanna biome were identified. We then employed a novel combination of survival analysis and remote sensing time series analysis to compare ecosystem characteristics and climatic drivers in areas experiencing breakpoints versus areas with stable ecosystem functioning. Key ecosystem factors increasing savanna breakpoint susceptibility were identified, namely higher soil sand content, flatter terrain and a cooler long-term mean temperature during the wet summer season. Moreover, the primary driver of changes in ecosystem functioning in arid savannas, as opposed to wetter tropical savannas, was found to be the increased frequency and severity of rainfall events, rather than drought pressures. This research highlights the importance of incorporating wetness severity metrics alongside drought metrics to comprehensively understand climate-ecosystem interactions leading to abrupt shifts in ecosystem functioning in arid biomes. The findings also emphasise the need to consider the underlying ecosystem characteristics, including soil, topography and vegetation composition, in assessing ecosystem responses to climate change. While this research primarily concentrated on the southern African savanna as a case study, the methodological robustness of this approach enables its application to diverse arid and semi-arid biomes for the assessment of climate-ecosystem interactions that contribute to abrupt shifts.

Dynamic free energy surfaces for sodium diffusion in type II silicon clathrates.

Earth abundant semiconducting type II Si clathrates have attracted attention as photovoltaic materials due to their wide band gaps. To realize the semiconducting properties of these materials, guest species that arise during the synthesis process must be completely evacuated from the host cage structure post synthesis. A common guest species utilized in the synthesis of Si clathrates is Na (metal), which templates the clathrate cage formation. Previous experimental investigations have identified that it is possible to evacuate Na from type II clathrates to an occupancy of less than 1 Na per unit cell. This work investigates the energetics, kinetics, and resulting mechanism of Na diffusion through type II Si clathrates by means of biased molecular dynamics and kinetic Monte Carlo simulations. Well-tempered metadynamics has been used to determine the potential of mean force for Na moving between clathrate cages, from which the thermodynamic preferences and transition barrier heights have been obtained. Kinetic Monte Carlo simulations based on the metadynamics results have identified the mechanism of Na diffusion in type II Si clathrates. The overall mechanism consists of a coupled diffusive process linked via electrostatic guest-guest interactions. The large occupied hexakaidechedral cages initially empty their Na guests to adjacent empty large cages, thereby changing the local electrostatic environment around the occupied small pentagonal dodecahedral cages and increasing the probability of Na guests to leave the small cages. This coupled process continues through the cross-over point that is identified as the point where large and small cages are equally occupied by Na guests. Further Na removal results in the majority of guests residing in the large cages as opposed to the small cages, in agreement with experiments, and ultimately a Na free structure.

Direct retroviral delivery of human cytochrome P450 2B6 for gene-directed enzyme prodrug therapy of cancer.

Human cytochrome P450 2B6 (CYP2B6) metabolizes the prodrug cyclophosphamide (CPA) to produce phosphoramide mustard that cross-links DNA leading to cell death. We have constructed a novel retroviral vector encoding CYP2B6 (designated "MetXia-P450") and used it to transduce the human tumor cell lines HT29 and T47D. MetXia-P450 transduction sensitised these cells to the cytotoxic effects of the prodrug CPA. Results from in vitro experiments demonstrated adverse effects on the clonogenic survival of cyclophosphamide-treated cells transduced with MetXia-P450. Cytotoxic activity accompanied by bystander effect was particularly evident in 3-D multicellular spheroid models suggesting that this in vitro system may be a more appropriate model for assessing the efficacy of gene directed-enzyme prodrug therapy (GDEPT). We have applied this approach in a clinically relevant gene therapy protocol on established subcutaneous tumor xenografts. These studies show for the first time the efficacy of a P450-based GDEPT strategy mediated by a direct retroviral gene transfer in vivo.

Analysis of 4070A envelope levels in retroviral preparations and effect on target cell transduction efficiency.

A number of stable producer cell lines for high-titer Mo-MuLV vectors have been constructed. Development has previously centered on increasing end-point titers by producing maximal levels of Mo-MuLV Gag/Pol, envelope glycoproteins, and retroviral RNA genomes. We describe the production yields and transduction efficiency characteristics of two Mo-MuLV packaging cell lines, FLYA13 and TEFLYA. Although they both produce 4070A-pseudotyped retroviral vectors reproducibly at >1 x 10(6) LFU ml(-1), the transduction efficiency of unconcentrated and concentrated virus from FLYA13 lines is poor compared with vector preparations from TEFLYA lines. A powerful inhibitor of retroviral transduction is secreted by FLYA13 packaging cells. We show that the inhibitory factor does not affect transduction of target cells by RD114-pseudotyped vectors. This suggests that the inhibitory factor functions at the level of envelope-receptor interactions. Phosphate starvation of target cells shows a two-fold increase in Pit2 receptor mRNA and causes some improvement in FLYA13 virus transduction efficiency. Western blots show that FLYA13 viral samples contain an eight-fold higher ratio of 4070A envelope to p30gag than that of virus produced by TEFLYA producer cell lines. This study correlates overexpression of 4070A envelope glycoprotein in retroviral preparations with a reduction of transduction efficiency at high multiplicities of infection. We suggest that TEFLYA packaging cells express preferable levels of 4070A compared with FLYA13, which not only enables high-titer stocks to be generated, but also facilitates a high efficiency of transduction of target cells.

Survey of Turkish systemic lupus erythematosus patients for a particular mutation of C1Q deficiency.

OBJECTIVE: Hereditary C1q deficiency is a rare disease and up to now only 41 cases have been reported. Since all but 3 cases developed SLE or SLE-like disease, C1q deficiency represents the most powerful disease susceptibility gene identified for the development of SLE in humans. A molecular defect in homozygous C1q deficiency has been identified in 13 families. Four of these families are Turkish in origin and they all share the same mutation which is a CAG to TAG change at codon 186 in the A chain. This led us to investigate whether this mutation might be found in Turkish SLE patients and whether it could cause increased disease susceptibility when expressed in the heterozygous form. METHODS: We screened 65 Turkish lupus patients and 49 healthy Turkish individuals by carrying out an amplification of exon 2 of the A chain and restriction enzyme analysis for the C1qA mutation. RESULTS: We found no other example of this mutation in either the homozygous or heterozygous forms. CONCLUSION: C1q deficiency is one of the very strong disease susceptibility genes in lupus and may cause SLE via a critical role in the physiological clearance of apoptotic cells. However, C1q deficiency caused by a particular mutation in the A chain in a heterozygous form is not found in the Turkish SLE population.

Identification of intervals on chromosomes 1, 3, and 13 linked to the development of lupus in BXSB mice.

OBJECTIVE: To identify intervals containing systemic lupus erythematosus (SLE) susceptibility alleles in the BXSB strain of mice. METHODS: We analyzed 286 (B10 x [B10 x BXSB]F1) backcross mice for a range of phenotypic traits associated with the development of SLE in BXSB mice. The mice were genotyped using 93 microsatellite markers, and the linkage of these markers to disease was studied by extreme-phenotype and quantitative trait locus analysis. RESULTS: The disease phenotype in these backcross mice was less severe than that in BXSB mice. However, antinuclear antibody production was increased compared with the parental strain. We identified 4 areas of genetic linkage to disease on chromosome 1 (Bxs1-4), 1 on chromosome 3 (Bxs5), and another interval on chromosome 13 which were associated with various aspects of the phenotype. Bxs4 and Bxs5 are located in regions not previously linked to disease in other models of SLE. CONCLUSION: SLE in the BXSB mouse model has a complex genetic basis and involves at least 5 distinct intervals located on chromosomes 1 and 3. There is evidence that different intervals affect particular aspects of the SLE phenotype.

Multiple lupus susceptibility loci map to chromosome 1 in BXSB mice.

BXSB mice spontaneously develop a lupus-like syndrome that is accelerated by the Yaa gene (Y-linked autoimmune accelerator). We studied the phenotype of disease in (B10 x BXSB)F1 and (BXSB x (B10 x BXSB)F1) backcross mice and genotyped 224 backcross animals to allow a microsatellite-based genome-wide linkage analysis to be conducted. In the backcross population, three intervals on chromosome 1 showed significant linkage to disease, suggesting that multiple loci contribute to the production of autoimmune disease. D1Mit5 at 32.8 cM was linked to development of nephritis (chi(2) = 15.68, p = 7.5 x 10(-5)), as was D1Mit12 at 63.1 cM (chi(2) = 20.17, p = 7.1 x 10(-6)). D1Mit403 at 100 cM was linked to anti-dsDNA Ab production (chi(2) = 17.28, p = 3.2 x 10(-5)). Suggestive linkages to antinuclear Abs and nephritis were identified on chromosome 3, to splenomegaly on chromosome 4, and to anti-ssDNA Ab production on chromosome 10. Chromosome 4 and the telomeric region of chromosome 1 have previously been linked to disease in other mouse models of systemic lupus erythematosus; however, the centromeric regions of chromosome 1 and chromosomes 3 and 10 are unique to BXSB. This implies that, though some loci may be common to a number of mouse models of lupus, different clusters of disease genes confer disease susceptibility in different strains of mice.

Choroidal neovascular membrane after laser-induced chorioretinal anastomosis.

PURPOSE: To treat a patient who had a choroidal neovascular membrane after laser-induced chorioretinal anastomosis for nonischemic central retinal vein occlusion. METHODS: A 70-year-old man underwent successful formation of a chorioretinal anastomosis for nonischemic central retinal vein occlusion. He subsequently developed a choroidal neovascular membrane at the site of the chorioretinal anastomosis. RESULTS: The choroidal neovascular membrane at the site of the chorioretinal anastomosis was treated successfully with argon laser photocoagulation. The anastomosis remained functional. CONCLUSION: We recommend that patients who have undergone laser-induced chorioretinal anastomosis for nonischemic central retinal vein occlusion be followed up closely for choroidal neovascular membrane formation.

Molecular basis of hereditary C1q deficiency associated with SLE and IgA nephropathy in a Turkish family.

Two siblings (case 1 and case 2) with homozygous C1q deficiency are described. Both presented with a photosensitive rash, and during follow-up case one developed SLE with nephrotic range proteinuria. Case 2 had microscopic hematuria with a past history of macroscopic hematuria. Renal biopsies revealed mesangioproliferative glomerulonephritis in case 1 and IgA nephropathy in case 2, a new finding in association with C1q deficiency. Since the classical pathway of complement plays a role in the development of antibody responses, the family was also evaluated for the immune response to hepatitis B vaccine. Antibody response to hepatitis B vaccine was normal in both affected members and the rest of the family. The A-, B- and C- chain genes of C1q were amplified by PCR and directly sequenced. A homozygous C to T point mutation was identified in genomic DNA isolated from the patients at codon 186 in the A chain that resulted in a premature stop codon. This mutation was present in both parents and both unaffected sibs in the heterozygous state. This mutation was identical to that previously described in a Slovakian family with C1q deficiency. Because of this finding, a series of 92 genomic DNA samples was screened from ethnically distinct patient groups with SLE to test the hypothesis that this mutation of C1q may be a widespread disease susceptibility gene. No further examples of this mutation were found.

Homozygous hereditary C1q deficiency and systemic lupus erythematosus. A new family and the molecular basis of C1q deficiency in three families.

OBJECTIVE: To describe a new kindred with Clq deficiency and to identify the molecular lesions responsible for complete functional C1q deficiency in this and 2 other previously described kindreds. METHODS: The A-, B-, and C-chain genes of C1q were amplified by polymerase chain reaction, cloned, and sequenced. The DNA sequence was checked for mutations. RESULT: Patient 1 had a homozygous G-to-A change at codon 6 of the C chain, causing an amino acid change from Gly to Arg. Patient 2 had a homozygous deletion of a C nucleotide at codon 43 of the C-chain, causing a frame shift, leading to a premature stop codon at codon 108. Patient 3 had a homozygous C-to-T mutation at amino acid position 41 of the C chain, resulting in a premature stop codon. CONCLUSION: In the homozygous state, the mutations are sufficient to cause complete deficiency of Clq. The mutation in patient 1 has been previously reported in a patient of different ethnic origin. A survey of a series of 158 DNA samples from patients with systemic lupus erythematosus showed no other examples of this mutant allele.

Empathic joy and the empathy-altruism hypothesis.

Three experiments tested whether empathy evokes egoistic motivation to share vicariously in the victim's joy at improvement (the empathic-joy hypothesis) instead of altruistic motivation to increase the victim's welfare (the empathy-altruism hypothesis). In Experiment 1, Ss induced to feel either low or high empathy for a young woman in need were given a chance to help her. Some believed that if they helped they would receive feedback about her improvement; others did not. In Experiments 2 and 3, Ss induced to feel either low or high empathy were given a choice of getting update information about a needy person's condition. Before choosing, they were told the likelihood of the person's condition having improved--and of their experiencing empathic joy--was 20%, was 50%, or was 80%. Results of none of the experiments patterned as predicted by the empathic-joy hypothesis; instead, results of each were consistent with the empathy-altruism hypothesis.

Effect of blunt trauma on the corneal endothelium.

Specular microscopy of central corneal endothelium was performed on 26 patients with a history of blunt uniocular trauma with hyphema. Compared with the uninjured fellow eye, the injured eye had a mean decrease in endothelial cell density (ECD) of 6.4%. In 12 patients with angle recession, the decrease in ECD was 12.2%, compared with 14 patients without angle recession with a decrease in ECD of 1.2%. In five patients with greater than 180 degrees of angle recession, the mean decrease in ECD was 21.2%. No significant decrease in ECD was noted to be associated with size of hyphema, iridodialysis, vitreoretinal abnormalities, or transiently increased intraocular pressure.

Separation and quantitation of some urinary arylalkylamines.

The arylalkylamines m- and p-tyramine, beta-phenylethylamine and tryptamine in their unconjugated forms have been identified and quantitated in urine collected from human volunteers. Their excretion levels (mean+/-standard error of the mean in mug/g creatinine) were, respectively, 67 +/- 5, 419 +/- 37, 4.6 +/- 1.2, and 82 +/- 11.