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Given the absence of approved treatments for pathogenic variants in Peripherin-2 (PRPH2), it is imperative to identify a universally effective therapeutic target for PRPH2 pathogenic variants. To test the hypothesis that formation of the elongated discs in presence of PRPH2 pathogenic variants is due to the presence of the full complement of rhodopsin in absence of the required amounts of functional PRPH2. Here we demonstrate the therapeutic potential of reducing rhodopsin levels in ameliorating disease phenotype in knockin models for p.Lys154del (c.458-460del) and p.Tyr141Cys (c.422 A > G) in PRPH2. Reducing rhodopsin levels improves physiological function, mitigates the severity of disc abnormalities, and decreases retinal gliosis. Additionally, intravitreal injections of a rhodopsin-specific antisense oligonucleotide successfully enhance the physiological function of photoreceptors and improves the ultrastructure of discs in mutant mice. Presented findings shows that reducing rhodopsin levels is an effective therapeutic strategy for the treatment of inherited retinal degeneration associated with PRPH2 pathogenic variants. Due to the abundance of pathogenic variants in Peripherin-2, causing peripherin-2-associated inherited retinal disorders, and the lack of any approved treatment, it is imperative to identify an effective therapeutic strategy. Here the authors show that reducing rhodopsin levels improves retinal function and structure and decreases inflammatory responses. [ABSTRACT FROM AUTHOR]

The mother-offspring relationship is paramount in most mammals and infant survival often depends on maternal investment. In species with prolonged periods of development or co-residence, mothers may continue to influence their offspring's outcomes beyond nutritional independence with benefits biased towards the philopatric sex. Chimpanzees (Pan troglodytes) are long-lived mammals with a protracted period of immaturity during which offspring continue to travel with their mothers. In contrast to most mammals, chimpanzees are also typically male philopatric. Here, we use over 50 years of demographic data from two communities in Gombe National Park, Tanzania, to examine the survival and longevity of both male and female chimpanzees that experienced maternal loss during three different age categories. Males who were orphaned between the ages of 0–4.99 years, 5–9.99 years, and 10–14.99 years all faced significantly lower survival than non-orphans and died earlier than expected. Females faced similarly reduced survival probabilities when orphaned between 0–4.99 and 5–9.99 years of age; however, females who experienced maternal loss between 10 and 14.99 years of age were no more likely to die than non-orphans. Females orphaned in this later age class also lived significantly longer beyond maternal loss than their male counterparts. As observed in other mammals, philopatric male chimpanzees may continue to benefit from their mother's ecological knowledge, whereas maternal influence on female offspring likely fades as they prepare to emigrate. These results emphasize how maternal influence on offspring outcomes can extend well beyond weaning, particularly for the philopatric sex. Significance statement: Mammalian mothers are crucial to their infant's survival and in species where offspring continue to live with their mothers after weaning, maternal influence may extend beyond dependence on mother's milk. While in most group-living mammals females remain in their natal group, chimpanzees typically display the opposite pattern with males residing alongside their mothers into adulthood. Using over 50 years of data on wild chimpanzees, we investigated the consequences of maternal loss both before and after weaning. We found that both males and females orphaned up to 10 years of age were less likely to survive than non-orphans; however, only males orphaned between 10 and 15 years also faced lower survival. These results emphasize how chimpanzee mothers continue to matter for offspring beyond infancy and provide novel data on reduced maternal influence on survival for daughters compared to sons. [ABSTRACT FROM AUTHOR]

Freshwater ecosystems are a major source of methane (CH4), contributing 0.65 Pg (in CO2 equivalents) yr−1 towards global carbon emissions and offsetting ~25% of the terrestrial carbon sink. Most freshwater CH4 emissions come from littoral sediments, where large quantities of plant material are decomposed. Climate change is predicted to shift plant community composition, and thus change the quality of inputs into detrital food webs, with the potential to affect CH4 production. Here we find that variation in phenol availability from decomposing organic matter underlies large differences in CH4 production in lake sediments. Production is at least 400-times higher from sediments composed of macrophyte litter compared to terrestrial sources because of inhibition of methanogenesis by phenol leachates. Our results now suggest that earth system models and carbon budgets should consider the effects of plant communities on sediment chemistry and ultimately CH4 emissions at a global scale. [ABSTRACT FROM AUTHOR]

Background/Objectives:Consumption of hydroxypropylmethylcellulose (HPMC), a viscous dietary fiber, lowers total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C). However, HPMC had not previously been studied in individuals receiving lipid drug therapy.Subjects/Methods:This randomized, double-blind crossover trial examined the lipid effects of HPMC in subjects with hypercholesterolemia on statin therapy. Men (n=5) and women (n=8) with LDL-C2.59 mmol/l after at least 4 weeks of stable-dose statin therapy, and a mean age of 58.6 years, were enrolled. Subjects received twice daily doses of either 2.5 g HPMC or control, delivered in a lemonade beverage for 4 weeks, then crossed over to receive the opposite treatment for an additional 4 weeks.Results:Mean baseline concentrations of TC, non-high-density lipoprotein cholesterol (non-HDL-C), LDL-C, HDL-C, triglyceride (TG), TC/HDL-C ratio and apolipoprotein (Apo) B were 4.95, 3.63, 3.03, 1.33, 1.30 and 3.89 mmol/l and 1.00 g/l, respectively. HPMC consumption resulted in significantly larger reductions (P<0.01 vs control for all) in TC (−10.9 vs −3.5%), non-HDL-C (−12.8 vs −2.9%), LDL-C (−15.7 vs −5.1%), TC/HDL-C ratio (−5.3 vs +1.3%) and Apo B (−8.7 vs −3.9%). There were no differences between treatments for changes in HDL-C (−5.2 vs −4.3%) or TG (+3.9 vs +8.9%).Conclusions:These results support the view that HPMC is an effective adjunct to statin therapy for further lowering atherogenic lipids and lipoproteins in men and women with primary hypercholesterolemia.European Journal of Clinical Nutrition (2009) 63, 1001–1007; doi:10.1038/ejcn.2009.9; published online 11 February 2009 [ABSTRACT FROM AUTHOR]

New sources of resistance to crown rust, Puccinia coronata f. sp. avenae (Eriks.), the major fungal disease of cultivated oat, Avena sativa L. (2 n = 6 x = 42), are constantly needed due to frequent, rapid shifts in the virulence pattern of the pathogen. Crown rust resistance identified in the diploid oat A. strigosa (Schreb.) (2 n = 2 x = 14) accession CI6954SP was transferred into cultivated oat using two methods: direct cross of the diploid to a hexaploid cultivar facilitated by embryo rescue, and initial cross of the diploid to a wild tetraploid oat to make a synthetic hexaploid for subsequent crossing to a hexaploid cultivar. Two tetraploids, a crown rust resistant A. murphyi (Ladiz.) accession P12 and a susceptible A. insularis (Ladiz.) accession INS-1, were used in the 2 x·4 x crosses. Resistant backcross-derived lines were recovered by both methods. Although the 2 x·4 x synthetic method did not require the laborious discovery and rescue of an infrequent initial hybrid embryo of the direct cross, the direct cross method provided more rapid backcross recovery of plants with high fertility, full transmission of resistance, and desired plant and seed phenotypes. A suppressor effect, present initially but segregating in backcrosses, appeared to come from the CI6954SP donor and is the same as, or analogous to, suppression by an oat line with the crown rust resistance gene Pc38. No resistance from A. murphyi P12 was detected in advanced generations when it was introduced either as a component of a synthetic hexaploid or in direct crosses to A. sativa, indicating suppression of its resistance in interploidy combinations. That the dominant resistance gene transferred from CI6954SP and a gene Pc94 introgressed earlier from a different A. strigosa accession may be the same or quite similar to one another is indicated by their in-common specificity to suppression of resistance expression, susceptibility to a newly recovered rust isolate, and close linkage to the molecular marker SCAR94-2. The introgressed resistance genes from the different sources, even if the same, may have different cultivar genomic introgression sites, which would allow tests of dosage effects on resistance expression. [ABSTRACT FROM AUTHOR]

It has been proposed that the development of diabetic complications may involve a depletion of cellular myo-inositol due to an increase in polyol (sorbitol) formation. We therefore initially examined the effect of diabetes on levels of these metabolites in isolated cerebral microvessels. Compared with microvessels from control rats, microvessels from diabetic animals showed no detectable alteration in myo-inositol levels and a small increase in sorbitol content. To assess whether myo-inositol depletion might occur in only certain microvascular cells, cultured bovine cerebral microvascular pericytes and endothelium were grown for 3 or 18-20 days at 1.1, 5.5, or 22.2 mmol/l glucose. Increased medium glucose concentration resulted in increased sorbitol content in both cell types after both periods of incubation ( p<0.05). In contrast, a significant decrease in myo-inositol content (22%, p<0.01) was observed only in pericytes grown for 18-20 days in the high glucose medium. Neither the adenosine 5′-triphosphate content nor the adenosine 5′-triphosphate/adenosine 5′-diphosphate (ATP/ADP) ratio of the pericytes was affected by the medium glucose concentration, indicating that the decrease in myo-inositol was not caused by a deficiency in the cellular energy state affecting the active transport of myo-inositol. These data suggest that myo-inositol depletion occurs selectively in the pericyte, a cell type known to be the site of early morphological changes in diabetes. Furthermore, the depletion apparently requires prolonged exposure to high glucose and is not due to a change in energy state. [ABSTRACT FROM AUTHOR]

A method for culturing endothelial cells (HCC-EC) from surgical specimens of human corpus cavernosum has been developed. The approach involves selective endothelial outgrowth from explants and may be generally applicable to tissue whose endothelium is not amenable to isolation by routine mechanical or enzymatic methods. The tissue is minced into pieces which are placed onto gelatin-or fibronectin-coated tissue culture plastic, and grown in medium suitable for microvascular endothelial cell growth (Carson and Haudenschild, In Vitro 22:344-354, 1986). By Days 5 to 7 EC colonies are found. Within a day or two after the appearance of the EC colonies, a non-EC cell type appears and, if undisturbed, quickly overgrows the EC. An exploitable temporal separation between the emergence of EC and non-EC is obtained when both conditioned medium (from bovine aortic endothelium) and retinal extract are present during the outgrowth period. Explants are removed by pipetting at the first sign of the emergence of the non-EC cell type. Once isolated, HCC-EC do not require conditioned medium but do require either retinal extract or acidic fibroblast growth factor for survival and growth. Approximately 60% of the first passage cultures are at least 80% EC as judged by DiI-Ac-LDL labeling. One corpus (0.3×0.3×0.5 cm) usually produces 120 cm of primary culture within 2 wk. These EC form contact-inhibited monolayers and stain positively for Factor VIII. They have a doubling time at 6th passage of 48 h and a plateau density of 5 to 7×10 cells/cm. The availability of such cultures should facilitate the study of endothelium-mediated responses which play an important role in the erectile function of human penile corpus cavernosum. [ABSTRACT FROM AUTHOR]