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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]

Highly differentiated and affiliative social relationships are observed in a variety of mammals, including primates, cetaceans, and social carnivores. Although there has been a transformation in our understanding of the form and function of social bonds in the past two decades, the role of early life social experiences in the development of bonds remains less clear. Few studies have examined whether social relationships during infancy and juvenility (aside from those between mothers and offspring) persist into adulthood. In this study, we used longitudinal data on wild chimpanzees (Pan troglodytes schweinfurthii) at Gombe National Park, Tanzania, to investigate the effects of party-level association during infancy and juvenility (hereafter immaturity) on affiliative relationships among adult males (the philopatric sex). In total, we examined behavioral data from focal follows between 1970 and 2015 (N = 23 adult males). We used maternal associations as proxies for the associations of immature males, and we measured adult male social relationships using party-level associations and grooming activity. We found that immature males that associated with individual adult males at higher rates had stronger relationships with those same adult males later in life. By contrast, rates of association between pairs of immature males did not predict the strength of their dyadic relationships as adults. Overall, these findings emphasize the importance of early socialization in male chimpanzee social development. These results also reinforce studies in mountain gorillas (Gorilla beringei) and bottlenose dolphins (Tursiops sp.), suggesting that the persistence of social relationships that do not involve the mother may be more likely to evolve in long-lived species where young adult males face challenges entering an adult hierarchy composed of stronger and/or more socially experienced competitors. [ABSTRACT FROM AUTHOR]

Key message: High-density haplotype analysis revealed significant haplotype sharing between ex-PVPs registered from 1976 to 1992 and key maize founders, and uncovered similarities and differences in haplotype sharing patterns by company and heterotic group. Proprietary inbreds developed by the private seed industry have been the major source for driving genetic gain in successful North American maize hybrids for decades. Much of the history of industry germplasm can be traced back to key founder lines, some of which were pivotal in the development of prominent heterotic groups. Previous studies have summarized pedigree-based relationships, genetic diversity and population structure among commercial inbreds with expired Plant Variety Protection (ex-PVP). However, less is known about the extent of haplotype sharing between historical founders and ex-PVPs. A better understanding of the relationships between founders and ex-PVPs provides insight into the haplotype and heterotic group structure among industry germplasm. We performed high-density haplotype analysis with 11.3 million SNPs on 212 maize inbreds, which included 157 ex-PVPs registered 1976–1992 and 55 public lines relevant to PVPs. Among these lines were 12 key founders identified in literature review: 207, A632, B14, B37, B73, LH123HT, LH82, Mo17, Oh43, OH7, PHG39 and Wf9. Our results revealed that, on average, 81.6% of an ex-PVP's genome is shared with at least 1 of these 12 founder lines and more than half when limited to B73, Mo17 and 207. Quantifiable similarities and contrasts among heterotic groups and major US seed industry companies were also observed. The results from this study provide high-resolution haplotype data on ex-PVP germplasm, confirm founder relationship trends observed in previous studies, uncover region-specific haplotype structure differences and demonstrate how haplotype sharing analysis can be used as a tool to explore germplasm diversity. [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]

Timeseries of observed and projected sea level changes for the 20th and 21st century are analyzed at various coastal locations around the world that are vulnerable to climate change. Observed time series are from tide gauges and altimetry, as well as from reconstructions over the last 50 years. CMIP5 coupled atmosphere-ocean model output of regional sea-level and associated uncertainty estimates are merged with scenario-independent contributions from GIA and dynamic ice to provide time series of coastal sea-level projections to the end of the 21st century. We focus on better quantifying the regional departure of coastal sea level rise from its global average, identify the reasons for the regional departure, and quantify the reasons for the uncertainty in these regional projections. Many of these coastal sea level projections are lower than the global mean change in sea level due to glacial isostatic adjustment, and gravitational changes from loss of land ice and terrestrially stored ground water. In most coastal regions, local deviations from the global mean vary up to ±20 cm which, depending on the location, differ substantially in their underlying causes. [ABSTRACT FROM AUTHOR]

Circuit mapping requires knowledge of both structural and functional connectivity between cells. Although optical tools have been made to assess either the morphology and projections of neurons or their activity and functional connections, few probes integrate this information. We have generated a family of photoactivatable genetically encoded Ca2+ indicators that combines attributes of high-contrast photolabeling with high-sensitivity Ca2+ detection in a single-color protein sensor. We demonstrated in cultured neurons and in fruit fly and zebrafish larvae how single cells could be selected out of dense populations for visualization of morphology and high signal-to-noise measurements of activity, synaptic transmission and connectivity. Our design strategy is transferrable to other sensors based on circularly permutated GFP (cpGFP). [ABSTRACT FROM AUTHOR]

We present regional sea-level projections and associated uncertainty estimates for the end of the 21 century. We show regional projections of sea-level change resulting from changing ocean circulation, increased heat uptake and atmospheric pressure in CMIP5 climate models. These are combined with model- and observation-based regional contributions of land ice, groundwater depletion and glacial isostatic adjustment, including gravitational effects due to mass redistribution. A moderate and a warmer climate change scenario are considered, yielding a global mean sea-level rise of 0.54 ±0.19 m and 0.71 ±0.28 m respectively (mean ±1 σ). Regionally however, changes reach up to 30 % higher in coastal regions along the North Atlantic Ocean and along the Antarctic Circumpolar Current, and up to 20 % higher in the subtropical and equatorial regions, confirming patterns found in previous studies. Only 50 % of the global mean value is projected for the subpolar North Atlantic Ocean, the Arctic Ocean and off the western Antarctic coast. Uncertainty estimates for each component demonstrate that the land ice contribution dominates the total uncertainty. [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]

Establishing the order of a dominance hierarchy among female chimpanzees ( Pan troglodytes) is complicated by the fact that they often forage solitarily, and aggressive interactions between them occur infrequently. Authors of previous studies have typically ranked females via the direction of submissive pant-grunts and the outcome of agonistic interactions. Given that higher rank correlates with higher reproductive success in female chimpanzees, assessing rank is important but may be limited by sparsely populated dominance matrices. I tested the hypothesis that rank predicts the direction of female approaches. There is a significant relationship among Gombe females between the frequency with which a female was approached and her dominance rank. Dominant females approached other females less often than they were approached. Though approached frequencies failed to meet the criteria for formal rank indicators, they may be useful as real indicators of subordination. Because approach interactions occur far more frequently than pant-grunts, they may be useful in assigning categorical rank when traditional dominance metrics are limited. [ABSTRACT FROM AUTHOR]

Researchers have reported a total of 31 infanticides in 4 different chimpanzee (Pan troglodytes) populations. Though infanticide is infrequent, low reproductive rates of females likely make it a strong selective pressure in the species. We report a new incident of intragroup infanticide in Gombe National Park, Tanzania, in which a community male attacked a 3.5-yr-old male. We then consider the infanticide in terms of adaptive and nonadaptive explanations for infanticide including the social pathology, by-product of male aggression, nutritive benefits, resource competition, and sexual selection hypotheses. The incident reported here is not well explained by any of them. While the infanticide is puzzling in terms of ultimate explanations for infanticide, it provides a good context in which to consider proximate mechanisms for offspring recognition. The incident provides some evidence that males may use their mating history with the mother to assess paternity likelihood. [ABSTRACT FROM AUTHOR]

Voltage-sensitive calcium channels (VSCC) open in response to external stimuli, including calcitropic hormones, that alter plasma membrane calcium (Ca2+) permeability. Ca2+ that enters the cell through these channels serves a second messenger function, eliciting cellular responses that include secretion and changes in gene expression. In osteoblasts, VSCCs serve as key regulators of Ca2+ permeability and are a major class of calcitropic hormone-sensitive Ca2+ channels present in the plasma membrane. The members of the VSCC family exist as a complex of polypeptide subunits that are comprised of a pore-forming α1 subunit, an intracellular β subunit, a dimer of disulfide-linked α2 and δ subunits, and in some tissues, a γ subunit. Previous studies in our laboratory have shown that the major functional α1 subunit present in osteoblasts is the α1C (CaV1.2). To determine the complement of auxiliary subunits present in rodent osteoblastic cells, we employed RT-PCR using a battery of subunit specific primers and appropriate tissue controls. Immunohistochemistry also was performed, using available subunit specific antibodies, to measure protein expression and localization. Cell types examined included MC3T3-E1 at various stages of differentiation, ROS 17/2.8 osteosarcoma, and primary cultures of rat calvarial osteoblasts. The results indicate that all cells expressed multiple β subunit classes and α2δ dimers, but no γ subunits, regardless of differentiation state. We propose a structure for the functional osteoblast VSCC that consists of α1, β, α2δ subunits and is devoid of a γ subunit. [ABSTRACT FROM AUTHOR]

Studies to assess osteopontin (OPN) localization in adult human bone using immunochemical techniques produce conflicting results due to variations in tissue processing or antibody immunoreactivity. The present study was designed to resolve these discrepancies using well-characterized antibodies and improved antigen detection. An anti-osteopontin (alpha-OPN) antiserum was developed that recognizes various soluble molecular weight forms of human OPN, including monomeric, cleaved, and dimerized products. An affinity column of full length recombinant human OPN (rOPN) coupled to support was used to purify alpha-OPN antibodies. Western analysis showed that the affinity-purified antibodies recognized numerous molecular weight forms of OPN. These antibodies were used to study the distribution of OPN in adult human bone using immunohistochemical techniques combined with an antigen retrieval protocol utilizing a newly developed antigen retrieval solution, Retriev-Alltrade mark (Bronco Technologies Inc, Pasadena, TX). Immunolocalization of OPN in archival bone specimens prior to antigen retrieval produced no demonstrable immunostaining even at high concentrations of alpha-OPN. Use of the antigen retrieval protocol restored OPN immunoreactivity, with strong staining apparent in cement lines, osteoblasts, osteocytes, canaliculi, osteoid, and bone matrix. We conclude that antigen retrieval restores immunochemical recognition of OPN in archival specimens containing bone without increasing nonspecific binding. [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]

Genetic improvement in plantation forestry relies significantly on conventional breeding techniques which have been used extensively to improve various characteristics in forest trees such as growth and form, volume yield, resistance to pathogens and quality of the end product. This review concentrates on molecular techniques which have been used successfully in agriculture and which have more recently become available to improve further characteristics of forest trees and introduce new traits which are currently not available in the breeding population. [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]