The long-term integrity of an articulating joint is dependent upon the nourishment of its cartilage component and the protection of the cartilage surface from friction-induced wear. Loss-of-function ...mutations in lubricin (a secreted glycoprotein encoded by the gene PRG4) cause the human autosomal recessive disorder camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP). A major feature of CACP is precocious joint failure. In order to delineate the mechanism by which lubricin protects joints, we studied the expression of Prg4 mRNA during mouse joint development, and we created lubricin-mutant mice. Prg4 began to be expressed in surface chondrocytes and synoviocytes after joint cavitation had occurred and remained strongly expressed by these cells postnatally. Mice lacking lubricin were viable and fertile. In the newborn period, their joints appeared normal. As the mice aged, we observed abnormal protein deposits on the cartilage surface and disappearance of underlying superficial zone chondrocytes. In addition to cartilage surface changes and subsequent cartilage deterioration, intimal cells in the synovium surrounding the joint space became hyperplastic, which further contributed to joint failure. Purified or recombinant lubricin inhibited the growth of these synoviocytes in vitro. Tendon and tendon sheath involvement was present in the ankle joints, where morphologic changes and abnormal calcification of these structures were observed. We conclude that lubricin has multiple functions in articulating joints and tendons that include the protection of surfaces and the control of synovial cell growth.
Abstract
Open Targets Genetics (https://genetics.opentargets.org) is an open-access integrative resource that aggregates human GWAS and functional genomics data including gene expression, protein ...abundance, chromatin interaction and conformation data from a wide range of cell types and tissues to make robust connections between GWAS-associated loci, variants and likely causal genes. This enables systematic identification and prioritisation of likely causal variants and genes across all published trait-associated loci. In this paper, we describe the public resources we aggregate, the technology and analyses we use, and the functionality that the portal offers. Open Targets Genetics can be searched by variant, gene or study/phenotype. It offers tools that enable users to prioritise causal variants and genes at disease-associated loci and access systematic cross-disease and disease-molecular trait colocalization analysis across 92 cell types and tissues including the eQTL Catalogue. Data visualizations such as Manhattan-like plots, regional plots, credible sets overlap between studies and PheWAS plots enable users to explore GWAS signals in depth. The integrated data is made available through the web portal, for bulk download and via a GraphQL API, and the software is open source. Applications of this integrated data include identification of novel targets for drug discovery and drug repurposing.
Martian meteorite Northwest Africa (NWA) 8114 – a paired stone to NWA 7034 – provides an opportunity to examine the thermal history of a martian regolith and study near-surface processes and ancient ...environmental conditions near an impact crater on Mars. Our study reports petrographic and alteration textures and focuses on pyroxene and iron oxide grains. Some of the pyroxene clasts show exsolution lamellae, indicating a high temperature magmatic origin and slow cooling. However, transmission electron microscopy reveals that other predominantly pyroxene clasts are porous and have partially re-crystallised to form magnetite and a K-bearing feldspathic glassy material, together with relict pyroxene. This breakdown event was associated with oxidation, with up to 25% Fe3+/ΣFe in the relict pyroxene measured using Fe-K XANES. By comparison with previous studies, this breakdown and oxidation of pyroxene is most likely to be a result of impact shock heating, being held at a temperature above 700 °C for at least 7 days in an oxidising regolith environment.
We report an approximate 40Ar-39Ar maximum age of 1.13–1.25 Ga for an individual, separated, augite clast. The disturbed nature of the spectra precludes precise age determination. In section, this clast is porous and contains iron oxide grains. This shows that it has undergone the high temperature partial breakdown seen in other relict pyroxene clasts, and has up to 25% Fe3+/ΣFe. We infer that the age corresponds to the impact shock heating event that led to the high temperature breakdown of many of the pyroxenes, after consolidation of the impact ejecta blanket.
High temperatures, above 700 °C, may have been maintained for long enough to remobilise and congruently partially melt some of the alkali feldspar clasts to produce the feldspar veins and aureoles that crosscut, and in some cases surround, the oxidised pyroxene. However, the veins could alternatively be the result of a hydrothermal event in the impact regolith. A simple Fourier cooling model suggests that a regolith of at least five metres depth would be sufficient to maintain temperatures associated with the pyroxene breakdown for over seven days.
Low temperature hydrous alteration took place forming goethite, identified via XRD, XANES and FTIR. Comparing with previous studies, the goethite is likely to be terrestrial alteration pseudomorphing martian pyrite.
Reductions in AIDS-related morbidity and mortality following the advent of combination antiretroviral therapy have coincided with relative increases in chronic non-AIDS end-organ diseases among HIV+ ...patients.
To examine the association of latest CD4+ counts with risk of non-AIDS diseases in a cohort of 1397 patients who initiate antiretroviral therapy.
CD4+ counts and HIV RNA levels along with fatal, and non-fatal, AIDS and non-AIDS diseases (liver, cardiovascular, renal, and cancer) were assessed over a median follow-up of 5 years. Cox proportional regression models were used to study risk associations.
A total of 227 patients experienced an AIDS event and 80 patients developed a non-AIDS disease event. Both AIDS and non-AIDS diseases rates (events/100 person-years), respectively, declined with higher latest CD4+ counts: 13.8 and 2.1 with latest CD4+ counts less than 200 cells/microl; 2.0 and 1.7 for counts of 200-350 cells/microl; and 0.7 and 0.7 for counts greater than 350 cells/microl. After adjusting for baseline covariates and the latest HIV RNA level, risk of AIDS and non-AIDS diseases were lowered by 44% (95% confidence interval for hazard ratio 0.50-0.62, P < 0.01) and 14% (95% confidence interval for hazard ratio 0.77-0.96, P = 0.01), respectively, for each 100 cell/microl higher latest CD4+ count.
Higher CD4+ counts on antiretroviral therapy are associated with lower rates of non-AIDS diseases and AIDS. These findings expand our understanding of the implications of HIV-related immunodeficiency and motivate randomized studies to evaluate the effects of antiretroviral therapy on a broad set of clinical outcomes at CD4+ counts greater than 350 cells/microl.
Examining complete gene knockouts within a viable organism can inform on gene function. We sequenced the exomes of 3222 British adults of Pakistani heritage with high parental relatedness, ...discovering 1111 rare-variant homozygous genotypes with predicted loss of function (knockouts) in 781 genes. We observed 13.7% fewer homozygous knockout genotypes than we expected, implying an average load of 1.6 recessive-lethal-equivalent loss-of-function (LOF) variants per adult. When genetic data were linked to the individuals' lifelong health records, we observed no significant relationship between gene knockouts and clinical consultation or prescription rate. In this data set, we identified a healthy PRDM9-knockout mother and performed phased genome sequencing on her, her child, and control individuals. Our results show that meiotic recombination sites are localized away from PRDM9-dependent hotspots. Thus, natural LOF variants inform on essential genetic loci and demonstrate PRDM9 redundancy in humans.
Low CD4+ increases risk for both AIDS- and non-AIDS-related morbidity and mortality. The magnitude of CD4+ recovery early after initial antiretroviral therapy (ART) is important in the ultimate ...duration of immune depletion.
We examined CD4+ recovery among 850 participants in the Community Program for Clinical Research on AIDS Flexible Initial Retrovirus Suppressive Therapies study with virologic suppression (ie, achieved an HIV RNA level <400 copies/mL) with 8 months of initial ART and determined subsequent risk for AIDS, non-AIDS diseases (non-AIDS cancers and cardiovascular, end-stage renal, and liver diseases), or death using Cox regression during a median 5-year follow-up.
Mean pretreatment CD4+ was 221 cells/microL; 18% (n = 149) had a poor CD4+ recovery (<50 cells/microL) after 8 months of effective ART, resulting in lower CD4+ over 5 years. Older age (hazard ratio 1.34/10 yrs, P = 0.003) and lower screening HIV RNA (hazard ratio 0.65 per log10 copies/mL higher, P = 0.001), but not screening CD4+, were associated with a poor CD4+ recovery. After 8 months of effective ART, 30 patients experienced the composite outcome of AIDS, non-AIDS, or death among participants with a poor CD4+ recovery (rate = 5.8/100 person-years) and 74 patients among those with an adequate recovery (>or=50 cells/muL; rate = 2.7/100 person-years) (adjusted hazard ratio = 2.24, P < 0.001). The risk of this composite outcome associated with a poor CD4+ recovery declined when ART was initiated at higher CD4+ counts (P < 0.01).
Impaired immune recovery, despite effective ART, results in longer time spent at low CD4+, thereby increasing risk for a broad category of HIV-related morbidity and mortality conditions.
The mineralogy of comet 81P/Wild 2 particles, collected in aerogel by the Stardust mission, has been determined using synchrotron Fe‐K X‐ray absorption spectroscopy with in situ transmission XRD and ...X‐ray fluorescence, plus complementary microRaman analyses. Our investigation focuses on the terminal grains of eight Stardust tracks: C2112,4,170,0,0; C2045,2,176,0,0; C2045,3,177,0,0; C2045,4,178,0,0; C2065,4,187,0,0; C2098,4,188,0,0; C2119,4,189,0,0; and C2119,5,190,0,0. Three terminal grains have been identified as near pure magnetite Fe3O4. The presence of magnetite shows affinities between the Wild 2 mineral assemblage and carbonaceous chondrites, and probably resulted from hydrothermal alteration of the coexisting FeNi and ferromagnesian silicates in the cometary parent body. In order to further explore this hypothesis, powdered material from a CR2 meteorite (NWA 10256) was shot into the aerogel at 6.1 km s−1, using a light‐gas gun, and keystones were then prepared in the same way as the Stardust keystones. Using similar analysis techniques to the eight Stardust tracks, a CR2 magnetite terminal grain establishes the likelihood of preserving magnetite during capture in silica aerogel.
Neglected tropical diseases are widespread, particularly in sub-Saharan Africa, affecting over 2 billion individuals. Control of these diseases has gathered pace in recent years, with increased ...levels of funding from a number of governmental or non-governmental donors. Focus has currently been on five major 'tool-ready' neglected tropical diseases (lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminthiasis and trachoma), using a package of integrated drug delivery according to the World Health Organization guidelines for preventive chemotherapy.
Success in controlling these neglected tropical diseases has been achieved in a number of countries in recent history. Experience from these successes suggests that long-term sustainable control of these diseases requires: (1) a long-term commitment from a wider range of donors and from governments of endemic countries; (2) close partnerships of donors, World Health Organization, pharmaceutical industries, governments of endemic countries, communities, and non-governmental developmental organisations; (3) concerted action from more donor countries to provide the necessary funds, and from the endemic countries to work together to prevent cross-border disease transmission; (4) comprehensive control measures for certain diseases; and (5) strengthened primary healthcare systems as platforms for the national control programmes and capacity building through implementation of the programmes.
The current level of funding for the control of neglected tropical diseases has never been seen before, but it is still not enough to scale up to the 2 billion people in all endemic countries. While more donors are sought, the stakeholders must work in a coordinated and harmonised way to identify the priority areas and the best delivery approaches to use the current funds to the maximum effect. Case management and other necessary control measures should be supported through the current major funding streams in order to achieve the objectives of the control of these diseases. For a long-term and sustainable effort, control of neglected tropical diseases should also be integrated into national primary healthcare systems.
Mali is endemic for all five targeted major neglected tropical diseases (NTDs). As one of the five 'fast-track' countries supported with the United States Agency for International Development (USAID) ...funds, Mali started to integrate the activities of existing disease-specific national control programs on these diseases in 2007. The ultimate objectives are to eliminate lymphatic filariasis, onchocerciasis and trachoma as public health problems and to reduce morbidity caused by schistosomiasis and soil-transmitted helminthiasis through regular treatment to eligible populations, and the specific objectives were to achieve 80% program coverage and 100% geographical coverage yearly. The paper reports on the implementation of the integrated mass drug administration and the lessons learned.
The integrated control program was led by the Ministry of Health and coordinated by the national NTD Control Program. The drug packages were designed according to the disease endemicity in each district and delivered through various platforms to eligible populations involving the primary health care system. Treatment data were recorded and reported by the community drug distributors. After a pilot implementation of integrated drug delivery in three regions in 2007, the treatment for all five targeted NTDs was steadily scaled up to 100% geographical coverage by 2009, and program coverage has since been maintained at a high level: over 85% for lymphatic filariasis, over 90% for onchocerciasis and soil-transmitted helminthiasis, around 90% in school-age children for schistosomiasis, and 76-97% for trachoma. Around 10 million people have received one or more drug packages each year since 2009. No severe cases of adverse effects were reported.
Mali has scaled up the drug treatment to national coverage through integrated drug delivery involving the primary health care system. The successes and lessons learned in Mali can be valuable assets to other countries starting up their own integrated national NTD control programs.
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