Lymphotoxin-alpha expression in the meninges causes lymphoid tissue formation and neurodegeneration.

Organized meningeal immune cell infiltrates are suggested to play an important role in cortical grey matter pathology in the multiple sclerosis brain, but the mechanisms involved are as yet unresolved. Lymphotoxin-alpha plays a key role in lymphoid organ development and cellular cytotoxicity in the immune system and its expression is increased in the CSF of naïve and progressive multiple sclerosis patients and post-mortem meningeal tissue. Here we show that persistently increased levels of lymphotoxin-alpha in the cerebral meninges can give rise to lymphoid-like structures and underlying multiple sclerosis-like cortical pathology. Stereotaxic injections of recombinant lymphotoxin-alpha into the rat meninges led to acute meningeal inflammation and subpial demyelination that resolved after 28 days, with demyelination being dependent on prior subclinical immunization with myelin oligodendrocyte glycoprotein. Injection of a lymphotoxin-alpha lentiviral vector into the cortical meningeal space, to produce chronic localized overexpression of the cytokine, induced extensive lymphoid-like immune cell aggregates, maintained over 3 months, including T-cell rich zones containing podoplanin + fibroblastic reticular stromal cells and B-cell rich zones with a network of follicular dendritic cells, together with expression of lymphoid chemokines and their receptors. Extensive microglial and astroglial activation, subpial demyelination and marked neuronal loss occurred in the underlying cortical parenchyma. Whereas subpial demyelination was partially dependent on previous myelin oligodendrocyte glycoprotein immunization, the neuronal loss was present irrespective of immunization. Conditioned medium from LTα treated microglia was able to induce a reactive phenotype in astrocytes. Our results show that chronic lymphotoxin-alpha overexpression alone is sufficient to induce formation of meningeal lymphoid-like structures and subsequent neurodegeneration, similar to that seen in the progressive multiple sclerosis brain.

Intra-articular Injection of Urinary Bladder Matrix Reduces Osteoarthritis Development.

Micronized porcine urinary bladder matrix (UBM) is an extracellular matrix biomaterial that has immunomodulatory and pro-regenerative properties. The objective of this study was to assess the ability of UBM to alter disease progression in a mouse model of post-traumatic osteoarthritis (OA). Ten-week-old wild-type C57BL/6 male mice underwent anterior cruciate ligament transection (ACLT) to induce OA. Two weeks after ACLT, UBM (50 mg/mL) or saline was injected into the mouse joint. At 4 and 8 weeks post-ACLT, cartilage integrity was assessed using OARSI scoring of histology, pain was evaluated, and joints were harvested for quantitative RT-PCR analysis of cartilage-specific and inflammatory gene expression. UBM-treated animals showed improved cartilage integrity at 4 and 8 weeks and reduced pain at 4 weeks compared to saline-injected mice. Animals injected with UBM expressed higher levels of genes encoding structural cartilage proteins, such as collagen2α1 and aggrecan, as well as anti-inflammatory cytokines, including interleukins 10 and 4. UBM decreased cartilage degeneration in the murine ACLT model of OA, which may be due to reduced inflammation in the joint and maintenance of high expression levels of proteoglycans.

Tissue matrix arrays for high-throughput screening and systems analysis of cell function.

Cell and protein arrays have demonstrated remarkable utility in the high-throughput evaluation of biological responses; however, they lack the complexity of native tissue and organs. Here we spotted tissue extracellular matrix (ECM) particles as two-dimensional (2D) arrays or incorporated them with cells to generate three-dimensional (3D) cell-matrix microtissue arrays. We then investigated the responses of human stem, cancer and immune cells to tissue ECM arrays originating from 11 different tissues. We validated the 2D and 3D arrays as representative of the in vivo microenvironment by means of quantitative analysis of tissue-specific cellular responses, including matrix production, adhesion and proliferation, and morphological changes after culture. The biological outputs correlated with tissue proteomics, and network analysis identified several proteins linked to cell function. Our methodology enables broad screening of ECMs to connect tissue-specific composition with biological activity, providing a new resource for biomaterials research and further understanding of regeneration and disease mechanisms.

The Contribution of Agriculture, Forestry and other Land Use activities to Global Warming, 1990-2012.

We refine the information available through the IPCC AR5 with regard to recent trends in global GHG emissions from agriculture, forestry and other land uses (AFOLU), including global emission updates to 2012. Using all three available AFOLU datasets employed for analysis in the IPCC AR5, rather than just one as done in the IPCC AR5 WGIII Summary for Policy Makers, our analyses point to a down-revision of global AFOLU shares of total anthropogenic emissions, while providing important additional information on subsectoral trends. Our findings confirm that the share of AFOLU emissions to the anthropogenic total declined over time. They indicate a decadal average of 28.7 ± 1.5% in the 1990s and 23.6 ± 2.1% in the 2000s and an annual value of 21.2 ± 1.5% in 2010. The IPCC AR5 had indicated a 24% share in 2010. In contrast to previous decades, when emissions from land use (land use, land use change and forestry, including deforestation) were significantly larger than those from agriculture (crop and livestock production), in 2010 agriculture was the larger component, contributing 11.2 ± 0.4% of total GHG emissions, compared to 10.0 ± 1.2% of the land use sector. Deforestation was responsible for only 8% of total anthropogenic emissions in 2010, compared to 12% in the 1990s. Since 2010, the last year assessed by the IPCC AR5, new FAO estimates indicate that land use emissions have remained stable, at about 4.8 Gt CO2 eq yr-1 in 2012. Emissions minus removals have also remained stable, at 3.2 Gt CO2 eq yr-1 in 2012. By contrast, agriculture emissions have continued to grow, at roughly 1% annually, and remained larger than the land use sector, reaching 5.4 Gt CO2 eq yr-1 in 2012. These results are useful to further inform the current climate policy debate on land use, suggesting that more efforts and resources should be directed to further explore options for mitigation in agriculture, much in line with the large efforts devoted to REDD+ in the past decade.

A closer look at age: deconstructing aggregate gonorrhea and chlamydia rates, California, 1998-2007.

BACKGROUND: Risk of gonorrheal (GC) and chlamydial (CT) infection is highly associated with age. Case rates typically are reported in 5-year categories. Highest rates are seen consistently in the 15- to 19-year and 20- to 24-year age groups for both genders. It is not clear how aggregate, age-specific rates mask finer differences in risk by single age across and within racial/ethnic groups. METHODS: California case-based surveillance data for 1998 through 2007 were used to calculate GC and CT rates by single age at diagnosis. The distribution of single gender and age-specific rates was compared with 5-year age-specific rates. Descriptive statistics for age by race/ethnicity were calculated, and trends over time were assessed. RESULTS: Female, single-age-specific GC and CT rates for 2007 increased strikingly during adolescence and then declined quickly. Male, single-age-specific GC rates declined more gradually than did CT rates. The rate for the aggregate 15- to 19-year-old age group fit the single-age rates poorly, particularly for females, who in 2007 had a peak rate at age 19 for GC (497 per 100,000) and for CT (3640 per 100,000), though the highest aggregate rate was for ages 20 to 24. Blacks had the youngest mean age for both GC and CT. Mean ages increased significantly from 1998 through 2007 for female GC and CT cases, as well as for male CT cases. CONCLUSIONS: Age and race/ethnicity data should be examined in finer detail than the 5-year aggregate data, in order to target sexually transmitted disease prevention and control interventions more effectively.

Receptor contributions to configural and elemental odor mixture perception.

Odor mixture perception can be configural (the mixture is qualitatively different from the components) or elemental (the components are recognizable). Some have argued that configural properties are dependent on chemical similarity and possible overlap at the receptor level. The authors show that a binary mixture in which both components activate the same receptor (17) has a configural odor, whereas a mixture that suppresses overlap has elemental odor properties. Rats trained to recognize mixtures of citronellal and octanal (strong 17 agonists) in many ratios rarely recognize the components, supporting configural representation of the odor mixture. However, when trained to recognize mixtures of citral (partial 17 agonist, inhibitor) and octanal, rats recognize 1 or both components over a wide range of ratios.