Whole transcriptomic network analysis using Co-expression Differential Network Analysis (CoDiNA)

Biological and medical sciences are increasingly acknowledging the significance of gene co-expression-networks for investigating complex-systems, phenotypes or diseases. Typically, complex phenotypes are investigated under varying conditions. While approaches for comparing nodes and links in two networks exist, almost no methods for the comparison of multiple networks are available and-to best of our knowledge-no comparative method allows for whole transcriptomic network analysis. However, it is the aim of many studies to compare networks of different conditions, for example, tissues, diseases, treatments, time points, or species. Here we present a method for the systematic comparison of an unlimited number of networks, with unlimited number of transcripts:Co-expression Differential Network Analysis (CoDiNA). In particular, CoDiNA detects linksandnodes that are common, specific or different among the networks. We developed a statistical framework to normalize between these different categories of common or changed network links and nodes, resulting in a comprehensive network analysis method, more sophisticated than simply comparing the presence or absence of network nodes. Applying CoDiNA to a neurogenesis study we identified candidate genes involved in neuronal differentiation. We experimentally validated one candidate, demonstrating that its overexpression resulted in a significant disturbance in the underlying gene regulatory network of neurogenesis. Using clinical studies, we compared whole transcriptome co-expression networks from individuals with or without HIV and active tuberculosis (TB) and detected signature genes specific to HIV. Furthermore, analyzing multiple cancer transcription factor (TF) networks, we identified common and distinct features for particular cancer types. These CoDiNA applications demonstrate the successful detection of genes associated with specific phenotypes. Moreover, CoDiNA can also be used for comparing other types of undirected networks, for example, metabolic, protein-protein interaction, ecological and psychometric networks. CoDiNA is publicly available as anRpackage in CRAN (https://CRAN. R-project.org/package=CoDiNA)

Social Vulnerability of the People Exposed to Wildfires in U.S. West Coast States

Understanding of the vulnerability of populations exposed to wildfires is limited. We used an index from the U.S. Centers for Disease Control and Prevention to assess the social vulnerability of populations exposed to wildfire from 2000–2021 in California, Oregon, and Washington, which accounted for 90% of exposures in the western United States. The number of people exposed to fire from 2000–2010 to 2011–2021 increased substantially, with the largest increase, nearly 250%, for people with high social vulnerability. In Oregon and Washington, a higher percentage of exposed people were highly vulnerable (\u3e40%) than in California (~8%). Increased social vulnerability of populations in burned areas was the primary contributor to increased exposure of the highly vulnerable in California, whereas encroachment of wildfires on vulnerable populations was the primary contributor in Oregon and Washington. Our results emphasize the importance of integrating the vulnerability of at-risk populations in wildfire mitigation and adaptation plans

The global wildland–urban interface

The wildland–urban interface (WUI) is where buildings and wildland vegetation meet or intermingle1,2. It is where human–environmental conflicts and risks can be concentrated, including the loss of houses and lives to wildfire, habitat loss and fragmentation and the spread of zoonotic diseases3. However, a global analysis of the WUI has been lacking. Here, we present a global map of the 2020 WUI at 10 m resolution using a globally consistent and validated approach based on remote sensing-derived datasets of building area4 and wildland vegetation5. We show that the WUI is a global phenomenon, identify many previously undocumented WUI hotspots and highlight the wide range of population density, land cover types and biomass levels in different parts of the global WUI. The WUI covers only 4.7% of the land surface but is home to nearly half its population (3.5 billion). The WUI is especially widespread in Europe (15% of the land area) and the temperate broadleaf and mixed forests biome (18%). Of all people living near 2003–2020 wildfires (0.4 billion), two thirds have their home in the WUI, most of them in Africa (150 million). Given that wildfire activity is predicted to increase because of climate change in many regions6, there is a need to understand housing growth and vegetation patterns as drivers of WUI change

Spatial and temporal residential density patterns from 1940 to 2000 in and around the Northern Forest of the Northeastern United States

Over the past 60 years, housing growth has outpaced population growth in the United States. Conservationists are concerned about the far-reaching environmental impacts of housing development, particularly in rural areas. We use clustering analysis to examine the pattern and distribution of housing development since 1940 in and around the Northern Forest, a heavily forested region with high amenity and recreation use in the Northeastern United States. We find that both proximity to urban areas and an abundance of natural amenities are associated with housing growth at the neighborhood level in this region. In the 1970s, counterurbanization led to higher rates of growth across rural areas. The Northern Forest now has extensive interface between forest vegetation and residential development, which has the potential to profoundly alter the ecological and social benefits of these forests.Keywords: Housing density, Amenity growth, Sprawl, Housing growth, Cluster analysis, Northern ForestKeywords: Housing density, Amenity growth, Sprawl, Housing growth, Cluster analysis, Northern Fores

Using structure locations as a basis for mapping the wildland urban interface

The wildland urban interface (WUI) delineates the areas where wildland fire hazard most directly impacts human communities and threatens lives and property, and where houses exert the strongest influence on the natural environment. Housing data are a major problem for WUI mapping. When housing data are zonal, the concept of a WUI neighborhood can be captured easily in a density measure, but variations in zone (census block) size and shape introduce bias. Other housing data are points, so zonal issues are avoided, but the neighborhood character of the WUI is lost if houses are evaluated individually. Our goal was to develop a consistent method to map the WUI that is able to determine where neighborhoods (or clusters of houses) exist, using just housing location and wildland fuel data. We used structure and vegetation maps and a moving window analysis, with various window sizes representing neighborhood sizes, to calculate the neighborhood density of both houses and wildland vegetation. Mapping four distinct areas (in WI, MI, CA and CO) the method resulted in amounts of WUI comparable to those of zonal mapping, but with greater precision. We conclude that this hybrid method is a useful alternative to zonal mapping from the neighborhood to the landscape scale, and results in maps that are better suited to operational fire management (e.g., fuels reduction) needs, while maintaining consistency with conceptual and U.S. policy-specific WUI definitions.Keywords: Structure locations, Wildland urban interface, MappingKeywords: Structure locations, Wildland urban interface, Mappin

The TREAT-NMD advisory committee for therapeutics (TACT): an innovative de-risking model to foster orphan drug development

Despite multiple publications on potential therapies for neuromuscular diseases (NMD) in cell and animal models only a handful reach clinical trials. The ability to prioritise drug development according to objective criteria is particularly critical in rare diseases with large unmet needs and a limited numbers of patients who can be enrolled into clinical trials. TREAT-NMD Advisory Committee for Therapeutics (TACT) was established to provide independent and objective guidance on the preclinical and development pathway of potential therapies (whether novel or repurposed) for NMD. We present our experience in the establishment and operation of the TACT. TACT provides a unique resource of recognized experts from multiple disciplines. The goal of each TACT review is to help the sponsor to position the candidate compound along a realistic and well-informed plan to clinical trials, and eventual registration. The reviews and subsequent recommendations are focused on generating meaningful and rigorous data that can enable clear go/no-go decisions and facilitate longer term funding or partnering opportunities. The review process thereby acts to comment on viability, de-risking the process of proceeding on a development programme. To date TACT has held 10 review meeting and reviewed 29 program applications in several rare neuromuscular diseases: Of the 29 programs reviewed, 19 were from industry and 10 were from academia; 15 were for novel compounds and 14 were for repurposed drugs; 16 were small molecules and 13 were biologics; 14 were preclinical stage applications and 15 were clinical stage applications. 3 had received Orphan drug designation from European Medicines Agency and 3 from Food and Drug Administration. A number of recurrent themes emerged over the course of the reviews and we found that applicants frequently require advice and education on issues concerned with preclinical standard operating procedures, interactions with regulatory agencies, formulation, repurposing, clinical trial design, manufacturing and ethics. Over the 5 years since its establishment TACT has amassed a body of experience that can be extrapolated to other groups of rare diseases to improve the community's chances of successfully bringing new rare disease drugs to registration and ultimately to marke

A Novel Putative miRNA Target Enhancer Signal

It is known that miRNA target sites are very short and the effect of miRNA-target site interaction alone appears as being unspecific. Recent experiments suggest further context signals involved in miRNA target site recognition and regulation. Here, we present a novel GC-rich RNA motif downstream of experimentally supported miRNA target sites in human mRNAs with no similarity to previously reported functional motifs. We demonstrate that the novel motif can be found in at least one third of all transcripts regulated by miRNAs. Furthermore, we show that motif occurrence and the frequency of miRNA target sites as well as the stability of their duplex structures correlate. The finding, that the novel motif is significantly associated with miRNA target sites, suggests a functional role of the motif in miRNA target site biology. Beyond, the novel motif has the impact to improve prediction of miRNA target sites significantly

Specialty grand challenge: renaming our section to “Carbon Dioxide Removal”

Peer Reviewe

Neutral sphingomyelinase mediates the co-morbidity trias of alcohol abuse, major depression and bone defects

Mental disorders are highly comorbid and occur together with physical diseases, which are often considered to arise from separate pathogenic pathways. We observed in alcohol-dependent patients increased serum activity of neutral sphingomyelinase. A genetic association analysis in 456,693 volunteers found associations of haplotypes of SMPD3 coding for NSM-2 (NSM) with alcohol consumption, but also with affective state, and bone mineralisation. Functional analysis in mice showed that NSM controls alcohol consumption, affective behaviour, and their interaction by regulating hippocampal volume, cortical connectivity, and monoaminergic responses. Furthermore, NSM controlled bone–brain communication by enhancing osteocalcin signalling, which can independently supress alcohol consumption and reduce depressive behaviour. Altogether, we identified a single gene source for multiple pathways originating in the brain and bone, which interlink disorders of a mental–physical co-morbidity trias of alcohol abuse—depression/anxiety—bone disorder. Targeting NSM and osteocalcin signalling may, thus, provide a new systems approach in the treatment of a mental–physical co-morbidity trias