A robust approach for electronic health record–based case-control studies with contaminated case pools

We consider analyses of case-control studies assembled from electronic health records (EHRs) where the pool of cases is contaminated by patients who are ineligible for the study. These ineligible patients, referred to as “false cases,” should be excluded from the analyses if known. However, the true outcome status of a patient in the case pool is unknown except in a subset whose size may be arbitrarily small compared to the entire pool. To effectively remove the influence of the false cases on estimating odds ratio parameters defined by a working association model of the logistic form, we propose a general strategy to adaptively impute the unknown case status without requiring a correct phenotyping model to help discern the true and false case statuses. Our method estimates the target parameters as the solution to a set of unbiased estimating equations constructed using all available data. It outperforms existing methods by achieving robustness to mismodeling the relationship between the outcome status and covariates of interest, as well as improved estimation efficiency. We further show that our estimator is root-n-consistent and asymptotically normal. Through extensive simulation studies and analysis of real EHR data, we demonstrate that our method has desirable robustness to possible misspecification of both the association and phenotyping models, along with statistical efficiency superior to the competitors.     

Molecular structure and the role of high‐temperature requirement protein 1 in skeletal disorders and cancers

Human high‐temperature requirement protein 1 (HTRA1) is a member of serine proteases and consists of four well‐defined domains—an IGFBP domain, a Kazal domain, a protease domain and a PDZ domain. HTRA1 is a secretory protein and also present intracellularly and associated with microtubules. HTRA1 regulates a broad range of physiological processes via its proteolytic activity. This review examines the role of HTRA1 in bone biology, osteoarthritis, intervertebral disc (IVD) degeneration and tumorigenesis. HTRA1 mediates diverse pathological processes via a variety of signalling pathways, such as TGF‐β and NF‐κB. The expression of HTRA1 is increased in arthritis and IVD degeneration, suggesting that HTRA1 protein is attributed to cartilage degeneration and disease progression. Emerging evidence also suggests that HTRA1 has a role in tumorigenesis. Further understanding the mechanisms by which HTRA1 displays as an extrinsic and intrinsic regulator in a cell type–specific manner will be important for the development of HTRA1 as a therapeutic target.     

Cyclooxygenase-2 is a neuronal target gene of NF-κB

Background  

NF-κB is implicated in gene regulation involved in neuronal survival, inflammmatory response and cancer. There are relatively few neuronal target genes of NF-κB characterized.     

Role of Adiponectin‐Notch pathway in cognitive dysfunction associated with depression and in the therapeutic effect of physical exercise

A substantial percentage of late‐life depression patients also have an cognitive impairment, which severely affects the life quality, while the co‐occurring mechanisms are still unclear. Physical exercise can ameliorate both depressive behaviors and cognitive dysfunction, but the molecular mechanisms underlying its beneficial effects remain elusive. In this study, we uncover a novel adipose tissue to hippocampus crosstalk mediated by Adiponectin‐Notch pathway, with an impact on hippocampal neurogenesis and cognitive function. Adiponectin, an adipocyte‐derived hormone, could activate Notch signaling in the hippocampus through upregulating ADAM10 and Notch1, two key molecules in the Notch signaling. Chronic stress inhibits the Adiponectin‐Notch pathway and induces impaired hippocampal neurogenesis and cognitive dysfunction, which can be rescued by AdipoRon and running. Inhibition Notch signaling by DAPT mimics the adverse effects of chronic stress on hippocampal neurogenesis and cognitive function. Adiponectin knockout mice display depressive‐like behaviors, associated with inhibited Notch signaling, impaired hippocampal neurogenesis and cognitive dysfunction. Physical exercise could activate Adiponectin‐Notch pathway, and improve hippocampal neurogenesis and cognitive function, while deleting adiponectin gene or inhibiting Notch signaling blocks its beneficial effects. Together, our data not only suggest that Adiponectin‐Notch pathway is involved in the pathogenesis of cognitive dysfunction associated with depression, but also contributes to the therapeutic effect of physical exercise. This work helps to decipher the etiology of cognitive impairment associated with depression and hence will provide a potential innovative therapeutic target for these patients.     

Global soil nitrogen cycle pattern and nitrogen enrichment effects: Tropical versus subtropical forests

Tropical and subtropical forest biomes are a main hotspot for the global nitrogen (N) cycle. Yet, our understanding of global soil N cycle patterns and drivers and their response to N deposition in these biomes remains elusive. By a meta-analysis of 2426-single and 161-paired observations from 89 published ¹⁵ N pool dilution and tracing studies, we found that gross N mineralization (GNM), immobilization of ammonium ($I_{{\mathrm{NH}}_4}$) and nitrate ($I_{{\mathrm{NO}}_3}$), and dissimilatory nitrate reduction to ammonium (DNRA) were significantly higher in tropical forests than in subtropical forests. Soil N cycle was conservative in tropical forests with ratios of gross nitrification (GN) to $I_{{\mathrm{NH}}_4}$ (GN/$I_{{\mathrm{NH}}_4}$) and of soil nitrate to ammonium (NO₃⁻/NH₄⁺) less than one, but was leaky in subtropical forests with GN/$I_{{\mathrm{NH}}_4}$ and NO₃⁻/NH₄⁺ higher than one. Soil NH₄⁺ dynamics were mainly controlled by soil substrate (e.g., total N), but climatic factors (e.g., precipitation and/or temperature) were more important in controlling soil NO₃⁻ dynamics. Soil texture played a role, as GNM and $I_{{\mathrm{NH}}_4}$ were positively correlated with silt and clay contents, while $I_{{\mathrm{NO}}_3}$ and DNRA were positively correlated with sand and clay contents, respectively. The soil N cycle was more sensitive to N deposition in tropical forests than in subtropical forests. Nitrogen deposition leads to a leaky N cycle in tropical forests, as evidenced by the increase in GN/$I_{{\mathrm{NH}}_4}$, NO₃⁻/NH₄⁺, and nitrous oxide emissions and the decrease in $I_{{\mathrm{NO}}_3}$ and DNRA, mainly due to the decrease in soil microbial biomass and pH. Dominant tree species can also influence soil N cycle pattern, which has changed from conservative in deciduous forests to leaky in coniferous forests. We provide global evidence that tropical, but not subtropical, forests are characterized by soil N dynamics sustaining N availability and that N deposition inhibits soil N retention and stimulates N losses in these biomes.     

C6orf106 accelerates pancreatic cancer cell invasion and proliferation via activating ERK signaling pathway

Molecular and Cellular Biochemistry - The extracellular matrix (ECM) is a major biomechanical environment for all cells in vivo, and tightly controls wound healing and cancer progression. Type I...