Major depressive disorder (MDD), one of the most frequently encountered forms of mental illness and a leading cause of disability worldwide1, poses a major challenge to genetic analysis. To date no robustly replicated genetic loci have been identified 2, despite analysis of more than 9,000 cases3. Using low coverage genome sequence of 5,303 Chinese women with recurrent MDD selected to reduce phenotypic heterogeneity, and 5,337 controls screened to exclude MDD, we identified and replicated two genome-wide significant loci contributing to risk of MDD on chromosome 10: one near the SIRT1 gene (P-value = 2.53×10−10) the other in an intron of the LHPP gene (P = 6.45×10−12). Analysis of 4,509 cases with a severe subtype of MDD, melancholia, yielded an increased genetic signal at the SIRT1 locus. We attribute our success to the recruitment of relatively homogeneous cases with severe illness.

Objective To examine infiltration of blood foamy monocytes, containing intracellular lipid droplets, into early atherosclerotic lesions and its contribution to development of nascent atherosclerosis. Approach and Results In apoE−/− mice fed western high-fat diet (WD), >10% of circulating monocytes became foamy monocytes at 3 days on WD and >20% of monocytes at 1 week. Foamy monocytes also formed early in blood of Ldlr−/−Apobec1−/− (LDb) mice on WD. Based on CD11c and CD36, mouse monocytes were categorized as CD11c−CD36−, CD11c−CD36+ and CD11c+CD36+. The majority of foamy monocytes were CD11c+CD36+, whereas most nonfoamy monocytes were CD11c−CD36− or CD11c−CD36+ in apoE−/− mice on WD. In wild-type mice, CD11c+CD36+ and CD11c−CD36+, but few CD11c−CD36−, monocytes took up cholesteryl ester–rich very-low-density lipoproteins (CE-VLDLs) isolated from apoE−/− mice on WD, and CE-VLDL uptake accelerated CD11c−CD36+–to–CD11c+CD36+ monocyte differentiation. Ablation of CD36 decreased monocyte uptake of CE-VLDLs. Intravenous injection of DiI-CE-VLDLs in apoE−/− mice on WD specifically labeled CD11c+CD36+ foamy monocytes, which infiltrated into nascent atherosclerotic lesions and became CD11c+ cells that were selectively localized in atherosclerotic lesions. CD11c deficiency reduced foamy monocyte infiltration into atherosclerotic lesions. Specific and consistent depletion of foamy monocytes (for 3 weeks) by daily intravenous injections of low-dose clodrosome reduced development of nascent atherosclerosis. Conclusions Foamy monocytes, which form early in blood of mice with hypercholesterolemia, infiltrate into early atherosclerotic lesions in a CD11c-dependent manner and play crucial roles in nascent atherosclerosis development.

The aim of this study was to evaluate the value of metagenomic next-generation sequencing (mNGS) in peripheral pulmonary infection management by comparing the diagnostic yield of mNGS and traditional pathogen detection methods on interventional specimens obtained by bronchoscopy. Patients and Methods: This study enrolled patients suspected with pulmonary infection who were admitted to Tianjin Medical University General Hospital from June 2018 to August 2019. Specimens were obtained from bronchoscopy for mNGS analysis and traditional pathogen detection (including bronchoalveolar lavage fluid microbial culture, smear microscopy, and lung biopsy histopathology), and the diagnostic yields were compared between mNGS and traditional methods to evaluate the diagnostic value of mNGS in peripheral pulmonary infection diagnosis. Results: In this study, by comparing mNGS with traditional pathogen detection, the results indicated that, first, mNGS identified at least one microbial species in almost 89% of the patients with pulmonary infection; second, mNGS detected microbes related to human diseases in 94.49% of samples from pulmonary infection patients who had received negative results from traditional pathogen detection; third, the accuracy and sensitivity of mNGS are higher than those of traditional pathogen detection; and, finally, mNGS could simultaneously detect and identify a large variety of pathogens. Conclusion: Metagenomic NGS analysis provided fast and precise pathogen detection and identification, contributing to prompt and accurate treatment of peripheral pulmonary infection.

Objective T cells, particularly CD8+ T cells, are major participants in obesity-linked adipose tissue (AT) inflammation. We examined the mechanisms of CD8+ T-cell accumulation and activation in AT and the role of CD11a, a β2 integrin. Approach and Results CD8+ T cells in AT of obese mice showed activated phenotypes with increased proliferation and interferon-γ expression. In vitro, CD8+ T cells from mouse AT displayed increased interferon-γ expression and proliferation to stimulation with interleukin-12 and interleukin-18, which were increased in obese AT. CD11a was upregulated in CD8+ T cells in obese mice. Ablation of CD11a in obese mice dramatically reduced T-cell accumulation, activation, and proliferation in AT. Adoptive transfer showed that CD8+ T cells from wild-type mice, but not from CD11a-deficient mice, infiltrated into AT of recipient obese wild-type mice. CD11a deficiency also reduced tumor necrosis factor-α–producing and interleukin-12–producing macrophages in AT and improved insulin resistance. Conclusions Combined action of cytokines in obese AT induces proliferative response of CD8+ T cells locally, which, along with increased infiltration, contributes to CD8+ T-cell accumulation and activation in AT. CD11a plays a crucial role in AT inflammation by participating in T-cell infiltration and activation.

Background Despite substantial research, uncertainty remains about the clinical and etiological heterogeneity of major depression (MD). Can meaningful and valid subtypes be identified and would they be stable cross-culturally? Method Symptoms at their lifetime worst depressive episode were assessed at structured psychiatric interview in 6008 women of Han Chinese descent, age ≥30 years, with recurrent DSM-IV MD. Latent class analysis (LCA) was performed in Mplus. Results Using the nine DSM-IV MD symptomatic A criteria, the 14 disaggregated DSM-IV criteria and all independently assessed depressive symptoms (n=27), the best LCA model identified respectively three, four and six classes. A severe and non-suicidal class was seen in all solutions, as was a mild/moderate subtype. An atypical class emerged once bidirectional neurovegetative symptoms were included. The non-suicidal class demonstrated low levels of worthlessness/guilt and hopelessness. Patterns of co-morbidity, family history, personality, environmental precipitants, recurrence and body mass index (BMI) differed meaningfully across subtypes, with the atypical class standing out as particularly distinct. Conclusions MD is a clinically complex syndrome with several detectable subtypes with distinct clinical and demographic correlates. Three subtypes were most consistently identified in our analyses: severe, atypical and non-suicidal. Severe and atypical MD have been identified in multiple prior studies in samples of European ethnicity. Our non-suicidal subtype, with low levels of guilt and hopelessness, may represent a pathoplastic variant reflecting Chinese cultural influences.

BackgroundThe symptoms of major depression (MD) are clinically diverse. Do they form coherent factors that might clarify the underlying nature of this important psychiatric syndrome?MethodSymptoms at lifetime worst depressive episode were assessed at structured psychiatric interview in 6008 women of Han Chinese descent, age ⩾30 years with recurrent DSM-IV MD. Exploratory factor analysis (EFA) and confirmatoryfactor analysis (CFA) were performed in Mplus in random split-half samples.ResultsThe preliminary EFA results were consistently supported by the findings from CFA. Analyses of the nine DSM-IV MD symptomatic A criteria revealed two factors loading on: (i) general depressive symptoms; and (ii) guilt/suicidal ideation. Examining 14 disaggregated DSM-IV criteria revealed three factors reflecting: (i) weight/appetite disturbance; (ii) general depressive symptoms; and (iii) sleep disturbance. Using all symptoms (n = 27), we identified five factors that reflected: (i) weight/appetite symptoms; (ii) general retarded depressive symptoms; (iii) atypical vegetative symptoms; (iv) suicidality/hopelessness; and (v) symptoms of agitation and anxiety.ConclusionsMD is a clinically complex syndrome with several underlying correlated symptom dimensions. In addition to a general depressive symptom factor, a complete picture must include factors reflecting typical/atypical vegetative symptoms, cognitive symptoms (hopelessness/suicidal ideation), and an agitated symptom factor characterized by anxiety, guilt, helplessness and irritability. Prior cross-cultural studies, factor analyses of MD in Western populations and empirical findings in this sample showing risk factor profiles similar to those seen in Western populations suggest that our results are likely to be broadly representative of the human depressive syndrome.

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