Studies on the highly pathogenic avian influenza (HPAI) H5N1 suggest that wild bird migration may facilitate its long‐distance spread, yet the role of wild bird community composition in its transmission risk remains poorly understood. Furthermore, most studies on the diversity–disease relationship focused on host species diversity without considering hosts’ phylogenetic relationships, which may lead to rejecting a species diversity effect when the community has host species that are only distantly related. Here, we explored the influence of waterbird community composition for determining HPAI H5N1 occurrence in wild birds in a continental‐scale study across Europe. In particular, we tested the diversity–disease relationship using both host species diversity and host phylogenetic diversity. Our results provide the first demonstration that host community composition—compared with previously identified environmental risk factors—can also effectively explain the spatial pattern of H5N1 occurrence in wild birds. We further show that communities with more higher risk host species and more closely related species have a higher risk of H5N1 outbreaks. Thus, both host species diversity and community phylogenetic structure, in addition to environmental factors, jointly influence H5N1 occurrence. Our work not only extends the current theory on the diversity–disease relationship, but also has important implications for future monitoring of H5N1 and other HPAI subtypes.

Background: Although increased early detection, diagnosis and treatment have improved the outcome of breast cancer patients, prognosis estimation still poses challenges due to the disease heterogeneity. Accumulating data indicated an evident correlation between tumor immune microenvironment and clinical outcomes. Objective: To construct an immune-related signature that can estimate disease prognosis and patient survival in breast cancer. Methods: Gene expression profiles and clinical data of breast cancer patients were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, which were further divided into a training set (n = 499), a testing set (n = 234) and a Meta-validation set (n = 519). In the training set, immune-related genes were recognized using combination of gene expression data and ESTIMATE algorithm-derived immune scores. An immune-related prognostic signature was generated with LASSO Cox regression analysis. The prognostic value of the signature was validated in the testing set and the Meta-validation set. Results: A total of 991 immune-related genes were identified. Twelve genes with nonzero coefficients in LASSO analysis were used to construct an immune-related prognostic signature. The 12-gene signature significantly stratified patients into high and low immune risk groups in terms of overall survival independent of clinical and pathologic factors. The signature also significantly stratified overall survival in clinical defined groups, including stage I/II disease. Several biological processes, such as immune response, were enriched among genes in the immune-related signature. The percentage of M 2 macrophage infiltration was significantly different between low and high immune risk groups. Timedependent ROC curves indicated good performance of our signature in predicting the 1-, 3-and 5-year overall survival for patients from the full TCGA cohort. Furthermore, the composite signature derived by integrating immune-related signature with clinical factors, provided a more accurate estimation of survival relative to molecular signature alone.

Robust expansion of adoptively transferred T cells is a prerequisite for effective cancer immunotherapy, but how many genes in the genome modulate T cell expansion remains unknown. Here, we perform in vivo and in vitro CRISPR screens to systematically identify genes influencing CD8 T cell expansion. In the mouse genome, $2,600 and $1,500 genes are required for optimal CD8 T cell expansion in vivo and in vitro, respectively. In vivo-specific CD8 T cell essential genes are enriched in metabolic pathways, including mitochondrial metabolism. The strongest repressor of CD8 T cell expansion is Roquin, the ablation of which drastically boosts T cell proliferation by enhancing cell-cycle progression and upregulation of IRF4. Roquin deficiency or IRF4 overexpression potently enhances anti-tumor immunity. These data provide a functional catalog of CD8 T cell fitness genes and suggest that targeting the Roquin-IRF4 axis is an effective strategy to enhance efficacy of adoptive transfer therapy for cancer.

Ca2+ in endoplasmic reticulum (ER) dictates T cell activation, proliferation, and function via store-operated Ca2+ entry. How naive T cells maintain an appropriate level of Ca2+ in ER remains poorly understood. Here, we show that the ER transmembrane protein VMP1 is essential for maintaining ER Ca2+ homeostasis in naive T cells. VMP1 promotes Ca2+ release from ER under steady state, and its deficiency leads to ER Ca2+ overload, ER stress, and secondary Ca2+ overload in mitochondria, resulting in massive apoptosis of naive T cells and defective T cell response. Aspartic acid 272 (D272) of VMP1 is critical for its ER Ca2+ releasing activity, and a knockin mouse strain with D272 mutated to asparagine (D272N) demonstrates all functions of VMP1 in T cells in vivo depend on its regulation of ER Ca2+. These data uncover an indispensable role of VMP1 in preventing ER Ca2+ overload and maintaining naive T cell survival.

OBJECTIVE To investigate the clinical effi cacy and toxic eff ect of the 3-dimensional conformal radiation therapy (3DCRT) for nonsmall cell lung cancer (NSCLC). METHODS Fi y-two patients with the Stage-I and IV NSCLC were treated with 3DCRT. Cross analysis of the clinical data was conducted in the comparison between the 52 cases with 3DCRT and the other 50 cases with the conventional radiation therapy (CRT). In the 3DCRT group, only the primary tumor and positive lymph-node draining area were included in the clinical target area, se ing 4 to 6 coplanar or non-coplanar irradiation fi elds, with 2 Gy or 3 Gy/fraction, 1 fraction a day and 5 fractions per week. The total dose ranged from a test dose (DT) of 66 Gy to 72 Gy. In the CRT group, the fi eld area contained the primary tumor plus the homolateral hilum of the lung, the mediastinum superior or hol-mediastinum, and opposed anteroposterior irradiation. When the dosage reached DT 36~40 Gy, an oblique portal administered radiation was conducted in order to avoid injuring the spinal cord. The DT was 1.8~2.0 Gy/fraction, 1 fraction a day, 5 fractions per week, with a total dose of 60 Gy to 70 Gy. RESULTSThe therapeutic effect (CR + PR) was 90.4% in the 3DCRT group, and was 72% in the CRT group. There was statistically signifi cant diff erence between the two groups, P < 0.01. There was a clinical symptom improvement a ained by 96.5% and 86.4% respectively in the two groups, and there was a statistically signifi cant diff erence between the groups, P < 0.01. The 6-month, 1 and 2-year overa1l survival rates were 92.3%, 75.0% and 42.3% in the 3DCRT group, and 76%, 60% and 30% in the CRT group, respectively. There was a significant difference in the 6-month overall survival rate between the groups, P < 0.05. There was no obvious signifi cant diff erence in the 1 and 2-year overa1l survival rates between the two groups, P > 0.05. The toxic reaction was 12.5% and 23.7% respectively in the 3DCRT and CRT groups. Acute radioactive esophagitis and leucopenia were markedly lower in the 3DCRT group than in the CRT group. There was a statistically signifi cant diff erence between the groups, P < 0.05. No toxic reaction of Stage-III and over was found in the 3DCRT group during radiation therapy. CONCLUSION The 3DCRT method has a satisfactory shortterm efficacy and improvement of clinical symptoms in treating NSCLC, with a mild toxic reaction and good tolerance in patients. It can be used for enhancing the tumor-control rate and be ering the quality of life.