Mechanistic modeling of the SARS-CoV-2 disease map.

Here we present a web interface that implements a comprehensive mechanistic model of the SARS-CoV-2 disease map. In this framework, the detailed activity of the human signaling circuits related to the viral infection, covering from the entry and replication mechanisms to the downstream consequences as inflammation and antigenic response, can be inferred from gene expression experiments. Moreover, the effect of potential interventions, such as knock-downs, or drug effects (currently the system models the effect of more than 8000 DrugBank drugs) can be studied. This freely available tool not only provides an unprecedentedly detailed view of the mechanisms of viral invasion and the consequences in the cell but has also the potential of becoming an invaluable asset in the search for efficient antiviral treatments

Defective extracellular matrix remodeling in brown adipose tissue is associated with fibro-inflammation and reduced diet-induced thermogenesis.

The relevance of extracellular matrix (ECM) remodeling is reported in white adipose tissue (AT) and obesity-related dysfunctions, but little is known about the importance of ECM remodeling in brown AT (BAT) function. Here, we show that a time course of high-fat diet (HFD) feeding progressively impairs diet-induced thermogenesis concomitantly with the development of fibro-inflammation in BAT. Higher markers of fibro-inflammation are associated with lower cold-induced BAT activity in humans. Similarly, when mice are housed at thermoneutrality, inactivated BAT features fibro-inflammation. We validate the pathophysiological relevance of BAT ECM remodeling in response to temperature challenges and HFD using a model of a primary defect in the collagen turnover mediated by partial ablation of the Pepd prolidase. Pepd-heterozygous mice display exacerbated dysfunction and BAT fibro-inflammation at thermoneutrality and in HFD. Our findings show the relevance of ECM remodeling in BAT activation and provide a mechanism for BAT dysfunction in obesity

Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial

Patients with rheumatoid arthritis (RA) receive highly targeted biologic therapies without previous knowledge of target expression levels in the diseased tissue. Approximately 40% of patients do not respond to individual biologic therapies and 5–20% are refractory to all. In a biopsy-based, precision-medicine, randomized clinical trial in RA (R4RA; n = 164), patients with low/absent synovial B cell molecular signature had a lower response to rituximab (anti-CD20 monoclonal antibody) compared with that to tocilizumab (anti-IL6R monoclonal antibody) although the exact mechanisms of response/nonresponse remain to be established. Here, in-depth histological/molecular analyses of R4RA synovial biopsies identify humoral immune response gene signatures associated with response to rituximab and tocilizumab, and a stromal/fibroblast signature in patients refractory to all medications. Post-treatment changes in synovial gene expression and cell infiltration highlighted divergent effects of rituximab and tocilizumab relating to differing response/nonresponse mechanisms. Using ten-by-tenfold nested cross-validation, we developed machine learning algorithms predictive of response to rituximab (area under the curve (AUC) = 0.74), tocilizumab (AUC = 0.68) and, notably, multidrug resistance (AUC = 0.69). This study supports the notion that disease endotypes, driven by diverse molecular pathology pathways in the diseased tissue, determine diverse clinical and treatment–response phenotypes. It also highlights the importance of integration of molecular pathology signatures into clinical algorithms to optimize the future use of existing medications and inform the development of new drugs for refractory patients

Çevreci Pazarlama ve Tüketicilerin Çevreci Tutumlarının Satın Alma Davranışlarına Etkileri İle İlgili Bir Uygulama

1980'lerde çevresel konuların dünyaya egemen olduğu söylenebilir. 1980'lerden beri, tüm yaşam biçimlerine önemli ölçüde etkisi olan çeşitli çevresel problemler arttığı için, tüketicilerin çevre duyarlılıklarında da artış olmuştur. Özellikle, toplumun genel görüşüne göre çeşitli çevresel problemlerin kaynağı iş dünyasıydı. Bu olaylar sosyal pazarlama ve çevreci (yeşil) pazarlama gibi anlayışların geliştirilmesine neden olmuştur. Bu çalışmada, çevrecilik, sosyal pazarlama, çevreci (yeşil) pazarlama ve çevreci tüketicilik hakkında mevcut literatür incelenmiş ve bir saha çalışması yürütülmüştür. Saha çalışması Adana'daki en büyük alışveriş merkezinden alışveriş yapan tüketiciler üzerinde gerçekleştirilmiştir. Bu çalışmada amaç; tüketicilerin çevreci tutumları ve tüketici davranışları arasındaki ilişkilerin sorgulanmasıdır. Araştırma sonuçları tüketicilerin çevreci duyarlılıkları ile satın alma davranışları arasında bir ilişki olduğunu göstermektedir. Sonuçlara göre yüksek çevreci hassasiyete sahip tüketicilerin, çevreci satın alma davranışlarının düzeyi de yüksektir.In the 1980's environmental issues had dominated the world. Since the 1980's there have been a progressive increase in consumer environmental consciousness, as increasing kinds of environmental problems put a strong impact on all forms of life. Specifically, society in general regarded business as the source of variety of environmental problems. These events caused to develop those concepts such as social marketing and environmental (green) marketing. In this study, the existing literature on the environmentalism, social marketing, environmental (green) marketing, and green consumerism has been examined and a field study conducted. The field study was conducted on the consumers shopping from the biggest shopping center in Adana. In this study the purpose was to investigate the relationship between consumer's environmental attitudes and consumer behaviors. The questionnaire results have indicated that there is a relationship between consumer environmental consciousnesses and consumer buying behavior. According to results consumer who has higher level of environmental consciousnesses, have also higher level of environmental buying behavior

Genotype x environment interaction and stability analysis of some Hungarian vetch (Vicia pannonica Crantz.) genotypes

The aim of this research was to determine genotype x environment interactions and stability parameters for forage and seed yield of some Hungarian vetch (Vicia pannonica Crantz.) genotypes. Seven Hungarian vetch genotypes were grown for forage and seed yield at three locations (Tekirdag, Kirklareli and Hayrabolu) in Trakya region of Turkey for two years (2002-2003 and 2003-2004 growing periods). The experiments were carried out as randomised complete block design with three replications. Genotype x environment interaction was investigated and the stabilities of genotypes were estimated by using regression coefficient (b(i)) and deviation from regression (S(2)d). Genotype x environment interaction was found to be statistically significant (P <= 0.01) in herbage yield, dry matter yield and seed yield of Hungarian vetch genotypes. Stability analysis indicated that the most stable genotypes were 84.1 and 42.1 for dry matter yield and 47.2 for seed yield. Genotype 56.3 can be recommended for favourable conditions in Trakya Region for forage and seed production. However, genotype 47.1 was well adapted to unfavourable environments for forage production in the region