Circadian control of tumor immunosuppression affects efficacy of immune checkpoint blockade.

The circadian clock is a critical regulator of immunity, and this circadian control of immune modulation has an essential function in host defense and tumor immunosurveillance. Here we use a single-cell RNA sequencing approach and a genetic model of colorectal cancer to identify clock-dependent changes to the immune landscape that control the abundance of immunosuppressive cells and consequent suppression of cytotoxic CD8+ T cells. Of these immunosuppressive cell types, PD-L1-expressing myeloid-derived suppressor cells (MDSCs) peak in abundance in a rhythmic manner. Disruption of the epithelial cell clock regulates the secretion of cytokines that promote heightened inflammation, recruitment of neutrophils and the subsequent development of MDSCs. We also show that time-of-day anti-PD-L1 delivery is most effective when synchronized with the abundance of immunosuppressive MDSCs. Collectively, these data indicate that circadian gating of tumor immunosuppression informs the timing and efficacy of immune checkpoint inhibitors.

Causal oscillations in the visual thalamo-cortical network in sustained attention in ferrets.

Sustained visual attention allows us to process and react to unpredictable, behaviorally relevant sensory input. Sustained attention engages communication between the higher-order visual thalamus and its connected cortical regions. However, it remains unclear whether there is a causal relationship between oscillatory circuit dynamics and attentional behavior in these thalamo-cortical circuits. By using rhythmic optogenetic stimulation in the ferret, we provide causal evidence that higher-order visual thalamus coordinates thalamo-cortical and cortico-cortical functional connectivity during sustained attention via spike-field phase locking. Increasing theta but not alpha power in the thalamus improved accuracy and reduced omission rates in a sustained attention task. Further, the enhancement of effective connectivity by stimulation was correlated with improved behavioral performance. Our work demonstrates a potential circuit-level causal mechanism for how the higher-order visual thalamus modulates cortical communication through rhythmic synchronization during sustained attention.

Effect of fangchinoline on oxidant status in male albino rats with streptozotocin-induced diabetes

BACKGROUND Diabetes is a metabolic disorder caused by defects in insulin production and activity. During disease progression, changes in lipid peroxidation cause structural modifications via production of free radicals. Fangchinoline is a well-known alkaloid present in Stephaniae tetrandrine S. Moore, which has demonstrated antioxidant, anticancer, and anti-inflammatory activities. RESULTS The present study analyzed the anti-diabetic and antioxidant effects of fangchinoline in male rats with streptozotocin-induced diabetes. Rats were divided into the following groups: normal control, diabetic, diabetic + fangchinoline 100 mg/kg, diabetic + fangchinoline 200 mg/kg and diabetic + glibencla mide 600 mg/kg. The treatment was administered orally for 45 consecutive days. Lipid peroxidation was substantially increased by >50% in the serum, as well as the liver, kidney, and heart tissues of diabetic rats. However, fangchinoline supplementation significantly reduced lipid peroxidation to near normal levels. Reactive oxygen species levels were substantially increased by >500% in the serum, as well as the liver, kidney, and heart tissues of diabetic rats. Fangchinoline supplementation reduced reactive oxygen species to near normal levels. Fangchinoline supplementation significantly improved superoxide dismutase, glutathione peroxidase, catalase, and reduced glutathione levels in diabetic rats. Total hexoses, sialic acid, hexosamines, and fucose were increased in diabetic rats, whereas fangchinoline supplementation significantly reduced these total hexoses, sialic acid, hexosamines, and fucose to near normal levels CONCLUSIONS Supplementation with fangchinoline led to significant attenuation of the levels of lipid peroxidation, ROS, and glycoprotein components such as total hexoses, hexosamines, sialic acid, and fucose, while improving antioxidant marker levels