The contribution of periaqueductal gray in the regulation of physiological and pathological behaviors.

Periaqueductal gray (PAG), an integration center for neuronal signals, is located in the midbrain and regulates multiple physiological and pathological behaviors, including pain, defensive and aggressive behaviors, anxiety and depression, cardiovascular response, respiration, and sleep-wake behaviors. Due to the different neuroanatomical connections and functional characteristics of the four functional columns of PAG, different subregions of PAG synergistically regulate various instinctual behaviors. In the current review, we summarized the role and possible neurobiological mechanism of different subregions of PAG in the regulation of pain, defensive and aggressive behaviors, anxiety, and depression from the perspective of the up-down neuronal circuits of PAG. Furthermore, we proposed the potential clinical applications of PAG. Knowledge of these aspects will give us a better understanding of the key role of PAG in physiological and pathological behaviors and provide directions for future clinical treatments.

Targeting the IRE1α-XBP1s axis confers selective vulnerability in hepatocellular carcinoma with activated Wnt signaling.

Liver-specific Ern1 knockout impairs tumor progression in mouse models of hepatocellular carcinoma (HCC). However, the mechanistic role of IRE1α in human HCC remains unclear. In this study, we show that XBP1s, the major downstream effector of IRE1α, is required for HCC cell survival both in vitro and in vivo. Mechanistically, XBP1s transactivates LEF1, a key co-factor of ß-catenin, by binding to its promoter. Moreover, XBP1s physically interacts with LEF1, forming a transcriptional complex that enhances classical Wnt signaling. Consistently, the activities of XBP1s and LEF1 are strongly correlated in human HCC and with disease prognosis. Notably, selective inhibition of XBP1 splicing using an IRE1α inhibitor significantly repressed the viability of tumor explants as well as the growth of tumor xenografts derived from patients with distinct Wnt/LEF1 activities. Finally, machine learning algorithms developed a powerful prognostic signature based on the activities of XBP1s/LEF1. In summary, our study uncovers a key mechanistic role for the IRE1α-XBP1s pathway in human HCC. Targeting this axis could provide a promising therapeutic strategy for HCC with hyperactivated Wnt/LEF1 signaling.

Whole-brain monosynaptic inputs to lateral periaqueductal gray glutamatergic neurons in mice.

OBJECTIVE: The lateral periaqueductal gray (LPAG), which mainly contains glutamatergic neurons, plays an important role in social responses, pain, and offensive and defensive behaviors. Currently, the whole-brain monosynaptic inputs to LPAG glutamatergic neurons are unknown. This study aims to explore the structural framework of the underlying neural mechanisms of LPAG glutamatergic neurons. METHODS: This study used retrograde tracing systems based on the rabies virus, Cre-LoxP technology, and immunofluorescence analysis. RESULTS: We found that 59 nuclei projected monosynaptic inputs to the LPAG glutamatergic neurons. In addition, seven hypothalamic nuclei, namely the lateral hypothalamic area (LH), lateral preoptic area (LPO), substantia innominata (SI), medial preoptic area, ventral pallidum, posterior hypothalamic area, and lateral globus pallidus, projected most densely to the LPAG glutamatergic neurons. Notably, we discovered through further immunofluorescence analysis that the inputs to the LPAG glutamatergic neurons were colocalized with several markers related to important neurological functions associated with physiological behaviors. CONCLUSION: The LPAG glutamatergic neurons received dense projections from the hypothalamus, especially nuclei such as LH, LPO, and SI. The input neurons were colocalized with several markers of physiological behaviors, which show the pivotal role of glutamatergic neurons in the physiological behaviors regulation by LPAG.

Adenosine and P1 receptors: Key targets in the regulation of sleep, torpor, and hibernation.

Sleep, torpor, and hibernation are three distinct hypometabolic states. However, they have some similar physiological features, such as decreased core body temperature and slowing heart rate. In addition, the accumulation of adenosine seems to be a common feature before entry into these three states, suggesting that adenosine and its receptors, also known as P1 receptors, may mediate the initiation and maintenance of these states. This review, therefore, summarizes the current research on the roles and possible neurobiological mechanisms of adenosine and P1 receptors in sleep, torpor, and hibernation. Understanding these aspects will give us better prospects in sleep disorders, therapeutic hypothermia, and aerospace medicine.

The functional implication of ATF6α in castration-resistant prostate cancer cells.

Stress in the endoplasmic reticulum (ER) may perturb proteostasis and activates the unfolded protein response (UPR). UPR activation is frequently observed in cancer cells and is believed to fuel cancer progression. Here, we report that one of the three UPR sensors, ATF6α, was associated with prostate cancer (PCa) development, while both genetic and pharmacological inhibition of ATF6α impaired the survival of castration-resistance PCa (CRPC) cells. Transcriptomic analyses identified the molecular pathways deregulated upon ATF6α depletion, and also discovered considerable disparity in global gene expression between ATF6α knockdown and Ceapin-A7 treatment. In addition, combined analyses of human CRPC bulk RNA-seq and single-cell RNA-seq (scRNA-seq) public datasets confirmed that CRPC tumors with higher ATF6α activity displayed higher androgen receptor (AR) activity, proliferative and neuroendocrine (NE) like phenotypes, as well as immunosuppressive features. Lastly, we identified a 14-gene set as ATF6α NE gene signature with encouraging prognostic power. In conclusion, our results indicate that ATF6α is correlated with PCa progression and is functionally relevant to CRPC cell survival. Both specificity and efficacy of ATF6α inhibitors require further refinement and evaluation.

Mass mortalities associated with viral nervous necrosis in Murray cod in China.

In December 2019, a mass mortality among cultured Murray cod (Maccullochella peelii peelii) fry occurred on a freshwater farm located at Foshan city of Guangdong province, China. The cumulative mortality was up to 45% within 15 days. The diseased fish showed clinical signs, including abnormal swimming behaviour, loss of appetite and dark body colouration before mass mortality. Samples of brain and retina tissues were collected from affected fish and subjected to reverse transcriptase polymerase chain reaction detection and virus isolation in cell culture. Approximately 430 bp product was detected from the brain and retina tissues and culture supernatant of betanodavirus-infected SSN-1 cells. The typical cytopathic effect of betanodavirus infection, which is characterized by vacuolation, was observed in SSN-1 cells at three days after inoculating with the tissue filtrate of diseased Murry cod fry, and the TCID50 of the infected SSN-1 cell supernatant was 107.8 . Histopathological examinations revealed vacuolation and necrosis in the brain and retina of naturally and experimentally infected Murray cod fry. Electron microscopic observation also showed the aggregation of numerous spherical, non-enveloped viral particles measuring 22-28 nm in diameter in the cytoplasm of betanodavirus-infected SSN-1 cells. Sequence and phylogenetic analysis based on RdRp and Cp genes further indicated that the betanodavirus isolated from Murray cod belonged to the RGNNV genotype. Much higher mortality was obtained in challenged Murray cod fry compared with the controls through immersion challenge. This study is the first report of the natural infection of betanodavirus in freshwater fish in China.