Proneurotrophins bind with high affinity to p75 neurotrophin receptor (p75 NTR ) and lack the capacity to bind Trk receptors, suggesting that proneurotrophins can elicit apoptosis via p75 NTR even in cells expressing survival-promoting Trk receptors. In the CNS, basal forebrain (BF) neurons are particularly vulnerable to degeneration in Alzheimer's disease, and are among the few populations of brain neurons that express p75 NTR throughout life. These neurons also express Trk receptors and may be concomitantly exposed to both proneurotrophins and mature neurotrophins during development, disease, or after injury. We investigated the interaction of mature and proneurotrophin signaling in these CNS neurons. Kainic acid-induced seizures elicited production of pro-NGF by BF astrocytes before caspase activation in p75

The transcription factor SOX2 is an essential regulator of pluripotent stem cells and promotes development and maintenance of squamous epithelia. We previously reported that SOX2 is an oncogene and subject to highly recurrent genomic amplification in squamous cell carcinomas (SCCs). Here, we have further characterized the function of SOX2 in SCC. Using ChIP-seq analysis, we compared SOX2-regulated gene profiles in multiple SCC cell lines to ES cell profiles and determined that SOX2 binds to distinct genomic loci in SCCs. In SCCs, SOX2 preferentially interacts with the transcription factor p63, as opposed to the transcription factor OCT4, which is the preferred SOX2 binding partner in ES cells. SOX2 and p63 exhibited overlapping genomic occupancy at a large number of loci in SCCs; however, coordinate binding of SOX2 and p63 was absent in ES cells. We further demonstrated that SOX2 and p63 jointly regulate gene expression, including the oncogene ETV4, which was essential for SOX2-amplified SCC cell survival. Together, these findings demonstrate that the action of SOX2 in SCC differs substantially from its role in pluripotency. The identification of the SCC-associated interaction between SOX2 and p63 will enable deeper characterization the downstream targets of this interaction in SCC and normal squamous epithelial physiology.

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Background: The coronavirus disease 2019 (COVID-19) epidemic met coincidentally with massive migration before Lunar New Year in China in early 2020. This study is to investigate the relationship between the massive migration and the coronavirus disease 2019 (COVID-19) epidemic in China. Methods: The epidemic data between January 25th and February 15th and migration data between Jan 1st and Jan 24th were collected from the official websites. Using the R package WGCNA, we established a scale-free network of the selected cities. Correlation analysis was applied to describe the correlation between the Spring Migration and COVID-19 epidemic. Results: The epidemic seriousness in Hubei (except the city of Wuhan) was closely correlated with the migration from Wuhan between January 10 and January 24, 2020. The epidemic seriousness in the other provinces, municipalities and autonomous regions was largely affected by the immigration from Wuhan. By establishing a scale-free network of the regions, we divided the regions into two modules. The regions in the brown module consisted of three municipalities, nine provincial capitals and other 12 cities. The COVID-19 epidemics in these regions were more likely to be aggravated by migration. Conclusions: The migration from Wuhan could partly explain the epidemic seriousness in Hubei Province and other regions. The scale-free network we have established can better evaluate the epidemic. Three municipalities (Beijing, Shanghai and Tianjin), eight provincial capitals (including Nanjing, Changsha et al.) and 12 other cities (including Qingdao, Zhongshan, Shenzhen et al.) were hub cities in the spread of COVID-19 in China.

Coronavirus disease 2019 (COVID-19) is currently under a global pandemic trend. The efficiency of containment measures and epidemic tendency of typical countries should be assessed. In this study, the efficiency of prevention and control measures in China, Italy, Iran, South Korea, and Japan was assessed, and the COVID-19 epidemic tendency among these countries was compared. Results showed that the effective reproduction number(Re) in Wuhan, China increased almost exponentially, reaching a maximum of 3.98 before a lockdown and rapidly decreased to below 1 due to containment and mitigation strategies of the Chinese government. The Re in Italy declined at a slower pace than that in China after the implementation of prevention and control measures. The Re in Iran showed a certain decline after the establishment of a national epidemic control command, and an evident stationary phase occurred because the best window period for the prevention and control of the epidemic was missed. The epidemic in Japan and South Korea reoccurred several times with the Re fluctuating greatly. The epidemic has hardly rebounded in China due to the implementation of prevention and control strategies and the effective enforcement of policies. Other countries suffering from the epidemic could learn from the Chinese experience in containing COVID-19.

Background and Purpose Intra‐islet heparan sulfate (HS) plays an important role in the maintenance of pancreatic islet function. The aim of this study was to investigate the effect mechanism of HS loss on the functioning of islets in diabetic mice. Experimental Approach The hypoglycaemic effect of a heparanase inhibitor, OGT2115, was tested in a streptozotocin‐induced diabetic mouse model. The islets in pancreatic sections were also stained to reveal their morphology. An insulinoma cell line (MIN6) and primary isolated murine islets were used to investigate the effect of OGT2115 in vitro. Key Results Intra‐islet HS was clearly lost in streptozotocin‐induced diabetic mice due to the increased heparanase expression in damaged islets. OGT2115 prevented intra‐islet HS loss and improved the glucose profile and insulin secretion in streptozotocin‐treated mice. The apoptosis of pancreatic beta cells and the infiltration of mononuclear macrophages, CD4‐ and CD8‐positive T‐cells in islets was reduced by OGT2115 in streptozotocin‐treated mice, but OGT2115 did not alter the direct streptozotocin‐induced damage in vitro. The expression of heparanase was increased in high glucose‐treated isolated islets but not in response to direct streptozotocin stimulation. Further experiments showed that high glucose stimuli could decreased expression of PPARγ in cultured islets, thereby relieving the PPARγ‐induced inhibition of heparanase gene expression. Conclusion and Implications Hyperglycaemia could cause intra‐islet HS loss by elevating the expression of heparanase, thereby aggravating inflammatory cell infiltration and islet damage. Inhibition of heparanase might provide benefit for pancreatic beta cell protection in Type 1 diabetes.

Aims/hypothesis Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is an autosomal recessive disorder characterised by lipodystrophy and insulin resistance. BSCL2 is caused by loss-of-function mutations in the Seipin gene (also known as Bscl2). Deletion of this gene in mice induces insulin resistance, glucose intolerance and a loss of adipose tissue. This study evaluated the effects of genetic deletion of Seipin on islet beta cell function. Methods We examined seipin expression in islet cells and measured glucose profiles, insulin synthesis, glucose-stimulated insulin secretion (GSIS), islet expression of peroxisome proliferator-activated receptor γ (PPARγ), levels of Pdx-1, Nkx6.1, Glut2 (also known as Slc2a2) and proinsulin mRNA, nuclear translocation of pancreatic duodenal homeobox 1 (PDX-1), islet numbers, and beta cell mass and proliferation in male and female Seipin-knockout homozygous (Seipin −/−) and heterozygous (Seipin +/−) mice. Results Male and female Seipin −/− mice displayed glucose intolerance, insulin resistance, hyperinsulinaemia and a lack of adipose tissue. By contrast, male but not female Seipin +/− mice showed glucose intolerance without adipose tissue loss or insulin resistance. Seipin was highly expressed in islet beta cells in wild-type mice. Expression of islet PPARγ was reduced in male Seipin −/− and Seipin +/− mice but not in female Seipin −/− or Seipin +/− mice. Treatment of male Seipin +/− mice with rosiglitazone corrected the glucose intolerance. Male Seipin +/− mice displayed a decrease in islet insulin concentration and GSIS with low expression of Pdx-1, Nkx6.1, Glut2 and proinsulin, and a decline in PDX-1 nuclear translocation; these changes were rescued by rosiglitazone administration. Male Seipin −/− mice showed obvious, but rosiglitazone-sensitive, increases in islet insulin concentration, islet number and beta cell mass and proliferation, with a notable decline in GSIS. Ovariectomised female Seipin +/− mice displayed glucose intolerance and deficits in insulin synthesis and secretion, with a decline in islet PPARγ level; these deleterious effects were reversed by administration of oestradiol or rosiglitazone. Jianwei Xiong and Peng Sun contributed equally to this work.

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