Endogenous protease nexin-1 protects against cerebral ischemia.

The serine protease thrombin plays a role in signalling ischemic neuronal death in the brain. Paradoxically, endogenous neuroprotective mechanisms can be triggered by preconditioning with thrombin (thrombin preconditioning, TPC), leading to tolerance to cerebral ischemia. Here we studied the role of thrombin's endogenous potent inhibitor, protease nexin-1 (PN-1), in ischemia and in tolerance to cerebral ischemia induced by TPC. Cerebral ischemia was modelled in vitro in organotypic hippocampal slice cultures from rats or genetically engineered mice lacking PN-1 or with the reporter gene lacZ knocked into the PN-1 locus PN-1HAPN-1-lacZ/HAPN-1-lacZ (PN-1 KI) exposed to oxygen and glucose deprivation (OGD). We observed increased thrombin enzyme activity in culture homogenates 24 h after OGD. Lack of PN-1 increased neuronal death in the CA1, suggesting that endogenous PN-1 inhibits thrombin-induced neuronal damage after ischemia. OGD enhanced β-galactosidase activity, reflecting PN-1 expression, at one and 24 h, most strikingly in the stratum radiatum, a glial cell layer adjacent to the CA1 layer of ischemia sensitive neurons. TPC, 24 h before OGD, additionally increased PN-1 expression 1 h after OGD, compared to OGD alone. TPC failed to induce tolerance in cultures from PN-1(-/-) mice confirming PN-1 as an important TPC target. PN-1 upregulation after TPC was blocked by the c-Jun N-terminal kinase (JNK) inhibitor, L-JNKI1, known to block TPC. This work suggests that PN-1 is an endogenous neuroprotectant in cerebral ischemia and a potential target for neuroprotection

Protein-phosphatase 1 and its role in long-term depression in the amygdala

The brain observes, detects, learns, and remembers signals coming from our external environment. In particular, it senses danger, and once detected, the related sensory signal, be it auditory, visual or somatosensory, triggers synaptic plasticity, enabling the brain to learn and remember the event. During Pavlovian fear conditioning, animals learn to associate a negative stimulus, such as a mild foot-shock, witha neutral stimulus, like a novel sound or context. This association leads to long-lasting changes in the animals’ behavior upon re-exposure to the neutral stimuli that, in rodent, is expressed by a “freezing” fear posture. Fortunately, these fear memories, in rodent and human, extinguish with repeated exposure to the neutral stimuli in absence of the negative stimulus. If fear extinction were impaired, however, one would live every day in an anxious state of exaggerated fear. Humans with post-traumatic stress disorder suffer from a persistent fear memory that is resistant to extinction. Although therapies based on extinction already exist, their efficiency is low and the majority of patients experience relapse. This thesis proposes that a detailed investigation of the molecular mechanisms underlying the synaptic plasticity of fear extinction will enable better treatment for anxiety disorders, and uses electrophysiology to step modestly in that direction.Fear memory formation and extinction occur principally in the amygdala, a brain area localized within the temporal lobe. The amygdala receives sensory stimuli primarily from the thalamus and cortex and long-term potentiation of thalamo-and cortico-amygdalar synaptic transmission is believed to underlie fear memory formation. In contrast, fear extinction is thought to involve long-termdepression of these circuits. My doctorate focused on understanding the molecular pathways underlying long-term depression of thalamo-and cortico-amygdalar projections. I found that thalamic and cortical inputs carry distinctmolecular pathways, such as distinct receptors localized at differentsites of long-term depression induction

Pathological brain plasticity and cognition in the offspring of males subjected to postnatal traumatic stress

Traumatic stress in early-life increases the risk for cognitive and neuropsychiatric disorders later in life. Such early stress can also impact the progeny even if not directly exposed, likely through epigenetic mechanisms. Here, we report in mice that the offspring of males subjected to postnatal traumatic stress have decreased gene expression in molecular pathways necessary for neuronal signaling, and altered synaptic plasticity when adult. Long-term potentiation is abolished and long-term depression is enhanced in the hippocampus, and these defects are associated with impaired long-term memory in both the exposed fathers and their offspring. The brain-specific gamma isoform of protein kinase C (Prkcc) is one of the affected signaling components in the hippocampus. Its expression is reduced in the offspring, and DNA methylation at its promoter is altered both in the hippocampus of the offspring and the sperm of fathers. These results suggest that postnatal traumatic stress in males can affect brain plasticity and cognitive functions in the adult progeny, possibly through epigenetic alterations in the male germline

The AKT1E17K Allele Promotes Breast Cancer in Mice

The gain-of-function mutation in the pleckstrin homology domain of AKT1 (AKT1E17K) occurs in lung and breast cancer. Through the use of human cellular models and of a AKT1E17K transgenic Cre-inducible murine strain (R26-AKT1E17K mice), we have demonstrated that AKT1E17K is a bona fide oncogene for lung epithelial cells. However, the role of AKT1E17K in breast cancer remains to be determined. Here, we report the generation and the characterization of a MMTV-CRE; R26-AKT1E17K mouse strain that expresses the mutant AKT1E17K allele in the mammary epithelium. We observed that AKT1E17K stimulates the development of mammary tumors classified as ductal adenocarcinoma of medium–high grade and presented a variety of proliferative alterations classified as adenosis with low-to-high grade dysplasia in the mammary epithelium. A subsequent immunohistochemical characterization suggested they were PR−/HER2−/ER+, basal-like and CK8−/CK10−/CK5+/CK14+. We also observed that, in parallel with an increased proliferation rate, tumors expressing mutant AKT1E17K presented an activation of the GSK3/cyclin D1 pathway in the mammary epithelium and cluster significantly with the human basal-like tumors. In conclusion, we demonstrate AKT1E17K is a bona fide oncogene that can initiate tumors at high efficiency in murine mammary epithelium in vivo

Артинские вести. 2021. № 061

This study was designed to determine the distribution and identity of potential intermediate snail hosts of Schistosoma spp. in Bengo, Luanda, Kwanza Norte and Malanje Provinces in north-western Angola. This is an area where infection with Schistosoma haematobium, causing urogenital schistosomiasis, is common but little is yet known about transmission of the disease. Angola has had a varied past with regard to disease control and is revitalising efforts to combat neglected tropical diseases. Snails were sampled from 60 water-contact points. Specimens of the genera Bulinus, Biomphalaria or Lymnaea were screened for trematode infections by inducing cercarial shedding. Snails were initially identified using shell morphology; subsequently a cytochrome c oxidase subunit 1 (cox1) gene fragment was amplified from a subset of snails from each site, for molecular identification. Cercariae were captured onto FTA cards for molecular analysis. Specimens of Bulinus angolensis collected from the original locality of the type specimen have been characterised and comparisons made with snails collected in 1957 held at the Natural History Museum, London, UK. In total snails of nine genera were identified using morphological characteristics: Biomphalaria, Bulinus, Gyraulus, Lanistes, Lentorbis, Lymnaea, Melanoides, Physa and Succinea. Significant for schistosomiasis transmission, was the discovery of Bulinus globosus, B. canescens, B. angolensis, B. crystallinus and Biomphalaria salinarum in their type-localities and elsewhere. Bulinus globosus and B. angolensis occurred in two distinct geographical areas. The cox1 sequence for B. globosus differed markedly from those from specimens of this species collected from other countries. Bulinus angolensis is more closely related to B. globosus than originally documented and should be included in the B. africanus group. Schistosoma haematobium cercariae were recovered from B. globosus from two locations: Cabungo, Bengo (20 snails) and Calandula, Malanje (5 snails). Schistosoma haematobium cercariae were identified as group 1 cox1 corresponding to the type common throughout the African mainland. Various freshwater bodies in north-western Angola harbour potential intermediate snail hosts for urogenital schistosomiasis, highlighting the need to map the rest of the country to identify areas where transmission can occur and where control efforts should be targeted. The molecular phylogeny generated from the samples confirmed that considerable variation exists in B. globosus, which is the primary snail host for S. haematobium in many regions of Africa

Changes in digestive cancer diagnosis during the SARS-CoV-2 pandemic in Italy: A nationwide survey

Background: The SARS-CoV-2 pandemic has had a huge impact on healthcare systems, resulting in many routine diagnostic procedures either being halted or postponed. Aims: To evaluate whether the diagnoses of colorectal, gastric and pancreatic cancers have been impacted by the SARS-CoV-2 pandemic in Italy. Methods: A survey designed to collect the number of histologically-proven diagnoses of the three cancers in gastroenterology services across Italy from January 1 to October 31 in 2017\u20132020. Non-parametric ANOVA for repeated measurements was applied to compare distributions by years and macro-areas. Results: Compared to 2019, in 2020 gastric cancer diagnoses decreased by 15.9%, CRC by 11.9% and pancreatic by 9.9%. CRC distributions showed significant differences between all years, stomach cancer between 2018 and 2020 and 2019\u20132020, and pancreatic cancer only between 2017 and 2019. The 2019\u20132020 comparison showed fewer CRC diagnoses in the North (-13.7%), Center (-16.5%) and South (-4.1%), fewer stomach cancers in the North (-19.0%) and South (-9.4%), and fewer pancreatic cancers in the North (-14.1%) and Center (-4.7%), with an increase in the South (+12.3%). Distributions of CRC and gastric cancer were significantly different between all years in the North. Conclusions: This survey highlights the concerning effects of the COVID-19 pandemic on the diagnostic yield of gastroenterology services for stomach, colorectal and pancreatic cancers in Italy

Changes in digestive cancer diagnosis during the SARS-CoV-2 pandemic in Italy: A nationwide survey

Background: The SARS-CoV-2 pandemic has had a huge impact on healthcare systems, resulting in many routine diagnostic procedures either being halted or postponed. Aims: To evaluate whether the diagnoses of colorectal, gastric and pancreatic cancers have been impacted by the SARS-CoV-2 pandemic in Italy. Methods: A survey designed to collect the number of histologically-proven diagnoses of the three cancers in gastroenterology services across Italy from January 1 to October 31 in 2017–2020. Non-parametric ANOVA for repeated measurements was applied to compare distributions by years and macro-areas. Results: Compared to 2019, in 2020 gastric cancer diagnoses decreased by 15.9%, CRC by 11.9% and pancreatic by 9.9%. CRC distributions showed significant differences between all years, stomach cancer between 2018 and 2020 and 2019–2020, and pancreatic cancer only between 2017 and 2019. The 2019–2020 comparison showed fewer CRC diagnoses in the North (-13.7%), Center (-16.5%) and South (-4.1%), fewer stomach cancers in the North (-19.0%) and South (-9.4%), and fewer pancreatic cancers in the North (-14.1%) and Center (-4.7%), with an increase in the South (+12.3%). Distributions of CRC and gastric cancer were significantly different between all years in the North. Conclusions: This survey highlights the concerning effects of the COVID-19 pandemic on the diagnostic yield of gastroenterology services for stomach, colorectal and pancreatic cancers in Italy