Sex differences in rapid nonclassical action of 17β‐oestradiol on intracellular signalling and oestrogen receptor α expression in basal forebrain cholinergic neurones in mouse

Rapid nonclassical effects of 17β‐oestradiol (E₂) on intracellular signalling have been identified in the basal forebrain, although the extent to which these actions may be different in males and females is unknown. Previous work has shown that E₂ rapidly phosphorylates cAMP responsive element binding protein (CREB) via ΕRα in female cholinergic neurones. Using this indicator, the present study examined whether nonclassical actions of E₂ occur in a sexually dimorphic manner within basal forebrain cholinergic neurones in mice. In addition, we investigated the expression and intracellular distribution of oestrogen receptor (ΕR)α in cholinergic neurones in female and male mice. Animals were gonadectomised and treated 2 weeks later with E₂. The number of CREB‐expressing cholinergic neurones was not altered in any of the brain regions after E₂ treatment in both males and females. However, E₂ treatment rapidly (< 15 minutes) increased (P < 0.05) the number of cholinergic neurones expressing phosphorylated CREB (pCREB) in the substantia innominata and medial septum but not in the striatum in female mice. By contrast, E₂ did not change pCREB expression in cholinergic neurones in male mice at any time point (15 minutes, 1 hour, 4 hours), irrespective of the neuroanatomical location. We also observed that, in females, more cholinergic neurones expressed nuclear ΕRα in all regions, whereas males showed more cholinergic neurones with cytoplasmic or both nuclear and cytoplasmic expression of ΕRα. Taken together, these results demonstrate a marked sex difference in the E₂‐induced nonclassical effect and intracellular distribution of ΕRα in basal forebrain cholinergic neurones in vivo.     

Minimizing the risk of community spread of COVID-19 via institutional quarantine of high-risk travelers with serial viral RNA testing: A successful experience from Macao SAR,China

Macao, a special administrative region (SAR) of the People’s Republic of China, is located in southern China and shares the border with mainland China. It is the most densely populated region in the world, with a population of 667400 and a total land area of 32.9 square kilometers in 2019. Since the first case diagnosed on January 22, 2020, there was a total of 45 laboratory-confirmed coronavirus disease 2019 (COVID-19) cases in Macao, of which 43 patients (96%) were imported cases. To date, all patients had been discharged successfully from Centro Hospitalar Conde de São Januário, a designated hospital to manage all COVID-19 patients in Macao. Eventually, no patient died, and no local community outbreak was noted. This opinion review describes the underlying factors that could have contributed to the successful experience in Macao SAR, China, which include the following: (1) Early implementation of containment measures; (2) Large-scale quarantine using hotel rooms to reduce the risk of a local outbreak; and (3) Multidisciplinary co-operation and transparency of information to the public. Although the successful experience in Macao SAR, China, may not be generalized to other regions, it should not be unreasonable to be well prepared with sufficient logistic support to conduct timely containment and early detection of episodic cases to prevent the backsliding of COVID-19 outbreak.     

Long-Term Immune Recovery After Hematopoietic Stem Cell Transplantation for ADA Deficiency: a Single-Center Experience

Journal of Clinical Immunology - Unconditioned hematopoietic stem cell transplantation (HSCT) is the recommended treatment for patients with adenosine deaminase (ADA)-deficient severe combined...     

Catabolic pathways regulated by mTORC1 are pivotal for survival and growth of cancer cells expressing mutant Ras

Oncogenic Ras stimulates macropinocytosis, a clathrin-independent endocytosis that increases the uptake of extracellular fluid. However, the functional significance of and regulatory mechanisms driving macropinocytosis in cancer cells remain largely unknown. Here, we show that extracellular macromolecules, such as albumin, internalized by Ras-expressing cells can support growth and survival under the nutrient-deprived conditions like those found in tumors. Moreover, we demonstrate that autophagy, a lysosome-mediated catabolic pathway, is required for the uptake and degradation of macropinocytic vesicles. Intracellular metabolites derived from macropinocytosis and autophagy directly influence the activity and localization of mTOR, which is ultimately responsible for the restoration of cell growth. Surprisingly, suppression of mTORC1, which typically triggers anabolic processes, facilitates macropinocytosis and thus supports cell growth and survival under the nutrient-deprived conditions. In a mouse xenograft model of pancreatic ductal adenocarcinoma, concomitant inhibition of macropinocytosis/autophagy and mTOR activity resulted in antitumor effects. These data suggest that novel anti-cancer strategies interrupting these metabolic processes and related signaling molecules may represent promising therapeutic avenues.     

Genetic Analysis in Bartter Syndrome from India

Bartter syndrome is a group of inherited, salt-losing tubulopathies presenting as hypokalemic metabolic alkalosis with normotensive hyperreninemia and hyperaldosteronism. Around 150 cases have been reported in literature till now. Mutations leading to salt losing tubulopathies are not routinely tested in Indian population. The authors have done the genetic analysis for the first time in the Bartter syndrome on two cases from India. First case was antenatal Bartter syndrome presenting with massive polyuria and hyperkalemia. Mutational analysis revealed compound heterozygous mutations in KCNJ1(ROMK) gene [p(Leu220Phe), p(Thr191Pro)]. Second case had a phenotypic presentation of classical Bartter syndrome however, genetic analysis revealed only heterozygous novel mutation in SLC12A gene p(Ala232Thr). Bartter syndrome is a clinical diagnosis and genetic analysis is recommended for prognostication and genetic counseling.