Differential effects of energy stress on AMPK phosphorylation and apoptosis in experimental brain tumor and normal brain

<p>Abstract</p> <p>Background</p> <p>AMP-activated protein kinase (AMPK) is a known physiological cellular energy sensor and becomes phosphorylated at Thr-172 in response to changes in cellular ATP levels. Activated AMPK acts as either an inducer or suppressor of apoptosis depending on the severity of energy stress and the presence or absence of certain functional tumor suppressor genes.</p> <p>Results</p> <p>Here we show that energy stress differentially affects AMPK phosphorylation and cell-death in brain tumor tissue and in tissue from contra-lateral normal brain. We compared TSC2 deficient CT-2A mouse astrocytoma cells with syngeneic normal astrocytes that were grown under identical condition <it>in vitro</it>. Energy stress induced by glucose withdrawal or addition of 2-deoxyglucose caused more ATP depletion, AMPK phosphorylation and apoptosis in CT-2A cells than in the normal astrocytes. Under normal energy conditions pharmacological stimulation of AMPK caused apoptosis in CT-2A cells but not in astrocytes. TSC2 siRNA treated astrocytes are hypersensitive to apoptosis induced by energy stress compared to control cells. AMPK phosphorylation and apoptosis were also greater in the CT-2A tumor tissue than in the normal brain tissue following implementation of dietary energy restriction. Inefficient mTOR and TSC2 signaling, downstream of AMPK, is responsible for CT-2A cell-death, while functional LKB1 may protect normal brain cells under energy stress.</p> <p>Conclusion</p> <p>Together these data demonstrates that AMPK phosphorylation induces apoptosis in mouse astrocytoma but may protect normal brain cells from apoptosis under similar energy stress condition. Therefore, using activator of AMPK along with glycolysis inhibitor could be a potential therapeutic approach for TSC2 deficient human malignant astrocytoma.</p

An observational study on passive immunity in Irish suckler beef and dairy calves: Tests for failure of passive transfer of immunity and associations with health and performance

peer-fundedThe study objectives were to: 1) evaluate the diagnostic performance of passive immunity tests for classification of failure of passive transfer (FPT) risk, based on their relationships with calf health and performance, and 2) describe the epidemiology of morbidity and mortality in suckler beef and dairy calves under Irish conditions. A total of 1392 suckler beef calves (n = 111 farms) and 2090 dairy calves (84 farms) were included in this observational study. Blood samples were collected by jugular venipuncture. Serum samples were analysed for total IgG concentration using an ELISA assay, total protein concentration by clinical analyser (TP – CA), globulin concentration, zinc sulphate turbidity (ZST) units, total solids percentage by Brix refractometer (TS – BRIX), and total protein concentration by digital refractometer (TP – DR). Crude and cause-specific morbidity, all-cause mortality, and standardised 205-day body weight (BW) were determined. Generalised linear mixed models were used to evaluate associations between suckler beef and dairy calves for morbidity, mortality, growth and passive immunity. Receiver operating characteristic (ROC) curves were constructed to determine optimal test cut-offs for classification of health and growth outcomes. Overall, 20% of suckler beef and 30% of dairy calves were treated for at least one disease event by 6 mo. of age. Suckler beef calves had greater odds of bovine respiratory disease (BRD; odds ratio (OR), 95% confidence interval (CI): 2.8, 1.2–6.5, P = 0.01), navel infection (5.1, 1.9–13.2, P < 0.001), and joint infection/lameness (3.2, 1.3–7.8, P = 0.01) during the first 6 mo. of life than dairy calves. In addition, from birth to 6 mo. of age, suckler beef calves had greater rates of navel infection (incidence rate ratio (IRR), 95% CI: 3.3, 1.3–8.4, P = 0.01), but decreased rates of diarrhoea (0.9, 0.2–0.9, P = 0.03) compared to dairy calves. Optimal test cut-offs for classification of morbidity and mortality outcomes in suckler beef calves ranged from 8 to 9 mg/ml ELISA, 56 to 61 g/l TP – CA, 26 to 40 g/l globulin, 12 to 18 ZST units, 8.4% TS – BRIX, and 5.3 to 6.3 g/dl TP – DR. Optimal test cut-offs for classification of morbidity and growth outcomes in dairy calves ranged from 10 to 12 mg/ml ELISA, 57 to 60 g/l TP – CA, 29 to 34 g/l globulin, 19 ZST units, 7.8 to 8.4% TS – BRIX, and 5.7 to 5.9 g/dl TP – DR

Pulmonary embolism severity before and during the COVID-19 pandemic

OBJECTIVES: Early in the coronavirus 2019 (COVID-19) pandemic, a high frequency of pulmonary embolism was identified. This audit aims to assess the frequency and severity of pulmonary embolism in 2020 compared to 2019. METHODS: In this retrospective audit, we compared computed tomography pulmonary angiography (CTPA) frequency and pulmonary embolism severity in April and May 2020, compared to 2019. Pulmonary embolism severity was assessed with the Modified Miller score and the presence of right heart strain was assessed. Demographic information and 30-day mortality was identified from electronic health records. RESULTS: In April 2020, there was a 17% reduction in the number of CTPA performed and an increase in the proportion identifying pulmonary embolism (26%, n = 68/265 vs 15%, n = 47/320, p < 0.001), compared to April 2019. Patients with pulmonary embolism in 2020 had more comorbidities (p = 0.026), but similar age and sex compared to 2019. There was no difference in pulmonary embolism severity in 2020 compared to 2019, but there was an increased frequency of right heart strain in May 2020 (29 vs 12%, p = 0.029). Amongst 18 patients with COVID-19 and pulmonary embolism, there was a larger proportion of males and an increased 30 day mortality (28% vs 6%, p = 0.008). CONCLUSION: During the COVID-19 pandemic, there was a reduction in the number of CTPA scans performed and an increase in the frequency of CTPA scans positive for pulmonary embolism. Patients with both COVID-19 and pulmonary embolism had an increased risk of 30-day mortality compared to those without COVID-19. ADVANCES IN KNOWLEDGE: During the COVID-19 pandemic, the number of CTPA performed decreased and the proportion of positive CTPA increased. Patients with both pulmonary embolism and COVID-19 had worse outcomes compared to those with pulmonary embolism alone

Hybridization from Guest-Host Interactions Reduces the Thermal Conductivity of Metal-Organic Frameworks

We experimentally and theoretically investigate the thermal conductivity and mechanical properties of polycrystalline HKUST-1 metal–organic frameworks (MOFs) infiltrated with three guest molecules: tetracyanoquinodimethane (TCNQ), 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane (F$_{4}$-TCNQ), and (cyclohexane-1,4-diylidene)dimalononitrile (H$_{4}$-TCNQ). This allows for modification of the interaction strength between the guest and host, presenting an opportunity to study the fundamental atomic scale mechanisms of how guest molecules impact the thermal conductivity of large unit cell porous crystals. The thermal conductivities of the guest@MOF systems decrease significantly, by on average a factor of 4, for all infiltrated samples as compared to the uninfiltrated, pristine HKUST-1. This reduction in thermal conductivity goes in tandem with an increase in density of 38% and corresponding increase in heat capacity of ∼48%, defying conventional effective medium scaling of thermal properties of porous materials. We explore the origin of this reduction by experimentally investigating the guest molecules’ effects on the mechanical properties of the MOF and performing atomistic simulations to elucidate the roles of the mass and bonding environments on thermal conductivity. The reduction in thermal conductivity can be ascribed to an increase in vibrational scattering introduced by extrinsic guest-MOF collisions as well as guest molecule-induced modifications to the intrinsic vibrational structure of the MOF in the form of hybridization of low frequency modes that is concomitant with an enhanced population of localized modes. The concentration of localized modes and resulting reduction in thermal conductivity do not seem to be significantly affected by the mass or bonding strength of the guest species

Characterization of an Orphan Diterpenoid Biosynthetic Operon from Salinispora arenicola

While more commonly associated with plants than microbes, diterpenoid natural products have been reported to have profound effects in marine microbe–microbe interactions. Intriguingly, the genome of the marine bacterium Salinispora arenicola CNS-205 contains a putative diterpenoid biosynthetic operon, terp1. Here recombinant expression studies are reported, indicating that this three-gene operon leads to the production of isopimara-8,15-dien-19-ol (4). Although 4 is not observed in pure cultures of S. arenicola, it is plausible that the terp1 operon is only expressed under certain physiologically relevant conditions such as in the presence of other marine organisms

Factors Affecting Disaster Resilience in Oman: Integrating Stakeholder Analysis and Fuzzy Cognitive Mapping

Planning for community resilience to disasters is a process that involves co‐ordinated action within and between relevant organizations and stakeholders, with the goal of reducing disaster risk. The effectiveness of this process is influenced by a range of factors, both positively and negatively, that need to be identified and understood so as to develop organizational capacity to build community resilience to disaster. This study investigates disaster planning and management in Oman, a country facing significant natural hazards, and with a relatively new system of institutional disaster management. Fuzzy cognitive mapping integrated with stakeholder analysis is used to identify relevant factors and their inter‐relationships, and hence provides an improved understanding of disaster governance. Developing an improved understanding of the complexity of this institutional behavior allows identification of opportunities to build greater resilience to disaster through improved planning and emergency response. We make recommendations for improved disaster management in Oman relating to governance (including improved plan dissemination and closer working with community organizations), risk assessment, public education, built environment development, and financing for disaster resilience