Alzheimer’s disease related transcriptional sex differences in myeloid cells

Sex differences have been identified in many diseases associated with dysregulated immune responses, including Alzheimer’s disease (AD), for which approximately two-thirds of patients are women. An accumulating body of research indicates that microglia may play a causal role in the pathogenesis of this disease. We hypothesised that sex differences in the transcriptome of human myeloid cells may contribute to the sex difference observed in AD prevalence. To explore this, we assessed bulk and single-nuclear RNA sequencing data sets generated from four human derived myeloid cell populations: post-mortem microglial nuclei, peripheral monocytes, monocyte-derived macrophages (MDMs) and induced pluripotent stem cell derived microglial-like cells (MGLs). We found that expression of AD risk genes, gene signatures associated with the inflammatory response in AD, and genes related to proinflammatory immune responses were enriched in microglial nuclei isolated from aged female donors without ante-mortem neurological disease, relative to those from males. In addition, these inflammation-associated gene sets were found to be enriched in peripheral monocytes isolated from postmenopausal women and in MDMs obtained from premenopausal individuals relative to age-matched males. Expression of these gene sets did not differ in MDMs derived from women whose blood was sampled across the menstrual cycle or in MGLs cultured with 17β-oestradiol. This suggests that the observed gene set enrichments in myeloid cells from women were not being driven by acute hormonal influences. Together, these data support the hypothesis that the increased prevalence of AD in women may be partly explained by a myeloid cell phenotype biased towards expression of biological processes relevant to AD

Архетип свобода у контексті французької політичної теорії та історії

Розглянуто сучасні підходи щодо аналізу політичної ментальності. У межах політологічного аналізу окреслено коло проблем, які потребують вирішення з використанням підходів психології. Зроблено висновок про те, що архетип “свобода” становить важливий елемент політичної ментальності французів.Modern approaches of analysis of political mentality are considered. Within the limits of political science analysis outlined circle of problems which need decision with the use of approaches of psychology. A conclusion is done that archetype freedom makes the important element of political mentality of French’s

Interrupted sitting improves acute postprandial glucose control without increasing risk of hypoglycaemia in people with type 1 diabetes [Conference abstract]

Background and aims: We have previously shown that interrupting prolonged periods of sitting with short, frequent light-intensity walking activity improves postprandial glucose levels in people with and at risk of Type 2 Diabetes. However, no research has investigated whether and how such an intervention affects postprandial glucose control, including the risk of hypoglycaemia, in people with Type 1 Diabetes (T1D). Therefore, we assessed the impact of short, frequent bouts of light-intensity walking on acute postprandial glycaemia in people with T1D. Materials and methods: In a randomised crossover design, ten inactive adults with T1D (6 men; mean±SD: 30±34.7 years) completed two fasted morning-time (~08:00am) laboratory visits each separated by a minimum of a 1-week washout. On each occasion participants consumed a standardised carbohydrate-based meal with their usual insulin dose determined by the carbohydrate-counting method; the meal and insulin dose was identical on each occasion. Following consumption of the meal, participants underwent two experimental conditions each lasting 4-hours: (1) uninterrupted sitting (SIT); or (2) sitting interrupted with 5-minute bouts of self-paced light-intensity walking every 30-minutes for a total of 4-hours (SIT-Less). Interstitial glucose responses were measured across the 4-hour postprandial period using continuous glucose monitoring (CGM). Results: Postprandial glucose concentrations increased with SIT whereas this rise was tempered with SIT-Less (SIT: Δ2.7±2.6 vs. SIT-Less Δ0.4±1.2 mmol/L p=.043). With SIT-Less, Time in Range (3.9-10 mmol/L) was significantly increased (SIT 114±114 vs. SIT-Less 288±36 minutes p=.008), time spent in hyperglycaemia was significantly reduced (SIT 94±86 vs. SIT-Less 9.5±24 minutes, p=.043), and glucose peak was significantly lower (SIT: Δ5.8±4.1 vs. SIT-Less 2.0±1.4 mmol/L p=.047). There were no episodes of hypoglycaemia in either condition. Conclusion: Interrupting sitting time, with brief regular bouts of light-intensity walking activity, significantly improves acute postprandial glycaemia in people with T1D without increasing the risk of acute hypoglycaemia. With low adherence to structured exercise and the ubiquity of sedentary behaviours, these preliminary findings suggest that interrupted sitting has the potential to be a safe, beneficial and practical means for improving postprandial glycaemia in people with T1D

Interrupted sitting improves 24-hour glucose control in people with type 1 diabetes [Conference abstract]

Background and aims: Interrupting prolonged periods of sitting with short, frequent light-intensity walking improves 24-hour glucose control Diabetologia in people with and at risk of Type 2 Diabetes. However, it is unknown whether and how such an intervention influences 24-hour glucose control, including risk of hypoglycaemia, in people with Type 1 Diabetes (T1D). Therefore, we evaluated the effect of short, frequent bouts of light-intensity walking on 24-hour glycaemia in people with T1D. Materials and methods: In a randomised crossover design, ten inactive adults with T1D (6 men; mean±SD: 30±34.7 years) completed two morning (~08:00am) laboratory visits in a fasted state, each separated by at least 1-week. On both visits, participants consumed a standardised carbohydrate-based meal with their usual insulin dose determined by the carbohydrate-counting method; the meal and insulin dose were identical on each visit. After consuming the meal, participants underwent two experimental conditions: (1) uninterrupted sitting (SIT); or (2) sitting interrupted with 5-minute bouts of light-intensity walking every 30- minutes for 4-hours (SIT-Less). Interstitial glucose responses were measured using continuous glucose monitoring (CGM) during the 4- hour laboratory visit for a further 20-hours under free-living conditions. Results: Compare to SIT, whole-day glycaemia was significantly lower following SIT-Less; 24-hour interstitial glucose Area Under the Curve was -14%[1.2%] under SIT-Less (p=0.023), accompanied by a significantly smaller average change in interstitial glucose from baseline (SIT: Δ1.5±2.5 vs. SIT-Less Δ-0.01±1.6 mmol/L, p=0.001), and lower average interstitial glucose peak (SIT:Δ7.7±3.0 vs. SIT-Less Δ3.9±1.4 mmol/L, p=0.002). Furthermore, with SIT-Less, Time in Range (TIR; 3.9-10 mmol/L), was significantly greater (TIR: SIT 991.5±286.86 vs. SIT-Less 1240.5±173.5 minutes, p=0.030), while time spent in hyperglycaemia was significantly lower (SIT 413.5±266.8 vs. SIT-Less 162±163.6 minutes, p=0.020). However, time spent in hypoglycaemia was similar between conditions (SIT 35±68.68 vs. SIT-Less 37.5±62.19 minutes, p=0.933). Glycaemic variability was lower with SIT-Less (CV%: SIT 29.4±7.6 vs. SIT-Less 22.1±7.5 %, p=0.021). Conclusion: Interrupting sitting time, with brief light-intensity walking activity, significantly improves whole-day glucose control in people with T1D. These preliminary findings suggest that interrupted sitting may serve as an effective and practical means of normalising daily glucose levels in people with T1D by increasing time in range and reducing glycaemic variability, without increasing the risk of hypoglycaemia

Automating data analysis for hydrogen/deuterium exchange mass spectrometry using data-independent acquisition methodology

Abstract We present a hydrogen/deuterium exchange workflow coupled to tandem mass spectrometry (HX-MS2) that supports the acquisition of peptide fragment ions alongside their peptide precursors. The approach enables true auto-curation of HX data by mining a rich set of deuterated fragments, generated by collisional-induced dissociation (CID), to simultaneously confirm the peptide ID and authenticate MS1-based deuteration calculations. The high redundancy provided by the fragments supports a confidence assessment of deuterium calculations using a combinatorial strategy. The approach requires data-independent acquisition (DIA) methods that are available on most MS platforms, making the switch to HX-MS2 straightforward. Importantly, we find that HX-DIA enables a proteomics-grade approach and wide-spread applications. Considerable time is saved through auto-curation and complex samples can now be characterized and at higher throughput. We illustrate these advantages in a drug binding analysis of the ultra-large protein kinase DNA-PKcs, isolated directly from mammalian cells