Genome instability and loss of protein homeostasis:converging paths to neurodegeneration?

Genome instability and loss of protein homeostasis are hallmark events of age-related diseases that include neurodegeneration. Several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis are characterized by protein aggregation, while an impaired DNA damage response (DDR) as in many genetic DNA repair disorders leads to pronounced neuropathological features. It remains unclear to what degree these cellular events interconnect with each other in the development of neurological diseases. This review highlights how the loss of protein homeostasis and genome instability influence one other. We will discuss studies that illustrate this connection. DNA damage contributes to many neurodegenerative diseases, as shown by an increased level of DNA damage in patients, possibly due to the effects of protein aggregates on chromatin, the sequestration of DNA repair proteins and novel putative DNA repair functions. Conversely, genome stability is also important for protein homeostasis. For example, gene copy number variations and the loss of key DDR components can lead to marked proteotoxic stress. An improved understanding of how protein homeostasis and genome stability are mechanistically connected is needed and promises to lead to the development of novel therapeutic interventions

The MindfulBreather: Motion Guided Mindfulness.

For millennia, humans have focused their attention on the breath to develop mindfulness, but finding a scientific way to harness mindful breathing has proven elusive. Existing attempts to objectively measure and feedback on mindfulness have relied on specialist external hardware including electroencephalograms or respirometers that have been impractical for the majority of people learning to meditate. Consequently, training in the key skill of breath-awareness has lacked practical objective measures and guidance to enhance training. Here, we provide a brief technology report on an invention, The MindfulBreather® that addresses these issues. The technology is available to download embedded in a smartphone app that targets, measures and feedbacks on mindfulness of breathing in realtime to enhance training. The current article outlines only the technological concept with future studies quantifying efficacy, validity and reliability to be reported elsewhere. The MindfulBreather works by generating Motion Guided Mindfulness through interacting gyroscopic and touchscreen sensors in a three phase process: Mindfulness Induction (Phase I) gives standardized instruction to users to place their smartphone on their abdomen, breathe mindfully and to tap only at the peak of their inhalation. The smartphone's gyroscope detects periodic tilts during breathing to generate sinusoidal waveforms. Waveform-tap patterns are analyzed to determine whether the user is mindfully tapping only at the correct phase of the breathing cycle, indicating psychobiological synchronization. Mindfulness Maintenance (Phase II) provides reinforcing pleasant feedback sounds each time a breath is mindfully tapped at the right time, and the App records a mindful breath. Lastly, data-driven Insights are fed back to the user (Phase III), including the number of mindful breaths tapped and breathing rate reductions associated with parasympathetic engagement during meditation. The new MGM technology is then evaluated and contrasted with traditional mindfulness approaches and a novel Psychobiological Synchronization Model is proposed. In summary, unlike existing technology, the MindfulBreather requires no external hardware and repurposes regular smartphones to deliver app-embedded Motion-Guided Mindfulness. Technological applications include reducing mindwandering and down-regulation of the brain's default mode through enhanced mindful awareness. By objectively harnessing breath awareness, The MindfulBreather aims to realize the ancient human endeavor of mindfulness for the 21st century

Morning exercise mitigates the impact of prolonged sitting on cerebral blood flow in older adults

Preventing declines in cerebral blood flow is important for maintaining optimal brain health with aging. We compared the effects of a morning bout of moderate-intensity exercise, with and without subsequent light-intensity walking breaks from sitting, on cerebral blood velocity over 8 h in older adults. In a randomized crossover trial, overweight/obese older adults (n = 12, 70 ± 7 yr; 30.4 ± 4.3 kg/m2), completed three acute conditions (6-day washout); SIT: prolonged sitting (8 h, control); EX+SIT: sitting (1 h), moderate-intensity walking (30 min), followed by uninterrupted sitting (6.5 h); and EX + BR: sitting (1 h), moderate-intensity walking (30 min), followed by sitting (6.5 h) interrupted with 3 min of light-intensity walking every 30 min. Bilateral middle cerebral artery velocities (MCAv) were determined using transcranial Doppler at 13 time points across the day. The temporal pattern and average MCAv over 8 h was determined. The pattern of MCAv over 8 h was a negative linear trend in SIT (P < 0.001), but a positive quadratic trend in EX + SIT (P < 0.001) and EX + BR (P < 0.01). Afternoon time points in SIT were lower than baseline within condition (P ≤ 0.001 for all). A morning dip in MCAv was observed in EX + SIT and EX + BR (P < 0.05 relative to baseline), but afternoon time points were not significantly lower than baseline. The average MCAv over 8 h was higher in EX + SIT than SIT (P = 0.007) or EX + BR (P = 0.024). Uninterrupted sitting should be avoided, and moderate-intensity exercise should be encouraged for the daily maintenance of cerebral blood flow in older adults. The clinical implications of maintaining adequate cerebral blood flow include the delivery of vital oxygen and nutrients to the brain

Exponential growth, high prevalence of SARS-CoV-2, and vaccine effectiveness associated with the Delta variant

SARS-CoV-2 infections were rising during early summer 2021 in many countries associated with the Delta variant. We assessed RT-PCR swab-positivity in the REal-time Assessment of Community Transmission-1 (REACT-1) study in England. We observed sustained exponential growth with average doubling time (June-July 2021) of 25 days driven by complete replacement of Alpha variant by Delta, and by high prevalence at younger less-vaccinated ages. Unvaccinated people were three times more likely than double-vaccinated people to test positive. However, after adjusting for age and other variables, vaccine effectiveness for double-vaccinated people was estimated at between ~50% and ~60% during this period in England. Increased social mixing in the presence of Delta had the potential to generate sustained growth in infections, even at high levels of vaccination

Growth and development of the Drosophila abdominal epithelium

The growth of multicellular organisms and their organs is a tightly regulated process, ensuring that each animal of a given species grows to its characteristic size and shape. A key regulator of organ size during development is Hippo signalling, a highly conserved tumour-suppressor pathway, which controls the activity of pro-growth transcriptional co-activator Yorkie (Yki). Multiple upstream cues regulate the activity of the Hippo pathway, including cell-cell contacts and mechanical strain. In this project I studied growth control in the Drosophila histoblasts, the precursor cells that give rise to the adult abdominal epidermis during pupal development. Histoblasts are specified during embryogenesis, however they remain quiescent until pupariation. During the early pupal stages, histoblasts undergo extensive proliferation, replacing the surrounding larval epithelial cells (LECS), which extrude from the epithelial layer and undergo apoptosis. Once histoblasts have covered the surface of the pupal abdomen, they undergo tissue growth arrest. Histoblast nests provide a highly genetically tractable model system that enables live imaging of cell proliferation and arrest of a developing tissue in vivo. A bespoke image analysis pipeline was created to segment and track histoblasts, with which I performed a detailed analysis of temporal and spatial changes of morphogenesis over an extensive developmental period. Furthermore, the histoblast model allows investigation of mechanical forces on tissue growth in a live, developing tissue. This was done through alteration of the mechanical environment of the histoblasts by genetically interfering with the surrounding LECs. I found that proliferation rate was unaffected by stretching or constraint, whereas changing the state of the basal extracellular matrix (ECM) has an impact on Yki activity and proliferation rates. Finally, I looked at possible biochemical mechanisms of Yki regulation by screening members of the Hippo signalling network, and I identified several candidates for further investigation

Quantitative assessment of placental morphology may identify specific causes of stillbirth

BACKGROUND: Stillbirth is frequently the result of pathological processes involving the placenta. Understanding the significance of specific lesions is hindered by qualitative subjective evaluation. We hypothesised that quantitative assessment of placental morphology would identify alterations between different causes of stillbirth and that placental phenotype would be independent of post-mortem effects and differ between live births and stillbirths with the same condition. METHODS: Placental tissue was obtained from stillbirths with an established cause of death, those of unknown cause and live births. Image analysis was used to quantify different facets of placental structure including: syncytial nuclear aggregates (SNAs), proliferative cells, blood vessels, leukocytes and trophoblast area. These analyses were then applied to placental tissue from live births and stillbirths associated with fetal growth restriction (FGR), and to placental lobules before and after perfusion of the maternal side of the placental circulation to model post-mortem effects. RESULTS: Different causes of stillbirth, particularly FGR, cord accident and hypertension had altered placental morphology compared to healthy live births. FGR stillbirths had increased SNAs and trophoblast area and reduced proliferation and villous vascularity; 2 out of 10 stillbirths of unknown cause had similar placental morphology to FGR. Stillbirths with FGR had reduced vascularity, proliferation and trophoblast area compared to FGR live births. Ex vivo perfusion did not reproduce the morphological findings of stillbirth. CONCLUSION: These preliminary data suggest that addition of quantitative assessment of placental morphology may distinguish between different causes of stillbirth; these changes do not appear to be due to post-mortem effects. Applying quantitative assessment in addition to qualitative assessment might reduce the proportion of unexplained stillbirths. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12907-016-0023-y) contains supplementary material, which is available to authorized users