Complex roles of myoglianin in regulating adult performance and lifespan

Myoglianin, the Drosophila homolog of the secreted vertebrate proteins Myostatin and GDF-11, is an important regulator of neuronal modelling, and synapse function and morphology. While Myoglianin suppression during development elicits positive effects on the neuromuscular system, genetic manipulations of myoglianin expression levels have a varied effect on the outcome of performance tests in aging flies. Specifically, Myoglianin preserves jumping ability, has no effect on negative geotaxis, and negatively regulates flight performance in aging flies. In addition, Myoglianin exhibits a tissue-specific effect on longevity, with myoglianin upregulation in glial cells increasing the median lifespan. These findings indicate complex role for this TGF-β-like protein in governing neuromuscular signalling and consequent behavioural outputs and lifespan in adult flies

Validation of a New Predictive Risk Model: Measuring the Impact of the Major Modifiable Risks of Death for Patients and Populations

Background: Modifiable risks account for a large fraction of disease and death, but clinicians and patients lack tools to identify high risk populations or compare the possible benefit of different interventions. Methods: We used data on the distribution of exposure to 12 major behavioral and biometric risk factors inthe US population, mortality rates by cause, and estimates of the proportional hazards of risk factor exposure from published systematic reviews to develop a risk prediction model that estimates an adult\u27s 10 year mortality risk compared to a population with optimum risk factors. We compared predicted risk to observed mortality in 8,241 respondents in NHANES 1988-1994 and NHANES 1999-2004 with linked mortality data up to the end of 2006

Spatial and temporal variability in recruitment of intertidal mussels around the coast of southern Africa

Intensity of intertidal mussel recruitment was compared across a range of different spatial and temporal scales around the coast of southern Africa between June 1995 and October 1996. Comparison of the east and west coasts revealed significantly higher recruit densities on the west coast, corresponding to larger adult densities. This difference between the two coasts reflects biogeographic disparities in mussel species composition, growth rates and spawning intensities, oceanographic conditions and productivity. Significant spatial variations in recruitment were recorded between regions 100–1000 km apart and between localities 1–25 km apart. Results suggest that the influence of dispersal processes on recruitment patterns acts at a relatively small scale, and may affect the distribution and abundance of adults among shores only a few kilometres apart. The high variability in recruitment intensities at a scale of metres indicates that larva! supply to the shore may be locally patchy, or that settlement preferences of recruits may be sensitive to subtle small-scale differences in adult density within mussel clumps. Small-scale differences in post-settlement mortality (e.g. owing to patchy predation pressure) may also play a role. This small-scale variability in recruitment is likely to reinforce the mosaic distribution of mussels evident on many of the shores. Significant temporal variability in recruit density was recorded, both between 3-monthly sampling intervals and interannually. Seasonal differences were absent for the north-west regions, whereas asynchronous seasonal patterns were displayed in the other regions. Results suggest that temporal cycles of recruitment are irregular and episodic, which may have important consequences for the dynamics of adults. Significant positive correlations were obtained between maximal recruitment and adult abundance, measured by density, or total number of adults on the shore (stock). This could be explained by the density-dependent role of adult conspecifics in providing suitable settlement habitat, or supply-side recruit limitation. These results have important implications for the management of exploited populations of mussels around the coast of southern Africa. Exploitation may influence recruitment success via at least two processes: reduction of larval supply by depletion of adult stock, and alteration of habitat suitable for settlement. Thus, overexploitation will compromise recruitment, which is itself the only mechanism of recovery. The west-coast mussel populations are likely to be more resilient to exploitation as recruitment is more predictable over time, stocks are larger and recruitment intensities high. This brings into question the present regulations for mussel harvesting because, paradoxically, more lenient regulations are applied on the east coast, where stocks and recruitment are low, than on the west coast, where biomass, recruitment and potential for recovery are high

Perioperative opioids and survival outcomes in resectable head and neck cancer: A systematic review.

BACKGROUND: Opioids are a mainstay in pain control for oncologic surgery. The objective of this systematic review is to evaluate the associations of perioperative opioid use with overall survival (OS) and disease-free survival (DFS) in patients with resectable head and neck cancer (HNC). METHODS: A systematic review of PubMed, SCOPUS, and CINAHL between 2000 and 2022 was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies investigating perioperative opioid use for patients with HNC undergoing surgical resection and its association with OS and DFS were included. RESULTS: Three thousand three hundred seventy-eight studies met initial inclusion criteria, and three studies representing 562 patients (intraoperative opioids, n = 463; postoperative opioids, n = 99) met final exclusion criteria. One study identified that high intraoperative opioid requirement in oral cancer surgery was associated with decreased OS (HR = 1.77, 95% CI 0.995-3.149) but was not an independent predictor of decreased DFS. Another study found that increased intraoperative opioid requirements in treating laryngeal cancer was demonstrated to have a weak but statistically significant inverse relationship with DFS (HR = 1.001, p = 0.02) and OS (HR = 1.001, p = 0.02). The last study identified that patients with chronic opioid after resection of oral cavity cancer had decreased DFS (HR = 2.7, 95% CI 1.1-6.6) compared to those who were not chronically using opioids postoperatively. CONCLUSION: An association may exist between perioperative opioid use and OS and DFS in patients with resectable HNC. Additional investigation is required to further delineate this relationship and promote appropriate stewardship of opioid use with adjunctive nonopioid analgesic regimens

Circadian Rhythms in Visual Responsiveness in the Behaviorally Arrhythmic Drosophila Clock Mutant ClkJrk

An organism's biological day is characterized by a pattern of anticipatory physiological and behavioral changes that are governed by circadian clocks to align with the 24-h cycling environment. Here, we used flash electroretinograms (ERGs) and steady-state visually evoked potentials (SSVEPs) to examine how visual responsiveness in wild-type Drosophila melanogaster and the circadian clock mutant ClkJrk varies over circadian time. We show that the ERG parameters of wild-type flies vary over the circadian day, with a higher luminance response during the subjective night. The SSVEP response that assesses contrast sensitivity also showed a time-of-day dependence, including 2 prominent peaks within a 24-h period and a maximal response at the end of the subjective day, indicating a tradeoff between luminance and contrast sensitivity. Moreover, the behaviorally arrhythmic ClkJrk mutants maintained a circadian profile in both luminance and contrast sensitivity, but unlike the wild-types, which show bimodal profiles in their visual response, ClkJrk flies show a weakening of the bimodal character, with visual responsiveness tending to peak once a day. We conclude that the ClkJrk mutation mainly affects 1 of 2 functionally coupled oscillators and that the visual system is partially separated from the locomotor circadian circuits that drive bouts of morning and evening activity. As light exposure is a major mechanism for entrainment, our work suggests that a detailed temporal analysis of electrophysiological responses is warranted to better identify the time window at which circadian rhythms are most receptive to light-induced phase shifting

Computational approaches for understanding the diagnosis and treatment of Parkinson's disease

This study describes how the application of evolutionary algorithms (EAs) can be used to study motor function in humans with Parkinson’s disease (PD) and in animal models of PD. Human data is obtained using commercially available sensors via a range of non-invasive procedures that follow conventional clinical practice. EAs can then be used to classify human data for a range of uses, including diagnosis and disease monitoring. New results are presented that demonstrate how EAs can also be used to classify fruit flies with and without genetic mutations that cause Parkinson’s by using measurements of the proboscis extension reflex. The case is made for a computational approach that can be applied across human and animal studies of PD and lays the way for evaluation of existing and new drug therapies in a truly objective way

Abnormal visual gain control and excitotoxicity in early-onset Parkinson's disease Drosophila models

The excitotoxic theory of Parkinson's disease (PD) hypothesises that a pathophysiological degeneration of dopaminergic neurons stems from neural hyperactivity at early stages of disease, leading to mitochondrial stress and cell death. Recent research has harnessed the visual system of Drosophila PD models to probe this hypothesis. Here, we investigate whether abnormal visual sensitivity and excitotoxicity occur in early-onset PD Drosophila models DJ-1Δ72, DJ1-Δ93, and PINK15. We used an electroretinogram to record steady state visually evoked potentials driven by temporal contrast stimuli. At 1 day of age, all early-onset PD mutants had a twofold increase in response amplitudes when compared to w- controls. Further, we found that excitotoxicity occurs in older early-onset PD models after increased neural demand is applied via visual stimulation. In an additional analysis, we used a linear discriminant analysis to test whether there were subtle variations in neural gain control that could be used to classify Drosophila into their correct age and genotype. The discriminant analysis was highly accurate, classifying Drosophila into their correct genotypic class at all age groups at 50-70% accuracy (20% chance baseline). Differences in cellular processes link to subtle alterations in neural network operation in young flies - all of which lead to the same pathogenic outcome. Our data are the first to demonstrate abnormal gain control and excitotoxicity in early-onset PD Drosophila mutants. We conclude that early-onset PD mutations may be linked to more sensitive neuronal signalling in prodromal animals that may cause the expression of PD symptomologies later in life

Correction: Metal complexes as a promising source for new antibiotics

Correction for ‘Metal complexes as a promising source for new antibiotics’ by Angelo Frei et al., Chem. Sci., 2020, 11, 2627–2639

Metal complexes as a promising source for new antibiotics

There is a dire need for new antimicrobial compounds to combat the growing threat of widespread antibiotic resistance. With a currently very scarce drug pipeline, consisting mostly of derivatives of known antibiotics, new classes of antibiotics are urgently required. Metal complexes are currently in clinical development for the treatment of cancer, malaria and neurodegenerative diseases. However, only little attention has been paid to their application as potential antimicrobial compounds. We report the evaluation of 906 metal-containing compounds that have been screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD) for antimicrobial activity. Metal-bearing compounds display a significantly higher hit-rate (9.9%) when compared to the purely organic molecules (0.87%) in the CO-ADD database. Out of 906 compounds, 88 show activity against at least one of the tested strains, including fungi, while not displaying any cytotoxicity against mammalian cell lines or haemolytic properties. Herein, we highlight the structures of the 30 compounds with activity against Gram-positive and/or Gram-negative bacteria containing Mn, Co, Zn, Ru, Ag, Eu, Ir and Pt, with activities down to the nanomolar range against methicillin resistant S. aureus (MRSA). 23 of these complexes have not been reported for their antimicrobial properties before. This work reveals the vast diversity that metal-containing compounds can bring to antimicrobial research. It is important to raise awareness of these types of compounds for the design of truly novel antibiotics with potential for combatting antimicrobial resistance