Ageing related thyroid deficiency increases brain-targeted transport of liver-derived ApoE4-laden exosomes leading to cognitive impairment

Alzheimer’s disease (AD) is the prevalent cause of dementia in the ageing world population. Apolipoprotein E4 (ApoE4) allele is the key genetic risk factor for AD, although the mechanisms linking ApoE4 with neurocognitive impairments and aberrant metabolism remains to be fully characterised. We discovered a significant increase in the ApoE4 content of serum exosomes in old healthy subjects and AD patients carrying ApoE4 allele as compared with healthy adults. Elevated exosomal ApoE4 demonstrated significant inverse correlation with serum level of thyroid hormones and cognitive function. We analysed effects of ApoE4-containing peripheral exosomes on neural cells and neurological outputs in aged or thyroidectomised young mice. Ageing-associated hypothyroidism as well as acute thyroidectomy augmented transport of liver-derived ApoE4 reach exosomes into the brain, where ApoE4 activated nucleotide-binding oligomerisation domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome by increasing cholesterol level in neural cells. This, in turn, affected cognition, locomotion and mood. Our study reveals pathological potential of exosomes-mediated relocation of ApoE4 from the periphery to the brain, this process can represent potential therapeutic target.Subject terms: Cognitive neuroscience, Alzheimer''s disease, Cellular neuroscience     

Nitrate increases cisplatin chemosensitivity of oral squamous cell carcinoma via REDD1/AKT signaling pathway

Although cisplatin is one of the chemotherapeutics most frequently used in oral squamous cell carcinoma (OSCC) treatment,it exerts multiple side effects and poo...     

Ancient and recent introgression shape the evolutionary history of pollinator adaptation and speciation in a model monkeyflower radiation (Mimulus section Erythranthe)

Inferences about past processes of adaptation and speciation require a gene-scale and genome-wide understanding of the evolutionary history of diverging taxa. In this study, we use genome-wide capture of nuclear gene sequences, plus skimming of organellar sequences, to investigate the phylogenomics of monkeyflowers in Mimulus section Erythranthe (27 accessions from seven species). Taxa within Erythranthe, particularly the parapatric and putatively sister species M. lewisii (bee-pollinated) and M. cardinalis (hummingbird-pollinated), have been a model system for investigating the ecological genetics of speciation and adaptation for over five decades. Across >8000 nuclear loci, multiple methods resolve a predominant species tree in which M. cardinalis groups with other hummingbird-pollinated taxa (37% of gene trees), rather than being sister to M. lewisii (32% of gene trees). We independently corroborate a single evolution of hummingbird pollination syndrome in Erythranthe by demonstrating functional redundancy in genetic complementation tests of floral traits in hybrids; together, these analyses overturn a textbook case of pollination-syndrome convergence. Strong asymmetries in allele sharing (Patterson’s D-statistic and related tests) indicate that gene tree discordance reflects ancient and recent introgression rather than incomplete lineage sorting. Consistent with abundant introgression blurring the history of divergence, low-recombination and adaptation-associated regions support the new species tree, while high-recombination regions generate phylogenetic evidence for sister status for M. lewisii and M. cardinalis. Population-level sampling of core taxa also revealed two instances of chloroplast capture, with Sierran M. lewisii and Southern Californian M. parishii each carrying organelle genomes nested within respective sympatric M. cardinalis clades. A recent organellar transfer from M. cardinalis, an outcrosser where selfish cytonuclear dynamics are more likely, may account for the unexpected cytoplasmic male sterility effects of selfer M. parishii organelles in hybrids with M. lewisii. Overall, our phylogenomic results reveal extensive reticulation throughout the evolutionary history of a classic monkeyflower radiation, suggesting that natural selection (re-)assembles and maintains species-diagnostic traits and barriers in the face of gene flow. Our findings further underline the challenges, even in reproductively isolated species, in distinguishing re-use of adaptive alleles from true convergence and emphasize the value of a phylogenomic framework for reconstructing the evolutionary genetics of adaptation and speciation.     

Behavioural versus physiological mediation of life history under predation risk

Predator-generated variation in prey energy intake remains the dominant explanation of adaptive response to predation risk in prey life history, morphology and physiology across a wide range of taxa. This "behavioural hypothesis" suggest that chemical or visual signals of predation risk reduce prey energy intake leading to a life history characterized by a small size and late age at maturity. However, size-selective predation can induce either smaller size-early age or large size-late age life history. The alternative "physiological hypothesis" suggests that size-selective cues decouple the relationship between energy and life history, acting instead directly on development. Here we use a series of experiments in a fish-daphnid predator-prey system to ask whether size-selective predator cues induce a physiological mediation of development, overshadowing behaviourally based changes in food intake. We found fish chemical cues reduce the net energy intake in Daphnia magna, suggesting a behaviourally mediated reduction in energy. Experimental manipulation of food levels show further that reductions in food lead to later but smaller size at maturity. However, in line with the physiological hypothesis, we show that D. magna matures earlier and at a smaller size when exposed to fish predation cues. Furthermore, our data shows that they do this by increasing their development rate (earlier maturity) for a given growth rate, resulting in a smaller size at maturity. Our data, from a classic size-selective predation system, indicate that predator-induced changes in this system are driven by physiological mediation of development rather than behavioural mediation of energy intake.     

Which Urban Migrants Default from Tuberculosis Treatment in Shanghai,China?

Background

Migration is a major challenge to tuberculosis (TB) control worldwide. TB treatment requires multiple drugs for at least six months. Some TB patients default before completing their treatment regimen, which can lead to ongoing infectiousness and drug resistance.

Methods

We conducted a retrospective analysis of 29,943 active TB cases among urban migrants that were reported between 2000 to 2008 in Shanghai, China. We used logistic regression models to identify factors independently associated with treatment defaults in TB patients among urban migrants during 2005-2008.

Results

Fifty-two percent of the total TB patients reported in Shanghai during the study period were among urban migrants. Three factors increased the odds of a treatment default: case management using self-administered therapy (OR, 5.84, 95% CI, 3.14-10.86, p<0.0005), being a retreatment case (OR, 1.47, 95% CI, 1.25-1.71, p<0.0005), and age >60 years old (OR, 1.33, 95% CI, 1.05-1.67, p=0.017). The presence of a cavity in the initial chest radiograph decreased the odds for a treatment default (OR, 0.87, 95% CI, 0.77-0.97, p=0.015), as did migration from central China (OR, 0.85, 95% CI, 0.73-0.99, p=0.042), case management by family members (OR, 0.73, 95% CI 0.66-0.81, p<0.0005), and the combination of case detection by a required physical exam and case management by health care staff (OR, 0.64, 95% CI, 0.45-0.93, p=0.019).

Conclusion

Among TB patients who were urban migrants in Shanghai, case management using self-administered therapy was the strongest modifiable risk factor that was independently associated with treatment defaults. Interventions that target retreated TB cases could also reduce treatment defaults among urban migrants. Health departments should develop effective measures to prevent treatment defaults among urban migrants, to ensure completion of therapy among urban migrants who move between cities and provinces, and to improve reporting of treatment outcomes.     

Effect of Acute and Chronic Administration of Methylphenidate on Mitochondrial Respiratory Chain in the Brain of Young Rats

Methylphenidate is commonly used for the treatment of attention deficit/hyperactivity disorder. There are still few works regarding the effects of methylphenidate on brain energy metabolism. Thus, in the present study we evaluated the effect of chronic administration of methylphenidate on the activities of mitochondrial respiratory chain complexes I and III in the brain of young rats. The effect of acute administration of methylphenidate on mitochondrial respiratory chain complexes I, II, III and IV in the brain of young rats was also investigated. For acute administration, a single injection of methylphenidate was given to rats on postnatal day 25. For chronic administration, methylphenidate injections were given starting at postnatal day 25 once daily for 28 days. Our results showed that complexes I and III were not affected by chronic administration of methylphenidate. Moreover, the acute administration of methylphenidate decreased complex I activity in cerebellum and prefrontal cortex, whereas complexes II, III and IV were not altered.     

Recommendations on treatment for IPF

Patient management in Idiopathic Pulmonary Fibrosis (IPF) is largely based on societal guidelines and recommendations. A recent update by the American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS) and Latin American Thoracic Association (ALAT) provided updated guidance on the diagnosis and management of IPF, along with recommendations on pharmacologic and non-pharmacologic approaches to patient management. The treatment guidance is based on GRADE criteria, which rates the quality of evidence according to previously published methodology. Here we discuss how to interpret the recent guideline updates and the implications of this guidance for clinical practice. In addition we discuss the assessment and recommendations for a number of pharmacological agents that have been the focus of clinical trials over the past years. Although no single pharmacological agent was recommended by the guidelines committee, we discuss how since then, more recent data have resulted in the approval of pirfenidone in Europe, and preliminary negative findings regarding the safety of a triple therapy regimen consisting of prednisone, azathioprine and N-acetylcysteine have raised the question of whether it is no longer a treatment option. As clinicians, we must interpret the available guidance and recommendations as we consider each individual patient and as we discuss the available clinical data and the patient’s own preferences in our approach to the management of this disease.