Gut microbiota links with cognitive impairment in amyotrophic lateral sclerosis: A multi-omics study

Recently, cognitive impairments (CI) and behavioral abnormalities in patients with amyotrophic lateral sclerosis (ALS) have been reported. However, the underlying mechanisms have been poorly understood. In the current study, we explored the role of gut microbiota in CI of ALS patients. We collected fecal samples from 35 ALS patients and 35 healthy controls. The cognitive function of the ALS patients was evaluated using the Edinburgh Cognitive and Behavioral ALS Screen. We analyzed these samples by using 16S rRNA gene sequencing as well as both untargeted and targeted (bile acids) metabolite mapping between patients with CI and patients with normal cognition (CN). We found altered gut microbial communities and a lower ratio of Firmicutes/ Bacteroidetes in the CI group, compared with the CN group. In addition, the untargeted metabolite mapping revealed that 26 and 17 metabolites significantly increased and decreased, respectively, in the CI group, compared with the CN group. These metabolites were mapped to the metabolic pathways associated with bile acids. We further found that cholic acid and chenodeoxycholic acid were significantly lower in the CI group than in the CN group. In conclusion, we found that the gut microbiota and its metabolome profile differed between ALS patients with and without CI and that the altered bile acid profile in fecal samples was significantly associated with CI in ALS patients. These results need to be replicated in larger studies in the future.VoRSUNY DownstateNeurologyN/

G protein-coupled receptor-mediated calcium signaling in astrocytes

Astrocytes express a large variety of G~protein-coupled receptors (GPCRs) which mediate the transduction of extracellular signals into intracellular calcium responses. This transduction is provided by a complex network of biochemical reactions which mobilizes a wealth of possible calcium-mobilizing second messenger molecules. Inositol 1,4,5-trisphosphate is probably the best known of these molecules whose enzymes for its production and degradation are nonetheless calcium-dependent. We present a biophysical modeling approach based on the assumption of Michaelis-Menten enzyme kinetics, to effectively describe GPCR-mediated astrocytic calcium signals. Our model is then used to study different mechanisms at play in stimulus encoding by shape and frequency of calcium oscillations in astrocytes.Comment: 35 pages, 6 figures, 1 table, 3 appendices (book chapter

The Effect of Perceived Stress, Family Companionship, and Mental Health on the Subjective Happiness of Chinese Healthcare Workers: A Mixed Research Method

Aim: This study aimed to understand the impact of perceived stress on the subjective happiness of Chinese healthcare workers (HCWs) and to further explore the chain-mediating role of family companionship and mental health. Background: In the face of tense doctor–patient relationships; a heavy workload; long working hours; seemingly endless shifts; potential professional title promotions; work performance assessments; and the difficult balance between family, work, and other aspects of life, HCWs are often under great pressure, which can endanger mental health and reduce subjective happiness. However, the role of healthcare workers’ active participation in family companionship in mental health and subjective happiness is not clear. Method: We used a mixed research design to collect data in two locations (Hospital A and Hospital B) in Wuhan, China. A self-distributed questionnaire was assigned to HCWs through the Research Electronic Data Capture survey. A total of 368 valid surveys were obtained. Results: Hospital A’s perceived stress level and mental health problems were more severe, while Hospital B had a higher subjective happiness score and more time to spend with their families. Subjective happiness was affected by children, education, occupation, health status, commuting time, and the scores of perceived stress and depression. The scores of perceived stress and mental health were significantly negatively associated with subjective happiness and family companionship, and there was a significant positive correlation between subjective happiness and family companionship. The results also showed that family companionship and mental health acted as serial mediators between perceived stress and subjective happiness. However, family companionship did not play a mediating role between perceived stress and subjective happiness. Most HCWs had work–family conflicts, and a high amount of work pressure and feelings of powerlessness and not having sufficient time were common when they accompanied their families. Conclusions: HCWs had a high level of perceived stress and psychological distress, and their subjective happiness score was lower than that of the general population. Many HCWs experienced negative emotions when taking care of their families. Only a small number of people had enough time to spend time with their families and perform more prominently in busier hospitals. More importantly, perceived stress can indirectly have an impact on subjective happiness through a chain-mediating effect of family companionship and mental health, and family companionship may not always promote subjective happiness unless mental health is maintained. Therefore, in the future, we can consider carrying out interventions based on family companionship and mental health among HCWs to promote the healthy and harmonious development of individuals, families, and hospitals

Durative sleep fragmentation with or without hypertension suppress rapid eye movement sleep and generate cerebrovascular dysfunction

Either hypertension or chronic insomnia is the risk factor of developing vascular dementia. Durative hypertension can induce vascular remodeling and is used for modeling small vessel disease in rodents. It remains undetermined if the combination of hypertension and sleep disturbance exacerbates vascular dysfunction or pathologies. Previously, we found chronic sleep fragmentation (SF) dampened cognition in young mice without disease predispositions. In the current study, we superimposed SF with hypertension modeling in young mice. Angiotensin II (AngII)-releasing osmotic mini pumps were subcutaneously implanted to generate persistent hypertension, while sham surgeries were performed as controls. Sleep fragmentation with repetitive arousals (10 s every 2 min) during light-on 12 h for consecutive 30 days, while mice undergoing normal sleep (NS) processes were set as controls. Sleep architectures, whisker-stimulated cerebral blood flow (CBF) changes, vascular responsiveness as well as vascular pathologies were compared among normal sleep plus sham (NS + sham), SF plus sham (SF + sham), normal sleep plus AngII (NS + AngII), and SF plus AngII (SF + AngII) groups. SF and hypertension both alter sleep structures, particularly suppressing REM sleep. SF no matter if combined with hypertension strongly suppressed whisker-stimulated CBF increase, suggesting the tight association with cognitive decline. Hypertension modeling sensitizes vascular responsiveness toward a vasoactive agent, Acetylcholine (ACh, 5 mg/ml, 10 μl) delivered via cisterna magna infusion, while SF exhibits a similar but much milder effect. None of the modeling above was sufficient to induce arterial or arteriole vascular remodeling, but SF or SF plus hypertension increased vascular network density constructed by all categories of cerebral vessels. The current study would potentially help understand the pathogenesis of vascular dementia, and the interconnection between sleep and vascular health

Changes in the composition of brain interstitial ions control the sleep-wake cycle

Sleep induction through ion changes How do we switch from sleep to arousal and back? Ding et al. found that a combination of modulatory neurotransmitters influenced the levels of extracellular ions in the brain (see the Perspective by Landolt and Holst). This influence was not driven by changes in local neuronal firing, suggesting direct effects of the neuromodulators on extracellular ion composition. However, these changes in interstitial ion levels could switch a brain from wakefulness to sleep. Changes in extracellular ions may thus be a cause, rather than a consequence, of sleep/wake-dependent changes in neuronal activity. Science , this issue p. 550 ; see also p. 517 </jats:p

Roles of External Forcing and Internal Variability in Global Marine Heatwaves Change During 1982–2021

Abstract As discrete prolonged extreme warm water events, marine heatwaves (MHWs) have become more frequent, stronger and longer‐lasting during the past several decades. The relative contributions of external forcing and internal variability to these changes and their underlying drivers remain unclear. Here, analyses of 90 simulations in CESM2 reveal that external forcing dominates the increasing frequency by causing the mean warming of sea surface temperature (SST), accounting for 82% of the observed trends. Both the mean warming and increased variance of SST contribute to the longer‐lasting MHWs during 1982–2021, with external forcing contributing 38% of the increase in the SST variance for global average. Internal variability, especially the Inter‐decadal Pacific Oscillation (IPO), is closely associated with regional MHW changes. The observed negative IPO trend during 1982–2021 is related to increasing, strengthening and longer‐lasting MHW over Kuroshio Extension, but decreasing and shorter‐lasting MHW over the Northeast Pacific Coast

Focal Solute Trapping and Global Glymphatic Pathway Impairment in a Murine Model of Multiple Microinfarcts

Microinfarcts occur commonly in the aging brain as a consequence of diffuse embolic events and are associated with the development of vascular dementia and Alzheimer's disease. However, the manner in which disperse microscopic lesions reduce global cognitive function and increase the risk for Alzheimer's disease is unclear. The glymphatic system, which is a brain-wide perivascular network that supports the recirculation of CSF through the brain parenchyma, facilitates the clearance of interstitial solutes including amyloid β and tau. We investigated whether glymphatic pathway function is impaired in a murine model of multiple microinfarcts induced by intraarterial injection of cholesterol crystals. The analysis showed that multiple microinfarcts markedly impaired global influx of CSF along the glymphatic pathway. Although suppression of global glymphatic function was transient, resolving within 2 weeks of injury, CSF tracers also accumulated within tissue associated with microinfarcts. The effect of diffuse microinfarcts on global glymphatic pathway function was exacerbated in the mice aged 12 months compared with the 2- to 3-month-old mice. These findings indicate that glymphatic function is focally disrupted around microinfarcts and that the aging brain is more vulnerable to this disruption than the young brain. These observations suggest that microlesions may trap proteins and other interstitial solutes within the brain parenchyma, increasing the risk of amyloid plaque formation. SIGNIFICANCE STATEMENT Microinfarcts, small (<1 mm) ischemic lesions, are strongly associated with age-related dementia. However, how these microscopic lesions affect global cognitive function and predispose to Alzheimer's disease is unclear. The glymphatic system is a brain-wide network of channels surrounding brain blood vessels that allows CSF to exchange with interstitial fluid, clearing away cellular wastes such as amyloid β. We observed that, in mice, microinfarcts impaired global glymphatic function and solutes from the CSF became trapped in tissue associated with microinfarcts. These data suggest that small, disperse ischemic lesions can impair glymphatic function across the brain and trapping of solutes in these lesions may promote protein aggregation and neuroinflammation and eventually lead to neurodegeneration, especially in the aging brain