RESUMO
Sleep and wake have global effects on brain physiology, from molecular changes1-4 and neuronal activities to synaptic plasticity3-7. Sleep-wake homeostasis is maintained by the generation of a sleep need that accumulates during waking and dissipates during sleep8-11. Here we investigate the molecular basis of sleep need using quantitative phosphoproteomic analysis of the sleep-deprived and Sleepy mouse models of increased sleep need. Sleep deprivation induces cumulative phosphorylation of the brain proteome, which dissipates during sleep. Sleepy mice, owing to a gain-of-function mutation in the Sik3 gene 12 , have a constitutively high sleep need despite increased sleep amount. The brain proteome of these mice exhibits hyperphosphorylation, similar to that seen in the brain of sleep-deprived mice. Comparison of the two models identifies 80 mostly synaptic sleep-need-index phosphoproteins (SNIPPs), in which phosphorylation states closely parallel changes of sleep need. SLEEPY, the mutant SIK3 protein, preferentially associates with and phosphorylates SNIPPs. Inhibition of SIK3 activity reduces phosphorylation of SNIPPs and slow wave activity during non-rapid-eye-movement sleep, the best known measurable index of sleep need, in both Sleepy mice and sleep-deprived wild-type mice. Our results suggest that phosphorylation of SNIPPs accumulates and dissipates in relation to sleep need, and therefore SNIPP phosphorylation is a molecular signature of sleep need. Whereas waking encodes memories by potentiating synapses, sleep consolidates memories and restores synaptic homeostasis by globally downscaling excitatory synapses4-6. Thus, the phosphorylation-dephosphorylation cycle of SNIPPs may represent a major regulatory mechanism that underlies both synaptic homeostasis and sleep-wake homeostasis.
Assuntos
Encéfalo/metabolismo , Homeostase , Fosfoproteínas/análise , Fosfoproteínas/metabolismo , Proteoma/análise , Proteômica , Sono/fisiologia , Animais , Encéfalo/fisiologia , Mutação com Ganho de Função , Masculino , Consolidação da Memória/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteoma/metabolismo , Privação do Sono/metabolismo , Privação do Sono/fisiopatologia , Sinapses/fisiologia , Vigília/fisiologiaRESUMO
Femtosecond lasers at fixed wavelengths above 1,000 nm are powerful, stable and inexpensive, making them promising sources for two-photon microscopy. Biosensors optimized for these wavelengths are needed for both next-generation microscopes and affordable turn-key systems. Here we report jYCaMP1, a yellow variant of the calcium indicator jGCaMP7 that outperforms its parent in mice and flies at excitation wavelengths above 1,000 nm and enables improved two-color calcium imaging with red fluorescent protein-based indicators.
Assuntos
Cálcio/análise , Corantes Fluorescentes/química , Microscopia de Fluorescência por Excitação Multifotônica/métodos , Animais , Drosophila , Feminino , Lasers , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Imagem Molecular , Córtex Somatossensorial/químicaRESUMO
OBJECTIVE: Temporary vascular access (TVA) is frequently used during the first dialysis in patients with chronic kidney disease (CKD), and it is associated with an increased risk of infection, central vein stenosis, and mortality. Here, factors associated with TVA in patients with CKD were explored. METHODS: This study included patients in a single-center CKD care program who initiated long-term renal replacement therapy. The primary outcome was TVA use at first dialysis. Factors possibly associated with TVA use were analyzed using Cox regression. RESULTS: Temporary vascular access was used in 53.2% of the patients at first dialysis. In total, 73.2% (n = 865) and 26.8% (n = 317) of the patients were on hemodialysis and peritoneal dialysis, respectively. Multivariate Cox regression analysis showed that TVA use in patients with CKD was associated with diabetes (hazard ratio [HR] 1.52, 95% confidence interval [CI] 1.28-1.81, p < 0.001), lower albumin (HR 0.82, 95% CI 0.75-0.91, p < 0.001), lower education level (HR 0.75, 95% CI 0.56-1.00, p = 0.055), and total care dependency (HR 1.92, CI 1.44-3.43, p = 0.003). CONCLUSION: Diabetes, education level, and care dependency are associated with TVA at dialysis initiation in patients with CKD.
Assuntos
Diabetes Mellitus , Falência Renal Crônica , Diálise Peritoneal , Insuficiência Renal Crônica , Humanos , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/terapia , Modelos de Riscos Proporcionais , Diálise Renal , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia , Fatores de RiscoRESUMO
BACKGROUND: Urothelial carcinoma of the bladder (UCB) is the second most common genitourinary cancer. This study aims to assess the diagnostic accuracy of CA125 in advanced UCB. METHODS: We searched prevalent studies in PubMed, the Cochrane Library, Scopus, Embase, the Web of Science China National Knowledge Infrastructure database, and Wanfang data before October 2022. Pooled sensitivity, specificity, and summary receiver operating characteristics were used to assess the diagnostic value of CA125. RESULTS: One thousand six hundred forty-one patients from 14 studies were analyzed. UCB stage T3-4N1 was defined as advanced UCB in ten studies; T2-4 was used in three studies; and N1M1 in one study. Patients' age was between 21 to 92, and 21% to 48.6% of patients were female. The pooled sensitivity was 0.695 (95% confidence interval (CI): 0.426-0.875). The pooled specificity was 0.846 (95% CI: 0.713-0.924). The diagnostic odds ratio was 8.138 (95% CI: 4.559-14.526). The AUC was 0.797. CONCLUSION: CA125 may provide significant diagnostic accuracy in identifying muscle-invasive, lymph node-involved, and distant metastatic tumors in patients with urothelial carcinoma of the bladder. Limited studies have been conducted on the prognostic role of CA125. More studies are needed for a meta-analysis on the prognostic role of CA125 in UCB.
RESUMO
CONTEXT: Individuals with diabetes mellitus (DM) are susceptible to various infections. OBJECTIVE: We estimated the risk of herpes zoster (HZ) among individuals with DM compared with individuals in the general population. METHODS: We searched the PubMed, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, and PerioPath databases from their inception to January 30, 2021, for studies on the risk of HZ in individuals with DM. Two authors independently screened all articles identified. The same 2 authors independently extracted the data. Four case-control studies and 12 cohort studies were included. RESULTS: Meta-analyses were performed using fixed and mixed-effects models. In the pooled analysis, individuals with DM had a higher risk of developing HZ (pooled relative risk [RR]: 1.38; 95% CI, 1.21-1.57) than individuals in the general population. The results were consistent in subgroup analyses stratified by type of diabetes, age, and study design. In individuals with DM, cardiovascular disease had an additive effect on increasing the risk of HZ (pooled RR: 1.19; 95% CI, 1.11-1.28). There was a linear dose-response association between age and the risk of HZ in individuals with DM. CONCLUSION: Individuals with DM have an increased risk of HZ compared with the general population. Varicella vaccination should be provided to individuals with DM regardless of their age, prioritizing older adults and those with cardiovascular disease. Varicella vaccination policies for individuals with DM should be updated based on the evidence.
Assuntos
Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus/epidemiologia , Herpes Zoster/epidemiologia , Vacina contra Varicela/administração & dosagem , Política de Saúde , Herpes Zoster/prevenção & controle , Humanos , Guias de Prática Clínica como Assunto , Fatores de Risco , Vacinação/normasRESUMO
Humic substances in groundwater and aquifer sediments from the arsenicosis and Blackfoot disease (BFD) affected areas in Bangladesh (Bengal delta plain) and Taiwan (Lanyang plain and Chianan plain) were characterized using fluorescence spectrophotometry and Fourier transform infrared (FT-IR) spectroscopy. The results demonstrate that the mean concentration of As and relative intensity of fluorescent humic substances are higher in the Chianan plain groundwater than those in the Lanyang plain and Bengal delta plain groundwater. The mean As concentrations in Bengal delta plain, Chianan plain, and Lanyang plain are 50.65 µg/l (2.8-170.8 µg/l, n=20), 393 µg/l (9-704 µg/l, n=5), and 104.5 µg/l (2.51-543 µg/l, n = 6), respectively. Average concentrations and relative fluorescent intensity of humic substances in groundwater are 25.381 QSU (quinine standard unit) and 17.78 in the Bengal delta plain, 184.032 QSU and 128.41 in the Chianan plain, and 77.56 QSU and 53.43 in the Lanyang plain. Moreover, FT-IR analysis shows that the humic substances extracted from the Chianan plain groundwater contain phenolic, alkanes, aromatic ring and amine groups, which tend to form metal carbon bonds with As and other trace elements. By contrast, the spectra show that humic substances are largely absent from sediments and groundwater in the Bengal delta plain and Lanyang plain. The data suggest that the reductive dissolution of As-adsorbed Mn oxyhydroxides is the most probable mechanism for mobilization of As in the Bengal delta plain. However, in the Chianan plain and Lanyang plain, microbially mediated reductive dissolution of As-adsorbed amorphous/crystalline Fe oxyhydroxides in organic-rich sediments is the primary mechanism for releasing As to groundwater. High levels of As and humic substances possibly play a critical role in causing the unique BFD in the Chianan plain of SW Taiwan.
Assuntos
Arsênio/análise , Monitoramento Ambiental , Sedimentos Geológicos/química , Substâncias Húmicas/análise , Poluentes Químicos da Água/análise , Adsorção , Arsênio/toxicidade , Bangladesh , Doenças do Pé/etiologia , Gangrena/etiologia , Substâncias Húmicas/toxicidade , Metais Pesados/análise , Espectrometria de Fluorescência , Espectroscopia de Infravermelho com Transformada de Fourier , Taiwan , Abastecimento de Água/análiseRESUMO
Real-time rendering of closed-loop visual environments is important for next-generation understanding of brain function and behaviour, but is often prohibitively difficult for non-experts to implement and is limited to few laboratories worldwide. We developed BonVision as an easy-to-use open-source software for the display of virtual or augmented reality, as well as standard visual stimuli. BonVision has been tested on humans and mice, and is capable of supporting new experimental designs in other animal models of vision. As the architecture is based on the open-source Bonsai graphical programming language, BonVision benefits from native integration with experimental hardware. BonVision therefore enables easy implementation of closed-loop experiments, including real-time interaction with deep neural networks, and communication with behavioural and physiological measurement and manipulation devices.
Assuntos
Realidade Aumentada , Comportamento Animal , Estimulação Luminosa , Design de Software , Vias Visuais/fisiologia , Percepção Visual , Animais , Gráficos por Computador , Humanos , Masculino , Camundongos Endogâmicos C57BL , Linguagens de Programação , Fatores de Tempo , Fluxo de TrabalhoRESUMO
The larval brain of Drosophila melanogaster provides an excellent system for the study of the neurocircuitry mechanism of memory. Recent development of neurogenetic techniques in fruit flies enables manipulations of neuronal activities in freely behaving animals. This protocol describes detailed steps for artificial induction of olfactory associative memory in Drosophila larvae. In this protocol, the natural reward signal is substituted by thermogenetic activation of octopaminergic neurons in the brain. In parallel, the odor signal is substituted by optogenetic activation of a specific class of olfactory receptor neurons. Association of reward and odor stimuli is achieved with the concomitant application of blue light and heat that leads to activation of both sets of neurons in living transgenic larvae. Given its operational simplicity and robustness, this method could be utilized to further our knowledge on the neurocircuitry mechanism of memory in the fly brain.
RESUMO
High arsenic abundance of 50-700µg/L in the groundwater from the Chianan Plain in southwestern Taiwan is a well-known environmental hazard. The groundwater-associated sediments, however, have not been geochemically characterized, thus hindering a comprehensive understanding of arsenic cycling in this region. In this study, samples collected from a 250m sediment core at the centre of the Chianan Plain were analyzed for arsenic and TOC concentrations (N=158), constituent minerals (N=25), major element abundances (N=105), and sequential arsenic extraction (N=23). The arsenic data show a prevalence of >10mg/kg with higher concentrations of 20-50mg/kg concentrated at 60-80 and 195-210m. Arsenic was extracted mainly as an adsorbate on clay minerals, as a co-precipitate in amorphous iron oxyhydroxide, and as a structural component in clay minerals. Since the sediments consist mainly of quartz, chlorite, and illite, the correlations between arsenic concentration and abundances of K2O and MgO pinpoint illite and chlorite as the major arsenic hosts. The arsenic-total iron correlation reflects the role of chlorite along with the contribution from amorphous iron oxyhydroxide as indicated by arsenic extraction data. Organic matter is not the dominant arsenic host for low TOC content, low arsenic abundance extracted from it, and a relatively low R(2) of the arsenic-TOC correlation. The major constituent minerals in the sediments are the same as those of the upriver metapelites, establishing a sink-source relationship. Composition data from two deep groundwater samples near the sediment core show Eh values and As(V)/As(III) ratios of reducing environments and high arsenic, K, Mg, and Fe contents necessary for deriving arsenic from sediments by desorption from clay and dissolution of iron oxyhydroxide. Therefore, groundwater arsenic was mainly derived from groundwater-associated sediments with limited contributions from other sources, such as mud volcanoes.
Assuntos
Arsênio/análise , Carbono/análise , Sedimentos Geológicos/análise , Poluentes Químicos da Água/análise , Monitoramento Ambiental , Água Subterrânea/química , Rios/química , TaiwanRESUMO
It has been postulated that associative memory is formed by at least two sets of external stimuli, CS and US, that are transmitted to the memory centers by distinctive conversing pathways. However, whether associative memory can be induced by the activation of only the olfactory CS and a biogenic amine-mediated US pathways remains to be elucidated. In this study, we substituted the reward signals with dTrpA1-mediated thermogenetic activation of octopaminergic neurons and the odor signals by ChR2-mediated optical activation of a specific class of olfactory neurons. We show that targeted activation of the olfactory receptor and the octopaminergic neurons is indeed sufficient for the formation of associative olfactory memory in the larval brain. We also show that targeted stimulation of only a single type of olfactory receptor neurons is sufficient to induce olfactory memory that is indistinguishable from natural memory induced by the activation of multiple olfactory receptor neurons.
Assuntos
Drosophila/fisiologia , Memória , Percepção Olfatória , Neurônios Receptores Olfatórios/fisiologia , Animais , Animais Geneticamente Modificados , Comportamento Animal , Marcação de Genes , Larva , Luz , OdorantesRESUMO
Sry, a single-copy gene on the Y-chromosome, acts dominantly to trigger differentiation of a testis from a gonadal primordium that otherwise develops into an ovary in mammals. Sry encodes a protein with a DNA-binding domain and probably acts as a transcription factor. However, the mode of SRY action in testis determination remains largely unknown. In the present study, we detected the endogenous SRY protein in normal XY fetal mouse gonads by Western blotting and immunohistochemistry. The tissue-specificity and ontogeny of the detected protein were consistent with those of Sry transcripts. Immunofluorescent double labeling revealed that the SRY protein was detected in the Sertoli cell lineage and was swiftly down-regulated concurrently with testis cord organization. Surprisingly, however, the SRY protein was detected in the entire gonad from the onset of its expression, not in parallel to the spatiotemporal pattern of testis cord organization. The SRY protein was also detected in the entire region of all B6.Y(TIR) fetal gonads, which were anticipated to undergo either partial or complete sex reversal. SRY down-regulation was considerably delayed, compared with control B6.XY gonads and was not associated with testis cord organization in B6.Y(TIR) gonads. We conclude that the testis-determining pathway is impaired at the site of SRY action in the B6.Y(TIR) gonad.