Spindle oscillations are generated in the dorsal thalamus and modulated by the thalamic reticular nucleus

Spindle waves occur during the early stage of slow wave sleep and are thought to arise in the thalamic reticular nucleus (TRN), causing inhibitory postsynaptic potential spindle-like oscillations in the dorsal thalamus that are propagated to the cortex. We have found that thalamocortical neurons exhibit membrane oscillations that have spindle frequencies, consist of excitatory postsynaptic potentials, and co-occur with electroencephalographic spindles. TRN lesioning prolonged oscillations in the medial geniculate body (MGB) and auditory cortex (AC). Injection of GABA~A~ antagonist into the MGB decreased oscillation frequency, while injection of GABA~B~ antagonist increased spindle oscillations in the MGB and cortex. Thus, spindles originate in the dorsal thalamus and TRN inhibitory inputs modulate this process, with fast inhibition facilitating the internal frequency and slow inhibition limiting spindle occurrence

FreeNoise: Tuning-Free Longer Video Diffusion via Noise Rescheduling

With the availability of large-scale video datasets and the advances of diffusion models, text-driven video generation has achieved substantial progress. However, existing video generation models are typically trained on a limited number of frames, resulting in the inability to generate high-fidelity long videos during inference. Furthermore, these models only support single-text conditions, whereas real-life scenarios often require multi-text conditions as the video content changes over time. To tackle these challenges, this study explores the potential of extending the text-driven capability to generate longer videos conditioned on multiple texts. 1) We first analyze the impact of initial noise in video diffusion models. Then building upon the observation of noise, we propose FreeNoise, a tuning-free and time-efficient paradigm to enhance the generative capabilities of pretrained video diffusion models while preserving content consistency. Specifically, instead of initializing noises for all frames, we reschedule a sequence of noises for long-range correlation and perform temporal attention over them by window-based function. 2) Additionally, we design a novel motion injection method to support the generation of videos conditioned on multiple text prompts. Extensive experiments validate the superiority of our paradigm in extending the generative capabilities of video diffusion models. It is noteworthy that compared with the previous best-performing method which brought about 255% extra time cost, our method incurs only negligible time cost of approximately 17%. Generated video samples are available at our website: http://haonanqiu.com/projects/FreeNoise.html.Comment: Project Page: http://haonanqiu.com/projects/FreeNoise.html Code Repo: https://github.com/arthur-qiu/LongerCrafte

JAK inhibitors in systemic juvenile idiopathic arthritis

ObjectiveSystemic juvenile idiopathic arthritis (SJIA) is characterized by excessive and inappropriate production of proinflammatory cytokines. Janus kinase inhibitors (JAKi) can block the downstream pathway of many cytokines. The use of JAKi in SJIA or macrophage activation syndrome (MAS) has only been described in a limited number of case reports. In this study, we aimed to assess the efficacy and potential adverse effects of JAKi in SJIA patients.MethodsPatients with SJIA who received JAKi and underwent at least one assessment of efficacy and safety after JAKi initiation were eligible for this study. Data were collected retrospectively from inpatient or outpatient medical records at JAKi initiation, at 1, 3, 6, 9, and 12 months, after disease flare, after JAKi discontinuation, or at the last follow-up.ResultsTen patients with SJIA were included in the study. At the start of JAKi treatment, all patients presented with active disease; five showed variable adverse effects secondary to glucocorticoids. Seven patients received tofacitinib (one later switched to ruxolitinib). Of these, only two patients showed a complete response of persistent arthritis associated with tocilizumab; tofacitinib was used without a biological DMARD only in two patients, together with MTX, showing a partial response; three patients were nonresponders. Four patients with SJIA-related MAS or persistent hyperferritinemia were treated with ruxolitinib. Ruxolitinib allowed a good response on MAS parameters in three of them. All these four patients required an adjunction or switch to canakinumab later. The median decrease in the daily glucocorticoid dose between JAKi initiation and the last follow-up was 90.6% in patients with complete remission and 77.4% in other patients. Three patients discontinued glucocorticoid treatment after the introduction of JAKi. Severe adverse events, notably serious infection or thrombosis, were not observed during JAKi treatment.ConclusionJAKi may be an alternative or adjuvant agent for SJIA patients, especially in those with persistently active disease, glucocorticoid-related adverse reactions, or SJIA-MAS

mGluR5 antagonism inhibits cocaine reinforcement and relapse by elevation of extracellular glutamate in the nucleus accumbens via a CB1 receptor mechanism.

Metabotropic glutamate receptor 5 (mGluR5) antagonism inhibits cocaine self-administration and reinstatement of drug-seeking behavior. However, the cellular and molecular mechanisms underlying this action are poorly understood. Here we report a presynaptic glutamate/cannabinoid mechanism that may underlie this action. Systemic or intra-nucleus accumbens (NAc) administration of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) dose-dependently reduced cocaine (and sucrose) self-administration and cocaine-induced reinstatement of drug-seeking behavior. The reduction in cocaine-taking and cocaine-seeking was associated with a reduction in cocaine-enhanced extracellular glutamate, but not cocaine-enhanced extracellular dopamine (DA) in the NAc. MPEP alone, when administered systemically or locally into the NAc, elevated extracellular glutamate, but not DA. Similarly, the cannabinoid CB1 receptor antagonist, rimonabant, elevated NAc glutamate, not DA. mGluR5s were found mainly in striatal medium-spiny neurons, not in astrocytes, and MPEP-enhanced extracellular glutamate was blocked by a NAc CB1 receptor antagonist or N-type Ca++ channel blocker, suggesting that a retrograde endocannabinoid-signaling mechanism underlies MPEP-induced glutamate release. This interpretation was further supported by our findings that genetic deletion of CB1 receptors in CB1-knockout mice blocked both MPEP-enhanced extracellular glutamate and MPEP-induced reductions in cocaine self-administration. Together, these results indicate that the therapeutic anti-cocaine effects of mGluR5 antagonists are mediated by elevation of extracellular glutamate in the NAc via an endocannabinoid-CB1 receptor disinhibition mechanism

LncRNA gas5 regulates granulosa cell apoptosis and viability following radiation by x-ray via sponging miR-205- 5p and Wnt/β-catenin signaling pathway in granulosa cell tumor of ovary

Purpose: To investigate the role of lncRNA gas5 in ovarian granulosa cells exposed to x-ray in granulosa cell tumor of ovary (GCTO). Methods: KGN cell line was exposed to X-ray to mimic the radiotherapy for GCSO patients in vitro, cell viability was checked by CCK8 assays. RNA expression of apoptosis-related genes was determined by quantitative reverse transcriptase-polymerase reaction (qRT-PCR) while Western Blot for biomarkers in wnt/β-catenin signaling. Differential expressions of lncRNA gas5 were examined after cells were exposed to a ray for 0,24,48hs. We over expressed gas5 and assessed resultant cell viability, apoptosis and signaling. The sponging between gas5 and miR-205-5p was verified by luciferase assay. CCK8, qRT-PCR and Western blot were applied to investigate the correlation between miR-205-5p, cell viability, and apoptosis after miR-205-5p augmentation. Similarly, interaction between gas5 and miR-205-5p was assessed after co-transfection of miR-205-5p mimics and oe-gas5. Finally, wnt inhibitor was used to study the role of signaling pathway in KGN cells. Results: Exposure of KGN to x-ray reduced cell viability and increased apoptosis. Gas5showed reduced expression in the cells, while miR-205-5p  expression increased. Gas5 upregulation protected the cells against apoptosis and contributed to cell viability and activation of wnt//β-catenin signaling. lncRNA gas5 targeted miR-205-5p and miR-205-5p mimics counteracted the functions of up-regulated lncRNA gas5, regulating Wnt/β-catenin signaling pathway. Inactivation of Wnt/β-catenin suppressed cell viability. Conclusions: lncRNA gas5 regulates cell apoptosis and viability following cellular radiation, thus presenting a potential therapeutic target for the application radiotherapy in GCTO patients. Keywords: Ovary, Proliferation, Apoptosis, lncRNA gas5, Radiotherapy, β-catenin signalin

LncRNA gas5 regulates granulosa cell apoptosis and viability following radiation by X-ray through sponging miR-205-5p and Wnt/β-catenin signaling pathway ingranulosa cell tumor of ovary

Purpose: The study explored the role of lncRNA gas5 in ovarian granulosa cells exposed to X-ray in granulosa cell tumor of  ovary(GCTO). Methods:Exposed the KGN cell line (KALANG, Beijing, China) to X-ray to mimic the radiotherapy for GCSO patients in vitro, cell viability was checked by CCK8 assays. RT-qPCR detected the RNA expression of apoptosis-related genes while Western Blot for biomarkers in wnt/β-catenin signaling. Differential expressions of lncRNA gas5 were examined after cells exposed to X ray for 0,24,48hs. We over expressed gas5 and assessed resultant cell viabilities, apoptosis and signaling. The sponging between gas5 and miR-205-5p was verified through Luciferase Assay. CCK8, RT-qPCR and Western Blot were applied for investigations into the correlation between miR-205-5p and cell viability and apoptosis after miR-205-5p augmentation. Similarly, the interactions between the gas5 and  miR-205-5p were assessed after co-transfection of miR-205-5p mimics and oe-gas5. Last, wnt inhibitor was used to study the role of signaling pathway in KGN cells. Results: Exposure of KGN toX-ray reduced cell viabilities and increased apoptosis. Gas5 had reduced expression in cells while  miR-205-5p increased. Gas5 upregulation could protect the cells from apoptosis and add to the cell viability and activation of wnt//β-catenin signaling. lncRNA gas5 targeted miR-205-5p and miR-205-5p mimics could counteract functions of up-regulated lncRNA gas5, regulating Wnt/β-catenin signaling pathway. Inactivation in Wnt/β-catenin could suppress cell viability. Conclusions: lncRNA gas5 regulated the cell apoptosis and viability after cellular radiation, which might be a potential therapeutic target to combine into radiotherapy for GCTO patients in clinical stage. Keywords: Ovary, proliferation, apoptosis, lncRNA gas5, x-ra

TTK kinase is essential for the centrosomal localization of TACC2

AbstractChromosome segregation in mitosis is orchestrated by dynamic interaction between spindle microtubule and the kinetochore. Our recent ultrastructural studies demonstrated a dynamic distribution of TTK, from the kinetochore to the centrosome, as cell enters into anaphase. Here, we show that a centrosomal protein TACC2 is phosphorylated in mitosis by TTK signaling pathway. TACC2 was pulled down by wild type TTK but not kinase death mutant, suggesting the potential phosphorylation-mediated interaction between these two proteins. Our immunofluorescence studies revealed that both TTK and TACC2 are located to the centrosome. Interestingly, expression of kinase death mutant of TTK eliminated the centrosomal localization of TACC2 but not other centrosomal proteins such as γ-tubulin and NuMA, a phenotype seen in TTK-depleted cells. In these centrosomal TACC2-liberated cells, chromosomes were lagging and mis-aligned. In addition, the distance between two centrosomes was markedly reduced, suggesting that centrosomal TACC2 is required for mitotic spindle maintenance. The inter-relationship between TTK and TACC2 established here provides new avenue to study centrosome and spindle dynamics underlying cell divisional control