Thuesengreer0096

Dendritic cells (DCs) regulate processes ranging from antitumor and antiviral immunity to host-microbe communication at mucosal surfaces. It remains difficult, however, to genetically manipulate human DCs, limiting our ability to probe how DCs elicit specific immune responses. Here, we develop a CRISPR-Cas9 genome editing method for human monocyte-derived DCs (moDCs) that mediates knockouts with a median efficiency of >94% across >300 genes. Using this method, we perform genetic screens in moDCs, identifying mechanisms by which DCs tune responses to lipopolysaccharides from the human microbiome. In addition, we reveal donor-specific responses to lipopolysaccharides, underscoring the importance of assessing immune phenotypes in donor-derived cells, and identify candidate genes that control this specificity, highlighting the potential of our method to pinpoint determinants of inter-individual variation in immunity. Our work sets the stage for a systematic dissection of the immune signaling at the host-microbiome interface and for targeted engineering of DCs for neoantigen vaccination.Cortical interneurons establish inhibitory microcircuits throughout the neocortex and their dysfunction has been implicated in epilepsy and neuropsychiatric diseases. Developmentally, interneurons migrate from a distal progenitor domain in order to populate the neocortex - a process that occurs at a slower rate in humans than in mice. In this study, we sought to identify factors that regulate the rate of interneuron maturation across the two species. Using embryonic mouse development as a model system, we found that the process of initiating interneuron migration is regulated by blood vessels of the medial ganglionic eminence (MGE), an interneuron progenitor domain. We identified two endothelial cell-derived paracrine factors, SPARC and SerpinE1, that enhance interneuron migration in mouse MGE explants and organotypic cultures. Moreover, pre-treatment of human stem cell-derived interneurons (hSC-interneurons) with SPARC and SerpinE1 prior to transplantation into neonatal mouse cortex enhanced their migration and morphological elaboration in the host cortex. Further, SPARC and SerpinE1-treated hSC-interneurons also exhibited more mature electrophysiological characteristics compared to controls. Overall, our studies suggest a critical role for CNS vasculature in regulating interneuron developmental maturation in both mice and humans.Many of the world's warm-blooded species are chronically infected with Toxoplasma gondii tissue cysts, including an estimated one-third of the global human population. The cellular processes that permit long-term persistence within the cyst are largely unknown for T. gondii and related coccidian parasites that impact human and animal health. Herein, we show that genetic ablation of TgATG9 substantially reduces canonical autophagy and compromises bradyzoite viability. Transmission electron microscopy revealed numerous structural abnormalities occurring in ∆atg9 bradyzoites. Intriguingly, abnormal mitochondrial networks were observed in TgATG9-deficient bradyzoites, some of which contained numerous different cytoplasmic components and organelles. ∆atg9 bradyzoite fitness was drastically compromised in vitro and in mice, with very few brain cysts identified in mice 5 weeks post-infection. Taken together, our data suggests that TgATG9, and by extension autophagy, is critical for cellular homeostasis in bradyzoites and is necessary for long-term persistence within the cyst of this coccidian parasite.

Dysphagia is a common but under-recognized complication of obstructive sleep apnea (OSA). However, the mechanisms remain poorly described. Accordingly, the aim of this study was to assess swallowing symptoms and use high-resolution pharyngeal manometry (HRPM) to quantify swallowing biomechanics in patients with moderate-severe OSA.

Nineteen adults (4 female, mean age 46±26-68y) with moderate-severe OSA underwent HRPM testing with 5,10 & 20 ml volumes of thin and extremely thick liquids. Data were compared to 19 age- and sex-matched healthy controls (mean age 46±27-68y). Symptomatic dysphagia was assessed using the Sydney Swallow Questionnaire (SSQ). Swallow metrics were analyzed using the online application swallowgateway.com. General linear mixed model analysis was performed to investigate potential differences between people with moderate-severe OSA and controls. Data presented are means (95% CI).

26% (5/19) of the OSA group but none of the controls reported symptomatic dysphagia (SSQ>234). Com pressure and velopharyngeal contractility.

This study aims to investigate if the use of a mandibular advancement device (MAD) is associated with neuroplasticity in corticomotor control of tongue and jaw muscles.

Eighteen healthy individuals participated in a randomized crossover study with 3 conditions for 2 weeks each baseline, wearing an oral appliance (OA sham MAD) or MAD during sleep. The custom-made MAD was constructed by positioning the mandible to 50% of its maximal protrusion limit. Transcranial magnetic stimulation (TMS) was applied to elicit motor evoked potentials (MEPs). The MEPs were assessed by constructing stimulus-response curves at four stimulus intensities 90%, 100%, 120%, and 160% of the motor threshold (MT) from the right tongue and right masseter, and the first dorsal interosseous muscles (FDI, control) at baseline, after the first and the second intervention.

There was a significant effect of condition and stimulus intensity both on the tongue and as well as on masseter MEPs (P < 0.01). Tongue and masseter MEPs were significantly higher at 120% and 160% following the MAD compared to the OA (P < 0.05). There were no effects of condition on FDI MEPs (P = 0.855).

The finding suggests that MAD induces neuroplasticity in the corticomotor pathway of the tongue and jaw muscles associated with the new jaw position. click here Further investigations are required in patients with obstructive sleep apnea (OSA) to see if this cortical neuroplasticity may contribute or perhaps predict treatment effects with MADs in OSA.

The finding suggests that MAD induces neuroplasticity in the corticomotor pathway of the tongue and jaw muscles associated with the new jaw position. Further investigations are required in patients with obstructive sleep apnea (OSA) to see if this cortical neuroplasticity may contribute or perhaps predict treatment effects with MADs in OSA.