Mogensenfriedman1688

Enzyme replacement therapy, in which a functional copy of an enzyme is injected either systemically or directly into the brain of affected individuals, has proven to be an effective strategy for treating certain lysosomal storage diseases. The inefficient uptake of recombinant enzymes via the mannose-6-phosphate receptor, however, prohibits the broad utility of replacement therapy. Here, to improve the efficiency and efficacy of lysosomal enzyme uptake, we exploited the strategy used by diphtheria toxin to enter into the endolysosomal network of cells by creating a chimera between the receptor-binding fragment of diphtheria toxin and the lysosomal hydrolase TPP1. We show that chimeric TPP1 binds with high affinity to target cells and is efficiently delivered into lysosomes. Further, we show superior uptake of chimeric TPP1 over TPP1 alone in brain tissue following intracerebroventricular injection in mice lacking TPP1, demonstrating the potential of this strategy for enhancing lysosomal storage disease therapy.Protein sorting in the secretory pathway is crucial to maintain cellular compartmentalization and homeostasis. In addition to coat-mediated sorting, the role of lipids in driving protein sorting during secretory transport is a longstanding fundamental question that still remains unanswered. Here, we conduct 3D simultaneous multicolor high-resolution live imaging to demonstrate in vivo that newly synthesized glycosylphosphatidylinositol-anchored proteins having a very long chain ceramide lipid moiety are clustered and sorted into specialized endoplasmic reticulum exit sites that are distinct from those used by transmembrane proteins. Furthermore, we show that the chain length of ceramide in the endoplasmic reticulum membrane is critical for this sorting selectivity. Our study provides the first direct in vivo evidence for lipid chain length-based protein cargo sorting into selective export sites of the secretory pathway.The Younger Dryas (YD) was a period of rapid climate cooling that occurred at the end of the last glaciation. Here, we present the first palaeoglacier-derived reconstruction of YD precipitation across Europe, determined from 122 reconstructed glaciers and proxy atmospheric temperatures. Positive precipitation anomalies (YD versus modern) are found along much of the western seaboard of Europe and across the Mediterranean. Negative precipitation anomalies occur over the Fennoscandian ice sheet, the North European Plain, and as far south as the Alps. This is consistent with a more southerly and zonal storm track, which is linked to a concomitant southern location of the Polar Frontal Jet Stream, generating cold air outbreaks and enhanced cyclogenesis, especially over the eastern Mediterranean. This atmospheric configuration resembles the modern Scandinavian (SCAND) circulation over Europe (a blocking high pressure over Scandinavia pushing storm tracks south and east), and by analogy, a seasonally varying palaeoprecipitation pattern is interpreted.The most critical problem in the treatment of neurodegenerative diseases is brain neuronal protection, which can be overcome by clearing pathological substances and regulating the immune environment. MALT1 inhibitor In the above treatment strategies, the traditional poor drug delivery problem is inevitable. Here, we show an engineering core-shell hybrid system named rabies virus glycoprotein (RVG) peptide-modified exosome (EXO) curcumin/phenylboronic acid-poly(2-(dimethylamino)ethyl acrylate) nanoparticle/small interfering RNA targeting SNCA (REXO-C/ANP/S). It is a nanoscavenger for clearing α-synuclein aggregates and reducing their cytotoxicity in Parkinson's disease neurons. The motor behavior of Parkinson's disease mice is substantially improved after REXO-C/ANP/S treatment. In particular, we demonstrate that REXO-C/ANP/S is also a nanoscavenger for clearing immune activation due to its natural immature dendritic cell EXO coating. Our findings show that REXO-C/ANP/S may serve as a platform for neurodegenerative diseases treatment.Spontaneous pneumomediastinum (SPM) and pneumothorax (PNX) unrelated to positive pressure ventilation has been recently reported as an unusual complication in cases of severe COVID-19 pneumonia. The presumed pathophysiological mechanism is diffuse alveolar injury leading to alveolar rupture and air leak. We present a case of COVID-19 pneumonia complicated on day 13 post admission by SPM, PNX and subcutaneous emphysema in a patient with no identifiable risk factors for such complication. The patient received medical treatment for his COVID-19 infection without the use of an invasive or non-invasive ventilator. Moreover, he is a non-smoker with no lung comorbidities and never reported a cough. He was eventually discharged home in stable condition. A comprehensive literature review revealed 15 cases of SPM developing in patients with COVID-19 pneumonia.A 24-year-old woman presented with bilateral blurring of her distance vision and 'dizzy spells'. She had no other neurological symptoms or medical history. She consulted an optometrist, and optical coherence tomography (OCT) was performed, which demonstrated papilloedema. She was referred to the local eye clinic for assessment and from there was referred for neurological assessment.Her initial investigations revealed no abnormalities, and brain imaging was reported to be normal. In the absence of an alternative diagnosis, idiopathic intracranial hypertension (IIH) was considered and a lumbar puncture was performed. This showed elevated protein but normal cerebrospinal fluid (CSF) pressure. MRI of the brain the next day revealed a large cerebellopontine lesion in keeping with vestibular schwannoma. She was referred to neurosurgery for operative management.This case highlights three interesting points the aetiology of her papilloedema without raised intracranial pressure, the decision to perform a lumbar puncture in suspected IIH and community OCT as a clinical adjunct.A teenage primigravida at 13 weeks of gestation presented with hyperemesis gravidarum of 45 days and a history of giddiness and inability to walk due to involuntary movements of limbs and eyes since 2 days. She was treated with intravenous fluids, thiamine and antiemetics. MRI brain showed hyperintensities in bilateral dorsomedial thalami, periaqueductal grey matter in T2-weighted and FLAIR images. A diagnosis of Wernicke encephalopathy was made and she was managed in intensive care unit and received injection thiamine as per the guidelines and her weakness and ataxia improved over 3 weeks and she was discharged at 17 weeks of pregnancy in good state of health.