Melgaardkrarup7741

Furthermore, the olfactory bulb and piriform cortex caused epilepsy and TAND in Tsc2 cKO mice, and neurodegeneration was observed. Immunohistology and immunophenotypic analysis of cells, and quantitative RT-PCR suggested that changes in microglial polarity were involved in the onset of TSC epilepsy and neuropsychiatric symptoms. Although the effect of mTORC1 inhibitors on TAND has not been established, the results of this study might help elucidate the mechanism of TAND pathogenesis and suggest that sirolimus may be a valuable therapeutic tool for TAND.Insulin-like growth factor 1 (IGF1) influences synaptic function in addition to its role in brain development and aging. Although the expression levels of IGF1 and IGF1 receptor (IGF1R) peak during development and decline with age, the adult brain has abundant IGF1 or IGF1R expression. Studies reveal that IGF1 regulates the synaptic transmission in neurons from young animals. However, the action of IGF1 on neurons in the adult brain is still unclear. Here, we used prefrontal cortical (PFC) slices from adult mice (∼8 weeks old) to characterize the role of IGF1 on excitatory synaptic transmission in pyramidal neurons and the underlying molecular mechanisms. We first validated IGF1R expression in pyramidal neurons using translating ribosomal affinity purification assay. Then, using whole-cell patch-clamp recording, we found that IGF1 attenuated the amplitude of evoked excitatory postsynaptic current (EPSC) without affecting the frequency and amplitude of miniature EPSC. Furthermore, this decrease in excitatory neurotransmission was blocked by pharmacological inhibition of IGF1R or conditional knockdown of IGF1R in PFC pyramidal neurons. In addition, we determined that IGF1-induced decrease of EPSC amplitude was due to postsynaptic effect (internalization of a-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid receptors [AMPAR]) rather than presynaptic glutamate release. Finally, we found that inhibition of metabotropic glutamate receptor subtype-1 (mGluR1) abolished IGF1-induced attenuation of evoked EPSC amplitude and decrease of AMPAR expression at synaptic membrane, suggesting mGluR1-mediated endocytosis of AMPAR was involved. Taken together, these data provide the first evidence that IGF1 regulates excitatory synaptic transmission in adult PFC via the interaction between IGF1R-dependent signaling pathway and mGluR1-mediated AMPAR endocytosis.Self-assembled nucleic acid nanostructures have been widely explored for gene therapy applications due to their unique advantages. Their roles are not limited to offer intracellular delivery platforms but additionally provide a biological function to induce targeted gene regulation. Here, we report a self-assembled artificial primary-miRNA (pri-miRNA) for achieving simultaneous multimodal gene regulation. Artificial pri-miRNAs are designed to play a role as substrate RNAs to recruit and interact with Drosha/DGCR8 (Microprocessor). Incorporation of functional RNA motifs and site-specific chemical modification of the primary miRNA are utilized for the biogenesis of two individual gene-regulating oligonucleotides. selleck compound Once they are cleaved by the endogenous Drosha/DGCR8 complex, basal strands and pre-miRNA can be generated inside of cells. In this study, we integrated basal strands with either SMN2 ASO or anti-miR21 to induce multimodal gene regulation. Microprocessing and subsequent gene regulation were first evaluated by measuring the activity of reporter pre-miRNA. Chemical modification on the primary miRNA was optimized through a series of in vitro Drosha cleavage tests and targeted gene silencing in cells. Primary miRNA with the basal ASO or anti-miR strands showed a successful in vitro activity and resulted in simultaneous multimodal gene regulation in cells. Artificial primary miRNA may offer synergistic therapeutic effects for treating various diseases, including spinal muscular atrophy and cancer.To improve the reliability of in vitro release studies of drug delivery systems, we developed a novel in vitro method for the evaluation of drug release from polymeric micelles in complex biological media. Polymeric micelles based on poly(N-2-hydroxypropyl methacrylamide)-block-poly(N-2-benzoyloxypropyl methacrylamide) (p(HPMAm)-b-p(HPMAm-Bz)) of which 10% of the chains was functionalized with biotin at the p(HPMAm) terminus were prepared using a solvent extraction method. The size of the micelles when loaded with a hydrophobic agent, namely paclitaxel (a clinically used cytostatic drug) or curcumin (a compound with multiple pharmacological activities), was around 65 nm. The biotin decoration allowed the binding of the micelles to streptavidin-coated magnetic beads which occurred within 10 min and reached a binding efficiency of 90 ± 6%. Drug release in different media was studied after the magnetic separation of micelles bound to the streptavidin-coated beads, by determination of the released drug in the media as well as the retained drug in the micellar fraction bound to the beads. The in vitro release of paclitaxel and curcumin at 37 °C in PBS, PBS containing 2% v/v Tween 80, PBS containing 4.5% w/v bovine serum albumin, mouse plasma, and whole mouse blood was highly medium-dependent. In all media studied, paclitaxel showed superior micellar retention compared to curcumin. Importantly, the presence of serum proteins accelerated the release of both paclitaxel and curcumin. The results presented in this study show great potential for predicting drug release from nanomedicines in biological media which in turn is crucial for their further pharmaceutical development.Alzheimer disease (AD) is a chronic disease characterized by a progressive decline in memory and cognition. AD progression is closely correlated with neuropathologic changes and accumulation of the two main hallmark lesions, senile plaques and neurofibrillary tangles. Nevertheless, deciphering the complex biological aspects of AD requires looking for the neuropathologic changes not only as the cause but also as the collective response to a disease process that is essential to maintaining life during aging but ultimately generates a nonfunctional brain. Chronic conditions, such as AD, represent a new homeostatic balance or disease state, where the organism responds or adapts to maintain life. The pathologic diagnosis of AD still remains the gold standard for precise diagnosis of dementia, commonly in conjunction with cognitive-memory tests and brain image scans. Herein, we present a general overview of the main neuropathologic hallmarks and features of AD and related dementia, revealing the key biological and functional changes as potential drivers of age-dependent brain failure related to AD. The present work reflects some of the main ideas presented during the American Society for Investigative Pathology Rous-Whipple Award Lecture 2021.

Protocolized team-based care has been shown to improve outcomes in cardiogenic shock (CS) in patients with end-stage heart failure (ESHF). This study tested the hypothesis that protocolized care improves survival by reducing multi-organ dysfunction prior to orthotopic heart transplantation (OHT) or durable left ventricular assist device (LVAD).

We developed a protocolized Recognize/rescue-Optimization-Stabilization-Exit/de-Escalation (ROSE) framework for CS due to ESHF. Six-month survival pre-ROSE (2014-2018) and post-ROSE (2018-2021) were compared. The Sequential Organ Failure Assessment (SOFA) score was calculated as a measure of multi-organ dysfunction pre-MCS and pre-"Exit" therapy (OHT, LVAD or recovery).

101 consecutive patients with CS due to ESHF who were deteriorating on inotropes (INTERMACS 1 or 2) were included (63 in Pre-ROSE and 38 in Post-ROSE). The proportions of patients who died on support (26 (41%) vs 11 (29%), p=0.213) or bridged to "Exit" therapy were comparable between Pre- and Post-ROSE OHT (28 (44%) vs 21 (55%), p=0.292); durable LVAD (8 (13%) vs 5 (13%), p=0.947); or recovery (1 (2%) vs 1 (3%), p=0.715). SOFA score prior to "Exit" therapy was higher Pre-ROSE compared to Post-ROSE (4 (2-7) vs 2 (1-5), p=0.012). Six-month survival from initial MCS (71% vs 41%, p=0.004) and in patients who underwent "Exit" therapy (100% vs 71%, p=0.001) were higher Post-ROSE vs Pre-ROSE, respectively. Higher pre-"Exit" SOFA score was associated with 6-month survival. None of the patients with Pre-"Exit" SOFA score≥9 survived at 6months.

Protocolization of CS care in ESHF improved six-month survival by improving multi-organ dysfunction (SOFA score) prior to OHT and LVAD implant.

Protocolization of CS care in ESHF improved six-month survival by improving multi-organ dysfunction (SOFA score) prior to OHT and LVAD implant.

Little is known about prevalence and predictors of myocardial infarction with non-obstructive coronary arteries (MINOCA) in Fabry disease (FD) and hypertrophic cardiomyopathy (HCM). We assessed and compared the prevalence and predictors of MINOCA in a large cohort of HCM and FD patients.

In this multicenter, retrospective study we enrolled 2870 adult patients with HCM and 267 with FD. The only exclusion criterion was documented obstructive coronary artery disease. MINOCA was defined according to guidelines. For each patient we collected clinical, ECG and echocardiographic data recorded at initial evaluation.

Overall, 36 patients had MINOCA during a follow-up period of 4.5±11.2years. MINOCA occurred in 16 patients with HCM (0.5%) and 20 patients with FD (7.5%; p<0.001). The difference between the 2 groups was highly significant, also after adjustment for the main clinical, ECG and echocardiographic variables (OR 6.12; 95%CI 2.80-13.3; p<0.001). In the FD population MINOCA occurred in 17 out of 96 patients with left ventricle hypertrophy (LVH, 17.7%) and in 3 out of 171 patients without LVH (1.7%; OR 12.0; 95%CI 3.43-42.3; p<0.001). At multivariable analysis, voltage criteria for LVH at ECG (OR 7.3; 95%CI 1.93-27.7; p=0.003) and maximal LV wall thickness at echocardiography (OR 1.15; 95%CI 1.05-1.27; p=0.002) maintained an independent association with MINOCA. No major significant differences were found in clinical, ECG and echocardiographic findings between HCM patients with or without MINOCA.

MINOCA was rare in HCM patients, and 6-fold more frequent in FD patients. MINOCA may be considered a red flag for FD and aid in the differential diagnosis from HCM.

MINOCA was rare in HCM patients, and 6-fold more frequent in FD patients. MINOCA may be considered a red flag for FD and aid in the differential diagnosis from HCM.

In recent years, some authoritative clinical studies have found that SGLT2 inhibitor can reduce cardiovascular risk in patients with diabetes, which may imply that SGLT2 inhibitor can play a role beyond lowering blood glucose. In this study, we explored the effect of empagliflozin on vascular atherosclerosis after removing the effect of diabetes.

The interaction between SGLT2 inhibitor and the AMPK(Adenosine 5'-monophosphate-activated protein kinase) signal pathway to attenuate atherosclerosis was studied in both spontaneously atherosclerotic mice in vivo and oxidized low-density lipoprotein(ox-LDL) induced macrophage inflammation model in vitro. In vivo experiment the aorta tree and aortic valve area were stained with oil red, and the level of inflammatory factors in the diseased tissue was evaluated by immunohistochemistry. Meanwhile, serum was collected to detect the levels of inflammatory factors. In vitro experiment, the RAW264.7 cell line was selected and ox-LDL was used to induce the release of proinflammatory factors, and different doses of empagliflozin were added.