Garrettjohannesen5984
The nuclear pore complex (NPC) is a large protein assembly that perforates the nuclear envelope and provides a sole gateway for traffic between the cytoplasm and the nucleus. The NPC controls the nucleocytoplasmic transport by selectively allowing cargoes such as proteins and mRNA to pass through its central channel, thereby playing a vital role in protecting the nuclear component and regulating gene expression and protein synthesis. The selective transport through the NPC originates from its exquisite molecular structure featuring a large scaffold and the intrinsically disordered central channel domain, but the exact mechanism underlying the selective transport remains elusive and is the subject of various, often conflicting, hypotheses. Moreover, recent studies have suggested a new role for the NPC as a mechanosensor, where the NPC changes its channel diameter depending on the nuclear envelope tension, altering the molecular transportability through this nanopore. In this mini-review, we summarize the current understandings of the selective nature of the NPC and discuss its emerging role in cellular mechanotransduction.The blood-brain barrier (BBB) is a specialized brain endothelial barrier structure that regulates the highly selective transport of molecules under continuous blood flow. Recently, various types of BBB-on-chip models have been developed to mimic the microenvironmental cues that regulate the human BBB drug transport. However, technical difficulties in complex microfluidic systems limit their accessibility. Here, we propose a simple and easy-to-handle microfluidic device integrated with a cell culture insert to investigate the functional regulation of the human BBB endothelium in response to fluid shear stress (FSS). Using currently established immortalized human brain microvascular endothelial cells (HBMEC/ci18), we formed a BBB endothelial barrier without the substantial loss of barrier tightness under the relatively low range of FSS (0.1-1 dyn/cm2). Expression levels of key BBB transporters and receptors in the HBMEC/ci18 cells were dynamically changed in response to the FSS, and the effect of FSS reached a plateau around 1 dyn/cm2. Similar responses were observed in the primary HBMECs. Taking advantage of the detachable cell culture insert from the device, the drug efflux activity of P-glycoprotein (P-gp) was analyzed by the bidirectional permeability assay after the perfusion culture of cells. The data revealed that the FSS-stimulated BBB endothelium exhibited the 1.9-fold higher P-gp activity than that of the static culture control. read more Our microfluidic system coupling with the transwell model provides a functional human BBB endothelium with secured transporter activity, which is useful to investigate the bidirectional transport of drugs and its regulation by FSS.Intra-peritoneal placement of alginate encapsulated human induced pluripotent stem cell-derived hepatocytes (hPSC-Heps) represents a potential new bridging therapy for acute liver failure. One of the rate-limiting steps that needs to be overcome to make such a procedure more efficacious and safer is to reduce the accumulation of fibrotic tissue around the encapsulated cells to allow the free passage of relevant molecules in and out for metabolism. Novel chemical compositions of alginate afford the possibility of achieving this aim. We accordingly used sulfated alginate and demonstrated that this material reduced fibrotic overgrowth whilst not impeding the process of encapsulation nor cell function. Cumulatively, this suggests sulfated alginate could be a more suitable material to encapsulate hPSC-hepatocyte prior to human use.Sterile fluid transfer between vessels is a key step in cell therapy manufacturing and requires specialised devices to maintain sterility of both vessels before, during and after the transfer. This review introduces two main types of devices for sterile fluid transfer in cell therapy manufacturing, namely single-use sterile connectors and tube welders. While these are excellent devices for infrequent moderate to large volume transfers, a new multiple-use aseptic connector may fill the gap for frequent small volume fluid transfers that are particularly important for autologous cell therapy manufacturing.Non-homologous end-joining (NHEJ)-mediated random integration in Yarrowia lipolytica has been demonstrated to be an effective strategy for screening hyperproducer strains. However, there was no multigene assembly method applied for NHEJ integration, which made it challenging to construct and integrate metabolic pathways. In this study, a Golden Gate modular cloning system (YALIcloneNHEJ) was established to develop a robust DNA assembly platform in Y. lipolytica. By optimizing key factors, including the amounts of ligase and the reaction cycles, the assembly efficiency of 4, 7, and 10 fragments reached up to 90, 75, and 50%, respectively. This YALIcloneNHEJ system was subsequently applied for the overproduction of the sesquiterpene (-)-α-bisabolol by constructing a biosynthesis route and enhancing the flux in the mevalonate pathway. The resulting strain produced 4.4 g/L (-)-α-bisabolol, the highest titer reported in yeast to date. Our study expands the toolbox of metabolic engineering and is expected to enable a highly efficient production of various terpenoids.This study aims to investigate the risk factors associated with impaired pulmonary diffusing capacity among patients with noncystic fibrosis bronchiectasis (NCFB) and compare the predictive value of several scoring systems for the impairment in these patients. Between July 2019 and June 2021, patients who were admitted to the hospital and diagnosed with NCFB were included in this study. Clinical data were collected and analyzed retrospectively. A total of 175 NCFB patients were included in the analysis. Multivariate logistic regression analysis revealed that impaired pulmonary diffusing capacity diagnosed by carbon monoxide diffusing capacity (DLCO) less then 80% prediction was associated with age, Reiff score, body mass index (BMI), comorbid chronic obstructive pulmonary disease (COPD), and interstitial lung disease (ILD). Disease duration, frequency of exacerbation, hemoglobin level, and COPD were independent risk factors for impaired pulmonary diffusing capacity diagnosed by DLCO/alveolar volume (VA) lesss then 80% prediction). In NCFB patients, several factors such as age, Reiff score, BMI, exacerbation frequency, disease duration, and comorbid COPD and ILD were associated with impaired pulmonary diffusing capacity, which requires more attention in managing those patients. In addition, several scoring methods, including a simple index of mMRC, showed a comparable and moderate performance for predicting pulmonary diffusing impairment and would facilitate the systematic evaluation of the diffusing capacity of NCFB patients.Several structured catalytic reactors for the direct synthesis of the DME reaction are compared with regard to catalyst hold-up, thermal conductivity, and volumetric productivity. Adherent and homogeneous catalyst layers were obtained by washcoating independent of the substrates' shape and alloy. Moreover, the substrate nature (FeCrAl, brass, or aluminum) and shape (parallel cell monoliths and open foams) do not modify in great extent the CO conversion values and selectivity to the different compounds. This is reasonable since the catalytic phases are the same in all cases and the existence of mass and heat-transfer limitations was negligible in the experimental conditions studied. Structuring by washcoating exhibits less catalyst inventory per reactor volume than a packed-bed monolith. However, completely packing a monolith with powder catalyst produced a decrease in the CO conversion of around 25% with respect to the coated monolith. Moreover, by means of using the obtained highest catalyst hold-up by washcoating (0.33 gcat/cm3) in a brass monolith and by increasing the reaction temperature, the temperature profiles are only slightly affected. This allows to work in an almost isothermal reactor with a volumetric productivity up to 0.20 LDME/h·cm3 at 573 K.
The recent nationally implemented clinical pathways for the treatment of substance use problems in Norway require mapping and assessing of patients' needs, challenges, and resources. However, there is a lack of tools for systematically mapping and assessing patients' social situations and social networks as part of the national guidelines. The aim of this article is to present a tool developed to map and assess the patient's social situation, and to propose approaches for promoting multiple psychological senses of community (MPSOC) through clinical pathways for treating substance use problems.
The proposed tool and approaches are developed based on findings in a previous in-depth collaborative study of MPSOC and recovery among people with substance use problems who received help and services from Norwegian municipalities.
The findings suggest that multiple communities (geographical, relational and ideal) and senses of communities (within and outside treatment) simultaneously can influence individual recovery processes from problematic substance use in both positive as well as negative ways. As such, these community dimensions are of central importance to include in mapping and assessing of patients' social situations, as well as in the promotion of MPSOC through clinical pathways.
The suggested tool and approaches can increase the likelihood of achieving key aims of the national clinical pathways. Most important, mapping, assessing and promoting MPSOC through clinical pathways may promote long-term recovery processes and positive recovery capital for persons with substance use problems.
The suggested tool and approaches can increase the likelihood of achieving key aims of the national clinical pathways. Most important, mapping, assessing and promoting MPSOC through clinical pathways may promote long-term recovery processes and positive recovery capital for persons with substance use problems.
Alcohol use disorders (AUDs) are associated with high risk of comorbidities and excess use of social and healthcare services. We examined health service use (HSU) frequencies of patients with AUD in comparison to those with type 2 diabetes mellitus (T2DM).
A random sample of individuals with AUD (
= 396) were identified based on ICD-10 codes and HSU patterns, morbidity and mortality were compared with age- and gender-matched T2DM controls (
= 792) using logistic regression analysis. Six years (2011-2016) of electronic health record (EHR) data from the North Karelia district in Finland were used.
Similarities in comorbidity patterns existed, although mental health comorbidity (odds ratio [
] 1.86) was more prevalent in the AUD group. The average annual HSU varied according to the groups T2DM patients had more continuous contact with public health nurses in primary care, whereas AUD patients were more likely to experience somatic specialised care hospitalisations (
11.30) and have frequent somatic primary healthcare doctor visits (
3.30) and frequent emergency room doctor visits in specialised care (
8.89). Furthermore, patients with AUD had a 7.5 times higher risk of death compared with T2DM patients.
This study identified rather similar comorbidity status for the AUD and T2DM patients, but their HSU patterns differed noticeably. AUD patients had higher frequencies of hospitalisation periods and emergency service use and were at a higher risk of death compared with T2DM patients, indicating greater challenges in the organisation of care for AUD patients compared with those having T2DM.
This study identified rather similar comorbidity status for the AUD and T2DM patients, but their HSU patterns differed noticeably. AUD patients had higher frequencies of hospitalisation periods and emergency service use and were at a higher risk of death compared with T2DM patients, indicating greater challenges in the organisation of care for AUD patients compared with those having T2DM.
