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This research has been conducted using the UK Biobank Resource.Synthetic biology requires well-characterized biological parts that can be combined into functional modules. One type of biological parts are transcriptional regulators and their cognate operator elements, which enable to either generate an input-specific response or are used as actuator modules. A range of regulators has already been characterized and used for orthogonal gene expression engineering, however, previous efforts have mostly focused on bacterial regulators. This work aims to design and explore the use of an archaeal TetR family regulator, FadRSa from Sulfolobus acidocaldarius, in a bacterial system, namely Escherichia coli. This is a challenging objective given the fundamental difference between the bacterial and archaeal transcription machinery and the lack of a native TetR-like FadR regulatory system in E. coli. The synthetic σ70-dependent bacterial promoter proD was used as a starting point to design hybrid bacterial/archaeal promoter/operator regions, in combination with the mKate2 fluorescent reporter enabling a readout. Four variations of proD containing FadRSa binding sites were constructed and characterized. While expressional activity of the modified promoter proD was found to be severely diminished for two of the constructs, constructs in which the binding site was introduced adjacent to the -35 promoter element still displayed sufficient basal transcriptional activity and showed up to 7-fold repression upon expression of FadRSa. Addition of acyl-CoA has been shown to disrupt FadRSa binding to the DNA in vitro. However, extracellular concentrations of up to 2 mM dodecanoate, subsequently converted to acyl-CoA by the cell, did not have a significant effect on repression in the bacterial system. This work demonstrates that archaeal transcription regulators can be used to generate actuator elements for use in E. coli, although the lack of ligand response underscores the challenge of maintaining biological function when transferring parts to a phylogenetically divergent host.<br /><br /> The purpose of this study was to investigate the effect of CYP3A7, CYP3A4, and CYP3A5 genetic polymorphisms in liver transplant recipients and donors on tacrolimus concentrations in the early stages after liver transplantation.<br /><br /> One hundred and thirty-eight liver transplant recipients and matched donors were genotyped for CYP3A7 (rs10211 and rs2257401), CYP3A4 (rs4646437 and rs2242480), and CYP3A5*3 (rs776746) polymorphisms. The relationships between dose-adjusted trough concentrations (C<br /><br /> /D) of tacrolimus and corresponding genotypes were investigated.<br /><br /> Recipient CYP3A polymorphisms were associated with tacrolimus concentrations. The CYP3A7 rs10211 AA carriers (186.2 vs 90.5, p&lt;0.001), CYP3A4 rs4646437 CC carriers (184.0 vs 88.8, p&lt;0.001), CYP3A4*1G rs2242480 CC carriers (189.8 vs 99.7, p&lt;0.001), and CYP3A5*3 rs776746 GG carriers (197.3 vs 86.0, p&lt;0.001) had an almost twofold increase in the tacrolimus C<br /><br /> /D compared to that of the non-carriers. We further investigated the effect of the combilimus starting dose in the early stages after liver transplantation.<br /><br />The large inter-individual variation in tacrolimus concentrations in the early stages after liver transplantation is influenced by genetic polymorphisms of CYP3A7, CYP3A4, and CYP3A5. Recipient (intestinal) CYP3A7, CYP3A4, and CYP3A5 polymorphisms seem to contribute more to such variation than donors. Therefore, the detection of CYP3A polymorphisms in recipients could help to predict the tacrolimus starting dose in the early stages after liver transplantation.No pharmacological treatments are yet approved for patients with cocaine use disorders. Cannabidiol, a constituent of the C. sativa plant has shown promising results in rodent models of drug addiction. However, the specific effects and mechanisms of action of cannabidiol in rodent operant models of extinction-based abstinence and drug-seeking relapse remain unclear. Cannabidiol (10 and 20 mg/kg, i.p.) was injected during extinction training to male CD-1 mice previously trained to self-administer cocaine (0.75 mg/kg/infusion). Then, we evaluated the reinstatement of cocaine seeking induced by cues and stressful stimuli (footshock). [https://www.selleckchem.com/products/abt-199.html read more] We found that cannabidiol (10 and 20 mg/kg) did not modulate extinction learning. After cannabidiol 20 mg/kg treatment, increased levels of CB1 receptor protein were found in the prelimbic and orbitofrontal regions of the prefrontal cortex, and in the ventral striatum; an effect paralleled by a reduction of striatal ∆FosB accumulation and an increment of GluR2 AMPA receptor subunits. Furthermore, cue-induced reinstatement of cocaine seeking was attenuated by cannabidiol. Unexpectedly, cannabidiol 20 mg/kg facilitated stress-induced restoration of cocaine-seeking behaviour. To ascertain the participation of CB1 receptors in these behavioural changes, we administered the CB1 antagonist AM4113 (5 mg/kg) before each reinstatement session. Both, the attenuation of cue-induced reinstatement and the facilitation of stress-induced reestablishment were abolished by AM4113 in cannabidiol 20 mg/kg-treated mice. Our results reveal a series of complex CB1-related changes induced by cannabidiol with a varying impact on the reinstatement of cocaine-seeking behaviour that could limit its therapeutic applications.<br /><br /> Schizophrenia is a heterogenous psychiatric disease, and deficit schizophrenia (DS) is a clinical subgroup with primary and enduring negative symptoms. Although previous neuroimaging studies have identified functional connectome alterations in schizophrenia, the modular organizations in DS and nondeficit schizophrenia (NDS) remain poorly understood. Therefore, this study aimed to investigate the modular-level alterations in DS patients compared with the NDS and healthy control (HC) groups.<br /><br /> A previously collected dataset was re-analyzed, in which 74 chronic male schizophrenia patients (33 DS and 41 NDS) and 40 HC underwent resting-state functional magnetic resonance imaging with eyes closed in a Siemens 3T scanner (scanning duration=8min). Modular- (intramodule and intermodule connectivity) and nodal- [normalized within-module degree (Z<br /><br /> ) and participation coefficient (PC<br /><br /> )] level graph theory properties were computed and compared among the three groups. Receiver operating characteristic curve (ROC) analasures were related to negative symptoms, general psychiatric symptoms, and neurocognitive function.<br /><br /> Our findings suggest that functional connectomes, especially SN, SMN, and VN, may capture the distinct and common disruptions of DS and NDS. These findings may help to understand the neuropathology of negative symptoms of schizophrenia and inform targets for treating different schizophrenia subtypes.<br /><br />Our findings suggest that functional connectomes, especially SN, SMN, and VN, may capture the distinct and common disruptions of DS and NDS. These findings may help to understand the neuropathology of negative symptoms of schizophrenia and inform targets for treating different schizophrenia subtypes.<br /><br /> The management of Optic Nerve Sheath Meningiomas (ONSM) has suffered a significant shift due to new radiation techniques. However, there is no conclusive information on which approach presents better results in the literature. This meta-analysis aims to evaluate the outcomes of different radiotherapy (RT) modalities in the management of ONSM.<br /><br /> A systematic review based on an electronic search was performed in MEDLINE, EMBASE, Cochrane, and Lilacs databases. Eligible studies included patients with ONSM treated with RT. Two reviewers independently assessed the eligibility of potential studies, extracted data, and performed the meta-analysis. Outcomes of interest were tumor control, visual acuity (VA), visual field, and complications.<br /><br /> Thirty-nine non-comparative studies involving 736 eyes with ONSM treated with RT were included. Six different techniques were studied 2-dimensional RT (2DRT), 3D-conformal RT (3CRT), Stereotactic Fractionation RT (SFRT), stereotactic radiosurgery (SRS), intensity-modulated RT (IMRT), and proton beam therapy (PBT). With a mean follow-up period of 46 months, tumor control was 97,4% (95% CI 98-100%). No difference was observed regarding the rate of final VA post-treatment among the modalities. The 3CRT showed substantially higher rates of complication than other techniques.<br /><br /> RT produces remarkable tumor control. New radiation modalities such as SFRT, IMRT, SRS, and PBT resulted in better therapeutic results with fewer complications than 2DRT and 3CRT. Thus, they should be the preferential choices for treating ONSM regardless of initial clinical presentation.<br /><br />RT produces remarkable tumor control. New radiation modalities such as SFRT, IMRT, SRS, and PBT resulted in better therapeutic results with fewer complications than 2DRT and 3CRT. Thus, they should be the preferential choices for treating ONSM regardless of initial clinical presentation.<br /><br /> Large radiotherapy (RT) planning imaging datasets with consistently contoured cardiovascular structures are essential for robust cardiac radiotoxicity research in thoracic cancers. This study aims to develop and validate a highly accurate automatic contouring model for the heart, cardiac chambers, and great vessels for RT planning computed tomography (CT) images that can be used for dose-volume parameter estimation.<br /><br /> A neural network model was trained using a dataset of 127 expertly contoured planning CT images from RT treatment of locally advanced non-small-cell lung cancer (NSCLC) patients. Evaluation of geometric accuracy and quality of dosimetric parameter estimation was performed on 50 independent scans with contrast and without contrast enhancement. The model was further evaluated regarding the clinical acceptability of the contours in 99 scans randomly sampled from the RTOG-0617 dataset by three experienced radiation oncologists.<br /><br /> Median surface dice at 3mm tolerance for all dedicated thoracic structures was 90% in the test set. Median absolute difference between mean dose computed with model contours and expert contours was 0.45Gy averaged over all structures. The mean clinical acceptability rate by majority vote in the RTOG-0617 scans was 91%.<br /><br /> This model can be used to contour the heart, cardiac chambers, and great vessels in large datasets of RT planning thoracic CT images accurately, quickly, and consistently. Additionally, the model can be used as a time-saving tool for contouring in clinic practice.<br /><br />This model can be used to contour the heart, cardiac chambers, and great vessels in large datasets of RT planning thoracic CT images accurately, quickly, and consistently. Additionally, the model can be used as a time-saving tool for contouring in clinic practice.<br /><br /> Late local recurrences and second primary breast cancers are increasingly common. Proton beam therapy (PBT) reirradiation (reRT) may allow safer delivery of a second definitive radiotherapy (RT) course. We analyzed outcomes of patients with recurrent or new primary breast cancer who underwent reRT.<br /><br /> In an IRB-approved retrospective study, patient/tumor characteristics, treatment parameters, outcomes, and toxicities were collected for all consecutive patients with recurrent or new primary non-metastatic breast cancer previously treated with breast or chest wall RT who underwent PBT reRT .<br /><br /> Forty-six patients received reRT using uniform (70%) or pencil beam (30%) scanning PBT. Median first RT, reRT, and cumulative doses were 60Gy (range 45-66Gy), 50.4Gy(RBE) (40-66.6Gy(RBE)), and 110Gy(RBE) (96.6-169.4Gy(RBE)), respectively. Median follow-up was 21 months. There were no local or regional recurrences; 17% developed distant recurrence. Two-year DMFS and OS were 92.0% and 93.6%, respectively. Nine of 13 (69.2%) patients who underwent implant or flap reconstruction developed capsular contracture, 3 (23.