Atrial flow regulator for drug-resistant pulmonary hypertension in a young child

This case describes the successful implantation of an Occlutech Atrial Flow Regulator in a young child with idiopathic pulmonary hypertension and recurrent syncope despite targeted combination therapy, with subsequent relief of symptoms.     

The proteome of Saccharomyces cerevisiae mitochondria

We performed a comprehensive approach to determine the proteome of Saccharomyces cerevisiae mitochondria. The proteins of highly pure yeast mitochondria were separated by several independent methods and analyzed by tandem MS. From >20 million MS spectra, 750 different proteins were identified, indicating an involvement of mitochondria in numerous cellular processes. All known components of the oxidative phosphorylation machinery, the tricarboxylic acid cycle, and the stable mitochondria-encoded proteins were found. Based on the mitochondrial proteins described in the literature so far, we calculate that the identified proteins represent approximately 90% of all mitochondrial proteins. The function of a quarter of the identified proteins is unknown. The mitochondrial proteome will provide an important database for the analysis of new mitochondrial and mitochondria-associated functions and the characterization of mitochondrial diseases.     

A prospective multicenter evaluation of immediately functionalized tapered conical connection implants for single restorations in maxillary anterior and premolar sites: 3-year results

Objectives

This multicenter prospective clinical trial investigated immediately provisionalized, anodized, conical connection, tapered implants with platform shifting in maxillary anterior and premolar sites.

Materials and methods

Patients requiring single-tooth implant-supported restorations in maxillary anterior and premolar sites were enrolled. Implants were immediately provisionalized and evaluated at insertion, 6 months, and annually thereafter. Outcome measures were marginal bone level change (ΔMBL), cumulative survival rate (CSR), and success rate, soft-tissue parameters, and oral health impact profile (OHIP). ΔMBL and Pink Esthetic Score were analyzed using Wilcoxon signed-rank tests. CSR was calculated using life table analysis. Other soft-tissue parameters were analyzed using sign tests.

Results

Of 94 enrolled patients (99 implants), 84 (88 implants) attended the 3-year follow-up. After an initial bone loss between implant insertion and 6 months (− 0.92 ± 1.23 mm), bone levels stabilized from 6 months to 3 years (0.13 ± 0.94 mm) with no significant change. The 3-year CSR was 98.9%, and the cumulative success rate was 96.9%. Papilla index scores of 2 or 3 were observed at 88.6% of sites at the 3-year visit compared with 32.8% at implant insertion. Improvements were observed for all other outcomes, including bleeding on probing, esthetics, plaque, and OHIP.

Conclusions

This restorative protocol was associated with high primary stability, patient satisfaction, stable bone levels, and an overall improvement of the soft tissue outcomes over a 3-year period.

Clinical relevance

The presented treatment is a viable option for single-tooth restorations of maxillary anterior teeth and premolars with successful short- to mid-long-term clinical outcomes.

     

Depression,psychological distress,and quality of life in patients with cardioverter defibrillator with or without cardiac resynchronization therapy

Congestive heart failure is frequent and leads to reduced exercise capacity, reduced quality of life (QoL), and depression in many patients. Cardiac resynchronization therapy (CRT) and implantable cardioverter defibrillators (ICD) offer therapeutic options and may have an impact on QoL and depression. This study was performed to evaluate physical and mental health in patients undergoing ICD or combined CRT/ICD-implantation (CRT-D). Echocardiography, spiroergometry, and psychometric questionnaires [Beck Depression Inventory, General World Health Organization Five Well-being Index (WHO-5), Brief Symptom Inventory and 36-item Short Form (SF-36)] were obtained in 39 patients (ICD: 17, CRT-D: 22) at baseline and 6-month follow-up (FU) after device implantation. CRT-D patients had a higher NYHA class and broader left bundle branch block than ICD patients at baseline. At FU, ejection fraction (EF), peak oxygen uptake, and NYHA class improved significantly in CRT-D patients but remained unchanged in ICD patients. Patients with CRT-D implantation showed higher levels of depressive symptoms, psychological distress, and impairment in QoL at baseline and FU compared to ICD patients. These impairments remained mostly unchanged in all patients after 6 months. Overall, these findings imply that there is a need for careful assessment and treatment of psychological distress and depression in ICD and CRT-D patients in the course of device implantation as psychological burden seems to persist irrespective of physical improvement.     

Taura syndrome virus IRES initiates translation by binding its tRNA-mRNA–like structural element in the ribosomal decoding center

In cap-dependent translation initiation, the open reading frame (ORF) of mRNA is established by the placement of the AUG start codon and initiator tRNA in the ribosomal peptidyl (P) site. Internal ribosome entry sites (IRESs) promote translation of mRNAs in a cap-independent manner. We report two structures of the ribosome-bound Taura syndrome virus (TSV) IRES belonging to the family of Dicistroviridae intergenic IRESs. Intersubunit rotational states differ in these structures, suggesting that ribosome dynamics play a role in IRES translocation. Pseudoknot I of the IRES occupies the ribosomal decoding center at the aminoacyl (A) site in a manner resembling that of the tRNA anticodon-mRNA codon. The structures reveal that the TSV IRES initiates translation by a previously unseen mechanism, which is conceptually distinct from initiator tRNA-dependent mechanisms. Specifically, the ORF of the IRES-driven mRNA is established by the placement of the preceding tRNA-mRNA–like structure in the A site, whereas the 40S P site remains unoccupied during this initial step.Protein synthesis relies on precise placement of the ORF within the ribosome during translation initiation. Canonical initiation in eukaryotes depends on a 7-methylguanosine cap at the 5′ terminus of mRNA and on extraribosomal initiation factors (1). Following a stepwise assembly, the 80S initiation complex contains the initiator methionyl-tRNA^Met and the AUG start codon in the peptidyl (P) site. Some viral mRNAs use alternative cap-independent mechanisms that involve internal ribosome entry sites (IRESs) (2). IRESs are folded RNA structures in the 5′ UTR that promote formation of the 80S initiation complex in the presence of fewer initiation factors than required for cap-dependent initiation (3).The ribosomal P-site employment in initiation is thought to be ubiquitous for cap-dependent and IRES-dependent translation (4). Of the four groups of known IRESs, the most streamlined mechanism has been described for IRESs from the Dicistroviridae family of arthropod-infecting viruses. The Dicistroviridae genome has two ORFs separated by an intergenic region (IGR). The IGR contains an IRES that drives translation of the second ORF without the aid of initiation factors (4). Based on phylogenetic analyses of the structural polyprotein ORF2 and IGR IRES, the Dicistroviridae viruses are divided into the genus Cripavirus [including cricket paralysis virus (CrPV), Drosophila C virus, and Plautia stali intestine virus (PSIV)] and Aparavirus [including Taura syndrome virus (TSV), Kashmir bee virus, and acute bee paralysis virus] (4). Biochemical studies suggest that despite differences between some secondary structure elements of Cripavirus and Aparavirus IRESs, the molecular mechanisms of translation initiation are similar (5). IGR IRESs can initiate translation on ribosomes from yeast, wheat, human, and other eukaryotic organisms, indicating that the molecular mechanism of IGR IRES-driven initiation in eukaryotes is conserved and is not species-specific (6–10).In contrast to cap-dependent initiation and initiation from other groups of IRESs, translation from IGR IRESs starts from a non-AUG start codon and does not involve initiator methionyl-tRNA^Met. Translation from the majority of IGR IRESs, including the CrPV and TSV IRESs, initiates with alanyl-tRNA^Ala (7, 9, 10). IGR IRESs contain three pseudoknots. At the 5′ region, pseudoknot II (PKII) and PKIII, which are critical for formation of the 40S•IRES and 80S•IRES complexes (8, 9), form a double-nested pseudoknot (11, 12). PKI, located immediately upstream of the start codon, forms a separate domain at the 3′ region of the IRES. This domain is essential for the function of IGR IRESs (13). The crystal structure of an isolated PKI of the CrPV IGR IRES shows that the pseudoknot resembles the anticodon stem loop of tRNA bound to a cognate mRNA codon (14, 15). Isolated PKI of CrPV and PSIV IRESs binds to the P site of the bacterial 70S ribosome, demonstrating that PKI has an affinity to the highly conserved tRNA binding sites on the ribosome (16).The molecular mechanism of translation initiation by IGR IRESs is not fully understood. The current view is that upon formation of the 80S•IRES complex, the PKI is placed in the P site on the small subunit, in a manner mimicking the initiator methionyl-tRNA^Met and the AUG codon (6–8, 10, 17). In this mode, the IRES would position the ORF on the ribosome by presenting the initiating alanine codon in the A (aminoacyl) site. The structural studies of the mechanism, however, have been inconclusive. Previous electron cryomicroscopy (cryo-EM) reconstruction of the CrPV IRES bound to human ribosomal 40S subunit revealed the IRES density spanning from the A site to beyond the exit (E) site (18). The interpretation of the 40S•IRES map favored a model in which PKI interacts with the P-site region (18), although the 20-Å map lacked detailed features in this location. Cryo-EM studies of the 80S ribosome-bound CrPV IRES suggested that upon subunit joining and 80S•IRES complex formation, the IRES may rearrange relative to the 40S subunit (18), and/or reposition PKI in the vicinity of the A and P sites, yet potentially present the downstream alanine codon in the A site (19). The density for the PKI region in these 20-Å and 7.3-Å cryo-EM reconstructions was, however, significantly weaker than that for the rest of the CrPV IRES (18, 19), and it remained unclear how the IGR IRESs initiate translation by accurately positioning the ORF on the 80S ribosome. We report here ∼6-Å cryo-EM structures of the initiation 80S complex bound with an intergenic IRES, which provide structural insights into the mechanism of IGR IRES-driven initiation.     

Structure-Based Design of Substituted Piperidines as a New Class of Highly Efficacious Oral Direct Renin Inhibitors

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Spatial distribution of human arachnoid trabeculae

Traumatic brain injury (TBI) is a common injury modality affecting a diverse patient population. Axonal injury occurs when the brain experiences excessive deformation as a result of head impact. Previous studies have shown that the arachnoid trabeculae (AT) in the subarachnoid space significantly influence the magnitude and distribution of brain deformation during impact. However, the quantity and spatial distribution of cranial AT in humans is unknown. Quantification of these microstructural features will improve understanding of force transfer during TBI, and may be a valuable dataset for microneurosurgical procedures. In this study, we quantify the spatial distribution of cranial AT in seven post-mortem human subjects. Optical coherence tomography (OCT) was used to conduct in situ imaging of AT microstructure across the surface of the human brain. OCT images were segmented to quantify the relative amounts of trabecular structures through a volume fraction (VF) measurement. The average VF for each brain ranged from 22.0% to 29.2%. Across all brains, there was a positive spatial correlation, with VF significantly greater by 12% near the superior aspect of the brain (p < .005), and significantly greater by 5%−10% in the frontal lobes (p < .005). These findings suggest that the distribution of AT between the brain and skull is heterogeneous, region-dependent, and likely contributes to brain deformation patterns. This study is the first to image and quantify human AT across the cerebrum and identify region-dependencies. Incorporation of this spatial heterogeneity may improve the accuracy of computational models of human TBI and enhance understanding of brain dynamics.     

Reductions in Whole-body Ownership in Borderline Personality Disorder – A Phenomenological Manifestation of Dissociation

ABSTRACT

Body ownership, i.e., the certainty that own body parts belongs to oneself, is a fundamental feature of self-consciousness. Patients with borderline personality disorder (BPD) often show symptoms of dissociation, describing a state of detachment from reality including their own body. However, up to now, there is no study that a) quantifies body ownership experiences in BPD, b) compares these experiences between the current and the remitted state of the disorder, and c) relates this kind of experience specifically to dissociation. In the present study, we assessed ownership for 25 body areas in current BPD patients (cBPD) and compared their ratings with those of remitted BPD patients (rBPD) and healthy controls (HC). We further related body ownership to dissociation and other relevant BPD markers on body area and subject level by applying multi-level analyses in the cBPD group. We found significantly reduced body ownership experiences in cBPD compared to HC, while there were no significant differences between these groups and rBPD. In cBPD, reduced body ownership was significantly related to dissociation when controlled for other BPD core features. Reduced body ownership might thus constitute a relevant marker for dissociation in current BPD which could further represent a target for therapeutic approaches.