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Background Stiff left atrial syndrome (SLAS) and pulmonary vein (PV) occlusion are rare yet potentially major life-long complications after radiofrequency ablation for atrial fibrillation. While mostly controlled by medical management, SLAS can progress to refractory congestive heart failure. Treatment of PV stenosis and occlusion remains a challenging problem with ongoing risk for recurrence regardless of techniques employed. Herein we present the case of a now 51-year-old male with acquired PV occlusion and SLAS who, over the course of eleven years, despite multiple interventions, ultimately required heart transplantation. Case presentation After undergoing three radiofrequency catheter procedures for paroxysmal atrial fibrillation (AF), a hybrid ablation was planned due to reappearance of symptomatic AF. Preoperative echocardiography and chest computed tomography (CT) revealed an occlusion of both left PVs. Furthermore, left atrial dysfunction, high pulmonary artery and pulmonary wedge pressures were diagnosed as well as an important reduction of the left atrial volume. The diagnosis of stiff left atrial syndrome was made. Primary surgical repair of the left-sided PVs was performed using a pericardial patch as a tubular neo-vein, combined with cryoablation in the left and right atrium to treat the patient’s arrhythmia. Initial results were favorable, however, after two years the patient experienced progressive restenosis with hemoptysis. Therefore, stenting of the common left PV was performed. Over the years, progressive right heart failure with severe tricuspid regurgitation developed, despite maximal medical therapy, which led to the need for heart transplantation. Conclusion The impact of PV occlusion and SLAS after percutaneous radiofrequency ablation can be lifelong and devastating for the clinical course of the patient. Since the presence of a small left atrium could be an important predictor for SLAS in case of redo ablation, preprocedural imaging should guide the operator to an algorithm of a decision-making containing lesion set, energy source, and safety of re-ablation.

Purpose: Verbal fluency tasks assess the ability to quickly and efficiently retrieve words from the mental lexicon by requiring subjects to rapidly generate words within a phonological or semantic category. This study investigated differences between cochlear implant users and normal-hearing peers in the clustering and time course of word retrieval during phonological and semantic verbal fluency tasks. Method: Twenty-eight children and adolescents (aged 9–17 years) with cochlear implants and 33 normal-hearing peers completed measures of verbal fluency, nonverbal intelligence, speech perception, and verbal short-term/working memory. Phonological and semantic verbal fluency tests were scored for total words generated, words generated in each 10-s interval of the 1-min task, latency to first word generated, number of word clusters, average cluster size, and number of word/cluster switches. Results: Children and adolescents with cochlear implants generated fewer words than normal-hearing peers throughout the entire 60-s time interval of the phonological and semantic fluency tasks. Cochlear implant users also had slower start latency times and produced fewer clusters and switches than normal-hearing peers during the phonological fluency task. Speech perception and verbal working memory scores were more strongly associated with verbal fluency scores in children and adolescents with cochlear implants than in normal-hearing peers. Conclusions: Cochlear implant users show poorer phonological and semantic verbal fluency than normal-hearing peers, and their verbal fluency is significantly associated with speech perception and verbal working memory. These findings suggest deficits in fluent retrieval of phonological and semantic information from long-term lexical memory in cochlear implant users.

O urbanismo rodoviarista do século XX aumentou as distâncias físicas e sociais nas cidades e agravou os problemas ambientais. Brasília, campo de experimentações do urbanismo moderno, não ficou de fora desse cenário e atualmente sofre com o espraiamento, a Via TransBrasília surge para conectar as Regiões Administrativas do eixo sul entre si e ao centro da capital. Este artigo propõe um estudo investigativo e avaliador do potencial de aplicação do Desenvolvimento Orientado ao Transporte Sustentável (DOTS) no futuro projeto da via, baseado nas Diretrizes Urbanísticas da Via TransBrasília (DIUR 03/2018) e analisado em duas etapas: “8 Princípios de um projeto DOTS: a Via TransBrasília se adequa a esses requisitos?” e “Etapas para a implementação de políticas e projetos DOTS”.

Arboviral diseases caused by flaviviruses, such as dengue, are a continuing threat and major concern worldwide, with over three billion people estimated to be living with the risk of dengue virus (DENV) infections. There are thus far no antiviral drugs available for treatment, and limited or no vaccines are available. Curcumin and seven synthetic analogues were evaluated for their antiviral activity against dengue virus serotype 2, yellow fever virus and Zika virus, as well as for their cytotoxicity in Vero cells, both by employing MTT assays. Compounds 6 and 7, which present a thiazolylhydrazone moiety, showed moderate activity against all three flaviviruses, with selectivity index (SI) values up to 4.45. In addition, the envelope protein (E) was predicted as the potential target inhibited by both compounds, supported by molecular docking and dynamics simulation analysis. We hope that this data can contribute to the development of new curcumin antiviral analogues in the near future and can help in the search for new promising compounds as potential therapeutic agents to treat flaviviruses infections.

Beca de Iniciación a la Investigación para estudiantes de Máster” of the University of Granada (Spain), Oficina de Asuntos Internacionales y Cooperación Externa (OAICE) of the Universidad de Costa Rica, Ministerio de Ciencia, Tecnología y Telecomunicaciones (MICITT) of the Government of Costa Rica and Fundación Carolina (Spain), TϋCAD2 is funded by the Federal Ministry of Education and Research (BMBF), Baden-Württemberg Ministry of Science as part of the Excellence Strategy of the German Federal and State Governments EXC 2180–390900677, ERANet program, Research in prevention of congenital Chagas disease: parasitological, placental and immunological markers (ERANet17/HLH-0142 (Cochaco), Instituto Carlos III, Ministerio de Sanidad, Gobierno de España; Fundación Ramón Areces “Interactoma de las exovesículas, Ministerio de Ciencia y Tecnología of the government of Spain funded the project PGC2018- 099424-B-I00, Proyect A-BIO-350-UGR18 I+D+i Proyect “Programa Operativo FEDER de Andalucía JJAA” 2014-2020

Aims Hybrid atrial fibrillation (AF) ablation is a promising approach in non-paroxysmal AF. The aim of this study is to assess the long-term outcomes of hybrid ablation in a large cohort of patients after both an initial and as a redo procedure. Methods and results All consecutive patients undergoing hybrid AF ablation at UZ Brussel from 2010 to 2020 were retrospectively evaluated. Hybrid AF ablation was performed in a one-step procedure: (i) thoracoscopic ablation followed by (ii) endocardial mapping and eventual ablation. All patients received PVI and posterior wall isolation. Additional lesions were performed based on clinical indication and physician judgement. Primary endpoint was freedom from atrial tachyarrhythmias (ATas). A total of 120 consecutive patients were included, 85 patients (70.8%) underwent hybrid AF ablation as first procedure (non-paroxysmal AF 100%), 20 patients (16.7%) as second procedure (non-paroxysmal AF 30%), and 15 patients (12.5%) as third procedure (non-paroxysmal AF 33.3%). After a mean follow-up of 62.3 months ± 20.3, a total of 63 patients (52.5%) experienced ATas recurrence. Complications occurred in 12.5% of patients. There was no difference in ATas between patients undergoing hybrid as first vs. redo procedure (P = 0.53). Left atrial volume index and recurrence during blanking period were independent predictors of ATas recurrence. Conclusion In a large cohort of patients undergoing hybrid AF ablation, the survival from ATas recurrence was 47.5% at ≈5 years follow-up. There was no difference in clinical outcomes between patients undergoing hybrid AF ablation as first procedure or as a redo.

Firms use job promotions to incentivize hard work from low-level employees and to sort employees according to their skills. Since these two functions are often in conflict, a firm’s promotion strategy tries to balance them. Our model extends prior research by identifying job similarity between current and future job as a driver of a firm’s promotion strategy. When compensation costs are high or external hiring options poor, then higher job similarity leads to fewer internal promotions. Otherwise, higher job similarity can lead to more internal promotions. These results help to explain why firms with different structures or from different industries apply different promotion strategies.

Inhibition of ABC transporters is a promising approach to overcome multidrug resistance in cancer. Herein, we report the characterization of a potent ABCG2 inhibitor, namely, chromone 4a (C4a). Molecular docking and in vitro assays using ABCG2 and P-glycoprotein (P-gp) expressing membrane vesicles of insect cells revealed that C4a interacts with both transporters, while showing selectivity toward ABCG2 using cell-based transport assays. C4a inhibited the ABCG2-mediated efflux of different substrates and molecular dynamic simulations demonstrated that C4a binds in the Ko143-binding pocket. Liposomes and extracellular vesicles (EVs) of Giardia intestinalis and human blood were used to successfully bypass the poor water solubility and delivery of C4a as assessed by inhibition of the ABCG2 function. Human blood EVs also promoted delivery of the well-known P-gp inhibitor, elacridar. Here, for the first time, we demonstrated the potential use of plasma circulating EVs for drug delivery of hydrophobic drugs targeting membrane proteins.

PDB file for the proposed binding of compound 1639 in the Human p38alpha structure. Associated methods are provided in the respective publication

Financial technology, also known as FinTech, has changed the way financial services are offered and used. Over the last few years, FinTech companies have become important providers to the Swiss financial sector by developing and offering innovative, technology-based solutions for the traditional financial service industry. Since the initial survey of the sector in 2016, it has been changing continuously. While the first few years were characterised by growth, last year's evaluation saw the first contraction in the number of FinTech companies based in Switzerland. In 2022, however, the Swiss FinTech sector successfully returned to a path of growth. At the end of 2022, Switzerland was home to a total of 437 FinTech companies, which corresponds to a growth of 14 percent compared to the previous year. This positive development is not least due to the good conditions in Switzerland — also in international comparison — which seem to be materialising again. It is also expressed in the increasing investment volumes in the Swiss FinTech sector, which, in contrast, have decreased at the global level. The dynamism of the sector is also reflected in the companies' business models, which is exemplified by the increasing focus on sustainability. The aim of this study is to assess the state and the evolution of the Swiss FinTech sector, drawing upon the methodology established in prior editions. The study endeavours to examine trends in the sector as a whole and in the specific business models of domestic FinTech companies and may offer insights for a diverse range of stakeholders within the Swiss financial sector, including FinTech companies, traditional financial institutions, and political decision-makers., + ID der Publikation: hslu_97160 + Art des Beitrages: Buch (Monographie) + Sprache: Englisch + Letzte Aktualisierung: 2023-04-11 16:18:51

A 57-year-old patient with a history of aortic and mitral mechanical valve replacement was admitted with recurrent implantable cardioverter device shocks and antitachycardia pacing therapies. On electrocardiogram, the clinical ventricular tachycardia (VT) was compatible with an antero-lateral peri-mitral basal exit. Because of the inability to access the left ventricle through a percutaneous approach, epicardial VT ablation was performed. The VT and a second VT, consistently induced and coming from the left ventricular apex, were successfully treated with epicardial cryoablation via median sternotomy under cardiopulmonary bypass.

Supplementary Fig. S3. Doxycyline-induced overexpression of Dicer in HCC cells. HepG2 (A) and Huh-7 (B) cells stably transfected with the inducible Dicer construct were incubated with or without doxycycline (Dox) for 24 h. C: HepG2 cells with the inducible Dicer construct were incubated for the indicated duration with or without doxycycline. A-C: The lysates were analyzed by immunoblotting using anti-Dicer and anti-β-actin antibodies. D: Western blot analysis of Dicer protein expression in Dicer-transgenic HepG2 xenografts from mice treated for 7 days with doxycycline (n = 3) or vehicle (n = 4), that were used for the experiment displayed in Fig. 5F. A-D: β-actin was used as endogenous control.

Table S1. Clinicopathological parameters of the patients with HCC. HBV, hepatitis B virus; HCV, hepatitis C virus

Purpose: A role of Dicer, which converts precursor miRNAs to mature miRNAs, in the tumor-promoting effect of hypoxia is currently emerging in some tumor entities. Its role in hepatocellular carcinoma (HCC) is unknown.Experimental Design: HepG2 and Huh-7 cells were stably transfected with an inducible Dicer expression vector and were exposed to hypoxia/normoxia. HepG2-Dicer xenografts were established in nude mice; hypoxic areas and Dicer were detected in HCC xenografts and HCCs from mice with endogenous hepatocarcinogenesis; and epithelial–mesenchymal transition (EMT) markers were analyzed by immunohistochemistry or by immunoblotting. The correlation between Dicer and carbonic anhydrase 9 (CA9), a marker of hypoxia, was investigated in resected human HCCs.Results: Hypoxia increased EMT markers in vitro and in vivo and led to a downregulation of Dicer in HCC cells. The levels of Dicer were downregulated in hypoxic tumor regions in mice with endogenous hepatocarcinogenesis and in HepG2 xenografts. In human HCCs, the levels of Dicer correlated inversely with those of CA9, indicating that the negative regulation of Dicer by hypoxia also applies to HCC patients. Forced expression of Dicer prevented the hypoxia-induced increase in hypoxia-inducible factor 1α (HIF1α), HIF2α, hypoxia-inducible genes (CA9, glucose transporter 1), EMT markers, and cell migration.Conclusions: We here identify downmodulation of Dicer as novel essential process in hypoxia-induced EMT in HCC and demonstrate that induced expression of Dicer counteracted hypoxia-induced EMT. Thus, targeting hypoxia-induced downmodulation of Dicer is a promising novel strategy to reduce HCC progression. Clin Cancer Res; 23(14); 3896–905. ©2017 AACR.

Supplementary Fig. S2. Tumor hypoxia increases EMT markers in HepG2 xenografts. Nude mice bearing HepG2 xenografts were sacrificed and the tumors were removed from the animals. Frozen sections of the tumors were stained with anti-E-cadherin (red) and anti-CA9 (green) and Hoechst (blue) and were examined by CLSM. (Scale bar: 30 µm).

Supplementary Information

Supplementary Fig. S1. Apoptosis is not responsible for down-regulation of Dicer in HepG2 under hypoxic conditions. Western blot analysis of protein extracts from HepG2 cells cultured for 24 h under hypoxia (1% O2) (H) or normoxia (N) using anti-cleaved caspase-3 antibody. For positive control, HepG2 cells were treated with BI 2536 for 48 h with the indicated concentrations.

Supplementary Figure S3: Body weight of HepG2 (A) and Huh-7 (B) xenograft-bearing mice treated with iRGD, control (Ctl.) peptide, PBS and sorafenib (Sora).

Supplementary Figure S1: Imaging of HCC by Gd-EOB-DTPA-enhanced MRI in TGFα/c-myc mice with an HCC.

Supplementary Figure S4: Effect of sorafenib with or without iRGD on MAPK phosphorylation levels in the HepG2 xenografts from the different treatment groups.

Salt-inducible kinases 1-3 (SIK1-3) are key regulators of the LKB1-AMPK pathway and play an important role in cellular homeostasis. Dysregulation of any of the three isoforms has been associated with tumorigenesis in liver, breast, and ovarian cancers. We have recently developed the dual pan-SIK/group I p21-activated kinase (PAK) chemical probe MRIA9. However, inhibition of p21-activated kinases has been associated with cardiotoxicityin vivo, which complicates the use of MRIA9 as a tool compound. Here, we present a structure-based approach involving the back-pocket and gatekeeper residues, for narrowing the selectivity of pyrido[2,3-d]pyrimidin-7(8H)-one-based inhibitors towards SIK kinases, eliminating PAK activity. Optimization was guided by high-resolution crystal structure analysis and computational methods, resulting in a pan-SIK inhibitor, MR22, which no longer exhibited activity on STE group kinases and displayed excellent selectivity in a representative kinase panel. MR22-dependent SIK inhibition led to centrosome dissociation and subsequent cell-cycle arrest in ovarian cancer cells, as observed with MRIA9, conclusively linking these phenotypic effects to SIK inhibition. Taken together, MR22 represents a valuable tool compound for studying SIK kinase function in cells.

Existing cochlear implant (CI) outcomes research demonstrates a high degree of variability in device effectiveness among experienced CI users. Increasing evidence suggests that verbal learning and memory (VLM) may have an influence on speech recognition with CIs. This study examined the relations in CI users between visual measures of VLM and speech recognition in a series of models that also incorporated spectro-temporal discrimination. Predictions were that (1) speech recognition would be associated with VLM abilities and (2) VLM would contribute to speech recognition outcomes above and beyond spectro-temporal discrimination in multivariable models of speech recognition.This cross-sectional study included 30 adult postlingually deaf experienced CI users who completed a nonauditory visual version of the California Verbal Learning Test-Second Edition (v-CVLT-II) to assess VLM, and the Spectral-Temporally Modulated Ripple Test (SMRT), an auditory measure of spectro-temporal processing. Participants also completed a battery of word and sentence recognition tasks.CI users showed significant correlations between some v-CVLT-II measures (short-delay free- and cued-recall, retroactive interference, and "subjective" organizational recall strategies) and speech recognition measures. Performance on the SMRT was correlated with all speech recognition measures. Hierarchical multivariable linear regression analyses showed that SMRT performance accounted for a significant degree of speech recognition outcome variance. Moreover, for all speech recognition measures, VLM scores contributed independently in addition to SMRT.Measures of spectro-temporal discrimination and VLM were associated with speech recognition in CI users. After accounting for spectro-temporal discrimination, VLM contributed independently to performance on measures of speech recognition for words and sentences produced by single and multiple talkers.3 Laryngoscope, 2022.

It is now widely accepted that there is a growing discrepancy between demand and access to adequate treatment for behavioral or mental health conditions in the United States. This results in immense personal, societal, and economic costs. One rapidly growing method of addressing this discrepancy is to integrate mental health services into the primary care setting, which has become the de facto service provider for these conditions. In this paper, we describe the development and implementation of a novel integrated care program in a large mid-western university-based healthcare system, drawn from the collaborative care model, and describe the benefits in terms of both health care utilization and depression outcomes. Limitations and proposed future directions are discussed.

OBJECTIVES: This study examined the performance of a group of adult cochlear implant (CI) candidates (CIC) on visual tasks of verbal learning and memory. Pre-operative verbal learning and memory abilities of the CIC group were compared with a group of older normal-hearing (ONH) control participants. Relations between pre-operative verbal learning and memory measures and speech recognition outcomes after 6 months of CI use were also investigated for a subgroup of the CICs. DESIGN: A group of 80 older adult participants completed a visually presented multi-trial free recall task. Measures of word recall, repetition learning, and the use of self-generated organizational strategies were collected from a group of 49 CICs, prior to cochlear implantation, and a group of 31 ONH controls. Speech recognition outcomes were also collected from a subgroup of 32 of the CIC participants who returned for testing six months after CI activation. RESULTS: CICs demonstrated poorer verbal learning performance compared to the group of ONH control participants. Among the pre-operative verbal learning and memory measures, repetition learning slope and measures of self-generated organizational clustering strategies were the strongest predictors of post-CI speech recognition outcomes. CONCLUSIONS: Older adult CI candidates present with verbal learning and memory deficits compared to older adults without hearing loss, even on visual tasks that are independent from the direct effects of audibility. Pre-operative verbal learning and memory processes reflecting repetition learning and self-generated organizational strategies in free recall were associated with speech recognition outcomes six months after implantation. The pattern of results suggests that visual measures of verbal learning may be a useful predictor of outcomes in post-lingual adult CICs.

Investors are much more likely to sue corporations and their auditors for overstated earnings reports than for understated reports. This asymmetry in litigation exposure is viewed as an important driver for conservative accounting practices in corporations because conservatism reduces the probability of overstatements and hence, investor litigation. This argument is incomplete, however, because it ignores that litigation concerns also affect the incentives of the auditor, which, in turn, affect the firm’s optimal reporting system. We find that the threat of litigation encourages firms to report more conservatively only when the auditor’s cost of detecting misstatements is relatively high but promotes less conservative reporting when the auditor’s cost of auditing is low. This paper was accepted by Brian Bushee, accounting

The expression of virulence factors essential for the invasion of host cells bySalmonella entericais tightly controlled by a network of transcription regulators. The AraC/XylS transcription factor HilD is the main integration point of environmental signals into this regulatory network, with many factors affecting HilD activity. Long chain fatty acids (LCFAs), which are highly abundant throughout the host intestine directly bind to, and repress HilD, acting as environmental cues to coordinate virulence gene expression. The regulatory protein HilE also negatively regulates HilD activity, through a protein-protein interaction. Both of these regulators inhibit HilD dimerisation, preventing HilD from binding to target DNA. We investigated the structural basis of these mechanisms of HilD repression. LCFAs bind to a conserved pocket in HilD, in a comparable manner to that reported for other AraC/XylS regulators, whereas HilE forms a stable heterodimer with HilD by binding to the HilD dimerisation interface. Our results highlight two distinct mechanisms by which HilD activity is repressed, which could be exploited for the development of new antivirulence leads.

The attached archives contain the Molecular Dynamics trajectories for MR22–SIK2 simulations, where names indicate the replica number accordingly. MR22_SIK2_raw_data.zip encompasses the raw data on MR22–SIK2 interactions in the *.dat format, separated for interaction components (i.e. Hydrophobic interactions/Hydrogen Bonding) for concatenated trajectories with the total length of 2.5μs.

The attached archives contain 5 replicas of a simulated system (1μs each) with the naming as following: MSTnumber_MRnumber. For each simulated system is attached an additional archive with the raw data on MSTnumber–MRnumber interactions in the *.dat format separated for interaction components (i.e. Hydrophobic interactions/Hydrogen Bonding) for concatenated trajectories with a total length of 5μs each. Furthermore, the *.csv files provide the raw MM-GBSA output for concatenated trajectories of a given system.

The attached archives contain 5 replicas of a simulated system (1μs each) with the naming as following: MSTnumber_MRnumber. For each simulated system is attached an additional archive with the raw data on MSTnumber–MRnumber interactions in the *.dat format separated for interaction components (i.e. Hydrophobic interactions/Hydrogen Bonding) for concatenated trajectories with a total length of 5μs each. Furthermore, the *.csv files provide the raw MM-GBSA output for concatenated trajectories of a given system.

Those files comprise trajectories of MD simulations of protein E dimers in presence of ligands of interest (see below). We also provide the data for the simulation interactions and RMSD/RMSF as raw data here enclosed. Methods and ligand specifications are provided in the respective manuscript.Trajectories were generated in Desmond and are provided in this format, alternative formats or specific frames are available upon request. a = apo x = lig xtal 6 = cpd6 7 = cpd7

PICO question In dogs diagnosed with osteoarthritis (OA), how safe is treatment with bedinvetmab, when compared to a placebo and how effective in long-term reduction of the severity of the clinical signs associated with OA-related pain? Clinical bottom line Category of research Treatment. Number and type of study designs reviewed Two papers were critically reviewed. One was a randomised, blinded, multi-arm laboratory safety study; the other a multi-center field trial consisting of a block-randomised, double blind, placebo-controlled phase, followed by a non-comparative, open-label case series study. Strength of evidence Weak. Outcomes reported One study rated the reduction of the severity of clinical signs associated with OA pain using owner Canine Brief Pain Inventory (CBPI) ratings and non-validated veterinary clinical assessments (VCAs). Safety was addressed by evaluating adverse health effects (AHEs), concentration of antidrug antibodies (ADAs), and clinical pathology. Significant improvements in pain scores and VCAs were reported in this treatment study. The second safety-only study used clinical observation to evaluate AHEs. Both studies reported AHEs. Conclusion A single study suggests that treatment with bedinvetmab is effective. Two studies support the drug having few AHEs. Both studies have significant design limitations preventing the evaluation of bedinvetmab effectiveness. There is weak / inconclusive evidence for long-term efficacy and short-term safety of OA treatment with bedinvetmab. The decision to use bedinvetmab remains dependent on the judgement and experience of the clinician. How to apply this evidence in practice The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient’s circumstances and owners’ values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources. Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care.

In a previous work, the common gonadotrophic hormone α-subunit (ag-GTHα), the ag-FSH β- and ag-LH β-subunit cDNAs, were isolated and characterized by our research group from A. gigas pituitaries, while a preliminary synthesis of ag-FSH was also carried out in human embryonic kidney 293 (HEK293) cells. In the present work, the cDNA sequence encoding the ag-growth hormone (ag-GH) has also been isolated from the same giant Arapaimidae Amazonian fish. The ag-GH consists of 208 amino acids with a putative 23 amino acid signal peptide and a 185 amino acid mature peptide. The highest identity, based on the amino acid sequences, was found with the Elopiformes (82.0%), followed by Anguilliformes (79.7%) and Acipenseriformes (74.5%). The identity with the corresponding human GH (hGH) amino acid sequence is remarkable (44.8%), and the two disulfide bonds present in both sequences were perfectly conserved. Three-dimensional (3D) models of ag-GH, in comparison with hGH, were generated using the threading modeling method followed by molecular dynamics. Our simulations suggest that the two proteins have similar structural properties without major conformational changes under the simulated conditions, even though they are separated from each other by a >100 Myr evolutionary period (1 Myr = 1 million years). The sequence found will be used for the biotechnological synthesis of ag-GH while the ag-GH cDNA obtained will be utilized for preliminary Gene Therapy studies.

no abstract available, + ID der Publikation: hslu_98035 + Art des Beitrages: Buch (Monographie) + Sprache: Englisch + Letzte Aktualisierung: 2023-05-22 12:28:04

Purpose: Verbal working memory (VWM) delays are commonly found in prelingually deaf youth with cochlear implants (CIs), albeit with considerable interindividual variability. However, little is known about the neurocognitive information-processing mechanisms underlying these delays and how these mechanisms relate to spoken language outcomes. The goal of this study was to use error analysis of the letter–number sequencing (LNS) task to test the hypothesis that VWM delays in CI users are due, in part, to fragile, underspecified phonological representations in short-term memory. Method: Fifty-one CI users aged 7–22 years and 53 normal hearing (NH) peers completed a battery of speech, language, and neurocognitive tests. LNS raw scores and error profiles were compared between samples, and a hierarchical regression model was used to test for associations with measures of speech, language, and hearing. Results: Youth with CIs scored lower on the LNS test than NH peers and committed a significantly higher number of errors involving phonological confusions (recalling an incorrect letter/digit in place of a phonologically similar one). More phonological errors were associated with poorer performance on measures of nonword repetition and following spoken directions but not with hearing quality. Conclusions: Study findings support the hypothesis that poorer VWM in deaf children with CIs is due, in part, to fragile, underspecified phonological representations in short-term/working memory, which underlie spoken language delays. Programs aimed at strengthening phonological representations may improve VWM and spoken language outcomes in CI users.

Isaac A Janson,1 Ellen M Bloom,1 Kisha C Hampton,1 Emily Riehm Meier,1 Angeli G Rampersad,1 William G Kronenberger2 1Indiana Hemophilia and Thrombosis Center, Indianapolis, IN, USA; 2Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USACorrespondence: Isaac A Janson, Indiana Hemophilia and Thrombosis Center, 8326 Naab Road, Indianapolis, IN, 46260, USA, Tel +1-317-871-0011, Fax +1-317-871-0010, Email ijanson@ihtc.orgIntroduction: Hydroxyurea reduces the incidence of vaso-occlusive episodes, stroke, and respiratory, cardiac, and renal damage in sickle cell disease by increasing fetal hemoglobin. However, because suboptimal adherence to hydroxyurea limits its effectiveness, understanding patient-specific barriers to hydroxyurea adherence could help improve adherence and health outcomes in patients with sickle cell disease. The aim of this single-site, prospective, IRB-approved study was to validate a 24-item patient- and caregiver-reported hydroxyurea treatment adherence questionnaire, the Hydroxyurea Evaluation of Adherence for Life (HEAL) scale.Methods: A sample of 24 adults with sickle cell disease and 16 caregivers of children with sickle cell disease completed the HEAL scale, and a subset of the original sample provided a second HEAL scale for test-retest reliability. HEAL scale results were validated against global adherence ratings from participants and health-care providers, records of access to pill bottles, and laboratory values for fetal hemoglobin and absolute neutrophil count.Results and Discussion: Results demonstrated excellent internal consistency for the HEAL Total score and eight (3-item) subscale scores (Dose, Remember, Plan, Cost, Understand, Effectiveness, Laboratory, and Pharmacy), as well as strong test-retest reliability for all HEAL scores except the Cost subscale. HEAL Total scores correlated significantly with validity measures, including global adherence ratings and lab values. The HEAL scale offers significant clinical potential for understanding adherence in individual sickle cell disease patients and significant research potential for characterizing adherence in persons with sickle cell disease who are treated with hydroxyurea.Keywords: sickle cell disease, treatment adherence, hydroxyurea, reliability, validity, scale development

Those files comprise trajectories of MD simulations of Mpro dimers in presence of covalently bound ligands of interest. We also provide the data for the simulation interactions and RMSD/RMSF as raw data here enclosed. Methods and ligand specifications are provided in the respective manuscript.Trajectories were generated in Desmond and are provided in this format, alternative formats or specific frames are available upon request.

SARS-CoV-2’s main protease (Mpro) interaction with ligands has been explored with a myriad of crystal structures, most of the monomers. Nonetheless, Mpro is known to be active as a dimer but the relevance of the dimerization in the ligand-induced conformational changes has not been fully elucidated. We systematically simulated different Mpro-ligand complexes aiming to study their conformational changes and interactions, through molecular dynamics (MD). We focused on covalently bound ligands (N1 and N3, ∼9 μs per system both monomers and dimers) and compared these trajectories against the apostructure. Our results suggest that the monomeric simulations led to an unrealistically flexible active site. In contrast, the Mpro dimer displayed a stable oxyanion-loop conformation along the trajectory. Also, ligand interactions with residues His41, Gly143, His163, Glu166 and Gln189 are postulated to impact the ligands' inhibitory activity significantly. In dimeric simulations, especially Gly143 and His163 have increased interaction frequencies. In conclusion, long-timescale MD is a more suitable tool for exploring in silico the activity of bioactive compounds that potentially inhibit the dimeric form of SARS-CoV-2 Mpro. Communicated by Ramaswamy H. Sarma

Although epicardial bipolar radiofrequency ablation should diminish the risk of esophageal thermal injury in comparison to an endocardial ablation, cases of lethal atrio-esophageal fistula have been reported. To better understand this risk and to reduce the possibility of a thermal injury, we monitored the esophageal temperature with the Circa S-Cath™ temperature probe during and immediately after the ablation while implementing three procedural safety measures. Twenty patients (15 males; 63 ± 10 years) were prospectively enrolled (November 2019–February 2021). All patients underwent an epicardial ablation procedure, including an antral left and right pulmonary vein isolation with bidirectional bipolar clamping, and a roof and inferior line using unidirectional bipolar radiofrequency. Three procedural preventive mitigations were implemented: (1) transesophageal echocardiographic visualization of the atrio-esophageal interface, with probe retraction before the energy delivery; (2) lifting the ablated tissue away from the esophagus during an energy application; and (3) a 30 s cool-off and irrigation period after the energy delivery. The esophageal temperature was recorded using an insulated multisensory intraluminal esophageal temperature probe (Circa S-Cath™). Of the 20 patients enrolled, 7 patients had paroxysmal atrial fibrillation (AF), 8 persistent AF and 5 longstanding persistent AF. The average maximum luminal esophageal temperature observed was 36.2 ± 0.7 °C (34.8–38.2 °C). In our clinical experience, no abrupt increase in the luminal esophageal temperature above the baseline was observed. Since no measurements exceeded the threshold of 39 °C, no prompt interruption of energy delivery was required. Intraluminal esophageal temperature monitoring is feasible and can be helpful in confirming correct catheter position and safe energy application in bipolar epicardial left atrial ablation. Intra-procedural preventive mitigations should be implemented to reduce the risk of esophageal temperature rises.

Völkerrechtsblog

Farnesoid X receptor (FXR) is a nuclear receptor with an essential role in regulating bile acid synthesis and cholesterol homeostasis. FXR activation by agonists is explained by an alpha AF-2-trapping mechanism; however, antagonism mechanisms are diverse. We discuss microsecond molecular dynamics (MD) simulations investigating our recently reported FXR antagonists 2a and 2 h. We study the antagonist-induced conformational changes in the FXR ligand-binding domain, when compared to the synthetic (GW4064) or steroidal (chenodeoxycholic acid, CDCA) FXR agonists in the FXR monomer or FXR/RXR heterodimer r, and in the presence and absence of the coactivator. Our MD data suggest ligand-specific influence on conformations of different FXR-LBD regions, including the alpha 5/alpha 6 region, alpha AF-2, and alpha 9-11. Changes in the heterodimerization interface induced by antagonists seem to be associated with alpha AF-2 destabilization, which prevents both co-activator and co-repressor recruitment. Our results provide new insights into the conformational behaviour of FXR, suggesting that FXR antagonism/agonism shift requires a deeper assessment than originally proposed by crystal structures.

The enzyme enoyl-ACP reductase (FabI) is the limiting step of the membrane's fatty acid biosynthesis in bacteria and a druggable target for novel antibacterial agents. The FabI active form is a homotetramer, which displays the highest affinity to inhibitors. Herein, molecular dynamics studies were carried out using the structure of FabI in complex with known inhibitors to investigate their effects on tetramerization. Our results suggest that multimerization is essential for the integrity of the catalytic site and that inhibitor binding enables the multimerization by stabilizing the substrate binding loop (SBL, L:195-200) coupled with changes in the H4/5 (QR interface). We also observed that AFN-1252 (naphtpyridinone derivative) promotes unique conformational changes affecting monomer-monomer interfaces. These changes are induced by AFN-1252 interaction with key residues in the binding sites (Ala95, Tyr146, and Tyr156). In addition, the analysis of water trajectories indicated that AFN-1252 complexes allow more water molecules to enter the binding site than triclosan and MUT056399 complexes. FabI-AFN-1252 simulations show accumulation of water molecules near the Tyr146/147 pocket, which can become a hotspot to the design of novel FabI inhibitors.

Those files comprise trajectories of MD simulations of ABCG2 dimers in presence of bound ligands of interest. We also provide the data for the simulation interactions and RMSD/RMSF as raw data here enclosed. Methods and ligand specifications are provided in the respective manuscript.Trajectories were generated in Desmond and are provided in this format, alternative formats or specific frames are available upon request.