Risk factors for transmission of carbapenem-resistant Acinetobacter baumannii in outbreak situations: results of a case-control study.

BACKGROUND: An increase in patients with multidrug-resistant organisms and associated outbreaks during the COVID-19 pandemic have been reported in various settings, including low-endemic settings. Here, we report three distinct carbapenem-resistant Acinetobacter baumannii (CRAB) outbreaks in five intensive care units of a university hospital in Berlin, Germany during the COVID-19 pandemic. METHODS: A case-control study was conducted with the objective of identifying risk factors for CRAB acquisition in outbreak situations. Data utilized for the case-control study came from the investigation of three separate CRAB outbreaks during the COVID-19 pandemic (August 2020- March 2021). Cases were defined as outbreak patients with hospital-acquired CRAB. Controls did not have any CRAB positive microbiological findings and were hospitalized at the same ward and for a similar duration as the respective case. Control patients were matched retrospectively in a 2:1 ratio. Parameters routinely collected in the context of outbreak management and data obtained retrospectively specifically for the case-control study were included in the analysis. To analyze risk factors for CRAB acquisition, univariable and multivariable analyses to calculate odds ratios (OR) and 95% confidence intervals (CI) were performed using a conditional logistic regression model. RESULTS: The outbreaks contained 26 cases with hospital-acquired CRAB in five different intensive care units. Two exposures were identified to be independent risk factors for nosocomial CRAB acquisition by the multivariable regression analysis: Sharing a patient room with a CRAB patient before availability of the microbiological result was associated with a more than tenfold increase in the risk of nosocomial CRAB acquisition (OR: 10.7, CI: 2.3-50.9), while undergoing bronchoscopy increased the risk more than six times (OR: 6.9, CI: 1.3-38.1). CONCLUSIONS: The risk factors identified, sharing a patient room with a CRAB patient and undergoing bronchoscopy, could point to an underperformance of basic infection control measure, particularly hand hygiene compliance and handling of medical devices. Both findings reinforce the need for continued promotion of infection control measures. Given that the outbreaks occurred in the first year of the COVID-19 pandemic, our study serves as a reminder that a heightened focus on airborne precautions should not lead to a neglect of other transmission-based precautions.

Low incidence of acute kidney injury in VLBW infants with restrictive use of mechanical ventilation.

BACKGROUND: We assessed the incidence of and risk factors for acute kidney injury (AKI) in very low birthweight infants (VLBW) in a center with a specific neonatal management protocol focusing on avoidance of early mechanical ventilation (MV). METHODS: This retrospective single center analysis includes 128 infants born in 2020 with a gestational age ≥ 22 weeks who were screened for AKI using the nKDIGO criteria. RESULTS: AKI was identified in 25/128 patients (19.5%) with eight of them (6.3%) presenting with severe AKI. Low gestational age, birthweight and 10-minute Apgar score as well as high CRIB-1 score were all associated with incidence of AKI. Forty-five percent of the infants with MV developed AKI vs. 8.9% of those without MV (p < 0.001). Early onset of MV and administration of more than 3 dosages of NSAIDs for patent duct were identified as independent risk factors for AKI in a logistic regression analysis. CONCLUSIONS: We report a substantially lower frequency of AKI in VLBW infants as compared to previous studies, along with a very low rate of MV. A neonatal protocol focusing on avoidance of MV within the first days of life may be a key factor to decrease the risk of AKI in immature infants.

The transmission risk of multidrug-resistant organisms between hospital patients and their pets - a case-control study, Germany, 2019 to 2022.

BackgroundCarriage of multidrug-resistant organisms (MDROs) in humans constitutes an important public health concern. Cross-transmission of bacteria between animals and humans has been demonstrated before.AimOur aim was to quantify the risk factor 'pet ownership' for MDRO colonisation in hospital patients.MethodsWe performed a matched case-control study from 2019 to 2022 in Berlin, Germany and compared MDRO-positive and MDRO-negative patients in terms of contact with pets and other risk factors for MDRO acquisition. Patients completed a questionnaire-based interview and provided nasal and rectal swabs. Pet owners provided swab samples from the throat and stool of their pets (dogs and cats). Phenotypically matching samples of owners and pets were analysed via whole genome sequencing.ResultsThe analyses included 2,891 patients. Reported pet ownership was 17.7% in MDRO-positives (154/871) and 23.4% in MDRO-negatives (472/2,020). Among 397 owner-pet pairs, we identified one pair sharing genotypically indistinguishable pathogens (0.3%). A risk factor analysis of pet ownership was performed for carriers of meticillin-resistant Staphylococcus aureus (MRSA) (OR = 0.662; 95% CI: 0.343-1.277), vancomycin-resistant enterococci (VRE) (OR = 0.764; 95% CI: 0.522-1.118) and multidrug-resistant Gram-negative bacteria (MDR-GNB) (OR = 0.819; 95% CI: 0.620-1.082). Colonisation with MDRO was rare in pets, and dogs were more often colonised than cats (MRSA: 0% vs 0%, VRE: 1.5% vs 1.0%, MDR-GNB: 17.2% vs 3.6%).ConclusionTransmission of MDROs between humans and pets is possible though rare. In an urban living space, neither cat nor dog ownership appears as a relevant risk factor for MDRO carriage in hospital patients.

Gene expression profiling in porocarcinoma indicates heterogeneous tumor development and substantiates poromas as precursor lesions.

BACKGROUND AND OBJECTIVES: Malignant sweat gland tumors are rare, with the most common being eccrine porocarcinoma (EP). Approximately 18% of benign eccrine poroma (EPO) transit to EP. Previous research has provided first insights into the mutational landscape of EP. However, only few studies have performed gene expression analyses. This leaves a gap in the understanding of EP biology and potential drivers of malignant transformation from EPO to EP. METHODS: Transcriptome profiling of 23 samples of primary EP and normal skin (NS). Findings from the EP samples were then tested in 17 samples of EPO. RESULTS: Transcriptome profiling revealed diversity in gene expression and indicated biologically heterogeneous sub-entities as well as widespread gene downregulation in EP. Downregulated genes included CD74, NDGR1, SRRM2, CDC42, ANXA2, KFL9 and NOP53. Expression levels of CD74, NDGR1, SRRM2, ANXA2, and NOP53 showed a stepwise-reduction in expression from NS via EPO to EP, thus supporting the hypothesis that EPO represents a transitional state in EP development. CONCLUSIONS: We demonstrated that EP is molecularly complex and that evolutionary trajectories correspond to tumor initiation and progression. Our results provide further evidence implicating the p53 axis and the EGFR pathway. Larger samples are warranted to confirm our findings.

Effect of artificial aging on fracture toughness and hardness of 3D-printed and milled 3Y-TZP zirconia.

PURPOSE: This study aimed to evaluate the impact of artificial aging on the fracture toughness and hardness of three-dimensional (3D)-printed and computer-aided design and computer-aided manufacturing (CAD-CAM) milled 3 mol% yttria-stabilized tetragonal zirconia polycrystals (3Y-TZP). MATERIALS AND METHODS: Forty bar-shaped specimens (45 × 4 × 3 mm) were prepared using two manufacturing technologies: 3D printing (LithaCon 3Y 210, Lithoz GmbH, Vienna, Austria; n = 20) and milling (Initial Zirconia ST, GC, Japan; n = 20) of 3Y-TZP. The chevron-notch beam method was used to assess the fracture toughness according to ISO 24370. Specimens from each 3Y-TZP group were divided into two subgroups (n = 10) based on the artificial aging process (autoclaving): nonaged and aged. Nonaged specimens were stored at room temperature, while aged specimens underwent autoclave aging at 134°C under 2 bar-pressure for 5 h. Subsequently, the specimens were immersed in absolute 99% ethanol using an ultrasonic cleaner for 5 min. Each specimen was preloaded by subjecting it to a 4-point loading test, with a force of up to 200 N applied for three cycles. Further 4-point loading was conducted at a rate of 0.5 mm/min under controlled temperature and humidity conditions until fracture occurred. The maximum force (Fmax) was recorded and the chevron notch was examined at 30 × magnification under an optical microscope for measurements before the fracture toughness (KIc) was calculated. Microhardness testing was also performed to measure the Vickers hardness number (VHN). A scanning electron microscope (SEM) coupled with an energy dispersive X-ray unit (EDX) was used to examine surface topography and chemical composition. X-ray diffraction (XRD) was conducted to identify crystalline structure. Data were statistically analyzed using two-way ANOVA and Student's t-test with a significance level of 0.05. RESULTS: The nonaged 3D-printed 3Y-TZP group exhibited a significantly higher fracture toughness value (6.07 MPa m1/2) than the milled 3Y-TZP groups (p < 0.001). After autoclave aging, the 3D-printed 3Y-TZP group maintained significantly higher fracture toughness (p < 0.001) compared to the milled 3Y-TZP group. However, no significant differences in hardness values (p = 0.096) were observed between the aged and nonaged groups within each manufacturing process (3D-printed and milled) independently. CONCLUSION: The findings revealed that the new 3D-printed 3Y-TZP produced by the lithography-based ceramic manufacturing (LCM) technology exhibited superior fracture toughness after autoclave aging compared to the milled 3Y-TZP. While no significant differences in hardness were observed between the aged groups, the 3D-printed material demonstrated greater resistance to fracture, indicating enhanced mechanical stability.

DECODE: a computational pipeline to discover T cell receptor binding rules.

MOTIVATION: Understanding the mechanisms underlying T cell receptor (TCR) binding is of fundamental importance to understanding adaptive immune responses. A better understanding of the biochemical rules governing TCR binding can be used, e.g. to guide the design of more powerful and safer T cell-based therapies. Advances in repertoire sequencing technologies have made available millions of TCR sequences. Data abundance has, in turn, fueled the development of many computational models to predict the binding properties of TCRs from their sequences. Unfortunately, while many of these works have made great strides toward predicting TCR specificity using machine learning, the black-box nature of these models has resulted in a limited understanding of the rules that govern the binding of a TCR and an epitope. RESULTS: We present an easy-to-use and customizable computational pipeline, DECODE, to extract the binding rules from any black-box model designed to predict the TCR-epitope binding. DECODE offers a range of analytical and visualization tools to guide the user in the extraction of such rules. We demonstrate our pipeline on a recently published TCR-binding prediction model, TITAN, and show how to use the provided metrics to assess the quality of the computed rules. In conclusion, DECODE can lead to a better understanding of the sequence motifs that underlie TCR binding. Our pipeline can facilitate the investigation of current immunotherapeutic challenges, such as cross-reactive events due to off-target TCR binding. AVAILABILITY AND IMPLEMENTATION: Code is available publicly at https://github.com/phineasng/DECODE. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Judging a book by its older adult cover: age-related expectations and parental preference for children's books.

As they typically have limited direct contact, children's attitudes towards older adults have more opportunity to be shaped by other social influences such as their parents and children's literature. Children's books have been noted for their tendency to portray older adults in stereotypical ways and their tendencies to underrepresent older adults. We investigated how the portrayal of older adults as major versus supporting characters, as well as parents' age-related expectations were related to parental preference for children's books. We designed 24 children's book covers that depicted an older adult as a main character, a younger adult as a main character, or only children. One-hundred-seventy-five parents of children ages 0-12 rated their preference for the covers, their age-related expectations for the books' stories, and their personal aging expectations. Parents preferred covers featuring only children, and this preference was stronger for parents with more positive personal aging expectations. Cover preference was further predicted by age-related story expectations. When parents expected a book to conform to older-age stereotypes, they liked that particular cover less. Controlling for parents' age-related story expectations for each book resulted in near equal levels of preference for all types of book covers. Carefully designed children's books could provide an opportunity to increased vicarious intergenerational contact. These finding suggests that parents' interest in selecting these books for their children will be higher when they do not perceive the books to align with older-age stereotypes. Supplementary information: The online version contains supplementary material available at 10.1007/s12144-023-04298-6.

Risk factors and outcomes associated with recurrent autoimmune hepatitis following liver transplantation.

BACKGROUND & AIMS: Autoimmune hepatitis can recur after liver transplantation (LT), though the impact of recurrence on patient and graft survival has not been well characterized. We evaluated a large, international, multicenter cohort to identify the probability and risk factors associated with recurrent AIH and the association between recurrent disease and patient and graft survival. METHODS: We included 736 patients (77% female, mean age 42±1 years) with AIH who underwent LT from January 1987 through June 2020, among 33 centers in North America, South America, Europe and Asia. Clinical data before and after LT, biochemical data within the first 12 months after LT, and immunosuppression after LT were analyzed to identify patients at higher risk of AIH recurrence based on histological diagnosis. RESULTS: AIH recurred in 20% of patients after 5 years and 31% after 10 years. Age at LT ≤42 years (hazard ratio [HR] 3.15; 95% CI 1.22-8.16; p = 0.02), use of mycophenolate mofetil post-LT (HR 3.06; 95% CI 1.39-6.73; p = 0.005), donor and recipient sex mismatch (HR 2.57; 95% CI 1.39-4.76; p = 0.003) and high IgG pre-LT (HR 1.04; 95% CI 1.01-1.06; p = 0.004) were associated with higher risk of AIH recurrence after adjusting for other confounders. In multivariate Cox regression, recurrent AIH (as a time-dependent covariate) was significantly associated with graft loss (HR 10.79, 95% CI 5.37-21.66, p <0.001) and death (HR 2.53, 95% CI 1.48-4.33, p = 0.001). CONCLUSION: Recurrence of AIH following transplant is frequent and is associated with younger age at LT, use of mycophenolate mofetil post-LT, sex mismatch and high IgG pre-LT. We demonstrate an association between disease recurrence and impaired graft and overall survival in patients with AIH, highlighting the importance of ongoing efforts to better characterize, prevent and treat recurrent AIH. LAY SUMMARY: Recurrent autoimmune hepatitis following liver transplant is frequent and is associated with some recipient features and the type of immunosuppressive medications use. Recurrent autoimmune hepatitis negatively affects outcomes after liver transplantation. Thus, improved measures are required to prevent and treat this condition.

TITAN: T-cell receptor specificity prediction with bimodal attention networks.

MOTIVATION: The activity of the adaptive immune system is governed by T-cells and their specific T-cell receptors (TCR), which selectively recognize foreign antigens. Recent advances in experimental techniques have enabled sequencing of TCRs and their antigenic targets (epitopes), allowing to research the missing link between TCR sequence and epitope binding specificity. Scarcity of data and a large sequence space make this task challenging, and to date only models limited to a small set of epitopes have achieved good performance. Here, we establish a k-nearest-neighbor (K-NN) classifier as a strong baseline and then propose Tcr epITope bimodal Attention Networks (TITAN), a bimodal neural network that explicitly encodes both TCR sequences and epitopes to enable the independent study of generalization capabilities to unseen TCRs and/or epitopes. RESULTS: By encoding epitopes at the atomic level with SMILES sequences, we leverage transfer learning and data augmentation to enrich the input data space and boost performance. TITAN achieves high performance in the prediction of specificity of unseen TCRs (ROC-AUC 0.87 in 10-fold CV) and surpasses the results of the current state-of-the-art (ImRex) by a large margin. Notably, our Levenshtein-based K-NN classifier also exhibits competitive performance on unseen TCRs. While the generalization to unseen epitopes remains challenging, we report two major breakthroughs. First, by dissecting the attention heatmaps, we demonstrate that the sparsity of available epitope data favors an implicit treatment of epitopes as classes. This may be a general problem that limits unseen epitope performance for sufficiently complex models. Second, we show that TITAN nevertheless exhibits significantly improved performance on unseen epitopes and is capable of focusing attention on chemically meaningful molecular structures. AVAILABILITY AND IMPLEMENTATION: The code as well as the dataset used in this study is publicly available at https://github.com/PaccMann/TITAN. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Reactivity of FeMoO4 in CsCl Fluxes and Formation of the Salt-Inclusion Type of Compounds.

The reactivity of FeMoO4 in CsCl fluxes has been investigated by thermal analysis and chemical reactions in evacuated silica ampules. The products have been characterized by ex situ X-ray diffraction methods. Metathesis reactions involving CsCl lead to the formation of Cs2Fe2(MoO4)3 and the salt adduct Cs2FeCl4·CsCl. A side reaction has been observed, which is associated with a decomposition of [MoO4]2- in CsCl fluxes yielding Cs2Mo2O7·CsCl, which contains the rare pyromolybdate anion, [Mo2O7]2-, located in the center of a ∞2[CsCl] hetero-honeycomb arrangement. This salt-inclusion type of compound has been studied further in terms of its formation starting from Cs2MoO4, MoO3, and CsCl. The intermediate adduct phase, Cs2MoO4·MoO3, contains uncharged ∞1[MoO2O2/2] chains that react with CsCl at elevated temperatures to Cs2Mo2O7·CsCl. Furthermore, the site preference for alkaline-metal cations (K+, Rb+, and Cs+) has been evaluated for a mixed substitution series. In accordance with the Pearson concept, the polarizability of the respect cation outweighs any size differences for the occupancy of the salt-intergrowth motif, the honeycomb part of the structure.

A blue light receptor that mediates RNA binding and translational regulation.

Sensory photoreceptor proteins underpin light-dependent adaptations in nature and enable the optogenetic control of organismal behavior and physiology. We identified the bacterial light-oxygen-voltage (LOV) photoreceptor PAL that sequence-specifically binds short RNA stem loops with around 20 nM affinity in blue light and weaker than 1 µM in darkness. A crystal structure rationalizes the unusual receptor architecture of PAL with C-terminal LOV photosensor and N-terminal effector units. The light-activated PAL-RNA interaction can be harnessed to regulate gene expression at the RNA level as a function of light in both bacteria and mammalian cells. The present results elucidate a new signal-transduction paradigm in LOV receptors and conjoin RNA biology with optogenetic regulation, thereby paving the way toward hitherto inaccessible optoribogenetic modalities.

[Aluminium release of glitter particles in removable orthodontic appliances]. / Freisetzung von Aluminium aus Glitzerpartikeln bei herausnehmbaren kieferorthopädischen Apparaturen.

BACKGROUND AND AIM: In order to support children's compliance with orthodontic treatment, glitter particles containing aluminium (Al) are often embedded in the acrylic of removable appliances. When worn for up to 16 h daily for 2-3 years, it can be assumed that Al ions diffuse into saliva over time. The aim of this study was to investigate the release of Al ions from the acrylic using different orthodontic wires. MATERIALS AND METHOD: Test specimens (surface area 5.65 cm2) were prepared from orthodontic resin and various wires; half contained aluminium glitter particles. The test specimens were placed in Petri dishes containing 50 ml of corrosion medium (pH 2.3) according to DIN EN ISO 10271 at 37 °C for 7 days. Inductively coupled plasma mass spectrometry (ICP-MS) was used to quantify the specific ions in the corrosion solution. RESULTS: Statistical analysis showed a significant difference in the concentration of Al ions between samples with and without glitter particles. Concentrations from samples with glitter reached up to 14,474 µg/l Al ions; samples without glitter contained on average 1260 µg/l. A small proportion of the Al ions may originate from the alloys of the wires. CONCLUSIONS: It should be investigated whether the aluminium concentration can lead to health risks for humans. In view of the findings, orthodontists should not offer appliances containing glitter in order to minimize aluminium uptake with saliva. It needs to be clarified whether the conditions found in the oral cavity lead to the same results as under the abovementioned conditions. Legislation should be developed to limit the release of aluminium from orthodontic products.

Seminiferous epithelium cycle staging based on the development of the acrosome in ram testis.

Testicular histopathology is considered the most sensitive and reliable method to detect the effects of chemicals on sperm production. To carry out a sensitive examination of testicular histopathology and interpret the changes require knowledge of spermatogenic stages. Spermatogenic staging based on acrosome development during spermiogenesis is conventionally performed in animal species routinely used for research and toxicity testing. In contrast, small ruminants, such as sheep and goats, are rarely used as animal models to evaluate toxicity in male reproductive organs. To the best of our knowledge, a comparable spermatogenic staging system in rams has not yet been fully characterised. Hence, this study aimed to adapt the existing spermatogenic staging based on acrosome development in bull testes to fit the seminiferous epithelium cycle of ram testes. The results show that spermatogenic staging based on acrosome development in bull testes can, with slight modifications, be efficiently used for the staging of ram testes.

A SARS-CoV-2 Spike Binding DNA Aptamer that Inhibits Pseudovirus Infection by an RBD-Independent Mechanism*.

The receptor binding domain (RBD) of the spike glycoprotein of the coronavirus SARS-CoV-2 (CoV2-S) binds to the human angiotensin-converting enzyme 2 (ACE2) representing the initial contact point for leveraging the infection cascade. We used an automated selection process and identified an aptamer that specifically interacts with CoV2-S. The aptamer does not bind to the RBD of CoV2-S and does not block the interaction of CoV2-S with ACE2. Nevertheless, infection studies revealed potent and specific inhibition of pseudoviral infection by the aptamer. The present study opens up new vistas in developing SARS-CoV2 infection inhibitors, independent of blocking the ACE2 interaction of the virus, and harnesses aptamers as potential drug candidates and tools to disentangle hitherto inaccessible infection modalities, which is of particular interest in light of the increasing number of escape mutants that are currently being reported.

Dynamical coring of Markov state models.

The accurate definition of suitable metastable conformational states is fundamental for the construction of a Markov state model describing biomolecular dynamics. Following the dimensionality reduction in a molecular dynamics trajectory, these microstates can be generated by a recently proposed density-based geometrical clustering algorithm [F. Sittel and G. Stock, J. Chem. Theory Comput. 12, 2426 (2016)], which by design cuts the resulting clusters at the energy barriers and allows for a data-based identification of all parameters. Nevertheless, projection artifacts due to the inevitable restriction to a low-dimensional space combined with insufficient sampling often leads to a misclassification of sampled points in the transition regions. This typically causes intrastate fluctuations to be mistaken as interstate transitions, which leads to artificially short life times of the metastable states. As a simple but effective remedy, dynamical coring requires that the trajectory spends a minimum time in the new state for the transition to be counted. Adopting molecular dynamics simulations of two well-established biomolecular systems (alanine dipeptide and villin headpiece), dynamical coring is shown to considerably improve the Markovianity of the resulting metastable states, which is demonstrated by Chapman-Kolmogorov tests and increased implied time scales of the Markov model. Providing high structural and temporal resolution, the combination of density-based clustering and dynamical coring is particularly suited to describe the complex structural dynamics of unfolded biomolecules.

The influence of enamel sandblasting on the shear bond strength and fractography of the bracket-adhesive-enamel complex tested in vitro by the DIN 13990:2017-04 standard.

OBJECTIVES: This study was conducted in order to investigate whether enamel sandblasting as an adjunct or substitute to the acid-etch technique has an effect on the shear bond strength (SBS) and fractography of the bracket-adhesive-enamel complex using the DIN 13990:2017-04 standard. MATERIALS AND METHODS: Upper central incisor brackets (discovery®, Dentaurum, Germany) were bonded using Transbond XT™ (3M Unitek, Germany) on bovine incisors prepared by four different methods (15 samples each): sandblasting with 27 µm Al2O3 at 1.2 bar (s), acid etching with 37.4% phosphoric acid (a), sandblasting with 27 µm Al2O3 at 1.2 bar followed by acid etching (s1a), and sandblasting with 50 µm Al2O3 at 5.7 bar followed by acid etching (s2a). The SBS and adhesive remnant index (ARI) were measured, followed by one-way analysis of variance and Fisher's exact tests at 5%. RESULTS: The SBS in groups s (5.6 ± 2.2 MPa), a (17.1 ± 4.3 MPa), s1a (18.3 ± 4.3 MPa), and s2a (18.5 ± 4.6 MPa) indicated that the s group was significantly inferior to all the other groups (p < 0.001). Likewise, the ARI analysis indicated a different performance of the s group (mostly ARI of 0) compared to the other groups (p < 0.001) and a tendency for different ARI between the a and s1a/s2a groups. CONCLUSIONS: In vitro enamel sandblasting could not substitute acid etching and did not offer improved SBS when used before acid etching, regardless of air pressure and powder granulation. Sandblasting without acid etching produced less residual resin on the tooth after debonding. CLINICAL RELEVANCE: The clinical use of adjunct enamel sandblasting prior to etching to enhance SBS has to be questioned.

Intrinsic MYH7 expression regulation contributes to tissue level allelic imbalance in hypertrophic cardiomyopathy.

HCM, the most common inherited cardiac disease, is mainly caused by mutations in sarcomeric genes. More than a third of the patients are heterozygous for mutations in the MYH7 gene encoding for the ß-myosin heavy chain. In HCM-patients, expression of the mutant and the wildtype allele can be unequal, thus leading to fractions of mutant and wildtype mRNA and protein which deviate from 1:1. This so-called allelic imbalance was detected in whole tissue samples but also in individual cells. There is evidence that the severity of HCM not only depends on the functional effect of the mutation itself, but also on the fraction of mutant protein in the myocardial tissue. Allelic imbalance has been shown to occur in a broad range of genes. Therefore, we aimed to examine whether the MYH7-alleles are intrinsically expressed imbalanced or whether the allelic imbalance is solely associated with the disease. We compared the expression of MYH7-alleles in non-HCM donors and in HCM-patients with different MYH7-missense mutations. In the HCM-patients, we identified imbalanced as well as equal expression of both alleles. Also at the protein level, allelic imbalance was determined. Most interestingly, we also discovered allelic imbalance and balance in non-HCM donors. Our findings therefore strongly indicate that apart from mutation-specific mechanisms, also non-HCM associated allelic-mRNA expression regulation may account for the allelic imbalance of the MYH7 gene in HCM-patients. Since the relative amount of mutant mRNA and protein or the extent of allelic imbalance has been associated with the severity of HCM, individual analysis of the MYH7-allelic expression may provide valuable information for the prognosis of each patient.

RNA and protein expression of herpesvirus entry mediator (HVEM) is associated with molecular markers, immunity-related pathways and relapse-free survival of patients with AML.

Immune checkpoint molecules are highly relevant as potential prognostic markers and therapeutic targets in malignant diseases. HVEM belongs to the TNF receptor family and provides stimulatory as well as inhibitory signals depending on the ligand. Abnormal HVEM expression has been described in various malignancies, but the role in AML is unknown. Here we report extensive data on HVEM surface protein expression analyzed by flow cytometry on bone marrow leukemic cells of 169 AML patients at diagnosis. An independent cohort of 512 AML patients was analyzed for HVEM mRNA expression in bone marrow samples by Affymetrix microarrays. Consistently for both cohorts and methods, we show that HVEM was differentially expressed and that expression levels were associated with defined genetic markers. HVEM expression was lower in cases with FLT3-ITD (p = 0.001, p < 0.001), with mutations in NPM1 (p = 0.001, p < 0.001) or with the combination of NPM1 mutation and FLT3 wild type (p = 0.049, p = 0.050), while a biallelic mutation in CEBPA correlated positively with higher HVEM expression (p = 0.015, p < 0.001). In a differential gene expression analysis, we found 13 genes including HOXA9, MEIS1 and MN1 that were closely associated with HVEM expression. Besides, four gene sets closely linked to immunity were enriched in HVEM (high) samples. Finally, high expression of HVEM was associated with a trend toward longer relapse-free survival. The results of this study provide new information on the potential significance of HVEM in AML.

A comparative experimental investigation of torque capabilities induced by conventional and active, passive self-ligating brackets.

INTRODUCTION: A proper selected bracket-archwire combination displays a determining factor in the efficacy of torque applied to a tooth at the final stages of an orthodontic treatment. The objective of the current study was to assess the torque capabilities of various bracket systems combined with diverse archwire materials and cross-sections. METHODS: The study comprised of four different 0.018-inch slot orthodontic brackets: the passive and the active self-ligating 1. Swiss Nonligating Bracket (SNB) and 2. SPEED and the metallic and the plastic conventional ligating 3. Mini Mono and 4. Brilliant, respectively, and four different archwire types: stainless steel and Nitinol: 0.016×0.016 inch and 0.016×0.022 inch. A 20 degrees labial crown torque (+20 degrees) and then a 20 degrees palatal crown torque (-20 degrees) were applied gradually on the upper right central incisor. Maximum torquing moments and torque play were registered. RESULTS: Highest torquing moments were expressed by combining SPEED® with 0.016×0.022 inch stainless steel archwire. Lowest moments, but highest torque loss were registered by inserting a 0.016×0.016 inch Nitinol archwire in conventional ligating brackets. CONCLUSIONS: Active self-ligating system manifests the best torque effectiveness. An evident dependence of the torque expression is displayed both on the type of ligation and on the material of the archwire.

The nervous system of Paludicella articulata - first evidence of a neuroepithelium in a ctenostome ectoproct.

INTRODUCTION: Comparatively few data are available concerning the structure of the adult nervous system in the Ectoprocta or Bryozoa. In contrast to all other ectoprocts, the cerebral ganglion of phylactolaemates contains a central fluid-filled lumen surrounded by a neuroepithelium. Preliminary observations have shown a small lumen within the cerebral ganglion of the ctenostome Paludicella articulata. Ctenostome-grade ectoprocts are of phylogenetic relevance since they are considered to have retained ancestral ectoproct features. Therefore, the ctenostome Paludicella articulata was analyzed in order to contribute to the basal neural bauplan of ctenostomes and the Ectoprocta in general. RESULTS: The presence of a lumen and a neuroepithelial organization of the nerve cells within the cerebral ganglion are confirmed. Four tentacle nerves project from the cerebral ganglion into each tentacle. Three of the tentacle nerves (one abfrontal and two latero-frontal nerves) have an intertentacular origin, whereas the medio-frontal nerve arises from the cerebral ganglion. Six to eight visceral nerves and four tentacle sheath nerves are found to emanate from the cerebral ganglion and innervate the digestive tract and the tentacle sheath, respectively. CONCLUSIONS: The situation in P. articulata corresponds to the situation found in other ctenostomes and supports the notion that four tentacle nerves are the ancestral configuration in Ectoprocta and not six as proposed earlier. The presence of a lumen in the ganglion represents the ancestral state in Ectoprocta which disappears during ontogeny in all except in adult Phylactolaemata and P. articulata. It appears likely that it has been overlooked in earlier studies owing to its small size.