Linear-Scaling Local Natural Orbital CCSD(T) Approach for Open-Shell Systems: Algorithms, Benchmarks, and Large-Scale Applications.

The extension of the highly optimized local natural orbital (LNO) coupled cluster (CC) with single-, double-, and perturbative triple excitations [LNO-CCSD(T)] method is presented for high-spin open-shell molecules based on restricted open-shell references. The techniques enabling the outstanding efficiency of the closed-shell LNO-CCSD(T) variant are adopted, including the iteration- and redundancy-free second-order Møller-Plesset and (T) formulations as well as the integral-direct, memory- and disk use-economic, and OpenMP-parallel algorithms. For large molecules, the efficiency of our open-shell LNO-CCSD(T) method approaches that of its closed-shell parent method due to the application of restricted orbital sets for demanding integral transformations and a novel approximation for higher-order long-range spin-polarization effects. The accuracy of open-shell LNO-CCSD(T) is extensively tested for radicals and reactions thereof, ionization processes, as well as spin-state splittings, and transition-metal compounds. At the size range where the canonical CCSD(T) reference is accessible (up to 20-30 atoms), the average open-shell LNO-CCSD(T) correlation energies are found to be 99.9 to 99.95% accurate, which translates into average absolute deviations of a few tenths of kcal/mol in the investigated energy differences already with the default settings. For more extensive molecules, the local errors may grow, but they can be estimated and decreased via affordable systematic convergence studies. This enables the accurate modeling of large systems with complex electronic structures, as illustrated on open-shell organic radicals and transition-metal complexes of up to 179 atoms as well as on challenging biochemical systems, including up to 601 atoms and 11,000 basis functions. While the protein models involve difficulties for local approximations, such as the spin states of a bounded iron ion or an extremely delocalized singly occupied orbital, the corresponding single-node LNO-CCSD(T) computations were feasible in a matter of days with 10s to 100 GB of memory use. Therefore, the new LNO-CCSD(T) implementation enables highly accurate computations for open-shell systems of unprecedented size and complexity with widely accessible hardware.

Impact of the degradation leachate of the polyacrylonitrile-based material UP2W on the retention of Ni(II), Eu(III) and Pu(IV) by cement.

The uptake of 63Ni(II), 152Eu(III) and 242Pu(IV) by hardened cement paste (HCP, CEM I) in the degradation stage II (pH ≈ 12.5, [Ca] ≈ 0.02 M) was investigated in the presence of a degradation leachate of UP2W, a polyacrylonitrile-based (PAN) material used as a filter aid in nuclear power plants. The degradation leachate with a concentration of dissolved organic carbon of ∼40 ppm was obtained from the degradation of UP2W in portlandite-buffered solutions for ca. 1100 days. Redox conditions in the Pu systems were buffered with hydroquinone, which defines mildly reducing conditions (pe + pH ≈ 10) where Pu(IV) is the predominant oxidation state. The degradation leachate investigated in this work is moderately sorbed by cement, with distribution ratios (Rd) of (0.35 ± 0.15) m3 kg-1. These values are 30 to 100 times greater than distribution ratios previously reported for proxy ligands of PAN degradation products, i.e., glutaric acid, α-hydroxyisobutyric acid and 3-hydroxybutyric acid. The presence of the degradation leachate induces a moderate decrease in the uptake of 63Ni(II), 152Eu(III) and 242Pu(IV) by cement, as compared to the sorption in the presence of the proxy ligands. Nevertheless, retention in the presence of the degradation leachate remains high for all investigated radionuclides, with Rd(63Ni(II)) ≈ 2 m3 kg-1, Rd(152Eu(III)) ≈ 100 m3 kg-1 and Rd(242Pu(IV)) ≈ 30 m3 kg-1. These observations possibly reflect that the multiple functionalities (-COOH, -OH, amide groups) expected in the macromolecules (10-15 kDa) present in the degradation leachate, can offer further binding/chelating capabilities compared to the small organic proxy ligands with at most bidentate binding.

DeepQMC: An open-source software suite for variational optimization of deep-learning molecular wave functions.

Computing accurate yet efficient approximations to the solutions of the electronic Schrödinger equation has been a paramount challenge of computational chemistry for decades. Quantum Monte Carlo methods are a promising avenue of development as their core algorithm exhibits a number of favorable properties: it is highly parallel and scales favorably with the considered system size, with an accuracy that is limited only by the choice of the wave function Ansatz. The recently introduced machine-learned parametrizations of quantum Monte Carlo Ansätze rely on the efficiency of neural networks as universal function approximators to achieve state of the art accuracy on a variety of molecular systems. With interest in the field growing rapidly, there is a clear need for easy to use, modular, and extendable software libraries facilitating the development and adoption of this new class of methods. In this contribution, the DeepQMC program package is introduced, in an attempt to provide a common framework for future investigations by unifying many of the currently available deep-learning quantum Monte Carlo architectures. Furthermore, the manuscript provides a brief introduction to the methodology of variational quantum Monte Carlo in real space, highlights some technical challenges of optimizing neural network wave functions, and presents example black-box applications of the program package. We thereby intend to make this novel field accessible to a broader class of practitioners from both the quantum chemistry and the machine learning communities.

Thermoelectric instabilities in a circular Couette flow.

The stability of a non-isothermal circular Couette flow is analyzed when subjected to a dielectrophoretic force field. Outward and inward heating configurations are considered when the inner cylinder is rotating and the outer cylinder is at rest. In addition, an alternating voltage is applied between the two cylinders to induce a radial electric buoyancy that acts on the dielectric fluid. The linear stability analysis provides the threshold for the first transition to instability, as well as the corresponding wavenumber and frequency of the modes. This article is part of the theme issue 'Taylor-Couette and related flows on the centennial of Taylor's seminal Philosophical Transactions paper (part 1)'.

Fracture Resistance and Microleakage around Direct Restorations in High C-Factor Cavities.

The aim of this research was to evaluate the mechanical impact of different direct restorations in terms of fracture resistance, and subsequent fracture pattern, in occlusal high C-factor cavities. Furthermore, the adaptation of different direct restorations in the form of gap formation was also evaluated. Seventy-two intact mandibular molars were collected and randomly distributed into three groups (n = 24). Class I occlusal cavities with standardized dimensions were prepared in all specimens. After adhesive treatment, the cavities were restored with direct restorations utilizing three different materials. Group 1: layered conventional packable resin composite (Filtek Ultimate), Group 2: bulk-fill resin composite (SDR), Group 3: bulk-fill short fibre-reinforced composite (SFRC; everX Posterior) covered with packable composite occlusally. Half of the restored specimens underwent static load-to fracture testing (n = 12/group), while the rest underwent sectioning and staining for microleakage evaluation and gap formation analysis. Fracture patterns were evaluated visually among the mechanically tested specimens. The layered composite restoration (Group 1) showed significantly lower fracture resistance compared to the bulk fill groups (Group 2, p = 0.005, Group 3, p = 0.008), while there was no difference in fracture resistance between the other groups. In terms of gap formation values, the layered composite restoration (Group 1) produced significantly higher gap formation compared to the bulk-fill groups (Group 2, p = 0.000, Group 3, p = 0.000). Regarding the fracture pattern, SFRC (Group 3) produced the highest number, while SDR (Group 2) produced the lowest number of repairable fractures. The use of bulk-fill resin composite (fibre or non-fibre-reinforced) for occlusal direct restorations in high C-factor cavities showed promising achievements regarding both fracture resistance and microleakage. Furthermore, the use of short fibre-reinforced bulk-fill composite can also improve the fracture pattern of the restoration-tooth unit. Bulk-fill materials provide a simple and effective solution for restoring and reinforcing high C-factor occlusal cavities.

Parker Solar Probe Observations of Solar Wind Energetic Proton Beams Produced by Magnetic Reconnection in the Near-Sun Heliospheric Current Sheet.

We report observations of reconnection exhausts in the Heliospheric Current Sheet (HCS) during Parker Solar Probe Encounters 08 and 07, at 16 R s and 20 R s , respectively. Heliospheric current sheet (HCS) reconnection accelerated protons to almost twice the solar wind speed and increased the proton core energy by a factor of ∼3, due to the Alfvén speed being comparable to the solar wind flow speed at these near-Sun distances. Furthermore, protons were energized to super-thermal energies. During E08, energized protons were found to have leaked out of the exhaust along separatrix field lines, appearing as field-aligned energetic proton beams in a broad region outside the HCS. Concurrent dropouts of strahl electrons, indicating disconnection from the Sun, provide further evidence for the HCS being the source of the beams. Around the HCS in E07, there were also proton beams but without electron strahl dropouts, indicating that their origin was not the local HCS reconnection exhaust.

Solubility of Ca(II), Ni(II), Nd(III) and Pu(IV) in the presence of proxy ligands for the degradation of polyacrylonitrile in cementitious systems.

The solubility of Ca(OH)2(cr), ß-Ni(OH)2(cr), Nd(OH)3(s) and PuO2(ncr, hyd) was investigated in cement porewater solutions containing glutarate (GTA), α-hydroxyisobutarate (HIBA) and 3-hydroxybutarate (HBA). These ligands were proposed as probable degradation products of UP2W, a polyacrylonitrile-based filter aid used in nuclear power plants. Results obtained in this work are compared with reported solubility data in the presence of iso-saccharinic acid (ISA), a polyhydroxocarboxylic acid resulting from cellulose degradation. None of the investigated proxy ligands shows any significant impact on the solubility of Ca(II), Nd(III) or Pu(IV) in cement porewater solutions. Although the formation of binary complexes M-L (M = Ca(II), Nd(III), An(IV); L = GTA, HIBA, HBA) under acidic conditions is described in the literature, these organic ligands cannot outcompete hydrolysis under hyperalkaline conditions. GTA, HIBA and HBA induce a slight increase in the solubility of ß-Ni(OH)2(cr) at [L]tot = 0.1 M. This observation supports the formation of stable Ni(II)-GTA, -HIBA and -HBA complexes in hyperalkaline conditions, although the exact stoichiometry of these complexes remains unknown. The comparison of these results with solubility data in the presence of ISA confirms the stronger complexation properties of the latter ligand. Even though HIBA and HBA are carboxylic acids containing one alcohol group, this comparison shows that additional alcohol groups are required to efficiently chelate the metal ion and outcompete hydrolysis. This conclusion is supported by DFT calculations on the Pu(IV)-OH-L systems (L = GTA, HIBA and HBA), which indicate that the complexation with the proxy ligands takes places through the carboxylate group. XRD of selected solid phases after equilibration with proxy ligands at [L]tot = 0.1 M confirms that Ca(II), Ni(II), Nd(III) and Pu(IV) starting solid materials remained mostly unaltered in the course of the experiments. However, the presence of new XRD features suggests the possible formation of secondary phases. These results allow assessment of the effect of the proposed proxy ligands on the solubility of key radionuclides and metal ions in cementitious systems relevant for low and intermediate level waste, and feed into on-going sorption studies evaluating the impact of UP2W degradation products on the uptake of radionuclides by cement.

Cross-tissue immune cell analysis reveals tissue-specific features in humans.

Despite their crucial role in health and disease, our knowledge of immune cells within human tissues remains limited. We surveyed the immune compartment of 16 tissues from 12 adult donors by single-cell RNA sequencing and VDJ sequencing generating a dataset of ~360,000 cells. To systematically resolve immune cell heterogeneity across tissues, we developed CellTypist, a machine learning tool for rapid and precise cell type annotation. Using this approach, combined with detailed curation, we determined the tissue distribution of finely phenotyped immune cell types, revealing hitherto unappreciated tissue-specific features and clonal architecture of T and B cells. Our multitissue approach lays the foundation for identifying highly resolved immune cell types by leveraging a common reference dataset, tissue-integrated expression analysis, and antigen receptor sequencing.

The biomechanical effect of root amputation and degree of furcation involvement on intracoronally splinted upper molar teeth - An in vitro study.

OBJECTIVES: The aim of this study was to evaluate the effect of the amount of periodontal support and the presence or absence of root amputation on the fracture resistance of intracoronally splinted maxillary molar teeth. MATERIALS AND METHODS: 48 extracted human upper first molars and 48 s premolars were included in the study. All teeth underwent standard mesio-occluso-distal (MOD) (molars) and standard occluso-distal (OD) (premolars) cavity preparation. After the preparation, all molars were root canal treated, and 48 molar-premolar units were created by intracoronal splinting. The units were randomly divided into 4 groups (Groups A-D, 12 units per group): in Groups C and D, the disto-buccal (DB) roots of the molars were amputated, while in Groups A and B, no root amputation was performed. All units were embedded in methacrylate resin at different levels: in Groups A and C, at 4 mm apically from the cemento-enamel junction (CEJ), while in Groups B and D, at 6 mm apically from the CEJ, mimicking the different stages of furcation involvement. All units were submitted first to dynamic and then to static, load-to-fracture mechanical testing. Fracture resistance values were recorded fracture mode was analysed. RESULTS: During the load-to-facture test, Groups A and B (without root amputation) were characterized by significantly higher fracture resistance values compared to Groups C and D (with root amputation) (p < 0.05). Regarding fracture mode, irreparable fracture was more frequent in Group D (with root amputation and advanced furcation involvement) than in any other group (n = 8). CONCLUSIONS: Root amputation has a negative effect on the fracture resistance of intracoronally splinted upper first molar-second premolar units with modeled furcation involvement.

Fracture Behavior and Integrity of Different Direct Restorative Materials to Restore Noncarious Cervical Lesions.

The purpose of this study was to analyze the fracture resistance and marginal leakage of noncarious cervical lesion (NCCL) restorations made of different restorative materials. Eighty upper premolars were randomly divided into four groups (n = 20/group). Standardized NCCL cavity preparations were performed on the buccal surface of the teeth and then restored with four different materials. Group 1: Packable resin composite (PC); Group 2: Highly flowable resin composite (HF); Group 3: Low flowable resin composite (LF); Group 4: Resin modified glass ionomer cement (RMGIC). After restorations were completed, cyclic and static fracture behavior was evaluated using a loading testing machine. Extra restored teeth were sectioned and then stained (n = 5/group). The specimens were viewed under a stereo microscope and the percentage of microgaps at the tooth-restoration interface was calculated. All restored teeth survived after fatigue loading. There was no statistically significant (p > 0.05) difference between the tested restorations after the static loading test. NCCLs restored with highly filled flowable composite showed the least microleakage among the tested groups (p < 0.05). The investigated restorative materials are acceptable for NCCL restorations in terms of fracture resistance and microleakage.

Cosolvent and Dynamic Effects in Binding Pocket Search by Docking Simulations.

The lack of conformational sampling in virtual screening projects can lead to inefficient results because many of the potential drugs may not be able to bind to the target protein during the static docking simulations. Here, we performed ensemble docking for around 2000 United States Food and Drug Administration (FDA)-approved drugs with the RNA-dependent RNA polymerase (RdRp) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a target. The representative protein structures were generated by clustering classical molecular dynamics trajectories, which were evolved using three solvent scenarios, namely, pure water, benzene/water and phenol/water mixtures. The introduction of dynamic effects in the theoretical model showed improvement in docking results in terms of the number of strong binders and binding sites in the protein. Some of the discovered pockets were found only for the cosolvent simulations, where the nonpolar probes induced local conformational changes in the protein that lead to the opening of transient pockets. In addition, the selection of the ligands based on a combination of the binding free energy and binding free energy gap between the best two poses for each ligand provided more suitable binders than the selection of ligands based solely on one of the criteria. The application of cosolvent molecular dynamics to enhance the sampling of the configurational space is expected to improve the efficacy of virtual screening campaigns of future drug discovery projects.

Fracture Behavior of Short Fiber-Reinforced Direct Restorations in Large MOD Cavities.

The aim of this research was to study the impact of using a short fiber-reinforced composite (SFRC) core on the fatigue performance and fracture behavior of direct large posterior composite restorations. Moreover, the influence of the consistency (flowable or packable) of occlusal composite coverage was assessed. A total of 100 intact molars were collected and randomly distributed into five groups (n = 20). Deep mesio-occlusal-distal (MOD) cavities were prepared in all groups. After adhesive treatment and rebuilding the missing interproximal walls with conventional composite, the specimens in four experimental groups were restored by an SFRC core (everX Flow), which was applied and cured either in bulk or in oblique layers (each 2 mm thick). Packable (G-aenial Posterior) or flowable (G-aenial Injectable) conventional composites were used as a final occlusal layer. The control group was restored with only packable conventional composite. Fatigue survival was measured for all specimens using a cyclic loading machine until a fracture occurred or a total of 25,000 cycles was achieved. Kaplan-Meyer survival analyses were conducted, followed by pairwise log-rank post hoc comparisons. The static load-bearing capacity of surviving teeth was tested using a universal testing machine. Fracture patterns were evaluated visually. There was no statistically significant (p > 0.05) difference in terms of survival between the tested groups. All groups for which flowable SFRC was used showed statistically significantly higher load-bearing capacities compared to the control group (p < 0.05). There were no significant differences regarding fracture resistance among the fiber-reinforced study groups. Regarding the fracture pattern during the survival analysis, all specimens that received SFRC showed a dominantly restorable type of fracture, while the control specimens presented a dominantly non-restorable type. The use of flowable SFRC as a reinforcing core for large MOD direct restorations showed promising achievements regarding fracture behavior.

Linear-Scaling Open-Shell MP2 Approach: Algorithm, Benchmarks, and Large-Scale Applications.

A linear-scaling local second-order Møller-Plesset (MP2) method is presented for high-spin open-shell molecules based on restricted open-shell (RO) reference functions. The open-shell local MP2 (LMP2) approach inherits the iteration- and redundancy-free formulation and the completely integral-direct, OpenMP-parallel, and memory and disk use economic algorithms of our closed-shell LMP2 implementation. By utilizing restricted local molecular orbitals for the demanding integral transformation step and by introducing a novel long-range spin-polarization approximation, the computational cost of RO-LMP2 approaches that of closed-shell LMP2. Extensive benchmarks were performed for reactions of radicals, ionization potentials, as well as spin-state splittings of carbenes and transition-metal complexes. Compared to the conventional MP2 reference for systems of up to 175 atoms, local errors of at most 0.1 kcal/mol were found, which are well below the intrinsic accuracy of MP2. RO-LMP2 computations are presented for challenging protein models of up to 601 atoms and 11 000 basis functions, which involve either spin states of a complexed iron ion or a highly delocalized singly occupied orbital. The corresponding runtimes of 9-15 h obtained with a single, many-core CPU demonstrate that MP2, as well as spin-scaled MP2 and double-hybrid density functional methods, become widely accessible for open-shell systems of unprecedented size and complexity.

Fatigue failure of anterior teeth without ferrule restored with individualized fiber-reinforced post-core foundations.

OBJECTIVES: The aim was to explore the survival of extensively damaged anterior teeth without ferrule restored with different fiber-reinforced composite (FRC) post-core foundations and composite crowns. MATERIALS AND METHODS: Sixty extracted upper central incisors were decoronated and randomly divided into four groups (n = 15). After endodontic treatment, the specimens were restored with different individualized fiber-reinforced post-core foundations as follows: control group (CTRL): multiple unidirectional FRC-post + dual-cure composite-core, PFC: multiple unidirectional FRC-post + packable short fiber-reinforced composite (SFRC), BPFC: Bioblock technique with only packable SFRC, BFFC: Bioblock technique with only flowable SFRC. After core build-up, the teeth were finalized with adhesively luted CAD/CAM composite crowns. Cyclic isometric loading (5 Hz) was applied at 100 N for 5000 cycles, and then 200 N and 300 N for 15,000 cycles each in a fluid chamber. The specimens were loaded until fracture occurred or when a total of 35,000 cycles were reached. Kaplan-Meyer survival analysis was conducted, followed by pairwise log-rank post hoc comparisons (Mantel-Cox). RESULTS: The survival rates of the control (8279 cycles) and PFC (6161 cycles) were significantly higher compared to BPFC (3223 cycles) and BFFC (2271 cycles) (p < 0.05). Regarding fracture pattern, nearly all specimens fractured in a restorable manner. CONCLUSIONS: For restoring extensively damaged anterior teeth, multiple unidirectional FRC posts are recommended. CLINICAL RELEVANCE: Although different FRC post/core systems are available for the restoration of damaged root canal treated anterior teeth, multiple unidirectional FRC posts tend to be a good option when the ferrule is missing.

Ansatz for the Jahn-Teller triplet instability.

A threefold degenerate electronic state is Jahn-Teller unstable with respect to symmetry lowering distortions, which transform as the five quadrupolar modes. The solution of the corresponding vibronic Hamiltonian is constructed using the analytical method introduced by Bargmann, as an alternative to existing group-theoretical techniques based on coefficients of fractional parentage. It involves the construction of an ansatz that incorporates SO(5) to SO(3) symmetry breaking. The resulting Jahn-Teller equations are derived and solved in terms of radial polynomials and Gegenbauer functions.

The MRCC program system: Accurate quantum chemistry from water to proteins.

MRCC is a package of ab initio and density functional quantum chemistry programs for accurate electronic structure calculations. The suite has efficient implementations of both low- and high-level correlation methods, such as second-order Møller-Plesset (MP2), random-phase approximation (RPA), second-order algebraic-diagrammatic construction [ADC(2)], coupled-cluster (CC), configuration interaction (CI), and related techniques. It has a state-of-the-art CC singles and doubles with perturbative triples [CCSD(T)] code, and its specialties, the arbitrary-order iterative and perturbative CC methods developed by automated programming tools, enable achieving convergence with regard to the level of correlation. The package also offers a collection of multi-reference CC and CI approaches. Efficient implementations of density functional theory (DFT) and more advanced combined DFT-wave function approaches are also available. Its other special features, the highly competitive linear-scaling local correlation schemes, allow for MP2, RPA, ADC(2), CCSD(T), and higher-order CC calculations for extended systems. Local correlation calculations can be considerably accelerated by multi-level approximations and DFT-embedding techniques, and an interface to molecular dynamics software is provided for quantum mechanics/molecular mechanics calculations. All components of MRCC support shared-memory parallelism, and multi-node parallelization is also available for various methods. For academic purposes, the package is available free of charge.

Fracture behavior of root-amputated teeth at different amount of periodontal support - a preliminary in vitro study.

BACKGROUND: The purpose of this study was to evaluate the effect of the amount of periodontal support on the fracture resistance of root-amputated maxillary molar teeth restored with either direct class. I. restorations or class II. mesio-occluso-distal (MOD) indirect overlay restorations with cuspal coverage. METHODS: Sixty sound maxillary first molars were collected and randomly divided into four groups. In Groups 1 and 2, MOD cavities were prepared and all cusps were reduced by 2 mm, whereas in Group 3 and 4, only a conservative Class I. cavity was prepared. Subsequently, root canal treatment was performed and the mesio-buccal roots were amputated. Groups 1 and 2 were restored with indirect composite overlay, while Groups 3 and 4 received direct composite fillings. After restoration, teeth were embedded as follows: Groups 1 and 3: normal bone level, Groups 2 and 4: furcation involvement. The specimens were submitted to static fracture resistance testing. Fracture thresholds and fracture patterns were measured and evaluated. RESULTS: Group 1 had the highest fracture resistance (2311,6 N) among the restored groups and showed statistically significant difference compared to Group 2 (p = 0.038) and Group 4 (p = 0.011). There was no statistically significant difference in terms of fracture resistance between the rest of the groups. In terms of the fracture patterns, Group 3 was characterized by the highest percentage (60%) of mostly favorable fractures, while the rest of the groups showed predominantly unfavorable ones. CONCLUSIONS: The amount of periodontal support seems to influence the fracture resistance of root-amputated and restored maxillary molars.

Limitations of high throughput methods for miRNA expression profiles in non-functioning pituitary adenomas.

Microarray, RT-qPCR based arrays and next-generation-sequencing (NGS) are available high-throughput methods for miRNA profiling (miRNome). Analytical and biological performance of these methods were tested in identification of biologically relevant miRNAs in non-functioning pituitary adenomas (NFPA). miRNome of 4 normal pituitary (NP) and 8 NFPA samples was determined by these platforms and expression of 21 individual miRNAs was measured on 30 (20 NFPA and 10 NP) independent samples. Complex bioinformatics was used. 132 and 137 miRNAs were detected by all three platforms in NP and NFPA, respectively, of which 25 were differentially expressed (fold change > 2). The strongest correlation was observed between microarray and TaqMan-array, while the data obtained by NGS were the most discordant despite of various bioinformatics settings. As a technical validation we measured the expression of 21 selected miRNAs by individual RT-qPCR and we were able to validate 35.1%, 76.2% and 71.4% of the miRNAs revealed by SOLiD, TLDA and microarray result, respectively. We performed biological validation using an extended number of samples (20 NFPAs and 8 NPs). Technical and biological validation showed high correlation (p < 0.001; R = 0.96). Pathway and network analysis revealed several common pathways but no pathway showed the same activation score. Using the 25 platform-independent miRNAs developmental pathways were the top functional categories relevant for NFPA genesis. The difference among high-throughput platforms is of great importance and selection of screening method can influence experimental results. Validation by another platform is essential in order to avoid or to minimalize the platform specific errors.

Pharmaceutical counselling about different types of tablet-splitting methods based on the results of weighing tests and mechanical development of splitting devices.

The division of tablets and adequate methods of splitting them are a complex problem in all sectors of health care. Although tablet-splitting is often required, this procedure can be difficult for patients. Four tablets were investigated with different external features (shape, score-line, film-coat and size). The influencing effect of these features and the splitting methods was investigated according to the precision and "weight loss" of splitting techniques. All four types of tablets were halved by four methods: by hand, with a kitchen knife, with an original manufactured splitting device and with a modified tablet splitter based on a self-developed mechanical model. The mechanical parameters (harness and friability) of the products were measured during the study. The "weight loss" and precision of splitting methods were determined and compared by statistical analysis. On the basis of the results, the external features (geometry), the mechanical parameters of tablets and the mechanical structure of splitting devices can influence the "weight loss" and precision of tablet-splitting. Accordingly, a new decision-making scheme was developed for the selection of splitting methods. In addition, the skills of patients and the specialties of therapy should be considered so that pharmaceutical counselling can be more effective regarding tablet-splitting.

MEN1 and microRNAs: The link between sporadic pituitary, parathyroid and adrenocortical tumors?

Sporadic tumors of the pituitary, parathyroids and adrenal cortex are unique, as their benign forms are very common, but malignant forms are exceptionally rare. Hereditary forms of these tumors occur in multiple endocrine neoplasia syndrome type 1 (MEN1). We hypothesize that the pathogenic link among the sporadic tumors of these organs of different germ layers might be represented by common molecular pathways involving the MEN1 gene and microRNAs (miR). miR-24 might be a microRNA linking the three tumor entities, but other candidates such as miR-142-3p and microRNAs forming the DLK1-MEG3 miRNA cluster might also be of importance.