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)'.

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.

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.

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.

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.

l-Arginine Pathway Metabolites Predict Need for Intra-operative Shunt During Carotid Endarterectomy.

OBJECTIVE/BACKGROUND: Asymmetric dimethylarginine (ADMA) inhibits nitric oxide (NO) synthesis and is a marker of atherosclerosis. This study examined the correlation between pre-operative l-arginine and ADMA concentration during carotid endarterectomy (CEA), and jugular lactate indicating anaerobic cerebral metabolism, jugular S100B reflecting blood-brain barrier integrity, and with factors of surgical intervention. METHODS: The concentration of l-arginine, ADMA, and symmetric dimethylarginine was measured in blood taken under regional anaesthesia from the radial artery of 55 patients prior to CEA. Blood gas parameters, concentration of lactate, and S100B were also serially measured in blood taken from both the radial artery and the jugular bulb before and after carotid clamping, and after release of the clamp. To estimate anaerobic metabolism, the jugulo-arterial ratio of CO2 gap/oxygen extraction was calculated. RESULTS: Positive correlation was found between pre-operative ADMA levels and the ratio of jugulo-arterial CO2 gap/oxygen extraction during clamp and reperfusion (p = .005 and p = .01, respectively). An inverse correlation was found between the pre-operative l-arginine concentration and jugular lactate at each time point (both p = .002). The critical pre-operative level of l-arginine was determined by receiver operator curve analysis. If l-arginine was below the cutoff value of 35 µmol/L, jugular S100B concentration was higher 24 h post-operatively (p = .03), and jugular lactate levels were increased during reperfusion (p = .02). The median pre-operative concentration of l-arginine was lower in patients requiring an intra-operative shunt than in patients without need of shunt (median: 30.3 µmol/L [interquartile range 24.4-34.4 µmol/L] vs. 57.6 µmol/L [interquartile range 42.3-74.5 µmol/L]; p = .002). CONCLUSION: High pre-operative ADMA concentration predicts poor cerebral perfusion indicated by elevated jugulo-arterial CO2 gap/oxygen extraction. Low pre-operative l-arginine concentration predicts the need for a shunt. The inverse correlation between pre-operative l-arginine concentration and both jugular lactate and S100B during carotid clamping suggests a protective role of the NO donor l-arginine.

Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer's mouse model.

Latrepirdine (Dimebon) is a pro-neurogenic, antihistaminic compound that has yielded mixed results in clinical trials of mild to moderate Alzheimer's disease, with a dramatically positive outcome in a Russian clinical trial that was unconfirmed in a replication trial in the United States. We sought to determine whether latrepirdine (LAT)-stimulated amyloid precursor protein (APP) catabolism is at least partially attributable to regulation of macroautophagy, a highly conserved protein catabolism pathway that is known to be impaired in brains of patients with Alzheimer's disease (AD). We utilized several mammalian cellular models to determine whether LAT regulates mammalian target of rapamycin (mTOR) and Atg5-dependent autophagy. Male TgCRND8 mice were chronically administered LAT prior to behavior analysis in the cued and contextual fear conditioning paradigm, as well as immunohistological and biochemical analysis of AD-related neuropathology. Treatment of cultured mammalian cells with LAT led to enhanced mTOR- and Atg5-dependent autophagy. Latrepirdine treatment of TgCRND8 transgenic mice was associated with improved learning behavior and with a reduction in accumulation of Aß42 and α-synuclein. We conclude that LAT possesses pro-autophagic properties in addition to the previously reported pro-neurogenic properties, both of which are potentially relevant to the treatment and/or prevention of neurodegenerative diseases. We suggest that elucidation of the molecular mechanism(s) underlying LAT effects on neurogenesis, autophagy and behavior might warranty the further study of LAT as a potentially viable lead compound that might yield more consistent clinical benefit following the optimization of its pro-neurogenic, pro-autophagic and/or pro-cognitive activities.

In silico analysis of pathways affected by differentially expressed microRNA in adrenocortical tumors.

BACKGROUND: MicroRNA are involved in the pathogenesis of several tumors, and several studies have been performed on the microRNA profile of adrenocortical tumors to date. The pathways affected by these microRNA, however, have not been analyzed yet by a systematic approach. AIM: To perform an in silico bioinformatics analysis of microRNA commonly altered in at least two studies and to decipher the pathways affected by microRNA in adrenocortical tumors. METHODS: Datasets on microRNA and mRNA expression have been retrieved from 5 and 3 studies, respectively. MicroRNA mRNA targets have been identified by our tissue specific target prediction pipeline, and mRNA have been subjected to Ingenuity Pathway Analysis. RESULTS: Thirty- nine microRNA were identified as commonly altered in two studies. Altogether 49,817 mRNA targets have been found for these microRNA. One-hundred and seventy-eight significant pathways associating with these have been identified and were found in all studies. We have selected 12 pathways involving retinoic acid signaling (lipopolysaccharide/ interleukin-1 mediated inhibition of retinoic X receptor (RXR) function, peroxisome proliferator-activated receptor (PPAR)α/RXRα activation, retinoic A receptor activation and PPAR signaling pathways) and cell cycle alterations (aryl hydrocarbon receptor signaling, growth arrest and DNA damage-inducible 45 signaling, integrin signaling, G2/M DNA damage checkpoint regulation, cyclins and cell cycle regulation and cell cycle control of chromosomal replication pathways) as these have been also established in our previous study on the functional genomics meta-analysis of adrenocortical tumors. Several microRNA have been identified that could affect these pathways. CONCLUSIONS: MicroRNA might affect several pathogenic pathways in adrenocortical tumors. Validation studies are required to confirm the biological relevance of these findings.

Severity of nocturnal cardiac arrhythmias correlates with intensity of sleep apnea in men.

Various cardiac arrhythmias frequently occur in patients with sleep apnea, but complex analysis of the relationship between their severity and the probable arrhythmogenic risk factors is conflicting. The question is what cardiovascular risk factors and how strongly they are associated with the severity of cardiac arrhythmias in sleep apnea. Adult males (33 with and 16 without sleep apnea), matched for cardiovascular co-morbidity were studied by polysomnography with simultaneous ECG monitoring. Arrhythmia severity was evaluated for each subject by a special 7-degree scoring system. Laboratory, clinical, echocardiographic, carotid ultrasonographic, ambulatory blood pressure, and baroreflex sensitivity values were also assessed. Moderate sleep apnea patients had benign, but more exaggerated cardiac arrhythmias than control subjects (2.53 ± 2.49 vs. 1.13 ± 1.64 degrees of cumulative severity, p < 0.05). We confirmed strong correlations between the arrhythmia severity and known arrhythmogenic risk factors (left ventricular ejection fraction and dimensions, right ventricular diameter, baroreflex sensitivity, carotid intima-media thickness, age, previous myocardial infarction, and also apnea-hypopnea index). In multivariate modelling only the apnea-hypopnea index indicating the sleep apnea intensity remained highly significantly correlated with the cumulative arrhythmia severity (beta = 0.548, p < 0.005). In conclusion, sleep apnea modifying cardiovascular risk factors and structures or functions provoked various nocturnal arrhythmias. The proposed scoring system allowed a complex analysis of the contribution of various triggers to arrhythmogenesis and confirmed the apnea-hypopnea index as an independent risk for nocturnal cardiac arrhythmia severity in sleep apnea.

Comparative analysis of IL-8 and CXCL-1 production by normal and cancer stromal fibroblasts.

It has been shown that fibroblasts within the stroma of malignant tumours can affect the tumour's biological character, influencing such properties as local aggressiveness and metastasis potential. This influence is asserted via paracrine secretion of multiple cell factors, including chemokines. This study demonstrates that both normal keratinocytes and cancer cells can stimulate the secretion of chemokines IL-8 and CXCL-1 from normal dermal fibroblasts and stromal fibroblasts from squamous cell carcinoma. The effect of epithelia on normal fibroblasts leads to a transient secretory change, in contrast to stromal fibroblasts which generate a more prolonged one. This observation demonstrates that stimulated expression of both IL-8 and CXCL-1 is not specific to cancer, supporting the hypothesis that similar mechanisms exist between wound healing and oncogenesis. It also shows that stromal fibroblasts isolated from a tumour have significantly different features from normal fibroblasts.

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.

Fibroblasts prepared from different types of malignant tumors stimulate expression of luminal marker keratin 8 in the EM-G3 breast cancer cell line.

It is widely recognized that stromal fibroblasts significantly influence biological properties of multiple tumors including breast cancer. However, these epithelial-mesenchymal interactions seem to be essential in tumor biology and it is not fully clear whether this interaction is tumor type-specific or has a more general non-specific character. To elucidate this question, we tested the effect of cancer-associated fibroblasts (CAFs) isolated from different types of tumors (breast cancer skin metastasis, cutaneous basal cell carcinoma and melanoma, squamous cell carcinoma arising from oral cavity mucous membrane) on the EM-G3 breast cancer cell line. The results were compared with control experiments using normal human dermal fibroblasts, 3T3 mouse fibroblasts, and 3T3 fibroblasts influenced by the fibroblasts prepared from the basal cell carcinoma. Our results demonstrated that expression of luminal marker keratin 8 was influenced only by CAFs prepared from any tested tumors. In contrast, all tested types of fibroblasts showed a strong stimulatory effect on the expression of basal/myoepithelial marker keratin 14. The CAFs also elevated the number of cells with positivity for both keratins 8 and 14 that are similar to ductal originated precursor cells. The expression of proliferation marker Ki67 was not influenced by any of the tested fibroblasts. In conclusion, our data indicate that CAFs are able to influence the phenotype of a breast cancer cell line and this effect is based on a tumor type-unspecific mechanism. Finally, a clear functional difference between normal and CAFs was demonstrated.

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.

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 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.

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.

Underexpression of C-myc in adrenocortical cancer: a major pathogenic event?

The protooncogene c-myc is a major factor in tumourigenesis. Whereas c-myc overexpression is considered to be a general feature of many tumours, we have recently demonstrated c-myc underexpression in adrenocortical cancer by a meta-analysis. We hypothesise that c-myc underexpression might be a central event in adrenortical tumourigenesis based on network topology modelling and previous experimental observations. In this brief hypothesis, we present our arguments and their possible relevance.