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Northern pike (Esox luciusL.) is one of the fish species whose production in freshwater aquaculture may increase in the next few years. One method of producing this species is to create monosex stocks of pike, as females grow faster, mature later and gain larger body sizes. They can be obtained in the process of gynogenesis. The aim of this research was to determine and optimize the conditions of UV irradiating European perch (Perca fluviatilisL.) spermatozoa to inactivate them genetically (first experiment). The aim of this study was also to confirm whether perch spermatozoa can be used to induce northern pike gynogenesis using thermal shock (second experiment). During first experiment the highest rate of haploid larvae (29.9 ± 0.85%) was noted in the group inseminated with perch sperm irradiated for 6 min (1548 J m-2). No viable embryos were observed in groups of eggs inseminated with sperm irradiated for more than 10 minutes (2580 J m-2). The heat shock applied 12 or 14 min after gamete activation, for 3 or 5 min at 34.0°C, resulted in obtaining of gynogenetic specimen due to retention of the second polar body in all experimental groups. The most efficient was heat shock applied 14 min after gamete activation and lasting 3 min, and resulted in 18.5 ± 1.3% of gynogenetic larvae for female B. Heat shock applied 12 min after gamete activation, lasting 3 min was also effective in the case of female A, resulting in obtaining of 16.5 ± 2.1% gynogenetic specimen.

IMPORTANCE: Correct diagnosis of ovarian cancer results in better prognosis. Adnexal lesions can be stratified into the Ovarian-Adnexal Reporting and Data System (O-RADS) risk of malignancy categories with either the O-RADS lexicon, proposed by the American College of Radiology, or the International Ovarian Tumor Analysis (IOTA) 2-step strategy. OBJECTIVE: To investigate the diagnostic performance of the O-RADS lexicon and the IOTA 2-step strategy. DESIGN, SETTING, AND PARTICIPANTS: Retrospective external diagnostic validation study based on interim data of IOTA5, a prospective international multicenter cohort study, in 36 oncology referral centers or other types of centers. A total of 8519 consecutive adult patients presenting with an adnexal mass between January 1, 2012, and March 1, 2015, and treated either with surgery or conservatively were included in this diagnostic study. Twenty-five patients were excluded for withdrawal of consent, 2777 were excluded from 19 centers that did not meet predefined data quality criteria, and 812 were excluded because they were already in follow-up at recruitment. The analysis included 4905 patients with a newly detected adnexal mass in 17 centers that met predefined data quality criteria. Data were analyzed from January 31 to March 1, 2022. EXPOSURES: Stratification into O-RADS categories (malignancy risk <1%, 1% to <10%, 10% to <50%, and ≥50%). For the IOTA 2-step strategy, the stratification is based on the individual risk of malignancy calculated with the IOTA 2-step strategy. MAIN OUTCOMES AND MEASURES: Observed prevalence of malignancy in each O-RADS risk category, as well as sensitivity and specificity. The reference standard was the status of the tumor at inclusion, determined by histology or clinical and ultrasonographic follow-up for 1 year. Multiple imputation was used for uncertain outcomes owing to inconclusive follow-up information. RESULTS: Median age of the 4905 patients was 48 years (IQR, 36-62 years). Data on race and ethnicity were not collected. A total of 3441 tumors (70%) were benign, 978 (20%) were malignant, and 486 (10%) had uncertain classification. Using the O-RADS lexicon resulted in 1.1% (24 of 2196) observed prevalence of malignancy in O-RADS 2, 4% (34 of 857) in O-RADS 3, 27% (246 of 904) in O-RADS 4, and 78% (732 of 939) in O-RADS 5; the corresponding results for the IOTA 2-step strategy were 0.9% (18 of 1984), 4% (58 of 1304), 30% (206 of 690), and 82% (756 of 927). At the 10% risk threshold (O-RADS 4-5), the O-RADS lexicon had 92% sensitivity (95% CI, 87%-96%) and 80% specificity (95% CI, 74%-85%), and the IOTA 2-step strategy had 91% sensitivity (95% CI, 84%-95%) and 85% specificity (95% CI, 80%-88%). CONCLUSIONS AND RELEVANCE: The findings of this external diagnostic validation study suggest that both the O-RADS lexicon and the IOTA 2-step strategy can be used to stratify patients into risk groups. However, the observed malignancy rate in O-RADS 2 was not clearly below 1%.

The American Association for Artificial Intelligence, in cooperation with Stanford University's Computer Science Department, presented its 2005 Spring Symposium Series Monday through Wednesday, March 21-23, 2005 at Stanford University in […], The American Association for Artificial Intelligence presented its 2005 Spring Symposium Series on Monday through Wednesday, March 21-23, 2005 at Stanford University in Stanford, California. The topics of the eight symposia in this symposium series were (1) AI Technologies for Homeland Security; (2) Challenges to Decision Support in a Changing World; (3) Developmental Robotics; (4) Dialogical Robots: Verbal Interaction with Embodied Agents and Situated Devices; (5) Knowledge Collection from Volunteer Contributors; (6) Metacognition in Computation; (7) Persistent Assistants: Living and Working with AI; and (8) Reasoning with Mental and External Diagrams: Computational Modeling and Spatial Assistance.

Gastrulation is a critical stage in embryonic development during which the germ layers are established. Advances in sequencing technologies led to the identification of gene regulatory programs that control the emergence of the germ layers and their derivatives. However, proteome-based studies of early mammalian development are scarce. To overcome this, we utilized gastruloids and a multilayered mass spectrometry-based proteomics approach to investigate the global dynamics of (phospho) protein expression during gastruloid differentiation. Our findings revealed many proteins with temporal expression and unique expression profiles for each germ layer, which we also validated using single-cell proteomics technology. Additionally, we profiled enhancer interaction landscapes using P300 proximity labeling, which revealed numerous gastruloid-specific transcription factors and chromatin remodelers. Subsequent degron-based perturbations combined with single-cell RNA sequencing (scRNA-seq) identified a critical role for ZEB2 in mouse and human somitogenesis. Overall, this study provides a rich resource for developmental and synthetic biology communities endeavoring to understand mammalian embryogenesis.

Heart 2004;90:70-76 Objective: To evaluate long term results and independent predictors of outcome of aortic valvoplasty. Design: Retrospective follow up study. Independent predictors of outcome identified by multiple logistic regression. [...]

Arabinogalactan is a biologically active water-soluble polysaccharide contained in great amounts in larch wood. A sulfate group introduced into the arabinogalactan molecule increases its biological activity and imparts new anticoagulant and hypolipedemic properties. A new method for the catalytic sulfation of arabinogalactan with ammonium sulfamate is proposed. The catalytic activity in the reaction of arabinogalactan sulfation with ammonium sulfamate has been investigated for both the base activators (urea and thiourea) and oxidants (KMnO4and K2Cr2O7). It has been shown that, in this process, the most effective activator is KMnO4, which ensures the highest (11.3 wt %) sulfur content in sulfated arabinogalactan. The effect of temperature and time of the arabinogalactan sulfation with ammonium sulfamate and the nature of solvents used on the sulfur content in sulfated arabinogalactan has been examined. It has been found that the highest (11.3%) sulfur content in the product is obtained by sulfation of arabinogalactan in 1,4-dioxane at a temperature of 90 °C for 4 h with the KMnO4activator. The introduction of a sulfate group into the arabinogalactan molecule has been confirmed by the FTIR and NMR spectroscopy data. The FTIR spectrum of sulfated arabinogalactan, in contrast to that of the initial arabinogalactan, includes an absorption band at 1249 cm−1. According to the 13C NMR spectroscopy data, the sulfate groups are located at carbon atoms C2 and C4 of the main galactan chain and at carbon atom C6 of the end galactose units of the main and side arabinogalactan chains. It has been established by gel permeation chromatography that, during the sulfation, the molecular mass of arabinogalactan molecules increases proportionally to the introduced sulfate groups. The absence of low molecular weight fractions is indicative of the absence of depolymerization under the conditions of sulfation and evolution of sulfated arabinogalactan.

The sensor trimming characteristics of on-chip programmable electronic circuitry based on an innovative planar thyristor design are investigated. It was shown that the integrated pressure sensor was very effective in determining accuracy, reliability and cost. The device functioned as a multi-functional element for testing and programming the trimming circuit. It was also shown that the modified sensor chip can be used in a combustion pressure sensor.

In this work, for the first time, we present the X-ray diffraction crystal structure and spectral properties of a new, room-temperature polymorph of teriflunomide (TFM), CSD code 1969989. As revealed by DSC, the low-temperature TFM polymorph recently reported by Gunnam et al. undergoes a reversible thermal transition at −40 °C. This reversible process is related to a change in Z’value, from 2 to 1, as observed by variable-temperature 1H–13C cross-polarization (CP) magic-angle spinning (MAS) solid-state NMR, while the crystallographic system is preserved (triclinic). Two-dimensional 13C–1H and 1H–1H double-quantum MAS NMR spectra are consistent with the new room-temperature structure, including comparison with GIPAW (gauge-including projector augmented waves) calculated NMR chemical shifts. A crystal structure prediction procedure found both experimental teriflunomide polymorphs in the energetic global minimum region. Differences between the polymorphs are seen for the torsional angle describing the orientation of the phenyl ring relative to the planarity of the TFM molecule. In the low-temperature structure, there are two torsion angles of 4.5 and 31.9° for the two Z’= 2 molecules, while in the room-temperature structure, there is disorder that is modeled with ∼50% occupancy between torsion angles of −7.8 and 28.6°. These observations are consistent with a broad energy minimum as revealed by DFT calculations. PISEMA solid-state NMR experiments show a reduction in the C–H dipolar coupling in comparison to the static limit for the aromatic CH moieties of 75% and 51% at 20 and 40 °C, respectively, that is indicative of ring flips at the higher temperature. Our study shows the power of combining experiments, namely DSC, X-ray diffraction, and MAS NMR, with DFT calculations and CSP to probe and understand the solid-state landscape, and in particular the role of dynamics, for pharmaceutical molecules.

We present a novel strategy for mapping the localization of guest molecules (GMs) in mesoporous materials by combining mechanochemistry with solid-state nuclear magnetic resonance (ssNMR) spectroscopy. To this end, we consider model guest–host systems of benzoic acid (BA) and para-fluorobenzoic acid (4-FBA) embedded in mesoporous MCM-41 material and examine the recently proposed loading (MeLo) procedure for efficient encapsulation of molecular species. Application of high-resolution NMR experiments (1H and 19F NMR) has allowed detection of a multimodal distribution of the spectral signals ascribed to embedded GMs. This peculiarity reflects the presence of distinct molecular ensembles subjected to intrinsically different local environments and exhibiting different dynamical behavior. Furthermore, a considerable fraction of an amorphous phase has been found as a byproduct of the ball-milling. The stability of the phase mixture was further checked by subjecting the samples to chemical and physical stimuli, and a detailed interpretation of the NMR data was corroborated by theoretical calculations. To this end, we have undertaken a challenge to predict the NMR spectra of the GMs@MCM-41 using advanced ab initiomolecular dynamics (AIMD) simulations, providing an accurate and exhaustive analysis of the NMR spectra. On the basis of the ab initiomodeling validated against the experimental results, we find that the multimodal signal distribution reflects the level of the pore filling, and can be ascribed to the presence of both interface and fluid molecular species trapped inside the pores. This has been confirmed for both BA@MCM-41 and 4-FBA@MCM-41 systems. The presence of the third, amorphous fraction can be linked to interstitial space between randomly ordered crystallites, pointing at the importance of the external surface in further stabilization of encapsulated materials. Altogether, a consistent experimental and theoretical methodology has been presented, paving the way for a more accurate analysis of complex nanoconfined systems.

Small, highly absorbing points are randomly present on the surfaces of the main interferometer optics in Advanced LIGO. The resulting nanometer scale thermo-elastic deformations and substrate lenses from these micron-scale absorbers significantly reduce the sensitivity of the interferometer directly though a reduction in the power-recycling gain and indirect interactions with the feedback control system. We review the expected surface deformation from point absorbers and provide a pedagogical description of the impact on power buildup in second generation gravitational wave detectors (dual-recycled Fabry–Perot Michelson interferometers). This analysis predicts that the power-dependent reduction in interferometer performance will significantly degrade maximum stored power by up to 50% and, hence, limit GW sensitivity, but it suggests system wide corrections that can be implemented in current and future GW detectors. This is particularly pressing given that future GW detectors call for an order of magnitude more stored power than currently used in Advanced LIGO in Observing Run 3. We briefly review strategies to mitigate the effects of point absorbers in current and future GW wave detectors to maximize the success of these enterprises.

Objective In chronic aortic insufficiency (AI), the method and degree of annular downsizing required to achieve durable coaptation in aortic valve repair (AVr) remains poorly defined. This study evaluated the relationship between leaflet size and annular diameter to predict adequate annular sizing in remodeling AVr.Methods Under regulatory supervision, 74 patients with chronic tri-leaflet AI underwent AVr using ring annuloplasty and leaflet reconstruction. Fifty-four (73%) had ascending aortic (n= 25) and/or root (n= 29) aneurysms, and aortic grafts were sized 5 to 7 mm larger than the rings. Intraoperatively, leaflet free-edge length (FEL) was measured with special ball sizers positioned in the coronary sinus, and “normal” annular diameter was predicted from the validated formula: Required “normal” diameter = FEL/1.5. “Normal” annular diameters predicted from FEL were compared with pathologic diameters measured intraoperatively with Hegar dilators, and both were correlated with gender, age, and BSA.Results Average age was 62.1 ± 13.3 years (mean ± SD), 73% (54/74) were male, and 96% (71/74) had moderate-to-severe AI. All patients had annular dilatation, with a pathologic diameter 26.6 ± 2.3 mm before repair, and a predicted “normal” diameter of 21.7 ± 1.7 mm (P< 0.001). Both predicted and pathologic annular diameters were larger in men (P< 0.001), but no relationship existed with age. BSA correlated with both predicted and pathologic diameters, although variability was large.Conclusions Based on a simple validated method to predict “normal” annular diameter, all patients with chronic AI have some degree of annular dilatation. This finding implies that most AVr should include annuloplasty, with adequate and precise annular reduction based on leaflet size.

Two, acyclic (1) and cyclic (2), steroidal molecular rotors containing 1,4-diethynyl-2,3-difluoro-phenylene units as rotators were investigated by means of single crystal X-ray diffraction, high resolution solid state NMR spectroscopy, and computer methods. The aim of this study was to understand and search for a correlation between the size of difluoro-phenylene units and free space in the crystal lattice required for molecular reorientation as well as the topology and time scale of dynamic processes. As a primary tool for analysis of molecular motions in the solid state, 1H–13C PISEMA, a technique which allows following the dynamics in the range of 10–3–10–6s, was employed. The PISEMA data defining the 1H–13C dipolar couplings, whose values are sensitive to local motion, were confronted with 13C CSA parameters. Our studies revealed that replacing hydrogen by fluorine in acyclic rotors has significant consequences for dynamic processes. In the case of hydrogen-substituted species, free rotation around the 1–4 axis of the benzene ring was proven. For fluorine derivatives 1, only small amplitude wobbling of aromatic residues was observed. The only large amplitude reorientation, a so-called π-jump around the 1–4 axis, was observed during the phase transition related with solvent migration from the crystal lattice. For cyclic rotors (2) two crystallographic forms 2A(triclinic, P1 space group) and 2B(monoclinic, P21space group) are established. The form 2Bcontaining a heptane molecule in the crystal lattice undergoes a thermal transition with large amplitude motion of building units of the steroidal frame. The high dynamics of the fluorinated rotator for 2Ais proven.

In this work, we present the comparison study of guanine and cytosine crystals based on the hydrogen bond (HB) dynamics. The ab initio molecular dynamics gave us a base for detailed analysis. The analysis of the trajectories by power spectrum generation, as well as the fluctuation of the interaction energies, showed large differences between HB networks in the considered crystals. The charge flow is present in the guanine molecule which forms the flat surfaces in the crystals. In the cytosine zigzag structure, the charge flow is blocked. The interaction energy is significantly less stabilizing in the cytosine structure than in the guanine. Finally, the possible influence of charge transfer on the melting temperature has been discussed.

Shock electrodialysis (SED) is a new electromembrane process for water desalination. The principle is similar to electrodeionization – the product should be ultrapure water, but the inlet water can be the same quality as the inlet to electrodialysis. The ion exchange resin is substituted by porous media and used ion exchange membranes are just of one type (i.e., two cation exchange membranes or two anion exchange membranes). The use of porous media is essential. Many physical and chemical phenomena including electroosmotic flow, electroconvection, surface conduction combined in the moment lead to the phenomena of a “–shock wave” and SED, respectively. The mechanism of the wave is represented by the formation of a sharp border in the water stream between the highly concentrated and ion-free zone. The whole process was studied by Prof. Martin Bazant’s group at MIT, Department of Chemical Engineering. The aim of this particular study is characterization and experimental testing of porous material as an essential component of SED. A variety of organic and synthetic porous materials were tested by various analytical methods and in the SED laboratory unit itself. The work reports an overview of commonly available and appropriate materials analogous to the glass frit used in the first prototypes developed by Bazant’s group. Considering the physical properties and behavior in experimental conditions and based on the results exhibiting stable desalination, we suggest the optimal porous material as well as the housing for this media. Finally, it is represented by quality of products, hydrodynamic resistance, prize of the porous material, availability and also by workability (machinability) for appropriate shape and also construction stability.

This work reports a theoretical study of infrared (IR) spectra of four nucleobases (adenine, cytosine, guanine, and thymine) in the crystalline state. The effects responsible for the fine spectral features were revealed, and the nonfundamental bands significantly contributing to the IR fingerprint region were successfully reproduced. Additionally, we compared the fundamental bands simulated for periodic models in harmonic approximation with the results obtained for finite models in anharmonic approximation. On this basis, we concluded that accurate description of the chemical neighborhood is more essential for the IR fingerprint region than the anharmonicity. Comparison with previous results indicates that the vibrational properties and the nature of intermolecular interactions of nucleobases in the crystalline state remain similar to those in solution. Therefore, the conclusions obtained for well-defined crystalline structures of nucleobases are general and helpful in understanding the vibrational spectra and properties of nucleobases and their derivatives. Finally, this work evidences that anharmonic force field based on finite models may be applied as an inexpensive correction to the harmonic spectrum of an infinite periodic system.

Abstract Cox's proportional hazards (CPH) model is quite likely the most popular modeling technique in survival analysis. While the CPH model is able to represent a relationship between a collection of risks and their common effect, Bayesian networks have become an attractive alternative with an increased modeling power and far broader applications. Our paper focuses on a Bayesian network interpretation of the CPH model (BN-Cox). We provide a method of encoding knowledge from existing CPH models in the process of knowledge engineering for Bayesian networks. This is important because in practice we often have CPH models available in the literature and no access to the original data from which they have been derived. We compare the accuracy of the resulting BN-Cox model to the original CPH model, Kaplan–Meier estimate, and Bayesian networks learned from data, including Naive Bayes, Tree Augmented Naive Bayes, Noisy-Max, and parameter learning by means of the EM algorithm. BN-Cox model came out as the most accurate of all BN approaches and very close to the original CPH model. We study two approaches for simplifying the BN-Cox model for the sake of representational and computational efficiency: (1) parent divorcing and (2) removing less important risk factors. We show that removing less important risk factors leads to smaller loss of accuracy. Highlights • Bayesian networks can be created from existing models, i.e. the CPH models, without access to data. • Resulting BN-Cox models produce results very close to the original CPH models. • Two approaches were studied to make BN-Cox models more computationally efficient. • BN-Cox models cannot be decomposed by parent divorcing. • Marginalizing least influential risk factors is recommended for model simplification. [ABSTRACT FROM AUTHOR]

Both major depression and posttraumatic stress disorder (PTSD) are characterized by inflammation, increased concentration levels of proinflammatory cytokines, decreased neurogenesis followed by neuroprogression, as well as mitochondrial and the hypothalamic-pituitary-adrenal axis dysfunction. Elevated levels of oxidative stress caused by an increased activity of prooxidants over antioxidants are also observed. Based on several reports, depressive episodes can lead to the sensitization of immune-inflammatory pathways. Thus, depression, PTSD, and depression comorbid with PTSD are associated with immune-inflammatory markers. The study aimed at evaluating concentration levels of iNOS, HO-1, IL-33, and MIP-1β in depression with and without PTSD.

Carbapenems, a family of β-lactam antibiotics, are among the most powerful bactericidal compounds in clinical use. However, as rational engineering of native carbapenem-producing microbes is not currently possible, the present carbapenem supply relies upon total chemical synthesis of artificial carbapenem derivatives. To enable access to the full diversity of natural carbapenems, we have engineered production of a simple carbapenem antibiotic within Escherichia coli. By increasing concentrations of precursor metabolites and identifying a reducing cofactor of a bottleneck enzyme, we improved productivity by 60-fold over the minimal pathway and surpassed reported titers obtained from carbapenem-producing Streptomycesspecies. We stabilized E. colimetabolism against antibacterial effects of the carbapenem product by artificially inhibiting membrane synthesis, which further increased antibiotic productivity. As all known naturally occurring carbapenems are derived from a common intermediate, our engineered strain provides a platform for biosynthesis of tailored carbapenem derivatives in a genetically tractable and fast-growing species.

We report a new solid-state multidimensional NMR approach based on the cross-polarization with variable-contact pulse sequence [Paluch, P.; Pawlak, T.; Amoureux, J.-P.; Potrzebowski, M. J.J. Magn. Reson.233, 2013, 56], with 1H inverse detection and very fast magic angle spinning (νR= 60 kHz), dedicated to the measurement of local molecular motions of 1H–15N vectors. The introduced three-dimensional experiments, 1H–15N–1H and hCA(N)H, are particularly useful for the study of molecular dynamics of proteins and other complex structures. The applicability and power of this methodology have been revealed by employing as a model sample the GB-1 small protein doped with Na2CuEDTA. The results clearly prove that the dispersion of 1H–15N dipolar coupling constants well correlates with higher order structure of the protein. Our approach complements the conventional studies and offers a fast and reasonably simple method.

Patients with schizophrenia are predisposed toward developing cardiovascular disease. Although neuroleptics affect the cardiovascular system, it is also important to consider the consequences of the disease itself such as lower physical activity due to living on disability pension, inadequate nutrition, and/or nicotine addiction, being more common among patients with schizophrenia versusthe general population. All these factors combined lead to an increased risk of death caused by cardiovascular conditions in schizophrenic patients. Individuals receiving typical antipsychotic drugs have been reported to have elevated concentrations of antiphospholipid antibodies, including anticoagulants and anticardiolipin antibodies. The presence of both antibodies is associated with an increased risk for thromboembolism. It is also likely that mental illness is accompanied by increased procoagulant activity. Patients with acute psychosis have been shown to have a statistically significant increase in the concentrations of D-dimer, P-selectin, and in the expression of platelet glycoprotein IIb/IIIa receptors. Learning about causes and mechanisms of venous thromboembolism could help to reduce or neutralize the adverse effects of antipsychotic treatment and facilitate the identification of appropriate markers necessary to monitor changes and provide preventive care against hazardous and potentially fatal complications such as deep venous thrombosis and pulmonary embolism. Before atypical neuroleptic treatment is administered to hospitalized patients, all possible risk factors for thromboembolism should be considered to allow the application of lower risk drugs. Also, other preventive measures should be taken into account, including hydration, compression stockings, regular exercise of lower extremities, and low-molecular-weight heparin injections.

Although power Doppler imaging has been used to quantify tissue and organ vascularity, many studies showed that limitations in defining adequate ultrasound machine settings and attenuation make such measurements complex to be achieved. However, most of these studies were conducted by using the output of proprietary software, such as Virtual Organ computer‐aided analysis (GE Healthcare, Kretz, Zipf, Austria); therefore, many conclusions may not be generalizable because of unknown settings and parameters used by the software. To overcome this limitation, our goal was to evaluate the impact of the flow velocity, pulse repetition frequency (PRF), and wall motion filter (WMF) on power Doppler image quantification using beam‐formed ultrasonic radiofrequency data. The setup consisted of a blood‐mimicking fluid flowing through a phantom. Radiofrequency signals were collected using PRFs ranging from 0.6 to 10 kHz for 6 different flow velocities (5–40 cm/s). Wall motion filter cutoff frequencies were varied between 50 and 250 Hz. The power Doppler magnitude was deeply influenced by the WMF cutoff frequency. The effect of using different WMF values varied with the PRF; therefore, the power Doppler signal intensity was dependent on the PRF. Finally, we verified that power Doppler quantification can be affected by the aliasing effect, especially when using a PRF lower than 1.3 kHz. The WMF and PRF greatly influenced power Doppler quantification, mainly when flow velocities lower than 20 cm/s were used. Although the experiments were conducted in a nonclinical environment, the evaluated parameters are equivalent to those used in clinical practice, which makes them valuable for aiding the interpretation of related data in future research.

Over the past decade we have seen a gradual increase in reports giving more support to the hypothesis that mildly or moderately increased values of serum prolactin have a role [...]

The phase 3, randomized Frontline Investigation of Revlimid and Dexamethasone Versus Standard Thalidomide (FIRST) trial investigating lenalidomide plus low-dose dexamethasone until disease progression (Rd continuous) vs melphalan, prednisone and thalidomide for 12 cycles (MPT) and Rd for 18 cycles (Rd18) in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM) showed that Rd continuous prolonged progression-free survival and overall survival compared with MPT. A subanalysis of the FIRST trial was conducted to determine the benefits of Rd continuous in patients with NDMM based on depth of response. Patients randomized 1:1:1 to Rd continuous, Rd18 or MPT were divided into subgroups based on best response: complete response (CR; n=290), ⩾very good partial response (VGPR; n=679), ⩾partial response (PR; n=1 225) or ⩽stable disease (n=299). Over 13% of patients receiving Rd continuous who achieved ⩾VGPR as best response did so beyond 18 months of treatment. Rd continuous reduced the risk of progression or death by 67%, 51% and 35% vs MPT in patients with CR, ⩾VGPR and ⩾PR, respectively. Similarly, Rd continuous reduced the risk of progression or death by 61%, 54% and 38% vs Rd18 in patients with CR, ⩾VGPR and ⩾PR, respectively. In patients with CR, ⩾VGPR or ⩾PR, 4-year survival rates in the Rd continuous arm (81.1%, 73.1% or 64.6%, respectively) were higher vs MPT (70.8%, 59.8% or 57.2%, respectively) and similar vs Rd18 (76.5%, 67.7% and 62.5%, respectively). Rd continuous improved efficacy outcomes in all responding patients, including those with CR, compared with fixed duration treatment.

Neurotrophin-4/5 (NT-4/5) and glutathione peroxidase-1 (GPX-1) have been shown to play a major role in neuronal processes including depression and posttraumatic stress disorder (PTSD). They protect the body from oxidative damage by affecting neuronal growth, development and plasticity. The aim of the study was to evaluate the concentrations of NT-4/5, GPX-1, tumor necrosis factor-α (TNF-α), and l-arginine in patients suffering from varying levels of depression severity, PTSD, and depression comorbid with PTSD.

Background: Neurotrophin-4/5 (NT-4/5) and glutathione peroxidase-1 (GPX-1) have been shown to play a major role in neuronal processes including depression and posttraumatic stress disorder (PTSD). They protect the body from oxidative damage by affecting neuronal growth, development and plasticity. The aim of the study was to evaluate the concentrations of NT-4/5, GPX-1, tumor necrosis factor-a (TNF-a), and l-arginine in patients suffering from varying levels of depression severity, PTSD, and depression comorbid with PTSD. Methods: The study involved 460 participants, 360 of whom were diagnosed with different types of depressive episodes. They included: 60 patients with mild depression (MD), 60 patients with moderate depression (MOD), 60 patients with severe depression (SeD), 60 patients with MD and PTSD (MD + PTSD), 60 patients with MOD and PTSD (MOD + PTSD), 60 patients with SeD and PTSD (SeD + PTSD), and 60 patients with PTSD alone. Each group of 60 subjects comprised 30 females and 30 males. The control group comprised 40 subjects. The 10th revision of the International Statistical Classification of Diseases and Related Health Problems was utilized to diagnose depression and PTSD. At 7 a.m. blood samples were collected and serum NT-4/5, GPX-1, TNF-a and l-arginine concentrations were assessed using the ELISA method. Results: Depressive episodes with and without PTSD and PTSD alone became more severe as the levels of TNF-a, l-arginine increased and the levels of NT-4/5, GPX-1 decreased. Conclusion: l-arginine, TNF-a, NT-4/5 and GPX-1 can be markers of depression severity in both males and females with first depressive episode with or without posttraumatic stress disorder.

Many pathogenic bacteria including Staphylococcus aureususe iron-chelating siderophores to acquire iron. Iron uptake oxidoreductase (IruO), a flavin adenine dinucleotide (FAD)-containing nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reductase from S. aureus, functions as a reductase for IsdG and IsdI, two paralogous heme degrading enzymes. Also, the gene encoding for IruO was shown to be required for growth of S. aureuson hydroxamate siderophores as a sole iron source. Here, we show that IruO binds the hydroxamate-type siderophores desferrioxamine B and ferrichrome A with low micromolar affinity and in the presence of NADPH, Fe(II) was released. Steady-state kinetics of Fe(II) release provides kcat/Kmvalues in the range of 600 to 7000 M–1s–1for these siderophores supporting a role for IruO as a siderophore reductase in iron utilization. Crystal structures of IruO were solved in two distinct conformational states mediated by the formation of an intramolecular disulfide bond. A putative siderophore binding site was identified adjacent to the FAD cofactor. This site is partly occluded in the oxidized IruO structure consistent with this form being less active than reduced IruO. This reduction in activity could have a physiological role to limit iron release under oxidative stress conditions. Visible spectroscopy of anaerobically reduced IruO showed that the reaction proceeds by a single electron transfer mechanism through an FAD semiquinone intermediate. From the data, a model for single electron siderophore reduction by IruO using NADPH is described.

ABSTRACTColorectal cancer (CRC), despite numerous therapeutic and screening attempts, still remains a major life-threatening malignancy. CRC etiology entails both genetic and environmental factors. Macroautophagy/autophagy and the unfolded protein response (UPR) are fundamental mechanisms involved in the regulation of cellular responses to environmental and genetic stresses. Both pathways are interconnected and regulate cellular responses to apoptotic stimuli. In this review, we address the epidemiology and risk factors of CRC, including genetic mutations leading to the occurrence of the disease. Next, we discuss mutations of genes related to autophagy and the UPR in CRC. Then, we discuss how autophagy and the UPR are involved in the regulation of CRC and how they associate with obesity and inflammatory responses in CRC. Finally, we provide perspectives for the modulation of autophagy and the UPR as new therapeutic options for CRC treatment.

Grinding and melting methods were employed for synthesis of pharmaceutical cocrystals formed by racemic (R/S) and entiomeric (S) ibuprofen (IBU) and nicotinamide (NA) as coformer. Obtained (R/S)-IBU:NA and (S)-IBU:NA cocrystals were fully characterized by means of advanced one- and two-dimensional solid state nuclear magnetic resonance (SS NMR) techniques with very fast magic angle spinning (MAS) at 60 kHz. The distinction in molecular packing and specific hydrogen bonding pattern was clearly recognized by analysis of 1H, 13C, and 15N spectra. It is concluded from these studies that both methods (grinding and melting) provide exactly the same, specific forms of cocrystals. Thermal solvent-free (TSF) approach was used for loading of (R/S)-IBU:NA and (S)-IBU:NA into the pores of MCM-41 mesoporous silica particle (MSP). The progress and efficiency of this process was analyzed by NMR spectroscopy. It has been confirmed that TSF method is an effective and safe technique of filling the MSP pores with active pharmaceutical ingredients (APIs). By analyzing the NMR results, it has been further proved that excess of IBU and NA components, which are not embedded into the pores during melting and cooling, crystallize on the MCM-41 walls preserving very specific arrangement, characteristic for crystalline samples. By investigating kinetic of release for (R/S)-IBU/MCM-41, (S)-IBU:NA/MCM-41, and (R/S)-IBU:NA/MCM-41 samples containing active components exclusively inside of the pores, it was revealed that release of IBU is much faster for the first of the samples compared to those containing IBU and NA inside the pores. The hypothesis that the rate of release of API can be controlled by specific composition of cocrystal embedded into the MSP pore was further supported by study of (R/S)-IBU:BA/MCM-41 sample with benzoic acid (BA) as coformer.

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This second part of the review series on quantum chemical methods in near infrared (NIR) spectroscopy covers the practical aspects involving applications of generalised second-order vibrational perturbation theory (GVPT2). Basic considerations are discussed here, with the aim of introducing experimental spectroscopists to the topic. The specifics of fully anharmonic calculations, the notably increased computational cost (when compared to routine harmonic vibrational calculations), the choice of software suite and hardware considerations, and various other factors with high importance for practical use of discussed theoretical methods are covered. These deliberations are directly compared to recent reports on the applications of anharmonic theoretical studies to the experimental NIR spectra of aliphatic alcohols and carboxylic acids.

Benign myxomas are the most common primary tumors in the left atrium of the heart, and they usually require urgent operative management. However, with the constant aging of the population and treatment of patients with severe concomitant diseases, an interesting question is the efficacy of the conservative approach. We present a case of a 75-year-old woman who was previously diagnosed with a left atrial myxoma, underwent an operation to resect it and then developed a recurrent tumor at the site of resection, which was found by control echocardiography 1.5 years later. She has been observed for over 10 years, as she repeatedly refused reoperation. In the setting of this example of a relatively favorable clinical course of left atrium myxoma, we discuss the current knowledge about the natural history of these tumors and the role of echocardiography in predicting their growth and complications.

The production of fatty acids from simple nutrients occurs via a complex biosynthetic pathway with dozens of intermediate compounds and multiple branch points. Despite its importance for microbial physiology and biotechnology, critical aspects of fatty acid biosynthesis, especially dynamics of in vivo regulation, remain poorly characterized. We have developed a liquid chromatography/mass spectroscopy (LC–MS) method for relative quantification of fatty acid synthesis intermediates in Escherichia coli, a model organism for studies of fatty acid metabolism. The acyl carrier protein, a vehicle for the substrates and intermediates of fatty acid synthesis, is extracted from E. coli, proteolytically digested, resolved using reverse-phase LC, and detected using electrospray ionization coupled with a tandem MS. Our method reliably resolves 21 intermediates of fatty acid synthesis, with an average relative standard deviation in ratios of individual acyl-ACP species to total ACP concentrations of 20%. We demonstrate that fast sampling and quenching of cells is essential to accurately characterize intracellular concentrations of ACP species. We apply our method to examine the rapid response of fatty acid metabolism to the antibiotic cerulenin. We anticipate that our method will enable the characterization of in vivo regulation and kinetics of microbial fatty acid synthesis at unprecedented detail and will improve integration of fatty acid synthesis into models of microbial metabolism.

ABSTRACTThe identification of nearly 3,500 cases of chikungunya virus (CHIKV) infection in U.S. residents returning in 2014 and 2015 from areas in which it is endemic has raised concerns within the transplant community that, should recently infected individuals become organ and/or tissue donors, CHIKV would be transmitted to transplant recipients. Thus, tests designed to detect recent CHIKV infection among U.S. organ and tissue donors may become necessary in the future. Accordingly, we evaluated 2 enzyme-linked immunosorbent assays (ELISAs) for CHIKV IgM readily available in the United States using 1,000 deidentified serum or plasma specimens collected from donors between November 2014 and March 2015. The Euroimmun indirect ELISA identified 38 reactive specimens; however, all 38 were negative for CHIKV IgG and IgM in immunofluorescence assays (IFAs) conducted at a reference laboratory and, thus, were falsely reactive in the Euroimmun CHIKV IgM assay. The InBios IgM-capture ELISA identified 26 reactive samples, and one was still reactive (index = 1.00) when retested using the InBios kit with a background subtraction modification to identify false reactivity. This reactive specimen was CHIKV IgM negative but IgG positive by IFAs at two reference laboratories; plaque reduction neutralization testing (PRNT) demonstrated CHIKV-specific reactivity. The IgG and PRNT findings strongly suggest that the InBios CHIKV IgM-reactive result represents true reactivity, even though the IgM IFA result was negative. If testing organ/tissue donors for CHIKV IgM becomes necessary, the limitations of the currently available CHIKV IgM ELISAs and options for their optimization must be understood to avoid organ/tissue wastage due to falsely reactive results.

Disrupted circadian rhythm of melatonin secretion in depression shows a relationship with the exacerbation of inflammatory processes. Proinflammatory mechanisms of depression are sustained by oxidative stress. This contributes to melatonin deficiency and to the malfunction of the defense mechanisms in the brain. Disrupted melatonin secretion in depression may have an influence on the concentrations of neurotrophic factors (NF), such as neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Disturbance in neurotrophin release may affect synaptic plasticity and cause exacerbation of neurodegenerative processes in the central nervous system. The aim of this study was to assess the concentrations of melatonin and NF of the brain in patients with varying levels of depression severity.

Stress may induce inflammatory changes in the immune system and activate pro-inflammatory cytokines and their receptors by activating the hypothalamic–pituitary–adrenal axis.

The degradation of drugs during melting was found to be one of the obstacles which restricts the application of the thermal solvent-free (TSF) method as a simple and efficient technique for loading active pharmaceutical ingredients (APIs) into the pores of mesoporous silica particles (MSPs). The naproxen (NPX) with melting point at 158 °C is an example of a drug which belongs to this group. In the current report we show that this limitation can be overcome by converting NPX into new crystallographic form by synthesis of cocrystal with significantly lower melting temperature as compared to pure compounds. In the course of the study it was found that picolinamide (PA) is an appropriate coformer which fulfills the assumed thermal requirements.