Oilseed plants of the Brassicaceae plant family are cultivated for food, feed and industrial purposes on large-scale in Europe. This review gives an overview of current market-oriented applications of new genomic techniques (NGTs) in relevant Brassicaceae oilseed crops based on a literature survey. In this respect, changes in oil quality, yield, growth and resistance to biotic and abiotic stress are goals in oilseed rape (B. napus) and camelina (C. sativa). Environmental risk assessment scenarios are developed for specific NGT applications in Brassicaceae oilseed crops with either a changed oil composition or with fitness related traits. In case of a changed oil composition an increase or decrease of polyunsaturated fatty acids (PUFA) demonstrates risks for health and survival of pollinators. In case of fitness related traits other risks were identified, i. e. an increased risk of spread and persistence of NGT plants. Furthermore, there are indications for potential disturbance of interactions with the environment, involving signalling pathways and reaction to stress conditions. It is shown that for a comprehensive risk assessment the technological potential of NGTs, the plants’ biology and the scale of releases have to be considered in combination. Therefore, the release of NGT plants into the environment for agricultural purposes will require risk assessment and monitoring of single traits as well as of combinatorial and long-term cumulative effects. In addition, risk management should develop concepts and measures to control and potentially restrict the scale of releases. This is especially relevant for NGT Brassicaceae in Europe which is a centre of diversity of this plant family.

A rapid synthesis of chiral sulfoxide-functionalized meta-terphenyl derivatives by a 2,5-[C4+C2] ring transformation reaction of pyrylium salts with in-situ generated enantio-merically pure .alpha.-sulfinylacetaldehydes is described. This synthetic method demonstrates for the first time the use of .alpha.-sulfinylacetaldehydes in a reaction sequence initiated by nu-cleophilic attack of pyrylium salts by .alpha.-sulfinylcarbanions to generate chiral aromatic systems. The method presented shows broad applicability starting with various methyl sulfoxides and a number of functionalized pyrylium salts, furnishing meta-terphenyls with complex substitution patterns from readily accessible starting compounds.

Finite element (FE) modeling is commonly used as a method to investigate the influence of medical devices, such as implants and screws and their effects on the biomechanical behavior of the spine. Another simulation method is a multi-body simulation (MBS), where the model is composed of several non-deformable bodies. MBS solvers generally require a very short computing time for dynamic tasks compared to an FE analysis. Considering this computational advantage, in this study, we examine whether parameters whose values are not known a priory can be determined with sufficient accuracy using MBS model. Therefore, we propose a Many-at-a-time sensitivity analysis method that allows approximating these a priory unknown parameters without requiring long simulation times. This method enables a high degree of MBS model optimization to be achieved in an iterative process. The sensitivity analysis method is applied to a simplified screw-vertebra model, consisting of an anterior anchor implant screw and vertebral body of C4. An experiment described in the literature is used as a basis for developing and assessing the potential of the method for sensitivity analysis and to validate the models action. The optimal model parameters for the MBS model were determined to be c=823224N/m for stiffness and d=488Ns/m for damping. The presented method of parameter identification can be used in studies including more complex MBS spine models or to set initial parameter values that are not available as initial values for FE models.

Input reconstruction problem is usually encountered in the areas such as virtual sensing, image restoration, sensor linearization, and communications. The input reconstruction problem can be seen as an inverse problem. Given a nominal system, two types of approaches are commonly used for solving the inverse problem. The first one is to directly invert the nominal system, and the second one is to derive an inversion of the nominal system in an indirect way. However, for the first type of approaches, system inversion cannot be directly conducted under some conditions such as there exist nonminimum-phase zeros in the nominal system, while for the second type of approaches, simultaneously guaranteeing stability and causality of the obtained inversion is still not solved well. In order to avoid the drawbacks existing in the two types of approaches, an alternative approach is proposed for input reconstruction. In this approach, the input signal is first modeled as the output of a state-space model, afterwards two Kalman filters for the model resulted by combining the input signal model and the nominal system model are implemented alternatively such that the input signal can be sequentially reconstructed in an infinite horizon. The proposed input reconstruction approach is applied in two examples, and simulation results can illustrate the effectiveness of the proposed approach.

Objectives: To compare the volumes and shapes of the coagulation zone (CZ) of a multi-probe RFA system (three RFA electrodes) and a single-probe MWA system from the same vendor in an ex-vivo bovine liver model. Material & Methods: A total of 48 CZs were obtained in bovine liver specimens with three different ablation system configurations (single-probe MWA vs. multi-probe RFA with 20 mm inter-probe distance [confluent CZ] vs. multi-probe RFA with 50 mm inter-probe distance [three individual CZ]) at 4-, 6-, 8-, and 10-min ablation time using a fixed ablation protocol. Ablation diameters were measured and ellipticity indices (EI) and volumes calculated. Calculations for all systems/configurations were compared. Results: Volumes and diameters increased with ablation time for all configurations. At 4- and 6-min ablation time volumes obtained with the RFA 50 mm setup, and at 8 and 10 min with the RFA 20 mm setup were the largest with 26.5 ± 4.1 mL, 38.1 ± 5.8 mL, 46.3 ± 4.9 mL, 48.4 ± 7.3 mL, respectively. The single-probe MWA could not reach the volumes of the RFA setups for any of the ablation times evaluated. EI were very similar and almost round for RFA 20 mm and single-probe MWA and differed significantly to the more ovoid ones for the RFA 50 mm configuration. Conclusion: The multi-probe RFA system employing three electrodes achieved significantly larger ablation volumes in both configurations (confluent CZ and three individual CZ) per time as compared to a single-probe MWA system in this ex-vivo bovine liver model.

The inverse system identification toolbox named INVSID 1.0 for MATLAB, which is used to identify the inversion of single-input single-output systems, is developed. The complete process of developing the toolbox is demonstrated. Afterwards, a numerical example is illustrated to describe how the toolbox can be used to solve inverse identification problems. Simulation results demonstrate the effectiveness of the toolbox.

Digital federated platforms and data cooperatives for secure, trusted and sovereign data exchange will play a central role in the construction industry of the future. With the help of platforms, cooperatives and their novel value creation, the digital transformation and the degree of organization of the construction value chain can be taken to a new level of collaboration. The goal of this research project was to develop an experimental prototype for a federated innovation data platform along with a suitable exemplary use case. The prototype is to serve the construction industry as a demonstrator for further developments and form the basis for an innovation platform. It exemplifies how an overall concept is concretely implemented along one or more use cases that address high-priority industry pain points. This concept will create a blueprint and a framework for further developments, which will then be further established in the market. The research project illuminates the perspective of various governance innovations to increase industry collaboration, productivity and capital project performance and transparency as well as the overall potential of possible platform business models. However, a comprehensive expert survey revealed that there are considerable obstacles to trust-based data exchange between the key stakeholders in the industry value network. The obstacles to cooperation are predominantly not of a technical nature, but of a competitive, predominantly trust-related nature. To overcome these obstacles and create a pre-competitive space of trust, the authors therefore propose the governance structure of a data cooperative model, which is discussed in detail in this paper.

SORL1 gene encodes LR11/SorLA, a protein that binds -amyloid precursor protein (bAPP) and drives its intracellular trafficking. SORL1 mutations occurring frequently in a subset of familial cases of Alzheimer’s disease (AD) have been documented but their pathogenic potential is not yet clear and questions remain concerning their putative influence on the physiopathological processing of bAPP. We have assessed the influence of three SORL1 mutations that were described as likely disease-causing and that were associated with either benign (SorLA924) or severe (SorLA141 and SorLA511) AD phenotypes. We examined the influence of wild-type and mutants SorLA in transiently transfected HEK293 cells expressing either wild-type or Swedish mutated bAPP on bAPP expression, secreted Ab and sAPPa levels, intracellular Ab40 and Ab42 peptides, APP-CTFs (C99 and C83) expressions, a-, b- and g-secretases expressions and activities as well as Ab and CTFs-degrading enzymes. These paradigms were studied in control conditions or after pharmacological proteasomal modulation. We also established stably transfected CHO cells expressing wild-type SorLA and established the colocalization of wild-type SorLA and bAPP. Overall, although we mostly confirmed previous data concerning the influence of wild-type SorLA on bAPP processing, we were unable to evidence significant alterations triggered by our set of SorLA mutants, whatever the cells or pharmacological conditions examined. Our study however does not rule out the possibility that other AD-linked SORL1 mutations could indeed affect bAPP processing and that pathogenic mutations examined in the present study could interfere with other cellular pathways/triggers in AD.

This is a study on fractals existing in music. The application case is the composition DIAPHONIES of Michael Paouris. Sliding-window fractal analysis indicate areas of continuous fractality dipped in non-fractal areas of possibly deterministic and stochastic nature. Diverging cases of pronounced non-fractal areas are addressed and also areas of mixed fractality and non-fractality. Many segments exhibit persistency-P (2

In this work, anchoring of cinchona derivatives to trifunctional cores (hub approach) was demonstrated to obtain size-enlarged organocatalysts. By modifying the cinchona skeleton in different positions, we prepared four C3-symmetric size-enlarged cinchona derivatives (hub-cinchonas), which were tested as organocatalysts and their catalytic activities were compared with the parent cinchona (hydroquinine) catalyst. We showed that in the hydroxyalkylation reaction of indole, hydroquinine provides good enantioselectivities (up to 73% ee), while the four new size-enlarged derivatives gave significantly lower values (up to 29% ee) in this reaction. Anchoring cinchonas to trifunctional cores was found to facilitate nanofiltration-supported catalyst recovery using PolarClean alternative solvent. The C3-symmetric size-enlarged organocatalysts were completely rejected by all the applied membranes, whereas the separation of hydroquinine was found to be insufficient using organic solvent nanofiltration. Furthermore, the asymmetric catalysis was successfully demonstrated in the case of Michael reaction of 1,3-diketones and trans-β-nitrostyrene using Hub3-cinchona (up to 96% ee) as a result of the positive effect of the C3-symmetric structure using a bulkier substrate. This means an increased selectivity of the catalyst in comparison to hydroquinine in the latter Michael reaction.

(1) Background: There is not much research about obesity in nursing homes although knowledge will help us to develop customized treatment plans and prevention strategies, which may help to decrease the burden for all persons involved. The objective of conducting this study was to describe the prevalence of obesity and the association between obesity and care problems in nursing home patients. (2) Methods: This study is a secondary data analysis of data collected in an annually performed cross-sectional study called “Nursing Quality Measurement 2.0”. A standardized and tested questionnaire was used to collect data. (3) Results: 1236 nursing home patients took part and 16.7% of them were obese. The multivariate logistic regression analysis results show that urinary incontinence is significantly associated with the presence of obesity (OR 2.111). The other care problems of pressure injuries, fecal and double incontinence, physical restraints, falls and pain were not associated with obesity. (4) Conclusion: The results indicate that, in the nursing home setting, health care staff should pay special attention to the patients’ nutritional and continence status and help patients maintain a normal, healthy weight. Conducting more studies with larger sample sizes is recommended, as this will allow differentiation among different obesity classes.

The reaction of arylidene-α-amino esters with electrophilic alkenes to yield the Michael type addition compounds is optimized using several phosphines as organocatalysts. The transformation is very complicated due to the generation of several final compounds, including those derived from the 1,3-dipolar cycloadditions. For this reason, the selection of the reaction conditions is a very complex task and the slow addition of the acrylic system is very important to complete the reaction. The study of the variation of the structural components of the starting imino ester is performed as well as the expansion of other electron-poor alkenes. The crude products have a purity higher than 90% in most cases without any purification. A plausible mechanism is detailed based on the bibliography and the experimental results. The synthesis of pyroglutamate entities, after reduction of the imino group and cyclization, is performed in high yields. In addition, the hydrolysis of the imino group, under acidic media, represents a direct access to glutamate surrogates.

The sustainable management of water scarcity is a global crucial issue. Germany has es- tablished efficient water management systems, but the agricultural sector still struggles with water scarcity as the demand surpasses the available water supply. The primary aim is to establish a framework for making water accessible for irrigation and additional use on households through the effective utilization of recycled water from wastewater treatment facilities. The research inquiries are focused on evaluating the changes in the agricultural irrigation model in CROPWAT, determining the spatial distribution of zonal severity, estimating the capacity of urban roof catchments, and evaluating the reduction volume of efficient water required from the existing wastewater treatment plant supply. According to the findings, the annual amount of water required for agriculture in the designated study location is approximately 2.9 million m3. Although there is no initial need for irrigation water, yet the demand for irrigation water increases during the development, active growth, and mature stages of maize, winter wheat, and wine grapes, reaching around 189mm, 225mm, and 62mm, respectively. According to our observation, the annual water supply in Weinstadt is around 4 million m3. On the other hand, the amount of water calculated from urban roof rainfall is estimated 0.8 million m3, which is considered valuable from an economic standpoint. This economically efficient volume of water would reduce the current treated water supply passes an opportunity for enhanced agricultural irrigation

The philosophy of testing statistical hypothesis is a natural consequence and functional extension of mathematical analysis of Probability. Along with the concept of recurrence when applied to random sequences and functions, it leads to the analysis of a priori and posterior which implies testing statistical hypothesis. Testing statistical hypothesis also involves algebraic, functional and dimensional considerations, which are found in the works of Laplace. Aspects of mathematical analysis such as universality of solutions, Laws of Large Numbers, Entropy, Information, and various functional dependencies are the main factors explained in the five properties that lead to implication of testing statistical hypothesis. Various interesting examples with modern scientific significance from genetics, astrophysics, and other areas give methodological access to answers of different problems and phenomena which are involved in the logic of testing statistical hypothesis.

Various 4-aminotetrahydropyridinylidene salts were treated with aldehydes in alkaline medium. Their conversion to 5-substituted -hydroxyketones in a one-step reaction succeeded only with an aliphatic aldehyde. Instead, aromatic aldehydes gave 5-substituted -aminoketones or a single -diketone. The new compounds were characterized by spectroscopic methods and a single crystal structure analysis. Some of them showed anticancer and antibacterial properties.

As the use of microbial inoculants in agriculture rises, it becomes important to understand how the environment may influence microbial ability to promote plant growth. This work examines whether there are light dependencies in the biological functions of Azospirillum brasilense, a commercialized prolific grass-root colonizer. Though classically defined as non-phototrophic, A. brasilense possesses photoreceptors that could perceive light conducted through its host’s roots. Evidence for light dependency of four microbial processes were examined and noted: biological nitrogen fixation (BNF), auxin biosynthesis, ATP biosynthesis, and iron and manganese uptake. Functional mutants of A. brasilense were leveraged and studied in light and dark environments: HM053 (high BNF and auxin production), ipdC (capable of BNF, deficient in auxin production), and FP10 (capable of auxin production, deficient in BNF). HM053 exhibited the highest rate of nitrogenase activity with the greatest light dependency comparing iterations in light and dark environments. The ipdC mutant showed similar behavior with relatively lower nitrogenase activity observed, while FP10 did not show a light dependency. Auxin biosynthesis showed strong light dependencies in HM053 and FP10 strains, but not for ipdC. Iron is involved in the BNF biological process, and light dependency was observed for microbial 59Fe2+ uptake in HM053 and ipdC, but not FP10. Surprisingly, a light dependency for 52Mn2+ uptake was only observed in ipdC. Finally, ATP biosynthesis was sensitive to light across all three mutants favoring blue light over red light compared to darkness with observed ATP levels in descending order for HM053 > ipdC > FP10.

An efficient stereoselective three-component reaction for the synthesis of spiro[4H-chromene-3,3’-oxindole] derivatives was realized through an organocatalyzed cascade Knoevenagel/Michael/cyclization reaction using a quinidine-derived squaramide as the catalyst. Under the optimized conditions, the reactions of isatins, malononitrile, and sesamol yield the desired spirooxindoles in good yields (75–87%) and moderate to high ee values (up to 90% ee). Two pairs of selected enantiomers were subjected to evaluate their antiproliferative activities on three types of human cancer cell lines using the MTT assay. The results indicated that stereoselectivity and electrical effect showed significant impact on activity. Enanotiomer R-3f exhibited optimal cytotoxic activity against U2OS cell line, which was close to the inhibitory activity of positive control, Adriamycin.

Iterated games, in which the same economic interaction is repeatedly played between the same agents, are an important framework for understanding the effectiveness of strategic choices over time. To date very little work has applied information theory to the information sets used by agents in order to decide what action to take next in such strategic situations. This article looks at the mutual information between previous game states and an agent's next action by introducing two new classes of games: ’invertible games’ and ‘cyclical games'. By explicitly expanding out the mutual information between past states and the next action we show under what circumstances these expressions can be simplified. These information measures are then applied to the Traveler's Dilemma game and the Prisoner's Dilemma game, the Prisoner's Dilemma being invertible, to illustrate their use. In the Prisoner's Dilemma a novel connection is made between the computational principles of logic gates and both the structure of games and the agents' decision strategies. This approach is applied to the cyclical game Matching Pennies to analyse the foundations of a behavioural ambiguity between two well studied strategies: ‘Tit-for-Tat' and ’Win-Stay, Lose-Switch'.

Snow is a vital environmental parameter and dynamically responsive to climate change, particularly in mountainous regions. Snow cover can be monitored at variable spatial scales using Earth Observation (EO) data. Long-lasting remote sensing missions enable the generation of multi-decadal time series and thus the detection of long-term trends. However, there have been few attempts to use these to model future snow cover dynamics. In this study, we therefore explore the potential of such time series to forecast the Snow Line Elevation (SLE) in the European Alps. We generate monthly SLE time series from the entire Landsat archive (1985-2021) in 43 Alpine catchments. Positive long-term SLE change rates are detected, with the highest rates (5-8 m/y) in the Western and Central Alps. We utilize this SLE dataset to implement and evaluate seven uni-variate time series modeling and forecasting approaches. The best results were achieved by Random Forests, with a Nash-Sutcliffe efficiency (NSE) of 0.79 and a Mean Absolut Error (MAE) of 258 m, Telescope (0.76, 268 m), and seasonal ARIMA (0.75, 270 m). Since the model performance varies strongly with the input data, we developed a Combined forecast based on the best performing methods in each catchment. This approach was then used to forecast the SLE for the years 2022-2029. In the majority of the catchments the shift of the forecast median SLE level retained the sign of the long-term trend. In cases where a deviating SLE dynamic is forecast a discussion based on the unique properties of the catchment and past SLE dynamics is required. In the future, we expect major improvements in our SLE forecasting efforts by including external predictor variables in a multi-variate modeling approach.

This paper deals with a generic methodology to evaluate the magnetic parameters of contactless power transfer systems. Neumann's integral has been used to create a matrix method that can model the magnetics of single coils (circle, square, rectangle). The principle of superposition has been utilised to extend the theory to multi-coil geometries such as double circular, double rectangle and double rectangle quadrature assuming linearity of magnetics. Numerical and experimental validation has been performed to validate the analytical models developed. A rigorous application of the analysis has been carried out to study misalignment and hence the efficacy of various geometries to misalignment tolerance. Comparison of single-coil and multi-coil shapes considering coupling variation with misalignment, power transferred and maximum efficiency is carried out.

Glioblastoma (GBM) is the most aggressive brain cancer. To model GBM in research, orthotopic brain tumor models, including syngeneic models like GL261 and genetically engineered mouse models like TRP, are used. In longitudinal studies, tumor growth and treatment response are typ-ically tracked with in vivo imaging, including bioluminescence imaging (BLI), which is quick, cost-effective, and easily quantifiable. However, BLI requires luciferase-tagged cells, and recent studies indicate that the luciferase gene can elicit an immune response, leading to tumor rejection and experimental variation. We sought to optimize the engraftment of two luciferase-expressing GBM models, GL261 Red-FLuc and TRP-mCherry-FLuc, showing differences in tumor take, with GL261 Red-FLuc cells requiring immunocompromised mice for 100% engraftment. Immuno-histochemistry and MRI revealed distinct tumor characteristics: GL261 Red-FLuc tumors were well-demarcated with densely packed cells, high mitotic activity, and vascularization. In con-trast, TRP-mCherry-FLuc tumors were large, invasive, and necrotic, with perivascular invasion. Quantifying tumor volume using the HALO® AI analysis platform yielded results comparable to manual measurements, providing a standardized and efficient approach for reliable high-throughput analysis of luciferase-expressing tumors. Our study highlights the importance of considering tumor engraftment when using luciferase-expressing GBM models, providing in-sights for preclinical research design.

DIEP-based breast reconstruction necessitates wide undermining at the abdominal donor-site, creating large wound areas. Flap harvesting is usually conducted using electrosurgical dissection devices. This study sought to compare the clinical outcomes in patients after using the PEAK PlasmaBlade (PPB) versus monopolar electrocautery (MPE). This retrospective cohort study included 128 patients with DIEP-based breast reconstruction. Patient characteristics as well as information on the postoperative course were collected and a comparative evaluation was conducted. The MPE group exhibited significantly (p* = 0.0324) higher abdominal drainage volume (351.11 ± 185.96 ml) compared to the PPB group (279.38 ± 183.38 ml). Subgroup analysis demonstrated that PPB significantly reduced postoperative wound fluid in patients with BMI > 30 kg/m² (p* = 0.0284), without prior neoadjuvant chemotherapy (p** = 0.0041), and among non-smokers (p = 0.0046). Furthermore, postoperative pain was significantly (p**** < 0.0001) lower in the PPB cohort. This study confirms the non-inferiority of the PEAK PlasmaBlade to conventional electrocautery for abdominal flap harvesting. The PPB demonstrated advantages, notably reduced drainage volume and lower postoperative pain levels. Recognizing patient subsets that benefit more from the PPB highlights the importance of personalized device selection based on patient characteristics.

Phosphorus is required by laying hens for a variety of biological functions. It is usually provided in excess, in a readily digestible inorganic form in diet formulations. However, this does not represent an efficient use of a finite resource and can result in water pollution. Plant bound phosphorus in phytate, is common in commercial poultry diets, and represents an alternate source of phosphorus, however poultry lacks the enzyme to digest it. By adding enzymes to their diets, the availability of this phytate-bound phosphorus can be increased allowing for the reduced inclusion of inorganic P in the diet formulation. Therefore, this study was conducted to examine the effect of a natural enzyme complex that contains phytase and xylanase in layer diets. Novogen Brown Classic layers (n=314) were fed one of two diets: (T1) control diet or (T2) control diet plus a natural mixed-enzyme product with both, phytase and xylanase. Experimental diets were provided for 12 days after which the excreta from each pen were collected for an additional three days to determine total retention and ileal digestibility of phosphorus and gross energy. At the end of the trial the birds were euthanized, and their ileal contents were collected. Productivity parameters were also recorded over the course of the study. The amount of phosphorus detected in the excreta of the control group was significantly higher than the amount detected in the enzyme-supplemented group (P<0.05). Both phosphorus retention and phosphorus ileal digestibility were significantly higher in the enzyme-supplemented birds (P<0.001). Gross energy digestibility was significantly higher in the enzyme-supplemented birds for both the total tract and ileal samples (P<0.001). There were only numerical improvements, not significant, in the layer productivity parameters. This study showed that the enzyme supplement can improve total retention and ileal digestibility of phosphorus and gross energy in older layers.

Smart manufacturing encompasses a category of manufacturing that employs computer-integrated capabilities and technologies to enhance supply chain optimization, production efficiency, and recyclability. Yet limited studies have been conducted to optimize these prospects from the perspective of low resource countries where such innovative studies have not been adequately explored. This paper aims to examine the implications of smart manufacturing practices (Smart Procurement, Smart Supply Chain, Smart Production Planning and Control, Automation and Industrial Robot, and Supply Chain Configuration) on pro-environmental behaviour and develop a baseline moderated mediation model to explain the relationship between smart manufacturing and pro-environmental behaviour with a role of green dynamic capability, and environmental orientation. This study is anchored on quantitative research approach, deductive reasoning, and explanatory design. Cross – sectional survey data have been obtained from 382 manufacturing companies in Ghana. Our hypotheses have been tested using Structural Equation Modelling and SMART-PLS version 3.8.9. The study has revealed that smart manufacturing practices significantly and positively relate to pro-environmental behaviour. Moreover, green dynamic capability and environmental orientation moderate the relationship between smart manufacturing and pro-environmental behaviour. The implications of the study include the emergence of a baseline model to guide policymakers, practitioners, and academicians to explain the relationship between smart manufacturing and sustainable manufacturing in the context of developing countries. Again, the social implication of the study includes the realisation of decent job and economic growth, responsible consumption and production as well as actions taken to combat climate change.

Mapping and prediction of inundated areas is increasingly important for climate change adaptation and emergency preparedness. Flood forecasting tools and flood risk models have to be compared to observed flooding patterns for training, calibration, validation and benchmarking. At regional to continental scale, satellite earth observation is the established method for surface water extent (SWE) mapping and several operational global-scale data products are available. However, the spatial resolution of satellite-derived SWE maps remains a limiting factor, especially in low-lying areas with complex hydrography, such as Denmark. We collected thermal imagery using an unmanned airborne system (UAS) for three areas in Denmark shortly after major flooding events. We combined the thermal imagery with an airborne lidar-derived high-resolution digital surface model of the country to retrieve high-resolution (40 cm) SWE maps. The resulting SWE maps were compared to low-resolution SWE maps derived from satellite earth observation (EO). We conclude that UAS have significant potential for SWE mapping at intermediate scales, can bridge the scale gap between ground observations and satellite EO and can be used to benchmark and validate SWE mapping products derived from satellite EO as well as models predicting inundation.

Surface velocity is traditionally measured with in situ techniques such as velocity probes (in shallow rivers) or Acoustic Doppler Current Profilers (in deeper water). In the last years, researchers have developed remote sensing techniques, both optical (e.g., image-based velocimetry techniques) and microwave (e.g., Doppler radar). These techniques can be deployed from Unmanned Aerial Systems (UAS), which ensure fast and low-cost surveys also in remotely-accessible locations. We compare the results obtained with a UAS-borne Doppler radar and UAS-borne Particle Image Velocimetry (PIV) in different rivers, which presented different hydraulic–morphological conditions (width, slope, surface roughness and sediment material). The Doppler radar was a commercial 24 GHz instrument, developed for static deployment, adapted for UAS integration. PIV was applied with natural seeding (e.g., foam, debris) when possible, or with artificial seeding (woodchips) in the stream where the density of natural particles was insufficient. PIV reconstructed the velocity profile with high accuracy typically in the order of a few cm s⁻¹ and a coefficient of determination (R²) typically larger than 0.7 (in half of the cases larger than 0.85), when compared with acoustic Doppler current profiler (ADCP) or velocity probe, in all investigated rivers. However, UAS-borne Doppler radar measurements show low reliability because of UAS vibrations, large instrument sampling footprint, large required sampling time and difficult-to-interpret quality indicators suggesting that additional research is needed to measure surface velocity from UAS-borne Doppler radar.

The Energy Performance of Buildings Directive 2010 calls for the Nearly Zero Energy Standard for new buildings from 2021 onwards: Buildings using “almost no energy” are powered by renewable sources or energy produced by the building itself. For residential buildings, this ambitious new standard has already been reached. But for other building types this goal is still far away. The potential of these buildings to meet a Nearly Zero Energy Standard was investigated by analyzing ten case studies representing non-residential buildings with different uses. The analysis shows that the primary characteristics common to critical building types are a dense building context with a very high degree of technical installation (such as hospital, research and laboratory buildings). The large primary energy demand of these types of buildings cannot be compensated by building and property-related energy generation including off-site renewables. If the future Nearly Zero Energy Standard were to be defined with lower requirements because of this, the state related properties of Bavaria suggest that the real potential energy savings available in at least 85% of all new buildings would be insufficiently exploited. Therefore, it would be useful to instead individualize the legal energy verification process for new buildings to distinguish critical building types such as laboratories and hospitals.

The ability to predict the skin sensitization potential of small organic molecules is of high importance to the development and safe application of cosmetics, drugs and pesticides. One of the most widely accepted methods for predicting this hazard is the rodent local lymph node assay (LLNA). The goal of this work was to develop in silico models for the prediction of the skin sensitization potential of small molecules that go beyond the state of the art, with larger LLNA data sets and, most importantly, a robust and intuitive definition of the applicability domain, paired with additional indicators of the reliability of predictions. We explored a large variety of molecular descriptors and fingerprints in combination with random forest and support vector machine classifiers. The most suitable models were tested on holdout data, on which they yielded competitive performance (Matthews correlation coefficients up to 0.52; accuracies up to 0.76; areas under the receiver operating characteristic curves up to 0.83). The most favorable models are available via a public web service at https://nerdd.zbh.uni-hamburg.de/skinDoctor/ that, in addition to predictions, provides assessments of the applicability domain and indicators of the reliability of the individual predictions.

Starting from acid chlorides, alkynes, tryptamines, and acroyl chloride, 21 densely substituted tetrahydro-beta-carbolines are prepared in a four-component one-pot reaction. In this study, the aza-Michael addition step to generate intermediate enaminones is optimized in the presence of ytterbium triflate. Moreover, apart from acroyl chloride, all reactants can be deployed in almost equimolar ratios, which increases the atom economy of the sequence. For mechanistic rationali-zation, the concluding aza-anellation was investigated by DFT calculations on potential inter-mediates and corresponding activation energies, revealing that the aza-anellation rather pro-ceeds via ene-reaction than via electrocyclization.

Grain quality, cooking quality and nutritional quality traits are some of the major attributes that enhance uptake and utilisation of improved cowpea varieties. Therefore, there is need for a better understanding of the genetic variation and inter-relationships among these quality traits in cowpea to integrate them in cowpea breeding programs. The study was conducted to determine genetic variability among 306 cowpea genotypes for grain quality, cooking quality and nutritional quality traits and to understand the interrelationships among these traits for exploitation in breeding programs. The results showed highly significant differences (P

The inherent dependency of deep learning models to labeled data is a well-known problem and one of the barriers that slows down the integration of such methods into different fields of applied sciences and engineering, in which experimental and numerical methods can easily generate a colossal amount of unlabeled data. This paper proposes an unsupervised domain adaptation methodology that mimics the peer review process to label new observations in a different domain from the training set. The approach evaluates the validity of a hypothesis using domain knowledge acquired from the training set through a similarity analysis, exploring the projected feature space to examine the class centroid shifts. The methodology is tested on a binary classification problem, where synthetic images of cubes and cylinders in different orientations are generated. The methodology improves the accuracy of the object classifier from 60% to around 90% in the case of a domain shift in physical feature space without human labeling.

The concept of a Social License to Operate (SLO) has become increasingly important in the sustainability literature in recent years. Having its origins in the business discourse of the mining industry with respect to limiting opposition to mining projects, the notion of a social contract above and beyond legal requirements has since become applied across a number of different industries. Despite the concepts adoption confusion exists over the practices and outcomes of SLO, and particularly the nature of engagement. Given this situation it is surprising that not more attention to the role of marketing, and social marketing in particular, in operationalizing the concept. The paper discusses the potential of social marketing to contribute to SLO. Economic, political and social relations are complex in SLO and exchange is intricate in such relational environments. A community-based social marketing orientation is proposed as a means to improve exchange relations and enhance engagement. Seven models of SLO related social marketing models are discussed with community-based social marketing and adaptive co-marketing models being regarded as the most positive for the achievement of an SLO. Potential barriers to adoption of these approaches are noted.

We address the problem of finding a unique graph embedding that best describes a graph's "topology". This issue is of particular interest in the chemistry of materials. Graphs that admit a tiling in 3-dimensional Euclidean space are termed tessellate, those that do not decussate. We give examples of decussate and tessellate graphs that are finite and 3-periodic. We conjecture that a graph has at most one tessellate embedding. We give reasons for considering this the default "topology" of periodic graphs.

The affinity constant, also known as the equilibrium constant, binding constant, equilibrium association constant, or the reciprocal value, the equilibrium dissociation constant (K_d), can be considered as one of the most important characteristics for any antibody-antigen pair. Many methods based on different technologies have been proposed and used to determine this value. However, since a very large number of publications and commercial datasheets do not include this information, significant obstacles in performing such measurements seem to exist. In other cases where such data are reported, the results have often proved to be unreliable. This situation may indicate that most of the technologies available today require a high level of expertise that does not seem to be available in many laboratories. In this paper, we present a simple approach based on standard immunoassay technology that is easy and quick to perform. It relies on the effect that the molar IC₅₀ approaches the K_d value in the case of infinitely small concentrations of the reagent concentrations. A two-dimensional dilution of the reagents leads to an asymptotic convergence to K_d. The approach has some similarity to the well-known checkerboard titration used for the optimization of immunoassays. A well-known antibody against the FLAG peptide, clone M2, was used as a model system and the results were compared with other methods. This approach could be used in any case where a competitive assay is available or can be developed. The determination of an affinity constant should belong to the crucial parameters in any quality control of antibody-related products and assays and should be mandatory in papers using immunochemical protocols.

This work investigated the isothermal holding time dependence of the densification, microstructure, weight loss and tensile properties of Fe-Mn-Si powder compacts. Elemental Fe, Mn and Si powder mixtures with a nominal composition of Fe-28Mn-3Si (in weight percent) were ball milled for 5h and subsequently pressed under a uniaxial pressure of 400 MPa. The compacted Fe-Mn-Si powder mixtures were sintered at 1200 ℃ for 0, 1, 2 and 3 h, respectively. In general, the density, weight loss and tensile properties increased with the increase of isothermal holding time. A significant increase in density, weight loss and tensile properties occurred in the compacts isothermally holding for 1 h, as compared to those with no isothermal holding. However, further extension of isothermal holding time (2 and 3 h) only played a limited role in promoting the density and tensile properties. The weight loss of the sintered compacts was mianly caused by the sublimation of Mn in Mn depletion region on the surface layer of the sintered Fe-Mn-Si compacts. The length of the Mn depletion region increased as isothermal holding time increased. A single α-Fe phase was detected on the surface of all the sintered compacts, and the locations beyond the Mn depletion region were comprised of a dual dominant γ-austenite and minor ε-martensite.

Aluminum, a contentious trace element found in the environment, has been demonstrated to have harmful effects on both humans and animals. In contrast, Sempervivum tectorum, an evergreen plant, has been found to offer numerous beneficial effects for both humans and animals. Therefore, this study aims to assess the protective effect of S. tectorum on certain reproductive biomarkers in male rats exposed to aluminum. Thirty-five Wistar rats were randomly divided into five groups: NTC (no-treatment control) received distilled water; NC (negative control) received drinking water containing 1 mg/L aluminum sulfate (AS); E1 received 1 mg/L AS along with an 8% S. tectorum extract; PC (positive control) received only 8% S. tectorum extract; E2 received 1 mg/L AS for three months followed by 8% extract for one month. The study analyzed testosterone, LH, FSH, body weight, and the histological structure of the testis, epididymis, and prostate, as well as the levels of zinc, manganese, copper, and iron in these organs. Significant decreases in body weight, testis, and epididymis size were observed in the aluminum-exposed groups compared to the control, whereas these decreases were not significant in the S. tectorum-treated groups compared to the control. Aluminum exposure led to significant decreases in testosterone and LH levels, with FSH levels showing a non-significant decrease in males, which were mitigated significantly by the administration of the plant extract. Histological analysis revealed alterations in the testis, epididymis, and prostate of the AS-exposed groups, including necrosis of seminiferous tubule epithelium and Leydig cells in the testis, and basal epithelial necrosis in the epididymis and prostate. Aluminum levels increased in all organs studied, while levels of zinc, copper, iron, and manganese decreased, showing a negative and significant correlation with aluminum levels. The aqueous extract of S. tectorum demonstrated a protective effect on certain studied biomarkers in male rats affected by aluminum exposure.

ZnO has many technological applications which largely depend on its properties that can be tuned by controlled synthesis. Ideally, the most convenient ZnO synthesis is carried out at room temperature in aqueous solvent. However, the correct temperature values are often loosely defined. In the current paper we performed synthesis of ZnO in aqueous solvent, by varying reaction and drying temperature by 10°C steps and monitored the synthesis products primarily by XRD. We found out that a simple direct synthesis of ZnO, without additional surfactant, pumping of freezing, required both a reaction (TP) and a drying (TD) temperature of 40°C. Higher temperatures also afford ZnO, but lowering any of the TP or TD below the threshold value results either in the achievement of Zn(OH)2 or in a mixture of Zn(OH)2/ZnO. A more detailed Rietveld analysis of the ZnO samples reveals a density variation with the synthesis temperature and an increase of the nanoparticles average size also verified by SEM images. The optical properties of ZnO obtained by UV-Vis reflectance spectroscopy indicate a red shift of the band gap by ~0.1 eV.

This paper will discuss Data, Information, Knowledge, and Wisdom, which is commonly referred to as DIKW. The DIKW Pyramid Model that is often referenced in both academics and practitioner circles will be discussed and shown to be faulty on several levels, including. a lack of definitional agreement. A new DIKW framework will be proposed that focuses on what the DIKW elements do in the way humans think, not what they are by definition. Information as a replacement for wasted physical resources in goal-oriented tasks will be a central organizing point. The paper will move the DIKW discussion to the computer-based concept of Digital Twins (DTs) and its augmentation of how we can use DIKW to be more effective and efficient. This will especially be the case as we move to Intelligent Digital Twins (IDT) with Artificial Intelligence (AI).

By using a systems biological perspective and available literature on human social interaction, grouping, and cohesiveness, a new coherent model is proposed that integrates existing social integration and neurobiological research into a theoretical neurobiological framework of personality and social interaction. This model allows for the coherent analysis of complex social systems and interactions within them, and proposes a framework for estimating group cohesiveness and evaluating group structures in order to build and organize optimized social groups. This „Neurobiological-Associative“ model proposes two primary feedback loops, with environmental conditioning (learning) being sorted into an associative model that modulates interaction with the social environment, and which impacts the second feedback loop involving the individuals' neurobiological capacity. In this paper, the concept of neurobiological capacity is developed and based upon contemporary research on intelligence, personality, and social behavior with a focus on the oxytocin, serotonin, and dopamine systems. The basis of social exclusion and group structure is thus, expressed in the very most simple terms, neurobiological compatibility and risk assessment modulated by an internal associative model.

Using the unique combination of atomically resolved atom probe tomography (APT) and volume averaged neutron (resonance) spin echo (NRSE and NSE) experiments, the influence of nano-scaled clusters on the spin relaxation in spin glasses was studied. For this purpose, the phase transition from the paramagnetic phase to the spin glass phase in a Fe-Cr spin glass with a composition of Fe_17.8Cr_82.2 was studied in detail by means of NRSE. The microstructure was characterised by APT measurements, which show local concentration fluctuations of Fe and Cr on a length scale of 2 to 5 nm, which lead i) to the coexistence of ferro- and anti-ferromagnetic clusters and ii) a change of the magnetic properties of the whole sample, even in the spin glass phase, where spins are supposed to be randomly frozen. We show that a generalized spin glass relaxation function, which was successfully used to describe the phase transition in diluted spin glasses, can also be used for fitting the spin dynamics in spin glasses with significant concentration fluctuations.

Considering that life on earth evolved about 3.7 billion years ago, vertebrates are young, appearing in the fossil record during the Cambrian explosion about 542 to 515 million years ago. Results from sequence analyses of genomes from bacteria, yeast, plants, invertebrates and vertebrates indicate that receptors for adrenal steroids (aldosterone, cortisol), and sex steroids (estrogen, progesterone, testosterone) also are young, with an estrogen receptor and a 3-ketosteroid receptor first appearing in basal chordates (cephalochordates: amphioxus), which are close ancestors of vertebrates. Through gene duplication and divergence of the 3-ketosteroid receptor, receptors that respond to androgens, glucocorticoids, mineralocorticoids and progestins evolved in vertebrates. Thus, an ancestral progesterone receptor and an ancestral corticoid receptor, the common ancestor of the glucocorticoid and mineralocorticoid receptors, evolved in jawless vertebrates (cyclostomes: lampreys, hagfish). This was followed by evolution of an androgen receptor, distinct glucocorticoid and mineralocorticoid receptors and estrogen receptor-α and -β in cartilaginous fishes (gnathostomes: sharks). Further evolution of mineralocorticoid signaling occurred with the evolution of aldosterone synthase in lungfish, a forerunner of terrestrial vertebrates. Adrenal and sex steroid receptors are not found in echinoderms: and hemichordates, which are ancestors in the lineage of cephalochordates and vertebrates. The evolution of steroid receptors at key nodes in the evolution of vertebrates, in which steroid receptors act as master switches to regulate differentiation, development, reproduction, immune responses, electrolyte homeostasis and stress responses, argues for an important role for steroid receptors in the evolutionary success of vertebrates, considering that the human genome contains about 22,000 genes, which is not much larger than genomes of invertebrates, such as Caenorhabditis elegans (~18,000 genes) and Drosophila (~14,000 genes).

There is much concern about disruption of endocrine physiology regulated by steroid hormones in humans, other terrestrial vertebrates and fish by industrial chemicals, such as bisphenol A, and pesticides, such as DDT. These endocrine-disrupting chemicals influence steroid-mediated physiology in humans and other vertebrates by competing with steroids for receptor binding sites, disrupting diverse responses involved in reproduction, development and differentiation. Here I discuss that due to evolution of the progesterone receptor (PR) and mineralocorticoid receptor (MR) after ray-finned fish and terrestrial vertebrates diverged from a common ancestor, each receptor evolved to respond to different steroids in ray-finned fish and terrestrial vertebrates. In elephant shark, a cartilaginous fish, ancestral to ray-finned fish and terrestrial vertebrates, both progesterone and 17,20-beta-dihydroxy-progesterone activate the PR. During the evolution of ray-finned fish and terrestrial vertebrates, the PR in terrestrial vertebrates continued responding to progesterone and evolved to weakly respond to 17,20-beta-dihydroxy-progesterone. In contrast, the physiological progestin for the PR in zebrafish and other ray-finned fish is 17,20-beta-dihydroxy-progesterone, and ray-finned fish PR responds weakly to progesterone. The MR in fish and terrestrial vertebrates also diverged to have different responses to progesterone. Progesterone is a potent agonist for elephant shark MR, zebrafish MR and other fish MRs, in contrast to progesterone’s opposite activity as an antagonist for aldosterone, the physiological mineralocorticoid for human MR. These different physiological ligands for fish and terrestrial vertebrate PR and MR need to be considered in applying data for their disruption by chemicals in fish and terrestrial vertebrates to each other.

The spillover of the terrorist activities of Boko Haram, a Nigerian jihadi group, into Cameroon’s northern region has resulted in security challenges and humanitarian activity opportunities for Christian churches. The insurgents have attacked and destroyed churches, abducted Christians, worsened Muslim-Christian relations, and caused a humanitarian crisis. Aggregately, these ensuing phenomena have adversely affected Christian churches in this region, triggering an aura of responses: coping strategies, humanitarian work among refugees, and inter-faith dialogue. These responses are predicated on Christianity’s potential as a resource for peace, compassion, and love. In this study we emphasize the role of Christian churches in dealing with the Boko Haram insurgency. It opens up with a contextualization of Boko Haram in Cameroon’s north. This is followed by an examination of the brutality meted out on Christians and church property. The final section is an examination of the spiritual, humanitarian and relief services provided by Christian churches. The paper argues that although Christian churches have suffered at the hands of Boko Haram insurgents, they have engaged in various beneficial responses underpinned by the Christian values of peace and love.

Modern gastroenterology, which occupies the pages of scientific journals without alternative, began as an initiative of manufacturers of diagnostic equipment. For widespread advertising, they selected practical doctors who were not familiar with the methodology of science and superficial knowledge of physiology. This is how a group led by DeMeester arose, which in 1976 published the DeMeester score, i.e., the normal limit for esophageal pH monitoring. pH <4, less than 4% of the time per day was considered normal, i.e., it was unreasonably claimed that such reflux is physiological. This article proves that this study was carried out with numerous methodological errors, which led to an erroneous conclusion. For a long time, pH monitoring was considered the gold standard and with its help hypotheses were proposed that form the basis of modern gastroenterology. The article proves the fallacy of 13 hypotheses, which are presented as theories. Numerous articles using pH monitoring have publicized this method. Practitioners became "great scientists", equipment manufacturers became successful businessmen. Over time, they found other groups of practitioners to promote devices for impedance ph monitoring, high-resolution manometry, and many others. At the same time, a network of reviewers who believe in the infallibility of the luminaries do not allow studies that contradict their faith to be published. Thus, fundamental science was destroyed, which alone could assess the harm of false research both for science and for patients. Conclusion This study provides a list of hypotheses, that were previously considered theories, but since scientific evidence has proven these assumptions to be false, they should be excluded from subsequent use and citation.

Providing data on usage patterns is key to assessing the reduced-risk potential of novel tobacco and nicotine products at a population level. We performed a nationwide cross-sectional survey of the general population in Japan to assess usage patterns after the introduction of tobacco heating products (THPs). Eligible participants were Japanese residents, aged 20 years or older who consented to complete the survey. Individuals living in institutions were excluded. A three-stage probability sampling method was applied that was geographically stratified by street blocks proportionate to population density. Respondents self-reported patterns of product use and reasons for THP use. Complete responses were available from 5,306 individuals, of whom 933.5 (17.6%) were current users, 984.2 (18.5%) were former users and 3388.4 (63.9%) were never users of tobacco products. Cigarettes were used by 14.6% of current tobacco product users and THPs by 5.3%. Cigarettes and THPs were used exclusively by 64.5% and 12.2%, respectively, and both were used by 12.7%. The most common reasons reported for THP use were perceived reduction in harm to self and others compared to cigarettes. While the prevalence of cigarette use in Japan is decreasing, THPs seem to be increasingly used as long-term alternatives to cigarette smoking.

Statistical modeling lies at the heart of product design and development throughout numerous engineering disciplines, especially since processing large amounts of data has become increasingly ubiquitous. While mathematical statistics provide elegant guidance pertaining to the question of whether or not some particular underlying modeling assumptions are justified and appropriate, when pursuing a more comprehensive assessment of product design and development other considerations often increase in significance. Therefore, we will examine and analyze the tedious interactions and implications of statistical modeling choices and product liability exposure. To the best of our knowledge, this paper is the first to draw attention to and explore some often overlooked or oversimplified dangers and pitfalls that enter the equation when product design heavily relies on statistical modeling. In particular, through a diligent analysis of both statistical and legal aspects we will explore how statistically optimal procedures may yield far from optimal outcomes in terms of product liability when applied to actual real life problems and why suboptimal nonparametric or robust approaches may constitute better alternatives.

Problem solving is one of the most important components of the human cognition that affects for ages the progress of the human society. Mathematical modelling is a special type of problem solving concerning problems related to science or everyday life situations. The present study is a review of the author’s earlier works on problem solving and mathematical modelling from the scope of Education. Its real goal is that it presents in a systematic way and in a few pages only the results of many years research on the subject. This helps the reader to get a comprehensive idea about a very important topic belonging to the core of Mathematics Education, which is very useful to those wanting to study deeper the subject and get directions for further research in the area.

Recently concluded, large-scale cancer genomics studies involving multiregion sequencing of primary tumors and paired metastases appear to indicate that many or most cancer patients have one or more “clonal" mutations in their tumors. Clonal mutations are those that are present in all of a patient’s cancer cells. Achilles Therapeutics is currently the only company specifically targeting clonal mutations. However, they are doing so with tumor-derived T cells. To address the potential limitations of immunotherapy, I have devised another approach for exploiting clonal mutations, which I call “Oncolytic Vector Efficient Replication Contingent on Omnipresent Mutation Engagement” (OVERCOME). The ideal version of OVERCOME would likely employ a bioengineered facultative intracellular bacterium. The bacterium would initially be attenuated, but (transiently) reverse its attenuation upon clonal mutation detection.

SETMAR is a protein lysine methyltransferase that is involved in several DNA processes, including DNA repair via the non-homologous end joining (NHEJ) pathway, regulation of gene expression, illegitimate DNA integration, and DNA decatenation. However, SETMAR is an atypical protein lysine methyltransferase since in anthropoid primates, the SET domain is fused to an inactive DNA transposase. The presence of the DNA transposase domain confers to SETMAR a DNA binding activity towards the remnants of its transposable element, which has resulted in the emergence of a gene regulatory function. Both the SET and the DNA transposase domains are involved in the different cellular roles of SETMAR, indicating the presence of novel and specific functions in anthropoid primates. In addition, SETMAR is dysregulated in different types of cancer, indicating a potential pathological role. While some light has been shed on SETMAR functions, more research and new tools are needed to better understand the cellular activities of SETMAR and to investigate the therapeutic potential of SETMAR.

The conventional explanation of delayed-choice experiments seems to violate our causal intuition. This apparent violation is caused by a misinterpretation of the conventional formulation of quantum mechanics. I reanalyze these experiments using advanced and time-symmetric formulations of quantum mechanics. All three formulations give the same experimental predictions, but the advanced and time-symmetric formulations violate our causal intuition that effects only happen after causes. I explore reasons why our causal intuition may be wrong at the quantum level. I also suggest how conventional causation might be recovered in the classical limit, and speculate on cosmological boundary conditions.

Stellar heated gas and dust makes a significant entropic/information energy contribution to the universe. At temperatures ~10⁷ the ~10⁸⁶ bits are equivalent to ~10⁷⁰J, equivalent to the energy equivalence of the universe’s ~10⁵³ kg ordinary baryon matter. A survey of stellar mass density measurements shows this dark energy contribution has a constant energy density that effectively mimics a cosmological constant over the redshift range z<1.35. The measurable difference between this information energy and a true cosmological constant is small, with a maximum difference of <2% in Hubble parameter at z~2. As information energy is significant and co-located with hot baryons it produces gravitational effects that resemble dark matter. Information energy is shown to be consistent with the dark matter effects observed in clusters of colliding galaxies (e.g. Bullet Cluster), with dark matter location specified by baryon location and strongest in regions of highest luminosity / temperature. The dark matter fraction measured in galaxy surveys more closely fits an information energy explanation than the fraction expected in the standard ɅCDM model. Information energy provides a solution to the cosmological coincidence problem and also would allow the cosmological constant to take the preferred zero value.

Structure quality of LuFeO3 epitaxial layers grown by pulsed-laser deposition on sapphire substrates with and without platinum interlayers has been investigated by in-situ high-resolution x-ray diffraction (reciprocal-space mapping). The parameters of the structure such as size and misorientation of mosaic blocks have been determined as functions of the thickness of LuFeO3 during the PLD growth and for different platinum interlayers thicknesses up to 40 nm. The x-ray diffraction results combined with ex-situ scanning electron microscopy and high-resolution transmission electron microscopy demonstrate that the Pt interlayer significantly improves the structure of LuFeO3 by reducing the misfit of the LuFeO3 lattice with respect to the material underneath.

Adeno-associated viral (AAV) vectors can be used for gene delivery. AAV.CAP-Mac was recently developed; it can cross the blood-brain barrier and transduce cells throughout the CNS. However, some brain regions were not transduced in adult rhesus monkeys. Additionally, AAV vectors can only package 5 kb of DNA. Also, AAV vectors may be genotoxic and cytotoxic, especially at high doses. Finally, AAV vectors are very expensive to produce at sufficiently high titers for treatment. Off-the-shelf cell-based delivery systems wherein the cells can infiltrate the target tissue and be hyper-motile would be ideal. Also, mRNA-based gene editing would be a transient treatment, and thus be much safer.

Lipofuscin is indigestible garbage that accumulates in the autophagic vesicles and cytosol of post-mitotic cells with age. Drs. Brunk and Terman postulated that lipofuscin accumulation is the main or at least a major driving factor in aging. They even posited that the evolution of memory is the reason why we get lipofuscin at all, as stable synaptic connections must be maintained over time, meaning that the somas of neurons must also remain in the same locale. In other words, they cannot dilute out their garbage over time through cell division. Mechanistically, their position certainly makes sense given that rendering a large percentage of a post-mitotic cell’s lysosomes useless must almost certainly negatively affect that cell and the surrounding microenvironment. It may be the case that lipofuscin accumulation is the main issue with regard to current age-related disease. Degradation in situ may be an insurmountable task currently. However, a method of systemic lipofuscin removal is discussed herein.

This review covers some of the central relationships between artificial intelligence, psychology, and economics through the lens of information theory, specifically focusing on formal models of decision-theory. In doing so we look at a particular approach that each field has adopted and how information theory has informed the development of the ideas of each field. A key theme is expected utility theory, its connection to information theory, and the Bayesian approach to decision-making and forms of (bounded) rationality. What emerges from this review is a broadly unified formal perspective derived from three very different starting points that reflect the unique principles of each field. Each of the three approaches reviewed can, in principle at least, be implemented in a computational model in such a way that, with sufficient computational power, they could be compared with human abilities in complex tasks. However, a central critique that can be applied to all three approaches was first put forward by Savage in {\it The Foundations of Statistics} and recently brought to the fore by the economist Binmore: Bayesian approaches to decision-making work in what Savage called `small worlds' but cannot work in `large worlds'. This point, in various different guises, is central to some of the current debates about the power of artificial intelligence and its relationship to human-like learning and decision-making. Recent work on artificial intelligence has gone some way to bridging this gap but significant questions still need to be answered in all three fields in order to make progress on these problems.

Here we present a fast and highly scalable community structure preserving network module detection that recursively integrates graph sparsification and clustering. Our algorithm, called SparseClust, participated in the most recent DREAM community challenge on disease module identification, an open competition to comprehensively assess module identification methods across a wide range of biological networks.

Research into the causes of neurotoxicity in Alzheimer’s Dementia (AD) has focused on neurofibrillary tangles and beta amyloid (Aβ) plaques. This paper proposes the heterodox theory that these hallmarks of AD are the visible effects, not direct causes of neuronal necrosis. Rather AD results from a combination of age-induced, disproportional decline in physiological support for aerobic metabolism, and dysregulation of the sleep cycle processes. The hypothesis is that the decimation of neurons in AD results from a combination of neurotoxicity and increased apoptosis caused by: 1. direct damage from toxic waste products of anaerobic glycolysis due to a progressive decline in the capacity of neurons to perform oxidative phosphorylation (OXPHOS) and an increased reliance on anaerobic glycolysis to meet metabolic needs; 2. impaired cellular repair and effluent release due to dysregulation of non-rapid eye movement (NREM) sleep allowing damage to cell membranes and synaptic junctions to accumulate inducing a chronic inflammatory response; 3. indirect damage from products produced by inflammatory reaction to toxic metabolites; 4. neuronal apoptosis from the AβPP-mediated pathway due to the age-induced decline of growth hormone (GH), GH-releasing hormone (GHRH) and insulin-like growth factor (IGF).

Extensive genome structure variation, such as copy number variations (CNVs) and presence/absence variations, is the basis for the remarkable maize genetic diversity; however, the effect of CNVs on maize herbivory defense remains largely underexplored. Here, we report that the naturally occurring duplication of the maize 9-lipoxygenase gene, ZmLOX5, leads to increased resistance of maize to herbivory by fall armyworms (FAW). Previously, we showed that ZmLOX5-derived oxylipins are required for defense against chewing insect herbivores and identified several inbred lines, including Yu796, that contained duplicated CNVs of ZmLOX5, referred to as Yu796-2×LOX5. To test whether introgression of the Yu796-2×LOX5 locus into the herbivore-susceptible B73 background that contains a single ZmLOX5 gene is a feasible approach to increase resistance, we generated a series of near-isogenic lines that contained either 2, 1 or 0 copies of the Yu796-2×LOX5 locus in the B73 background by six back crosses (BC6). Droplet digital PCR (ddPCR) confirmed the successful introgression of the Yu796-2×LOX5 locus in B73. The resulting B73-2×LOX5 inbred line displayed increased resistance against FAW associated with increased expression of ZmLOX5, increased wound-induced production of its primary oxylipin product, the α-ketol, 9-hydroxy-10-oxo-12(Z),15(Z)-octadecadienoic acid (9,10-KODA), and the downstream defense hormones regulated by this molecule, 12-oxo-phytodienoic acid (12-OPDA) and abscisic acid (ABA). Surprisingly, wound-induced JA-Ile production was not increased in B73-2×LOX5, resulting from the increased JA catabolism. Furthermore, B73-2×LOX5 displayed enhanced drought tolerance likely due to increased ABA and 12-OPDA content. Taken together, this study revealed that the duplicated CNV of ZmLOX5 quantitively contributes to maize antiherbivore defense and presents proof-of-concept evidence that the introgression of naturally occurring duplicated CNVs of a defensive gene into the productive, but susceptible, crop varieties is a feasible breeding approach for enhancing plant resistance to herbivory and tolerance to abiotic stress.

Through the use of a simplified model of consciousness this paper illustrates the symptoms of schizophrenia linked to neocortical structures and functions. It makes the case that the bewildering and varied presentation of symptoms in schizophrenia can be analyzed and explained using such models. The model is used to illustrate the central thesis of the paper, that schizophrenia is a disorder of neurogenesis which leads to progressive neurochemical, functional and neurophysiological changes that create the characteristic behaviors of the disease.

Several methods of processing wood into strong, durable products for the construction industry provide transformative opportunities to substitute for less sustainable building materials. Carbon storage is a further advantage, with the added possibility of combustion for bioenergy at end of life. Intense research activity in this area is expected to open up new markets for wood fiber during the lifetime of trees now being planted. Here, wood-derived materials are classified according to the particle size, from metres to nanometres, into which the wood is fragmented before reconstitution. Materials made by densifying or chemically modifying solid wood with no fragmentation are already in production for exterior doors, window frames and cladding, with improved uniformity and stability compared with unmodified wood. Pre-commercial developments promise further gains in durability and strength. Emerging developments extend these process technologies to wood that has been chipped or stranded or pulped, retaining the above advantages over raw timber for weather-facing applications and adding processability by moulding or extrusion. Crucially, the raw material does not then need to be sawn timber but can be bioenergy-grade wood biomass. This will facilitate afforestation strategies that combine the aims of carbon sequestration and biodiversity.

Vitamin K occupies a unique and often obscured place among its fellow fat-soluble vitamins. Evidence is mounting however, that vitamin K (VK) may play an important role in the visual system apart from the hepatic carboxylation of hemostatic related proteins. However, to our knowledge, no review covering the topic has appeared in the medical literature. Recent studies have confirmed that matrix Gla protein (MGP), a vitamin K-dependent protein (VKDP), is essential for the regulation of intraocular pressure in the mouse. The PREDIMED (Prevención con Dieta Mediterránea) study, a randomized trial involving 5860 adults at risk for cardiovascular disease, demonstrated a 29% reduction in the risk of cataract surgery in participants with the highest tertile of dietary vitamin K1 (PK) intake compared with the lowest tertile. However, the specific requirements of the eye and visual system (EVS) for VK, and what might constitute an optimized VK status, is currently unknown and largely unexplored. It is the intention therefore of this narrative review to provide an introduction concerning VK and the visual system, review ocular VK biology, and to provide some historical context to recent discoveries. Potential opportunities and gaps in current research efforts will be touched upon, in the hope of raising awareness, and encouraging continued VK related investigations in this important and highly specialized sensory system.

This article challenges the assumption that journals and peer review are essential for developing, evaluating and disseminating scientific and other academic knowledge. It suggests a more flexible ecosystem, and examines some of the possibilities this might facilitate. The market for academic outputs should be opened up by encouraging the separation of the dissemination service from the evaluation service. Publishing research in subject-specific journals encourages compartmentalising research into rigid categories. The dissemination of knowledge would be better served by an open access, web-based repository system encompassing all disciplines. There would then be a role for organisations to assess the items in this repository to help users find relevant, high-quality work. There could be a variety of such organisations which could enable reviews from peers to be supplemented with evaluation by non-peers from a variety of different perspectives: user reviews, statistical reviews, reviews from the perspective of different disciplines, and so on. This should reduce the inevitably conservative influence of relying on two or three peers, and make the evaluation system more critical, multi-dimensional and responsive to the requirements of different audience groups, changing circumstances, and new ideas. Non-peer review might make it easier to challenge dominant paradigms, and expanding the potential audience beyond a narrow group of peers might encourage the criterion of simplicity to be taken more seriously - which is essential if human knowledge is to continue to progress.

This paper discusses recent developments in creep, over a wide range of temperature, that mqy change our understanding of creep. The five-power law creep exponent (3.5 to 7) has never been explained in fundamental terms. The best the scientific community has done is to develop a natural three power-law creep equation that falls short of rationalizing the higher stress exponents that are typically five. This inability has persisted for many decades. Computational work examining the stress-dependence of the climb rate of edge dislocations we may rationalize the phenomenological creep equations. Harper-Dorn creep, “discovered” over 60 years ago has been immersed in controversy. Some investigators have insisted that a stress exponent of one is reasonable. Others believe that the observation of a stress exponent of one is a consequence of dislocation network frustration. Others believe the stress exponent is artificial due to the inclusion of restoration mechanisms such as dynamic recrystallization or grain growth that is not of any consequence in the five power-law regime. Also, the experiments in the Harper-Dorn regime, which accumulate strain very slowly (sometimes over a year) may not have attained a true steady state. New theories suggest that absence or presence of Harper-Dorn may be a consequence of the initial dislocation density. Novel experimental work suggests that power-law breakdown may be a consequence of a supersaturation of vacancies which increase self-diffusion.

The emergence of carbapenemase-producing Enterobacteriaceae has limited therapeutic options and presents a major public health problem. Resistances against carbapenems in this bacterial family are mostly conveyed by metallo-beta-lactamases (MBL) including VIM, which are often encoded on resistance plasmids. We characterized four VIM-positive isolates that were obtained as part of a routine diagnostic screening from two laboratories in north-eastern Germany be-tween June and August 2020. Whole-genome sequences were generated to address a) their phylo-genetic properties, b) their plasmid content, and c) the underlying mechanisms of resistance and virulence. In addition, we performed phenotypic antibiotic and mercury resistance analyses. The genomic analysis revealed three different bacterial species including C. freundii, E. coli and K. oxytoca with four different sequence types. All isolates were geno- and phenotypically multi-drug-resistant (MDR). Three isolates of four carried identical VIM-1-resistance plasmids, which – in addition – encoded for a mercury resistance operon and showed some similarity to two ex-ternal plasmid sequences. The distribution of virulence features among the genomes was limited. Our results highlight the circulation of an identical VIM-1-resistance plasmid in three of four bacterial isolates of different Enterobacteriaceae in north-eastern Germany.

In light of climate changes, technological development and the use of renewable energy sources are considered very important nowadays, both in newly-designed structures and reconstructed historic building, resulting in the reduction of the commercial energy consumption and CO2 environmental emissions. This paper explores the possibilities of improving the energy efficiency of heritage sacred buildings by utilizing photovoltaic systems. As an exceptionally significant cultural good, the Cathedral of St. Michael the Archangel in Belgrade shall serve as a case study, with the aim of examining the methods of mounting photovoltaic (PV) panels, by taking into account the fact that the authenticity and the aesthetic value of this cultural monument must remain intact. A comparative analysis of the two options for installing PV panels on the southwestern roof of the church was performed using simulations in PVgis and PVsist V6.84 software, with the aim of establishing the most efficient option in terms of power generation. The simulation results show that photovoltaic panels can produce 151650 kWh (Option 1) and 150894 kWh (Option 2) per year, while the required amount of energy is 42726.77 kWh. The electricity produced exceeds the electricity requirements for the decorative lighting of the Cathedral Church, so it can be used for other purposes in the sacral complex.

In light of climate changes, technological development and the use of renewable energy sources are considered very important nowadays, both in newly-designed structures and reconstructed historic building, resulting in the reduction of the commercial energy consumption and CO₂ environmental emissions. This paper explores the possibilities of improving the energy efficiency of heritage sacred buildings by utilizing photovoltaic systems. As an exceptionally significant cultural good, the Cathedral of St. Michael the Archangel in Belgrade shall serve as a case study, with the aim of examining the methods of mounting photovoltaic (PV) panels, by taking into account the fact that the authenticity and the aesthetic value of this cultural monument must remain intact. A comparative analysis of the two options for installing PV panels on the southwestern roof of the church was performed using simulations in PVgis and PVsist V6.84 software, with the aim of establishing the most efficient option in terms of power generation. The simulation results show that photovoltaic panels can produce 151650 kWh (Option 1) and 150894 kWh (Option 2) per year, while the required amount of energy is 42726.77 kWh. The electricity produced exceeds the electricity requirements for the decorative lighting of the Cathedral Church, so it can be used for other purposes in the sacral complex.

We consider the role information energy can play as a source of dark energy. Firstly, we note that, if stars and structure had not formed in the universe, elemental bits of information describing the attributes of particles would have exhibited properties similar to the cosmological constant. The Landauer equivalent energy of such elemental bits would be defined identical in form and value to the characteristic energy of the cosmological constant. But, with the formation of stars and structure, stellar heated gas and dust now provides the dominant contribution to information energy with the characteristics of a dynamic, transitional, dark energy. At low redshift, z<~1.35, this dark energy emulates the cosmological constant with a near constant energy density, w=−1.03±0.05, and an energy total similar to the mc² of the universe's ∼10⁵³ kg of baryons. At earlier times, z>~1.35, information energy was phantom, differing from the cosmological constant, Λ, by a CPL parameter difference of ∆w_o=−0.03±0.05 and ∆w_a=−0.79±0.08, values sufficient to account for the H₀ Tension. Information dark energy agrees with most phenomena as well as Λ, while exhibiting characteristics that resolve many tensions and problems of ΛCDM: the cosmological constant problem; the cosmological coincidence problem; the H₀ and σ₈ tensions. As this proposed dark energy source is not usually considered, we identify the expected signature in H(a) that will enable the role of information dark energy to be falsified by experimental observation.

Analysis of land use/land cover (LULC) in the catchment areas is the first action toward safeguarding the freshwater resources. The LULC information in the watershed has gained popularity in the natural science field as it helps water resource managers and environmental health specialists develop natural resource conservation strategies based on available quantitative information. Thus, remote sensing is the cornerstone in addressing environmental-related issues at the catchment level. In this study, the performance of four machine learning algorithms (MLAs), such as Random Forests (RF), Support Vector Machine (SVM), Artificial Neural Networks (ANN), and Naïve Bayes (NB) was investigated to classify the catchment into nine relevant classes of the undulating watershed landscape using Landsat 8 Operational Land Imager (L8-OLI) imagery. The assessment of the MLAs were based on the visual inspection of the analyst and the commonly used assessment metrics, such as user’s accuracy (UA), producers’ accuracy (PA), overall accuracy (OA), and kappa coefficient. The MLAs produced good results, where RF (OA= 97.02%, Kappa= 0.96), SVM (OA= 89.74 %, Kappa= 0.88), ANN (OA= 87%, Kappa= 0.86), and NB (OA= 68.64 Kappa= 0.58). The results show the outstanding performance of the RF model over SVM and ANN with a small margin. While NB yielded satisfactory results, which could be primarily influenced by its sensitivity to limited training samples. In contrast, the robust performance of RF could be due to an ability to classify high-dimensional data with limited training data.

Jamoytius kerwoodi, is a primitive, eel-like jawless vertebrate found uniquely in an Early Silurian (Llandovery epoch; 444-433 Ma) horizon near Lesmahagow, Scotland. This species is a rare component of a low-diversity dominantly nektonic detritus and herbivorous fauna living over an anoxic bottom and is found at the transition from a marine-influenced, probably brackish-water, deep-water basin to a shallower-water, less saline and likely freshwater basin. In the absence of true teeth, Jamoytius was probably a detritivore or herbivore feeding on Ceratiocaris. Jamoytius may be a direct ancestor of living lampreys, especially as their ectoparasitic mode of life might have evolved from ancestral microphagous filterers or herbivores.

The current report represents a case of a 77-year-old man with Parkinson’s disease who died three weeks after receiving his third COVID-19 vaccination in January 2022. The patient was first vaccinated in May 2021 with the ChAdOx1 nCov- 19 vector vaccine, followed by two more doses with the BNT162b2 mRNA vaccine in July and December 2021. The family of the deceased requested an autopsy due to the ambivalent clinical features noted before death. The underlying illness (Parkinson’s disease) was confirmed by autopsy. However, no sign of a florid COVID-19 was discovered. Meanwhile, the immunohistochemical staining of the brain and heart revealed previously undiagnosed conditions. The brain, in distinctive, revealed multifocal necrotizing encephalitis with massive inflammatory lymphocyte infiltrates. In addition, the heart showed signs of serious myocarditis. Finally, immunohistochemical staining revealed that the SARS-CoV-2 spike protein was evident in the tissues investigated. Based on these immunohistochemical findings, it appears that the inflammatory changes in the patient's brain tissues are most likely the result of immunological processes. Concurrently, the absence of SARS-CoV-2 nucleocapsid-protein was evidenced, indicating that the detected spike-protein is unrelated to a SARS-CoV-2 infection. If such an infection was the cause of the spike protein, the SARS-CoV-2 nucleocapsid protein would also be detectable. As a consequence, the confirmed presence of the spike protein had to be attributed to the previous vaccination with the BNT162b2 mRNA vaccine that the deceased patient had received.

While the importance of continuous monitoring of electrocardiographic (ECG) or photoplethysmographic (PPG) signals to detect cardiac anomalies is generally accepted in preventative medicine, there remain major barriers to its actual widespread adoption. Most notably, current approaches tend to lack real-time capability, exhibit high computational cost, and be based on restrictive modeling assumptions or require large amounts of training data. We propose a lightweight and model-free approach for the online detection of cardiac anomalies such as ectopic beats in ECG or PPG signals based on the change detection capabilities of Singular Spectrum Analysis (SSA) and nonparametric rank-based cumulative sum (CUSUM) control charts. The procedure is able to quickly detect anomalies without requiring the identification of fiducial points such as R-peaks and is computationally significantly less demanding than previously proposed SSA-based approaches. Therefore, the proposed procedure is equally well suited for standalone use and as an add-on to complement existing (e.g. heart rate (HR) estimation) procedures.

An immune-inflammatory response is accompanied by increased nitro-oxidative stress. The aims of this mechanistic review are to review: a) the role of redox sensitive transcription factors and enzymes, ROS/RNS production and the activity of cellular antioxidants on the activation and performance of macrophages, dendritic cells, neutrophils, T cells, B cells and natural killer cells; b) the involvement of high-density lipoprotein (HDL), apolipoprotein (Apo)A1, paraoxonase (PON)-1, and oxidized phospholipids in the regulation of the immune response; and c) the detrimental effects of hypernitrosylation and chronic nitro-oxidative stress on the immune response. The redox changes during immune-inflammatory responses are orchestrated by the actions of nuclear factor (NF)-κB, HIF1alpha, the mechanistic target of rapamycin (mTor), the phosphatidylinositol 3‑kinase (PI3K) / protein kinase B (AKT) signalling pathway, mitogen-activated protein (MAP) kinases, 5' AMP-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor (PPAR). The performance and survival of individual immune cells is under redox control and sensitive to intracellular and extracellular levels of ROS/RNS and is heavily influenced by cellular anti-oxidants including the glutathione and thioredoxin systems, nuclear factor erythroid 2-related factor 2 (Nrf-2), and the HDL complex. Chronic nitro-oxidative stress and hypernitrosylation inhibit the activity of those antioxidant systems, the tricarboxylic acid cycle, mitochondrial functions, and the metabolism of immune cells. In conclusion, those redox-associated mechanisms modulate metabolic reprogramming of immune cells, macrophage and T helper cell polarization, phagocytosis, production of pro- versus anti-inflammatory cytokines, immune training and tolerance, chemotaxis, pathogen sensing, antiviral and antibacterial effects, Toll-like receptor activity, and endotoxin tolerance.

This study aims to systematically review and meta-analyze the nitro-oxidative stress (O&NS)/antioxidant (ANTIOX) ratio in the peripheral blood of people with mild cognitive impairment (MCI). We searched PubMed, Scopus, Google Scholar, and Web of Science for articles published from inception until July 31, 2021. Forty-six studies on 3.798 MCI individuals and 6.063 healthy controls were included. The O&NS/ANTIOX ratio was significantly higher in MCI than in controls with a Standardized Mean Difference (SMD)=0.378 (95% CI: 0.250; 0.506). MCI individuals showed increased lipid peroxidation (SMD=0.774, 95%CI: 4.416; 1.132) and O&NS-associated toxicity (SMD=0.621, CI: 0.377; 0.865) and reduced glutathione (GSH) defenses (SMD=0.725, 95%CI: 0.269; 1.182) as compared with controls. MCI was also accompanied by significantly increased homocysteine (SMD=0.320, CI: 0.059; 0.581), but not protein oxidation, and lowered non-vitamin (SMD=0.347, CI: 0.168; 0.527) and vitamin (SMD=0.564, CI: 0.129; 0.999) antioxidant defenses. The results show that MCI is at least in part due to increased neuro-oxidative toxicity and suggest that treatments targeting lipid peroxidation and the GSH system may be used to treat or prevent MCI.

Modern concepts in irreversible thermodynamics are applied to system transformation and degradation analyses. Phenomenological entropy generation (PEG) theorem is combined with the Degradation-Entropy Generation (DEG) theorem for instantaneous multi-disciplinary, multi-scale, multi-component system characterization. A Transformation-Phenomenological Entropy Generation (TPEG) theorem and space materialize with system and process defining elements and dimensions. The near-100% accurate, consistent results and features in recent publications demonstrating and applying the new TPEG methods to frictional wear, grease aging, electrochemical power systems cycling—including lithium-ion battery thermal runaway—metal fatigue loading and pump flow, are collated herein, demonstrating the practicality of the new and universal PEG theorem, and the predictive power of models that combine and utilize the PEG and DEG theorems. The methodology is useful for design, analysis, prognostics, diagnostics, maintenance and optimization.

A deterministic compartment model for the transmission dynamics of onchocerciasis with nonlinear incidence functions in two interacting populations is studied. The model is quantitatively analyzed to investigate it's local asymptotic behavior with respect to disease-free and endemic equilibria. It is shown, using Routh-Hurwitz criteria, that the disease-free equilibrium is locally asymptotically stable when the basic reproduction number is less than the unity. When the reproduction number is greater than the unity, we prove the existence of a locally asymptotically stable endemic equilibrium. Furthermore, bifurcation analysis was done by investigating the possibility of the co-existence of the equilibria of the model at R0<0 but near R0=0 by Center Manifold Theory.

This is a case study of a 55-year-old patient who died four months after receiving the mRNA-vaccine BNT162b2 (Pfizer-BioNTech) against COVID-19 as a second dose, following an initial vaccination with the ChAdOx1 nCov-19 vector vaccine (AstraZeneca) two months earlier. The autopsy diagnosis revealed general atherosclerosis. The histopathologic analyses of cardiac tissue demonstrated the presence of a thrombus occluding the right coronary artery (RCA) without evidence of plaque rupture. As a substitute trigger of clotting, the RCA presented with characteristics of acute lymphocytic vasculitis that extended to vasa vasorum in the adventitia and vessels in adjacent adipose tissue. Microthrombi were occasionally detected in these small vessels. It was obvious that lymphocytic myocarditis had been a chronic ongoing process temporally distinct from acute myocardial infarction. The myocardium contained patchworks of fibrotic areas alongside foci of displaying acute inflammation and fresh myocyte damage. SARS-CoV-2 Spike protein, but not nucleocapsid protein was sporadically detected in vessel walls by immunohistochemical assay. The cause of death was determined to be acute myocardial infarction and lymphocytic myocarditis. These findings indicate that myocarditis, as well as thrombo-embolic events following injection of spike-inducing gene-based vaccines, are causally associated with a injurious immunological response to the encoded agent. Because of the fact that the immune response to a first gene-based vaccination is very low in comparison with the immune response to the second vaccination, the found adverse events has rather to be attributed to the mRNA-based second vaccination as to the initial vector-based one.

Thin supported inorganic mesoporous membranes are used for removal of salts, small molecules (PFAS, dyes, polyanions) and particulate species (oil droplets) from aqueous sources with high flux and selectivity. Nano-filtration membranes can reject simple salts with 80-100% selectivity through a space charge mechanism. Rejection by size selectivity can be near 100% since the membranes can have a very narrow size distribution. Mesoporous membranes have received par-ticular interest due to their (potential) stability at operational conditions and defouling operations. More recently membranes with extreme stability became interesting with the advent of in-situ fouling mitigation by means of ultrasound, emitted from within the membrane structure. For this reason we explored the stability of available and new membranes with accelerated lifetime tests in aqueous solutions at various temperatures and pH values. Of the available ceria, titania, mag-netite membranes none were actually stable at all test conditions. In earlier work, it was already established that meso-porous alumina membranes have very poor stability. A new nano-filtration membrane was made of cubic zirconia membranes that exhibited a near perfect stability. A new ultra-filtration membrane was made of amorphous silica that was fully stable in ultrapure water at 80°C. This work provides details of membrane synthesis, stability characterization and actual sta-bility data.

Blood-derived products (BP) like citrate-platelet-rich plasma (CPRP) or hyperacute serum (HAS) are known to contain many growth factors. Combined mitogenic and DNA damaging stimuli might lead to increased senescent cell burden and altered senescence-associated secretory pheno-type (SASP). Therefore, the senescent state was extensively tested by γH2AX staining, p21 Q-PCR and western blot, growth curves and senescence associated ß-galactosidase staining. Two main treatments with BP were performed early (immediately after etoposide) and late (after addition-al 11days). Effects of the BP treatment was evaluated by IL-6 and IL-8 measurement as well as collagen (COL1) and p21 mRNA expression. Additionally, XTT assays, cell size measurements, viability assays, and cell number calculations were performed. HAS treated cells in early treat-ment had the lowest observed IL-6 and IL-8. In contrast, there was a clear inflammatory response for IL-8 on HAS and CPRP treated cells in late treatment. For COL1 expression an upregulation in early treatment could be shown, meanwhile cells in the late treatment group remained unaf-fected. In CPRP treated cells, the COL1 expression decreased. All in all, BP treatment seems to have slightly positive effects regarding skin rejuvenation.

Lipophilic oligonucleotide derivatives are a potent approach to the intracellular delivery of nucleic acids. The binding of these derivatives to serum albumin is a major determinant of their fate in the body, as its structure contains several sites of high affinity for hydrophobic compounds. This study focuses on the features of self-association and non-covalent interactions with human serum albumin of novel self-penetrating oligonucleotide derivatives. The study revealed that the introduction of a triazinyl phosphoramidate modification bearing two dodecyl groups at the 3' end region of the oligonucleotide sequence has a negligible effect on its affinity for the complementary sequence. Dynamic light scattering verified that the amphiphilic oligonucleotides under study can self-assemble into micelle-like particles ranging from 8 to 15 nm in size. The oligonucleotides with dodecyl groups form stable complexes with human serum albumin with a dissociation constant of approximately 10-6 M. The oligonucleotide micelles are simultaneously destroyed upon binding to albumin. Using an electrophoretic mobility shift assay and affinity modification, we examined the ability of DNA duplexes containing triazinyl phosphoramidate oligonucleotides to interact with Ku antigen and PARP1, as well as the mutual influence of PARP1 and albumin or Ku antigen and albumin upon interaction with DNA duplexes. These findings, together with the capability of dodecyl-containing derivatives to effectively penetrate different cells, such as HEK293 and T98G, indicate that the oligonucleotides under study can be considered as a platform for the development of therapeutic preparations with a target effect.

Most patients with classic Hodgkin lymphoma (cHL) are cured with combination chemotherapy, but approximately 10-20% will relapse and another 5-10% will have primary refractory disease. The treatment landscape of relapsed/refractory (R/R) cHL has evolved significantly over the past decade following the approval of brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate, and the PD-1 inhibitors, nivolumab and pembrolizumab. These agents have significantly expanded options for salvage therapy prior to autologous hematopoietic cell transplantation (AHCT), post-transplant maintenance, and treatment of relapse after AHCT, which have led to improved survival in the modern era. In this review, we highlight our approach to management of R/R cHL in 2023 with a focus on choosing first salvage therapy, post-transplant maintenance, and treatment of relapse after AHCT. We also discuss management of older adults and transplant-ineligible patients who require a separate approach. Finally, we review novel immunotherapy approaches in clinical trials, including combinations of PD-1 inhibitors with other immune-activating agents as well as novel antibody-drug conjugates, bispecific antibodies, and cellular immunotherapies. Ongoing studies assessing biomarkers of response to immunotherapy and dynamic biomarkers such as circulating tumor DNA may further inform treatment decisions and enable a more personalized approach in the future.

Diabetic foot ulcers (DFUs) significantly affect the lives of patients and increase the risk of hospital stay and amputation. We suggest a remote-monitoring platform for better DFU care. This system uses digital health metrics (scaled from 0 to 10, where higher scores indicate a greater risk of slow healing) to provide a comprehensive overview through a visual interface. The platform features smart offloading devices that capture behavioral metrics such as offloading adherence, daily steps, and cadence. Coupled with remotely measurable frailty and phenotypic metrics, it offers an in-depth patient profile. Additional demographic data, wound characteristics, and clinical parameters, such as cognitive function, were integrated, contributing to a comprehensive risk factor profile. We evaluated the feasibility of this platform with 124 DFU patients over 12 weeks; 39% experienced unfavorable outcomes such as dropout, adverse events, or non-healing. Digital biomarkers were benchmarked (0-10), categorized into low, medium, and high risk for unfavorable outcomes, and visually represented using color-coded radar plots. The initial results of case reports illustrate the value of this holistic visualization to pinpoint the underlying risk factors for unfavorable outcomes, including a high number of steps, poor adherence, and cognitive impairment. Although future studies are needed to validate the effectiveness of this visualization in personalizing care and improving wound outcomes, early results in identifying risk factors for unfavorable outcomes are promising.

As common industrial by-products, airborne engineered nanomaterials are considered important environmental toxicants to monitor due to their potential health risks to humans and animals. The main uptake routes of airborne nanoparticles are nasal and/or oral inhalation, which are known to enable the transfer of nanomaterials into the blood stream resulting in rapid distribution in the body. Consequently, mucosal barriers present in nose, buccal and lung have been identified and intensively studied as the key tissue barrier to nanoparticle translocation. Despite decades of research, surprisingly little is known about the differences among various mucosa tissue types to tolerate nanoparticle exposures. One limitation in comparing nanotoxicological data sets can be linked to a lack of harmonization and standardization of cell-based assays, where a) different cultivation conditions such as air-liquid interface or submerged cultures, b) varying barrier maturity and c) diverse media substitutes have been used. The current comparative nanotoxicological study therefore aims at analyzing the toxic effects of nanomaterials on four human mucosa barrier models including nasal (RPMI2650), buccal (TR146), alveolar (A549), and bronchial (Calu-3) mucosal cell lines to better understand the modulating effects of tissue maturity, cultivation conditions and tissue type using standard Transwell cultivations at liquid-liquid and air-liquid interfaces. Overall, cell size, confluency, tight junction localization, and cell viability as well as barrier formation using 50% and 100% confluency was monitored using trans-epithelial-electrical resistance (TEER) measurements and Presto Blue assays of immature (e.g. 5 days) and mature (e.g. 22 days) cultures in the presence and absence of corticosteroids such as hydrocortisone. Results of our study show that cellular responses to increasing nanoparticle exposures are highly cell type specific, where bronchial mucosal cell barriers models cultivated under ALI conditions showed less tolerance to acute ZnO nanoparticle exposures. Additionally, stronger toxicities are found using early mucosa barriers compared to later barrier models being maturated under air-liquid cultivation conditions.

The mechanistic influences of dopamine (DA) signaling and impact on motor function is nearly always interpreted from changes in nigrostriatal neuron terminals in striatum. This is a standard practice in studies of human Parkinson’s disease (PD) and aging, and related animal models of PD and aging-related parkinsonism. However, despite dozens of studies indicating an ambiguous relationship between changes in striatal DA signaling and motor phenotype, this perseverating focus on striatum continues. Although DA release in substantia nigra (SN) was first reported almost 50 years ago. assessment of nigral DA signaling changes in relation to motor function is rarely considered. Whereas DA signaling has been well-characterized in striatum at all 5 steps of neurotransmission (biosynthesis and turnover, storage, release, reuptake, and post-synaptic binding) in the nigrostriatal pathway, the depth of such interrogations in the SN, outside of cell counts, is sparse. However, there is sufficient evidence that these steps in DA neurotransmission in the SN are operational and regulated autonomously from striatum, and are present in human PD and aging, and related animal models. To complete our understanding of how nigrostriatal DA signaling affects motor function, it is past time to include interrogation of nigral DA signaling. This brief review highlights evidence that changes in nigral DA signaling at each step in DA neurotransmission are autonomous from those in striatum and changes in the SN alone can influence locomotor function. Accordingly, for full characterization of how nigrostriatal DA signaling affects locomotor activity, interrogation of DA signaling in SN is essential.

The instability of traveling pulses in nonlinear diffusion problems is inspected on the example of Gunn domains in semiconductors. Mathematically the problem is reduced to the calculation of the "energy" of the ground state in Schrödinger equation with a complicated potential. A general method to obtain the bottom-part spectrum of such equations based on the approximation of the potential by square wells is proposed and applied. Possible generalization of the approach to other types of nonlinear diffusion equations is discussed.

We synthesized iron(II)-triazole spin crossover compounds of the type [Fe(atrz)3]X2 and incorporated and deposited them on electrospun polymer nanofibers. In view of possible applications, we chose iron(II)-triazole-complexes that are known to exhibit spin crossover close to ambient temperature. Therefore we used the complexes [Fe(atrz)3]Cl2 and [Fe(atrz)3](2ns)2 (2ns = 2Naphthalenesulfonate) and analyzed them with IR-, UV/Vis and Mossbauer spectroscopy and with a SQUID magnetometer. The synthesized complexes were then in one attempt deposited on fibers of polymethylmethacrylate (PMMA) and in another attempt incorporated into core-shell like PMMA fiber structures. This was done via two different electrospinning methods. Deposition was performed by uniaxial electrospinning and incorporation was performed by coaxial electrospinning. The obtained polymer-complex-composites were then further investitgated by the same methods as the pure complexes as well as by SEM pictures and EDX measurements. The analysis by UV/Vis spectroscopy, Mössbauer spectroscopy and temperature-depended magnetic measurements with the SQUID magnetometer showed that the spin crossover properties were maintained and were not changed after the electrospinning processes and that the complexes were not harmed during the procedure.

The energy loss of photons due to the cosmological red shift is interpreted, here, as a periodical process of transferring electromagnetic field energy into the space. The transferred energy portions are independent on photon energy if this transfer occurs with their frequency. The amounts of periodically released energy are so small that the related ultra-long wave length photons have to be understood as perfectly delocalized. Thus, the described point of view bridges the quantum micro cosmos with the macro cosmos. It is proposed to regard this energy exchange as a typical property of universal time arrow and to interpret the “large numbers”, in particular the dimensionless reciprocal of product of Hubbles constant and Planck time as the fundamental parameter describing cosmic evolution.

The method of doublet frequency distance (DFD-) maps was applied, here, for visualization of DNA sequence structures of yeast chromosomes. The colour scale “rainbow” of the Octave programming tool is well suited for such visualization. The DFD-maps are generated by comparison of the differences in the number of all base doublets in a shifting frame with all other positions of this frame in a regarded DNA sequence section. This procedure can be applied from DNA-sections of between a few hundred bases (bps) up to a complete chromosome with a million or more bps. An orthogonal DFD-map pattern dominates all chromosomes and its parts. It can be interpreted by a large number of successive mutation events during evolution. In contrast, diagonal patterns indicate duplications of sequence sections and multiple tandem repeats. These periodic structures are found in several chromosomes and are more or less regular or noised. The larger tandem repeat in the subtelomeric region of chromosome 12 presents a characteristic example of a nested multiple-repeat structure. Its pattern in the DFD-map illustrates obviously a temporal order of duplication and mutation events leading to a hierarchical sequence architecture.

Object. Utilization of pedicle screws (PS) for spine stabilization is common in spinal surgery. With reliance on visual inspection of anatomical landmarks prior to screw placement, the free-hand technique requires a high level of surgeon skill and precision. Three-dimensional (3D) computer-assisted virtual neuronavigation improves the precision of PS placement and minimize steps. Methods. Twenty-three patients with degenerative, traumatic, or neoplastic pathologies received treatment via a novel three-step PS technique that utilizes a navigated power driver in combination with virtual screw technology. 1) Following visualization of neuroanatomy using intraoperative CT, a navigated 3-mm match stick drill bit was inserted at anatomical entry point with screen projection showing virtual screw. 2) Navigated Stryker Cordless Driver with appropriate tap was used to access vertebral body through pedicle with screen projection again showing virtual screw. 3) Navigated Stryker Cordless Driver with actual screw was used with screen projection showing the same virtual screw. One hundred and forty-four consecutive screws were inserted using this three-step, navigated driver, virtual screw technique. Results. Only 1 screw needed intraoperative revision after insertion using the three-step, navigated driver, virtual PS technique. This amounts to a 0.69% revision rate. One hundred percent of patients had intraoperative CT reconstructed images to confirm hardware placement. Conclusions. Pedicle screw placement utilizing the Stryker-Ziehm neuronavigation virtual screw technology with a three step, navigated power drill technique is safe and effective.

New technologies have resulted in a better understanding of blood and lymphatic vascular heterogeneity at the cellular and molecular levels. Meanwhile, we still need to learn more about the heterogeneity of the cardiovascular and lymphatic systems between different species at the anatomical and functional levels. Even the deceptively simple question of the functions of fish lymphatic vessels has yet to be conclusively answered. The most common interpretation assumes a similar dual setup of the vasculature in zebrafish and mammals: on the one hand, there is the cardiovascular, circulatory system, and on the other hand, the lymphatic vascular system, in which the unidirectional flow is derived from surplus interstitial fluid and returned into the cardiovascular system. A competing interpretation questions the identity of the lymphatic vessels in fish as at least some of them receive their flow from arteries via specialised anastomoses, neither requiring an interstitial source for the lymphatic flow nor stipulating unidirectionality. In this alternative view, the “fish lymphatics” are a specialised subcompartment of the cardiovascular system, called the “secondary vascular system” (SVS). Many of the contradictions found in the literature appear to stem from the fact that the SVS develops in part or its entirety from an embryonic lymphatic vascular system by transdifferentiation. Future research needs to establish the extent of embryonic transdifferentiation of lymphatics into SVS blood vessels. Similarly, more insight is needed into the molecular regulation of vascular development in fish. Most fish do feature more than the five VEGF genes and three VEGF receptor genes that we know from mice or humans, and the relative tolerance of fish to whole genome and gene duplications could underlie the evolutionary diversification of the vasculature. This review discusses the key elements of the fish lymphatics versus the SVS and attempts to draw a picture coherent with the existing data, including the phylogenetic knowledge.

(1) Background: This work aimed to conduct the first comparative study providing long-term data about patient reported outcome measures as well as donor-site scar assessment and aesthetic evaluation of the reconstructed breasts in patients with DIEP versus PAP flap breast reconstruction. (2) Methods: This prospective, single-center, matched cohort study included a total of 36 patients after DIEP and PAP flap breast reconstruction. Evaluation was done using the Breast-Q and POSAS questionnaire as well as the Breast Aesthetic Scale for cosmetic analysis by four plastic surgeons. (3) Results: Post-operative Breast-Q evaluation revealed no significant differences between both patient groups for the categories physical well-being donor-site, physical well-being breast and satisfaction with the breast. Scar evaluation of the donor-site region showed equivalent results for the thigh and the abdomen concerning the overall opinion of patients and observers. There was no significant difference between both methods of reconstruction for all aspects of breast aesthetics. (4) Conclusions: Similar results of donor-site morbidity, scar quality and aesthetic outcome of the breast in both the DIEP and PAP patient group have been demonstrated. Hence, in cases suitable for both types of reconstruction, the decision can be based on factors such as patients’ lifestyle, leisure activities and preferences.

Prokaryotic genomes are dynamic tapestries that are strongly influenced by mobile genetic elements (MGEs), including transposons (Tn’s), plasmids, and bacteriophages. Of these, miniature inverted-repeat transposable elements (MITEs) are undoubtedly the least studied MGEs in bacteria and archaea. This review explores the diversity and distribution of MITEs in prokaryotes and describes what is known about their functional roles in the host and involvement in genomic plasticity and evolution.

Silver eel were sampled in 1981 and 1983 in River Brede, Denmark, with outlet to the North Sea. Yellow eel in River Køge-Lellinge, Denmark, with outlet to the Baltic Sea were sampled 1965-1968. Silver eel were aged by burning the otoliths. Silver male ages varied from 4 to 25 years, lengths 30.8 to 45.3 cm, and female silver eel varied from 7 to 25 years, lengths 42.3 to 77.3 cm. von Bertalanffy trajectories of length-at-age of male and female yellow eel were calculated in both rivers. Younger yellow eel had significantly higher annual growth rate compared to older age groups, and females grew significantly faster than males. Two models for natural mortality M were used to estimate number of glass eel needed to produce number of silver eel for each sex and silver age group. Annual silver eel production from River Brede Å was 49.2 kg ha-1, demanding 2,894 glass eel ha-1 and in River Køge-Lellinge, the silver eel production was 48.5 kg ha-1, demanding 5,570 glass eel ha-1. It was calculated that one (0.29 g) thousand glass eel contribute to 8.8 kg silver eel in River Køge-Lellinge, and 17.0 kg silver eel in River Brede. To fulfill the Danish EMP in rivers requires annual stocking of 33 tons or 9.4 million reared on-grown eel (3.5 g) to compensate for 183 tons lost silver eel.

Friction stir processing (FSP), a severe plastic deformation process, was applied on commercially pure Ti to obtain an improved microstructure. The process yielded a refined microstructure and higher mechanical properties at room temperature (RT). Yet the microstructure was found to contain bright bands demonstrating high hardness values of about 500 HV. High resolution scanning electron microscopy (HRSEM) as well as electron back scattering diffraction (EBSD) analysis indicated that these bands were composed of extra-fine equiaxed α-Ti grains with an average radius of 1-2 microns. In addition, a retained β-phase was detected at the boundaries of these α-Ti grains, together with a small quantity of separate β grains. The results of a fractography study conducted on broken tensile specimens showed that the FSP’ed material was free of defects and that the fracture started at these bands. It is proposed that these bright bands are due to excessive deformation occurring during the processing stage, leading to an accelerated dynamic recrystallization (DRX) process. In turn, these heavy deformation regions act as a strengthening constituent, making the material superior to the parent material as far as its mechanical RT properties are concerned. Consequently, this means that FSP of CP-Ti has the potential to serve as an industrial means of improving the mechanical properties of the material.

The ongoing challenge to ensure a sustainable and affordable energy supply forces industrial companies to implement appropriate measures. These measures typically lead to an increased system complexity, which has to be addressed during operation. Whereas existing approaches from the field of supervisory and optimal control appear to be capable of mastering this issue, these are still not adopted in industry. Therefore, this work presents a procedure model for the systematic development of application-oriented operating strategies for industrial energy supply systems. The procedure model combines research approaches from the fields of sequencing control and approximate MPC to extract rule-based operating strategies. By splitting the procedure model into five phases, expert knowledge can be integrated in a target-oriented manner. Subsequently to the description, the procedure model is exemplary applied to the example of an industrial heating supply system. Throughout an optimization study, the developed operating strategy is compared to a MPC strategy as well as a baseline strategy. Whereas the conventional MPC approach is the upper bound with regard to optimality, the developed operating strategy is able to generate comparable results. Compared to the baseline strategy, a relative reduction in operating expenses of 5.4 % to 37.0 % are achieved in this specific use case.

Hypertrophic Cardiomyopathy (HCM) is a common inherited disorder characterized by unexplained left ventricular hypertrophy, with or without left ventricular outflow tract (LVOT) obstruction. Single nuclei RNA-sequencing (snRNA-seq) of both obstructive and nonobstructive HCM patient samples have revealed alterations in communication between various cell types but a direct and integrated comparison between the two HCM phenotypes has not been reported. We performed a bioinformatic analysis of HCM snRNA-seq datasets from obstructive and nonobstructive patient samples to identify differentially expressed genes and distinctive patterns of intercellular communication. Differential gene expression analysis revealed 37 differentially expressed genes, predominantly in cardiomyocytes but also in other cell types, relevant to aging, muscle contraction, cell motility and the extracellular matrix. Intercellular communication was generally reduced in HCM, affecting the extracellular matrix, growth factor binding, integrin binding, PDGF binding and SMAD binding, but with increases in adenylate cyclase binding, calcium channel inhibitor activity, and serine-threonine kinase activity in nonobstructive HCM. Increases in neuron to leukocyte and dendritic cell communication, in fibroblast to leukocyte and dendritic cell communication and in endothelial cell communication to other cell types, largely through changes in expression of integrin-b1 and its cognate ligands, were also noted. These findings indicate both common and distinct physiological mechanisms affecting the pathogenesis of obstructive and nonobstructive HCM and provide opportunities for personalized management of different HCM phenotypes.

Specific proteolytic cleavages turn on, modify, or turn off the activity of vascular endothelial growth factors (VEGFs). Proteolysis is most prominent among the lymph­angiogenic VEGF-C and VEGF-D, which are synthesized as precursors that need to undergo enzymatic removal of their C- and N-terminal propeptides before they can activate their receptors. The activating cleavage of VEGF-C is mediated by at least five different proteases: plasmin, ADAMTS3, prostate-specific antigen, cathepsin D, and thrombin. All of these proteases except for ADAMTS3 can also activate VEGF-D. Processing by different proteases results in distinct forms of the "mature" growth factors, which differ in affinity and receptor activation potential. The “default” VEGF-C-activating enzyme ADAMTS3 does not activate VEGF-D and therefore, VEGF-C and VEGF-D do function in different contexts. VEGF-C itself is also regulated in different contexts by different proteases. During embryonic development, ADAMTS3 activates VEGF-C. In contrast, thrombin and plasmin likely activate VEGF-C/-D during tissue injury-induced lymphangiogenesis, and PSA and cathepsin D perhaps during tumor-associated pathological lymphangio­genesis. Additionally, cathepsin D from saliva might activate latent VEGF-C/-D upon wound licking, thereby accelerating healing. Similar to tyrosine kinase receptors and VEGFs themselves, these activating proteases could be targeted to modulate angiogenesis and lymphangiogenesis in relevant diseases.

Alzheimer's disease (AD) has been the subject of extensive investigation as to its biological underpinnings. However, this has produced little of therapeutic benefit or indeed provided any accepted biomarkers that could tailor treatment. This chapter reviews data on the main pathophysiologic processes that have been widely shown to be altered in AD, including circadian dysregulation, mitochondrial dysfunction, gut dysbiosis, and immune-glia-platelet activation. It is proposed that alterations in the gut microbiome, including gut dysbiosis and increased gut permeability drive changes in mitochondrial function that are intimately associated with significant variations in sirtuin expression. Both mitochondria-located and nucleus/cytoplasm located sirtuins can act on mitochondrial function in different cells and body systems to co-ordinate the ageing-associated changes that underpin AD. The sirtuins are therefore key aspect to a developmental model of AD that is more 'holistic' in perspective, thereby providing a framework for the detection of earlier biomarkers and more successful treatment for the heterogenous nature of AD pathoetiology.

The dynamic equilibrium of iron homeostasis has an important role in sustaining metabolic and neurological functions during human life. Iron excretion is modest and unregulated hence this overall equilibrium is tightly regulated in normal conditions by increasing deficient or limiting excessive iron assimilation. Here we focus on neural tissue overload, dyshomeostasis that is preceded by excessive assimilation, disturbances in internal homeostasis or both. Normal steps in iron homeostasis include its uptake across the apical membrane of the enterocytes in a mildly acidic duodenal milieu by the major importer of ferrous iron, Divalent Metal Transporter 1 (DMT1) (Nramp2/DCT1/SLC11A2, solute carrier family 11 member 2) [1, 2], responsible for the uptake of Non-Transferrin Bound Iron (NTBI) and divalent metals [3], passage through enterocytes bound to a chaperone and crossing the basal membrane via the only known cellular ferrous iron exporter, ferroportin [4] with the iron bound to transferrin (Tf) as it exits. Cells in peripheral tissues largely utilize circulating iron after uptake by receptor-mediated endocytosis of Tf-bound Iron [5]. Derangement of duodenal NTBI absorption of iron and heavy metals is influenced by systemic iron metabolism associated with inflammation that leads to iron accumulation into peripheral tissues and potential development of neurodegenerative diseases, involving distribution and fine regulation of DMT1 also in the central nervous system, where inflammatory-related acidosis influences DMT1 uptake, via its action as a proton cotransporter. Pharmacological strategies to inhibit NTBI transport selectively will be illustrated in relationship to protection, particularly neuroprotection, against iron overload associated with acidosis, inflammation, neuroinflammation and subsequent neurodegeneration.

Cancers arise from the accumulation of somatic genome mutations, with varying contributions of intrinsic (i.e. genetic predisposition) and extrinsic (i.e. environmental) factors. For the understanding of malignant clones, precise information about their genomic composition has to be correlated with morphological, clinical and individual features, in the context of the available medical knowledge. Rapid improvements in molecular profiling techniques, the accumulation of large amount of data in genomic alterations in human malignancies and the expansion of bioinformatic tools and methodologies have facilitated the understanding of the molecular changes during oncogenesis, and their correlation with clinico-pathological phenotypes. Far beyond a limited set of "driver" genes, oncogenomic profiling has identified a large variety of somatic mutations; and whole genome sequencing studies of healthy individuals have improved the knowledge of heritable genome variation. Nevertheless, main challenges arise from the skewed representation of individuals from varying population backgrounds in biomedical studies, and also through the limited extend in which some cancer entities are represented in the scientific literature. Content analyses of oncogenomic publications could provide guidance for the planning and support of future studies aiming at filling prominent knowledge gaps.

The increasing popularity of porphyrins and hydroporphyrins for application in a variety of biomedical (photodynamic therapy, fluorescence tagging and imaging, photoacoustic imaging) and technical (chemosensing, catalysis, light harvesting) applications is also associated with the growing number of methodologies that enable their solubilization in aqueous media. Natively, the vast majority of synthetic porphyrinic compounds are not water-soluble. Moreover, any water-solubility imposes several restrictions on the synthetic chemist on when to install solubilizing groups in the synthetic sequence, and how to isolate and purify these compounds. This review summarizes the chemical modifications to render synthetic porphyrins water-soluble, with a focus on the work since 2000. Where available, practical data such as solubility, indicators for the degree of aggregation, and special notes for the practicioner are listed. We hope that this review will guide synthetic chemists through the many strategies known to make porphyrins and hydroporphyrins water soluble.