(−)-N-Phenethyl analogs of optically pure N-norhydromorphone were synthesized and pharmacologically evaluated in several in vitro assays (opioid receptor binding, stimulation of [³⁵S]GTPγS binding, forskolin-induced cAMP accumulation assay, and MOR-mediated β-arrestin recruitment assays). “Body” and “tail” interactions with opioid receptors (a subset of Portoghese’s message-address theory) were used for molecular modeling and simulations, where the “address” can be considered the “body” of the hydromorphone molecule and the “message” delivered by the substituent (tail) on the aromatic ring of the N-phenethyl moiety. One compound, N-p-chloro-phenethynorhydromorphone ((7aR,12bS)-3-(4-chlorophenethyl)-9-hydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one, 2i), was found to have nanomolar binding affinity at MOR and DOR. It was a potent partial agonist at MOR and a full potent agonist at DOR with a δ/μ potency ratio of 1.2 in the ([³⁵S]GTPγS) assay. Bifunctional opioids that interact with MOR and DOR, the latter as agonists or antagonists, have been reported to have fewer side-effects than MOR agonists. The p-chlorophenethyl compound 2i was evaluated for its effect on respiration in both mice and squirrel monkeys. Compound 2i did not depress respiration (using normal air) in mice or squirrel monkeys. However, under conditions of hypercapnia (using air mixed with 5% CO₂), respiration was depressed in squirrel monkeys. Full article

As a result of asymmetry in practical problems, the Lognormal distribution is more suitable for data modeling in biological and economic fields than the normal distribution, while biases of maximum likelihood estimators are regular of the order $O\left(n^{-1}\right)$ , especially in small samples. It is of necessity to derive logical expressions for the biases of the first-order and nearly consistent estimators by bias correction techniques. Two methods are adopted in this article. One is the Cox-Snell method. The other is the resampling method known as parametric Bootstrap. They can improve maximum likelihood estimators performance and correct biases of the Lognormal distribution parameters. Through Monte Carlo simulations, we obtain average root mean squared error and bias, which are two important indexes to compare the effect of different methods. The numerical results reveal that for small and medium-sized samples, the performance of analytical bias correction estimation is superior than bootstrap estimation and classical maximum likelihood estimation. Finally, an example is given based on the actual data. Full article

Recent studies point out that not only the daily intake of energy and nutrients but the time of day when they are ingested notably regulates lipid metabolism and cardiovascular risk (CVR). Therefore, the aim of the study was to assess if the type of fat ingested at breakfast can modify lipid metabolism in women with CVR. A randomized, crossover clinical trial was performed. Sixty volunteers were randomly assigned to a (A) polyunsaturated fatty acid (PUFA)-rich breakfast, (B) saturated fatty acid (SFA)-rich breakfast, or (C) monounsaturated fatty acid (MUFA)-rich breakfast. Plasma lipoprotein and apolipoprotein subfractions were determined. Our data showed that the PUFA-rich breakfast decreased lipoprotein (a) (Lp(a)), very low-density lipoproteins (VLDL), and intermediate-density lipoproteins (IDL), and increased high-density lipoproteins (HDL). A similar trend was observed for the MUFA-rich breakfast, whereas the SFA-rich breakfast, although it decreased VLDL, also increased IDL and reduced HDL. The PUFA-rich breakfast also decreased β-lipoproteins and apolipoprotein-B. In summary, varying the type of fat eaten at breakfast is enough to significantly modify the lipid metabolism of women with CVR, which can be of great relevance to establish new therapeutic strategies for the treatment of these subjects. Full article

Recent extreme rainfall events produced severe flooding across North Carolina’s Coastal Plain, revealing deep vulnerabilities in many communities. Climate change is expected to exacerbate these problems by further increasing rainfall intensity and the frequency of extreme rainfall events. Due to the risks posed by these changing rainfall patterns, a shift in the approach to infrastructure planning and management is needed for many floodprone communities, particularly in regard to managing streams and floodplains in urban areas. This study proposes a framework for systematically evaluating stream restoration in combination with engineered improvements to culvert and bridge crossings to identify and optimize options for mitigating extreme events in urban areas. To illustrate the methodology, extensive hydraulic modeling was conducted to test four different strategies for reducing flooding along a channelized and armored stream, Big Ditch, located in Goldsboro, North Carolina, USA. The results indicate that neither floodplain restoration nor infrastructure modification alone could alleviate flooding along Big Ditch. Rather, a combination approach would be required to mitigate flooding, which could result in substantial benefits for storms in excess of the 100-year event. The results suggest that shifting to a multi-faceted approach to improve resiliency to extreme events could improve public safety and reduce future damages due to flooding. Full article

The paper presents the Triads Geometric Consistency Index ( $T-GCI$ ), a measure for evaluating the inconsistency of the pairwise comparison matrices employed in the Analytic Hierarchy Process (AHP). Based on the Saaty’s definition of consistency for AHP, the new measure works directly with triads of the initial judgements, without having to previously calculate the priority vector, and therefore is valid for any prioritisation procedure used in AHP. The $T-GCI$ is an intuitive indicator defined as the average of the log quadratic deviations from the unit of the intensities of all the cycles of length three. Its value coincides with that of the Geometric Consistency Index ( $GCI$ ) and this allows the utilisation of the inconsistency thresholds as well as the properties of the $GCI$ when using the $T-GCI$ . In addition, the decision tools developed for the $GCI$ can be used when working with triads ( $T-GCI$ ), especially the procedure for improving the inconsistency and the consistency stability intervals of the judgements used in group decision making. The paper further includes a study of the computational complexity of both measures ( $T-GCI$ and $GCI$ ) which allows selecting the most appropriate expression, depending on the size of the matrix. Finally, it is proved that the generalisation of the proposed measure to cycles of any length coincides with the $T-GCI$ . It is not therefore necessary to consider cycles of length greater than three, as they are more complex to obtain and the calculation of their associated measure is more difficult. Full article

Observed social networks are often considered as proxies for underlying social networks. The analysis of observed networks oftentimes involves the identification of influential nodes via various centrality measures. This paper brings insights from research on adversarial attacks on machine learning systems to the domain of social networks by studying strategies by which an adversary can minimally perturb the observed network structure to achieve their target function of modifying the ranking of a target node according to centrality measures. This can represent the attempt of an adversary to boost or demote the degree to which others perceive individual nodes as influential or powerful. We study the impact of adversarial attacks on targets and victims, and identify metric-based security strategies to mitigate such attacks. We conduct a series of controlled experiments on synthetic network data to identify attacks that allow the adversary to achieve their objective with a single move. We then replicate the experiments with empirical network data. We run our experiments on common network topologies and use common centrality measures. We identify a small set of moves that result in the adversary achieving their objective. This set is smaller for decreasing centrality measures than for increasing them. For both synthetic and empirical networks, we observe that larger networks are less prone to adversarial attacks than smaller ones. Adversarial moves have a higher impact on cellular and small-world networks, while random and scale-free networks are harder to perturb. Also, empirical networks are harder to attack than synthetic networks. Using correlation analysis on our experimental results, we identify how combining measures with low correlation can aid in reducing the effectiveness of adversarial moves. Our results also advance the knowledge about the robustness of centrality measures to network perturbations. The notion of changing social network data to yield adversarial outcomes has practical implications, e.g., for information diffusion on social media, influence and power dynamics in social systems, and developing solutions to improving network security. Full article

Dietary diversity (DD) is a key component of a high-quality diet, providing the adequate nutrient requirements. However, the role of DD on prostate cancer (PCa) is still uncertain. The aim of this study was to evaluate the relationship between DD, adequate nutrient intake and PCa, according to the aggressiveness of the tumor. The CAPLIFE (CAP: prostate cancer; LIFE: lifestyles) study is a population-based case-control study including a total of 402 incident PCa cases and 302 controls. The DD score (DDS), adjusted by total energy intake, was collected through a validated food frequency questionnaire. Nutrient adequacy was defined according to European Dietary Recommendation Intake for men. The aggressiveness of PCa was determined according to the International Society of Urology Pathology classification. The association between DDS, nutrient intake and PCa was assessed by logistic regression models with adjustment for potential confounding factors. DDS was similar for PCa cases and controls, independent of PCa aggressiveness. According to each food group DDS, the protein group showed the highest mean score in all the subgroups analyzed. However, no differences were observed for each of the DDS components. The DDS, the variety of the group’s food intake, and the adequate nutrient intake, were not associated with PCa. Full article

This paper examines and updates the rank-size distribution of cities and municipalities in Bangladesh between 1990 and 2019 based on two criteria: (1) built-up urban areas; and (2) population. The distribution of built-up urban areas and population are compared to provide a robust theoretical underpinning of Zipf’s law for future urban developmental planning framework. The data on built-up urban areas is extracted from land cover classification using Google Earth Engine and the population data is obtained from the decennial censuses. The comparison of the conformity to Zipf’s law indicated contradictory results. While a greater proportion of the population has been increasingly concentrated in the smaller and midsized cities over the last three decades, built-up urban areas, on the other hand, have been mostly clustered in two largest cities— Dhaka and Chittagong—accounting for 50 to nearly 60 percent of the total built-up urban areas. These results shed light on the magnitude of continued spatial inequalities in urban development amongst cities and municipalities in Bangladesh despite there being an overall increase of evenness in the distribution of population over time. These results imply an unsustainable rate of urban expansion in Bangladesh and reinforce the need for the exploration of policies and regulations targeted at guiding the rate and direction of evenness in urban expansion. Full article

Pancreatic ductal adenocarcinoma (PDAC), accounting for 90% of all pancreatic tumors, is a highly devastating disease with poor prognosis and rising incidence. The lack of available specific diagnostics tests and the limited treatment opportunities contribute to this pejorative issue. Over the last 10 years, a growing interest pointing towards mesothelin (MSLN) as a promising PDAC-associated antigen has emerged. The limited expression of MSLN in normal tissues (peritoneum, pleura and pericardium) and its overexpression in 80 to 90% of PDAC make it an attractive candidate for therapeutic management of PDAC patients. Moreover, its role in malignant progression related to its involvement in tumor cell proliferation and resistance to chemotherapy has highlighted the relevance of its targeting. Hence, several clinical trials are investigating anti-MSLN efficacy in PDAC. In this review, we provide a general overview of the different roles sustained by MSLN during PDAC progression. Finally, we also summarize the different MSLN-targeted therapies that are currently tested in the clinic. Full article

(1) Background: Osteonecrosis (ON) of the femoral head is a disabling disease for which limited treatment options exist. Identifying therapeutic targets of its evolution could provide crucial insights into multi-targeted approaches. The aim of this pilot study was to assess the histopathological features of patients with non-traumatic femoral head (NTFH) and post-traumatic femoral head (PTFH) ON to produce a fresh vision for clinical use. (2) Methods: We got biopsies from patients with different ON stages, according to the ARCO system. Samples from multi-organ donors were used as controls. Histological and immunohistochemical evaluations were performed on the osteochondral unit. (3) Results: The PTFH group displayed several fibrotic reactions, a small stem cell pool and a lower international cartilage repair society (ICRS)-I score than NTFH, which instead presented intact cartilage similar to the controls. Immunostaining for collagen I and autotaxin confirmed these features in the PTFH group, which displayed top levels of MMP-13 involved in cartilage loss and reduced CB-2 in the underlying bone. Both groups manifested a similar pattern of apoptotic and pain mediators. (4) Conclusions: The different histopathological features suggest a multi-disciplinary and multi-targeted approach for ON. Further studies are necessary to measure the effect size to gain clinical evidence. Full article

The relevance of mannosyldiinositolphosphorylceramide [M(IP)₂C] synthesis, the terminal complex sphingolipid class in the yeast Saccharomyces cerevisiae, for the lateral organization of the plasma membrane, and in particular for sphingolipid-enriched gel-like domains, was investigated by fluorescence spectroscopy and microscopy. We also addressed how changing the complex sphingolipid profile in the plasma membrane could influence the membrane compartments (MC) containing either the arginine/ H⁺ symporter Can1p (MCC) or the proton ATPase Pma1p (MCP). To achieve these goals, wild-type (wt) and ipt1Δ cells, which are unable to synthesize M(IP)₂C accumulating mannosylinositolphosphorylceramide (MIPC), were compared. Living cells, isolated plasma membrane and giant unilamellar vesicles reconstituted from plasma membrane lipids were labelled with various fluorescent membrane probes that report the presence and organization of distinct lipid domains, global order, and dielectric properties. Can1p and Pma1p were tagged with GFP and mRFP, respectively, in both yeast strains, to evaluate their lateral organization using confocal fluorescence intensity and fluorescence lifetime imaging. The results show that IPT1 deletion strongly affects the rigidity of gel-like domains but not their relative abundance, whereas no significant alterations could be perceived in ergosterolenriched domains. Moreover, in these cells lacking M(IP)₂C, a clear alteration in Pma1p membrane distribution, but no significant changes in Can1p distribution, were observed. Thus, this work reinforces the notion that sphingolipid-enriched domains distinct from ergosterol-enriched regions are present in the S. cerevisiae plasma membrane and suggests that M(IP)₂C is important for a proper hydrophobic chain packing of sphingolipids in the gel-like domains of wt cells. Furthermore, our results strongly support the involvement of sphingolipid domains in the formation and stability of the MCP, possibly being enriched in this compartment. Full article

We aimed to study the hypothesis of socioeconomic equalization in health among Armenian adolescents participating in the Health Behavior in School-Aged Children 2013/14 survey. Classes corresponding to the ages 11, 13, and 15 were selected using a clustered sampling design. Multiple logistic regression analyses were used. In a nationally representative sample of 3679 students, adolescents with a low family socioeconomic position (SEP) had greater odds of reporting less than good health (odds ratio (OR) = 2.81, 95% CI = 2.25–3.51), low psychosocial well-being (OR = 1.94, 95% CI = 1.44–2.61), or psychosomatic symptoms (OR = 1.29, 95% CI = 1.07–1.56). Low levels of material well-being were associated with a higher likelihood of reporting less than good health (OR = 1.32, 95% CI = 1.06–1.65) or low psychosocial well-being (OR = 1.27, 95% CI = 1.04–1.54). The presence of both risk factors had a synergistic effect on having low psychosocial well-being (P-interaction = 0.031). Refuting the equalization hypothesis, our results indicate that low SEP might be strongly related to adolescent health in middle-income countries such as Armenia. Low material well-being also proved important, and, for further research, we hypothesized an association via decreased peer social status and compromised popularity. Full article

Eucalyptus spp. are among the most suitable species for biomass production, even for the firewood derived from medium-rotation coppice (MRC). The general problem of wood is that it cannot be utilized immediately because of the high moisture content, which in the combustion process would reduce remarkably the yield of energy. In this context, outdoor storage of whole stems without branches (WS), outdoor storage of whole stems with branches (WSB), open shed storage of firewood logs in mesh bags (OSF), and outdoor firewood logs in mesh bags (ODF) of Eucalyptus spp woody biomass were compared in term of moisture and dry matter loss to evaluate the most convenient form of storing biomass deriving from a medium-rotation coppice. During the storage period, ODF showed higher moisture values than OSF, WSB, and WS, underlining that moisture reduction is related to local climatic conditions, pile size and permeability (compaction). However, at the end of the storage period, the four options reached a similar moisture to the commercial one of fuel wood (around 15%). WSB showed the highest loss of dry matter (18%), which can be ascribed to the drying and falling process of the leaves. In conclusion, the qualitative and quantitative characteristics of the biomass were similar after the different storage systems, producing firewood suitable for new market opportunities. Full article

The combustible fraction of municipal solid waste (MSW) is called refuse-derived fuel (RDF). RDF is a blend of heterogeneous materials and thus its handling is challenging. Pelletization is an efficient treatment to minimize the heterogeneity. In this research, typical RDF compositions were prepared by mixing several mass fractions of paper, plastic, household organic and wood. The collected compositions were ground, wetted to 20% moisture content (wet basis) and pelletized. Increasing the plastic content from 20% to 40% reduced the pelletization energy but increased the pellet’s calorific value. Pellets with higher plastic content generated more dust when exposed to shaking. Making durable pellets with 40% plastic content needed an increase in die temperature from 80 °C to 100 °C. Increasing the paper content from 30% to 50% increased the durability but consumed higher energy to form pellets. Paper particles increased the friction between pellet’s surface and die wall as was evident from expulsion energy. Force versus displacement curve for material compression revealed that the RDF compositions have rigid material characteristics. Full article

Alzheimer’s disease is a neurodegenerative disorder for which there is a continuous search of drugs able to reduce or stop the cognitive decline. Beta-amyloid peptides are composed of 40 and 42 amino acids and are considered a major cause of neuronal toxicity. They are prone to aggregation, yielding oligomers and fibrils through the inter-molecular binding between the amino acid sequences (17–42) of multiple amyloid-beta molecules. Additionally, amyloid deposition causes cerebral amyloid angiopathy. The present study aims to identify, in the existing literature, natural plant derived products possessing inhibitory properties against aggregation. The studies searched proved the anti-aggregating effects by the thioflavin T assay and through behavioral, biochemical, and histological analysis carried out upon administration of natural chemical compounds to transgenic mouse models of Alzheimer’s disease. According to our present study results, fifteen secondary metabolites from plants were identified which presented both evidence coming from the thioflavin T assay and transgenic mouse models developing Alzheimer’s disease and six additional metabolites were mentioned due to their inhibitory effects against fibrillogenesis. Among them, epigallocatechin-3-gallate, luteolin, myricetin, and silibinin were proven to lower the aggregation to less than 40%. Full article

With the continuous increase in new energy installed capacity, the slowdown in the growth of social power consumption, the pressure created by high coal prices, and the reduction in on-grid electricity tariffs, the challenges facing the survival and development of thermal power generation enterprises are becoming more severe. Hence, based on the cost–benefit analysis method, this paper proposes a diversified operating benefit analysis and decision model for thermal power generation enterprises that includes four profit models: power sales, peak load regulation (without oil), peak load regulation (with oil), and generation right trading. The opportunity cost of peak load regulation and generation rights trading was considered, and six scenarios were designed. An empirical analysis was conducted by selecting a thermal power enterprise in Ningxia, Northwest China, as an example, using scenario and sensitivity analyses. The results show that under the diversified business model, thermal power generation enterprises can more effectively avoid the risks when the external environment changes and significantly improve its economic benefits. The consumption of new energy can be promoted, and positive social effects will be achieved. Therefore, the findings will help the thermal power generation enterprises to face these challenges. Full article