Multiple sclerosis is an autoimmune disorder where both T cells and B cells are implicated in pathology. However, it remains unclear how these two distinct populations cooperate to drive disease. There is ample evidence from studies in both MS patients and mouse models that Th17, B cells, and follicular T helper (TFH) cells contribute to disease. This review article describes the literature that identifies mechanisms by which Th17, TFH, and B cells cooperatively drive disease activity in MS and EAE. The curation of this literature has identified that CNS-infiltrating TFH cells act with TH17 cell to contribute to an inflammatory B cell response in neuroinflammation. This demonstrates that TFH cells and their products are promising targets for therapies in MS.

Predation is a driving force of organismal ecology and evolution. Predator-prey interactions, constrained by other environmental factors and historical contingency, shape physical and behavioral phenotypes of organisms on both sides of the interaction arrow. Yet despite the universality of trophic interactions in biology, study of the ecology and evolution of anti-predator defense is challenging because these interactions tend to be brief and unpredictable, and thus gathering direct evidence requires patience and serendipity. The evolution of prey defenses can be studied by DNA sequencing followed by phylogenetic analysis, and the ecology can be studied by field observation and bringing tractable systems into the lab. However, animal models generally do not allow genetic manipulation, strict control of environmental variables, or detailed observation of evolution in real time, all of which are important for demonstrating evolutionary causes and consequences. Developing complementary microbial predator-prey systems can help overcome this hurdle. There is an extensive body of work on microbial experimental evolution, and many microbes come with well-characterized genomes and established methods for genetic manipulation. As understanding of microbial ecology and the mechanisms of their trophic interactions grows apace, these systems are poised to make valuable contributions to our understanding of how predator behaviors evolve, why certain anti-predator defenses evolve and not others, and how multiple defenses function together in a single defense portfolio. These systems will enable us to both test hypotheses formulated from the study of larger organisms and to propose new ones that can be tested in larger organisms with existing methods.

We investigated the response of the Manila clam Venerupis philippinarum to possible temperature and salinity changes in a holding facility. First, clams were exposed to four temperatures for 15 days. Valve closure and survival of clams exposed to seawater at 18℃ were higher than that of those exposed to seawater at 24℃. Second, clams were exposed to six salinities for 15 days. Survival of clams exposed to two salinity fluctuation conditions (24–30 and 27–24 psu) was lower than that of clams exposed to constant 30 psu conditions. Valve closures of clams exposed to constant low salinity conditions (24 psu) and two salinity fluctuation conditions (24–30 and 27–24 psu) were higher than of those exposed to constant 30 psu conditions. Lastly, clams were exposed to two different temperatures and three different salinities conditions for 8 days. Valve closure and survival decreased significantly under the combination of 24℃ and 18 psu. These results suggest that an increase in temperature or a wider range of salinity fluctuations are detrimental to the survival of the Manila clam. The synergistic effect of temperature and salinity stressors may decrease the survival period of clams compared to the effect of a single stressor.

The amount and spatial distribution of foliage in a tree canopy have fundamental functions in ecosystems as they affect energy and mass fluxes through photosynthesis and transpiration. They are usually described by the Leaf Area Index (LAI) and the Leaf Area Density (LAD), which can be measured through a variety of methods, including voxel-based methods applied to LiDAR point clouds. A theoretical study recently compared the numerical errors arising from different voxel-based estimation methods for Plant Area Density (PAD) based on Beer’s law-based, contact frequency and Maximum-Likelihood Estimation, showing that the bias-corrected Maximum Likelihood Estimator was theoretically the most efficient. However, this earlier study i) ignored wood volumes; ii) neglected vegetation clumping inside the voxel; iii) ignored instrument characteristics in terms of effective footprint, iv) was limited to a single viewpoint. In practice, retrieving LAD from PAD is not straightforward, vegetation is not randomly distributed in volumes of interest, beams are divergent and forestry plots are usually sampled from more than one viewpoint, to mitigate the effect of occlusion. In the present short communication, we extend the previous efficient formulation to actual field conditions to i) account for the presence of both wood volumes and wood hits, ii) rigorously include correction terms for vegetation and instrument characteristics, iii) integrate multiview data. A numerical comparison with other methods commonly used to combine information from different viewpoints led to error reduction, especially in poorly-explored volumes, which are frequent in actual canopies. Beyond its concision, completeness and efficiency, this new formulation -which can be applied to multiview TLS, but also UAV LiDAR scanning - can help reducing errors in LAD estimation.

For a dynamical system, it is known that the existence of a Lyapunov density implies almost global stability of an equilibrium. It is then natural to ask whether the existence of a common Lyapunov density for a nonlinear switched system implies almost global stability, in the same way as a common Lyapunov function implies global stability for nonlinear switched systems. In this work, the answer to this question is shown to be affirmative as long as switchings satisfy a dwell-time constraint with an arbitrarily small dwell time. As a straightforward extension of this result, we employ multiple Lyapunov densities in analogy with the role of multiple Lyapunov functions for the global stability of switched systems. This gives rise to a minimum dwell time estimate to ensure almost global stability of nonlinear switched systems, when a common Lyapunov density does not exist. The results obtained for continuous-time switched systems are based on some sufficient conditions for the almost global stability of discrete-time non-autonomous systems. These conditions are obtained using the duality between Frobenius-Perron operator and Koopman operator.

In recent years, autonomous robots have proven capable of solving tasks in complex environments. In particular, robot manipulations in activities of daily living (ADL) for service robots have been in wide use. However, manipulations such as loading a dishwasher or folding laundry are difficult to automate robustly. In addition, manipulations of grasping multiple objects in domestic environments present difficulty. To perform those applications better, we developed robotic systems based on shared autonomy by combining the cognitive skills of a human operator with autonomous robot behaviors. In this work, we present techniques for integration of a shared autonomy system for assistive mobile manipulation and new strategies to support users in the domestic environment. We demonstrate that the robot can grasp multiple objects with random size at known and unknown table heights. Specifically, we developed three strategies for manipulation. From experimental results, we observed that the first strategy has the highest success rate (70% for random objects) up to 70 cm table height. Two other strategies perform better for 80 cm to 100 cm table height. The success rate of the second and third strategies shows an average 63.3% and 73.3%, respectively, for grasping random objects. We also demonstrated these strategies using two intuitive interfaces, a visual interface in rviz and a voice user interface with speech recognition, which are suitable for elderly people. In addition, the robot can select strategies automatically in random scenarios, which make the robot intelligent and able to make decisions independently in the environment. We obtained interesting results showing that the robot adapts to the environmental variation automatically. After these experimental demonstrations, our robot shows the capabilities for employment in domestic environments to perform actual tasks.

Proteasome inhibitors, like bortezomib, play a key role in the treatment of multiple myeloma (MM); however, most patients eventually relapse and eventually show multiple drug resistance, and the molecular mechanisms of this resistance remain unclear. The present study examines the expression of previously-described genes that may influence resistance to bortezomib treatment at the mRNA level (ABCB1, CXCR4, MAF, MARCKS, POMP, PSMB5, RPL5, TXN and XBP1). mRNA expression was determined in 73 MM patients treated with bortezomib-based regimens (30 bortzomib-sensitive and 43 bortezomib-refractory patients) and 11 healthy controls. RPL5 was significantly down-regulated in multiple myeloma patients as compared with healthy controls. Moreover, POMP was significantly up-regulated in MM patients refractory to bortezomib-based treatment. In multivariate analysis, high expression of PSMB5 and CXCR and autologous stem cell transplantation were independent predictors of progression-free survival, and high expression of POMP and RPL5 was associated with shorter overall survival.

A very high parking occupancy can negatively influence the traffic performance of an area by causing very long cruising times. A very low parking occupancy, on the other hand, is inefficient from a space utilization perspective. Thus, this paper proposes a framework to compute the optimal parking occupancy rate over a given time horizon based on a macroscopic traffic and parking model. This rate is set high enough to ensure an efficient usage of the parking infrastructure. However, it should also guarantee a high likelihood of finding parking in order to eliminate the drivers’ time wasted in cruising for parking and the added congestion it causes. The model outputs are based on small data collection efforts and low computational costs, and they can be generated without complex simulation software using a simple numerical solver. Multiple vehicle types are included into our methodology allowing us to generate insights about the optimal parking occupancy with or without differentiated parking (i.e., parking for specific vehicles, such as fuel and electric vehicles). In times of a modal shift towards electric vehicles, cities can use our model to evaluate how much parking supply (with battery charging opportunities) they would like to dedicate to electric vehicles in order to achieve optimal traffic and parking results, and whether a differentiated or semi-differentiated parking policy is desirable. We illustrate our framework in a case study of a central area within the city of Zurich, Switzerland, showing the traffic and parking impacts (e.g., average searching time for parking, total revenue created by parking fees, optimal parking occupancy rate) for different proportions of fuel and electric vehicles in the parking demand and/or supply. Our results confirm that optimal occupancy rates are between and for most realistic scenarios. We then discuss how these rates might change depending on various demand and supply relationships, and according to different parking policies. We show that equal proportions between electric vehicles in the demand and their parking spaces in the supply lead to the best traffic performance in the area. We also provide the tools for cities to analyze their loss in performance if they do not react, e.g., to an increasing demand for electric vehicles over time. Moreover, we illustrate how some of these risks can be mitigated by having more flexible parking policies, e.g., allowing electric vehicles to use parking spaces for fuel vehicles.

We construct a family of two-step optimal fourth order iterative methods for finding single root of non-linear equations. We generalize these methods to simultaneous iterative methods for determining all the distinct as well as multiple roots of single variable non-linear equations. Convergence analysis is present for both cases to show that the order of convergence is four in case of single root finding method and is twelve for simultaneous determination of all roots of non-linear equation. The computational cost, Basin of attraction, efficiency, log of residual and numerical test examples shows, the newly constructed methods are more efficient as compared to the existing methods in literature.

Mechanical power and motion are often transmitted by the gear-rotor-bearing system. When there are fitting clearances between the housing and outer ring in bearings, complex vibration responses will be generated, which makes the operating status difficult to identify. Therefore, for analyzing dynamic responses, a dynamic model of gear-rotor-bearing systems with bearing fitting clearances is proposed. In the model, the bearing system with fitting clearances and gear pair system are combined, and the coupling relationship is determined by the gyroscopic mo-tion of the shaft. The friction force and collision force caused by fitting clearances are also con-sidered, which are simulated by the Coulomb friction model and Hertz theory. The result shows that the meshing stiffness will also be excited by the bearing displacement. When there are fit-ting clearances on the bearing, the amplitude modulation of the bearing outer raceway to the system time-domain response is intensified, and the multiple harmonic frequency of bearings and gear pairs are generated on the spectrum, as well as defect frequencies of gear pairs. As the fitting clearance is increased, the higher multiple harmonic responses will be caused. Although the response amplitude of the gearbox is increased by raising the input speed, multiple harmon-ic responses are suppressed, which makes the system mainly vibrate at the fundamental fre-quency. Then, the dynamic model and the vibration analysis are experimentally verified.

Bottlenose dolphin (Tursiops truncatus) belongs to the Cetartiodactyla and similarly to the other cetaceans represent the most successful mammalian colonization of the aquatic environment. Here we report a genomic, evolutionary and expression study of Tursiops truncatus T cell receptor beta (TRB) genes. Although the organization of the dolphin TRB locus is similar to that of the other artiodactyl species, with three in tandem D-J-C clusters located at its 3’ end, its uniqueness is given by the reduction of the total length due essentially to the absence of duplications and to the deletions that have drastically reduced the number of the germline TRBV genes. We have analyzed the relevant mature transcripts from two subjects. The simultaneous availability of rearranged TRA and TRB cDNA from the peripheral blood of one of the two specimens, and the human/dolphin amino acids multi sequence alignments, allowed us to calculate the most likely interactions at the protein interface between the alpha/beta heterodimer in complex with major histocompatibility class I (MH1) protein. Interacting amino acids located in the CDR-IMGT of the dolphin variable V alpha and beta domains were identified. According to comparative modelisation, the atome pair contact sites analysis between the human MH1 grove (G) domains and the TR V domains confirms conservation of the structure of the dolphin TR/pMH.

According to the French Agency for Food, Environmental and Occupational Health & Safety, electromagnetic hypersensitivity affects more than 3 million people in France, and headaches are a very frequent cause of complaint in electrohypersensitive patients, to the point of dominating the clinical picture. These headaches share characteristics with migraine pathology, and clinical improvement with anti-migraine therapy has led us to consider that the headache in the electrohypersensitive patient may be a variant of the migraine disease mediated by the TRPA1 receptor, which if confirmed, would offer effective therapeutic possibilities to relieve the electrohypersensitive patient.

Methods are currently lacking to prove artificial general intelligence (AGI) safety. An AGI ‘hard takeoff’ is possible, in which first generation AGI1 rapidly triggers a succession of more powerful AGIn that differ dramatically in their computational capabilities (AGIn≪AGIn+1). No proof exists that AGI will benefit humans or of a sound value-alignment method. Numerous paths toward human extinction or subjugation have been identified. We suggest that probabilistic proof methods are the fundamental paradigm for proving safety and value-alignment between disparately powerful autonomous agents. Interactive proof systems (IPS) describe mathematical communication protocols wherein a Verifier queries a computationally more powerful Prover and reduces the probability of the Prover deceiving the Verifier to any specified low probability (e.g., 2-100). IPS procedures can test AGI behavior control systems that incorporate hard-coded ethics or value-learning methods. Mapping the axioms and transformation rules of a behavior control system to a finite set of prime numbers allows validation of ‘safe’ behavior via IPS number-theoretic methods. Many other representations are needed for proving various AGI properties. Multi-prover IPS, program-checking IPS, and probabilistically checkable proofs further extend the paradigm. In toto, IPS provides a way to reduce AGIn↔AGIn+1 interaction hazards to an acceptably low level.

The increased deployment of IoT devices in specific areas results in an interference among them and the quality of communications can be severely degraded. To deal with this interference issue, the IEEE 802.11ax standard has been established in hyper-densely wireless networking systems. The 802.11ax adopts a new candidate technology that is called multiple network allocation vector in order to mitigate the interference problem. In this paper, we point out potential problem in multiple network allocation vector which can cause delays to the communication among IoT devices in hyper-dense wireless networks. Furthermore, this paper introduces an adaptive beam alignment algorithm for interference issue resolution. In addition, we analyze potential delays of communications among IoT devices under interference conditions. Lastly, we simulate our proposed algorithm in densely deployed environment and show that the interference issue can be mitigated and the IEEE 802.11ax-based IoT devices can utilize the air interface more fairly compared to conventional IEEE 802.11 distributed coordination function.

Risk attitudes are relevant factors affecting the production and investment decisions at farm level. They are key factors that are related to farmers’ attitudes towards environment and climate change. Several methodological approaches are available to measure the level of stated risk of an economic agent. The Multiple Price List (MPL) method is one of the methods that is gaining relevance. In this study we apply the MPL and relate the risk outcomes with farmers’ characteristics and their perception towards environment and climate change. Data was collected using a face to face survey carried out for a group of 370 agricultural producers of the irrigation district located in northwest of Mexico. Results showed an average risk of about 0.32, locating the agricultural producers of the region in a group with risk aversion, according to the MPL scale. The heterogeneity analysis showed that the socioeconomic factors and the perceptions towards climate change are related to the farmers´ stated risk level. Farmers who are young women with propensity to use public support to invest were shown to be greater risk lovers. Farmers in the region have perceived climate change to a greater extent like floods, hail, diseases and pests, and changing vegetation.

Multiple Sclerosis (MS) has a well established link with Epstein-Barr virus (EBV) and a growing association with human endogenous retroviruses (HERVs). In this review, we described how these two pieces may interact in MS pathogenesis

With the advancement of photoelectric technology and computer image processing technology, the visual measurement method based on point clouds is gradually applied to the 3D measurement of large workpieces. Point cloud registration is a key step in 3D measurement, and its registration accuracy directly affects the accuracy of 3D measurements. In this study, we designed a novel MPCR-Net for multiple partial point cloud registration networks. First, an ideal point cloud was extracted from the CAD model of the workpiece and was used as the global template. Next, a deep neural network was used to search for the corresponding point groups between each partial point cloud and the global template point cloud. Then, the rigid body transformation matrix was learned according to these correspondence point groups to realize the registration of each partial point cloud. Finally, the iterative closest point algorithm was used to optimize the registration results to obtain a final point cloud model of the workpiece. We conducted point cloud registration experiments on untrained models and actual workpieces, and by comparing them with existing point cloud registration methods, we verified that the MPCR-Net could improve the accuracy and robustness of the 3D point cloud registration.

Two sufi women take part in activities related to sufism and create an attraction point in the secular side in Turkey.The most striking point is that both women do not wear headscarves although they are muslim women. This article attempts to show how sufi women Cemalnur Sargut and Hayatnur Artıran have idealized a Muslim woman's identity, the work they are doing to achieve this ideal, their attidue toward Rebublic values, and the effects of these attidues on their followers. This article was created from my doctoral thesis and based on Qualitative research which has been established on the basis of 2-year long participant observation and data obtained from in-depth and focus interviews. 31 women and 20 men were interviewed in depth and focus interviews.The main conclusions of my qualitative research are that the influence of theese sufi women is related with process of modernization by accelerating the establishment of the republic in Turkey. It seems that a perception has established concerning that “public apparency’’ of woman will disappear if the “apparency of body’’ disappears and the woman will return to its role which had relapsed into silence for centuries. Besides not using the headscarf, religious conversation have been created by theese sufi women in the balance of religion, philosophy and science and the fact that they are conducting their works under secular institutions such as foundations and associations have also been observed to have a very important effect on seculer side.

The language we use to describe the past can have a strong influence on the audience’s interpretation of our story. In our experiment, we explore, using 3 different conditions, how the framing and language of an accident report can affect the audience’s proposed solutions to manage the problems found. We find that the approach used to create an accident report can have a powerful influence on the audience’s decision making. Whether we are describing an accident in a similar manner to a crime, using a systems approach or we are accepting of multiple stories which are not linear or coherent, the methods we use to capture and communicate the story have a profound impact on the actions decided upon by the reader.

Aiming at the problem that the performance of Adaptive Kalman filter estimation will be affected when the statistical characteristics of the process and measurement noise matrix are inaccurate and time-varying in the linear Gaussian state-space model, an algorithm of Multi-fading factor and update monitoring strategy adaptive Kalman filter based variational Bayesian is proposed. Inverse Wishart distribution is selected as the measurement noise model, the system state vector and measurement noise covariance matrix are estimated with the variational Bayesian method. The process noise covariance matrix is estimated by the maximum a posteriori principle, and the update monitoring strategy with adjustment factors is used to maintain the positive semi-definite of the updated matrix. The above optimal estimation results are introduced as time-varying parameters into the multiple fading factors to improve the estimation accuracy of the one-step state predicted covariance matrix. The application of the proposed algorithm in target tracking is simulated. The results show that compared with the current filters, the proposed filtering algorithm has better accuracy and convergence performance, and realizes the simultaneous estimation of inaccurate time-varying process and measurement noise covariance matrices.

Recently, Kayyalha et al. (Phys. Rev. Lett., 2019, 122, 047003) reported on anomalous enhancement of the self-field critical currents, I_c (sf,T), at low temperatures in Nb/BiSbTeSe₂-nanoribbon/Nb Josephson junctions. The enhancement was attributed to the low-energy Andreev bound states arising from winding of the electronic wave function around the circumference of the topological insulator BiSbTeSe₂ nanoribbon. In this paper, we show that identical enhancement in I_c(sf,T) and in the upper critical field, B_c2(T), at approximately same reduced temperatures, were reported by several research groups in atomically thin junctions based on a variety of Dirac-cone materials (DCM) earlier. Our analysis shows that in all these S/DCM/S systems the enhancement is due to a new superconducting band opening. Taking in account that several intrinsic superconductors also exhibit the effect of new superconducting band(s) opening when sample thickness becomes thinner than the out-of-plane coherence length, we strength our previous proposal that there is a new phenomenon of additional superconducting band(s) opening in atomically thin films.

Targeted radionuclide therapy (TRT) has recently seen a surge in popularity, with the use of radionuclides conjugated to small molecules and antibodies. Similarly, immunotherapy also has shown promising results – an example being chimeric antigen receptor (CAR) T-cells therapy in hematologic malignancies. Moreover, TRT and CAR T therapies possess unique features that require special consideration when determining how to dose, time, and sequence combination treatments, including the distribution of TRT dose in the body, the decay rate of the radionuclide, and the proliferation and persistence of the CAR-T cells. These characteristics complicate additive or synergistic effects of combination therapies and warrant a mathematical treatment which includes these dynamics in relation to the proliferation and clearance rates of the target tumor cells. Here we combine two previously published mathematical models in a multiple myeloma setting to explore the effects of dose, timing, and sequencing of TRT and CAR-T cell based therapies. We find that for a fixed TRT and CAR-T cell dose, the tumor proliferation rate is the most important parameter in determining the best timing of TRT and CAR T therapies.

Obesity has become a rising global health problem affecting adults’ quality of life. The objective of this study was to describe the prevalence of obesity in Indonesian adults based on the cluster of islands. The study was also aimed to identify the risk factors of obesity in each island cluster. This study analysed secondary data of Indonesian Basic Health Research 2018. Our data for analysis comprised 688,638 adults (>=15 years) randomly selected using proportionate to population size throughout Indonesia. We included 20 variables for sociodemographic and obesity-related risk factors for analysis. Obese status was defined using Body Mass Index (BMI) >= 27.5 kg/m2. Our current study defined seven major islands cluster as the unit analysis consisting of 34 provinces in Indonesia. Descriptive analysis was conducted to determine the characteristics of the population and to calculate the prevalence of obesity within provinces in each of the island’s clusters. Multivariate logistic regression analyses to calculate odds ratios (ORs) was performed using R version 3.6.3. The study results showed that all island clusters had at least one province with an obesity prevalence of more than 20%. Six out of twenty variables, comprising four diet factors (consumption of sweet food, high-salt food, meat food, and carbonated drinks) and two other factors (mental health disorders and smoking behaviour), varied across the island clusters. In conclusion, there was a variation of obesity prevalence of the provinces within and between island clusters. Variation of risk factors raised in each cluster island suggested the government rethink and reframe the intervention to address obesity.

Multiple mRNA isoforms of the same gene are produced via alternative splicing, a biological mechanism that regulates protein diversity while maintaining genome size. Alternatively spliced mRNA isoforms of the same gene may sometimes have very similar sequence, but they can have significantly diverse effects on cellular function and regulation. The products of alternative splicing have important and diverse functional roles, such as response to environmental stress, regulation of gene expression, human heritable and plant diseases. The mRNA isoforms of the same gene, such as the apoptosis associated CASP3 gene, can have dramatically different functions. The shorter mRNA isoform product CASP3-S inhibits apoptosis, while the longer CASP3-L mRNA isoform promotes apoptosis. Despite the functional importance of mRNA isoforms, very little has been done to annotate their functions. The recent years have however seen the development of several computational methods aimed at predicting mRNA isoform level biological functions. These methods use a wide array of proteo-genomic data to develop machine learning-based mRNA isoform function prediction tools. In this review, we discuss the computational methods developed for predicting the biological function at the individual mRNA isoform level.

Keywords: Chemical Intolerance, Drug Intolerance, Food Intolerance, QEESI, BREESI, Multiple Chemical Sensitivity, Toxicant-induced Loss of Tolerance, Prevalence

Multiple Myeloma (MM) is one of the incurable types of cancer in plasma cells. While immense progress has been made in the treatment of this malignancy, a large percentage of patients were unable to adapt to such therapy. Additionally, these therapies might be associated with significant diseases and are not always tolerated well in all patients. Since cancer in plasma cells has no cure, patients develop resistance to treatments, resulting in R/R MM. BCMA is primarily produced on mature B cells. Its up-regulation and activation are associated with multiple myeloma in both murine and human models, indicating that this might be an effective therapeutic target for this type of malignancy. Additionally, BCMA's predictive value, association with effective clinical trials, and capacity to be utilized in previously difficult to observe patient populations, imply that it might be used as a biomarker for multiple myeloma. Numerous kinds of BCMA-targeting medicines have demonstrated antimyeloma efficacy in individuals with refractory/relapsed MM, including CAR T-cell treatments, ADCs, bispecific antibody constructs. Among these medications, CART cell-mediated BCMA therapy has shown significant outcomes in multiple myeloma clinical trials. This review article outlines CAR T cell mediated BCMA medicines have the efficiency to change the therapeutic pattern for multiple myeloma significantly.

Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative autoimmune disease characterized by aberrant infiltration of immune cells into the central nervous system (CNS) and by the loss of myelin. Sclerotic lesions and various inhibitory factors hamper remyelination processes within the CNS. MS patients typically experience gradual cognitive and physical disabilities as the disease progresses. The etiology of MS is still unclear and emerging evidence suggests that microbiome composition could play a much more significant role in disease pathogenesis than was initially thought. Initially believed to be isolated to the gut microenvironment, we now know that the microbiome plays a much broader role in various tissues and is essential in the development of the immune system. Here, we present some of the unexpected roles that the microbiome plays in MS and discuss approaches for the development of next-generation treatment strategies.

The power-generation capacity of grid-connected photovoltaic (PV) power systems is increasing. As output power forecasting is required by electricity market participants and utility operators for the stable operation of power systems, several methods have been proposed using physical and statistical approaches for various time ranges. A short-term (30 min ahead) forecasting method has been previously proposed by our laboratory for geographically distributed PV systems using motion estimation. This study focuses on an important parameter for estimating the proposed motion and optimizing the parameter. This parameter is important because it is associated with the smoothness of the vector field, which is the result of motion estimation and influences the forecasting accuracy. In the periods with drastic power output changes, the evaluation was conducted on 101 PV systems located within a circle of 15-km radius in the Kanto region of Japan. The results indicate that the absolute mean error of the proposed method with the optimized parameter is 10.3%, whereas that of the persistent prediction method is 23.7%. Therefore, the proposed method is effective in forecasting for periods when PV output changes drastically in a short time.

Multiple lines of evidence indicate that CD8$^+$ T cells are important in the control of HIV-1 (HIV) replication. However, CD8$^+$ T cells induced by natural infection cannot eliminate the virus or reduce viral loads to acceptably low levels in most infected individuals. Understanding the basic quantitative features of CD8$^+$ T-cell responses induced during the course of HIV infection may therefore inform us about the limits that HIV vaccines, which aim to induce protective CD8$^+$ T-cell responses, must exceed. Using previously published experimental data from a cohort of HIV-infected individuals with sampling times from acute to chronic infection we defined the quantitative properties of CD8$^+$ T-cell responses to the whole HIV proteome. In contrast with a commonly held view, we found that the relative number of HIV-specific CD8$^+$ T-cell responses (response breadth) changed little over the course of infection (first 400 days post-infection), with moderate but statistically significant changes occurring only during the first 35 symptomatic days. This challenges the idea that a change in the T-cell response breadth over time is responsible for the slow speed of viral escape from CD8$^+$ T cells in the chronic infection. The breadth of HIV-specific CD8$^+$ T-cell responses was not correlated with the average viral load for our small cohort of patients. Metrics of relative immunodominance of HIV-specific CD8$^+$ T-cell responses such as Shannon entropy or the Evenness index were also not significantly correlated with the average viral load. Our mathematical-model-driven analysis suggested extremely slow expansion kinetics for the majority of HIV-specific CD8$^+$ T-cell responses and the presence of intra- and interclonal competition between multiple CD8$^+$ T-cell responses; such competition may limit the magnitude of CD8$^+$ T-cell responses, specific to different epitopes, and the overall number of T-cell responses induced by vaccination. Further understanding of mechanisms underlying interactions between the virus and virus-specific CD8$^+$ T-cell response will be instrumental in determining which T-cell-based vaccines will induce T-cell responses providing durable protection against HIV infection.

Worldwide, over 2.2 million people are suffered from multiple sclerosis (MS), a multifactorial demyelinating disease of the central nervous system. MS is characterized by a wide range of motor, autonomic, and psychobehavioral symptoms including depression, anxiety, and dementia. The blood, cerebrospinal fluid, and postmortem brain samples of MS patients evidenced the disturbance of reduction-oxidation (redox) homeostasis such as the alterations of oxidative and antioxidative enzyme activities and the presence of degradation products. This review article discussed the components of redox homeostasis including reactive chemical species, oxidative enzymes, antioxidative enzymes, and degradation products. The reactive chemical species covered frequently discussed reactive oxygen/nitrogen species, infrequently featured reactive chemicals such as sulfur, carbonyl, halogen, selenium, and nucleophilic species that potentially act as reductive as well as pro-oxidative stressors. The antioxidative enzyme systems covered the nuclear factor erythroid-2-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 (KEAP1) signaling pathway. The NRF2 and other transcriptional factors potentially become a biomarker sensitive to the initial phase of oxidative stress. Altered components of the redox homeostasis in MS were discussed in search of a diagnostic, prognostic, predictive, and/or therapeutic biomarker. Finally, monitoring a battery of reactive chemical species, oxidative enzymes, antioxidative enzymes and degradation products helps evaluate the redox status of MS patients to expedite building personalized treatment plans for the sake of better quality of life.

Apathy in patients with Parkinson's disease (PD) is one of the least studied manifestations of a wide range of neuropsychiatric disorders (PND). The frequency of apathy in PD, according to various researchers, is 17–80%. Structural and neurochemical changes associated with PD are considered as the leading pathophysiological factors of apathy. Possible general pathophysiological mechanisms of apathy and hypokinesia, depression, executive (frontal) cognitive functions, sleep disorders in PD are discussed. The basis of the pathophysiological commonality of apathy, hypokinesia, and executive functions is probably bilateral disturbances in the functional connections of the stratum and dorsolateral, medial parts of the prefrontal cortex. The combination of apathy and depression in PD may be due to dysfunction of the structures of the limbic system and the medial orbital prefrontal cortex responsible for motivational determined behavior. The variability of the relationship between apathy and hypokinesia, depression, cognitive impairments, sleep disorders at different stages of PD may be associated with the phenomenological heterogeneity of apathy.Apathy worsens the quality of life, makes a significant contribution to disorders of both household and social adaptation of PD patients. It is promising to study the possibility of correcting apathy using dopaminergic therapy. Against the background of the appointment of pramipexole (1.5-3.0 mg / day) to 20 patients with PD (middle stage, according to Hen-Yar-2.5) to correct movement disorders after 4-6 weeks of therapy, a statistically significant positive dynamics of apathy were noted. According to the total assessment of the scale of apathy SE Starkstein (AS). As a result of the study, no statistically significant correlation was found between the dynamics of the total apathy indicator and the dynamics of motor symptoms of PD according to the unified rating scale for assessing PD (“Motor functions”), which, we believe, indicates an independent effect of pramipexole therapy in relation to motivational disorders.

Automatic recognition methods for non-stationary EEG data collected from EEG sensors play an essential role in neurological detection. The integrative approaches proposed in this study consists of Symlet wavelet processing, a gradient boosting machine, and a grid search optimizer for a three-level classification scheme for normal subjects, intermittent epilepsy, and continuous epilepsy. Fourth-order Symlet wavelets were adopted to decompose the EEG data into five time-frequency sub-bands, whose statistical features were computed and used as classification features. The grid search optimizer was used to automatically find the optimal parameters for training the classifier. The classification accuracy of the gradient boosting machine was compared with that of a support vector machine and a random forest classifier constructed according to previous descriptions. Multiple-index were used to evaluate the Symlet wavelet transform-gradient boosting machine-grid search optimizer classification scheme, which provided better classification accuracy and detection effectiveness than has recently reported in other work on three-level classification of EEG data.

The frame construction of an apartment complex that consists of multiple buildings encounters various uncertainties, owing to the complex relationships among units of work. Currently, the period of such a construction is calculated based on the number of floors of the highest building in the complex. This study quantitatively analyzes an apartment frame construction period using a queue model and evaluates the validity of the estimated period. In this regard, a methodology is proposed for analyzing the construction period by applying the concept of a customer and a server. A case study on the duration of an apartment frame construction is conducted with Korea Land and Housing Corporation, which has supplied the largest number of apartments in South Korea. It was found that the stable state of a queue system was observed when the rate of server utilization was applied to the basement and aboveground floors. However, a stable state was not reached on the ground floor. This study includes non-working days in its calculation and quantitatively analyzes uncertainty factors during construction. Therefore, the findings can be practically utilized to quantitatively plan the durations of work units in an apartment frame construction.

Mediterranean catchments are characterized by significant spatial and temporal hydrological variability caused by the interaction of natural as well human-induced abiotic and biotic factors. This study investigates the (non-)linearity rainfall-runoff relationship at multiple temporal scales in representative small Mediterranean catchments (i.e., < 10 km2) to achieve a better understanding of the hydrological response. Rainfall-runoff relationship was evaluated in 44 catchments at annual and event –203 events in 12 of these 44 catchments– scales. A linear rainfall-runoff relation was observed at annual scale with higher scatter in pervious than impervious catchments. Larger scattering was observed at event scale, although pervious lithology and agricultural land use promoted significant rainfall-runoff linear relations in winter and spring. These relationships were particularly analysed during five hydrological years in Es Fangar catchment (3.35 km2; Mallorca, Spain) as a temporal downscaling to assess intra-annual variability in which antecedent wetness conditions played a significant role in runoff generation.

The pH-related metabolic paradigm has rapidly grown in cancer research and treatment. In this contribution, this recent oncological perspective has been laterally for the first time in order to integrate neurodegeneration within the energetics of the cancer acid-base conceptual frame. At all levels of study, molecular, biochemical, metabolic and clinical, the intimate nature of both processes appears to be opposite mechanisms occurring at the far ends of a physiopathological intracellular pH/extracellular pH (pHi/pHe) spectrum. This wide-ranged original approach now permits an increase in our understanding of these opposite processes, cancer and neurodegeneration, and, as a consequence, allows to propose new avenues of treatment based upon the intracellular and microenvironmental hydrogen ion dynamics regulating and deregulating the biochemistry and metabolism of both cancer and neural cells. Under the same perspective, the etiopathogenesis and special characteristics of multiple sclerosis (MS) becomes an excellent model for the study of neurodegenerative diseases and, utilizing this pioneering approach, we find that MS appears to be a metabolic disease even before an autoimmune one. Also within this paradigm, several important aspects of MS, from mitochondrial failure to microbiota functional abnormalities, are analyzed in depth.

As the number of ships for marine transportation increases with the advancement of global trade, encountering multiple ships in marine traffic becomes common. This situation raises the risk of collision of the ships; hence this paper proposes a novel Fuzzy-logic based intelligent conflict detection and resolution algorithm, where the collision courses and possible avoiding actions are analyzed by considering ship motion dynamics and the input and output fuzzy membership functions are derived. As a conflict detection module, the Collision Risk (CR) is measured for each ship by using a scaled nondimensional Distance to the Closest Point of Approach (DCPA) and Time to the Closest Point of Approach (TCPA) as inputs. Afterwards, the decisions for collision avoidance are made based on the calculated CR, encountering angle and relative angle of each ship measured from others. In this regard, the rules for the Fuzzy interface system are defined in accordance with the COLREGs, and the whole system is implemented on the MATLAB Simulink platform. In addition, to deal with the multiple ship encounters, the paper proposes a unique maximum-course and minimum-speed change approach for decision making, which has been found to be efficient to solve Imazu problems, and other complicated multiple-ship encounters.

Non-orthogonal multiple access (NOMA) has been investigated to support massive connectivity for Internet-of-things (IoT) networks. However, since most IoT devices suffer from limited power and decoding capabilities, it is not desirable to pair a large number of devices simultaneously, which encourages two-user NOMA grouping. Additionally, most existing techniques have not considered the diversity in the target QoS of IoT devices, which may lead to spectrum inefficiency. Few investigations have partially considered that issue by using an order-based power allocation (OPA) approach, where the power is allocated according to the order to the user's target throughput within a priority-based NOMA (PNOMA) group. However, this does not fully capture the effects of diversity in the values of the users' target throughputs. In this work, we handle both problems by considering a throughput-based power allocation (TPA) approach, that captures the QoS diversity, within a three-users PNOMA group as a compromise between spectral efficiency and complexity. Specifically, we investigate the performance of a time-division PNOMA (TD-PNOMA) scheme, where the transmission time is divided into two-time slots with two-users per PNOMA group. The performance of such TD-PNOMA is compared with a fully PNOMA (F-PNOMA) scheme, where the three users share the whole transmission time, in terms of the ergodic capacity under imperfect successive interference cancellation (SIC). The results reveal the superiority of TPA compared with OPA approach in both schemes, besides that the throughput of both schemes can outperform each other under imperfect SIC based on the transmit signal-to-noise ratio and the deployment scenarios.

Machine reading comprehension aims to teach machines to understand a text like a human, and is a new challenging direction in Artificial Intelligence. Datasets play an important role while describing or building an algorithm for machine reading comprehension. The type of answers we required from developed algorithm depends on datasets.The datasets are classified into two types, namely datasets with extractive answers and datasets with descriptive answers. This article summarize both datasets with an example of each type to get better insight of datasets in machine reading comprehension and which datasets to use depending the requirements.

Multiple Myeloma (MM) is the second most common type of hematological disease and, although it is rare among patients under 40 years of age, its incidence rises in elderly subject. MM manifestations are usually known with the abbreviation CRAB (hyperCalcemia, Renal failure, Anaemia, and lytic Bone lesions). In particular, the extent of the bone disease is negatively related to a decreased patients’ quality of life and, in general, bone disease in MM increases both morbidity and mortality. The detection of lytic bone lesions on imaging, especially CT and MRI, is becoming crucial from the clinical viewpoint to separate asymptomatic from symptomatic MM patients and the detection of focal lytic lesion in these imaging data is becoming relevant even when no clinical symptoms are present. Therefore, radiology is pivotal in the staging and accurate management of patients with MM even in early phases of the disease. In this review we describe the opportunities offered by quantitative imaging and radiomics in multiple myeloma. At present time there is still high variability in the choice between various imaging methods to study MM patients and high variability in image interpretation with suboptimal agreement among readers even in tertiary centres. Therefore, the potential of medical imaging for patients affected by MM is still to be completely unveiled. In the next years, new insights to study MM with medical imaging will derive from artificial intelligence (AI) and radiomics usage in different bone lesions and from the wide implementations of quantitative methods to report CT and MRI. Eventually, medical imaging data can be integrated with the patient's outcomes with the purpose to find radiological biomarkers for predicting the disease prognostic flow and its therapeutic response.

The discovery of microRNAs (miRNAs) has fundamentally transformed our understanding of gene regulation. The competing endogenous RNA (ceRNA) hypothesis postulates that not only messenger RNAs but also other RNA transcripts, such as long non-coding RNAs and pseudogenes, can act as natural miRNA sponges. These RNAs influence each other’s expression levels by competing for the same pool of miRNAs through miRNA response elements on their target transcripts, thereby modulating gene expression and protein activity. In recent years, these ceRNA regulatory networks have gained considerable attention in cancer research. Several studies have identified cancer-specific ceRNA networks. Nevertheless, prior bioinformatic analyses have focused on long non-coding RNAs-associated ceRNA networks. Here, we identify an extended-ceRNA network (including both long non-coding RNAs and pseudogenes) shared across a group of four hormone-dependent (HD) cancers, i.e., prostate, breast, colorectal, and endometrial cancers, using data from The Cancer Genome Atlas (TCGA). We performed a functional enrichment analysis for differentially expressed genes in the shared ceRNA network of HD cancers, followed by a survival analysis to determine their prognostic ability. We identified two long non-coding RNAs, nine genes, and seventy-four miRNAs in the shared ceRNA network across four HD cancers. Among them, two genes and forty-one miRNAs were associated with at least one HD cancer survival. This study is the first to investigate pseudogene associated ceRNAs across a group of related cancers and highlights the value of this approach to understanding shared molecular pathogenesis in a group of related diseases.

Human ether-a-go-go-related gene (hERG) potassium channel is well-known contributor to drug-induced cardiotoxicity and therefore an extremely important target when performing safety assessments of drug candidates. Ligand-based approaches in connection with quantitative structure active relationships (QSAR) analyses have been developed to predict hERG toxicity. Availability of the recent published cryogenic electron microscopy (cryo-EM) structure for the hERG channel opened the prospect for using structure-based simulation and docking approaches for hERG drug liability predictions. In recent time, the idea of combining structure- and ligand-based approaches for modeling hERG drug liability has gained momentum offering improvements in predictability when compared to ligand-based QSAR practices alone. The present article demonstrates uniting the structure-based SILCS (site-identification by ligand competitive saturation) approach in conjunction with physicochemical properties to develop predictive models for hERG blockade. This combination leads to improved model predictability based on Pearson’s R and percent correct (represents rank-ordering of ligands) metric for different validation sets of hERG blockers involving diverse chemical scaffold and wide range of pIC50 values. The inclusion of the SILCS structure-based approach allows determination of the hERG region to which compounds bind and the contribution of different chemical moieties in the compounds to blockade, thereby facilitating the rational ligand design to minimize hERG liability.

The involvement of macular function in its preganglionic elements, during the neurodegenerative process of multiple sclerosis (MS), is controversial. In this case-control observational and retrospective study, we assessed multifocal electroretinogram (mfERG) responses from 41 healthy Controls, 41 relapsing-remitting MS patients without optic neuritis (ON) (MS-noON Group), 47 MS patients with ON: 27 with full recovery of high-contrast best corrected visual acuity (BCVA) (MS-ON-G Group) and 20 with poor recovery of BCVA (MS-ON-P Group). MfERG N1 and P1 implicit times (ITs), and N1-P1 response amplitude densities (RADs) were measured from concentric rings (R) with increasing foveal eccentricity: 0-5° (R1), 5-10° (R2), 10-15° (R3), 15-20° (R4), 20- 25° (R5), and from retinal sectors [superior, nasal, inferior and temporal] between 0-15° and 0- 25°. In MS-ON-P Group, mean mfERG RADs detected from R1 (0-5°) and from the central nasal quadrant (0-15°) were significantly reduced (p<0.01) with respect to those of Control, MS-noON and MS-ON-G Groups. No other significant differences between Groups for any mfERG parameters were found. Our results suggest that in MS, exclusively after ON with poor recovery of BCVA, the neurodegenerative process can induce dysfunctional mechanisms involving photoreceptors and bipolar cells of the fovea and of the more central nasal macular area.

This paper proposes a model to evaluate business projects to get into an incubator, allowing to rank them in order of selection priority. The model combines the Momentum method to build prospective scenarios and the Multiple Criteria Decision Making (MCDM) method TOPSIS-2N to rank the alternatives. Six business projects were evaluated to be incubated. The Momentum method made it possible for us to create an initial core of criteria for the evaluation of incubation projects. The TOPSIS-2N method supported the decision to choose the company to be incubated by ranking the alternatives in order of relevance. Our evaluation model has improved the existing models used by incubators. This model can be used and / or adapted by any incubator to evaluate the business projects to be incubated. The set of criteria for the evaluation of incubation projects is original and the use of prospective scenarios with a MCDM method to evaluate companies to be incubated does not exist in the literature.

To investigate the dynamics of land surface temperature (LST) in Afghanistan in the period 2000-2021 and to assess the impact of such factors as soil moisture, precipitation, and vegetation coverage on it, remotely sensed soil moisture data from Land Data Assimilation System (FLDAS), precipitation data from Climate Hazards Group Infra-Red Precipitation with Station (CHIRPS), and NDVI and LST from Moderate Resolution Imaging Spectroradiometer (MODIS) were downloaded and correlations between them were analyzed using the regression method. The result shows that the LST in Afghanistan has a slightly decreasing, but insignificant trend during the study period (R=0.2, p-value=0.25), while vegetation coverage, precipitation, and soil moisture had an increasing trend. It was revealed that soil moisture has the highest impact on LST (R=0.7, p-value=0.0007), and the soil moisture, precipitation, and vegetation coverage explain almost 80% of spring (R2=0.73) and summer (R2=0.76) LST variability in Afghanistan. The LST variability analysis done separately for Afghanistan’s rivers subbasins shows that the LST of the Amu Darya subbasin had an upward trend in the study period, while for the Kabul subbasin the trend was downward.

Assuming the Multiple Point Principle (MPP) as a new law of Nature, we considered the existence of the two degenerate vacua of the Universe: a) the first Electroweak (EW) vacuum at $v_1\approx 246$ GeV—“true vacuum”, and b) the second Planck scale “false vacuum” at $v_2 \sim 10^{18}$ GeV. In these vacua, we investigated different topological defects. The main aim of the paper is an investigation of the black-hole-hedgehogs configurations as defects of the false vacuum. In the framework of the $f(R)$ gravity, described by the Gravi-Weak unification model, we considered a black-hole solution, which corresponds to a “hedgehog”—global monopole, that has been “swallowed” by the black-hole with mass core $M_{BH}\sim 10^{18}$ GeV and radius $\delta\sim 10^{-21}$ GeV$^{-1}$. Considering the results of the hedgehog lattice theory in the framework of the $SU(2)$ Yang-Mills gauge-invariant theory with hedgehogs in the Wilson loops, we have used the critical value of temperature for the hedgehogs’ confinement phase ($T_c\sim 10^{18}$ GeV). This result gave us the possibility to conclude that the SM shows a new physics (with contributions of the $SU(2)$-triplet Higgs bosons) at the scale $\sim 10$ TeV. This theory predicts the stability of the EW-vacuum and the accuracy of the MPP.

Multiple myeloma (MM) is a genetically complex disease that results from a multistep transformation of normal to malignant plasma cells in the bone marrow. However, the molecular mechanisms responsible for the initiation and heterogeneous evolution of MM remain largely unknown. A fundamental step needed to understand the oncogenesis of MM and its response to therapy is the identification of driver mutations. The introduction of gene expression profiling (GEP) in MM was an important step in elucidating the molecular heterogeneity of MM and its clinical relevance. Since some mutations in myeloma occur in non-coding regions, studies based on the analysis of mRNA provide more comprehensive information on the oncogenic pathways and mechanisms relevant to MM biology. In this review, we discuss the role of gene expression profiling in understanding the biology of multiple myeloma together with the clinical manifestation of the disease, as well as its impact on treatment decisions and future directions.

In this paper we deal with the resolution of a fuzzy multiobjective programming problem using the level sets optimization. We compare it to other optimization strategies studied until now and we propose an algorithm to identify possible Pareto efficient optimal solutions.

In recent years, there have been frequent reports on the adverse effects of synthetic cannabinoid (SC) abuse. SCs cause psychoactive effects, similar to those caused by marijuana, by binding and activating cannabinoid receptor 1 (CB1R) in the central nervous system. The aim of this study was to establish a reliable quantitative structure-activity relationship (QSAR) model to correlate the structures and physicochemical properties of various SCs with their CB1R-binding affinities. We prepared 15 SCs and their derivatives (tetrahydrocannabinol [THC], naphthoylindoles, and cyclohexylphenols) and determined their binding affinity to CB1R, which is known as a dependence-related target. We calculated the molecular descriptors for dataset compounds using an R/CDK (R package integrated with CDK, version 3.5.0) toolkit to build QSAR regression models. These models were established and statistical evaluations were performed using the mlr and plsr packages in R software. The most reliable QSAR model was obtained from the partial least squares regression method via external validation. This model can be applied in vivo to predict the addictive properties of illicit new SCs. Using a limited number of dataset compounds and our own experimental activity data, we built a QSAR model for SCs with good predictability. This QSAR modeling approach provides a novel strategy for establishing an efficient tool to predict the abuse potential of various SCs and to control their illicit use.

This paper will discuss the application of statistic modeling to interpret a health system crisis in Sri Lanka due to COVID- 19.A strong focus on the preventive approach and the contact tracing with the utilization of available resources in a rational manner describes Sri Lanka’s response towards COVID- 19 prevention and mitigation. The early contact tracing, preemptive quarantining, isolation, and treatment were implemented as a concerted effort. This approach, proven efficient during the early phase of the pandemic, was sustainable when there was a rapid increase in the COVID- 19 patients since July 2021, exceeding the health system capacity.The country’s COVID- 19 situation during the period from 01st of August 2021 to 31st of October 2021 was taken into consideration. Variables used for analysis were; total number of cases, recovered cases, comorbid and O₂ dependent patients, ICU patients, and deaths. The regression model was applied to analyze the data by using the EViews 12 (x64) software application.The correlation coefficients of all the independent variables under consideration implies that they have a strong positive relationship with the number of deaths occurred during the said period. According to the computed multiple linear regression model, the number of positive cases and O₂ dependents have a positive relationship with the dependent variable. Further, the Durbin- Watson stat value of the model and multicollinearity test reflect that it is free from serial correlation thereby the model is fit. From the perspective of epidemiological control, these findings highlight the importance of keeping the number of cases within the limits of health system capacity.

We introduce the Transformation Flower Approach (TFA), a Theory of Change that attends to multiple value creation and institutional change as a dual design challenge. We highlight how the TFA integrates social scientific theories and models relevant for transformative change (in particular focusing on pathways, leverage points, governance, power, and values) and demonstrate its practical value by an application to the ongoing transformation of the Dutch food system. By providing a holistic, transdisciplinary and practically relevant approach that aims to support new social contract formation, the TFA goes beyond other transformative change approaches. Based on the notion of pathways, it offers a toolbox that aids in working towards desired futures, involving both incumbents and challengers in an effort to harness untapped yet proximal potentials in a forward-looking way. By embracing an innovation approach, it not only promises to circumvent resistance to change, but also serves as a step-by-step approach to identify options for multiple value creation and effective cooperation. We demonstrate the analytical and practical value of the TFA by discussing action perspectives at various levels and scales in the context of the Dutch food system transition, including (1) area-oriented approaches, (2) acceleration agendas for specific transformation pathways, and (3) actor-specific transformation flowers. In developing these, we emphasize the importance of interdependencies between leverage points. Our approach helps to identify opportunities to link transformative options (the what), actors (the who) and levers (the how) in dynamic interaction to embark on transformative pathways.

Introduction: Multiple sclerosis (MS) is a demyelinating, chronic, inflammatory and autoimmune disease of the central nervous system (CNS) with axonal degeneration, presenting a progressive and variable course. MS patients usually have complications, such as bladder dysfunction, presence of urinary symptoms and Urinary Tract infection (UTI), which is one of the three most common non-neurological complications in MS patients. Objective: Analyze the most diverse aspects of UTI in MS patients, focusing on risk factors, prevalence, hospitalization and mortality rates of UTIs in this group. Methods: A non-systematic review of articles published on PubMed in the last 10 years with the search terms "Urinary Tract Infection" AND "Multiple Sclerosis". Discussion: MS patients have a high UTI prevalence, mainly due to the occurrence of urinary disorders in these patients. The most common symptoms of UTI in MS patients are urinary urgency, polyuria, nocturia, urinary retention, and incontinence. Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae were the most found organisms and treatment is based on antibiotic therapy. Moreover, UTIs can precipitate outbreaks, worsen the disease, causing more damage and a severe neurological condition deterioration. Therefore, UTIs in this group are associated with a high hospitalizations rate and a high mortality rate. Conclusion: UTI represents a great risk and concern in MS patients. The high prevalence, hospitalization rate and mortality rate of UTI in MS is worrying, such as the cause-consequence relationship between UTIs and the use of corticosteroids in outbreaks. Therefore, it is important to be aware of a UTI in this group to make early diagnoses, adequate management, and new infections prevention. Thus, further studies are needed to thoroughly analyze each nuance of this important comorbidity for MS patients.

Life cycle assessment (LCA) is used frequently as a decision support tool for evaluating different design choices of products based on their environmental impacts. A life cycle usually comprises several phases of varying timespan. The amount of emissions generated from different life cycle phases of a product could be significantly different from one another. In conventional LCA, the emissions generated from the life cycle phases of a product are aggregated at the inventory analysis stage, which is then used as an input for life cycle impact assessment. However, when the emissions are aggregated, the temporal variability of inventory data is ignored, which may result in inaccurate environmental impact assessment. Besides, the conventional LCA does not consider the environmental impact of circular products with multiple use cycles. It poses difficulties in identifying the hotspots of emission-intensive activities with the potential to mislead conclusions and implications for both practice and policy. To address this issue and to analyse the embedded temporal variations in inventory data in a CE context, the paper proposes to calculate the emission intensity for each life cycle phase. It is argued that calculating and comparing emission intensity, based on the timespan and amount of emissions for individual life cycle phases, at the inventory analysis stage of LCA offers a complementary approach to the traditional aggregate emission-based LCA approach. In a circular scenario, it helps to identify significant issues during different life cycle phases and the relevant environmental performance improvement opportunities through product, business model and supply chain design.

Sequence alignment and comparison through pairwise, multiple, global and local techniques are the main principles that underpin comparative genomics. However, most of the algorithms used are alignment-based which imposed some limitations on their use and application. In an attempt to provide an alignment-free alternative approaches, a methodology of comparative optinalysis and statistical mirroring was used and adopted to provide a suitable alternative for multiple genomic sequence comparison. In this article, methods comparison with MUSCLE, MUFFT, Clustal Omega, and T-Coffee was designed to assess the suitability and statistical power of statistical mirroring as an alternative method for multiple genomic sequences comparison using different sets of logically generated biological sequence datasets with different problems and computational complications. The results of the comparisons validate that statistical mirroring is a suitable alignment-free alternative approach for multiple genomic sequence comparison. The applied method (statistical mirroring) distinguishes itself over MUSCLE, MUFFT, Clustal Omega, and T-Coffee in specificity to a position-specific changes, specificity to a base-specific changes, cladogram and phylogenetic linearity, alignment independency, computational simplicity, and limit of input capacity.

The persistence of geographic inequities in vaccination coverage often evidences the presence of zero-dose and missed communities and vulnerabilities to vaccine-preventable diseases. These inequities were exacerbated in many places during the COVID-19 pandemic, due to severe disruptions to vaccination services. Understanding changes in zero-dose prevalence and associated risk factors in the context of the COVID-19 pandemic is, therefore, critical to designing effective strategies to reach vulnerable populations. Using data from nationally representative household surveys conducted before the COVID-19 pandemic in 2018 and during the pandemic in 2021 in Nigeria, we fitted Bayesian geostatistical models to map the distribution of three vaccination coverage indicators: receipt of DTP1, MCV1 and any of the four basic vaccines (BCG, OPV0, DTP1 and MCV1), and corresponding zero-dose estimates independently at 1x1 km resolution and the district level during both time periods. We also explored changes in the factors associated with non-vaccination at the national and regional levels using multilevel logistic regression models. Our results revealed no increases in zero-dose prevalence due to the pandemic at the national level, although considerable increases were observed in a few districts. We found substantial subnational heterogeneities in vaccination coverage and zero-dose prevalence both before and during the pandemic, showing broadly similar patterns in both time periods. Areas with relatively higher zero-dose prevalence occurred mostly in the north and a few places in the south in both time periods. We also found consistent areas of low coverage and high zero-dose prevalence using all three zero-dose indicators, revealing areas in greatest need. At the national level, risk factors related to socioeconomic/ demographic status (e.g., maternal education), maternal access to and utilization of health services and remoteness were strongly associated with the odds of zero dose in both time periods, while those related to communication were mostly relevant before the pandemic. These associations were also supported at the regional level, but we additionally identified risk factors specific to zero dose in each region; for example, communication and cross-border migration in the northwest. Our findings can help guide tailored strategies to reduce zero-dose prevalence and boost coverage levels in Nigeria.

Paper-based microfluidic analysis devices (μPADs) have attracted attention as a cost-effective platform for point-of-care testing (POCT), food safety, and environmental monitoring. Recently, three-dimensional (3D)-μPADs have been developed to improve the performance of μPADs. For accurate diagnosis of diseases, however, 3D-μPADs need to be developed to simultaneously detect multiple biomarkers. Here, we report a 3D-μPADs platform for the detection of multiple biomarkers that can be analyzed and diagnosed with a smartphone. The 3D-μPADs were fabricated using a 3D digital light processing printer and consisted of a sample reservoir (300 µL) connected to 24 detection zones (of 4 mm in diameter) through 8 microchannels (of 2 mm in width). With the smartphone application, eight different biomarkers related to various diseases were detectable in concentrations ranging from normal to abnormal conditions: glucose (0–20 mmol/L), cholesterol (0–10 mmol/L), albumin (0–7 g/dL), alkaline phosphatase (0–800 U/L), creatinine (0–500 µmol/L), aspartate aminotransferase (0–800 U/L), alanine aminotransferase (0–1000 U/L), and urea nitrogen (0–7.2 mmol/L). These results suggest that 3D-µPADs can be used as a POCT platform for simultaneous detection of multiple biomarkers.

In this work, we have developed a non-ordinary state-based peridynamic model for multiple crack initiation and propagation due to compression-compression fatigue load. In each loading cycle, the fatigue loading is redistributed among the peridynamic solid body, leading to the progressive fatigue damage initiation and propagation in an autonomous fashion. The proposed fatigue model parameters are firstly validated by 3D numerical benchmark tests, and then it is applied to simulate widespread fatigue damage evolution of the aircraft wing corner box. The modified constitutive damage model has been implemented into the peridynamics framework at finite strain. Furthermore, the criterion algorithm from multiple initiation to propagation is discussed. It is shown that the numerical results obtained from peridynamics simulations are in general agreement with those from the experiment data. The comparison of experimental and numerical results indicates that the proposed non-ordinary state-based peridynamics fatigue model has the ability to capture the multiple crack initiation and propagation and other features of the aluminium alloy material.

Multiple sclerosis (MS) and necrotizing periodontitis (NP) are two diseases whose aetiology and pathophysiology do not seem to have a common link; however, the treatment of MS with monoclonal antibodies and the decrease in humoral immunity that this entails can be a trigger or an aggravation in patients who present NP. We present a clinical case of NP in which its clinical manifestations, treatment and evolution during therapy with ocrelizumab are reflected. During the evolution of the case, a rapid progression of NP was evidenced. During her evolution, the patient suffered bilateral pneumonia due to COVID requiring treatment with corticosteroids and antibiotics, which led to clinical relief of her NP. Given this important clinical finding, we consider of great interest the regulated dental monitoring of those patients with MS before, during and after the administration of monoclonal antibodies to prevent periodontal deterioration.

The formation of high-melting-point Cu₆Sn₅ interconnections is crucial to overcome the collapse of Sn-based micro-bumps and produce reliable intermetallic interconnections in three-dimensional (3D) package. However, because of the multiple reflows in 3D package manufacturing, Cu₆Sn₅ interconnections will experience the cyclic polymorphic transitions in the solid state. The repeated and abrupt change in the Cu₆Sn₅ lattice due to the cyclic polymorphic transitions can cause extreme strain oscillations, producing damages at the surface and in the interior of the Cu₆Sn₅ matrix. Moreover, because of the polymorphic-transition-induced grain splitting and superstructure phase formation, the reliability of Cu₆Sn₅ interconnections will thus face great challenges in 3D package. In addition, the Cu₆Sn₅ polymorphic transition is structure-dependent, and the η′↔η polymorphic transition will occur at the surface while the η′↔ηs↔η polymorphic transition will occur in the deep matrix. Our results can provide in-depth understandings of structural evolution and damage mechanism of Cu₆Sn₅ interconnections in real 3D package manufacturing.

In this paper, spatial pulse position modulation (SPPM) is used as a case study to investigate the performance of the optical spatial modulation (SM) technique in outdoor atmospheric turbulence (AT). A closed-form expression for the upper bound on the asymptotic symbol error rate (SER) of SPPM in AT is derived and validated by closely-matching simulation results. The error performance is evaluated in weak to strong AT conditions. As the AT strength increases from the weak to strong, the channel fading coefficients become more dispersed and differentiable. Thus, a better error performance is observed under moderate-to-strong AT compared to weak AT. The performance in weak AT can be improved by applying unequal power allocation to make FSO links more distinguishable at the receiver. Receive diversity is considered to mitigate irradiance fluctuation and improve the robustness of the system to turbulence-induced channel fading. The diversity order is computed as half of the number of detectors. Performance comparisons, in terms of energy and spectral efficiencies, are drawn between the SPPM scheme and conventional MIMO schemes such as repetition coding and spatial multiplexing.

Tremor is a prevalent symptom associated with multiple conditions, including Essential Tremor (ET), Parkinson’s disease (PD), multiple sclerosis (MS), stroke, and trauma. The surgical management of tremor evolved from stereotactic lesions to deep-brain stimulation (DBS), which allowed safe and reversible interference with specific neural networks. This paper reviews the current literature on DBS for tremor, starting with a detailed discussion of current tremor targets (Vim, Raprl, caudal Zi, Vo and STN) and continuing with a discussion of results obtained when performing DBS in the various aforementioned tremor syndromes. Future directions for DBS research are then briefly discussed.

Soil quality assessment based on crop yields and identification of key indicators of it can be used for better management of agricultural production. In the current research, the weighted additive soil quality index (SQIw), factor analysis (FA) and multiple linear regression (MLR) method are used to assess the soil quality of rainfed winter wheat fields with two soil orders on 53.20 km2 of agricultural land in western Iran. A total of 18 soil quality indicators were determined for 100 soil samples (0-20 cm depth) from two soil orders (Inceptisols and Entisols). The soil properties measured were: pH, soil texture, organic carbon (OC), cation exchange capacity (CEC), electrical conductivity (EC), soil microbial respiration (SMR), carbonate calcium equivalent (CCE), soil porosity (SP), bulk density (BD), exchangeable sodium percentage (ESP), mean weight diameter (MWD), available potassium (AK), total nitrogen (TN), available phosphorus (AP), available Fe (AFe), available Zn (AZn), available Mn (AMn), and available Cu (ACu). Mean wheat grain yield for the two years for all of the 100 sampling sites was also gathered. The SQIw was calculated using two weighting methods (FA and MLR) and maps were created using a digital soil mapping framework. The soil indicators taken in the minimum data set (MDS) were AK, clay, CEC, AP, SMR, and sand. The correlation between the MLR weighting technique (SQI-M) and the rainfed wheat yield (r=0.62) was slightly larger than that the correlation of yield with the FA weighted technique (SQI-F) (r=0.58). Results showed that the means of both SQI-M and SQI-F and rainfed wheat yield for Inceptisols were higher than for Entisols although these differences were not statistically significant. Both SQI-M and SQI-F showed that areas with Entisols had lower proportions of good soil quality grades (Grade I and II), and higher proportions of poor soil quality grades (Grade IV and V) compared to Inceptisols. Based on these results, soil type must be considered for soil quality assessment in future studies to maintain and enhance soil quality and sustainable production. The overall soil quality of the study region was of poor and moderate grades. To improve soil quality, it is therefore recommended that effective practices such as the implementation of scientific integrated nutrient management involving the combined use of organic and inorganic fertilizers in rainfed wheat fields be promoted.

World Health Organization (WHO) provides the guideline for managing the Particulate Matter (PM) level because when the PM level is higher, it threats the human health. For managing PM level, the procedure for measuring PM value is needed firstly. We use Tapered Element Oscillating Microbalance (TEOM)-based PM measuring sensors because it shows higher cost-effectiveness than Beta Attenuation Monitor (BAM)-based sensor. However, TEOM-based sensor has higher probability of malfunctioning than BAM-based sensor. In this paper, we call the overall malfunction as an anomaly, and we aim to detect anomalies for the maintenance of PM measuring sensors. We propose a novel architecture for solving the above aim that named as Hypothesis Pruning Generative Adversarial Network (HP-GAN). We experimentally compare the several anomaly detection architectures to certify ours performing better.

The prevalence of food allergy has increased over the last decades and consequently the food labeling policies have improved over the time in different countries to regulate allergen presence in foods. In particular, Reg 1169 in EU mandates the labelling of 14 allergens whenever intentionally added to foods, but the inadvertent contamination by allergens still remains uncovered topic. In order to warn consumers on the risk of cross-contamination occurring in certain categories of foods, a precautionary allergen labelling system has been put in place by food industries on voluntary basis. In order to reduce the overuse of PAL, reference doses and action limits have been proposed by the VITAL project representing a guide in this jeopardize scenario. Development of sensitive and reliable mass spectrometry methods are therefore of paramount importance in this regard to check the contamination levels in foods. In this paper we describe the development of a managed time MRM method based on a triple quadrupole platform for milk and egg quantification in processed food. The method was in house validated and allowed to achieve levels of proteins lower than 0.2mg of total milk and egg proteins respectively in cookies, challenging the doses recommended by VITAL. The method was finally applied to cookies labeled as milk and egg-free. This method could represent in perspective a promising tool to be implemented along the food chain to detect even tiny amounts of allergens contaminating food commodities.

The lytic bone disease is a hallmark of multiple myeloma, being present in about 80% of patients with newly diagnosed MM, and in more during the disease course. The myeloma associated bone disease (MBD) severely affects the morbidity and quality of life of the patients. MBD defines treatment demanding MM. In recent years, knowledge of the underlying pathophysiology has increased, and novel imaging technologies, medical and non-pharmaceutical treatments have improved. In this review, we highlight the major achievements in understanding, diagnosing and treating MBD. For diagnosing MBD, low-dose whole-body CT is now recommended over conventional skeletal survey, but also more advanced functional imaging modalities, such as diffusion-weighted MRI and PET/CT are increasingly important in the assessment and monitoring of MBD. Bisphosphonates have, for many years, played a key role in management of MBD, but denosumab is now an alternative to bisphosphonates, especially in patients with renal impairment. Radiotherapy is used for uncontrolled pain, for impeding fractures and in treatment of impeding or symptomatic spinal cord compression. Cement augmentation has been shown to reduce pain from vertebral compression fractures. Cautious exercise programs are safe and feasible and may have the potential to improve the status of patients with MM.

Breast cancer is a leading cause of death among women. Conventional screening methods, such as mammography, and ultrasound diagnosis are expensive and have significant limitations. Digital Image Elasto Tomography (DIET) is a new noninvasive breast cancer screening system that has a potential to be a low cost and reliable breast cancer screening tool. It is based on modal analysis of the breast mass, and stereographic 3D image analysis to detect the stiffer abnormal tissues. However, camera sensor noise, especially Gaussian noise is a major source of Optical Flow (OF) error in this approach to tumor detection. This work studies the performance of different conventional filters, including the standard Gaussian filter tool to remove this noise and produce more robust screening results. A radical approach, Multiple Frame Noise Removal (MFNR) is proposed, for use in this type of medical image processing instead of a Gaussian filter or other typical image noise removal tools. Its a multiple frame noise removal method where Probability Density Function (PDF) of noise is extracted from the multiple images by characterizing the same pixel positions in multiple images. The noise becomes deterministic, and hence easily removed. The proposed algorithm was applied to a data set from 10 phantom breast tests with a prototype DIET system, and 10 in-vivo samples from healthy women. Comparisons were made to an optimal Gaussian filter form that is commonly used. Reductions in OF error using these digitally imaged data sets was used to compare performance. Refinement of the images for medical applications requires higher PSNR, which was successfully achieved by using MFNR algorithm. In this study, the algorithm was used to improve the imaging results of a DIET system. The conventional wisdom that states that noise removal and detail preservation are contrasting effects is

A lightweight image encryption algorithm based on chaos induction via a 5-dimensional hyperjerk oscillator (5DHO) is presented. First, the dynamics of our 5DHO network is investigated and shown to exhibit up to five coexisting hidden attractors in the state space that depend exclusively on the system’s initial values. Further, a simple implementation of the circuit was used to validate its ability to exhibit chaotic dynamical properties. Second, an Arduino UNO platform is used to confirm the usability of our oscillator in digital implementation of the system. Finally, an efficient image encryption application is executed using the proposed chaotic networks based on the use of permutation-substitution sequences. The superior qualities of the proposed strategy are traced to the dynamic set of keys used in the substitution process which heralds the generation of the final ciphered image. Based on the results obtained from the entropy analysis (7.9976), NPCR values (99.62), UACI tests (33.69) and encryption execution time for 512x512 images (0.1179 sec), the proposed algorithm is adjudged to be fast and robust to differential and statistical attacks relative to similar approaches.

The emerging advancements in separation and classification of various biological matters (e.g., living cells and proteins) using magnetic levitation (MagLev) technology have proven to be effective for improving disease diagnostics. MagLev technique has the capacity to detect and separate useful diagnostic biomarkers from biocomplex environments (e.g., blood and plasma), minimizing the unpleasant daunting task of sample preparations and labeling procedures. Here, we demonstrate the capability of this technique combined with image analysis and machine learning approaches for discriminating the various types of multiple sclerosis (MS) as an important model disease. To arrive at a systematic expert system, we combined robust statistical analysis with machine learning to (1) detect and remove outliers from the raw MagLev image datasets; then (2) process the images and output a low dimensional representation of massive data without losing the main statistical features; and finally (3) predict the MS clinical disease type (Relapsing-Remitting, Primary–Progressive, or Secondary–Progressive) using a classifier. This is expected to improve MS diagnostics since the current practices rely solely on clinical observation and central nervous system imaging, making management approaches are often reactional and inefficient. Thus, there is a need to identify the disease type early on. MagLev is expected to improve MS diagnostics, thereby aiding in prognosis and guiding adequate treatment choices before the patient exhibits signs of permanent neurological deficits.

Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of plasma cells in the bone marrow (BM) microenvironment. Despite the progress made in treatment, some MM patients still die within the first year of diagnosis. Numerous studies investigating microRNA (miRNA) expression patterns suggest they may be good prognostic markers. The primary aim of this study was to analyze the expression of selected miRNAs in the serum of MM patients subsequently treated with bortezomib-based regimens and determine their potential to predict early mortality. The study was conducted in 69 prospectively-recruited patients with newly-diagnosed MM admitted to the Department of Hematology of the Copernicus Memorial Hospital, Lodz (Poland) between 2017 and 2021. Among them, 17 patients experienced death within 12 months of diagnosis. The expression of 31 selected miRNAs was determined using miRCURY LNA miRNA Custom PCR Panel. The obtained clinical data included patient characteristics on diagnosis, treatment regimen, response to treatment, and follow-up. Differential expression analysis found two miRNAs to be significantly downregulated in the early mortality group: hsa-miR-328-3p (fold change- FC: 0.72, p=0.0342) and hsa-miR-409-3p (FC: 0.49, p=0.0357). Univariate and multivariate logistic regression analyses were performed to assess the early mortality rate. The final model consisted of hsa-miR-409-3p, hsa-miR-328-3p, age and R-ISS 3. It yielded an area under the curve (AUC) of 0.863 (95%CI: 0.761-0.965) with 88.2% sensitivity and 77.5% specificity. Further external validation of our model is necessary to confirm its clinical value.

In this paper, initially a mathematical model is formulated for transient frequency of power system considering time delays which occur while transmitting the control signals in open communication infrastructure. Time delay negligence in a power system leads to improper measurement of frequency variation in power system. The study of impact of time delays on the stability of power system is performed by estimating the decay rate of frequency wave form using Kalman Filter (KF). In power system, there is a possibility of multiple time delays. This paper also focusses on developing Interacting Multiple Model (IMM) Algorithm with multiple model space using Kalman Filter (KF) as state estimator tool. The multiple time delays in power system is considered as multiple model space. The result shows that KF provides better estimate of correct model for a particular input-set. The qualitative properties of Riccati difference equation (RDE) in terms of state error covariance of IMMKF are also analyzed and presented.

A progressive and chronic neurological condition called MSA (Multiple System Atrophy) is characterized clinically by varying degrees of dysautonomia, cerebellar ataxia, and parkinsonism. The concept of mitochondrial dysregulation in MSA is one perspective in handling this neurodegenerative disease. Damage to functional mitochondria is driven by the presence of ɑ-Synuclein-induced mitochondrial localization. The goal of MSA treatment up until now has been to reduce symptoms. One of the innovations in the treatment of MSA could be the novel idea based on mitochondrial reprogramming pathways. Mitochondrial reprogramming can be done in various ways in which the use of hydrogen, magnesium and low-dose hydrogen peroxide.

Traditional discrimination techniques for Euler deconvolution use only the color spectrums of structural indexes, without considering the spatial distribution characteristics and inherent relationships among the Euler solutions to separate adjacent causative sources. In the present study, a new approach was developed for discriminating uncorrelated Euler solutions from coherent solutions based on the focusing levels indicated by the probability density distributions generated using multivariate kernel density estimations (KDE). A novel multiple coverage technique was proposed by using a series of different sized moving windows over gridded gravity data, which formed tight clusters of Euler solutions for different sized causative sources. The results of the probability density distributions were obtained using a 3-D KDE method for the Euler solution subsets {x, y, z} of synthetical models, and real data from a survey conducted in British Columbia (Canada) which had successfully established more credible and meaningful geological models when compared with three other subsets.

Multiple Sclerosis (MS) is a progressive neurodegenerative disease that affects more than 2 million people worldwide. Increasing knowledge about MS in different populations has advanced our understanding of disease epidemiology and variation in the natural history of MS among White and minority populations. In addition to differences in incidence, African American (AA) and Hispanic patients have greater disease burden and disability in earlier stages of disease compared to White patients. To further characterize MS in AA and Hispanic populations, we conducted a retrospective chart analysis of 112 patients treated at an MS center in Houston, Texas. Here, we describe differences in clinical presentation, MRI findings, treatment regimens, disability progression, and relapse rate. We found that patients who were evaluated by a neurologist at symptom onset had significantly decreased odds of greater disability [defined as Expanded Disability Status Scale (EDSS) &gt; 4.5] at last presentation compared to patients who were not evaluated by a neurologist (OR: 0.04, 95% CI: 0.16-0.9). We also found that active smokers had significantly increased odds of greater disability both at diagnosis and at last clinical encounter compared to nonsmokers (OR: 2.44, 95% CI: 1.10-7.10, OR= 2.44, 95% CI: 1.35-6.12, p= 0.01, respectively). Assessment of the degree of brain atrophy and progression over time along with enumeration of T1, T2, and gadolinium-enhancing brain lesions did not reveal differences across groups.

Objective: The purpose of this study was to investigate the effects of Crocin on brain neuroterophins, cognition, sensory and motor dysfunction and compare to fingolimod effects in experimental model of demyelination with Ethidium Bromide EB in female Wistar rats. Methods: Animals were assigned in to 8 groups; Sham, Sham operated (ShOp), EAE, crocin treated (Cr5,10,20 mg/kg), Vehicle, Fingolompd (Fing) and fingolimod + crocin (Cr+Fing). Demyelination was induced by single dose injection of 10 μl of EB 0.1% into the fourth ventricle of the brain. Crocin and fingolimod were applied for 21 days, daily, oral gavage. BDNF, NGF1, nerve conduction velocities, tail flake latency, balance and behavioral variables were sampled and analyzed by paired t-test and ANOVA test with repeated post hoc measurements. Results: The results showed that crocin improves all studied factors, but remarkable imrovments were observed in dosage of 10 mg/kg. Crocin (10mg/kg) and fingolimod (1mg/kg) significantly improved cognition variables in open field test, sensory and motor nerve conduction velocity, tail flick latency and clinical signs (p<005). In addition, applying of crocin co-administered with fingolimod led to significant increases in all assessed factors, greater than crocin or fingolimod intervention alone (α≤0.001). Conclusion: Based on the current findings, crocin can improve the level of brain neurotrophins, exploratory behavior and nerve conduction after demyelination as close as fingolimod results. So, crocins can be considered as a neuro supportive agent in the management of degenerative diseases maybe similar to fingolimod mechanism.

Abstract: Long noncoding RNAs (lncRNAs) are deregulated in human cancers and are associated with disease progression. Plasmacytoma Variant Translocation 1 (PVT1), an lncRNA, is located adjacent to MYC, linked to multiple myeloma (MM). PVT1 is expressed in MM and is associated with carcinogenesis, however, its role and regulation machinery remain uncertain. We examined PVT1/MYC expression through real time PCR in plasma cells purified from 59 MGUS and 140 MM patients. MM cell lines KMS11, KMS12PE, OPM2, and RPMI8226 were treated with JQ1, a MYC superenhancer inhibitor, or MYC inhibitor 10058-F4. The expression levels of PVT1 and MYC were significantly higher in MM than in MGUS (p &lt; 0.0001), and showed positive correlation with disease progression (r = 0.394, p &lt; 0.0001). JQ1 inhibited cell proliferation and decreased the expression levels of MYC and PVT1. However, 10054-F4 did not alter the expression level of PVT1. The positive correlation between MYC and PVT1 in patients, synchronous downregulation of MYC and PVT1 by JQ1, and no effect of MYC inhibitor on PVT1 expression suggest that the expression of these two genes is coregulated by a superenhancer. Cooperative effects between these two genes may contribute to MM pathogenesis and progression.

The purpose of the study is to empirically analyze the effect of quality of governance on tax revenue in South Africa. This is done by analyzing a time series dataset covering 1996 to 2020. The study used voice and accountability, regulatory quality, government effectiveness, control of corruption, political stability and rule of law as proxies of quality of governance. Multiple regression analysis was performed to test hypotheses. Based on the regression results, all quality of governance variables in South Africa have a negative effect on tax revenue except corruption control. The findings of this study also include policy recommendations. The government of South Africa must design and implement effective ways to combat poor governance, which results in a tax revenue shortfall.

To assess cognitive impairment and affective symptoms and their association with damage to normal-appearing white matter (NAWM) in patients with clinically isolated syndrome (CIS), we compared neuropsychological test scores between patients with CIS and healthy controls, and examined correlations between these and proton magnetic resonance spectroscopy (1H-MRS) outcomes in patients with CIS. Forty patients with CIS and 40 healthy participants were tested with the set of neuropsychological tests, the Beck Depression Inventory (BDI) and the Hospital Anxiety and Depression Scale (HADS). Single-voxel 1H-MRS was performed on frontal and parietal NAWM of patients with CIS to assess ratios of N-acetyl-aspartate (NAA) to creatine (Cr), myo-inositol (mI), and choline (Cho), as well as mI/Cr and Cho/Cr ratios. Patients with CIS had lower cognitive performance, higher scores for the BDI and anxiety subscale of HADS than healthy controls. There were significant correlations between the following neuropsychological tests and metabolic ratios in the frontal NAWM: Stroop Color-Word Test and Cho/Cr, Symbol Digit Modalities Test and mI/Cr as well as NAA/mI, Go/no-go reaction time and NAA/Cho as well as NAA/mI, Californian Verbal Learning Test and NAA/Cr. BDI scores were related to frontal NAA/mI and parietal NAA/Cr and Cho/Cr ratios, whereas HADS-depression scores were associated with frontal NAA/Cr and NAA/mI, and parietal NAA/Cr and Cho/Cr ratios. HADS-anxiety correlated with parietal NAA/Cr ratio. This study suggests that neurochemical changes in the NAWM assessed with single-voxel 1H-MRS are associated with cognitive performance and affective symptoms in patients with CIS.

The Bacillus Calmette-Guérin (BCG) vaccine has been used for over one hundred years to protect against the most lethal infectious agent in human history, tuberculosis. Over four billion BCG doses have been given and, worldwide, most newborns receive BCG. A few countries, including the United States, did not adopt the WHO recommendation for routine use of BCG. Moreover, within the past several decades, most of Western Europe and Australia, having originally employed routine BCG, have discontinued its use. This review article articulates the impacts of those decisions. The associated consequences include increased tuberculosis, increased infections caused by non-tuberculous mycobacteria (NTM), increased autoimmune disease (autoimmune diabetes and multiple sclerosis) and increased neurodegenerative disease (Parkinson’s disease and Alzheimer’s disease). This review also offers an emerged zoonotic pathogen, Mycobacterium avium ss. paratuberculosis (MAP) as a mostly unrecognized NTM that may have a causal role in some, if not all, of these diseases. Current clinical trials with BCG for varied infectious, autoimmune and neurodegenerative diseases have brought this century-old vaccine to the fore due to its presumed immuno-modulating capacity. With its historic success and strong safety profile, the new and novel applications for BCG may lead to its universal use –putting the Western World back onto the road not taken.

In this paper, we present an extended version of the Hadi-Vencheh model for multiple criteria ABC inventory classification. The proposed model is a nonlinear weighted product model (WPM) which determines a common set of weights for all the items. Our proposed nonlinear WPM incorporates multiple criteria with different measure units, without converting the performance of each inventory item in terms of each criterion into a normalized attribute value, thereby providing an improvement over the model proposed by Hadi-Vencheh. Our study mainly includes various criteria for ABC classification, and demonstrates an efficient algorithm for solving nonlinear programming problems in which the feasible solution set does not have to be convex. The algorithm presented in this study improves the solution efficiency of the Canonical Coordinates Method (CCM) algorithm substantially when applied to large scale, nonlinear programming problems. The modified algorithm was tested to compare our proposed model results to the results derived using the Hadi-Vencheh model and demonstrate the algorithm's efficacy. The practical implications of the study are to develop an efficient nonlinear optimization solver by optimizing the quality of existing solutions, thus improving time and space efficiency.

Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease that affects the nervous system. Peripheral blood leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNA-CN) are potential biomarkers of disability and neurological damage. The present work evaluated LTL and mtDNA-CN in 75 relapsing-remittent MS (RRMS) patients 50 of whom had an Expanded Disability Status Scale (EDSS) 0 to 3 (mild-moderate disability), and 25 had an EDSS of 3.5 to 7 (severe disability). Absolute LTL and absolute mtDNA-CN were measured via real-time polymerase chain reaction (qPCR). The LTL and mtDNA-CN were significantly lower in RRMS severe disability than in RRMS mild-moderate disability (3.924 ± 0.124 vs 2.854 ± 0.092, p<00001; 75.14 ± 1.77 vs 68.06 ± 1.608, p<0.00001, respectively). The LTL and mtDNA-CN showed a linear correlation in RRMS with mild-moderate disability (r=0.2986, p=0.0351). In addition, in a binary logistic regression model the LTL can predict severe disability (AUC=0.697, p=0.0031, cutoff ≤ 3.0875 Kb, sensitivity= 73.1%, specificity=62.5%), the prediction is improved by including age to the model (AUC=0.765, <0.0001, sensitivity=78.26%, specificity=81.25%). Aging is closely linked to the development of disability in RRMS and can be evaluated through LTL and mtDNA-CN absolute quantification.

While there are many models of epidemic evolution perhaps the basis for such models finds itself in the lumped behavior expressed through the so-called SIR model (Susceptible, Infectious, Recovered) from which spring many related models. This paper discusses multiple analytic solutions to that equation including those that are available in closed analytic form and those for which at least one final integral has to be done numerically, so-called quasi-analytic solutions. The solutions are intrinsically time-dependent of course. The hope is that such an investigation will lead to a better understanding of when and how models can be of use in studying the dynamical evolution of diseases including, perhaps, the great influenza pandemic of 1918 together with later pandemics and epidemics not excluding the Covid-19 pandemic of the present day.

Multiple myeloma (MM) is an incurable, diverse cancer in which abnormal plasma cells produce and release monoclonal immunoglobulin (Ig), also known as monoclonal protein or M protein. MM is always preceded by monoclonal gammaglobulinemia of unknown significance (MGUS) and smoldering multiple myeloma (SMM). Diagnosis of MM is made from a bone marrow sample, which involves analysis of the appearance of plasma cells. Quantification of CD138+ plasma cells in core biopsies is performed using techniques such as immunohistochemistry, flow cytometry, fluorescence in situ hybridization (FISH) and conventional cytogenetics. Urinalysis includes total protein by immunofixation and 24-hour urine by serum protein electrophoresis. FISH probes should detect the presence of at least del 13, del 17p, t(4;14), t(11;14), t(14;16), and 1q21 amplifications. Indeed, next-generation sequencing (NGS) has become an increasingly important tool in the diagnosis and treatment of MM. It can be used to identify genetic mutations, copy number changes, and clonal structures to help determine disease prognosis and treatment strategies. NGS can identify subclonal populations of cancer cells that are resistant to therapy and may lead to disease relapse, and can be used to identify potential targets for personalized therapy. For example, NGS can identify mutations in genes involved in drug resistance, enabling the selection of drugs that may be more effective in treating a patient's cancer. This systematic review analyzes 182 papers to determine the position and role of NGS in the diagnosis of MM. We first analyze the platforms and sample types used in the selected studies, and then start discussing the results.

Multiple myeloma (MM) is characterized by the malignant proliferation of monoclonal plasma cells in the bone marrow with an elevation in monoclonal paraprotein, renal impairment, hypercalcemia, lytic bony lesions, and anemia. Immune cells and associated cytokines play a significant role in MM growth, progression, and dissemination. While some cytokines and their clinical significance are well described in MM biology, others remain relatively unknown. The aim of the present study was to assess the impact of pretreatment serum levels of 27 selected cytokines on progression-free survival (PFS) and overall survival (OS) in MM patients before first-line therapy with bortezomib-based regimens. Serum cytokine levels were assayed with a Bio-Rad Bio-Plex Pro Human Cytokine 27-Plex Assay on the MAGPIX Multiplex Reader and the Bio-Plex® 200 System (Bio-Rad) including IL-1β, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, Eotaxin, FGF, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α, and VEGF. A total of 61 MM patients were examined. Most patients received a bortezomib, cyclophosphamide and dexamethasone (VCD) chemotherapy regimen. In the final multivariate model, IL-13 cytokine level (HR 0.1411, 95% CI: 0.0240-0.8291, p = 0.0302), and ASCT (HR 0.3722, 95% CI: 0.1826-0.7585, p=0.0065) significantly impacted PFS. Furthermore, ASCT (HR 0.142, 95% CI: 0.046-0.438, p=0.0007), presence of bone disease at diagnosis (HR 3.826, 95% CI: 1.471-9.949, p=0.0059) and two cytokine levels- IL-1Ra (HR 1.017, 95% CI: 1.004-1.030, p= 0.0091) and IL-4 (HR 0.161, 95% CI: 0.037-0.698, p = 0.0147) were independent predictors of OS. Three clusters of MM patients were identified with different cytokine profiles. In conclusion, serum pretreatment levels of IL-13 and IL-4 are predictors of better PFS and OS, respectively, whereas IL-1Ra pretreatment levels negatively impact OS in MM patients treated with bortezomib-based chemotherapy. Cytokine signature profile may have a potential influence on the outcome of patients treated with bortezomib.

A multi-server parallel system dispatches the incoming job, which contains kn tasks into n servers. A job is considered to be computed if all the tasks associated with the job are processed. One job’s tasks can be encoded into at least kn “replicas” such that the job is considered to be served if any kn replicas finishing computation. In this paper, we analyze the random scheduling policy of a multi-server computing system under discrete time model in terms of Quality of Exponent (QoE), which is defined as the probability exponent that a typical job can be computed within a given number of time slots. We let kn/n be a constant. Assuming that any task of any job can be randomly dispatched by a “scheduler” to any server, and computing each task takes exactly one time slot. We divide the calculation of probability exponent into two parts, exponent of numerator and exponent of denominator. For the denominator, we give the almost exact exponent using Lagrange multiplier method, while for the numerator, an upper bound of the numerator’s exponent is provided. In addition, we also express the exponent in terms of information theoretical quantities and reconsider both of exponents in the context of large deviation theory.

Multiple myeloma (MM) has witnessed improved patient outcomes through advancements in therapeutic approaches. Notably, allogeneic stem cell transplantation, proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies have contributed to enhanced quality of life. Recently, a promising avenue has emerged with chimeric antigen receptor (CAR) T cells targeting B-cell maturation antigen (BCMA), expressed widely on MM cells. To mitigate risks associated with allogenic T cells, we investigated the potential of BCMA CAR expression in natural killer cells (NKs), known for potent cytotoxicity and minimal side effects. Using the NK-92 cell line, we co-expressed BCMA CAR and soluble tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) employing the PiggyBac transposon system. Engineered NK cells (CAR-NK-92-TRAIL) demonstrated robust cytotoxicity against a panel of MM cell lines and primary patient samples, outperforming unmodified NK-92 cells with a mean difference in viability of 45,1% (± 26,1%, depending on the target cell line). Combination therapy was explored with the proteasome inhibitor bortezomib (BZ) and γ-secretase inhibitors (GSI), leading to a significant synergistic effect in combination with CAR-NK-92-TRAIL cells. This synergy was evident in cytotoxicity assays where a notable decrease in MM cell viability was observed in combinatorial therapy compared to single treatment. In summary, our study demonstrate the therapeutic potential of the CAR-NK-92-TRAIL cells for the treatment of MM. The synergistic impact of combining these engineered NK cells with BZ and GSI supports further development of allogeneic CAR-based products for effective MM therapy.

The object detection task is usually affected by complex backgrounds. In this paper, a new image object detection method is proposed, which can perform multi-feature selection on multi-scale feature maps. By this method, a bidirectional multi-scale feature fusion network is designed to fuse semantic features and shallow features to improve the detection effect of small objects in complex backgrounds. When the shallow features are transferred to the top layer, a bottom-up path is added to reduce the number of network layers experienced by the feature fusion network, reducing the loss of shallow features. In addition, a multi-feature selection module based on the attention mechanism is used to minimize the interference of useless information on subsequent classification and regression, allowing the network to adaptively focus on appropriate information for classification or regression to improve detection accuracy. Because the traditional five-parameter regression method has severe boundary problems when predicting objects with large aspect ratios, the proposed network treats angle prediction as a classification task. The experimental results on the DOTA dataset, the self-made DOTA-GF dataset and the HRSC 2016 dataset show that, compared with several popular object detection algorithms, the proposed method has certain advantages in detection accuracy.

In recent decades, power consumption has become an essential factor in attracting the attention of integrated circuit (IC) designers. Multiple-valued logic (MVL) and approximate computing are some techniques that could be applied to integrated circuits to make power-efficient systems. By utilizing MVL-based circuits instead of binary logic, the information conveyed by digital signals increases, and this reduces the required interconnections and power consumption. On the other hand, approximate computing is a class of arithmetic computing used in systems where the accuracy of the computation can be traded-off for lower energy consumption. In this paper, we propose novel designs for exact and inexact ternary multipliers based on carbon-nanotube field-effect transistors (CNFETs). The unique characteristics of CNFETs make them a desirable alternative to MOSFETs. The simulations are conducted using Synopsys HSPICE. The proposed design is compared against existing ternary multipliers. The results show that the proposed exact multiplier reduces energy consumption by up to 6X. At the same time, the best inexact design improves energy efficiency by up to 35X compared to the latest state-of-the-art methods. Using the imprecise multipliers for image processing provides evidence that these proposed designs are a low-power system with an acceptable error.

The paper portrays a linear model for synchronous prediction of the dissolved oxygen (DO) level in a protected urban lake by using independent variables in real-time monitoring of the water quality parameters. Multi-linear regression and machine learning techniques were applied to the Dissolved Oxygen (DO) using the basic four parameters of Water Quality Index (WQI). Three real-time industry standard sensors PHEHT, CTZN, OPTOD were used for sampling, data was then interpolated through ArcGIS kriging method. 25 correlations were checked through the ML algorithm, a correlation heat map was produced and the top five relations were taken under consideration and validated by r-score and root mean squared error (RMSE) to develop the linear regression model. The performance of the model was validated through the RMSE, mean squared error (MSE), and mean absolute error (MAE) the r2 accuracy came to 0.983 when it is checked against the sample data. The suggested model can be used as a technique for unknown or malfunctioned sensor’s null DO data prediction.

Magnetic resonance elastography (MRE) has revealed sexual dimorphism in brain stiffness in healthy individuals and multiple sclerosis (MS) patients. In the animal model of MS, experimental autoimmune encephalomyelitis (EAE), we showed previously that inflammation-induced brain softening was associated with alterations of the extracellular matrix (ECM). However, it remained unclear whether the brain ECM presents sex-specific properties that can be visualized by MRE. Therefore, we aimed here at quantifying sexual dimorphism in brain viscoelasticity in association with ECM changes in healthy and inflamed brains. Multifrequency MRE was applied to the midbrain of healthy and EAE mice of both sexes to quantitatively map regional stiffness. To define differences in brain ECM composition, gene expression of the key basement membrane components laminin (Lama4, Lama5), collagen (Col4a1, Col1a1) and fibronectin (Fn1) was investigated by RT-qPCR. We showed that the healthy male cortex expressed less Lama4, Lama5, Col4a1 but more Fn1 (all p < 0.05) than the healthy female cortex, which was associated with 9% softer properties (p = 0.044) in that region. At peak EAE, cortical softening was similar in both sexes compared to healthy tissue, with an 8% difference remaining between males and females during EAE (p < 0.001). Cortical Lama4, Lama5 and Col4a1 expression increased 2 to 3-fold in EAE in both sexes while Fn1 decreased only in males (all p < 0.05). No significant sex differences in stiffness were detected in other brain regions. In conclusion, sexual dimorphism in the ECM composition of cortical tissue in the mouse brain is reflected by in vivo stiffness measured with MRE and should be considered in future studies by sex-specific reference values.

The aim of this study was to investigate the potential of converting potato peel waste into bio ethanol using an in-house produced multi-enzyme preparation. To achieve this, a variety of pre-treatment strategies, including thermal, chemical, and thermo-chemical methods, were applied to the potato peels. These included boiling for 30 and 60 min, steam at varying pressures and times, and different concentrations of chemicals such as H2SO4, HNO3, CH3COOH, HCl, NaOH, Ca(OH)2, KOH, NH3, and H2O2, either alone or in combination with steam. The pre-treated potato peels were then enzymatically hydrolyzed using a crude multi-enzyme cocktail derived from solid-state fermentation of wheat bran by a natural variety of Aspergillus niger P-19, containing cellulases, hemicellulases, pectinase, and amylases. The most effective pre-treatment combination was found to be 3% H2SO4 followed by steam under pressure and enzymatic hydrolysis using the crude multi-enzyme preparation. This combination resulted in the highest yield of reducing sugars (141.04 ±12.31 g/l) with a 98.49% carbohydrate conversion at a 20% substrate loading, giving an ethanol yield of 43.2 g/l. Furthermore, supplementing the medium with peptone, (NH4)(H2PO4), and ZnSO4 at 0.1%w/v each with 22% and 24% solid, respectively, resulted in appreciable yields of 51.67 and 54.75 g/l, further enhancing the ethanol yield.

Art organizations are increasingly focusing on enhancing the visitor experience to attract a wider audience. The aim objective of this study was to explore the key factors that influence the visitor experience of offline art exhibitions and to use a mixed methods to data collection and analysis. The research process was divided into three stages. In the first stage, we conducted semi-structured interviews with 12 respondents by dividing the exhibition experience into three time periods: pre, during, and post-visit. We extracted seven factors affecting visitor experience through qualitative content analysis including marketing, motivation, physical environment, exhibit quality, participation, technology and service facilities; in the second stage, we developed an assessment scale and pretested it; in the third stage, we collected 725 questionnaires to validate the factors of visitor experience in art exhibitions. The results of linear regression analyses showed that all seven key factors had a significant impact on visitor experience. This study constructed a scale to assess the factors of art exhibition experience, which provides theoretical sup-port for in-depth study of art exhibition experience and useful guidance for planning and design-ing art exhibitions to improve the quality of visitors' experience of art exhibitions.

We are concerned with the use of some classical spectral collocation methods as well as with the new software system Chebfun in order to compute high order (index) eigenpairs of singular as well as regular Schrodinger eigenproblems. We want to highlight both the qualities as well as the shortcomings of these methods and evaluate them vis-a-vis the usual ones. In order to resolve a boundary singularity we use Chebfun with the simple domain truncation technique. Although this method is equally easy to apply with spectral collocation, things are more nuanced in the case of these methods. A special technique to introduce boundary conditions as well as a coordinate transform which maps an unbounded domain to a nite one are the ingredients. A challenging set of "hard" benchmark problems, for which usual numerical methods (f. d., f. e. m., shooting etc.) fail, are analysed. In order to separate "good"and "bad"eigenvalues we estimate the drift of the set of eigenvalues of interest with respect to the order of approximation and/or scaling of domain parameter. It automatically provides us with a measure of the error within which the eigenvalues are computed and a hint on numerical stability. We pay a particular attention to problems with almost multiple eigenvalues as well as for problems with a mixed (continuous) spectrum. In the latter case we try to numerically highlight its existence. Special attention will be paid to the higher eigenpairs (the pair of eigenvalue and the corresponding eigenfunction approximated by an eigenvector spanning its nodal values).

Ligand-based virtual screening (LBVS) is a promising approach for rapid and low-cost screening of potentially bioactive molecules in the early stage of drug discovery. Compared with traditional similarity-based machine learning methods, deep learning frameworks for LBVS can more effectively extract high-order molecule structure representations from molecular fingerprints or structures. However, the 3D conformation of a molecule largely influences its bioactivity and physical properties, and has rarely been considered in previous deep learning-based LBVS methods. Moreover, the relative bioactivity benchmark dataset is still lacking. To address these issues, we introduce a novel end-to-end deep learning architecture trained from molecular conformers for LBVS. We first extracted molecule conformers from multiple public molecular bioactivity data and consolidated them into a large-scale bioactivity benchmark dataset, which totally includes millions of endpoints and molecules corresponding to 954 targets. Then, we devised a deep learning-based LBVS called EquiVS to learn molecule representations from conformers for bioactivity prediction. Specifically, graph convolutional network (GCN) and equivariant graph neural network (EGNN) are sequentially stacked to learn high-order molecule-level and conformer-level representations, followed by attention-based deep multiple-instance learning (MIL) to aggregate these representations and then predict the potential bioactivity for the query molecule on a given target. We conducted various experiments to validate the data quality of our benchmark dataset, and confirmed EquiVS achieved better performance compared with 10 traditional machine learning or deep learning-based LBVS methods. Further ablation studies demonstrate the significant contribution of molecular conformation for bioactivity prediction, as well as the reasonability and non-redundancy of deep learning architecture in EquiVS. Finally, a model interpretation case study on CDK2 shows the potential of EquiVS in optimal conformer discovery. The overall study shows that our proposed benchmark dataset and EquiVS method have promising prospects in virtual screening applications.

Guessing effects frequently occur in testing data in educational or psychological applications. Different item response models have been proposed to handle guessing effects in dichotomous test items. However, it has been pointed out in the literature that the oftenemployed three-parameter logistic model poses implausible assumptions regarding the guessing process. The four-parameter guessing model has been proposed as an alternative to circumvent these conceptual issues. In this article, the four-parameter guessing model is compared with alternative item response models for handling guessing effects through a simulation study and an empirical example. It turned out that model selection for item response models should be rather based on the AIC than the BIC. However, the RMSD item fit statistic used with typical cutoff values was found to be ineffective in detecting misspecified item response models. Furthermore, sufficiently large sample sizes are required for sufficiently precise item parameter estimation. Moreover, it is argued that the criterion of statistical model fit should not be the sole criterion of model choice. The item response model used in operational practice should be valid with respect to the meaning of the ability variable and the underlying model assumptions. In this sense, the four-parameter guessing model could be the model of choice in educational large-scale assessment studies.

In this paper, we propose a method to find all efficient solutions of an interval multiple objective linear programming (IMOLP) problem with interval coefficients in the objective functions, the constraint matrix and the right-hand side vector. The set of all efficient solutions of an IMOLP problem can completely supply information to the decision makers in finding their most preferred solutions but, up to now, not all solutions of an IMOLP problem can be found by known methods. A numerical example is given to illustrate the working of the proposed method.

Neurodegeneration is a major problem in neuroscience and medicine as it causes and worsens many neurological and psychiatric disorders. It involves gradual loss of neurons at different levels of the brain, affecting cognition, emotion, behavior, consciousness, and attention. Understanding the causes and consequences of neurodegeneration is crucial for identifying the risk factors, biomarkers, and treatments. However, the current therapies are mostly symptomatic and ineffective. Therefore, new and innovative methods, such as noninvasive brain stimulation (NIBS), are needed to modulate brain activity and plasticity in a safe and reversible manner. This field is rapidly developing, with a focus on exploring new clinical applications, mechanisms, and combinations of NIBS and drugs. This special issue covers the latest progress and challenges in the study of neurodegeneration in cognitive impairment and mood disorders from the experimental, clinical, and translational perspectives. It addresses the complexity and diversity of these conditions, the lack of disease-modifying treatments, the ethical and practical issues of conducting research in vulnerable and diverse populations, the integration and interpretation of data from multiple sources and modalities, and the development and validation of novel methods such as NIBS, artificial intelligence, and drug repurposing. Collaborative efforts among various stakeholders are needed to improve our knowledge and treatment of neurodegeneration underlying cognitive impairment and mood disorders.

This article proposes the use of intranasal rifampin as a means to improve protein homeostasis and disaggregate misfolded proteins in the age-related neurodegenerative proteinopathies. Alzheimer’s disease, Parkinson’s disease, multi-system atrophy, Lewy body dementia, frontotemporal dementia, amyotrophic lateral sclerosis and Huntington’s disease are all, at the core, proteinopathies. Although these diseases varying greatly in the specific disease-associated proteins, anatomic sites of the abnormal protein deposition and clinical presentations, what they have in common is disruption of normal “housekeeping” functions related to protein homeostasis, proteostasis. The prospect of pharmacologically augmenting autophagic capacity with a known drug repurposed to improve proteostasis is attractive; to accomplish these ends with an inexpensive drug with relative ease of delivery adds to the attractiveness. Rifampin can be delivered to the brain via the intranasal route. Rifampin has been used for decades primarily against mycobacterial infection; it has been given with intravenous, oral, intrathecal and topical routes including as eyedrops and nasal spray. Rifampin disaggregates toxic oligomers in vitro; given intranasally, rifampin improves memory and clears pathologic proteins in animal models of the proteinopathies. Rifampin acts as both a gatekeeper and a housekeeper against the abnormal proteins of these diseases. This article suggests the merit of a clinical trial with intranasal rifampin to boost protein homeostasis in the most common age-related neurodegenerative proteinopathy, Alzheimer’s disease. The primary outcome of such a trial is change in risk of Alzheimer’s pathology as measured by plasma-based amyloid peptide 42/40 testing pretreatment and follow-up testing after 6 months of intranasal rifampin.

At 100% penetration, intermittent renewable energy causes outages. To flatten the leaping supply and demand curves of renewable energy, an energy storage medium and carrier are required. The Hydrogen energy stotrage system (HydESS), which combines a proton exchange membrane (PEM)-based water electrolysis (WE) system and a fuel cell (FC), has the quickest response time, the longest duration, and the greatest storage capacity. HOMER tools for techno-economic analysis are used to evaluate the HydESS hybrid system. Kyiv, Ukraine, is appealing due to its spatial-temporal wind speed, solar irradiance, and energy security. With an LCOE of $0.245 kWh−1 and 9.3% fuel cell power output, the most feasible solution is onshore wind turbine-coupled PEMFC HydESS. As a result 1,000-kW wind power, 250-kW PEMFC, 250-kW PEMWE, and 441-kW BESS are optimized to serve a 3,900 kWh day academic residence load. When compared to a diesel generator and a BESS, the hybrid HydESS reduces CO2 emissions by 4,132 tons over a 25-year period. The LCOE of a hybrid HydESS system is determined by the SOFC lifetime rather than the PEMFC's 2% difference between 40,000 and 50,000 h with the same rated power. This study recommends accelerating PEMFC development with fluctuation-endurable materials and design.

Lenalidomide-based regimens are effective treatment options for patients with relapsed/refractory multiple myeloma (RRMM). However, they are associated with an increased risk of infectious complications. This study examines the clinical factors influencing the occurrence of infection in MM patients treated with lenalidomide and dexamethasone (Rd). A retrospective analysis of all patients who received the Rd regimen between 2017-2021 at our institution was performed. The study group consisted of 174 patients and the median age was 65 years. Most patients (n=110, 63.2%) received the Rd treatment in second-line treatment. The majority of patients (64.3%) received bortezomib-based regimens in the first line of treatment. The median progression-free survival was 12.6 (95% CI: 9.5 – 16.2) months, and the median overall survival was 22.3 (95% CI: 15.9 – 28.6) months. The overall response rate was 64.1%, 12.7% of patients achieved complete response and 20.4% had a very good partial response. In multivariate logistic regression analysis, hypoalbuminemia (OR 4.2, 95%CI:1.6-11.2, p= 0.0039), autologous hematopoietic stem cell transplantation (AHSCT) before Rd (OR 2.6, 95% CI:1.0- 6.7, p= 0.048) and anemia grade ≥3 (OR 5.0, 95%CI: 1.8-14.0, p= 0.002) were independent factors related to the occurrence of infections. In conclusion, in this large cohort of RRMM patients, AHSCT before Rd regimen therapy, hypoalbuminemia and anemia during treatment were identified as three independent factors influencing the frequency of infections during Rd therapy. Patients with established risk factors may benefit from optimal supportive therapy.

In recent years, new treatments have been studied for relapsed-refractory multiple myeloma (RRMM), including two CAR-T products and a variety of non CAR-T agents. Since direct comparisons between these innovative treatments are not available, indirect comparisons can be of interest. Reconstruction of individual patient data from Kaplan-Meier graphs (Shiny method) has been employed in numerous reports that have validated its performance. In the present review, we evaluated six treatments proposed for RRMM including two CAR-T products (ciltacabtagene autoleucel and idecabtagene vicleucel) and four treatments not based on a CAR-T (melflufen plus dexamethasone, isatuximab plus dexamethasone, selinexor, and belantamab). The end-point was overall survival (OS); the Shiny method was used to generate reconstructed survival curves. Our results showed statistically significant differences in OS across these treatments. Compared with pharmacological treatments, CAR-T products significantly prolonged OS with an improvement of remarkable clinical relevance. In particular, ciltacabtagene autoleucel showed better OS than idecabtagene vicleucel. As regards non CAR-T treatments, the ranking in OS was headed by isatuximab plus dexamethasone, followed by belantamab, selinexor, and melflufen plus dexamethasone. In conclusion, while the Shiny method has confirmed its validity in reconstructing individual patient data, our indirect comparisons have offered some original clues to better interpret the information on OS published in these studies.

Introduction: Unlike cigarette smoking, secondhand smoke (SHS) has not been as well described as an environmental risk for Multiple sclerosis (MS) nor as a risk factor for disease progression. We systematically reviewed the association between SHS and the risk of onset and/or progression of MS.Methods: We systematically screened MEDLINE/PUBMED, Science Direct, LILACs, and SCIELO searching for publications between January 1st , 2010, and July 5, 2021 with the following keywords: “multiple sclerosis and smoking”; “multiple sclerosis and passive smoking”; “multiple sclerosis and secondhand smoking”. An 11-year filter was applied from 2010 to 2021. Results: Fifteen articles were included in this review, which consisted of systematic reviews with meta-analysis (N = 2), systematic reviews (N = 2), and observational studies (N = 11). Both meta-analyses reported an impact of SHS on MS onset among secondhand smokers. One of the systematic reviews selected two observational studies showing the association between SHS and MS development, and one study that did not find a significant association between SHS and the risk of MS development. The other systematic review identified selected eight articles showing a relationship between SHS and MS. Seven observational studies reported higher odds of MS onset when associated with SHS. Four observational studies did not show a relationship between SHS and MS onset or progression.Discussion: Most articles showed a positive association between SHS exposure and the risk of developing MS. On the other hand, an association between SHS and a higher risk for MS progression could not be established.