Molecular iodine (I2) induces apoptotic, antiangiogenic, and antiproliferative effects in breast cancer cells. Little is known about its effects on the tumor immune microenvironment. We studied the effect of oral (5 mg/day) I2 supplementation alone (I2) or together with conventional chemotherapy (Cht+I2) on the im-mune component of breast cancer tumors from a previously published pilot study conducted in Mexico. RNA-seq, I2 and Cht+I2 samples showed significant increases in expression of Th1 and Th17 pathways. Tumor immune composition determined by deconvolution analysis revealed significant increases in M0 macrophages and B lymphocytes in both I2 groups. Real-time RT-PCR showed that I2 tumors overexpress T-BET (p = 0.019) and interferon-gamma (IFNγ; p = 0.020) and silence tumor growth factor-beta (TGFβ; p = 0.049); whereas in Cht+I2 tumors, GATA3 is silenced (p = 0.014). Preliminary methylation analysis shows that I2 activates IFNγ gene promoter (by increasing its unmethylated form) and silences TGFβ in Cht+I2. In conclusion, our data showed that I2 supplements induce the activation of the immune response and that when combined with Cht, the Th1 pathways are stimulated. The molecular mechanisms involved in these responses are being analyzed, but preliminary data suggest that methylation/demethylation mechanisms could also participate.

Purpose: This study aimed to determine the efficacy and safety of Oncoxin as an antitumoral supplement, and to describe its mechanism of action. Methods: We performed this scoping review according to the recommendations of the Joanna Briggs Institute and included patients older than 18 years-old who have any kind of tumor and receive Oncoxin as a supplement. We focused on the efficacy in terms of antitumoral properties, quality of life and survival, safety in terms of adverse events, and the mechanism of action. We did not limit for language or setting. We searched MEDLINE (Pubmed), EMBASE (Scopus), LILACS, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to nowadays. Results: We found a promising increment of survival when taking Oncoxin as a supplementary treatment. Additionally, the quality of life increased in terms of Karnofsky and EORTC scales. Regarding the mechanism of action, studies suggest it modifies inflammatory mediators’ expression, as evidenced by the reduction of COX-2, IL-1β, IL-6, TNF-α, IL-1β, IL-12, and IFN-γ. Besides, it promotes an arrest in the progression of cells from G1 into S, along with an increase in p27 and a decrease in cyclin D1 and pRb. Conclusions: We found promising complementary effects of Oncoxin to the standard treatment of cancer patients in diverse scenarios, with putative robust mechanisms of action. In addition to clinically relevant impacts verified in clinical trials, as well as it decreases the levels of pro-inflammatory cytokines, it can also decrease cytokines with antitumor activity such as IFN-γ, which should be further explored in larger trials and the long term.

β-glucan is a generic term for insoluble dietary fibers exerting various effects on the immune system. As a group, β-glucans are non-cellulose polysaccharides composed of a glucopyranose as the main constituent sugar with β configuration, having a β- (1,3)-linked glucopyranose main chain as a common feature. β-glucans are absorbed through the intestine. Since the 1980s, there have been many studies reporting various effects of β-glucans on the immune system, including reports on receptors, that have slowly clarified their recognition system and action mechanisms. However, these studies focused mostly on treatments of infectious diseases and tumors; thus, the effects of β-glucans ingested in food as dietary fiber and their mechanisms of action remain largely unknown. The uptake of β-glucan into the body may be resemble that of proteins, which are soluble polymers, and insoluble material such as dietary fiber. Dietary fibers have varied structures, with wide-ranging solubility and physiological effects. Understanding whether these substances are actually taken up, how they exert their effects, and their metabolism after being taken up are important issues when considering the functionality and safety of dietary fibers.

Abstract: Role of gut microbiome in human health is becoming apparent. The major functional impact of gut microbiome is transmitted through the microbial metabolites that are produced in the gut and interact with host cells either in the local gut environment or get absorbed in the circulation to impact distant cells/organs. Short chain fatty acids (SCFAs) are the major microbial metabolites that are produced in the gut through fermentation of non-digestible fibers. SCFAs are known to function through various mechanism, however, their signaling through free-fatty acid receptor 2 and 3 (FFAR2/3; type of G-coupled protein receptors) is new therapeutic approach. FFAR2/3 are widely expression in diverse cell types in human and mice, and functions as sensors of SCFAs to change several physiological and cellular functions. FFAR2/3 modulates neurological signaling, energy metabolism, intestinal cellular homeostasis, immune response and hormone synthesis. FFAR2/3 functions through Gi and/or Gq signaling, that is mediated through specific structural features of SCFAs-FFAR2/3 bindings and modulating specific signaling pathway. In this review, we discussed the wide-spread expression and structural homologies between human and mice FFAR2/3, and their role in different human health conditions. This information can unlock opportunities to weigh the potential of FFAR2/3 as drug target to prevent human diseases.

Nonalcoholic steatohepatitis (NASH), which is characterized by liver steatosis, inflammation and fibrosis, is the most severe variation of nonalcoholic fatty liver disease (NAFLD). This disease is a consequence of several metabolic alterations such as type 2 diabetes and dyslipidemia that trigger different pathways of cell dysfunction and systemic inflammation which ultimately affect the liver. Furthermore, those mechanisms activate a complex cascade of immune response after repeated cell aggression. In the liver cytokines and interleukins interact with network of innate immune cells, including Kupffer cells (KCs), dendritic cells (DCs), lymphocytes and hepatic stellate cells (HSC). These cells translate those signals into immune responses and pathologic hepatic changes during the development of NASH. In this scenario the development of fibrosis is the most important change since it is an adaptive mechanism that in the short time has the objective of repair the damaged tissue but after prolonged injury it progresses to parenchymal scarring, cellular dysfunction and finally to organ failure. Finally, since NASH is an important cause of liver cirrhosis; this review addresses the cellular pathways of fibrosis in the setting of NASH explained by the interaction between immune and hepatic cells.

Dengue virus (DENV), being one of the lethal pathogens in the hot climatic regions of the world, have been extensively studied to decipher its mechanism of pathogenesis and missing links of its life cycle. With respect to the entry of DENV, multiple receptors have been recognised in different cells of the human body. However, scientists still argue whether these identified receptors are the exclusive entry mediators for the virus. Adding to the complexity, DENV has been reported to be infecting multiple organ types in its human host. Also, more than one receptor in a particular cell has been discerned to take part in mediating the ingress of DENV. In this review, we aim to discuss about the different cells of the human immune system that support DENV infection and their corresponding receptors that DENV deploy to gain access to the cells.

T-cell mediated immune responses should be regulated to avoid the development of autoimmune or chronic inflammation diseases. Several mechanisms have been described to regulate this process, namely death of overactivated T cells by cytokine deprivation, suppression by T regulatory cells (Treg), induction of expression of immune checkpoint molecules such as CTLA-4 and PD-1, or activation-induced cell death (AICD). In addition, activated T cells release membrane microvesicles called exosomes during these regulatory processes. In this review, we revise the role of exosome secretion in the different pathways of immune regulation described to date and its importance in the prevention of autoinmune disease. Expression of membrane-bound death ligands on the surface of exosomes during AICD, or the more recently described transfer of miRNA or even DNA inside T-cell exosomes are molecular mechanisms that will be analyzed.

Coinfection of B virus (HBV) and hepatitis Delta virus (HDV) lead to severe forms of progressive liver diseases. However, commercially available antiviral drugs have shown considerable adverse effects and low efficacy in managing these patients. Thus, there is a pressing need to develop new, innovative, and evidence-based therapies for these pathological entities. In line with this, some investigators have attempted to develop anti-viral drugs targeting HBV/HDV coinfection. In another development, investigators have also attempted to establish immune therapy targeting for HBV infection as recovery or effective control of HBV infection also lead to efficient control of HDV infection. This review has discussed an account of the evolving antiviral and immune therapeutic drugs for HBV/HDV infection. Also, based on current scientific knowledge how we have described the pros and cons of these drugs as no suitable drug has been developed during the last forty years for treating HBV infection except the availability of two” repurposed drugs”; interferons and its derivatives and nucleoside analogs, for managing HBV or HBV/HDV coinfection. It seems that an evolving and innovative therapeutic regimen that combines both antiviral drugs and immune modulators may be the best and realistic option for management of HBV/HDV coinfection.

Progression of oral squamous cell carcinoma (OSCC) has been associated with an escape of tumor cells from the host immune surveillance due to an increased knowledge of its underlying molecular mechanisms and its modulation by the tumor microenvironment and immune cell repertoire. In this study the expression of HLA class I (HLA-I) antigens and of components of the antigen processing machinery (APM) was analyzed in 160 pathologically classified human papilloma virus (HPV)-negative OSCC lesions and correlated to the intra-tumoral immune cell response, IFN- signaling and to the patients outcome. A heterogeneous, but predominantly lower constitutive protein expression of HLA-I APM components was found in OSCC sections when compared to non-neoplastic cells. Tumoral HLA-I APM component expression was further categorized into the three major phenotypes HLA-Ihigh/APMhigh, HLA-Ilow/APMlow and HLA-Idiscordant high/low/APMhigh. In the HLA-Ihigh/APMhigh group, the highest frequency of intra-tumoral CD8+ T cells and lowest number of CD8+ T cells close to FoxP3+ cells was found. Patients within this group presented the most unfavorable survival, which was significantly evident in stage T2 tumors. Despite a correlation with the number of intra-tumoral CD8+ T cells, tumoral JAK1 expression as a surrogate marker for IFN- signaling was not associated with HLA-I/APM expression. Thus, the presented findings strongly indicate the presence of additional factors involved in the immunomodulatory process of HPV-negative OSCC with a possible tumor-burden-dependent complex network of immune escape mechanisms beyond HLA-I/APM components and T cell infiltration in this tumor entity.

Progression of oral squamous cell carcinoma (OSCC) has been associated with an escape of tumor cells from the host immune surveillance with growing evidence of its underlying molecular mechanisms and its interaction with the immune cell control. In this study the expression of HLA class I (HLA-I) antigens and of components of the antigen processing machinery (APM) was analyzed in 160 consecutive human papilloma virus (HPV)-negative OSCC lesions and correlated to tumor specific parameters, the intratumoral immune cell response and to the patients outcome. A heterogeneous, but predominantly lower constitutive protein expression of HLA-I APM components was seen in OSCC sections when compared to non-neoplastic cells. Based on the expression levels of HLA-I APM components three main OSCC subgroups were detected and categorized into HLA-Ihigh/APMhigh, HLA-Ilow/APMlow and HLA-Idiscordant high/low/APMhigh phenotypes. In the HLA-Ihigh/APMhigh group, the highest frequency of intratumoral CD8+ T cells and lowest number of CD8+ T cells close to FoxP3 cells was found. Despite being associated with the highest T cell infiltration, patients within this group presented the most unfavorable survival, which was most evident in stage T2 tumors. Thus, the presented findings strongly indicate the presence of additional factors involved in the immunomodulatory process of HPV-negative OSCC with a possible tumor-burden-dependent complex network of immune escape mechanisms beyond HLA-I/APM components and T cell infiltration in this tumor entity.

In this paper, a new type of self-excited thermomechanical oscillator containing an oscillating shape memory alloy (SMA) filament with two symmetrically arranged spheres is investigated. The self-excitation of the oscillations is due to a heater of constant temperature, which causes periodic contractions of the filament when it approaches it. The contracted filament moves away from the heater a distance sufficient to cool it. Under the action of the weight of the spheres, the cooled filament re-approaches the heater, causing the above processes to repeat periodically. On the basis of experimental studies, approximating functions of the heater's heat field distribution are derived. A dynamic model of the oscillator has been created, in which the minor and major hysteresis in the SMA alloy and the distribution of the heat field around the heater have been taken into account. By numerical solutions of the differential equations, the laws of motion of the spheres are obtained. The displacements of the spheres in two perpendicular directions were measured using an experimental system. The obtained experimental results validate the proposed dynamic model and its assumptions with a high degree of confidence. Conclusions are drawn about the stochastic nature of the oscillations due to the hysteresis properties of the SMA and the temperature variation of the natural frequency of the oscillating system.

This paper illustrates an experimental activity for the closed-loop position control of an actuator made using shape memory alloy (SMA) wire. A solution with the self-sensing effect was implemented to miniaturize the systems, i.e., without external sensors. A proportional control algorithm was initially used, demonstrating the idea's feasibility: the wire can behave simultaneously as an actuator and sensor. An experimental investigation was subsequently conducted for the optimization of the developed actuator. As for the material, a Flexinol wire, Ni-Ti alloy, with a diameter of 0.150 mm and a length of 200 mm, was used. Preliminarily, a characterization of the SMA wire at constant and variable loads was carried out: the characteristics detected are elongation vs. electric current and elongation vs. electrical resistance. The control system is PC-based with a data acquisition card (DAQ). A drive board has been designed and built to read the wire's electrical resistance and power it by pulse width modulation (PWM). A notable result is that the actuator works with good precision and in dynamic conditions, even when it is called to support a load up to 65% different from that for which the electrical resistance-length correlation has previously been experimentally obtained, on which the control is based. This opens up the possibility of using the actuator in a counteracting configuration with a spring, which makes hardware implementation and control management simple.

Benveniste’s experiments – known in the lay press as the “water memory” phenomenon – are generally considered to be a closed case. However, the amount of data generated by twenty years of well-conducted experiments prevents closing the file so simply. An issue, which has been little highlighted so far, merits to be emphasized. Indeed, if Benveniste failed to persuade his peers of the value of his experiments, it was mainly because of a stumbling block, namely the difficulty of convincingly proving the causal relationship between the supposed cause (“informed water”) and the experimental outcomes in different biological models. To progress in the understanding of this phenomenon, we abandon the idea of any role of water in these experiments (“water memory” and its avatars). In other words, we assume that control and test conditions that were evaluated were all physically identical; only their respective designations (labels) differentiated them. As a consequence, labels (“controls” vs. “tests”) and the corresponding states of the biological system (no change vs. change) are independent variables. We show in this article how simple considerations based on probability theory allow to build a probability model where the order of measurements matters. This model provides an alternative explanation to Benveniste’s experiments where water plays no role and where the place of the experimenter is central.

Background: Despite hearing aids adequately compensate for hearing loss, a substantial proportion of the population leave their hearing difficulties untreated. Even though this is a well-known clinical issue, the optimal approach to address this issue during the hearing rehabilitation process is still unclear. Purpose: The present study aims to characterise behavioural and neurophysiological auditory and cognitive processing skills in experienced hearing aid users versus those with normal hearing, aimed at providing clinicians with the evidence required to adequately manage the expectations of their clients, thus indirectly reinforcing hearing-aid adoption within the adult population with hearing loss. Research design: Behavioural tests included auditory, cognitive, and speech-in-noise tasks; and neurophysiological testing included cortical auditory evoked potentials evoked by a /da/ stimulus presented at 65 dB SPL. The tests were selected based on previous literature supporting specific speech-understanding skills. Study sample: Ten participants (7 female, 21—68 years) with bilateral, mild-moderate to moderately-severe sensorineural hearing loss (HL), and 10 with clinically normal hearing (NH, 8 female, 19—62 years) participated in the study. Data collection and analysis: Behavioural data was analysed using multivariate analysis of variance (MANOVA) and neurophysiological analysis used measurements such as independent t-test, time-frequency analysis and inter-trial phase coherence. Results: The NH and HL groups presented similar scores in all the behavioural tasks. Time-frequency analysis revealed a statistically significantly reduction in alpha (8–12 Hz) synchronisation at the centro-frontal electrodes in the HL group – a brain activity pattern that has been associated with listening effort, inhibition and selective attention. Conclusions and significance: Results support the conclusion that hearing aids are effective in compensating for the audibility of their users, enabling them to perform at similar levels than their normal-hearing peers. However, the reduced alpha synchronisation observed in the HL population indicates that adequate audibility does not extend to improved neural responses. Future studies need to investigate the induced activity in speech understanding paradigms to explore the auditory processing differences at cortical level. The results are only from a small sample size but the findings have the potential to support clinicians in managing adequately the expectations of their clients in regards the benefits of hearing aid technologies.

An association of food sources with odors prominently guides foraging behavior in animals. To understand the interaction of olfactory memory and food preferences, we used glucose-averse (GA) German cockroaches. Multiple populations of cockroaches evolved a gustatory polymorphism where glucose is perceived as a deterrent and enables GA cockroaches to avoid eating glucose-containing toxic baits. Comparative behavioral analysis using an operant conditioning paradigm revealed that learning and memory guide foraging decisions. Cockroaches learned to associate specific food odors with fructose (phagostimulant, reward) within only a 1 hr conditioning session, and with caffeine (deterrent, punishment) after only three 1 hr conditioning sessions. Glucose acted as reward in wild type (WT) cockroaches, but GA cockroaches learned to avoid an innately attractive odor that was associated with glucose. Olfactory memory was retained for at least 3 days after three 1 hr conditioning sessions. Our results reveal that specific tastants can serve as potent reward or punishment in olfactory associative learning, which reinforces gustatory food preferences. Olfactory learning therefore reinforces behavioral resistance of GA cockroaches to sugar-containing toxic baits. Cockroaches may also generalize their olfactory learning to baits that contain the same or similar attractive odors even if they do not contain glucose.

Shape-memory hydrogels (SMH) are as multifunctional, actively-moving polymers of interest in biomedicine. In loosely crosslinked polymer networks gelatin chains may form triple helices, which can act as temporary netpoints in SMH, depending on the presence of salts. Here, we show programming and initiation of the shape-memory effect of such networks based on a thermomechanical process compatible with the physiological environment. The SMH were synthesized by reaction of glycidylmethacrylated gelatin with OEG α,ω-dithiols of varying crosslinker length and amount. Triple helicalization of gelatin chains is shown directly by wide-angle X-ray scattering and indirectly via the mechanical behavior at different temperatures. The ability to form triple helices increased with the molar mass of the crosslinker. Hydrogels had storage moduli of 0.27-23 kPa and Young’s moduli of 215-360 kPa at 4 °C. The hydrogels were hydrolytically degradable, with full degradation to water soluble products within one week at 37 °C and pH = 7.4. A thermally-induced shape-memory effect is demonstrated in bending as well as in compression tests, in which shape recovery with excellent shape recovery rates Rr close to 100% were observed. In the future, the material presented here could be applied e.g. as self-anchoring devices mechanically resembling the extracellular matrix.

Alcohol and nicotine are widely-abused legal substances worldwide. Relapse to alcohol or tobacco seeking and consumption after abstinence is a major clinical challenge, and is often evoked by cue-induced craving. Therefore, disruption of the memory for the cue-drug association is expected to suppress relapse. Memories have been postulated to become labile shortly after their retrieval, during a “memory reconsolidation” process. Interference with the reconsolidation of drug-associated memories has been suggested as a possible strategy to reduce or even prevent cue-induced craving and relapse. Here, we surveyed the growing body of studies in animal models and in humans assessing the effectiveness of pharmacological or behavioral manipulations in reducing relapse by interfering with the reconsolidation of alcohol and nicotine/tobacco memories. Our review points to the potential of targeting the reconsolidation of these memories as a strategy to suppress relapse to alcohol drinking and tobacco smoking. However, we discuss several critical limitations and boundary conditions, which should be considered to improve the consistency and replicability in the field, and for development of an efficient reconsolidation-based relapse prevention therapy.

The present work studies a swelling porous-elastic system with viscoelastic damping. We establish a general and optimal decay estimate which generalizes some recent results in the literature. Our result is established without imposing the usual equal-wave-speed condition associated with similar problems in literature.

In this era of technology, programming has become more significant than ever before. Python and C++ are both widely used programming languages. Python, the most popular programming language in today’s world, is a high-level object-oriented language whereas C++, the language behind most operating systems, is a low-level object-oriented language. In this paper, we present a comparative study of Python and C++. This paper discusses the introduction to these languages, their memory management techniques, and the reasons behind their program execution speed. Furthermore, we analyzed the execution time and memory used by multiple algorithms in both the languages with best, average, and worst cases. They are also compared with respect to the benefits and issues related to them. Results indicate that C++ is faster than Python in execution speed but Python serves as a better language for beginners due to its simplicity. Moreover, for the best results, the language should be selected according to the type of project.

This paper studies long economic series to assess the long-lasting effects of pandemics. We analyze if periods of time that cover pandemics have a change in trend and persistence in growth, and in level and persistence in unemployment. We find that there is an upward trend in the persistence level of growth across the centuries. In particular, shocks originated by pandemics in recent times seem to have permanent effect in growth. Moreover, our results show that the unemployment rate increases and it becomes more persistent after a pandemic. In this regard, our findings support the design and implementation of counter-cyclical policies to soften the shock of the pandemic.

The current global pandemic of coronavirus disease 2019 (COVID-19) caused by the coronavirus SARS-CoV-2 has already had a major adverse impact on the world due to the exponentially increasing deaths due to the disease and the extreme actions taken by the world community to prevent its spread. It is important to explore novel methods of reducing the illnesses and fatality rates of the coronavirus-infected patients. Since the weakness of the immune system is one of the major contributing factors for the illnesses caused by such viruses, and since inflammation is a major contributing factor for the mortality of COVID-19 patients, interventions that boost the immune system and/or are anti-inflammatory may reduce the COVID-19 incidence and the mortality due to the disease. A large variety of interventions are known to improve the immune response and/or reduce inflammation. However, all the interventions would not be applicable or acceptable to everyone and so the interventions would need to be individualized based on individual circumstances and preferences. This approach, known as “Individualized Interventions to Improve the Immune Response”, or the I⁴R approach, should be studied in pilot clinical trials urgently, in order to potentially reduce the harm caused by the current coronavirus pandemic.

It is estimated that pancreatic cancer will be the 2^nd leading cause of cancer-related deaths globally by 2030, highlighting the ongoing lack of effective treatment options in this devastating condition. There is a lack of reliable prognostic or predictive markers in pancreatic cancer to guide management decisions, whether for systemic chemotherapy, molecularly targeted therapies, or immunotherapies. To date, the results for targeted agents and immunotherapies in unselected populations of chemo-refractory pancreatic cancer have not met expectations. The reasons for this lack of efficacy of immunotherapy in pancreatic cancer are incompletely understood. The challenges in pancreatic cancer include the physical barrier created by the dense desmoplastic stroma surrounding the tumor, chemokine-mediated exclusion of T cells, poor antigenicity, paucity of infiltrating T cells within the tumor, ultimately leading to an immunosuppressive microenvironment. A better understanding of the role of inflammation in pancreatic cancer, its tumor microenvironment and individualized patient-related features, be they molecular, clinical or histopathological would enable a more effective tailored approach to the management of pancreatic cancer. In this review, the role of inflammation, the immune tumor microenvironment and potential immune biomarkers in pancreatic cancer are explored.

Dry eye syndrome (DES) has become increasingly prevalent due to the prolonged use of digital devices in modern society. Individual supplementation with lutein or docosahexaenoic acid (DHA) demonstrated potential benefits for eye health. This study aimed to investigate the effects of lutein plus DHA complex supplementation on DES, visual function, and memory in healthy individuals. Thirty-four participants, aged 40~60 years, received lutein/DHA complex supplements (containing 10 mg free-form lutein, 200 mg DHA, 30 mg red algae extract (astaxanthin), phosphatidylserine, and vitamin A) for 12 weeks. Ophthalmological examinations and memory tests were carried out, and a questionnaire was administered at weeks 0, 6, and 12 of the study. After 12 weeks of the intervention, the tear break-up time had significantly increased, and intraocular pressure (IOP) had significantly decreased. This suggests that lutein/DHA complex supplementation may reduce the IOP and offer potential benefits for DES, as indicated by improved tear stability.

Brain hemispheres develop rather symmetrically except in the case of pathology or intense training. As school experience is a form of training, the current study tested the influence of pedagogy on morphological development through the cortical thickness (CTh) asymmetry index (AI). First, we compared CTh AI of 111 students aged 4 to 18 with 77 adults aged > 20. Second, we investigated CTh AI in the students, as a function of schooling background (Montessori or traditional). At the whole-brain level, CTh AI was not different between the adult and student groups, even when controlling for age. However, the pedagogical experience was found to impact CTh AI in the temporal lobe, within the parahippocampal (PHC) region. The PHC has a functional lateralization, with the right PHC having a stronger involvement in spatiotemporal context encoding, while the left PHC is involved in semantic encoding. We observed CTh asymmetry toward the left PHC for participants enrolled in Montessori schools and toward the right for participants enrolled in traditional schools. As these participants were matched on age, intelligence, home life, and socioeconomic conditions, we interpret this effect found in memory-related brain regions to reflect differences in learning strategies. Pedagogy modulates how new concepts are encoded, with possible long-term effects on knowledge transfer.

Nature provides plenty of good examples for simple and very efficient joint assemblies. One example is the enormously flexible cervical spine of American barn owls, which consists of 14 cervical vertebrae. Each pair of vertebrae produces a comparatively small individual movement in order to provide a large overall movement of the entire cervical spine. The biomimetic replication of such joints is difficult due to the delicate and geometric unrestricted joint shapes as well as the muscles that have to be mimicked. Using X-ray as well as micro computed tomography images and with the utilisation of additive manufacturing, it is possible to produce the owl neck vertebrae in scaled-up form, to analyse them and then to transfer them into technically usable joint assemblies. The muscle substitution of these joints is realised by smart materials actuators in the form of shape memory alloy wire actuators. This actuator technology is outstanding for its muscle-like movement and for its enormous energy density [1,2]. The disadvantage of this wire actuator technology is the low rate of contraction, which means that a large length of wire has to be installed to generate adequate movement. For this reason, the actuator wires are integrated into additively manufactured carrier components to mimic the biological joints. This results in joint designs that compensate for the disadvantages of the small contraction of the actuators by intelligently installing large wire lengths on comparatively small installation spaces, while also providing a sufficient force output. With the help of a test rig, the developed technical joint variants are examined and evaluated. This demonstrates the technical applicability of this bionic joints.

The dynamics of suspended sediment involves inherent non-linearity and complexity as a result of the presence of both spatial variability of the basin characteristics and temporal climatic patterns. As a result of this complexity, the conventional sediment rating curve (SRC) and other empirical methods produce inaccurate predictions. Deep neural networks (DNNs) have emerged as one of the advanced modeling techniques capable of addressing inherent non-linearity in hydrological processes over the last few decades. DNN algorithms are used to perform predictive analysis and investigate the interdependencies among the most pivotal water quantity and quality parameters i.e., discharge, suspended sediment concentration (SSC), and turbidity. In this study, the Long short-term memory (LSTM) algorithm of DNNs is used to model the discharge-suspended sediment relationship for the Stony Clove Creek. The simulations were run using primary data on discharge, SSC and turbidity. For the development of the DNN models and examining the effects of input vectors, combinations of different input vectors (namely discharge, and SSC) for the current and previous days are considered. Furthermore, a suitable modelling approach with an appropriate model input structure is suggested based on model performance indices for the training and testing phases. The performance of developed models is assessed using statistical indices such as root mean square error (RMSE), mean absolute error (MAE), and coefficient of determination (R2). Statistically, the performance of DNN-based models in simulating the daily SSC performed well with observed sediment concentration series data. The study demonstrates the suitability of the DNN approach for simulation and estimation of daily SSC, opening up new research avenues for applying hybrid soft computing models in hydrology.

This article presents the implementation of a model to estimate the future price of commodities in the Brazilian market from time series of short-term technical evaluation. For this, data from two databases were used, one referring to the foreign market (opening values, maximum, minimum, closing, closing adjustment and volume) and the other, from the Brazilian market (the price of the day), considering commodities, sugar, cotton, corn, soybean and wheat. Subsequently, the technical indicators were calculated from the TA-Lib technical analysis library. Pearson’s correlation coefficient was applied, records with low correlation were removed, and then the database was consolidated. From the pre-processed data, Long Short-Term Memory (LSTM) recurrent neural networks were used to perform data prediction at the one and three day interval. These models were evaluated using the mean square error (MSE), obtaining results between 0.00010 and 0.00037 on test data one day ahead, and from 0.00017 to 0.00042 three days ahead. However, based on the results obtained, it was observed that the developed model obtained a promising forecasting performance for all the commodities evaluated. As a main contribution, there is the consolidation of databases that can be used in future scientific research. Furthermore, based on its interpretation, it can assist in decision making regarding the buying and selling of commodities to increase financial gains.

A Shape Memory Alloy (SMA) enabled Overtopping Wave Energy Converter (OWEC) that maximizes its overtopping discharge, and thus energy output under different wave conditions is presented. Among all the parameters affecting the overtopping discharge rate, the crest freeboard height is the most influential one to control the overtopping discharge rate and the stored overtopping volume behind it. Currently, all the OWEC crest freeboard heights are fixed by design to maximize the discharge rate on one particular sea state. In the present study, we show that the SMA can adjust the crest freeboard height through a control system based on the sea state and achieve an optimal overtopping discharge rate. A scaled OWEC model is built in the lab with its crest freeboard height controlled by springs made of SMA. The length (and thus tension) of the springs is controlled by temperature changes by changing the passing current through the springs. By adjusting the length of the springs based on the incoming wave condition, we adjust the freeboard to an optimal height known to generate a maximum overtopping discharge rate for energy conversion. This smart material-enabled design can maximize the overtopping discharge and thus the output power of the OWEC under various wave conditions. Furthermore, the simplicity of using SMA springs as the actuator leads to the minimum number of moving mechanical parts, which can remarkably decrease maintenance costs. As the proof of concept, two types of tests are conducted in the laboratory using the same OWEC model under several random wave trains generated from spectra with different significant wave heights - one type with a fixed crest freeboard height and the other type featuring the adjustable crest freeboard height controlled by the springs. The substantial increase of harvested output power in the OWEC with the adjustable crest freeboard height may pave the way for more efficient wave energy conversion systems.

Working memory refers to the capability of the nervous system to selectively retain short-term memories in an active state. The long-standing viewpoint is that neurons play an indispensable role and working memory is encoded by synaptic plasticity. Furthermore, some recent studies have shown that calcium signaling assists the memory processes and the working memory might be affected by the astrocyte density. Over the last few decades, growing evidence has also revealed that astrocytes exhibit diverse coverage of synapses which are considered to participate in neuronal activities. However, very little effort has yet been made to attempt to shed light on the potential correlations between these observations. Hence, in this article we will leverage a computational neuron-astrocyte model to study the short-term memory performance subject to various astrocytic coverage and we will demonstrate that the short-term memory is susceptible to this factor. Our model may also provide plausible hypotheses for the various sizes of calcium events as they are reckoned to be correlated with the astrocytic coverage.

Executive functions comprise top-down cognitive processes that exert control over information processing, from acquiring information to issuing a behavioural response. These cognitive processes of inhibition, working memory and shifting underpin complex cognitive skills, such as episodic memory and planning, which have been repeatedly investigated in several bird species in recent decades. Until recently, avian executive functions were studied in relatively few bird species, but have gained traction in comparative cognitive research following MacLean and colleagues’ large-scale study (2014). Therefore, in this review paper, relevant previous findings are collected and organized to facilitate further investigations of these core cognitive processes in birds. This review can assist in integrating findings from avian and mammalian cognitive research and further current understanding of executive functions’ significance and evolution.

Ag+ pollution is great of harm to the human body and the biology. Therefore, it is an urgent need to develop inexpensive and accurate detection methods. Herein, lignin-derived structural memory carbon nanodots (CSM-dots) with outstanding fluorescence property were fabricated via a green method, which reserve functional and structural units of the precursor molecules. The CSM-dots could specifically bind Ag+, accompanied with a remarkable fluorescence quenching response. This “turn-off” fluorescence behavior was used for Ag+ determination in a linear range of 5-290 μM with the detection limit as low as 500 nM. Furthermore, the finding showed that this sensing nano-platform was successfully used for Ag+ determination in real samples and intracellular imaging, showing great potential in biological and environmental monitoring applications.

Deep neural networks (DNNs) have made a huge impact in the field of machine learning by providing unbeatable humanlike performance to solve real-world problems such as image processing and natural language processing (NLP). Convolutional neural network (CNN) and recurrent neural network (RNN) are two typical architectures that are widely used to solve such problems. Time sequence-dependent problems are generally very challenging, and RNN architectures have made an enormous improvement in a wide range of machine learning problems with sequential input involved. In this paper, different types of RNN architectures are compared. Special focus is put on two well-known gated-RNN’s Long Term Short Memory (LSTM) and Gated Recurrent Unit (GRU). We evaluated these models on the task of force estimation system in pouring. In this study, four different models including multi-layers LSTM, multi-layers GRU, single-layer LSTM and single-layer GRU) were created and trained. The result suggests that multi-layer GRU outperformed other three models.

Neurological disorders, such as amyotrophic lateral sclerosis, Parkinson’s disease, and Alzheimer’s disease, are commonly associated with persistent neuro-inflammation, and there is an urgent need to discover new therapeutic agents that may target the various pathways involved in neurodegeneration. In this study, we investigated the therapeutic potential of folecitin, a flavonoid isolated from Hypericum oblongifolium, against lipopolysaccharide (LPS)-induced oxidative stress associated with neurodegeneration, amyloidogenic Aβ production pathway, and memory dysfunction in mice. LPS was administered i.p. at 250 µg/kg/day for 3 weeks, followed by the administration of folecitin at a dose of 30 mg/kg/day for the last two weeks. A Western blot technique was used to assess the expression of different proteins involved in oxidative stress, neurodegeneration, and neuronal synapse. Results indicated that folecitin significantly reduced LPS-induced apoptotic neurodegeneration, including the expression of BAX, Caspase-3, and PARP-1 proteins, inhibited BACE1, and the amyloidogenic Aβ production pathway. Folecitin improved both pre- and post-neuronal synapse, as well as memory dysfunction. Furthermore, folecitin significantly activated endogenous antioxidant proteins such as Nrf-2 and HO-1 via stimulating the phosphorylation of Akt proteins. These findings suggest that folecitin may be a suitable lead to design new drugs for neurotoxin-triggered neurodegenerative disorders.

Recent evidence has highlighted the critical role of memory cells in maintaining lifelong food allergies, thereby identifying these cells as therapeutic targets. IgG⁺ memory B cells replenish pools of IgE-secreting cells upon allergen exposure, which contract thereafter due to the short lifespan of tightly regulated IgE-expressing cells. Advances in the detection and highly dimensional analysis of allergen-specific B and T cells from allergic patients have provided insight on their phenotype and function. The newly identified Th2A and Tfh13 populations represent a leap in our understanding of allergen-specific T cell phenotypes, though how these populations contribute to IgE memory responses remains poorly understood. Within, we discuss the mechanisms by which memory B and T cells are activated, integrating knowledge from human systems and fundamental research. We then focus on memory reactivation; specifically, on the pathways of secondary IgE responses. Throughout, we identify areas of future research which will help identify immunotargets for a transformative therapy for food allergy.

Abstract Women victims of abuse can suffer neuropsychological sequelae that affect memory and attention, as well psychopathological disorders such as depression. These consequences affect their daily life and physical and psychological health. Objective: To analyze sequelae that affect attention and memory, as well a possible association of these sequelae to depression. Method: A total of 68 women victims of gender-based violence participated in the study. The participants were between 15 and 62 years of age and resided in Spain at the time of data collection. The Luria DNA Battery (Neuropsychological Diagnosis of Adults) by Manga and Ramos (2000); and the Beck Depression Inventory were applied. Results: Women victims of gender-based violence suffer neuropsychological sequelae, presenting low short-term memory and attentional control; and score low on the Luria-DNA battery. Of these women, 60% suffer from some relevant type of depression, and there are significant differences according to their degree of memory. Through the HJ-Biplot, a direct relationship was found between memory and attentional control with the total score of the Luria battery. On the other hand, an inverse relationship was found between short-term memory and depression. Lastly, three well-differentiated gender clusters of women victims of gender-based violence were identified. Conclusions: A lower rate of depression is observed in women victims of abuse when they have a more intact short-term memory.

Purpose of the study was to explore the association of cognition with hazardous drinking, binge drinking and alcohol use disorder in schizophrenia and schizoaffective disorder. Cognitive deficits are common in schizophrenia. Alcohol might be associated with additional cognitive impairment in schizophrenia patients. The study population included 3362 schizophrenia and schizoaffective disorder patients in Finland. Hazardous drinking was screened with the AUDIT-C (Alcohol Use Disorders Identification Test for Consumption) screening tool. Binge drinking was obtained from the AUDIT-C. Alcohol use disorder (AUD) diagnoses were obtained from the national registrar data. Participants performed two computerized tasks from the Cambridge automated neuropsychological test battery (CANTAB) on tablet computer: the 5-choice serial reaction time task (5-CSRTT), or, reaction time (RT) test and the Paired Associative Learning (PAL) test. Association of alcohol use with RT test and PAL test was analyzed with log-linear regression and logistic regression, respectively. After adjustment for age, education and age at first psychotic episode, hazardous drinking in females was associated with lower median RT. Compared to never binge drinkers, male and female participants drinking 6 or more doses of alcohol monthly or less had lower median RT. In the PAL test both first trial memory score (FTMS) and total errors adjusted score (TEAS) were associated with better performance in males drinking 6 or more doses of alcohol weekly or more and in females drinking 6 or more doses monthly or less. Higher PAL TEAS was associated with AUD in females Some positive associations between alcohol and cognition were found in male and female schizophrenia and schizoaffective disorder patients with hazardous drinking and binge drinking.

Learning dental procedures is a complex task involving the development of fine motor skills. The reported use of theories and/ or evidence for designing learning activities to develop the fine motor skills needed for dental practice is limited. The aim of this review is to explore the available body of knowledge related to learning fine motor skills in dentistry. Evidence from studies investigating motor skill learning highlights the negative impact of self-focus and self-regulation on learning outcomes, particularly during the early stages of learning. The development of activities and schedules that enable novices to demonstrate characteristics similar to experts, without the reported long period of ‘deliberate practice’, is clearly of value. Outcomes of learning implicitly are important in dentistry because working under stressful conditions is common, either during undergraduate study or in practice. It is suggested that learning implicitly in the simulation stage can reduce disrupted performance when transitioning to clinical settings. Therefore, further investigation of effective methods for learning dental fine motor skills is indicated, using approaches that result in robust performance, even under stressful conditions.

Thermal shape memory polymers (SMPs) find increasing applications in biology and medicine due to their promising potential for improved biocompatibility. In such applications, the inevitable penetration of small molecules from the ambient fluid into the polymer influences the shape recovery process and often leads to a reduction of the temperature, at which shape recovery takes place. We show here via molecular dynamics simulations that the size of additive molecules plays a key role for this process. While the effect of concentration on the recovery rate is monotonic in the investigated range, a non-monotonic dependence on the size of additive molecules emerges at temperatures close to the glass transition. This work thus identifies the additives’ size to be a qualitatively novel parameter for switching the recovery process in polymer-based shape memory materials.

Neurodevelopmental disorders arise from genetic and/or from environmental factors and are characterized by different degrees of intellectual disability. The mechanisms that govern important processes sustaining learning and memory, which are severely affected in intellectual disability, have classically been thought to be exclusively under neuronal control. However, this vision has recently evolved into a more integrative conception, in which astroglia, rather than just acting as metabolic supply and structural anchoring for neurons, interact at distinct levels modulating neuronal communication and possibly also cognitive processes. Recently, genetic tools have made it possible to specifically manipulate astrocyte activity unraveling novel functions that involve astrocytes in memory function in the healthy brain. However, astrocyte manipulation has also underscored potential mechanisms by which dysfunctional astrocytes could contribute to memory deficits in several neurodevelopmental disorders revealing new pathogenic mechanisms in intellectual disability. Here, we review the current knowledge about astrocyte dysfunction that might contribute to learning and memory impairment in neurodevelopmental disorders, with special focus on Fragile X syndrome and Down syndrome.

A premise of statistical learning research is that learners attend to and learn the frequencies of repeating or co-occurring elements in the input. When the input is a series of words, participants readily learn the frequencies of phoneme sequences, that is, to learn phonotactic frequencies. Inherent to the concepts of both frequency and phonotactics is order, or the temporal structure of the input. Order is similarly inherent to statistical learning, yet the effect of order on statistical learning is not well understood. In the present study, adult participants learned the relative frequencies of eight item-medial consonant sequences, for example, the /mk/ in /nʌmkət/. Across five ordering conditions, both familiarization and test stimuli were independently ordered and randomized, thus allowing for a relatively broad search for order effects in an established statistical learning paradigm. Participants learned the target frequencies equivalently across the five ordering conditions, indicating no modulating effect of order. Nevertheless, participants also approached the task by applying idiosyncratic, structured orders to their responses. The result is an unexpected but robust effect of order. Both the results and the design of the study also allow for increased integration of statistical learning with memory and other aspects of cognition.

The mechanization of agricultural activities has led to indiscriminate deposition of toxic xenobiotics, including organophosphates in the biomes, and this has led to intoxication characterized with deleterious oxidative and neuronal changes. This study investigated the consequences of oxidative and neurogenic disruptions that follow exposure to two organophosphates, chlorpyrifos (CPF) and dichlorvos (DDVP) on neuro-cognitive performance and anxiety-like behaviors in rats Thirty-two adult male Wistar rats (150 – 170g) were randomly divided into 4 groups, orally exposed to normal saline (NS), DDVP (8.8mg/kg), CPF (14.9mg/kg) and DDVP+CPF for 14 consecutive days. On day 10 of exposures, anxiety-like behaviors and amygdala dependent fear learning were assessed using Open Field and Elevated Plus Maze paradigms respectively, while spatial working memory was assessed on day 14 in the Morris water maze paradigm, following 3 training trials each on days 11, 12 and 13. On day 15, the rats were euthanized, and their brains excised, hippocampus and amygdala removed, 5 of which were homogenized and centrifuged to analyze nitric oxide (NO) metabolites, total reactive oxygen species (ROS), and acetylcholinesterase (AChE) activity, and the other three processed for histology (cresyl violet stain) and proliferative marker (Ki67 immunohistochemistry). Marked (p≤0.05) loss in body weight, AChE depletion, and overproduction of both NO and ROS were observed after repeated exposure to individual and combined doses of CPF and DDVP. Insults from DDVP exposure appeared more severe owing to the observed greater losses in the body weights of exposed rats. There was also a significant (p≤0.05) effect on the cognitive behaviors recorded from the exposed rats, and these deficits were related to the oxidative damage and neurogenic cell loss in the hippocampus and the amygdala of the exposed rats. Taken together, these results provided an insight that oxidative and neurogenic damages are central to the severity of neuro-cognitive dysfunction and increased anxiety-like behaviors that follow organophosphate poisoning.

In modern Commercial Off-The-Shelf (COTS) multicore systems, cores can produce several simultaneous memory requests. The processing of such requests over the memory controller negatively impacts the interference delay triggered by running parallel tasks on the platform. In this paper, we propose a software-based testing approach for analyzing memory interference delay, when cores are exposed to extensive read/write requests that access in parallel their Cache Coherent Interconnect. The hardware targeted in this work is the well-known LayerScape QorIQ LS2085A, which can be approached as a potential successor to the Freescale QorIQ P4080. The test analysis was conducted based on a bare-metal operating system that we developed to guarantee a deterministic execution environment at all time points. Our testing was accomplished using a set of carefully designed synthetic benchmarks as well as TACLeBench benchmarks.

In The Work of the Dead: A Cultural History of Mortal Remains, Thomas Laqueur argues that the work of the dead is carried out through the living and through those who remember, honour, and mourn the dead. Further, he maintains that the brutal or careless disposal of the corpse “is an attack of extreme violence”. To treat the dead body as if it does not matter or as if it were ordinary organic matter would be to deny its humanity. From Laqueur’s point of view it is inferred that the dead are believed to have rights and dignities that are upheld through rituals, practices, and beliefs of the living. Drawing on dark tourism scholarship and cultural memory theory, this paper examines the display of human bones at Sedlec Ossuary, Czech Republic and the tourist culture that has built up around the site. Primarily, my writing calls into question the commoditization of burial places as a conceivable violation of the human rights of the dead. My research is driven by a number of questions: What is it that draws tourists to burial grounds and how do heritage sites negotiate visitor experiences? What are the ethical boundaries when a final resting place with bodies on display is also marketed as a tourist site? Do the dead have human rights and how are the living responsible for preserving those rights?

In this work, we consider a one-dimensional laminated beam in the case of non-equal wave speeds with only one infinite memory on the effective rotation angle. In this case, we establish the general decay result for the energy of solution without any kind of internal or boundary control. The main result is obtained by applying the method used in Guesmia et al. (Electron. J. Differential Equations 193: 1-45, 2012) and the second-order energy.

In the current paper, a residual generation filter with finite memory structure is proposed for sensor fault detection. The proposed finite memory residual generation filter provides the residual by real-time filtering of fault vector using only the most recent finite observations and inputs on the window. It is shown that the residual given by the proposed residual generation filter provides the exact fault for noise-free systems. The proposed residual generation filter is specified to the digital filter structure for the amenability to hardware implementation. Finally, to illustrate the capability of the proposed residual generation filter, numerical examples are performed for the discretized DC motor system having the multiple sensor faults.

Using recent developments in econometrics and computational statistics we consider the estimation of the instantaneous rate of asset return process when the underlying Data Generating Mechanism (DGM) is an Ornstein-Uhlenbeck process, driven by fractional noise, and sampled at fixed intervals of length h. To address the problem we adopt throughout the paper an exact discretization approach. This enable us to exploit the fact that a flow sampling scheme arises naturally when observing the DGM. For, while the instantaneous rate of return process is unobservable at points in time, its time integral over successive observations is observable since it equals the increment of log-prices. Exact discretization delivers an ARIMA(1,1,1) model for log-prices with a fractional driving noise. Building on the resulting exact discretization formulae and covariance function, a new Markov Chain Monte Carlo (MCMC) scheme is proposed and we examine the properties of both the time and frequency domain likelihoods / posteriors through Monte Carlo. For the exact discrete model we adopt a general sampling interval of length h. This allow us to determine the optimal choice of h independent of the sample size. An empirical application using high frequency stock price data is presented showing the relevance of aggregation over time issues in modelling asset prices.

Fowlpox virus (FPV) has been used as a vector for many years. To date, surprisingly, very little data exist on the persistence of fowlpox vaccines in chicken tissues, or what kind of immune cells respond to the vaccination at the site of inoculation. Although both humoral and cellular mediated immunity (CMI) play a part in overall immunity against FPV, little is known regarding the cell-mediated immune responses to FPV infection. The main aim of this paper was to measure persistence of the recombinant fowlpox vaccine in the skin tissues following vaccination. The results showed that the recombinant FPVs do not persist for long, and are cleared by 6 days post-vaccination (dpv). The response of immune cells (macrophages, B cells, CD4+ and CD8+ T cells) that infiltrating the site of vaccination was estimated.

Gliomas are central nervous system (CNS) derived tumors that originate from glial cells and affect six per 100,000 people in the United States. They are the most common form of CNS neoplasm and are highly diffusely infiltrative to surrounding brain tissue. Gliomas of diffusive nature are classified into different subcategories: astrocytomas, oligodendrogliomas, and ependymomas. Computed tomography (CT) and Magnetic Resonance Imaging (MRI) are used to determine tumor category and spread which may dictate treatment options. This paper focuses on emerging treatments of chemotherapy management with temozolomide and Avastin as well as emerging immune modulation treatment with vaccinations, manipulation of cellular checkpoints CTLA-4 and PD-1, co-receptor modulation of neuropilin-1, CAR-T cell therapy, and CRISPR-Cas9 gene editing. The employment of TMZ and BEV has been supported in the literature, however, more research is necessitated to fully optimize regimens and to avoid immune- and toxicity-related effects of these drugs. Moreover, an even closer consideration is warranted for current immunotherapies as they are in their infancy compared to TMZ and BEV. Thus, although promising emerging treatment options, therapies involving cancer vaccines, ICIs, immune modulation of neuropilin-1, CAR-T, and CRISPR-Cas9 technology require further investigation into their long-term efficacy and utility in treating gliomas.

Abstract: The centrepiece of this analytical review is the metabolism of hydroxyapatite in its natural, bone, and synthetic forms, where the mitochondria-mediated mechanism may serve as the leading mechanism. The possibility that osteoblast mitochondria play an important role in the initial stages of bone mineralisation is discussed. Furthermore, the paper highlights the key role of mitochondria in the metabolism of synthetic hydroxyapatite.Differences between the results of in vivo and in vitro studies using synthetic hydroxyapatite of different morphologies are also detailed. It is noted that long-term infiltration with immune cells and in vivo studies are necessary to adequately evaluate hydroxyapatite as a bone-plastic material.Particular attention is given to the interaction of hydroxyapatite with immune cells and its ability to affect the ribosomes and mitochondria of cells. Due to its mechanical properties, scalability and potential use for the treatment of extensive bone defects of tumor origin, hydroxyapatite is a promising material.This study also highlights the importance of further development of in vitro research methods in the context of their biomimeticity. Overall, this work offers a theoretical direction for future studies of hydroxyapatite as a bone grafting material and emphasises the value of in vivo studies.

CD147/Basigin, a transmembrane glycoprotein belonging to the immunoglobulin super family, is a multifunctional molecule with various binding partners. CD147 binds to monocarboxylate transporters (MCTs) and supports their expression on plasma membranes. MCTs play an important role in glycolysis, the enzymatic conversion of glucose to pyruvate and adenosine triphosphate (ATP). Pyruvate is further converted to lactic acid which is exported from the cytoplasm by MTC-1 and MCT-4 to maintain intracellular pH and a stable metabolic state. Under physiological conditions, cellular energy production is induced by mitochondrial oxidative phosphorylation. Glycolysis usually occurs under anaerobic conditions, whereas cancer cells depend on glycolysis under aerobic conditions. T cells also require glycolysis for differentiation, proliferation, and activation. Human malignant melanoma cells expressed higher levels of MCT-1 and MCT-4, co-localized with CD147 on the plasma membrane and showed an increased glycolysis rate compared to normal human melanocytes. Silencing of CD147 by siRNA abrogated the membrane expression of MCT-1 and MCT-4 and disrupted glycolysis, inhibiting cancer cell activity. The differentiation of CD4+ T cells into Th17 cells is a pivotal process in the development of various immune disorders, including psoriasis. Studies using CD147-deficient mice demonstrated the involvement of CD147 in psoriasis. MCT-1 was absent on CD4+ T cells in CD147-deficient mice. Naïve CD4+ T-cells from CD147-deficient mice show low potential for differentiation into Th17 cells. Imiquimod-induced skin inflammation was significantly milder in CD147-deficient mice than in wild-type mice. These findings indicate that CD147/Basigin is involved in the development of malignant tumors and T cell mediated immunological disorders via regulation of glycolysis.

Radiotherapy for cancer has been known to affect the responses of immune cells, especially those of CD8+ T cells that play a pivotal role in anti-tumor immunity. Clinical success of immune checkpoint inhibitors led to an increasing interest into the ability of radiation to modulate CD8+ T cell responses. Recent studies that carefully analyzed the CD8+ T cell responses following radiotherapy suggest the beneficial roles of radiotherapy on anti-tumor immunity. In addition, numerous clinical trials that evaluate the efficacy of combining radiotherapy with immune checkpoint inhibitors are undergoing. In this review, we summarize the current status of knowledge regarding the changes of CD8+ T cells following radiotherapy from various preclinical and clinical studies. Furthermore, key biologic mechanisms that underlie such modulation, including both direct and indirect effects, are described. Lastly, we discuss the current evidence and essential considerations for harnessing radiotherapy as a combination partner for immune checkpoint inhibitors.

Epstein Barr Virus (EBV) has been recognized for its ability to transform B lymphocytes and for its association with different types of cancers including Hodgkin lymphoma. In addition, EBV may also modulate the microenvironment of HL. In this study, we aimed to investigate the prevalence of EBV among HL cases in Ethiopia and to assess the tissue cellular composition of EBV-related and EBV-unrelated cases. We constructed a tissue microarray (TMA) of 126 consecutive cases of classical HL (cHL) and nodular lymphocyte predominant HL (NLPHL) from a tertiary cancer centre, Tikur Anbessa Hospital, Addis Ababa, Ethiopia, and evaluated a panel of immunohistochemical markers. The quantification of immune cells was performed using HALO 2.3, a platform for image analysis from Indica Lab Inc. A total of 77/126 (61.1%) of HL cases expressed LMP1/EBER. Infiltration of CD8+, T-bet+ and FOXP3+ cells was higher in the microenvironment of EBV-related HL, with P values of <0.001, 0.006 and <0.001, respectively. In contrast, the expression of PD1 was higher in the microenvironment of EBV-unrelated HL cases (P = 0.001). Unlike in Western countries, the majority of HL cases in Ethiopia were associated with EBV. As FoxP3+ and PD1-expressing cells are thought to participate in down regulation of the immune response by different mechanisms, this finding highlights the previously unrecognized possibility that distinct immunosuppressive mechanisms may be ongoing within EBV positive and negative HL types. This may have important prognostic and therapeutic implications.

The noncoding RNAs (ncRNAs) are small transcript sequences that do not encode proteins but participate in the regulation of gene expression at the post-transcriptional level playing important biological roles such as proliferation and differentiation. In the tumor microenvironment, the dysregulated immunological response can participate in the progression and negative phenotype of cancer, the variability of switch cell differentiation and activation of the different immune cell lineages showed differential regulation by the type of cancer. Recent evidence showed that the upregulation of lncRNA can be used as a biomarker and predictive indicator for cancer progression. The use of lncRNA to turn off the tumor immune response and activate the anti-tumoral immune response is day by day a promising reality for the control of cancer. However, is imperatively elucidated the role of each ncRNA identified as well as its respective molecular pathways regulated, including the immune checkpoints, before its application at the clinical level. The correct delivery of lncRNA or mimics to inhibit its expression using the most efficient carriers to the cell or cellular organelle is a science that should continue to be developed.

The tumor microenvironment of colorectal cancer (CRC) is heterogenous; thus, it is likely that multiple immune-related and inflammatory markers are simultaneously expressed in the tumor. The aim of this study was to identify immune-related and inflammatory markers expressed in freshly frozen CRC tissues and to investigate whether they are related to the clinicopathological features and prognosis of CRC. Seventy patients with CRC who underwent curative surgical resection between December 2014 and January 2017 were included in this study. Tissue samples were obtained from tumor and non-tumor areas in the patients’ colons. The concentrations of immune-related markers (APRIL/TNFSF13, BAFF, LAG-3, PD-1, PD-L1, and CTLA-4) and inflammatory markers (CHIT, MMP-3, osteocalcin, pentraxin-3, sTNF-R1, and sTNF-R2) in the samples were measured using the Bio-plex Multiplex Immunoassay system. The concentrations of APRIL/TNFSF13, BAFF, and MMP-3 in the samples were significantly high; thus, we conducted analyses based on the cutoff values for these three markers. The high APRIL/TNFSH13 expression group showed a significantly higher rate of metastatic lesions than the low expression group, whereas the high MMP-3 expression group had higher CEA levels, more lymph node metastases, and more advanced disease stages than the low expression group. The five-year disease-free survival of the high MMP-3 expression group was significantly shorter than that of the low expression group (65.1% vs. 90.2%, p=0.033). This study provides evidence that the APRIL/TNFSF13, BAFF, and MMP-3 pathway is overexpressed CRC tissues and is associated with unfavorable clinicopathological features and poor prognosis in CRC patients. These markers could serve as diagnostic or prognostic biomarkers for CRC.

Over the last decade, the therapeutic scenario for advanced non-small-cell lung cancer (NSCLC) has undergone a major paradigm shift. Immune checkpoint inhibitors (ICIs) have shown a meaningful clinical and survival improvement in different settings of the disease. However, the real benefit of this therapeutic approach remains controversial in selected NSCLC subsets, such as those of the elderly with active brain metastases or oncogene-addicted mutations. This is mainly due to the exclusion or underrepresentation of these patient subpopulations in most of the pivotal phase III studies; this precludes the generalization of the ICI efficacy in this context. Moreover, no predictive biomarkers of ICI response exist that can help with patient selection for this therapeutic approach. Here, we critically summarize the current state of ICI efficacy in the most common “special” NSCLC subpopulations.

The approval of monoclonal antibodies against programmed death-ligand 1 (PD-L1) and programmed cell death protein (PD1), has changed the landscape of cancer treatment. To date, many Immune Checkpoint Inhibitors (ICIs) have been approved by the FDA for the treatment of metastatic cancer as well as locally recurrent advanced cancer. However, immune-related adverse events (irAEs) of ICIs highlight the need for biomarker analysis with strong predictive value. Liquid biopsy is an important tool for clinical oncologists to monitor cancer patients and administer or change appropriate therapy. CTCs frequently express PD-L1 and this constitutes a clinically useful and non-invasive method to assess PD-L1 status in real time. This review summarizes all the latest findings about the clinical significance of CTC for the management of cancer patients during administration of immunotherapy and mainly focuses on the assessment of PD-L1 expression in CTCs.

Malaria remains a major public health problem worldwide, with eradication efforts thwarted by drug and insecticide resistance and the lack of a broadly effective malaria vaccine. In continuously exposed communities, polyclonal infections are thought to reduce the risk of severe disease and promote the establishment of asymptomatic infections. We sought to investigate the relationship between the complexity of P. falciparum infection and underlying host adaptive immune responses in an area with high prevalence of asymptomatic parasitaemia in Cameroon. A cross-sectional study of 353 individuals aged 2 to 86 years (median age = 16 years) was conducted in five villages in the Centre Region of Cameroon. Plasmodium falciparum infection was detected by multiplex nested PCR in 316 samples, of which 278 were successfully genotyped. Of these, 60.1% (167/278) were polyclonal infections, the majority (80.2%) of which were from asymptomatic carriers. Host-parasite factors associated with polyclonal infection in the study population included peripheral blood parasite density, participant age and village of residence. The number of parasite clones per infected sample increased significantly with parasite density (r = 0.3912, p<0.0001) but decreased with participant age (r = -0.4860, p<0.0001). Parasitaemia and number of clones per sample correlated negatively with total plasma levels of IgG antibodies to three highly reactive P. falciparum antigens (MSP-1p19, MSP-3 and EBA175) and two soluble antigen extracts (merozoite and mixed stage antigens). Surprisingly, we observed no association between the frequency of polyclonal infection and susceptibility to clinical disease as assessed by the recent occurrence of malarial symptoms or duration since the previous fever episode. Overall, the data indicate that in areas with high perennial transmission of P. falciparum, parasite polyclonality is dependent on underlying host adaptive immune responses, with the majority of polyclonal infections occurring in persons with low levels of protective anti-plasmodial antibodies.

Programmed-death-1 (PD-1) receptor plays a major physiological role in maintainance of im-mune tolerance, and, by interaction with its ligands (PD-L1 and PD-L2), prevents the develop-ment of multiple immune-mediated diseases. There is growing evidence of an important role of PD-1/PD-L1 pathway in pathogenesis of psoriasis. 84 subjects with psoriasis were included into the study, together with 29 healthy subjects as a control group. 28 of psoriatic patients were treated with biologice therapy (TNF-alpha, interleukin (IL)-12/23 or IL-17 inhibitors). Amounts of PD1 and PD-L1 positive T-cells in peripheral blood were evaluated using flow cytometry. Significantly lower levels of peripheral blood mononuclear cells (PBMCs) with the expression of PD-1 and PD-L1 were found in psoriatic patients when compared to healthy individuals, i.e. CD3/PD1, CD3/PDL1, CD4/PD1, CD4/PDL1, CD8/PDL1, CD19/PD1, CD19/PDL1 positive cells. Biologic treatment resulted in elevation of CD3/PDL1, CD8/PDL1 and decrease of CD8/PD1 posi-tive PBMCs. Our results confirm previous observations of disrupted PD-1/PD-L1 pathway in psoriasis, and that this disturbances may play an important role in development of the disease. Biologic drugs may reverse several abnormalities observed within this pathway, which may ex-plain their excellent efficacy in the treatment of psoriasis. Further research should be conducted to fully explain the results obtained.

There has been no significant efficacy in treatment for osteosarcoma (OS) metastasis after nearly four decades of trials. This motivates us to elucidate OS therapies according to their four bidirectional mutation stages. To refresh the OS therapy status quo, the historical developments and clinical advancements are briefly described. However, the main issue of metastasis remains unresolved, accounting for 90% of pulmonary metastasis deaths. Thus, this metastasis problem is related to immune evasion and chemoresistance that are being induced after long-term treatment by the use of immunotherapy for tumorigenesis. Therefore, it is rationale to discuss the relationship cycles of mutation stages including tumorigenesis, metastasis, immune evasion, and chemoresistance. Even though many combinational and targeted therapies have been developed to intensify these mutation treatments, successful clinical translations with higher cure rates are still rare. Through this review, an in-depth understanding of the bidirectional relationship between the four OS mutation stages and their respective therapies is provided. Herein, we summarise the medicines used to treat tumorigenesis, including COLGALT2 inhibitors, Tra2B, and AGAP1, miR-148a and miR-21-5p EVs, and the lncRNA LIFR-AS1. Following the medicines used to treat metastasis are AXL, miR-135a-5p, mRNA BCL6, TGFβ1, Tim-3, SOCS5, CASC15, KLF3-AS1, PDCD4, ATG5, and Rab22a-NeoF1. Then the medicines used to treat immune evasion are N-cadherin, anti-IL-9, USP12 inhibitor, IgG-4+ B-cells, LAP inhibitor, anti-Wnt2 mAb, anti-αvβ8 integrin, HK2-mediated IκBα, IDO inhibitor with NO, and TGF-βRII with anti-IgG1. Finally, the medicines used to treat chemoresistance are DHFR, FPGS, HSP-90AA1, XCT-790, ATKI, and IGF1. As a result, this contribution is expected to serve as a reference and guide for scientists and clinicians.

Background: Diffuse glioma is a malignant human brain cancer that is hard to overcome. This represents a high risk of mortality. The current challenge is limited to the control of tumor progression and survival improvement. Immunotherapy consists of stimulating the immune system in order to eliminate the non-self-elements that damage the human body, including cancer cells. However, in human glioma, the current immunotherapeutic targets did not show significant benefit. In this study, we aimed at evaluating the expression and potential role of a new immunosuppressive molecule, TIGIT in glioma patients. Methods: A cohort of 667 patients from the TCGA database along with a cohort of 53 Moroccan patients, were analyzed in order to assess the role of TIGIT in human glioma progression and to estimate whether blocking this immune checkpoint molecule would be of a potential therapeutic benefit. Real time RT-PCR from fresh human biopsies and RNAseq data analysis were performed in this study. Results: Our results showed that high expression of TIGIT had prognostic value with some known clinical glioma risk factors such as sex, age and IDH mutation status. High expression of TIGIT was positively associated with advanced grades of glioma. Interestingly, elevated rates of TIGIT were significantly associated to elevated levels of other inhibitory immune checkpoint molecules (PD-1, VISTA and Tim-3) in human glioma patients, also TIGIT showed strong association with Treg cell-secreted cytokines (TGF-beta and IL-10), indicating the high potential involvement of TIGIT in immunosuppression in human glioma. Moreover, we reported that high TIGIT expressing CD8 T-cells displayed more surface inhibitory molecules and, elevated levels of Treg cells and FoxP3 were linked to higher rates of TIGIT, supporting the likely involvement of TIGIT in the suppression of the intra-tumoral immune cells. Finally, high expression of TIGIT was significantly linked to advanced histological subtypes of glioma and was associated with poor overall survival in human glioma. Conclusion: TIGIT blockade might be of valuable therapeutic benefit in patients with advanced glioma.

We have previously discussed the pathological characteristics, clinical characteristics, detection methods, pathogenesis, and treatment of Epstein–Barr virus (EBV)-positive gastric cancer, but we have not discussed the unique immune microenvironment in EBV-positive gastric cancer. Here, we reviewed studies on the immune microenvironment in EBV-positive gastric cancer and found that CD8+ T lymphocytes and a small number of CD204+ macrophages infiltrate the immune microenvironment in EBV-positive gastric cancer. Moreover, immune checkpoints, such as IDO1 and PD-L1, are expressed at high levels in EBV-positive gastric cancer. Lastly, we also analyzed the mechanisms underlying the formation of the immune microenvironment in EBV-positive gastric cancer. Our findings and conclusions have significance in clinical guidance and provide research direction for basic experiments.

Gut microbiota is considered a key player modulating the efficacy of immune checkpoint inhibitor therapy. The study investigated the association between response to the anti-PD-1 therapy and the baseline gut microbiome in the Polish cohort of melanoma patients, alongside selected agents modifying the microbiome. Sixty-four melanoma patients enrolled for the anti-PD-1 therapy and 10 healthy subjects were recruited. Response to the treatment was assessed according to the response evaluation criteria in solid tumors, and patients were classified as responders or non-responders. The association between selected extrinsic factors and response was investigated using questionnaire-based analysis, and metataxonomics of the microbiota. The Bacteroidota to Firmicutes ratio was higher, and the richness was decreased in the responders. The abundance of Prevotella copri and Bacteroides uniformis was related to the response, whereas non-responder gut microbiota was enriched with Faecalibacterium prausnitzii and Desulfovibrio intestinalis, and some unclassified Firmicutes. Dietary patterns, including plant, dairy, and fat consumption, but also gastrointestinal tract functioning were significantly associated with the therapeutic effects of the therapy. The specific gut microbiota alongside diet were found associated with response to the therapy in the Polish population of melanoma patients.

Morinda citrifolia (noni) fruit juice has the potential to influence immune system function. This review discusses results from several human and animal studies that provide insight into the potential mechanisms of action by which noni juice exerts its immunomodulatory effects. Increased natural killer cell activity is a likely a major contributor to the improved health outcomes and increased survival times described in case reports and as observed in LLC and S180 tumor bearing mice. Increased interferon-gamma (IFN-γ) production is also an important mechanism of action through which noni improves immune function. IFN-γ promotes natural killer cell activity and phagocytosis, activities both seen in human and bovine studies as well as in rodents. Noni promotes regulatory cytokine expression, such as IL-2 which stimulates CD4+ T cell differentiation. Noni juice appears to influence this process via kinase 1/2 (ERK1/2) protein kinase B (Akt) and nuclear factor-kappa-beta signaling. As oxidative status is known to influence immune function, this review also discusses the notable antioxidant properties of noni juice that have been demonstrated in human trials.

Background: LncRNA and pyroptosis play important roles in cancer development and tumor immune microenviroment. However, pyroptosis-related lncRNAs (PRLs) in ovarian cancer have not been identified and its impact on prognosis and immune response are not fully understood. Methods: Using pearson correlation analysis, PRLs were screened. Subsequently, we constructed a prognosis signature by using LASSO cox regression. In addition, the association between risk score and cancer immune environment was analyzed. Results: In TCGA-RNA-seq cohort (n=377), 32 prognostic PRLs were selected and a 7-gene signature were developed and had high accuracy in predicting the OS of ovarian cancer patients. Stratification analysis suggested that it might serve as an independent prognostic indicator. Except to clinical outcome, the signature was significantly associated with tumor immune microenvironment. Patients with high risk score exhibited lower infiltration abundance of MHC class Ⅰ cells, Type Ⅰ IFN response and immunotherapy response. In ovarian cancer, TYMSOS was highly expressed and its high expression was associated with worse OS. TYMSOS deletion in ovarian cancer cell lines inhibited the cell proliferation, invasion and migration, indicating that it might serve as a novel biomarker in ovarian cancer. Conclusions: The prognostic PRLs signature constructed in this work is available for prognostic prediction and immune microenvironment infiltration in ovarian cancer.

Abstract: Oxidative metabolism is crucial for leukemic stem cell (LSC) function and drug resistance in acute myeloid leukemia (AML). Mitochondrial metabolism also affects the immune system and therefore the antitumor response. Modulation of oxidative phosphorylation (OxPHOS) has emerged as a promising approach to improve therapy outcome for AML patients. However, the effect of mitochondrial inhibitors on the immune compartment in the context of AML is yet to be explored. Immune checkpoints such as the ecto-nucleotidase CD39 and programmed dead ligand 1 (PD-L1) have been reported to be expressed in AML and linked to chemoresistance and poor prognosis. In the present study, we first demonstrated that a novel selective electron transfer chain complex (ETC) I inhibitor, EVT-701, decreased OxPHOS metabolism of murine and human cytarabine (AraC)-resistant leukemic cell lines. Furthermore, we showed that, while AraC induced immune response regulation by increasing CD39 expression and by reinforcing interferon-γ/PD-L1 axis, EVT-701 reduced CD39 and PD-L1 expression in vitro in a panel of both murine and human AML cell lines, especially upon AraC treatment. Altogether, this work uncovers a non-canonical function of ETCI in controlling CD39 and PD-L1 immune checkpoints, thereby improving the anti-tumor response in AML.

Background: Post-operative delirium in elderly with hip fracture is associated with various adverse clinical outcomes. Nevertheless, the pathophysiological processes underpinning delirium have remained elusive. The aim of this study is to explore the associations between delirium and its features and immune-inflammatory and blood gas biomarkers.Methods: In this prospective study we examined 65 patients who underwent a hip fracture surgery and assessed the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU), Richmond Agitation-Sedation Scale (RASS), and Delirium Rating Scale Revised-98 (DRS-R-98) before and during 4 days after the surgery. Complete Blood Count (CBC) and venous blood gas markers were obtained at the same time points.Results: Delirium was observed in 19 patients and was accompanied by significantly increased pO2, number of white blood cells, neutrophil percentage, and neutrophil/lymphocyte ratio, and lower mean platelet volume (MPV) (after adjusting for age, central nervous system (CNS) disease, blood loss during surgery, sleep disorders, and body mass index. The severity of delirium was associated with lowered number of platelets and MPV. Psychomotor disorders were associated with lower bicarbonate levels. The requirement of physical restraint of the patients was predicted by increased percentages of neutrophils and lymphocytes. Prior CNS disease was together with these biomarkers a significant predictor of delirium and severity of delirium. Conclusion: Delirium and psychomotor disorders following hip fracture and surgery may be caused by immune-inflammatory and oxidative stress pathways probably attributable to an aseptic inflammatory process. Oxygen administration may aggravate these pathways.

Cancer-associated fibroblasts (CAF) form the basis of tumor microenvironment and possess immunomodulatory functions by interacting with other cells surrounding tumor, including T lymphocytes, macrophages, dendritic cells and natural killer cells. Ionizing radiation is a broadly-used method in radiotherapy to target tumors. In mammalian cells, ionizing radiation induces various types of DNA damages and DNA damage response. Being unspecific, radiotherapy affects all the cells in tumor microenvironment, including the tumor itself, CAFs and immune cells. CAFs are extremely radio-resistant and do not initiate apoptosis even at high doses of radiation. However, following radiation, CAFs become senescent and produce a distinct combination of immunoregulatory molecules. Radiosensitivity of immune cells varies depending on the cell type due to inefficient DNA repair in, for example, monocytes and granulocytes. In this minireview, we are summarizing recent findings on the interaction between CAF, ionizing radiation and immune cells in the tumor microenvironment.

The immune system is a dynamic network of cells and cytokines are the major mediators of immune responses which combat pathogens. Based on the cytokine production, effector T cells differentiate into subsets known as Th1, Th2, Th17 or Treg (T regulatory). This system serves as a barrier to intracellular pathogens, bacterial infections and stimulates the production of reactive oxygen species (ROS), reactive nitrogen intermediates (RNI) and nitric oxide (NO), which diffuses across membranes and engulfs intracellular pathogens. Oxidative stress occurs when ROS, reactive nitrogen species (RNS) production and antioxidant defences become imbalanced. Oxidative stress generated by infected cells produces a substantial amount of free radicals which enables killing of intracellular pathogens. Intracellular pathogens are exposed to endogenous ROS as part of normal aerobic respiration, also aexogenous ROS and RNS are generated by the host immune system in response to infection. Nanoparticles which are designed for drug delivery are capable of trapping the desired drug in the particles which protects the drug from enzymatic degradation in a biological system. The small (subcellular) size of nanoparticles enables higher intracellular uptake of the drug which results in the reduction of the concentration of free drugs reducing their toxic effect. Research on the modulation of immune response and oxidative stress using nanoparticles used to encapsulate drugs has yet to be explored fully. In this review we illustrate the immune activation and generation of oxidative stress properties which are mediated by nanoparticle encapsulated drug delivery systems which can make the therapy more effective in case of diseases caused by intracellular pathogens.

Coronavirus and COVID-19 infections continue to wreak havoc across the world. Interestingly, the COVID-19 infections and deaths display a clear seven-day cycles. Mathematical analysis using linear mixed-effects models show that this periodicity is not due to reporting errors. We hypothesize that these COVID-19 cycles are related to natural immune cycles which also oscillate every seven days. These immune cycles are regulated by stress and mediated through the endocrine and the central nervous systems. Our routine activities and lifestyle of more stressful weekdays flanked by less stressful, relaxing weekends define the seven-day immune cycles. The synchronized low immunity levels in the population is responsible for repeated seven-day waves of pathogenic infections such as COVID-19. The new understanding of the role of immune oscillations will help in developing strategies to enhance our immunity through modified lifestyle and better, innovative prophylactic and therapeutic approaches against infectious diseases.

Objective: To examine associations between chemokines and menstrual cycle associated symptoms (MCAS). Methods: Forty-one women completed the Daily Record of Severity of Problems (DRSP) rating scale during 28 consecutive days of the menstrual cycle. MCAS is diagnosed when the total daily DRSP score during the menstrual cycle is > 0.666 percentile. We assayed plasma CCL2, CCL5, CCL11, CXCL8, CXCL10, EGF, IGF-1, and PAI-1 at days 7, 14, 21 and 28 of the menstrual cycle. Results: CCL2, CCL5, CCL11 and EGF are significantly higher in women with MCAS than in those without. Increased CCL2, CXCL10, CXCL8, CCL11 and CCL5 levels are significantly associated with DRSP scores while CCL2 is the most significant predictor explaining 39.6% of the variance. The sum of the neurotoxic chemokines CCL2, CCL11 and CCL5 is significantly associated with the DRSP score and depression, physiosomatic, breast-craving and anxiety symptoms. The impact of chemokines on MCAS symptoms may differ between consecutive weeks of the menstrual cycle with CCL2 being the most important predictor of increased DRSP levels during the first two weeks, and CXCL10 or a combination of CCL2, CCL11 and CCL5 being the best predictors during week 3 and 4, respectively. Discussion: The novel case definition “MCAS” is externally validated by increased levels of uterus-associated chemokines and EGF. Those chemokines are involved in MCAS and are regulated by sex hormones and modulate endometrium functions and brain neuro-immune responses, which may underpin MCAS symptoms. As such, uterine-related chemokines may link the uterus with brain functions via a putative uterine-chemokine-brain axis.

Lassa virus (LASV) is responsible for a type of acute viral haemorrhagic fever referred to as Lassa fever. Lack of adequate treatment and preventive measures against LASV resulted in a high mortality rate in its endemic regions. In this study, a multi-epitope vaccine was designed using immunoinformatics as a prophylactic agent against the virus. Following a rigorous assessment, the vaccine was built using T-cell (N_CTL=8 and N_HTL=6) and B-cell (N_LBL=4) epitopes from each LASV-derived protein with suitable linkers and adjuvant. The physicochemistry, immunogenic potency and safeness of the designed vaccine (~68 kDa) were assessed. In addition, chosen CTL and HTL epitopes of our vaccine showed 97.37% worldwide population coverage. Besides, disulphide engineering also improved the stability of the chimeric vaccine. Molecular docking of our vaccine protein with toll-like receptor (TLR2) showed binding efficiency followed by dynamic simulation for stable interaction. Furthermore, higher levels of cell-mediated immunity and rapid antigen clearance were suggested by immune simulation and repeated-exposure simulation, respectively. Finally, the optimized codons were used in in silico cloning to ensure higher expression within E. coli K12 bacterium. With further assessment both in vitro and in vivo, we believe that our proposed peptide-vaccine would be potential immunogen against Lassa fever.

There is now evidence that major depression is accompanied by lowered serum zinc, an immune-inflammatory biomarker. However, the effect of anti-inflammatory drugs as adjuvant to antidepressants on serum zinc and copper in relation to pro- and anti-inflammatory cytokines are not studied. The aim of the present work is to examine the effects of treatment with sertraline with and without ketoprofen on serum levels of zinc and copper in association with immune-inflammatory biomarkers in drug-naïve major depressed patients. We measured serum zinc and copper, interleukin (IL)-1β, IL-4, IL-6, IL-18, interferon (IFN)-γ, and transforming growth factor (TGF)-β1 in 40 controls and 133 depressed patients. The clinical efficacy of the treatment was measured using the Beck Depression Inventory-II (BDI-II) at baseline and 8 weeks later. In drug-naïve major depressed patients we found significantly reduced baseline levels of serum zinc and copper in association with upregulation of all cytokines, indicating activation of the immune-inflammatory responses system (IRS) as well as the compensatory immune regulatory system (CIRS). Treatment with sertraline significantly increased zinc and decreased copper levels, while ketoprofen did not have a significant add-on effect on zinc but attenuated the suppressant effects of sertraline on copper levels. During treatment, there was a significant inverse association between serum zinc and activation of the IRS/CIRS. The improvement in the BDI-II during treatment was significantly associated with increments in serum zinc coupled with attenuation of the IRS/CIRS. In conclusion, lower serum zinc is a hallmark of depression, while increments in serum zinc and attenuation of the immune-inflammatory response during treatment appear to play a role in the clinical efficacy of sertraline. Intertwined changes in zinc levels and the immune response play a role in the pathophysiology of major depression and participate in the mechanisms underpinning the clinical efficacy of antidepressants.

Astragalus membranaceus (AM) and Panax ginseng (PG) are two herbal products with a long history of clinical usage in traditional Chinese medicine (TCM), used in treating a variety of diseases especially in stimulating or inhibiting the immune system. To elucidate the immunity effect of these two traditional Chinese medicine on animal model, four pharmacodynamic indexes (spleen index, thymus index, splenic lymphocyte proliferation and cytotoxic activity of natural killer (NK) cells) were observed on mice. Furthermore, metabolic profiles of plasma were also analyzed by ultra-performance liquid chromatography quadrupole-time-of-flight mass spectrometry (UPLC-Q/TOF-MS, LC-MS) method. All mice were intragastric administrated at three doses (low dose, moderate dose and high dose) once daily for 30 days. Principal components analysis (PCA) and orthogonal projection to latent structure discriminant analysis (OPLS-DA) were performed on LC-MS spectra of plasma, showing that all administration groups developed the disturbance of internal milieu, compared to the blank control (BC) group. Besides, correlation analysis was conducted between pharmacodynamic index and metabolic index. It indicated that uracil, lysoPC(18:3(6Z,9Z,12Z)), sphinganine, LPA(0:0/16:0), UDP-glucuronate, PC(14:0/18:0) were five main endogenous substances, much closely related to four immunological indexes. Glycerophospholipid metabolism was found in both AM and PG groups. Pyrimidine metabolism and sphingolipid metabolism were closely regulated in AM groups. Energy metabolism (starch and sucrose metabolism, Pentose and glucuronate interconversions, together with glycerolipid metabolism) and glycerolipid metabolism were found in PG groups. These findings could contribute to the understanding of mice plasmatic metabolic profiling after long-term administration. Comparative immune-related metabolomic analysis of AM and PG was obtained on the base of pathway analysis of immune-related biomarkers. PG groups trended to have effect on cytotoxic activity of NK cells. AM groups trended to effect thymus index. Our work provides a detailed interpretation of immunological characteristics in different traditional Chinese medicine on metabonomic level.

Lung cancer remains the leading cause of cancer-related death and it is usually diagnosed in advanced stages (stage III or IV). Recently, the availability of targeted strategies and of immunotherapy with checkpoint inhibitors (ICI) has favorably changed patient prognosis. Treatment outcome is closely related to tumor biology and interaction with the host immune microenvironment (TME). Whether for targeted therapies the response relies on the presence of specific genetic alterations in tumor cells, for ICI accurate biomarkers of response are lacking and clinical outcome likely depends on multiple factors, host and tumor-related. This paper is an overview of the ongoing research on predictive factors both from in-vitro/ex-vivo analysis (ranging from conventional pathology to molecular biology) and in-vivo analysis, where molecular imaging is showing an exponential growth and use due to the technological advancement and to the new bioinformatics approaches applied to image analyses that allow specific features recovery in specific tumor subclones.

As a result of the cancer immunotherapy revolution hundreds of clinical trials of the newly approved immunotherapies are now under way to improve responses. Not unexpectedly, the 2018 Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo for their development of cancer therapy by blockade of co-inhibitory signals. While success stories of terminal cancer patients achieving complete remissions are accumulating, not enough research has been done into the risks of the new therapies. Since the use of immunotherapy is becoming more common, and is expected to develop into first- and second-line treatments, immunotoxicity and autoimmunity are emerging as the nemesis of immunotherapy. Immune-related adverse events (IrAEs) could affect any tissue, their incidence may reach up to 90% of patients and toxicity is dose-dependent. While the combination of two immune checkpoint inhibitors (ICIs) increased efficacy, the incidence of severe adverse events was also increased. Apparently, ICIs cannot be restricted to the targeted anti-tumor T cell population. The long lasting objective of cancer regression can only be achieved by paying a price: tolerance to healthy self tissues is compromised. In the face of an ipilimumab induced pan-lymphocytic activation, a therapeutic paradigm shift is required. The task is not desperately trying to put the genie back in the bottle by immune suppressive treatments, but instead harnessing the autoimmune forces by an off label low-dose combined anti-CTLA-4 and anti-PD1 antibody blockade, which is supplemented with conventional interleukin-2 stimulation and hyperthermia. The proof-of-principle of the low-dose-combination therapy was demonstrated in a heavily pre-treated triple negative breast cancer (TNBC) patient with far advanced pulmonary metastases and severe shortness of breath, who had exhausted all conventional treatment. Her pulmonary metastases went into complete remission with transient WHO I-II diarrhea and skin rash. She lived for 27 months after starting the low-dose-combination therapy. She had recurrence as a sternal mass and pleural metastases up to 3 cm. Since the low-dose-combination protocol consists only of approved drugs and treatments, this exceptional response should instigate further research efforts.

Immune checkpoint inhibitors (ICIs), including anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death-1 (PD-1) antibodies, have initiated a new era in the treatment of malignant melanoma. ICIs can be used in various settings, including as first-line, adjuvant, and neoadjuvant therapy. In the scope of this review, we examined clinical studies utilizing ICIs in the context of treating oral mucosal melanoma, a rare disease albeit with an extremely poor prognosis, with a specific focus on unraveling the intricate web of resistance mechanisms. The absence of a comprehensive review focusing on ICIs in oral mucosal melanoma is notable. Therefore, this review seeks to address this deficiency by offering a novel and thorough analysis of the current status, potential resistance mechanisms, and future prospects of applying ICIs specifically to oral malignant melanoma. Clarifying and thoroughly understanding these mechanisms will facilitate the advancement of effective therapeutic approaches and enhance the prospects for patients suffering from oral mucosal melanoma.

Immune checkpoint inhibition therapy (ICIT) is an emerging field in oncology especially opening new horizons to chemotherapy refractory patients. This paper provides deep insight into immune related adverse events (irAEs) posing a major challenge and drawback to ICIT, and presents right management strategies for very complex complications. Moreover, for the first time in literature, a non-linear mathematical model is introduced to measure the ICIT success rate and to decide about the optimum ICIT duration. Furthermore, a strategy is presented to overcome or to delay the progression after initial good response in a subset of patients.

A calibrated mathematical model of antiviral immune response to SARS-CoV-2 infection is developed. The model considers the innate and antigen-specific responses to SARS-CoV-2 infection. Recently published data sets from human challenge studies with SARS-CoV-2 were used for parameter estimation. Understanding the regulation of multiple intertwined reaction components of the immune system is necessary for linking the clinical phenotypes of COVID-19 with the kinetics of immune responses. Consideration of multiple immune reaction components in a single calibrated mathematical model allowed us to address some fundamental issues related to pathogenesis of COVID-19, i.e. sensitivity of the peak viral load to parameters characterizing the specific response components, the kinetic coordination of the individual responses, and the factors favoring a prolonged viral persistence. The model provides a tool for predicting the infectivity of patients, i.e. the amount of virus which is transmitted via droplets from the person infected with SARS-CoV-2, depending on the time of infection. The thresholds in the relative unbalance between innate and adaptive response parameters which lead to a prolonged persistence of SARS-CoV-2 due to the loss of a kinetic response synchrony/coordination were identified.

With the escalation of size and complexity of modern Denial of Service attacks, there is a need for research in the context of Machine Learning (ML) used in attack execution and defense against such attacks. This paper investigates the potential use of ML in generating behavioral telemetry data using Long-Short Term Memory network and spoofing requests for the analyzed traffic to look legitimate. For this research, a custom testing environment was built, that listens for mouse and keyboard events and analyzes them accordingly. While the economic feasibility of this attack currently limits its immediate threat, advancements in technology could make it more cost-effective for attackers in the future. Therefore, proactive development of countermeasures remains essential to mitigate potential risks and stay ahead of evolving attack methods.

Abstract: Social media has become a vital tool in ensuring productivity among Undergraduates, as studies have shown an increased number of users globally. This study assessed the impact of social media usage on undergraduates’ academic performance and working memory. Participants from three different universities such as the University of Georgia (UG), Eastern European University (EEU), and Batumi State University (BSU) completed this study using online google forms. UG and EEU are in the capital city, and BSU is in Batumi City. The study questionnaires were approved by the institutional review board before the data collection. Descriptive analyses were assessed for all study populations, characteristics, frequencies, percentages, means, and standard deviations using Statistical Package for Social Science (SPSS Inc., Chicago, IL, version 25.0 for Windows) software. 41.3% were male students, as most of the participants were foreign students living and studying in Georgia. Male students had the risk of ‘conflict’ with families and friends because of social media. Female students are at increased risk of using social media as an ‘escape’ from negative feelings. 89.7% of students that perform physical activities, considering their academic workload had the risk of preoccupation complaints. 87.9% felt dissatisfied regularly because they wanted to spend more time on social media. Utilization of social media differed based on the characteristics of the participants such as age, gender, and geography. We observed the increase in prevalence of social media addiction, its effect on academic performance and working memory among undergraduate students.

In this study, additive manufacturing of reinforced parts using metallic wire as both a reinforcement component and a shape memory stimulus through Fused Deposition Modeling (FDM) was investigated. A Shape Memory Polymer (SMP) restores its original shape and recovers it upon specific stimuli. This research employed chromium-nickel metal wire as a reinforcing component to enhance mechanical properties and introduce the capability for thermal stimulation of polylactic acid (PLA) via electrical current using the "in-situ impregnation" method within FDM process. Reinforced specimens were fabricated with wire with two diameters of 0.1 and 0.15 mm, along with two volume percentages of 5 and 10. Comprehensive evaluations encompassing mechanical (tensile and flexural) and thermal properties of the printed specimens were conducted. The outcomes revealed a significant enhancement in both tensile and flexural properties of the polymer matrix due to the embedding metallic wire, even under elevated temperatures during bending test. Furthermore, the thermal properties of the reinforced specimens were examined by subjecting them to various voltages, resulting in temperature ranging from 36.4 to 150.1°C. These findings highlight the ability to tailor a wide range of mechanical properties and shape recovery in the reinforced specimens by carefully selecting the wire volume fraction, voltage, and wire diameter, thus regulating the materials properties with specific application requirements.

Resistive random-access memory has emerged as a promising non-volatile memory technology, garnering substantial attention due to its potential for high operational performance, low power consumption, and scalability. Two-dimensional nanostructured materials play a pivotal role in RRAM devices, offering enhanced electrical properties and physical attributes that contribute to overall device improvement. In this study, self-rectifying switching behavior in RRAM devices is proposed based on molybdenum disulfide nanocomposites decorated with palladium on SiO2/Si substrates. The integration of Pd and MoS2 at the nanoscale effectively mitigates leakage currents decreasing from cross-talk in the RRAM array, eliminating the need for a separate selector device. The successful demonstration of the expected RRAM switching behavior follows the application of a Pd nanoparticle coating. The fabricated Pd-MoS2 synaptic device showed a high current ratio for forward/reverse current higher than 60 at a low resistance state and observed a memory on/off ratio of 103 performing stable resistance switching behavior.

The purported cognitive benefits associated with nicotine and its metabolites in the brain are a matter of debate. In this review, the impact of the pharmacologically active metabolite of a nicotine derivative produced by bacteria (6-hydroxy-L-nicotine) on memory, oxidative stress, and the activity of the cholinergic system in the brain was examined. A search in the PubMed, Science Direct, Web of Science, and Google Scholar databases, limiting entries to those no later than July 2023, was conducted. The search focused specifically on articles pertaining to nicotine metabolites, memory, oxidative stress, cholinergic system activity, as well as enzymes or pathways related to nicotine degradation in bacteria. The preliminary search resulted in 696 articles, and following the application of exclusion criteria, 185 articles were deemed eligible for inclusion. This review focuses on experimental studies supporting nicotine catabolism in bacteria, and the chemical and pharmacological activities of nicotine and its metabolite 6-hydroxy-L-nicotine.

Astragaloside IV (AIV) – triterpenoid saponin from the Astragalus mongholicus roots with the proved acetylcholinesterase (AChE)-inhibitory capability was used as the substance with the potential to attenuate memory impairment. Scopolamine (SCOP), antagonist of muscarinic cholinergic receptors and lipopolysaccharide (LPS), neuroinflammation inducer were used to impair memory processes in the passive avoidance (PA) test in mice. This memory impairment in the SCOP-treated mice was attenuated by the earlier intraperitoneal (ip) administration of AIV in the dose of 25 mg/kg. The reduction of memory impairment by LPS was not observed, therefore AIV does not reverse memory impairments through the anti-inflammatory mechanisms. All the studied doses of AIV did not affect basic locomotor activity of mice. As a result of the post-mortem analysis of mice body tissues, the largest content of AIV was determined in the kidneys, then in the spleen, liver and the smallest one in brain by mass spectrometry.

Long Covid is a term used for patients who have recovered from COVID-19 but exhibit persistent cognitive dysfunction, including mental confusion, difficulties in attention, impairment in executive functions and slow movements, among other common symptoms. A study was conducted with 65 patients who had a positive RT-PCR diagnosis and reported symptoms of cognitive impairment, such as memory loss and attention difficulties after recovery. The patients underwent neuropsychological evaluation and completed questionnaires on cognition, mood, and quality of life. During the cognitive screening, 71% of the patients showed alterations, with deficits in visual memory (69%), language (54%), visuospatial construction (49%), verbal episodic memory (37%), executive functions (36%), attentional abilities (34%), and premorbid intelligence (12%). It is important to highlight the need for treatments and further studies to understand the long-term side effects of this disease.

Shape Memory Polymer (SMP) actuators are smart materials that adapt and switch shape in response to environmental conditions, allowing controlled and dynamic building systems. The integrated SMP strip enabled the adaptive facade shading system to operate independently and with flexibility under certain thermoresponsive conditions to regulate building performance. This study aims to improve adaptive façade performance in a hot-humid climate by determining optimal thermal activation factors for the shape memory polymer. This was achieved by comprehensively examining and analysing the impact of various SMP activation parameters on energy efficiency, thermal comfort, and visual comfort. In addition, dynamic IES-VE building energy simulation was used to evaluate the thermal performance of the adaptable facade. The results were validated using a multicriteria approach to compare with the existing glass façade of a high-rise apartment. The results showed that the coactivation technique, which combines solar radiation and air temperature triggers, proved to be the most efficient strategy to improve the performance of the adaptive façade. This strategy minimised heat gain, lowered indoor temperatures, reduced glare, and enhanced daylight comfort, resulting in notable energy savings through reduced cooling consumption. The study concluded that the utilisation of SMP actuators with fine-tuning activation parameters significantly optimised adaptive façade performance, promoting functionality, efficiency, and sustainability in buildings.

Fluctuating stock prices make it difficult for investors to see investment opportunities. One tool that can help investors overcome this is forecasting techniques. Long Short-Term Memory (LSTM) is one of deep learning methods used in forecasting time series. The training and success of deep learning is strongly influenced by the selection of hyperparameters. This research uses a hybrid method between the Genetic Algorithm (GA) and LSTM to find a suitable model for predicting stock prices. GA is used in optimizing the architecture such as the number of epochs, window size, and the number of LSTM units in the hidden layer. Tuning optimizer is also carried out using several optimizers to achieve the best value. From method that has been applied, it shows that the method has a good level of accuracy with MAPE values below 10% in every optimizer used. The error rate generated is quite low, in case-1 with a minimum RMSE value of 93.03 and 94.40, & in case-2 with an RMSE value of 104.99 and 150.06 during training and testing. A fairly stable and small value is generated by setting it using the Adam Optimizer.

In this study, we demonstrate how the incorporation of appropriate feature engineering together with the selection of a Machine Learning (ML) algorithm that best suits the available dataset, leads to the development of a predictive model for transformation temperatures that can be applied to a wide range of shape memory alloys. We develop a gradient boosting ML surrogate model capable of predicting Martensite Start, Martensite Finish, Austenite Start, and Austenite Finish transformation temperatures with an average accuracy of more than 95% by explicitly taking care of potential distribution changes when modeling different alloy systems. We included heat treatment, rolling, extrusion processing parameters, and alloy system categorical features in the model input features to achieve more accurate and realistic results. In addition, using Shapley values, which are calculated based on the average marginal contribution of features to all possible coalitions, this study was able to gain insights into the governing features and their effect on predicted transformation temperatures, providing a unique opportunity to examine the critical parameters and features in martensite transformation temperatures.

This study examined the relationship among the three domains of executive function (EF; cognitive shifting, inhibitory control, and working memory) to test the applicability of the unity-diversity model in preschoolers using both behavioral and fNIRS approaches. Altogether 58 Chinese preschoolers (34 boys, 24 girls, Mage = 5.86 years, SD = 0.53, Age range = 4.83-6.67 years) were administered the Dimensional Card Change Sort (DCCS), go/no-go, and missing scan task. Their brain activations in the prefrontal cortex during the tasks were examined using fNIRS. First, the behavioral results indicated that the missing scan task scores (working memory) correlated with the DCCS (cognitive shifting) and go/no-go tasks (inhibitory control). But the latter two did not correlate with each other. Second, the fNIRS results demonstrated that the prefrontal activations during the working memory task correlated with those in the same regions during the cognitive shifting and inhibitory control tasks. Still, the latter two did not correlate. The behavioral and neuroimaging evidence jointly indicates that the unity-diversity model of EF does apply to Chinese preschoolers.

In a collaborative forecasting task, experts may have unequal authority levels. However, this has rarely been considered reasonably in the existing fuzzy collaborative forecasting methods. In addition, experts may not be willing to discriminate their authority levels. To address these issues, an auto-weighting fuzzy weighted intersection (FWI) fuzzy collaborative intelligence approach is proposed in this study. In the proposed auto-weighting FWI fuzzy collaborative intelligence approach, experts’ authority levels are automatically and reasonably assigned based on their past forecasting performances. Subsequently, the auto-weighting FWI mechanism is established to aggregate experts’ fuzzy forecasts. The theoretical properties of the auto-weighting FWI mechanism have been discussed and compared with those of the existing fuzzy aggregation operators. After applying the auto-weighting FWI fuzzy collaborative intelligence approach to a case of forecasting the yield of a DRAM product from the literature, its advantages over several existing methods were clearly illustrated.

Beer fermentation is typically monitored by periodic sampling and off-line analysis. In-line sensors would remove the need for time-consuming manual operation and provide real-time evaluation of the fermenting media. This work uses a low-cost ultrasonic sensor combined with machine learning to predict the alcohol concentration during beer fermentation. The highest accuracy model (R2=0.952, MAE=0.265, MSE=0.136) used a transmission-based ultrasonic sensing technique along with the measured temperature. However, the second most accurate model (R2=0.948, MAE=0.283, MSE=0.146) used a reflection-based technique without the temperature. Both the reflection-based technique and the omission of the temperature data are novel to this research and demonstrate the potential for a non-invasive sensor to monitor beer fermentation.

Shape memory alloys (SMAs) are increasingly used in the fields of aviation, automotive and biomedicine due to their unique properties. Nickel-Titanium (NiTi) alloy materials, which are one of the shape memory alloys, are among the most frequently used alloy materials. The shape memory and super elastic effects of NiTi alloys, high ductility and deformation hardening make it difficult to shape burr. An additional problem is the formation of a white layer during machining. In this study, surface milling operations were performed in dry cutting conditions with uncoated cutting tools with different nose radii. The processing parameters were determined based on the experience gained as a result of the preliminary tests. Tungsten carbide cutting tools with different nose radii (0.4mm and 0.8mm) were used for the milling operations. Milling was carried out at three different cutting speeds (20, 35, 50 m/min), feed rates (0.03, 0.07, 0.14 mm/tooth), and a constant axial cutting depth (0.7 mm). As a result of our experimental studies, the best tool life was found to be in 0.8 mm nose radius cutting tools at 20 m/min cutting speed and 0.03 mm/tooth feed rate (0.264 mm). The minimum average surface roughness was found after milling with 0.8 mm nose radius cutting tool at 20 m/min cutting speed and 0.03 mm/tooth feed rate (0.346 μm). It has been determined that increasing the cutting tool nose radius reduces both the flank wear over the cutting tool and the average surface roughness.

In this study, we report a new epoxy acrylate based shape memory polymer(SMP) fabricated by Liquid crystal display (LCD) Stereolithographic 3D printing. The printed 3D object has a high resolution and high transparency in visible light region. The uniaxial tensile tests showed enhanced tensile toughness and tunable mechanical properties. The fix-recovery and cycle tests indicated high shape recovery properties including high shape recovery rate and excellent cycling stability. In addition, a smart electrical valve actuator was fabricated that can be used in fast heat or electricity responsive electrical circuits. LCD 3D printing provides a low-cost and high efficient way to fabricate fast responsive SMP, which can be used in wide applications in various fields on aerospace engineering, biomedical devices, soft robots and electronic devices.

Long-term potentiation (LTP) is a molecular basis of memory formation. Here, we demonstrate that LTP critically depends on muscle fructose 1,6-bisphosphatase 2 (Fbp2) – a glyconeogenic enzyme and moonlighting protein protecting mitochondria against stress. We show that LTP induction regulates Fbp2 association with neuronal mitochondria and Camk2, and that the Fbp2-Camk2 interaction correlates with Camk2 autophosphorylation. Silencing of Fbp2 expression or simultaneous inhibition and tetramerization of the enzyme with a synthetic effector mimicking the action of physiological inhibitors (NAD⁺ and AMP) abolishes Camk2 autoactivation and blocks formation of the early phase of LTP and expression of the late phase LTP markers. Astrocyte-derived lactate reduces NAD⁺/NADH ratio in neurons and thus, diminishes the pool of tetrameric and increases the fraction of dimeric Fbp2. We therefore hypothesize that this NAD⁺-level-dependent increase of the Fbp2 dimer/tetramer ratio might be a crucial mechanism in which astrocyte-neuron lactate shuttle stimulates LTP formation.

Modeling brain dynamics to better understand and control complex behaviors underlying various cognitive brain functions are of interests to engineers, mathematicians, and physicists from the last several decades. With a motivation of developing computationally efficient models of brain dynamics to use in designing control-theoretic neurostimulation strategies, we have developed a novel data-driven approach in a long short-term memory (LSTM) neural network architecture to predict the temporal dynamics of complex systems over an extended long time-horizon in future. In contrast to recent LSTM-based dynamical modeling approaches that make use of multi-layer perceptrons or linear combination layers as output layers, our architecture uses a single fully connected output layer and reversed-order sequence-to-sequence mapping to improve short time-horizon prediction accuracy and to make multi-timestep predictions of dynamical behaviors. We demonstrate the efficacy of our approach in reconstructing the regular spiking to bursting dynamics exhibited by an experimentally-validated 9-dimensional Hodgkin-Huxley model of hippocampal CA1 pyramidal neurons. Through simulations, we show that our LSTM neural network can predict the multi-time scale temporal dynamics underlying various spiking patterns with reasonable accuracy. Moreover, our results show that the predictions improve with increasing predictive time-horizon in the multi-timestep deep LSTM neural network.

Background: Previous papers have developed a statistical mechanics of neocortical interactions (SMNI) fit to short-term memory and EEG data. Adaptive Simulated Annealing (ASA) has been developed to perform fits to such nonlinear stochastic systems. An N-dimensional path-integral algorithm for quantum systems, qPATHINT, has been developed from classical PATHINT. Both fold short-time propagators (distributions or wave functions) over long times. Previous papers applied qPATHINT to two systems, in neocortical interactions and financial options. Objective: In this paper the quantum path-integral for Calcium ions is used to derive a closed-form analytic solution at arbitrary time that is used to calculate interactions with classical-physics SMNI interactions among scales. Using fits of this SMNI model to EEG data, including these effects, will help determine if this is a reasonable approach. Method: Methods of mathematical-physics for optimization and for path integrals in classical and quantum spaces are used for this project. Studies using supercomputer resources tested various dimensions for their scaling limits. In this paper the quantum path-integral is used to derive a closed-form analytic solution at arbitrary time that is used to calculate interactions with classical-physics SMNI interactions among scales. Results: The mathematical-physics and computer parts of the study are successful, in that there is modest improvement of cost/objective functions used to fit EEG data using these models. Conclusions: This project points to directions for more detailed calculations using more EEG data and qPATHINT at each time slice to propagate quantum calcium waves, synchronized with PATHINT propagation of classical SMNI.

The effects of tyrosine on plasma response and cognition in aging are unknown. We assessed the dose-dependent response to tyrosine administration in older adults in both plasma tyrosine concentrations and working memory performance. In this double blind randomized cross-over trial 17 older adults (aged 60-75 years) received a single administration of 100, 150 or 200 mg/kg body weight of tyrosine. For comparison, 17 young adults (aged 18-35 years) received a dose of 150 mg/kg body weight of tyrosine. Tyrosine plasma concentrations were determined before and 90, 120, 150, 180, 210 and 240 minutes after tyrosine intake. Working memory was assessed using the N-back task at 90 minutes after tyrosine administration. Older adults showed a dose-dependent increase in plasma tyrosine concentrations (p<.001), and the plasma response was higher than for young adults with the same dose (p<.001). Load-dependent working memory performance decreased with higher doses of tyrosine (p=.048), especially in older adults with greater dose-dependent plasma tyrosine responses (p=.035). Our results show an age-related increase in plasma tyrosine response, which was associated with a dose-dependent decline in cognitive functioning in older adults.

In this paper, we study a one-dimensional Bresse-Cattaneo system with infinite memories and time-dependent delay term (the coefficient of which is not necessarily positive) in the internal feedbacks. First, it is proved that the system is well-posed by means of the Hille-Yosida theorem under suitable assumptions on the relaxation functions. Then, without any restriction on the speeds of wave propagations, we establish the exponential or general decay result by introducing suitable energy and Lyapunov functionals.

Background: The Liver Imaging Reporting and Data System (LI-RADS) combines standardized terminology with a classification system for imaging findings in patients with HCC, therefore rendering diagnostic biopsy unnecessary in many cases. This retrospective study included 23 patients with a biopsy diagnosis of HCC, performed either before or after local interventional procedures, in order to evaluate the histopathologic changes induced by previous procedures and their potential influence on the response to immune therapy. Material and Methods: The study encompassed a cohort of patients diagnosed with Hepatocellular Carcinoma (HCC). Diagnosis was established through contrast-enhanced computer tomography or magnetic resonance imaging that identified LI-RADS-5 nodules in conjunction with historical liver disease and elevated alpha-fetoprotein (AFP) levels, or through histological examination confirming positivity for glypican3, heat shock protein70, and glutamine synthetase. The study detailed the liver disease etiology, LI-RADS scores, characteristics and dimensions of HCC nodules, serum AFP concentrations, Edmondson-Steiner grading, and the expression of programmed cell death ligand 1 (PD-L1) in the tumor cells. Results: Among the study's cohort of Hepatocellular Carcinoma (HCC) patients, a portion had not received any prior treatments, while the remainder experienced local HCC recurrence following trans-arterial chemoembolization or radiofrequency ablation. Observations indicated elevated alpha-fetoprotein (AFP) levels in those who had not undergone any previous interventions, showing statistical significance. The Edmondson-Steiner classification predominantly identified grade III differentiation across patients, irrespective of their treatment history. Furthermore, an increase in intra-tumoral programmed cell death ligand 1 (PD-L1) expression was noted in patients who had not been subjected to previous therapies. Conclusion: Liver biopsy offers valuable insights for patients with Hepatocellular Carcinoma (HCC), assisting in the tailoring of immune therapy strategies, particularly in cases of recurrence following prior local interventions.

Recently, immunotherapy has arisen as a novel treatment approach for patients with colorectal cancer (CRC), but the effectiveness of immunotherapy varies in these patients. We hypothesized that immune checkpoint molecules (ICMs), which are the targets of immunotherapy, are often exhibit concomitantly. Our objective was to investigate the patterns of ICM expression in patients with CRC and the differences in ICM expression based on the microsatellite instability status. Immunohistochemical expression of programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), and lymphocyte-activation gene 3 (LAG-3) in the tumor center and periphery was assessed in patients with non-metastatic colorectal cancer. We enrolled 83 patients with CRC: 40 with microsatellite stable (MSS) and 43 with microsatellite instability-high (MSI-H). PD-L1 was more frequently expressed in the tumor center in patients with MSI-H than that in patients with MSS (18 [41.9 %] vs. 3 [7.5 %], respectively; P &lt; 0.001), and the same trend was observed for TIM-3 expression (30 [69.8 %] vs. 19 [47.5 %], respectively; P = 0.047). Concomitant expression of two or more ICMs was more frequently observed than no expression or expression of a single molecule in both MSS and MSI-H groups; 34 (79.7 %) patients with MSI-H and 23 (57.5 %) with MSS showed ICM expression at the tumor center, whereas 34 (79.7 %) patients with MSI-H and 22 (55 %) with MSS showed expression at the tumor periphery. Patients with the genetic characteristics of MSI-H showed higher expression levels of ICMs than that in patients with MSS, and predominantly, two or more ICMs were concurrently expressed. Our findings highlight the potential efficacy of the dual-blockade approach in immunotherapy, particularly in patients with MSI-H CRC.