Viviparity is made possible by the placenta, a structure acquired relatively recently in the evolutionary history of eutherian mammals. Compared to oviparity, it increases the survival rate of the fetus, owing to the eutherian placenta. Questions such as “How was the placenta acquired?” and “Why is there diversity in placental morphology among mammalian species?” remain largely unsolved. Our present understanding of the molecules regulating placental development remains unclear, owing in no small part to the persistent obscurity surrounding the molecular mechanisms underlying placental acquisition. Many genes that characterize eutherian placental morphology likely evolved to be expressed at the fetal-maternal interface concurrently with those during embryogenesis. Therefore, identifying these genes, how they were acquired, and how they came to be expressed specifically at the fetal-maternal interface will shed light on some crucial molecular mechanisms underlying placental evolution. Exhaustive studies support the hypothesis that endogenous retroviruses (ERVs) could be evolutional driving forces for trophoblast cell fusion and placental structure in mammalian placentas including those of the bovine species. This review focuses on bovine ERVs (BERVs) and their expression and function in the placenta.

Over the past few decades, phototherapy, encompassing the utilization of both natural and artificial light, has emerged as a dependable and non-invasive strategy for addressing a diverse range of illnesses, diseases, and infections. This therapeutic approach, primarily known for its efficacy in treating skin infections such as herpes and acne lesions, involves the synergistic use of specific light wavelengths and photosensitizers like methylene blue. Photodynamic therapy, as it is termed, relies on the generation of antimicrobial reactive oxygen species (ROS) through the interaction between light and externally applied photosensitizers. Recent research, however, has highlighted the intrinsic antimicrobial properties of light itself, marking a paradigm shift in focus from exogenous agents to the inherent photosensitivity of molecules found naturally within pathogens. Chemical analyses have identified specific organic molecular structures and systems, including porphyrins and conjugated C=C bonds, as pivotal components in molecular photosensitivity. Given the prevalence of these systems in organic life forms, there is an urgent need to investigate the potential impact of phototherapy on individual molecules expressed within pathogens and discern their contributions to the antimicrobial effects of light. This review delves into the recently unveiled key molecular targets of phototherapy, offering insights into their potential downstream implications and therapeutic applications. By shedding light on these fundamental molecular mechanisms, we aim to advance our understanding of phototherapy's broader therapeutic potential and contribute to the development of innovative treatments for a wide array of microbial infections and diseases.

Microchimerism is the presence of cells in an individual that have originated from another individual. The most common form of microchimerism is fetomaternal microchimerism, i.e., cells from a fetus pass through the placenta and establish cell lineages within the mother. Microchimerism was also described after transplantation of human organs in human recipients. Consequently, microchimerism may also be expected in xenotransplantation using pig cells or organs. Indeed, microchimerism was described in patients after xenotransplantations as well as in non-human primates after transplantation of pig organs. Here for the first time a comprehensive review of microchimerism in xenotransplantation is given. Since pig cells contain porcine endogenous retroviruses (PERVs) in their genome, detection of proviral DNA in the transplant recipients may be misinterpreted as infection of the recipient with PERV. To prevent this, methods discriminating between infection and microchimerism are described. This knowledge will be important for the interpretation of screening results in forthcoming human xenotransplantations.

Background: There is now evidence that immune and opioid systems show functional reciprocal relationships and that both systems may participate in the pathophysiology of major depression (MDD). Objective: The present study was carried out to delineate differences between MDD patients and healthy controls in dynorphin and kappa opioid receptor (KORs) in association with levels of β-endorphins and mu opioid receptors (MORs), interleukin-6 (IL-6) and IL-10. Method: The present study recruited 60 drug-free male participants with MDD aged 24-70 year and 30 age-matched healthy males as control group and measured serum levels of dynorphin, KOR, β-endorphin, MOR, IL-6 and IL-10. Results: Serum dynorphin, KOR, β-endorphin and MOR are significantly increased in MDD as compared with controls. The increases in the dynorphin/KOR system and β-endorhin/MOR system are significantly intercorrelated and are both strongly associated with increased IL-6 and IL-10 levels. Dynorphin, β-endorphin, KOR and both cytokines showed a good diagnostic performance for MDD versus controls, whereby both opioid peptides and cytokines show a bootstrapped (n=2000) area under the receiver operating curve of 0.972. KOR and the dynorphin/KOR system are both significantly decreased in depressed subjects with comorbid nicotine dependence. Conclusion: Our findings suggest that in MDD, immune activation is associated with a simultaneous activation of dynorphin/KOR and β-endorhin/MOR signaling and that these opioid systems may participate in the pathophysiology of depression by a) exerting immune regulatory activities attenuating the primary immune response; and b) modulating reward responses and mood as well as emotional and behavioral responses to stress.

The stock beta coefficient literature extensively discusses the proper methods for the estimation of beta as well as its use in asset valuation. However, there are relatively few references with respect to the appropriate time horizon that investors should utilize when evaluating the risk-return relationship of a stock. We examine the appropriate time horizon for beta estimation differentiating our results by sector according to the Industry Classification Benchmark. We employ data from the NYSE and we estimate varying lengths of beta employing data from 30 to 250 trading days. The constructed beta series is then examined for the presence of breaks using the endogenous structural break literature. Results show evidence against the use of betas that employ more than 90 trading days of data provisional to the sector under study.

With the breakthroughs and innovative developments in nanotechnology, research on the application of nanomedicine in cancer therapy has so far seen tremendous expansion and success. Intelligent stimulus-responsive nanocarriers are an emerging field of research and have great interest in cancer therapy owing to the fascinating properties such as excellent targeting function, high drug loading capacity, and targeted on-demand release properties. Responsive nanomaterials can be designed and constructed according to the dosing context and therapeutic needs, at the same time, activated by internal bio-stimuli (pH, redox, and enzymes) and/or external stimuli (ultrasound, light, temperature, and magnetic), respectively. What’s more, smart nanocarriers are also utilized for the precise and controllable release of antitumor drugs from cancer tissues and cells to achieve efficient diagnosis and treatment of tumors. Deeply investigated, responsive nanocarriers have attracted considerable attention due to their ability to release precisely at tumor-specific sites. Herein, we review the recent advances of novel stimuli-responsive nanocarriers in the field of cancer therapy. Finally, the challenges and application prospects of smart nanocarriers are further elaborately discussed.

Coproporphyrins I and III (CP-I and CP-III) are established as substrates of hepatic sinusoidal organic anion transporting polypeptides (Oatps), multidrug resistance-associated protein 3 (Mrp3), and canalicular transporter Mrp2. We aimed to evaluate the potential of plasma CP-I and CP-III concentrations to indicate functional changes in hepatic transporters in nonalcoholic stea-tohepatitis (NASH) rodent models using modeling and simulation approach. Mechanistic copro-porphyrins (CP-I and CP-III) models in rats and mice were constructed based on metabolism, transport, and elimination pathways in rodents. To parameterize the rat mechanistic model, we measured CP concentrations in plasma, liver, bile, and urine in healthy control Sprague Dawley rats. The mouse mechanistic model was parameterized using published data. The rat and mouse CP models described the steady-state levels of CP-I and CP-III in plasma, liver, and bile. The model recapitulated the observed high plasma CP-III / CP-1 ratio (9- and 3-fold in rats and mice, respec-tively) and elimination pathways of CP-I (>90% via biliary secretion) and CP-III (equal via bile and urine). Rat CP model was further validated with the published rat fistula model. The simulated increased plasma CP-I concentrations (4-fold), resulted from decreased Oatp activity (0.6-fold) and increased Mrp3 activity (3-fold) were comparable to those observed in bile-duct ligated NASH model. Sensitivity analysis revealed that 90% inhibition of Oatp and Mrp2 leads to a 4-fold and 2.5-fold increase in plasma CP-I levels, respectively. Additionally, we demonstrated the utility of the mechanistic CP models in testing hypothesis and understanding the mechanisms of the ob-served plasma CPs disposition in the Oatp knockout (KO) mice, bile-duct ligation NASH mice, and Mrp2 deficient TR- rats. Collectively, using a mechanistic model, we conclude that CP-I is a robust and predictable marker for assessing change in the activity of Oatps and Mrps in animal models. Our analysis suggests that efflux transporters (Mrp2 and Mrp3) can play an important role in the disposition of CP-I along with Oatp transporters in rodents.

Adventitious roots play a crucial role inr the nourishment and propagation of arboreal vegetation. In order to shed light on the physiological and biochemical characteristics of the challenging-to-propagate mulberry tree species, an investigation was conducted. This study aimed to compare the responses of various root morphological indicators, endogenous hormones, and oxidase activities in the "Yueshenda 10" fruit mulberry, at different stages of treatment. The ultimate objective was to identify the factors influencing the process of root development. The findings revealed a distinct '/\' pattern in the levels of IAA and JA within the cuttings. Conversely, the changes in ABA, ZR and GA3 exhibited a '/\/' pattern. The fluctuation of IAA/ABA values followed a '\/\' mode, whereas the IAA / ZR values initially increased, followed by a subsequent decrease. The correlation between the initial concentrations of these five endogenous hormones and the rooting rate displayed variations. Notably, IAA demonstrated the strongest association with the rooting rate, exhibiting a positive correlation with both IAA and ZR. Regarding the activity of three antioxidant enzymes (IAAO, POD and PPO), a '/\' trend was observed, wherein the enzyme activity increased under ABT1 treatment. However, the peak activity levels of the enzymes appeared during different periods: germination, induction, and expression, respectively. Overall, the most effective treatment for promoting root development and significantly enhancing the root growth parameters of mulberry was found to be 800mg/L ABT1. Exogenous hormone treatment expedited the synthesis of antioxidant enzymes, thereby shortening the rooting time and facilitating root formation.

Xenotransplantation is, like allotransplantation, usually associated with microchimerism, e.g., the presence of cells from the donor in the recipient. Microchimerism was reported in first xenotransplantation trials in humans as well as in most preclinical trials in non-human primates (for review see Denner, Viruses 2023, 15, 190). When using pigs as xenotransplantation donors, their cells contain porcine endogenous retroviruses (PERVs) in their genome. That makes it difficult to discriminate between microchimerism and PERV infection of the recipient. Here, we demonstrate which virological methods should be used to identify microchimerism, first of all screening for porcine cellular genes. Using porcine short interspersed nuclear sequences (SINES), which have hundred thousands of copies in the pig genome significantly increased the sensitivity of the screening for pig cells. Second, absence of PERV RNA demonstrated an absence of viral genomic RNA or expression as mRNA. Finally, absence of antibodies against PERV proteins conclusively demonstrated an absence of a PERV infection. When applying these methods for analyzing baboons after pig heart transplantation, microchimerism could be demonstrated in all animals. These methods can be used in future clinical trials.

The adapted Posner spatial cue-target paradigm was used to explore the relationship between exogenous temporal attention caused by rhythm and endogenous and exogenous spatial attention. The study was divided into two experiments. In Experiment 1, 33 participants used arrow cues to orient endogenous spatial attention and rhythm to orient exogenous temporal attention. In Experiment 2, with 29 participants, exogenous spatial attention was directed by highlighting the cue box. Exogenous temporal attention was directed by rhythm. Experiment 1 indicated that RTs were faster for attended targets than the unattended. The main effect of temporal attention was significant, with RTs being faster for synchrony and late compared to early. RTs were faster for late compared to synchrony. The main effect of stimulus repetition was significant, with faster RTs for targets when the rhythmic cue consisted of five compared to four. The interaction between spatial attention and temporal attention was not significant. Experiment 2 demonstrated that exogenous spatial attention only exhibited IOR under early four stimulus repetitions. The main effect of temporal attention was significant, with RTs being faster for synchrony and late compared to early. The main effect of stimulus repetition was significant, with faster RTs for targets when the rhythmic cue consisted of five compared to four. The interaction between spatial attention and temporal attention was significant. The results indicated that rhythmic temporal attention supported foreperiod effects. Exogenous temporal attention and endogenous spatial attention independently affect behavior, while exogenous temporal attention and exogenous spatial attention mutually influenced behavior.

Auckland Island pigs represent an inbred population of feral pigs isolated on the subantarctic island for over 100 years. The animals have been maintained under pathogen-free conditions in New Zealand, they are well characterized virologically and have been used as donor sources in first clinical trials of porcine neonatal islet cell transplantation for the treatment of human diabetes patients. The animals do not carry any of the xenotransplantation-relevant viruses and in the first clinical trials no porcine viruses including porcine endogenous retroviruses (PERVs) have been transmitted to the human recipients. PERVs pose a special risk in xenotransplantation since they are part of the pig genome. When the copy number of PERVs in these animals was analyzed using droplet digital PCR and primers binding to a conserved region of the polymerase gene (PERVpol), a copy number typical for Western pigs was found, confirming previous phylogenetic analyses of microsatellites and mitochondrial analyses showing a closer relationship to European pigs than to Chinese pigs. When kidney cells from very young piglets were analyzed, only around 20 PERVpol copies were detected. Using these cells as donors in somatic cell nuclear transfer (SCNT), animals were born showing a PERVpol copy numbers between 35 and 56. This data indicates that Auckland Is-land pigs have a similar copy number in comparison with other Western pig breeds and that the copy number is higher in adult animals compared with cells from young piglets. Most im-portantly, PERV-C free animals were selected and the absence of additional eight porcine viruses was demonstrated.

Auckland Island pigs represent an inbred population of feral pigs isolated on the subantarctic island for over 100 years. The animals have been maintained under pathogen-free conditions in New Zealand, they are well characterized virologically and have been used as donor sources in first clinical trials of porcine neonatal islet cell transplantation for the treatment of human dia-betes patients. The animals do not carry any of the xenotransplantation-relevant viruses and in the first clinical trials no porcine viruses including porcine endogenous retroviruses (PERVs) have been transmitted to the human recipients. PERVs pose a special risk in xenotransplantation since they are part of the pig genome. When the copy number of PERVs in these animals was analyzed using droplet digital PCR, a copy number typical for Western pigs was found, confirming previous phylogenetic analyses of microsatellites and mitochondrial analyses showing a closer relationship to European pigs than to Chinese pigs. When kidney cells from very young piglets were analyzed, only around 20 PERVpol copies were detected. Using these cells as nuclear donors in a somatic cell nuclear transfer (SCNT), animals were born showing PERVpol copy numbers between 35 and 56. This data indicates that Auckland Island pigs have a lower copy number in comparison with other Western pig breeds and that the copy number is higher in adult animals compared with cells from young piglets. Most importantly, PERV-C free animals were selected and the absence of additional eight porcine viruses was demonstrated.

The changing epidemiology of Staphylococcus aureus has created several gaps in its population structure and emergence of strains. Two global shifts in the aftermath of the past methicil-lin-resistant S. aureus (MRSA) pandemic are: a rise in healthcare-associated infections and evolu-tion of cutaneous and soft tissue infections with high morbidities and mortalities. Furthermore, bitter lessons from COVID-19 showed S. aureus necrotizing-pneumonia and skin conditions ag-gravating Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and Monkeypox manifestations. Limited data and paucity of high-quality evidence exist for many key clinical questions. Using clinical microbiology, molecular characterization, hospital data on age and in-fection sites, and antibiograms, we have investigated S. aureus infection patterns. We showed that age-specific distribution in both intensive care unit (ICU) and non-ICU revealed highest infection rates (94.7%) in senior-patients >50 years; most were MRSA (81.99%). However, specific distribu-tions of geriatric MRSA and MSSA rates were 46.5% and 4.6% in ICU and 35.48% and 8.065% in non-ICU, respectively. Intriguingly, age groups 0-20 years showed uniquely similar MRSA pat-terns in ICU and non-ICU patients (13.9%, 9.7%, respectively) and MSSA in ICU (11.6%). In age groups 20-50 years, MRSA were 2-fold in non-ICU (35%) than ICU (18.6%). Interestingly, highly significant association was found between infection-site and age-groups (P-value .000). Skin in-fections remained higher in all ages; pediatrics 32.14%, adults 56%, and seniors 25% while res-piratory infections were lower in pediatrics (14.3%) and adult 17%), and highest in seniors (38%). Blood and “other” sites in pediatrics recorded (28.6%; 25%, respectively), slightly lower in adults (18.6%; 8.6%) and seniors (14%); 22.8%), respectively. Further, significant association existed between infection-site and MRSA (Chi-Square Test, P-value .002). The common cutaneous infec-tions across all age-groups and the significant association of MRSA to geriatric-respiratory infec-tions have a high potential for skin-carriage as reservoir for endogenous infection. The similar frequencies of both lineages in youth in all settings imply MSSA-carriage as potential evolutionary origins for MRSA. These findings have important clinical implications for strategic planning in patient management and S. aureus control particularly in age-specific infections and vigilance for potential viral coinfections.

Simian endogenous retrovirus, SERV, is a successful germ line invader restricted to Old World monkey (OWM) species. (1) Background: The availability of high quality primate genomes warrants a study of the characteristics, evolution and distribution of SERV proviruses; (2) Methods: Cercopithecinae OWM genomes from public databases were queried for the presence of full length SERV proviruses. A dataset of 81 Cer-SERV genomes was generated and analyzed; (3) Results: Full length Cer-SERV proviruses were mainly found in terrestrial OWM, and less so in arboreal, forest- dwelling monkeys. Phylogenetic analysis confirmed the existence of two genotypes, Cer-SERV-1 and Cer-SERV-2, with Cer-SERV-1 showing evidence of recent germ line expansions. Long Terminal Repeat (LTR) variation indicated that most proviruses were of a similar age, and were estimated to be between <0.3 and 10 million years old. Integrations shared between species were relatively rare. Sequence analysis further showed extensive CpG methylation-associated mutation, variable Primer Binding Site (PBS) use with Cer-SERV-1 using PBSlys3 and Cer-SERV-2 using PBSlys1,2, and the recent gain of LTR motifs for transcription factors active during embryogenesis in Cer-SERV-1; (4) Conclusions: sequence analysis of 81 SERV proviruses from Cercopithecinae OWM genomes provides evidence for the adaptation of this retrovirus to germ line reproduction.

The neural system has limited resources to interact with the environment, and this is where attention comes into play. Attention is a complex process that provides numerous benefits, but there has been a longstanding debate about the mechanisms involved in attentional orientation. Two widely proposed mechanisms are top-down and bottom-up, which relate to the organism's current behavioral goal and the salience of environmental stimuli, respectively. However, distinguishing between these mechanisms can be challenging in both behavioral and neural studies. This review introduces a new conceptualization in which both top-down and bottom-up mechanisms are viewed as aspects of the same process. This unified approach aims to prepare the organism to face stimuli and events based on its prior experiences, immediate (the current task that he/she is aware of), and innate (to be alive) demands.

Recent studies have shown that the endogenous cannabinoid system (ECS) of the brain is essentially involved in the pathogenesis of Parkinson's disease (PD), influencing its symptoms by regulating the level of endogenous cannabinoids and altering the activation of cannabinoid receptors (CBR). Therefore, modulation of ECS with new drugs developed for this purpose may prove to be a promising strategy in the treatment of PD. However, fine regulation of ECS is quite a challenge due to the functional diversity of CBR in the basal ganglia. Our review analyses the effects of ECS modulators on experimental PD models and in patients with PD, as well as presents the outlooks for the development of new cannabinoid drugs for the treatment of motor and non-motor symptoms in PD.

Climate justice as a commons is conceived as the intertemporal climate equity and equal- ity exchange amongst generations. Sustainability, intended as the interplay amongst the economy, the society, the environment, and the governance, is essential to forge the climate justice theoretical framework. On this base, the study attempts to model intertemporal choice amongst generations in these four domains, making use of an over- lapping generations (OLG) model. The proxies detected are GDP growth (economy), environmental quality (environment), and labor growth, and environmental investment (society) as assumptions. The governance dimension is captured by the di¤erence in wealth between young and old generations. The work aims at replying to the follow- ing research question: Which are the conditions for sustainable development such that climate justice holds? The intra-intergenerational exchange is de…ned in two periods, while the individual provides their preferred economic and environmental choice mix as consumption-saving. This study shows that sustainable growth is achievable only with increased young e¤ort and less leisure and consumption.

Cardiotonic glycoside toxins, originally isolated from plants or amphibians, have been proposed as mammalian cardiotonic hormones. This paper is a review and update of the discovery of [i] a new class of steroid hormones, [ii] the path for their biosynthesis and [iii] some preliminary data on their function. The compounds are phosphoester conjugates and share a characteristic structural feature, a lactone ring, with [a] one class of synthetic potassium sparing diuretics and with [b] plant and amphibian cardiotonic steroids. Purification was initially monitored by cross reaction with steroid sulfate assays and later with digoxin-specific assays. Six compounds were purified by HPLC to near homogeneity and characterized by Tandem mass spectroscopy (MS-MS) and 31P-NMR. Three were digoxin-like materials (DLM) with 23 carbon atoms. The two extra carbon atoms form a spiral lactone E-ring. Several additional spiral lactones have been identified by MS-MS. In a pilot study, based on MS analysis, we evaluated phosphocholine steroid levels in individual serum samples in patients with pre-eclampsia (n=20). The control group of normotensive pregnant women (n=20) was used to estimate the mean and standard deviation. Twelve of the women with pre-eclampsia had a z-score over 2 for at least one of the four phosphocholine steroids. In contrast, only 1 sample from the normotensive women had a z-score over 2. The observation that there are two patterns, one with elevated phosphocholine steroid levels and one without the elevation, suggests that there may be two different underlying causes of pre-eclampsia. We now need to extend the study to determine which pattern predicts progression to life-threatening hypertension in pregnant women. This pilot study illustrates that it is possible to evaluate individual endogenous cardiotonic hormones without relying on antibodies developed to plant or amphibian toxins.

Cancer stem cells (CSCs) are one of the cell types that account for cancer heterogeneity. They arrest in the G0 phase and generate non-CSC progeny by self-renewing and pluripotency activity, resulting in tumor recurrence, metastasis, and chemoresistance. One CSC can stimulate tumor relapse and can re-grow a metastatic tumor. So, CSC is a promising target for eradicating tumors, and developing an anti-CSC method has become a top priority in cancer therapy. In recent years competing endogenous RNA (ceRNA) have emerged as an important class of post-transcriptional regulators that affect gene expression via competition for microRNA (miRNA) binding. Furthermore, aberrant ceRNA expression is associated with tumor progression. To overcome therapeutic resistance due to CSCs, we need to improve our existing understanding of the mechanisms by which ceRNAs are implicated in CSC-related relapse. Thus, this review was designed in order to discuss the role of ceRNAs in CSCs function. We reviewed the role of ceRNAs in acquiring CSCs characteristics in the form of different pathways including Rho GTPase/F-actin_ Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) (Hippo), Wnt/β-catenin pathway, transforming growth factor (TGF)-b–urothelial carcinoma-associated 1 (UCA1)–Slug pathway, etc. Finally, considering the comprehensive impacts of the ceRNA network on different pathways, a treatment strategy driving the ceRNA network might be effective. Targeting ceRNAs may open the path for new cancer therapeutic targets and can be used in clinical research.

Increasing evidence points to the role of endogenous retroviruses (ERVs) in driving cancer cell proliferation. The purpose of this study was to explore the possibility of repurposing antiretroviral agents to inhibit ERVs as a new approach in cancer treatment. We found that an integrase strand-transfer inhibitor, dolutegravir (DTG), effectively inhibited the proliferation of multiple cancer cell lines and its antiproliferative potency was positively correlated with the expression levels of the human endogenous retrovirus type K (HERV-K). DTG inhibited the expression of HERV-K in multiple human cancer cell lines and the mouse mammary tumor virus (MMTV) in the murine 4T1 mammary cancer cell line. We chose the fast-growing BT-20 cell line as a model to study the in vitro antiproliferative mechanisms of DTG. BT-20 cells overexpressing both HERV-K env and pol genes became more resistant to DTG than cells transduced with vector alone. Knockdown of HERV-K also increased DTG resistance of BT-20 cells. The antiproliferative effect of DTG correlated with enhanced expression of E-cadherin and reduction in cell motility and invasiveness. Surprisingly, DTG stimulated expression of the env gene of MMTV in vivo and promoted metastasis of 4T1 tumor cells to the lungs. Taken together, our data support a role of ERVs in tumor development and encourage further search for antiretroviral agents to treat malignancies in which endogenous retroviruses are active.

This article explores the impact of farmers’ vocational training on their income. Survey data concerning agricultural product quality and agricultural product sales were collected by the research team in Yantai City, China. An endogenous transformation regression model (ESR) was then used to analyze the impact of training on farmers’ family income, and the income mechanism was further tested. The results from the empirical analysis suggest that (1) Participating in training can significantly increase farmers’ income; (2) Farmers who pay more attention to the quality of their agricultural products during the production process are more likely to see their incomes increase after participating in the training.

In this study, the prevalent methodology for design of the industrial policy in developing countries was critically assessed, and it was shown that the mechanism and content of classical method is fundamentally contradictory to the goals and components of the endogenous growth theories. This study, by proposing a new approach, along settling Schumpeter's economic growth theory as a policy framework, designed the process of entering, analyzing and processing data as the mechanism of the industrial policy in order to provide "theoretical consistency" and "technical and Statistical requirements" for targeting the growth stimulant factor effectively.

To efficiently use its finite resources, the visual system selects for further processing only a subset of the rich sensory information. Visual masking and spatial attention control the information transfer from visual sensory-memory to visual short-term memory. There is still a debate whether these two processes operate independently or interact, with empirical evidence supporting both arguments. However, recent studies pointed out that earlier studies showing significant interactions between common-onset masking and attention suffered from ceiling and/or floor effects. Our review of previous studies reporting metacontrast-attention interactions revealed similar artifacts. Therefore, we investigated metacontrast-attention interactions by using an experimental paradigm in which ceiling/floor effects were avoided. We also examined whether metacontrast masking is differently influenced by endogenous and exogenous attention. We analyzed mean absolute-magnitude of response-errors and their statistical distribution. Our results support the hypothesis that metacontrast and endogenous/exogenous attention are largely independent with negligible likelihood for interactions. Moreover, statistical modeling of the distribution of response-errors suggests weak interactions modulating the probability of “guessing” behavior for some observers in both types of attention. Nevertheless, our data suggest that any joint effect of attention and metacontrast can be adequately explained by their independent and additive contributions.

We investigated whether cigarette smoking and dietary acid load (DAL) are associated with the risk of chronic obstructive pulmonary disease (COPD) in middle-aged healthy Korean men. Healthy men without diagnosed chronic disease (40-64 yrs) from the KNHANES-VI (2013–2015) included in the analysis (n=774) were subdivided by smoking status and DAL levels as estimated by the net endogenous acid production (NEAP) quartile. Current smokers tended to have a higher risk of COPD than non-smokers before and after the adjustment. When divided by the DAL quartile, the Q4 tended to have a higher risk of COPD than the Q1. Additionally, current smokers with lower (Q2), modest (Q3), and highest NEAP scores (Q4) showed more than 4-fold higher risks of COPD than the non-smokers with the lowest NEAP scores (Q1). Ex–smokers with higher NEAP scores (Q3 and Q4) showed more than 4-fold higher risks of COPD than the Q1. Interestingly, the risk of COPD was also more than 6-fold higher in non-smokers with the highest NEAP scores compared to the Q1. NEAP scores and smoking status synergistically increased the risk of COPD in middle-aged healthy Korean men. It suggests that DAL levels are an important factor for the prevention and management of COPD.

nutrition, macro and micronutrients, bone health, exercise, exogenous and endogenous microRNA, epigenetics

To meet the growing interest in the development of innovative biological nutrient removal (BNR) alternatives for energy neutrality, resource recovery, and decarbonization, the adsorption/bio-oxidation (A/B) process has been widely studied for carbon capture and shortcut nitrogen (N) removal, while limited research has focused on incorporating enhanced biological phosphorus (P) removal (EBPR), mainly due to the differential carbon usage characteristics of functionally relevant microorganisms. Here, a full-scale pilot testing with an integrated system combining A-stage high-rate activated sludge (HRAS) with B-stage partial (de)nitrification/anammox and side-stream EBPR (HRAS-P(D)N/A-S2EBPR) was conducted treating real municipal wastewater. The results demonstrated that, despite the low influent carbon load, the B-stage P(D)N-S2EBPR system achieved effective and stable P removal performance, especially when the volatile fatty acid (VFA) load from A-stage was elevated. Sludge fermentation in both A-stage and B-stage promoted carbon redistribution and likely provided more competitive advantages for ammonium-oxidizing bacteria and polyphosphate accumulating organisms, leading to carbon-efficient shortcut N removal mainly through partial nitrification pathway and influent carbon-independent EBPR simultaneously. Exposure to high VFA levels was considered a potential selection factor for the suppression of nitrite-oxidizing bacteria in the system. The involvement of internal carbon-accumulating organisms would potentially play an important role in endogenous denitrification. This study provided new insights into the effects of incorporating side-stream EBPR into the A/B process on microbial ecology, metabolic activities, and system performance.

Detection methods have been developed to prevent transmission of zoonotic or xenozoonotic porcine viruses after transplantation of pig organs or cells to the recipient (xenotransplantation). Eleven xenotransplantation-relevant viruses including porcine cytomegalovirus, a porcine roseolovirus (PCMV/PRV), porcine lymphotropic herpesviruses -1, -2, -3 (PLHV-1, 2, 3), porcine parvovirus (PPV), porcine circovirus 2, 3, 4 (PCV2, 3, 4), hepatitis E virus genotype 3 (HEV3), porcine endogenous retrovirus-C (PERV-C) and recombinant PERV-A/C have been selected. In the past, several pig breeds, minipigs and genetically modified pigs generated for xenotransplantation had been analyzed using these methods. Here, spleen, liver and blood samples from 10 German slaughterhouse pigs were screened using both, PCR-based and immunological assays. Five viruses: PCMV/PRV, PLHV-1, PLHV-3 and PERV-C were found in all animals, and PCV3 in one animal. Some animals were latently infected with PCMV/PRV as only virus-specific antibodies were detected. Others were also PCR positive in spleen and/or liver, indicative of an ongoing infection. These results provide important information on the viruses that infect German slaughterhouse pigs and together with results of previous studies revealed that the methods and test strategies efficiently work under field conditions.

Smallholder farmers in Ethiopia face increasing challenges from climate change and variability, which threaten their food security and livelihoods. This study examines how adopting single and combined climate change adaptation practices affects their vulnerability to food insecurity in Bench Maji Zone, southwest Ethiopia. Through multistage sampling, data was gathered from 390 rural households in four climate-prone districts. The study examines the impacts resulting from both individual and combined implementations of adaptation techniques. These techniques encompass crop management practices, soil and water conservation measures, and livelihood portfolio diversification strategies. The study employed the multinomial endogenous treatment effect regression model to address selection bias and endogeneity resulting from various sources of heterogeneity, whether observed or unobserved. The results show that farmers who adopted adaptation practices were less vulnerable to food insecurity than those who did not. The study also finds that adopting multiple practices has a more significant impact than adopting single practices. Our findings suggest that implementing climate change adaptation strategies can increase the resilience of smallholder farmers in the study area and decrease their vulnerability to food insecurity. The study recommends supporting farmers in adopting these strategies through research and development, information dissemination, and collaborations among farmers, researchers, and extension services.

This paper investigates the theoretical foundation for developing renewable geothermal resources locally. For this reason, we pay attention to the role of communities in geothermal development. This study presents arguments for a framework that approaches the geothermal resources as an endogenous factor of community development. To analyse it, we create a model that explains the local economic characters of the geothermal exploitation beyond its geological conditions. It aims to conceptualise a community based geothermal development standard referring to the endogeneity principle. Geothermal energy is given attention since the characteristics of this resource determine its use locally. We argue that the role of communities in geothermal exploitation is pivotal in the process of green growth for further expansion of geothermal energy use.

Suicidal behaviour is a public health problem whose magnitude is both substantial and increasing. Since many individuals seek medical treatment following a suicide attempt, strategies aimed at reducing further attempts in this population are a valid and feasible secondary prevention approach. An evaluation of the available evidence suggests that existing treatment approaches have limited efficacy in this setting, highlighting the need for innovative approaches to suicide prevention. Existing research on the neurobiology of social pain has highlighted the importance of this phenomenon as a risk factor for suicide, and has also yielded several attractive targets for pharmacological preventive strategies. In this paper, the available evidence related to these targets is synthesized and critically evaluated. The way in which social pain is related to the “anti-suicidal” properties of recently approved treatments, such as ketamine and psilocybin, is also examined. Such strategies may be effective for the short-term reduction of suicidal ideation and behaviour in individuals who have made a suicide attempt suicide prevention, particularly in cases where social pain is identified as a contributory factor. These pharmacological approaches may be effective regardless of the presence or absence of a specific psychiatric diagnosis.

To estimate the recreational value provided by the Foy’s Lake annually using the most applicable model for on-site data is the main objective of this study. Adhere to the objective of this study; Individual Travel Cost Method (ITCM) has been applied and Zero Truncated Poisson Regression Model has been found plausible among other models to estimate consumer surplus. Based on the findings of the study, an estimate of the consumer surplus or recreational benefits per trip per visitor can be recommended as BDT 5,875 or US $ 73.44 and counting the consumer surplus per trip per visitor, the annual recreational value (total consumer surplus) provided by the lake is found to be BDT 321 million or US $ 40.2 million.

Evaluating the economic and environmental effects of farmers' green production behaviors holds important reference value for promoting sustainable agricultural development, alleviating agricultural non-point source (NPS) pollution, and achieving the organic combination of environmental protection and economic development. This paper utilizes survey data from 1,345 farm households in the main rice production areas of Jiangxi Province, China, using the example of reduced fertilizer application (RFA) among rice farmers. By constructing a DEA—SBM model with undesirable outputs to measure environmental effects, and applying an endogenous switching model to test the economic and environmental effects of farmers' adoption of green production technologies. The study found that: (1)The behavior of RFA by farmers has a significant positive impact on their net profit per mu(NPPA), helping farmers increase their income, with the increase ranging from 2.05% to 6.54%. (2)The behavior of RFA by farmers has a significant positive impact on agricultural green productivity(AGP), contributing to the improvement of the environment, with the improvement ranging from 44.09% to 45.35%. (3)Heterogeneity analysis found inconsistencies in the income-enhancing and environmental-enhancing effects at different quantiles of NPPA and AGP. Therefore, attention should be placed on improving the agricultural product quality supervision system under the market circulation mechanism, creating land scale conditions conducive to the promotion and application of fertilizer reduction technologies, and promoting the implementation of externality internalization compensation systems.

Background: Endogenous Candida endophthalmitis (ECE) is a rare but sight-threatening disease. Patients with ECE present with various clinical signs and symptoms, which can complicate the diagnosis. The aim of this report was to describe the characteristic features of ECE on optical co-herence tomography (OCT) and OCT angiography (OCTA). Another objective was to demon-strate the outcomes of treatment and to diagnose macular complications caused by intraocular inflammation. Case presentation: A 41-year-old woman with a history of acute intermittent por-phyria presented with a progressive vision loss in her left eye. Left-eye OCT revealed findings consistent with a fungal etiology, which was confirmed by the culture of swabs collected from a central vein catheter. The outcomes of intravenous fluconazole treatment were not satisfactory, and the patient developed recurrent attacks of porphyria, suggesting a porphyrogenic effect of systemic antifungal therapy. Repeated intravitreal injections with amphotericin B led to a gradu-al regression of inflammatory lesions. However, follow-up examinations revealed active macular neovascularization on both OCT and OCTA. The patient was administered intravitreal bevaci-zumab. Conclusions: This case highlights the importance of OCT and OCTA as valuable noninva-sive imaging techniques for the identification of ECE, the monitoring of its clinical course, and the diagnosis of macular complications.

There is clinical concern about the combined use of alcohol and opiates. Several lines of evidence support an interaction between alcohol and the endogenous opioid system. Thus, we hypothesized that ethanol by causing the release of opioid peptides may sensitize the system to the action of exogenous opioids such as morphine. In this study, using the place conditioning paradigm as an animal model of reward, we determined whether a morphine challenge would alter the pre-established preference induced by ethanol conditioning in mice, and whether this response was mediated by the mu opioid receptor (MOP). Given that ethanol exposure stimulates the release of opioid peptides, we also assessed the role of beta-endorphin (β-END) and enkephalins (ENKs) in this response. Mice lacking MOP, β-END and/ or ENKs as well as their respective wild-type controls were tested for baseline place preference on day 1, conditioned with ethanol (2 g/kg) versus saline on days 2 to 4 and then tested under a drug-free state for postconditioning place preference on day 5. On day 8, mice received a single injection of morphine (5 mg/kg) and were tested for place preference. On each test day, mice were placed in the central neutral chamber and allowed to freely explore the conditioning chambers. The amount of time that mice spent in each chamber was recorded. We found that a challenge dose of morphine given on day 8 enhanced the CPP response in mice previously conditioned with ethanol. This response was abolished in MOP null mice, confirming the role of MOP in this response. Although this enhanced response was not altered in mice lacking either β-end or ENKs compared to their wild-type littermates/controls, it was completely blunted in mice lacking both β-end and enkephalins. Together, these results suggest that these opioid peptides jointly mediate the crosstalk between the rewarding actions of morphine and ethanol.

With the current increase in the demand from animal and agricultural products, management of agrowaste has become critical to avoid greenhouse gas emissions. The present article investigates the applicability of ammonium bicarbonate synthesis via flash distillation to valorize and stabilize several types of anaerobic digestate produced from individual fermentations of amino acids. Prior to the development of the model in Aspen Plus v12, the description of the system aqua-ammonia-carbon dioxide provided by the electrolyte non-random two-liquid property method was validated with empirical data available in the literature. The content of CO₂ in the digestate was found to be responsible of the OH alkalinity (0.4 equivalents of acid/kg digestate), while the partial and total alkalinities (0.8 eq/kg digestate) were essentially derived from the content of NH₃. The most suitable conditions for the flash distillation were 95 ⁰C and 1 bar with the condensation occurring at 25 ⁰C. However, in order to attain the precipitation of NH₄HCO₃ in the distillate, it was necessary to consider digestates with a moisture content of 50 wt.%, since the minimum levels of inorganic nitrogen and inorganic carbon were not attained otherwise. Even under these conditions, few amino acids (i.e. arginine, glycine, and histidine) were able to provide an anaerobic digestate, upon fermentation, that would be suitable for NH₄HCO₃ stabilization. Despite alanine digestate and glutamine digestate presented sufficient concentrations of inorganic nitrogen and inorganic carbon, the NH₄HCO₃-stabilization was not feasible due to the limited volatilization of NH₃. The process of stabilization with a capacity of a tonne of digestate per hour was improved by adding hydrochloric acid or sodium hydroxide at rates 44 kg/h, leading to production of 34 kg NH₄HCO₃/h. The economic viability of this process needs to be investigated considering not only the market value of the isolated inorganic fertilizer but the carbon credits saved, resulting from handling a more stabilized organic manure. Furthermore, given the role of the volatile elements of the biogas as endogenous stripping agents, it is recommended to use a fresh and saturated digestate as feed for the flash distillation.

Nitric oxide (NO) is synthesized and is involved in various physiological and developmental process regulation in all kingdoms of life. Fungi have been less explored in terms of endogenous NO biology than mammals, plants, and bacteria. In this review, we summarize and discuss the studies to date on intracellular NO biosynthesis and function in fungi. Two mechanisms for NO biosynthesis, NO synthase (NOS)-mediated arginine oxidation, and nitrate and nitrite reductase-mediated nitrite reduction, are most frequently reported. Furthermore, we summarize the multifaceted functions of NO in fungi, as well as its role as a signaling molecule in fungal growth regulation, development, abiotic stress, virulence regulation, and metabolism. Finally, we present potential directions for future research on fungal NO biology.

The successful advancement of xenotransplantation has led to the development of highly sensitive detection systems for the screening for potentially zoonotic viruses in donor pigs and preventing their transmission to the recipient. To validate these methods, genetically modified pigs generated for xenotransplantation, numerous minipig and other pig breeds have been tested, thereby increasing our knowledge concerning the pig virome and the distribution of pig viruses. Of particular importance are the porcine cytomegalovirus, a porcine roseolovirus (PCMV/PRV) and the hepatitis E virus genotype 3 (HEV3). PCMV/PRV has been shown to reduce the survival time of pig transplants in non-human primates and was also transmitted in the first pig heart transplantation to a human patient. Here, we determined the sensitivities of our methods to detect PCMV/PRV, HEV3, porcine lymphotropic herpesvirus - 1 (PLHV-1), PLHV-2, PLHV-3, porcine circovirus 2 (PCV2), PCV3, PCV4 and porcine parvovirus 1 (PPV1) efficiently and used the methods to screen indigenous Greek black pigs. Since porcine endogenous retroviruses (PERVs) of type A and B are integrated in the genome of all pigs, but PERV-C is not, the animals were screened for PERV-C and PERV-A/C. Our detection methods were sensitive and detected PCMV/PRV, PLHV-1, PLHV-1, PLHV-3, PVC3 and PERV-C in most animals. PPV1, HEV3, PCV4 and PERV-A/C were not detected. These data are of great interest since the animals are healthy and very resistant to diseases.

In this study, we present case studies to explore the dynamics of implementation and maintenance of health interventions. We analyze how specific interventions are built and eroded, how the building and erosion mechanisms are interconnected, and why we can see significantly different erosion rates across otherwise similar organizations. We use multiple comparative obesity prevention case studies to provide empirical information on the mechanisms of interest, and use qualitative systems modeling to integrate our evolving understanding into an internally consistent and transparent theory of the phenomenon. Our preliminary results identify reinforcing feedback mechanisms, including design of organizational processes, motivation of stakeholders, and communication among stakeholders, which influence implementation and maintenance of intervention components. Over time, these feedback mechanisms may drive a wedge between otherwise similar organizations, leading to distinct configurations of implementation and maintenance processes.

Excessive high fat diet (HFD) consumption can induce food addiction which is believed to involve the communication between the hypothalamus and mesolimbic dopaminergic neurons, originating in the ventral tegmental area (VTA) and projecting to the nucleus accumbens (NAc). These brain regions are densely populated with opioid receptors, raising the possibility that these receptors, and particularly mu opioid receptors (MORs), are involved in mediating reward induced by palatable foods. This study sought to investigate the involvement of MORs in high fat diet (HFD)-induced reward and if there is any difference between male and female subjects in this response. We also assessed if exposure to HFD would potentiate the rewarding action of oxycodone, a relatively selective MOR agonist. The place conditioning paradigm was used to determine if conditioning for a short time (STC, 2 h) or long time (LTC, 16 h) with HFD induces reward or alters the rewarding action of oxycodone. Male and female C57BL/6J mice as well as MOR knockout and wildtype mice of both sexes were tested for basal place preference on day 1 and then conditioned with HFD in one chamber and regular chow diet (RCD) in another chamber and tested for place preference again after three sets of STC and again after a set of LTC. Each set consisted of two conditioning with RCD and two conditioning with HFD. Controls were conditioned with RCD in both conditioning chambers. Following the last place preference test, mice were treated with oxycodone and conditioned in the HFD-paired chamber and saline in the RCD-paired chamber for one hour once a day to explore the possibility if the HFD could alter oxycodone reward. The result showed that HFD induced conditioned place preference (CPP) in both male and female subjects following the LTC. This response was further potentiated after oxycodone conditioning. The latter response was mediated via MORs, as it was blunted in MOR knockout mice. However, HFD-induced CPP was observed following LTC in only female MOR knockout mice, suggesting for sexual dimorphism in this response.

Fresh water springs are unique natural resources in Florida, currently under threat from increasing groundwater pumping and pollution resulting from a variety of sources. This paper estimates current recreation benefits from visiting springs using the travel cost method and elicits residents’ willingness to contribute for springs restoration using the contingent valuation method. It further compares the performance of count data models correcting for endogenous stratification and truncation, and finds that the annual consumer surplus per person per trip is between $20 and $43. Furthermore, visitors are willing to contribute $12 to $14 per person per trip for springs restoration without reducing trip demand.

Digital agricultural technology extension service and sustainable food production have attracted attention from academia. However, the association between digital agricultural technology extension service and sustainable food production has not yet been fully investigated. This research investigates the average and heterogeneous impacts of digital agricultural technology extension service use on eco-efficiency among 1302 maize producing farmers from Northeast China major maize producing area in 2022 to fill this knowledge gap. The slack-based measure model with undesirable outputs is applied to calculate the eco-efficiency of maize production. To obtain an unbiased estimation of the average effect, the self-selection problem generated by observable and unobservable factors is solved by the endogenous switching regression model. Quantile regression is utilized to analyze the heterogeneous effect. Notably, the mediated effects model is utilized to examine the potential mechanism between them. Our findings indicate that digital agricultural technology extension service use can increase maize production's eco-efficiency. Digital agricultural technology extension service users would reduce eco-efficiency by 0.148 (21.11%) if they had not used the digital agricultural technology extension service. Digital agricultural technology extension service nonusers would improve eco-efficiency by 0.214 (35.20%) if they had used it. The robustness check reconfirms the results. Moreover, digital agricultural technology extension service use is more helpful to maize farmers who have lower eco-efficiency than those who have higher eco-efficiency. Digital agricultural technology extension service use can improve eco-efficiency of maize production through the application of organic fertilizers, green pesticides and biodegradable agricultural films.

According to the International Agency for Research on Cancer (IARC) of the World Health Organization (data of year 2020), Breast Cancer (BC) is one of the most common cancer types worldwide, with large geographical variations occurring between countries and world regions and highest incidence rates in countries that have undergone economic transition. The risk factors for BC include women ageing, genetic mutations, reproductive history, dense breast tissues, personal history of BC or specific non-cancerous breast diseases, family history of breast or ovarian cancer, previous treatment using radiation therapy, and exposure to hormone-like drugs such as diethylstilbestrol (DES). Additional risk factors include being overweight or having obesity after menopause, and taking hormones. MicroRNAs (miRNAs or miRs) are small non-coding RNA molecules that have an essential role in gene expression and are significantly linked to the tumor development and angiogenesis process in different types of cancer, including BC. In the last years, the knowledge about miRNAs role in BC has significantly improved, and complex interactions among coding and non-coding RNA has been elucidated. In this context, an increasing number of papers had been published regarding the role of miR-125 in BC. In this review, we summarize the state-of-the-art about this research topic in addition to elaborating on the need to set novel ethical and legal standards for the governance of such innovations in healthcare.

The plant graft healing process is an intricate development influenced by numerous endogenous and environmental factors. This process involves the histological changes, physiological and biochemical reactions, signal transduction, and hormone exchanges in the grafting junction. Studies have shown that applying exogenous plant growth regulators can effectively promote the graft healing process and improve the quality of grafted plantlets. However, the physiological and molecular mechanism of graft healing formation remains unclear. In our present study, transcriptome changes in the melon and cucurbita genomes were analyzed between control and NAA treatment, and we provided the first view of complex networks to regulate graft healing under exogenous NAA application. The results showed that the exogenous NAA application could accelerate the graft healing process of oriental melon scion grafted onto squash rootstock through histological observation, increase the SOD, POD, PAL, and PPO activities during graft union development and enhance the contents of IAA, GA3, and ZR except for the IL stage. The DEGs were identified in the plant hormone signal-transduction, phenylpropanoid biosynthesis, and phenylalanine metabolism through transcriptome analysis of CK vs. NAA at the IL, CA, and VB stage by KEGG pathway enrichment analysis. Moreover, the exogenous NAA application significantly promoted the expression of genes involved in the hormone signal-transduction pathway, ROS scavenging system, and vascular bundle formation.

Clinical work conducted over the last seventeen years at the EEG Institute in Los Angeles and by other neurofeedback providers around the world has demonstrated the utility of extending frequency-based neurofeedback deep into the infra-low frequency (ILF) region, using the method of endogenous neuromodulation described herein. The method is characterized by the absence of any overt reinforcements, which makes it possible to extend the clinical reach to extremely low frequencies. As the training frequency is lowered, the signal becomes more difficult to discriminate, and ultimately it can only be discerned by the brain itself, in the process of endogenous neuromodulation. The method emulates how the brain does skill learning in general: It must observe itself performing the skill, with feedback on its performance. While the immediate target of ILF neurofeedback is enhanced self-regulatory competence--with symptomatic relief and functional recovery the secondary consequences, progressive lowering of the target frequencies has led to improved outcomes in application to challenging dysfunctions such as episodic suicidality, migraine, seizures, and bipolar mood swings. The work has also yielded insights into how the frequency domain is organized. The training proceeds best at frequencies that are specific to each individual, and these are referred to as optimal response frequencies (ORFs). These frequencies differ for various placements but stand in two fixed relationships to one another, one that holds over the EEG spectral range, and another that holds over the entire ILF range. Training in the ILF region engages the dynamics of the glial-neuronal networks, which govern tonic, resting state regulation. The collective clinical experience with ILF neuromodulation within a large practitioner network supports the case for making protocol-based, individualized ‘homeodynamic’ regulation a therapeutic priority, particularly for our most impacted clinical populations: addiction, trauma formations, traumatic brain injury, and the dementias. The case is made for further outcome studies and foundational research.

Background: Objectives. The objective of this study was to compare the efficacy of direct current stimulation (DCS) applied at the transcranial, suboccipital and spinal level on experimental sensory modalities and pain outcome measures in healthy subjects. The hypothesis of this study was that systematic analysis of the efficacy of DCS on modulating evoked thermal and mechanical pain modalities and mechanisms such as endogenous pain modulation in healthy individuals would reveal sensitive outcome measures help develop this technique for the control of chronic pain. Materials and Methods. Database searches were conducted up to December 2019 for randomized controlled trials that performed sham-controlled DCS of experimental sensory modalities and pain outcomes following transcranial, suboccipital and spinal locations in healthy participants. Standardized mean differences with 95% confidence intervals were calculated for sensory modalities, including random-effect metanalysis. Results: Thirty-one studies were included for analysis (647 participants). A significant decrease in pain intensity for active vs sham transcranial stimulation was identified for pain intensity (n=158; SMD=0.79; 95% CI=0.56 to 1.02), a significant increase in heat pain threshold (n=222; SMD=1.16; 95% CI=0.95 to 1.37), and a significant increase in cold pain threshold (n = 155; SMD = 0.77, 95% CI 0.53 to 1.01). No significant modulation of pressure pain threshold was identified with DCS and only a limited number of studies focused on experimental pain modulation following neuromodulation at the suboccipital or spinal level. Conclusions: These results show significant transcranial DCS neuromodulation of pain intensity and on thermal pain modalities. Future studies should focus on endogenous pain and sensory modality modulation with sham-controlled DCS applied at transcranial, suboccipital and spinal locations.

This article reevaluates the Woesean concept of crossing a ‘Darwinian threshold’ from pre-genomic communality, as prevailing in an ancestral ‘progenote’ state, to vertically stable lineages of autonomous and self-similar cells. This transition from collective trunk-line evolution to Darwinian speciation is dependent on the generation of modular organismal genomes. The same general principle should be valid at subcellular levels, allowing the emergence of semi-autonomous genomic agents, such as viruses and plasmid-carrying endogenous vesicles with organelle-like properties. As compartmentalized agents of endogenous nature could start with smaller genomes than those required for fully autonomous cells, it is conjectured that stable subcellular lineages emerged earlier than their cellular counterparts. Referring to the recent ‘pre-endosymbiont hypothesis’, it is proposed that free-living bacteria (the first ‘prokaryote’ cells) arose by ‘lineage escape’ from plasmid-bearing organelle-like compartments, evolving inside the internally complexifying ‘paracells’ of the progenote community. The double-membrane envelopes of diderm bacteria may have resulted from cell-biological processes facilitating cellular lineage escape. The later emergence of archaeal cells (resembling bacteria in ‘prokaryote’ appearance with unichromosomal genomes) and eukaryotic organisms (with compartmented cells and multichromosal genomes) can also be interpreted in terms of this modified progenote hypothesis. Conceivably, the multichromosomal genomes of eukaryotes were bundled in endogenous nuclear compartments to organize a ‘nuclear-cytoplasmic lineage’, which became vertically stable by perfecting mitosis/meiosis-like divisions and yet retained some intra-species population confluence by sexual division-fusion cycles.

Cardiotonic steroids (CTS) are a group of steroid compounds derived from certain plants and animals. CTS are selective inhibitors of Na,K-ATPase, so for a long time they were widely used for medical purposes to treat heart failure and some other diseases. However, over time, doctors gradually began to refuse this group of drugs due to their narrow therapeutic range and a number of serious side effects. However, in parallel with the rise and fall of interest in CTS as a drug, interest in them as a single class of high-affinity Na,K-ATPase inhibitors has only increased. Numerous data on the effect of CTS on signaling cascades and cell viability made impelling a search for a rationale for the existence of such a subtle biological regulator. A large number of studies devoted to the potential use of CTS in the treatment of neurodegenerative, oncological, immune and other diseases "revitalized" the already "written off" group of the drugs. If initially the role of exogenous (mainly plant origin) CTS was studied, then by the 90s of the XX century the study of the role of endogenous CTS and their regulatory effects became a popular trend in biology and physiology. The role of endogenous CTS was studied in details in the pathogenesis of cardiovascular diseases [1]. A large number of researchers have unanimously stated that endogenous CTS are very complex regulators of the development of pathological processes; however, the exact cause-and-effect relationship that would unambiguously explain the processes of synthesis, utilization, and the role of endogenous CTS has not yet been established. The effects of CTS in the frame of various regulatory schemes have been described, but the predominant number of studies was devoted to arterial hypertension, heart and renal failure, cancer [2–4], aging [5,6], and neuroinflammation. The effects of both endo- and exogenous CTS on blood cells and have been studied to a much lesser extent.

The increasing frequency of male cancer coupled with the reduction in male fertility seen worldwide motivated us to seek a potential evolutionary link between these two phenomena, concerning the reproductive transcriptional modules observed in cancer and the expression of cancer-testis-antigens (CTA). The phylostratigraphy analysis of the human genome allowed us to link the early evolutionary origin of cancer by reproductive life cycles of the unicellulars and early multicellulars, potentially driving soma-germ transition, female meiosis and parthenogenesis of polyploid giant cancer cells (PGCCs), with the expansion of the CTA multi-families, very late during evolution. CTA adaptation was aided by retrovirus domestication in the unstable genomes of mammals, for protecting male fertility in stress conditions, particularly that of humans, as compensation for the energy consumption by a large complex brain which also exploited retrotransposition. We found that the early and late evolutionary branches of human cancer are united by the immunity-proto-placental network, which evolved in the Cambrian and shares stress regulators with the finely-tuned sex determination system. We further propose that social stress and endocrine disruption caused by environmental pollution with organic materials, which alter sex determination in male foetuses and further spermatogenesis in adults, bias the development of PGCC-parthenogenetic cancer by default.

The development of nucleic acid sequencing technology and the unprecedented availability of metadata has evidenced that 45% of human genome constituted by transposable elements (TEs) is not only transcriptionally active but also physiologically needed. Aberrant regulation of TEs, and of human retroviral endogenous sequences (HERVs) in particular, associates with several neurologic and autoimmune diseases, including the Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) frequently comorbid with fibromyalgia (FM). However, no study has yet addressed whether abnormal expression of these sequences correlates with FM. The work presented here shows, for the first time, that in fact HERVs of the H, K and W types are overexpressed in the cells of the immune system of FM patients with or without comorbid ME/CFS. The patients with increased HERV expression (N=14) presented increased levels of interferon (INF-β and INF-γ) but unchanged levels of TNF-α. In support of our proposal that TE activation is a contributor to FM, we find that the tRNA pools are decreased in comparison to matched healthy participants (N=14). The findings reported here could explain the flu-like symptoms FM patients present with in the absence of concomitant infections. Future work towards identifying specific genomic loci differentially affected in FM and ME/CFS is granted.

Human endogenous retroviruses (HERV) are remnants of ancient retroviral infections that, over millions of years, became integrated into the human genome. While normally inactive, environmental stimuli such as infections have contributed to the transcriptional reactivation of HERV promoting pathological conditions including the development of autoimmunity, neurodegenerative disease and cancer. What infections then trigger HERV activation? Mycobacterium avium subspecies paratuberculosis (MAP) is a pluripotent driver of human disease. Aside from granulomatous diseases Crohn’s, sarcoidosis and Blau syndrome, MAP is associated with autoimmune disease: type one diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis and autoimmune thyroiditis. MAP is also associated with Parkinson’s disease. Autoimmune diabetes, multiple sclerosis and rheumatoid arthritis are the diseases with the strongest MAP/HERV association. There are several other diseases associated with HERV activation including diseases whose epidemiology and/or pathology would prompt speculation for a causal role of MAP. These include non-solar uveal melanoma, colon cancer, glioblastoma and amyotrophic lateral sclerosis (ALS). This article further points to MAP infection as a contributor to autoimmunity, neurodegenerative disease and cancer via unsilencing of HERV. We examine the link between the ever-increasing number of MAP- associated diseases, the MAP/HERV intersection with these diverse medical conditions and propose treatment opportunities based upon this association.

In the context of healthcare technology management (HTM) in Saudi Arabia and the Gulf region, this study addresses a significant gap by exploring both external and internal risk factors affecting HTM performance. Previous research has primarily focused on modeling or predicting failures in medical devices, mostly examining internal (endogenous) factors that impact device performance and the development of optimal service strategies. However, a comprehensive investigation of external (exogenous) factors has been notably absent. This research introduces a novel hierarchical risk management framework, designed to accommodate the broad array of healthcare technologies, not limited to medical devices. It significantly advances the field by thoroughly investigating and validating a comprehensive set of 53 risk factors and assessing their influence on HTM. Additionally, this study embraces the perspective of enterprise risk management (ERM) and expands it to identify and incorporate a wider range of risk factors, offering a more holistic and strategic approach to risk assessment in healthcare technology management. The findings reveal that several external and internal factors previously underexplored significantly impact HTM performance. Notably, the Fuzzy AHP survey identified “design risk” under facility and environmental risks as the highest risk for HTM in the region. Furthermore, the study reveals that three out of the top ten risks are related to “facility and internal environmental” factors, six are related to technological endogenous factors, and only one is related to managerial factors. This distribution underscores the critical areas for intervention and the need for robust facility and technology management strategies. In conclusion, this research not only fills a critical void by providing a robust framework for healthcare technology risk assessment but also broadens the scope of risk analysis to include a wider array of technologies, thereby enhancing the efficacy and safety of healthcare interventions in the region. Additionally, the proposed hierarchy provides insights into the underlying risk factors for healthcare technology management, with potential applications extending beyond the regional context to a global scale. Moreover, the equation we propose offers a novel perspective on the key risk factors involved in healthcare technology management, presenting insights with far-reaching implications applicable not only regionally but also on a global level. This framework also supports sustainability goals by encouraging the efficient and responsible utilization and management of healthcare technologies, essential for ensuring the long-term economic and environmental sustainability of medical technology use.