This research evaluates the importance of renewable power and conventional fuels consumption in the economic growth of 20 African EMDEs towards sustainable development. Due to the evidence of slope heterogeneity alongside cross-sectional dependence, the author applies second-generational econometric techniques for heterogeneous panel data. After detecting the long-term relationship among all variables using Westerlund panel-data cointegration test, the long-run estimates are computed by AMG, MG and CCEMG estimators, which indicates that nonrenewable and renewable energy usage fosters African EMDEs' economic growth. Besides, capital, government expenditure, and trade openness also encourage economic growth. Moreover, the causality analysis (using Dumitrescu and Hurlin test) supports the feedback effects among the selected variables and economic growth. The findings provide critical implications for sustainable energy policies that contribute to the sustainable development of African EMDEs. Energy; Economics; Economic development; Economic growth; Macroeconomics; Econometrics; Energy economics; African EMDEs; Renewable power and conventional fuels consumption; Sustainable development. ConventAlthough the linkage between energy usage and economic growth has been documented by numerous studies in the past four decades, it remains the center of controversy regarding energy policies . And ideBased on the aforesaid explanation, the objective of this study is examining the long-run relationship and the causality between renewable and nonrenewable energy consumption and the economic growth in African Emerging Market and Developing Economies (EMDEs) from 1990 to 2014. Based on the research objective, the hypotheses of this study are: (i) Renewable power consumption and nonrenewable energy usage positively affect economic growth; (ii) The feedback hypothesis  is supported. In order to conduct this empirical study, we apply “second-generation” econometric techniques to solve the heterogeneous panel problem for the model based on the extended version of the Cobb-Douglas production function.This study contributes to the existing literature in several ways. First, EMDEs in general and African EMDEs in particular are rapidly integrated with the global economy; nevertheless, they face the challenges of power security alongside weak standards of environmental-protection . From thThe main findings of this study include: (1) Nonrenewable energy usage per capita and renewable energy consumption per capita stimulate GDP per capita. (2) There exist two-way relationship between nonrenewable energy usage and GDP per capita as well as between renewable energy usage and GDP per capita, thus demonstrating the presence of the feedback hypothesis between the two components of energy consumption (nonrenewable fuels and renewable power) and economic growth. (3) This study witnesses that gross fixed capital formation per capita, the government expenditure per capita and the trade openness per capita positively affect GDP per capita. Besides, the feedback effects among those variables and economic growth. (4) The analysis results of AMG, MG and CCEMG estimators are consistent and very similar in terms of the signs and magnitudes of the coefficients, which signifies the robustness of estimation.The rest of this article is as follows: Section 2The growth hypothesis mentions the unidirectional effect of energy usage on economic growth that higher energy utilization facilitates more economic activities. Thus, energy conservation policies are deemed having negative impacts on economic growth. (2) The conservation hypothesis assumes one-way causation from economic growth to energy consumption. In other words, more economic activities boost energy usage. Hence, energy conservation policies do not affect economic growth. (3) The feedback hypothesis supposes bidirectional causality between energy usage and economic growth. Accordingly, energy conservation policies can affect economic growth efficiency, and economic growth can also influence energy consumption. (4) The neutrality hypothesis argues that energy consumption and economic growth have no impact on each other. Consequently, energy conservation policies aiming to reduce power consumption have no influence on economic growth.Since the study of Based on the literature review, it can be observed that there are 3 branches of research regarding the association between energy consumption and economic growth. The first one is about studying the relationship between all energy usage and economic growth. The second one is about examining the linkage between renewable energy consumption and economic growth. And the final one is about studying the connection between the consumption of 2 energy types (non-renewable and renewable) and economic growth. As the research objective relates to the inspection and comparison of the impacts of renewable energy usage and nonrenewable energy consumption on economic growth as well as the detection of the causation between the energy variables and economic growth, we will present a thorough review of some notable studies in this research branch.2 emissions and economic growth in EU-16 countries from 1996 to 2014. Dumitrescu and Hurlin Panel causality analysis indicated that a feedback mechanism among the consumption of renewable and nonrenewable power, and economic growth. 2 emissions, trade openness, and government expenditure on economic growth in 45 Emerging Market and Developing Economies during 1990–2014 by utilizing AMG, CCEMG and MG estimators. Furthermore, using Dumitrescu-Hurlin panel causality, their findings also supported the feedback hypothesis between nonrenewable and renewable energy usage and economic growth.33.1The main objective of this research is examining the roles of renewable and nonrenewable power usage consumption as one of the determinants of sustainable development in African EMDEs. The empirical model used in this study is based on the baseline model of the Cobb-Douglas production function, as follows:According i and t indicate country and year respectively. The final element, Transform 3.2This work uses balanced panel data with 500 observations between the years 1990 and 2014 of 20 African Emerging Market and Developing Economies classified by Morgan Stanley Capital Income including Algeria, Arab Republic of Egypt, Islamic Republic of Iran, Jordan, Lebanon, Morocco, Saudi Arabia, Tunisia, Botswana, Cameroon, Republic of the Congo, Cote d'Ivoire, Gabon, Ghana, Kenya, Mozambique, Nigeria, Senegal, Sudan and Tanzania.The data is collected from two sources, subject to the availability of the data. First, GDP, capital, trade openness, and government expenditure are provided by World Development Indicators (WDI) database of the The correlation matrix of the variables is given in 3.3Traditional econometric techniques ignore the existence of CSD and slope heterogeneity. Thus, when CSD and slope heterogeneity occur, first-generation econometric methods can be biased and unreliable . To avoiFirst, the author conducts CSD test and the slope homogeneity test respectively proposed by Second, in case CSD appears, the cross-sectionally augmented Dickey-Fuller (CADF) and the cross-sectionally augmented Im-Pesaran-Shin (CIPS) panel unit root test will be utilized to check for the stationary properties of variables. The aforementioned unit root tests are deemed second-generation ones which were developed by Third, to check the cointegrated relationship among the variables, the author employs Fourth, after affirming the cointegration of the variables, the author applies the panel AMG estimator  is rejected. Otherwise, we do not reject the null hypothesis.3.3.2In panel data analysis, it is necessary to inspect if cross-sectional heterogeneity occurs because when the panel is heterogeneous, the assumption of slope homogeneity might create misleading estimation . To test3.3.3To test for the stationarity of the variables in the panel data with cross-sectional dependence, The CIPS test is stated as:The results of CADF test and CIPS test will indicate the stationarity of the variables. Specifically, when the test statistics are bigger than the critical values, we reject the null hypothesis and conclude the stationary properties of the variables. Otherwise, we cannot reject the null hypothesis (i.e. the data has unit root).3.3.4Common techniques, such as The 3.3.5To estimate the long-run parameters in heterogeneous panel data, The first step is combining the unobserved common factor with the time dummies in the following equation:The second step is obtaining the MG estimator for AMG by averaging the slopes of each unit:It is noticeable that the AMG estimator remains efficient and unbiased regardless of the cross-section and time dimensions in panel data . For rob3.3.6To test causality in heterogeneous panel data, The null hypothesis of Dumitrescu and Hurlin causality test is no causation in the panel. The alternative hypothesis states that there exists causal relationship in at least a unit. The hypotheses are as follows:The result of Dumitrescu and Hurlin causality test is indicated by the comparison between p-values and significance levels. If the former are smaller than the latter, the null hypothesis is rejected. In contrast, the null hypothesis cannot be rejected.Dumitrescu and Hurlin proposed the Wald test statistic  research hypothesis regarding the positive impacts of renewable and nonrenewable energy usage on economic growth. Although the findings show that the contribution of renewable energy consumption to economic growth is still not as big as the nonrenewable one, our study supports the economic benefits of activating relevant environmentally-friendly energy sources. In the long-run, renewable energy can lead to economic sustainability when the nonrenewable sources are limited over time. Moreover, regarding the sustainable development objective, it is possible to find clean, reasonably-cheap, available and easily-accessible-to-everybody energy from renewable sources because their distribution is dispersed and they can solve the energy imbalance between rural and urban areas  research hypothesis is validated. Based on the feedback hypothesis, it is implied that the increase in power consumption can facilitate economic growth, and vice versa, economic growth can boost energy usage, which signifies that energy conservation policies can lower economic growth efficiency; therefore, the transition in the energy consumption structure from nonrenewable to renewable sources is a useful solution for African EMDEs' sustainable development. African EMDEs can raise the penetration of renewable energy sources in their power system in the situation that fossil-fuel utilization stimulates carbon dioxide emissions and other problems relating to severe climate change. Besides, the findings also demonstrate the feedback mechanism between renewable energy consumption and nonrenewable energy consumption, which implies that a strategic combination of producing and consuming these two kinds of power in an energy portfolio can help achieve reasonably-priced and widely-accessible energy services as well as the reduction in climate change and its consequences.According to the results in 5African EMDEs have integrated quickly to the global economy; however, they face the challenges of energy security and environmental degradation. This study aims to find the ways in which African EMDEs can pursue green economy through constructing effective power policies in the circumstance of sustainable development goal. So as to attain the research objective, we build the model to assess the long-term impacts of energy components, along with other factors, on economic growth. In addition, the causation between energy components in energy consumption structure and economic growth is evaluated by Dumitrescu and Hurlin causality analysis. Empirically, this study employs the extended production function considering the roles of nonrenewable fuels usage and renewable power consumption alongside important factors such as capital, trade openness, and government expenditure in the economic growth. The data is balanced and covers the period 1990–2014 for African EMDEs. Due to the presence of slope heterogeneity and cross-sectional dependence, this work utilizes second-generation econometric techniques for heterogeneous panel. Accordingly, CADF and CIPS tests are used for checking the stationarity of the variables, and the outcomes indicate that all variables are stationary at first difference. Next, Westerlund panel cointegration test is conducted, and the author detects the cointegration between economic growth and other independent variables. The long-run estimation based on Augmented Mean Group (AMG) estimator demonstrates that nonrenewable energy use, renewable energy consumption, capital, trade openness, and government expenditure positively impact economic growth in African EMDEs. The robustness of estimation is confirmed by CCEMG and MG estimators. Moreover, this study validates the feedback hypothesis  between each component of energy usage and economic growth in African EMDEs.We observe that both renewable and nonrenewable energy consumption positively affect economic growth in the long-run. Our results are consistent with prior studies such as From our findings, it can be observed that both renewable and nonrenewable energy are important to economic growth whey they foster economic growth in the long-run. Hence, energy conservation policies can lower economic growth efficiency. Our results imply that policy-makers should focus not only on the increase of renewable energy but also the increase of nonrenewable power in order to support economic growth. Besides, the interdependence of renewable energy, nonrenewable power and economic growth demonstrates that energy is crucial for economic growth, and economic growth also boosts energy consumption. It is important to notice that utilizing different energy sources can facilitate economic growth and reduce environmental degradation when renewable energy is beneficial in decelerating climate change and suiting sustainable development objectives . ConsequIn this study, we use non-renewable and the renewable energy consumption at the aggregated level for discovering the power consumption – economic growth linkage. Hence, we suggest that further researches in the energy-growth nexus can focus on the renewable energy consumption at the disaggregated level  and the nonrenewable energy consumption . Besides, future researches can implement detailed examination of the relationship between energy usage and economic growth by disaggregating data into different industries in order to clearly assess the energy policies that contribute to the sustainable development objective in African EMDEs. Moreover, researches conducted at country level are also helpful for designing specific sustainable development for each country in African EMDEs. Finally, in the future, subject to the availability and reliability of data, it can be very interesting that studies with the same topic can consider different control variables as well as more advanced models and econometric techniques.Hoang Phong Le & Dang Thi Bach Van: Conceived and designed the experiments; Performed the experiments; Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data; Wrote the paper.European Union's Horizon 2020 research and innovation programme under Marie Skłodowska-Curie grant agreement No. 734712. This work was also supported by the 10.13039/100007839University of Economics Ho Chi Minh City.This work was supported by the The authors declare no conflict of interest.No additional information is available for this paper.


The presence of shaped stone balls at early Paleolithic sites has attracted scholarly attention since the pioneering work of the Leakeys in Olduvai, Tanzania. Despite the persistent presence of these items in the archaeological record over a period of two million years, their function is still debated. We present new results from Middle Pleistocene Qesem Cave on the use of these implements as percussion tools. Use-wear and abundant bone and fat residues found on ten shaped stone balls indicate crushing of fresh bones by thrusting percussion and provide direct evidence for the use of these items to access bone marrow of animal prey at this site. Two experiments conducted to investigate and verify functional aspects proved Qesem Cave shaped stone balls are efficient for bone processing and provide a comfortable grip and useful active areas for repeated use. Notably, the patina observed on the analyzed items precedes their use at the cave, indicating that they were collected by Qesem inhabitants, most probably from older Lower Paleolithic Acheulian sites. Thus, our results refer only to the final phases of the life of the items, and we cannot attest to their original function. As bone marrow played a central role in human nutrition in the Lower Paleolithic, and our experimental results show that the morphology and characteristics of shaped stone ball replicas are well-suited for the extraction of bone marrow, we suggest that these features might have been the reason for their collection and use at Qesem Cave. These results shed light on the function of shaped stone balls and are consistent with the significance of animal fat in the caloric intake of Middle Pleistocene humans as shown by the archeozoological evidence at Qesem Cave and possibly beyond. Leakey’s suggestion was later criticized, and other definitions were proposed. Sahnouni [Shaped stone balls (henceforth SSBs) are a remarkable component at sites of the Oldowan and Acheulian cultural complexes in Africa –8, Asia Sahnouni , for exaSahnouni , used asSahnouni –20 or asSahnouni . The secSahnouni , 22, hamSahnouni , 7, 23, The presence of SSBs at Qesem Cave, Israel (420–200ka) marks the latest appearance of this type of artifacts in the Lower Paleolithic Levant and represents the end of a long tradition of over two million years of producing and using SSBs. A residue and use-wear study yielded significant data regarding ten well-preserved SSBs  from Qesem Cave, shedding new light on the use of these items. While the original function of these tools is impossible to study due to the cover of patina, we demonstrate that the cave inhabitants selected and collected specifically old, patinated SSBs from outside the cave and then used them in thrusting percussion actions for crushing fresh animal bones to access the marrow. Collecting artifacts produced elsewhere and bringing them to the cave was a behavioral pattern familiar to the Qesem inhabitants. A plethora of evidence shows that they regularly selected, collected, and transported older (sometimes patinated) lithic blanks, which were then used, sometimes in a manner of recycling, inside the cave –30. SeveDistinct use-wear traces and residues observed on SSBs found at Qesem Cave associate them with bone-breaking activities. Still, a question should be raised: If this is the case, why were these specific items chosen for such particular activity? In this paper we will discuss the results of the functional analysis and suggest, based on archaeological data and experimental work, that the SSBs were indeed selected by the cave’s inhabitants due to their distinctive man-made morphological characteristics, which were best suited for marrow extraction tasks. We suggest that SSBs’ are yet another example of the production of a tool with a particular morphology according to the activity (and grasping/handling process) for which it was designed –34—in thThe Middle Pleistocene archaeological site of Qesem Cave is located on the western slopes of the Samaria hills, 12 km east of the Mediterranean. Various methods suggested dating human occupation at the cave started at ca. 420 ka and ended prior to 200 ka –38. The The site yielded a rich faunal assemblage mostly dominated by bones of fallow deer, supplemented by red deer, horses, aurochs, wild pigs, wild asses, tortoises, and birds –44. Manychaîne opératoire that includes well-selected flint nodules, core shaping, blade production (including blades and retouched blades), use, and discard [The lithic assemblages are characteristic of the Acheulo-Yabrudian Cultural Complex of the late Lower Paleolithic period in the Levant . Blade-d discard –51. Quin discard . Several discard –29. In a discard . Amudian discard . The int discard . HoweverTwenty-nine SSBs found at Qesem Cave include spheroids and sub- spheroids, and also five split half-balls, out of which ten items yielded residue and use-wear traces. The other nineteen tools display neither observable functional traces nor residues accumulated before or after their patination . The SSBs were concentrated in particular Amudian contexts of the lower stratigraphic sequence of the cave . One groNo permits were required for the described study, which complied with all relevant regulations. All specimens described in the manuscript were excavated under permits granted by the Israel Antiquity Authority to RB and AG and are stored at the repository of Institute of Archaeology, Tel-Aviv University. The specimens are available upon request.The SSBs were made of hard, carbonate rocks (either limestone or dolomite), with the exception of one made of flint. These massive carbonates are different from the highly weathered Turonian limestone that builds the cave area, which is covered by colluvial materials and even some calcrete. Remarkably, whereas the lithic assemblages of Qesem comprise hundreds of thousands of flint items, only a few carbonate rock artifacts  were recovered . The absIn this study, several SSB replicas were produced . The reduction strategy required careful planning  and higDiet and Ancient Technology Laboratory (at Sapienza University of Rome) (1) using a digital stereomicroscope  and (2) using a metallographic microscope .The function of the SSBs was revealed by an integrated use-wear and residue analysis. Methods and criteria for identifying, describing, and interpreting macro- and micro-wear and residues on stone tools were based on well-known literature in the field of functional studies of material culture , 54–66. Following the analysis of the surface patinas and the post-depositional modifications affecting the archeological tools, the state of preservation of the residues was analyzed at low and high magnification. Particular care was taken in understanding the stratigraphic relation between the residues and post-depositional concretions, particles of soil as well as functional modifications. Only residues characterized by a strict correlation with the use-wear traces were considered reliable.Residues were described according to their appearance, using variables such as morphology, texture, color, and birefringency. Possible alteration caused by post-depositional modification and/or mechanical stresses affecting the appearance of the residues and related to use were also documented. Morphological features of animal structures were recorded along with their spatial distribution over the tools –69.The interpretation of archaeological residues was based on the comparison with an experimental macro-residues collection (see below) as well as using the available literature on experimental residues on stone tools , 70–74.Functional traces were described following the tribology-based variables proposed by Adams . These vFollowing the analysis and documentation of residues on the archaeological tools, SSBs were washed with a 2% solution of demineralized water and neutral phosphate detergent (Derquim®) to allow the correct observation of the micro-traces, sometime hindered by the presence of residues and soil particles adhering the surfaces. As the direct observation of micro-polishes under the metallographic microscope was prevented by the height of the archeological tools as well as by the working distances of the objectives, silicon molds of the areas characterized by use-wear traces were made using Provil Novo Light Fast Heraeus®. Silicon casts were made only on a selection of tools in order not to damage archaeological surfaces (the silicon may stain surfaces), if macro-traces and residues were diagnostic.A series of experiments was carried out in order to verify archaeological results. In particular, use-wear traces and residues identified on SSBs served as a basis for designing specific experimental activities, which included first replicating and tracing the shaping process of the SSBs, and then testing the SSB replicas in bone crushing activities aimed at marrow extraction. We also used unmodified limestone and dolomite cobbles of different sizes and characteristics in the same experimental activities.Ten out of twenty-nine items showed developed use-wear traces and/or residues . All SSBSince use-wear traces and residues overlay on top of the weathered areas of the items, a hypothetical timeline was established for their life history. First came the shaping of the typical ball or polyhedron ; next came the development of the surface patina; last, patinated SSBs were collected, brought to the cave, and used . To datFor all the reasons exposed so far, our use-wear and residue data refer to the most recent use of the SSBs exclusively A variety of macro-and micro-wear traces were observed on the  shaped, angular ridges of the SSBs : Micro-fResidues were exceptionally preserved on eight tools and distributed across their surfaces. Archaeological residues have morphological features, appearance, color, and distribution compatible with compact and spongy bone, organic bone glossy film, collagen fibers, and animal fatty matters observed on experimental stone balls used in bone marrow extraction activities. In particular, on the top of the prominent ridges, residues appear as spots of organic film with a glossy and often striated appearance. They coexist with spots of crushed amorphous white residues consistent with bone fat and collagen fibers  sometimeA preliminary evaluation of the nature of use-wear and residue on the archaeological SSBs has been conducted using percussion tools from the experimental reference collection at DANTE—Diet and Ancient Technology Laboratory in Rome (Sapienza University). Overall, this preliminary experimentation allowed us to evaluate patterns of use-wear and residue distribution while attempting a preliminary functional evaluation of the material worked using the SSBs from Qesem cave. The replicas of percussion tools had prominent ridges and morphology similar to the archaeological finds and were used to process different types of organic matter.In addition to the abovementioned reference collection, two more experimental trials were conducted in order to investigate and test specific functional features of the archaeological finds.The first experimental trial (EXP-1) was conducted by IC, CL, AG and EA as a way to test the efficiency of limestone unshaped cobbles compared to shaped cobbles in processing fresh bones by thrusting percussion. Results of this trial were key role for interpreting macro and micro-traces observed on the archaeological SSBs. The experimental activities were chosen on the basis of the archaeological evidence, namely the use-wear and residues observed on the Qesem SSBs as well as considering the rich assemblage of animal bone recovered at the site –42. ThreThe second experimental trial (EXP-2) was conducted by JR, RB, IC, AG and EA as a way to specifically test the efficiency of SSBs in fresh bone crushing activity aimed at extracting bone marrow. Through this trial, macro-detachments developed on SSBs, sometimes changing their morphology, were documented together with diagnostic use-wear features and residues produced during the specific activity.Three replicas were produced by JB and used in this experiment , Fig 8 tIn the case of replica n.2 carbonate rock selected was not retrieved from the immediate surroundings of Qesem Cave. As previously stated, a preliminary geological survey indicated that the limestone originating from the natural formation of the cave itself (the Turonian Bi’na Formation ) was of During the EXP-2 different variables were taken into consideration such as the tool size and material, the size of the bone, and the anatomical part chosen for the experimentation. In order to test whether skill levels influenced the effectiveness of SSBs in general, two experienced and three unexperienced individuals participated in the experimental session of bone breaking.All bones were prepared by removing the periosteum using a flint flake. A total of 11 bones were broken . All individuals broke the bones by means of direct hammerstone percussion, including the use of four SSB replicas  with theThe SSB replicas were found to be very efficient for crushing animal bones , and no impact led to a significant change of their original morphology.Residues associated to bone crushing were localized on the prominent ridges of the experimental replicas as well as inside the negative scars related to the technological procedure of tool shaping. Four different types of residues have been recognized: (a) collagen fibers and fragments of periosteum tissue; (b) amorphous reddish animal matter; (c) amorphous whitish animal matter; (d) small particles of crushed bone. Collagen fibrils were abundant and often found in association with particle of periosteum tissue . Their dMacro-traces were localized on the prominent ridges of the tools , which aInterestingly, no macro-flakes such as those observed on the archaeological sample developed on the experimental replicas (at 20x of magnification). Different explanations could explain the discrepancies with the archaeological data. In particular, experimental results could be due to the specific force and types of gestures used by the experimenter during the percussion activity; to the size and hardness of the crushed bones; and, finally, also to the repetitiveness of the actions performed. Understanding entirely the formation of these variables goes beyond the scopes of this article and would require a wider and more detailed experimentation.Use-wear and bone residues on ten SSBs indicate that the inhabitants of Qesem Cave favored the use of shaped, somewhat angular, stone balls made of carbonate rocks to crush fresh animal bones to access fat: mostly marrow and possibly grease too Figs  and 14. In particular the experimental results indicate that the level of experience in bone breaking certainly affected the time required for processing the bone. We thus infer that planning, precision, and know-how were required for selecting adequate tools and for properly using them for the task. Remarkably, damage related to bone breakage activities is observed on the faunal record throughout the stratigraphic sequence of the cave, while SSBs were found only in particular Amudian contexts. At this stage of our research, it is still early to provide a coherent explanation for this state of affairs. However, we do not argue that bone breakage at the cave was accomplished only by the use of SSBs, and it is most reasonable that other hammerstones were used for this purpose as well  direct evidence of the use of this type of artifacts. They clearly confirm the function of SSBs and their role within the toolkit of Qesem Cave inhabitants. The people of Qesem were well-acquainted with the landscape around the cave, which was also favored by earlier Lower Paleolithic groups. Thus, the landscape was rich in relics of earlier groups, some of which were well-suited to the needs of the cave’s inhabitants. These patinated relics might have been selected from ancient Acheulian sites, e.g., the late Acheulian sites of Jaljulia or Eyal, located 6–12 km north of Qesem (see ), the laS1 Data(DOC)Click here for additional data file.


Over the last two decades, the explosion of experimental, computational, and high-throughput technologies has led to critical insights into how the brain functions in health and disease. It has become increasingly clear that the vast majority of brain activities result from the complex entanglement of genetic factors, epigenetic changes, and environmental stimuli, which, when altered, can lead to neurodegenerative and neuropsychiatric disorders. Nevertheless, a complete understanding of the molecular mechanisms underlying neuronal activities and higher-order cognitive processes continues to elude neuroscientists. Here, we provide a concise overview of how the interaction between the environment and genetic as well as epigenetic mechanisms shapes complex neuronal processes such as learning, memory, and synaptic plasticity. We then consider how this interaction contributes to the development of neurodegenerative and psychiatric disorders, and how it can be modeled to predict phenotypic variability and disease risk. Finally, we outline new frontiers in neurogenetic and neuroepigenetic research and highlight the challenges these fields will face in their quest to decipher the molecular mechanisms governing brain functioning. Once phosphorylated, CREB1 was found to recruit the HAT CREB-binding protein (CBP) to the promoter of the transcriptional co-activator CCAAT/enhancer-binding protein (CEBP), leading to enhanced histone acetylation and the expression of synaptic plasticity and memory-associated genes  in 1984 who first hypothesized that epigenetic modifications in terms of DNA methylation could store the memory of previously experienced stimuli, an idea that was later followed up by the molecular biologist Robin Holliday  and increased CTCF-mediated long-range interactions  refined measurement; (2) functional validation; (3) integrated computational modeling.We refer to refined measurement as the need to complement fundamental observations coming from large populations of individuals or multiple brain regions with tissue-specific and cell-type-specific analyses. A promising approach to achieve this resolution is the use of single-cell sequencing-based technologies, which enable us to capture multiple features of individual cells with high-throughput methods -Cas9 genetic variation has recently moved within experimental reach thanks to a technique that allows to edit—directly Last, advances in the field of computational neuroscience are already allowing to build incredibly detailed models of neuronal connections and functioning within and across different brain areas, and such programs are currently already underway on different continents. By gathering information on the anatomical structure, electrophysiological properties, spatial positions, and connections of neurons, several large-scale brain simulators have been developed and keep being refined. So far, these brain models can be employed to successfully mimic synaptically connected networks of hundreds, thousands, or even more neurons, but are still unable to predict sensory stimulations or human behaviors  levels of analysis and in integrative, holistic approaches reaching beyond the nucleus. Within an individual, the combination thereof is poised to lead to apprehension for the full complexity of the multi-leveled structure of brain functioning, or malfunctioning. Within a population, such a research approach will be able to single out individuals at risk or bay for neurodegenerative and neuropsychiatric conditions and thereby pave the way for more personalized treatment approaches. Most importantly, this research endeavor will not only foster our understanding of how our brain functions but ultimately also of who we are.DMC and JG wrote the article. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The remodeling of extracellular matrix (ECM) within the intestine tissues, which simultaneously involves an increased degradation of ECM components and excessive intestinal fibrosis, is a defining trait of the progression of inflammatory bowel diseases (IBDs), which include ulcerative colitis (UC) and Crohn’s disease (CD). The increased activity of proteases, especially matrix metalloproteinases (MMPs), leads to excessive degradation of the extracellular matrix and the release of protein and glycoprotein fragments, previously joined with the extracellular matrix, into the circulation. MMPs participate in regulating the functions of the epithelial barrier, the immunological response, and the process of wound healing or intestinal fibrosis. At a later stage of fibrosis during IBD, excessive formation and deposition of the matrix is observed. To assess changes in the extracellular matrix, quantitative measurement of the concentration in the blood of markers dependent on the activity of proteases, involved in the breakdown of extracellular matrix proteins as well as markers indicating the formation of a new ECM, has recently been proposed. This paper describes attempts to use the quantification of ECM components as markers to predict intestinal fibrosis and evaluate the healing process of the gut. The markers which reflect increased ECM degradation, together with the ones which show the process of creating a new matrix during IBD, allow the attainment of important information regarding the changes in the intestinal tissue, epithelial integrity and extracellular matrix remodeling. This paper contains evidence confirming that ECM remodeling is an integral part of directional cell signaling in the progression of IBD, and not only a basis for the ongoing processes. Inflammatory bowel diseases (IBD), including two main conditions: Crohn’s disease (CD) and ulcerative colitis (UC) are chronic and relapsing inflammatory diseases of the gastrointestinal tract, which have become a global healthcare burden in the 21st century. In CD, the inflammation may occur in any part of the gastrointestinal tract; however, it is usually located in the last region of the ileum and the colon, and the lesions usually stay next to healthy regions of the intestine [The extracellular matrix is a highly dynamic structure present in all tissues, which undergoes controlled remodeling. During this process, both quantitative and qualitative changes of its components take place in order to control homeostasis and tissue architecture . Matrix Metalloproteinases are a group of zinc-dependent endopeptidases, whose main function is remodeling extracellular matrix components. These enzymes are synthesized by fibroblasts and other types of connective tissues cells, as well as by leukocytes, monocytes, macrophages and endothelial cells, and then released into the extracellular space in an inactive form (proMMP). The enzyme is activated by proteolytic cleavage in the propeptide region. The activity of metalloproteinases is precisely regulated at the transcription and translation level, and by endogenous inhibitors, such as α2-macroglobulin and tissue inhibitors of metalloproteinases (TIMPs) ,5,6,7. IThe substrates for metalloproteinases are extracellular matrix proteins, including collagens, fibronectin, laminin, vitronectin or tenascin. The increased MMP activity in IBD patients promotes ECM degradation and causes an increase in the amount of its components released into circulation. In response to proinflammatory cytokines and interactions between cells—or between cells and the extracellular matrix—MMPs are regulated at the transcription level. The most investigated MMPs in IBD are collagenases , gelatinases , stromelysins , matrilysin MMP-7) and macrophage elastase MMP-12). The role of individual metalloproteinases in modulating the progression of IBD is summarized in  and macr. The rolcollagenases  plays an important role in IBD progression, and they only occur in inflamed tissues [A group of  tissues . MMP-1 p tissues ,15. MMP- tissues .In turn, the proinflammatory role of MMP-13 is due to its ability to activate endostatin and release TNF-α from the membranes, which affects the integrity of the intestinal epithelial barrier .Gelatinases  are responsible for most processes throughout IBD progression, including collagen breakdown, similar to collagenases. This action prevents intestinal fibrosis and neutrophil infiltration into the intestinal tissue. MMP-2 participates in remodeling of collagen structures [ructures . In IBD ructures . MMP-9 pructures ,14.Stromelysins (MMP-3 and MMP-10) play an important role in wound healing, as they cause ECM protein degradation, which allows the endothelial cells, epithelial cells and fibroblasts to detach and reconnect to the ECM in a controlled manner [d manner .They also facilitate cell migration through the damaged tissue, which promotes angiogenesis, re-epithelialization and granulation of wounds. Furthermore, MMP-3 causes the release of endostatin from collagen particles; it strongly inhibits the proliferation of endothelial cells, migration and angiogenesis . MMP-7 tDuring inflammation or healing processes within the intestine, an overexpression of a number of MMPs, undetectable in the healthy gut  is observed. It has been shown that increased MMP-1 expression can be seen in the mucous membrane of the colon in IBD patients and it correlates with an exacerbation of the inflammation ,20. The Apart from MMPs, the process of extracellular matrix remodeling throughout IBD also involves neutrophil elastases and meprins. Neutrophil elastase is a serine protease, produced mainly by neutrophil granulocytes. Its activity is higher during inflammation, which causes increased elastin degradation and promotes the inflammatory process even more. The third discussed group of enzymes—meprins—are zinc-dependent proteases necessary for the homeostasis of gut microbiome. They are responsible for the breakdown of ECM proteins, such as type IV collagen, laminin and nidogen. On one hand, proper intestinal tissue metabolism requires proper functioning of cells responsible for the synthesis of ECM components; on the other hand, it depends on the activity of specific proteases which degrade them. In a properly functioning tissue, the activity of preteolytic enzymes is subject to complex control processes. MMP expression and the balance between their levels and the levels of tissue metalloproteinases inhibitors is crucial for proper homeostasis of the extracellular matrix in intestinal tissues. Disturbing this balance may lead to intestinal fibrosis. Intestinal fibrosis is a common complication in patients with long-term IBD and interleukin-13 is a potent inducer of tissue fibrosis in IBD patients . VariousThe processes catalyzed by the enzymes which participate in rebuilding the ECM are irreversible, and the activity of enzymes has to be regulated at the level of transcription, translation, secretion, and activation; it is limited by metalloprotease inhibitors within the tissues. This introduces a higher level of control, mainly in the regulation of the immune system. The proteolysis of ECM and basal membrane proteins, which involves ECM proteases, makes it easier for immune cells to migrate up to the mucous membrane of the intestine ,25. The Research indicates that single nucleotide polymorphism (SNP) within the promoters of genes encoding metalloproteinases influences the expression of these enzymes and therefore the development of IBD ,36,37,38Researchers also bring attention to the MMP inhibitors that show therapeutic potential in the treatment of IBD. The tested inhibitors are expected to reduce the expression of MMPs and therefore positively affect the course of the disease ,39,40. FThe regulatory role in maintaining ECM integrity during IBDs is played by molecular mechanisms based on signaling pathways which involve hyaluronan (HA). Hyaluronan is an unbranched, unsulfated glycosaminoglycan, whose polymerization level reflects the integrity of the HA matrix; the presence of fragmented HA parts with a low molecular weight, on the other hand, reflects its degradation. HA participates in wound healing, proliferation and migration of cells and modulating the inflammatory process. This unsulfated GAG which does not form covalent bonds with proteins, can also bind water in its polysaccharide net, providing proper hydration to the matrix, which allows cell migration and substance diffusion. Hyaluronan actively participates in many diseases, including IBD, and its level increases in the inflamed regions. During excessive inflammation, these polymers are cleaved to fragments of lower molecular weight that take on signaling roles . The regAs an ECM component, hyaluronan has shown minimal adhesive properties towards leukocytes in proper conditions; throughout IBD, not only is there an increase in its synthesis, but it also forms complexes with trypsin inter-α inhibitor, which are highly adhesive towards leukocytes and exacerbate the inflammation.The deposition of hyaluronan fragments in the intestine is related to the inflammatory state during IBD ,42,43. CThus, the deposition of hyaluronan fragments and HA–HC matrix with strong adhesive properties induces the infiltration of leukocytes towards the intestinal lumen, which leads to the activation of an inflammatory response ,43. On tFurthermore, studies on mice and rats have shown that HA synthesis precedes the infiltration of inflammatory cells and therefore promotes inflammation. For this reason, controlling HA levels on the surface of cells may play a regulatory role during IBD . The chrThe role of hyaluronan in IBD pathophysiology is also related to the fact that it possesses the ability to regulate the function of intestinal epithelium, whose integrity is vital for preventing the formation of blood clots ,55,56,57It has also been shown that thrombin, which participates in the coagulation and is necessary for converting fibrinogen to fibrin, can also interact with HA–HC fragments . FurtherIn summary, hyaluronan participates in inducing and maintaining the inflammation, in the coagulation process, and in modulating the remission and activity of the disease. Inflammation and coagulation are two interconnected processes which reinforce and support each other, finally leading to the inhibition of damage progression. Molecules which mediate inflammation and clotting, such as HA, may contribute to both weakening and aggravating disease, depending on the structure. The HA–HC also supports the recruitment of inflammatory cells. A prolonged inflammation leads to impaired epithelial function, increased thrombus formation, tissue damage and an increased disease activity ,61,62,63laminin (LN) determined in the serum of IBD patients [In order to detect changes in the extracellular matrix in the course of IBD, attention was also paid to the potential diagnostic and/or prognostic utility of determining other components of the extracellular matrix in the blood. One of the new diagnostic markers is the concentration of patients ,69,70,71patients ,69,70.One of the most investigated ECM components of the intestinal tissues are also heparan sulfate proteoglycans (HSPG). It has been shown that HSPGs promote intestinal regeneration, which suggests that they play a role in the homeostasis of intestinal stem cells (ISCs). The HSPGs, whose presence has been noticed on the basal surface of epithelial cells and which play a vital role in maintaining proper functions of the intestinal barrier, include syndecans ,73,74. TOther proposed biomarkers of intestinal fibrosis include the level of extracellular matrix proteins in serum, including fibronectin. Fibronectin (FN) is an extracellular glycoprotein which binds with various matrix components . ThroughCharacteristic for inflammatory bowel diseases, the process of intensified and abnormal remodeling of ECM components is associated with an excessive and chronic inflammatory response in the intestinal tissue. In turn, the degree and depth of intestinal lesions can be assessed by quantifying the concentration of blood markers that have been released as a result of increased protease activity ,83 KeratSo far, there are no known markers which would allow diagnosis and differential diagnosis between UC and CD and possession of the required sensitivity and specificity. Extending the research on ECM may help to identify a component of the extracellular matrix that could supplement or even replace the currently used invasive, time-consuming and expensive colonoscopy and histopathological techniques. Research has shown that fecal MMP-9 concentration reflects the activity of bowel inflammation and mucosal healing in UC . The resOther research involved evaluating the potential diagnostic value of measuring TIMP levels, in tissue samples obtained from intestinal tissues, as markers of inflammation severity during IBD ,89,90,91Raised considerable interest can be observed in relation to glycosaminoglycan/proteoglycan-based diagnostic tools. The most important extracellular matrix component evaluated as a potential IBD biomarker is hyaluronan. This glycan, along with the enzymes and binding proteins responsible for its synthesis and degradation, may directly modulate the progression of the disease by controlling the recruitment of immune cells and releasing proinflammatory cytokines. Hyaluronan particles may therefore modulate both the progression and the remission of the disease. HA particles or the products of its degradation, which stimulate the expression of genes regulating the inflammatory processes, may be a marker of disease progression. Research has shown that the presence of HA–HC complexes may exacerbate the disease. Further research—aimed at evaluating disturbed interactions between immunological cells and HA–HC, direct blocking of the HA–HC matrix synthesis and a selective degradation of HA–HC in experimental models of colitis—are necessary for isolating the molecular paths which allow this polymer to regulate the inflammation and may lead to designating HA–HC a marker of inflammation in IBD ,47,53,54Inflammatory bowel disease leads to the degradation and fibrosis of tissues. Disturbed ECM remodeling during IBD is closely related to an increased activity of MMPs. This leads to excessive degradation of extracellular matrix components, the release of proteins and glycoproteins that build the extracellular matrix into the local tissue and the circulation. Additionally, ECM remodeling is a key mechanism that contributes to the development of IBD and is associated with the accumulation of HA fragments that enable wound healing and contribute to intestinal fibrosis. Any change involving the ECM affects cellular processes, and since ECM also acts as a reservoir for signaling molecules, such a change also induces signaling pathways, generating major switches in the regulation of immune system and other physiological processes. Further research into the molecular mechanisms underlying the remodeling and degradation of ECM would create the basis for the discovery of a component of ECM that would be useful both for the recognition of CD and UC, and for differential diagnosis.


Nowadays, the integration of Wireless Sensor Networks (WSN) and the Internet of Things (IoT) provides a great concern for the research community for enabling advanced services. An IoT network may comprise a large number of heterogeneous smart devices for gathering and forwarding huge data. Such diverse networks raise several research questions, such as processing, storage, and management of massive data. Furthermore, IoT devices have restricted constraints and expose to a variety of malicious network attacks. This paper presents a Secure Sensor Cloud Architecture (SASC) for IoT applications to improve network scalability with efficient data processing and security. The proposed architecture comprises two main phases. Firstly, network nodes are grouped using unsupervised machine learning and exploit weighted-based centroid vectors for the development of intelligent systems. Secondly, the proposed architecture makes the use of sensor-cloud infrastructure for boundless storage and consistent service delivery. Furthermore, the sensor-cloud infrastructure is protected against malicious nodes by using a mathematically unbreakable one-time pad (OTP) encryption scheme to provide data security. To evaluate the performance of the proposed architecture, different simulation experiments are conducted using Network Simulator (NS3). It has been observed through experimental results that the proposed architecture outperforms other state-of-the-art approaches in terms of network lifetime, packet drop ratio, energy consumption, and transmission overhead. In the last few years, wireless sensor networks (WSNs) gained a lot of research interest from the research community due to its dynamic nature and wide range of applications ,2. A WSNIn recent years, many solutions have been presented to improve the routing and energy efficiency for limited constraints networks, however, most of them overlooked data authentication and security in the presence of malicious nodes. The dynamic nature of Internet of Things (IoT) systems allow an enormous number of heterogeneous physical and virtual objects and are interconnected via the Internet ,13,14,15To transmit data packets towards the BS, the presented solution is categorized into chain based, tree-based, and cluster-based routing protocols. Chain and tree-based routing protocols forward data packets to the root node using the next-hop selection method usually based on distance factor. However, such methods have a high latency ratio and therefore they are not appropriate for large scale networks ,24,25. OThis article presents a secure sensor-cloud architecture for IoT based WSN to provide data security and easy to scale with efficient network performance. The proposed architecture’s scope is the deployment of IoT-based WSN in the environment of smart cities. Numerous IoT sensors, identified with unique tags, are distributed in a smart city scenario to sense, gather, and forward data via intermediate gateways or cluster heads towards the BS. The BS is further connected with the cloud server using wireless communication technologies, such as WIFI, 4G, 5G, etc. After receiving the data from gateways or cluster heads, the BS uploads the data related to smart cities on the cloud server via the Internet. The proposed architecture integrates the deployment of IoT-based WSN with cloud infrastructure, therefore, the technologies of smart cities communicate, transfer, and analyze important data to maintain the urban operations. Additionally, due to the limited constraints of IoT sensors, they may be disposed to failure that may slow down the data processing in smart cities. Moreover, malicious or compromised entities can lead to disruption in the data sensing and transmission, which results in critical information that may be lost. Such a situation degrades various operations and services for both the community and city infrastructure. Hence, the deployment of IoT-based WSN in the context of smart cities requires a more robust and secure communication solution to improve the functionalities of an urban area network. The proposed SASC architecture provides significant improvements over existing solutions in terms of higher level of data privacy, integrity, and robust authentication. Firstly, the SASC divides network nodes into various clusters based on dynamic pivotal positioning. The clustering of nodes allows a resourceful load distribution inside each cluster and improves network lifetime. Secondly, to cope with efficient data storage and processing capabilities under restricted constraint nodes, integrating WSNs with cloud infrastructure is adopted. In the end, the proposed SASC gives a secure and authentic algorithm for data protection and node validation in an insecure and unreliable communication environment. The proposed security algorithm requires the least computational time and space capabilities with ease to implement. The aforesaid contributions of the proposed SASC offer a remarkable impact on constraint devices under untrustworthiness and dynamic environment. Additionally, the proposed algorithm provides the node level authentication process to identify malicious nodes and to generate networks more consistent with efficient data delivery performance. The rest of the paper is organized as follows. Recently, smart devices called sensor nodes provided an opportunity to design and maintain the network architecture for information gathering and forwarding. Sensor nodes are mostly dispersed randomly in a self-configured mode for various applications such as fire detection, smart cities, smart home, healthcare, and agriculture ,34,35. SIn cloud computing ,42,43, eClustering solutions ,52,53 prIn , the autAuthors in  proposedIn , the autBased on the literature review, it is seen that sensor-cloud is used in various applications such as healthcare, military, smart cities and environmental and monitoring, etc. Due to the unreliable and dynamic infrastructure of such applications, energy efficiency, data security, and node-level authentication are the most demanding challenges. It is observed that most of the proposed solutions do not consider the limitations of low powered sensors while developing a sensor-cloud solution. Although some of the existing sensor-cloud solutions decrease the overhead of network nodes, they lack the optimal data aggregation and routing decision. On the other hand, the knowledge-based security models improve energy efficiency and network lifetime, but these solutions offer data reliability with the additional cost of computation and energy consumption on sensor nodes due to events initiation and management. Furthermore, most of the proposed sensor-cloud solutions do not focus on the measurement of data security and node-level authentication in the presence of malicious threats, which result in compromised network trustworthiness. Therefore, it is concluded from the aforesaid solutions that the sensor-cloud infrastructure is suitable for large-scale network regions to increase network scalability with the addition of proper data management. However, the constraints of low powered sensor nodes should be taken into consideration while developing a solution. Therefore, the main contribution of the proposed solution is to develop a secure and authentic sensor-cloud architecture for the improvement of data gathering and energy efficiency. Moreover, the proposed architecture offers lightweight cryptosystems to estimate data security in terms of confidentiality, integrity, and authentication. Besides, with the integration of cloud to sensor networks, the proposed architecture optimizes computational overheads on sensor nodes with minimum energy consumption.This section presents a brief introduction of the proposed secure sensor cloud architecture of IoT based on WSNs. The detail of its algorithms is to be argued in the subsequent subsections. In the first algorithm, network nodes are divided into centroid-based regions and various clusters are represented based on the nodes locality. Unlike other solutions that compute centroid values for the consideration of position factor, our proposed algorithm makes use of both distance and energy factors in weighted means to determine the centroid vectors. Accordingly, quantifiable analysis is being exploited based on the network status. Afterward, the generated clusters are self-organized by using computed centroid vectors and an appropriate cluster head is selected within each cluster to gather and forward sensors’ data towards the BS. In the second algorithm, the sensed data is stored on cloud infrastructure for further processing and retrieving purposes, which results in decreased computational overhead and improved network lifetime. Furthermore, to secure sensors’ data that is stored on cloud infrastructure against malicious threats, the proposed algorithm gives a lightweight security scheme based on the OTP mechanism. The proposed security scheme exploits exclusive-OR (XOR) bitwise operation by the integration of both data bits and random secret keys. The random secret keys are made using a pseudorandom number generator (PRNG) algorithm ,64, whicIn the beginning, the initiation component is executed to construct the neighborhood tables and the adjustment of initial routing paths. The BS floods its identity (ID) and location Basically, in mathematical and engineering applications, the centroid is an arithmetic mean position of the points in a given space S. Unlike other solutions, the proposed SASC makes use of both energy and distance factors to compute the centroid vector. In traditional solutions, the position and weight of nodes do not change during network operations. Thus, the computation of centroids only in the use of position factor is useless. Hence, in robust and dynamic environments, SASC incorporates an energy aspect of nodes along with their distance information in a weighted manner to compute the function In Equation (1), the contribution of both weighting parameters, i.e., α and β, must be equal to 100% such that α + β = 1. In practice, the BS is a more powerful node and has no constraints in terms of resources as compared to other sensor nodes. Based on the position of nodes, the BS computes k number of centroids .For authenticating the cluster heads . Upon receiving the encrypted data, the cloud server first decrypts the data using its private key Moreover, the private-public key is the combination of well-defined security techniques and offers prevention from impersonation attacks. Both the public and private keys are mathematically related but not the same and provide robust authentication against impersonation attacks. Furthermore, only the public key is globally known via a publicly accessible directory while the private key is to keep secret. The robust authentication of the cluster heads is performed by the BS, which separates the original data In this section, the performance of the proposed SASC architecture is evaluated and compared with secure and authentication protocols, i.e., SEER and SecLEACH. The proposed SASC offers an energy-efficient and data gathering for traditional applications, e.g., WSN, and also presents various kinds of intelligence and secure data routing through IoT sensors. In the simulation setup, we deploy randomly 100 to 500 sensors in the squared sized observing area. The number of malicious nodes is fixed to 10 and dispersed randomly. The malicious nodes broadcast the false route reactions and forwarded the data packets towards unauthorized nodes or can drop the data packets. Public keys are generally known to all sensors via a publicly accessible directory that is made on the cloud server, however, private keys do not need to distribute and therefore they cannot be compromised. All nodes except the BS are limited constraints in terms of memory, storage, processing, and battery power. The transmission power of all the nodes is fixed to 20 m. In the beginning, all nodes have a uniform energy resource of 5J. The numerical results of the proposed SASC architecture are measured against other algorithms in terms of network lifetime, packet drop ratio, energy consumption, average end to end delay, and transmission overhead. This section provides results of the proposed scheme in comparison with other two popular methods, i.e., secure and authentication protocol, SEER and SecLEACH, concerning network lifetime, packet drop ratio, energy consumption, end-to-end delay, and transmission overhead.In this section, the numerical results of the proposed SASC architecture with other solutions perform in terms of network lifetime. This section presents the analysis of the packet drop ratio between SASC and other existing solutions. In This paper presents a secure and authentic sensor cloud architecture, named SASC, for intelligent IoT system, which aims to guarantee data routing through secure and reliable communication links. The proposed solution offers lightweight cryptosystems to enhance security in terms of data confidentiality, integrity, and robust authentication between IoT sensors under the presence of malicious entities. The SASC architecture guides sensor nodes to send data packets on trustworthiness and authentic data forwarders while balancing the energy consumption over the network field. Additionally, integrating the cloud infrastructure to sensor networks, the proposed solution offers high quality and cost-effective communication services for IoT systems with minimal overhead. Furthermore, the SASC handles and processes all sensed data with the support of network scalability and integrity. The numerical results of SASC architecture reveal significant improvements in different network parameters as compared to other solutions. However, the proposed architecture still lacks for meeting the robust and security requirements for multi-hop communications. Furthermore, non-repudiation and playback network attacks are overlooked in the proposed SASC architecture. Therefore, we aim to improve the performance of the proposed architecture by analyzing some more misbehaving threats among cluster heads and generate an efficient and trusted end-to-end routing delivery for longer communication regions.


The reasons for the development of diseases in the transition period of dairy cows are manifold and highly farm- and cow-specific. Nevertheless, links exist between the degree of negative energy balance (NEB) and disease susceptibility, which suggest a mutual adverse relationship between immune and productive functions. Glucose is the most essential fuel and precursor for both immune cells and mammary epithelial cells (MEC). While the delivery of glucose by the intermediary metabolism is not always able to keep up with whole-body demands, trade-offs between mammary and immune cells emerge. The prioritization of mammary supply during early lactation is a physiologic principle in all mammals. In contrast, tremendous increases in milk yield and the specific demand for glucose in high-yielding dairy cows resulting from decades of selection for milk production override the evolutionary principles of nutrient partitioning. Therefore, high-producing dairy cows face an increased risk of glucose shortages in their immune cells, particularly during early lactation.Immune cell functions such as phagocytosis and synthesis of immunometabolites, as well as immune cell survival, proliferation and differentiation, largely depend on an adequate availability of glucose by immune cells. During inflammation, the glucose demands of the immune system may increase to amounts similar to those required for high milk yields. Similar metabolic pathways are involved in the adaptation to both lactation and inflammation, including changes in the somatotropic axis and glucocorticoid response, as well as adipokine and cytokine release. They affect (i) cell growth, proliferation and activation, which determines the metabolic activity and thus the glucose demand of the respective cells; (ii) the overall availability of glucose through intake, mobilization and gluconeogenesis; and (iii) glucose uptake and utilization by different tissues. Metabolic adaptation to inflammation and milk synthesis is interconnected. An increased demand of one life function has an impact on the supply and utilization of glucose by competing life functions, including glucose receptor expression, blood flow and oxidation characteristics. In cows with high genetic merits for milk production, changes in the somatotropic axis affecting carbohydrate and lipid metabolism as well as immune functions are profound. The ability to cut down milk synthesis during periods when whole-body demand exceeds the supply is limited. Excessive mobilization and allocation of glucose to the mammary gland are likely to contribute considerably to peripartal immune dysfunction. Animal welfare concerns, as well as the economic implications of the high prevalence of production diseases ,2,3 and After parturition, high-producing dairy cows generally enter a negative energy balance (NEB), because their level of dry matter intake (DMI) does not meet the demands imposed by the onset of milk production . Consequ+) through pentose phosphate pathway as well as the production of ATP, which are required for the synthetic processes depend on the availability of glucose. During peak lactation, mammary epithelial cells (MEC) are able to retrieve up to 2.7 kg of glucose per day from the plasma pool at a milk level of 40 kg [In dairy cows, the amount of glucose required to fuel milk production outreaches by far energy expenditures of other life functions like reproduction or maintenance . Besidesof 40 kg . On the of 40 kg . Recent of 40 kg . In otheof 40 kg . These cAccording to the resource allocation theory , resourcAs for the relationship between productive and other life functions in dairy cows it was hypothesized that cows with high genetic merit for milk production cover their demand by an increase in feed intake, while cows with low genetic merit—if they do consume more feed—accumulate body reserves . ConsequBecause most organs and tissues lack autonomy to control their nutrient access, the organism needs prioritization rules that coordinate nutrient partitioning between different life functions in all situations where demand exceeds supply. In this regard, different concepts of regulation have been established and adapted to dairy cow physiology. In the concept of homeorhesis, nutrient partitioning is described as a function of biological needs that alternates cyclically between storing and mobilization of energy from body tissues and the associated prioritization of reproductive and productive functions . FollowiHowever, environmental and nutritional stressors associated with varying quality and quantity of feedstuffs, social stress, climate variability and extremes, poor hygiene, technical failure, etc. also affect supply and demand of nutrients independent of the physiological state ,36. In tThe concept of allostasis goes beyond the concepts of homeostasis and homeorhesis by assuming dynamic set points emerging from the integration of both the requirements of different tissues at different physiological states and current nutritional, social and housing conditions . In dairProinflammatory signaling promotes similar metabolic adaptations, as does the lactational “reprogramming” with the aim of maximizing glucose availability to the respective cell types . These cMorphological changes required for mammary growth, morphogenesis, and milk synthesis are created during gestation, with ductal elongation and lobulo-alveolar development being mediated through high plasma concentration of prolactin, growth hormone (GH) and gonadotropic steroids progesterone and estrogen before parturition ,43. SubsTo meet the sudden increase in demand during early lactation, further alterations in the endocrine setup support dairy cows to metabolically adapt to lactation. Besides the above-mentioned hormones, insulin, thyroid hormones, glucocorticoids and the gonadotropic axis are main effectors of the new catabolic physiology and plasma concentrations of these hormones typically fluctuate at the transition from a pregnant to a lactating physiology . EspeciaInsulin signaling is particularly essential for a successful adaptation to lactation by affecting the rate of lipolysis, the rate of uptake and transport of glucose and fatty acids to different tissues, and the expression of key enzymes at the metabolic crossroads of glucose and fatty acid metabolism ,53. A maMoreover, allocation patterns that regulate the flow of nutrients between different tissues within the organism change according to the new dominant physiological state of lactation. Again, these changes are related to the ‘uncoupled’ somatotropic axis and in particular, to the phenomenon of reduced insulin sensitivity in peripheral tissues of postpartum dairy cows ,63,64,65In peripheral tissues, modest reductions ,75 or noIn summary, a complex endocrine network develops to increase glucose availability to the mammary gland. If precursor supply or hepatic synthetic capacity are inadequate, the sudden increase in mammary demand for glucose at the onset of lactation is the main driver of the hypermetabolic reaction that affects a variety of metabolic pathways, tissues and organs within the organism.Immune cell activity and inflammation are not only essential for pathogen elimination but are part of the coordinated reaction of the organism to all kinds of stressors, including infective and non-infective, metabolic and environmental stressors. After parturition, dairy cows experience an inflammatory-like status, which is systemically linked to the inherent stress of parturition, social and nutritional changes and the endotoxin-releasing processes of ruminal adaptation and uterine tissue reorganization ,78. The Whatever the origin of inflammation, the accumulation of proinflammatory processes implies a supply with energy that adequately meets the requirements of immune response. Qualitatively, the costs of immune activation include (1) a general elevation of metabolic rates due to a rise in body temperature, (2) reduced nutrient availability following anorexic effects of proinflammatory signaling, (3) the precursors and energy needed to fuel the synthesis of acute-phase proteins and immunoglobulins, (4) altered priorities for nutrient utilization in other tissues, (5) the costs associated with the repair of damaged tissues and (6) increased turnover rates of the leukocyte pool . AlthougIn fact, cells of the innate and adaptive immunity rely largely on the uptake of glucose and the storage of glycogen, because glucose supports proliferation, survival and differentiation as well as essential functions like phagocytosis and ROS production . MoreoveNot surprisingly, leukocytes trigger a number of metabolic pathways that increase the glucose supply to these cells while reducing consumption of glucose by other tissues. First references describing the link between inflammation and insulins actions date far back . By now All mammals favor the supply of nutrients to the mammary gland during early lactation. In contrast, the increases in milk yield and the specific demand for glucose required for high milk yields override evolutionary principles of nutrient partitioning . BecauseThe phenomenon of reduced immune cell competence is well established in peripartal dairy cows. It is broadly characterized by a dysfunction of PMN, macrophages and lymphocytes, including an impairment of viability, survival, phagocytosis and respiratory burst capacity . StudyinThe aforementioned relationships suggest that the substantial but transient suppression of immune functions before parturition is related to the physiological adaptation to lactation. However, not only cell number and proliferation, but also functionality of immune cells is impaired strongest when MEC start the abundant synthetic activity of lactogenesis as was demonstrated by the transient loss of expression of vascular factors and antimicrobial chemokines ,113,114.Accordingly, cows with severe NEB have a reduced ability to clear uterine infection postpartum. The active uterine inflammatory response in these cows was associated with impaired local insulin-receptor signaling . In the Nevertheless, experimentally induced negative energy balance in advanced lactation was repeatedly shown to be unable to cause alterations of inflammation and immune cell function that are as severe as those occurring during early lactation ,130,131.As addressed previously, the usefulness of plasma glucose as an indicator of a cow’s metabolic status is unsure due to the tight regulation of glucose homeostasis . HoweverGenerally, dietary energy supply affects glucose oxidation and transport in leukocytes in ruminants ,135 and Decreases in lactose yield as well as decreases in the mRNA-abundance of the ALA-subunit of lactose synthase were reported in hypoglycemic cows ,141. Sim4 cfu of diluted E. coli per quarter or 1000 µg LPS [In fact, high-producing dairy cows were shown to be unable to reduce milk synthesis during early lactation in particular, while being able to reduce milk synthesis during induced energy deficiency at 100 days in milk, even if induced NEB was more severe compared to early-lactation NEB . Accordi0 µg LPS  decrease0 µg LPS . Daily s0 µg LPS . Osmotic0 µg LPS .Further evidence for an antagonistic, yet dysbalanced relationship between metabolic pathways involved in adaptation to lactation and adaptation to inflammation is derived from studies examining the effect of the characteristic endocrine alterations required for high milk yields. Compared to low or medium genetic merit cows, high genetic merit cows show lower plasma concentrations of glucose, insulin and IGF-1, as well as higher plasma concentrations of GH ,152, whiThe management of high-producing dairy cows should aim for a maximal reduction in metabolic and environmental stress to reduce the energy demand of regulatory systems. Although the specific demand of an activated immune system is difficult to assess, tendencies may be estimated from plasma levels of inflammatory markers, as it has been recently suggested by Trevisi and Minuti . MoreoveFurthermore, dry off feeding and heifer management should be optimized, as it was repeatedly shown that nutrition during these life stages affects availability and allocation of nutrients during early lactation . For insNEB is commonly thought to identify metabolically instable situations associated with increased risk of disease in dairy cows. However, overall energy balance disregards the reliance of immune cells on glucose as their essential metabolite and synthetic precursor. Although both proinflammatory signaling and lactational reprogramming promote several similar metabolic pathways with the aim of maximizing glucose availability to the respective cell types (lactocytes or leukocytes), adaptation to lactation clearly shifts nutrient partitioning to the favor of the mammary gland. Adaptations are mediated primarily by hormones of the somatotropic axis and affect both mobilization and allocation, including specific regulation of blood flow and receptor expression patterns in peripheral, mammary and immune tissues. Additionally, decades of performance-oriented selection of dairy cows enhanced these patterns substantially by increasing the amount of mammary epithelial cells as well as the metabolic and endocrine setup required to support the demand of these cells. Due to the central role of glucose for milk production and immune cell function, glucose balance is especially submitted to competitive allocation dynamics and is at risk of being overstressed in the early postpartum, high-producing dairy cow, as indicated by reduced responsiveness of lactose synthesis and milk yield to energy or glucose restriction, or other stressors. Therefore, we hypothesize that the uncoupling of the somatotropic axis in cows with high genetic merit for milk production implies, at least in part, an uncoupling of the mammary gland from life function trade-offs. To address possible impacts of glucose shortage on the immune defense, research should focus on the dynamics of glucose supply and demand of immune cells in high producing dairy cows during different periods of lactation.


Sprouted grains are widely appreciated food ingredients due to their improved, nutritional, functional, organoleptic and textural properties compared with non-germinated grains. In recent years, sprouting has been explored as a promising green food engineering strategy to improve the nutritional value of grains and the formation of secondary metabolites with potential application in the functional foods, nutraceutical, pharmaceutical and cosmetic markets. However, little attention has been paid to the impact of sprouting on the chemical composition, safety aspects, techno-functional and chemopreventive properties of sprouted seeds and their derived flours and by-products. The six articles included in this Special Issue provide insightful findings on the most recent advances regarding new applications of sprouted seeds or products derived thereof, evaluations of the nutritional value and phytochemical composition of sprouts during production or storage and explorations of their microbiological, bioactive and techno-functional properties. Sprouted grains, usually designated as a seed with a visible radicle, have been used as food ingredients for many years, based on the general belief they provide significant nutritional, flavor, and textural benefits over non-germinated seed counterparts. In recent years, sprouting has been explored as a promising green food engineering strategy to improve the nutritional value of grains as well as to synthesize secondary metabolites with potential applications in the functional foods, nutraceutical, pharmaceutical and cosmetic markets. In this context, the industry has increasingly launched products containing or made of sprouted seeds. During seed sprouting, a multitude of changes occur, moving from molecular to macroscopic structures. Sprouting reactivates seed metabolism leading to the catabolism and degradation of macronutrients and antinutritional compounds and the biosynthesis of secondary metabolites with potential health benefits. These changes impact the nutritional value and health-promoting potential of the edible seeds. Many researchers around the world have proposed successful strategies such as elicitation to find the optimal environmental conditions during sprout growth able to promote the desired outcomes.This Special Issue includes six outstanding papers describing examples of the most recent advances in new applications of sprouted seeds or products derived thereof, evaluations of the nutritional value, phytochemical composition and microbiological quality of sprouts during production or storage and explorations of their bioactive and techno-functional properties.® application in order to ensure the microbial safety of lentils sprouts without affecting the germination rate and sprout length. Rebollo-Herran et al. [2+, Mn2+, Fe3+) and/or inhibitors  revealed to be an effective method to decrease the activity of polyphenol oxidase isoenzymes and to prevent enzymatic browning of lentil sprouts during storage and processing.The Special Issue gathers a group of three papers exploring the biochemical composition, nutritional and bioactive properties as well as microbial safety of sprouts obtained from lentil seeds. In this frame, Santos et al.  conducten et al.  focused n et al.  isolatedThe Special Issue follows with a short series of articles describing the influence of sprouting on the chemical composition, bioactive and techno-functional properties of cereal flours and milling by-products. In this context, the study of Rico et al.  describeAnother study conducted by Damazo-Lima et al.  reportedTo conclude, the present Special Issue consists of six papers addressing recent advances on the nutritional, bioactive, techno-functional and safety aspects of sprouted grains and their derived flours and by-products, providing insightful information for both the food industry and consumers.


In the context of this comparison, we consider three challenges that must be addressed in the engineering of myocardial tissue: recapitulation of myocardial architecture, vascularization of the tissue, and modulation of the immune system. In addition to reviewing and analyzing current progress, we recommend specific strategies for the generation of tissue engineered myocardial patches for heart regeneration and repair.Heart disease is the leading cause of death in the United States among both adults and infants. In adults, 5-year survival after a heart attack is <60%, and congenital heart defects are the top killer of liveborn infants. Problematically, the regenerative capacity of the heart is extremely limited, even in newborns. Furthermore, suitable donor hearts for transplant cannot meet the demand and require recipients to use immunosuppressants for life. Tissue engineered myocardium has the potential to replace dead or fibrotic heart tissue in adults and could also be used to permanently repair congenital heart defects in infants. In addition, engineering functional myocardium could facilitate the development of a whole bioartificial heart. Here, we review and compare  Heart disease is the leading cause of death in the United States . Each yeThe architecture of tissue—the composition and arrangement of its ECM and various cell types—is critically important to the function of all tissue types. As a whole, the heart is designed as an elegant and intricate system of valves, conduits, and pumping chambers that drives blood circulation throughout the body. The muscular heart walls are composed of a thick myocardial layer sandwiched between two single-cell layers called the endocardium (blood-contacting surface) and the epicardium (outer layer of heart). Both the epicardium and endocardium are essential for proper myocardial development, growth, and remodeling , 8. In tIn addition to cardiomyocytes, the myocardium is innervated, heavily vascularized, and populated by resident macrophages and cardiac fibroblasts  19, 20), 2019, 2in situ tissue engineering approach aims to provide a remodelable scaffold and to harness the natural healing response  to achieve native tissue architecture and function , however the regenerative potential of the heart is notoriously limited. Thus, far, no combination of signaling factors and/or ECM components has been shown to drive significant myocardial regeneration. Therefore, a scaffold alone, even if loaded with signaling factors, is unlikely to drive sufficient cardiomyocyte proliferation and migration necessary for total regeneration.In engineering this complex myocardial tissue, the necessary degree of architectural recapitulation is unknown. The function . Numeroufunction –30. In afunction –36. The in vitro tissue engineering approach seeks to create living heart tissue prior to implant by combining a scaffold with cardiomyocytes  of cardiac fibroblasts derived from these two cell layers.Homogenous co-culture of iPSC-CM with other cell types yields clear benefits, but none of these patch designs have sought to recapitulate the trilayer organization  of heart muscle despite the critical signaling roles that these cell layers play on cardiac fibroblast behavior, cardiomyocyte proliferation, and tissue organization. This is likely due to the longstanding difficulty of attaining endocardial and epicardial cells. However, the increasing number of protocols for the differentiation of iPSC-derived endocardial  and epicin vitro tissues. While electrical and mechanical conditioning can also drive iPSC-CM maturation, 3D co-culture with endothelial cells (EC) and stromal cells appears vital in maximizing the functional maturity of iPSC-CM. Early attempts at vascularized cardiac tissues showed that in porous polymer scaffolds, EC combined with embryonic fibroblasts formed networks that did not disrupt the contractility of embryonic stem cell-derived cardiomyocytes. Additionally, the presence of EC increased the proliferation of immature cardiomyocytes and increased the maturation of non-dividing cardiomyocytes  and CX3CL1 [chemokine (C-X3-C motif) ligand 1] cytokines and their associated receptors, CCR2 and CX3CR1 . FollowiHowever, the infiltration of inflammatory cells is not always an adverse response, and in fact may be leveraged to enhance tissue-engineering strategies. The majority of research into this space has been tested using direct injection of cells into infract zones. It was originally believed cell therapy acts via integration of seeded cells, though it is now thought to act through paracrine signaling and recruitment of autologous cells . The infin situ or in vitro approach, must consider the pre-existing inflamed status of ischemic myocardium as it may alter the regenerative outcome of the implanted biomaterial.While much of the work in modulating the inflammatory response has focused on injectable approaches, the inflammatory response is equally important in the context of TEMPs. The structure, pore size, material composition, and surface topology of scaffold materials affect the host inflammatory response by modulating cell recruitment, infiltration, and activation . The souin situ (acellular) tissue engineering strategy would require a suturable, biodegradable scaffold loaded with angiogenic and immunomodulatory signaling factors that encourage both angiogenesis and a healing immune response. However, given the extremely low proliferation rate of cardiomyocytes, we believe that an in vitro (cellularized) tissue engineering approach is the most promising. We think that such a TEMP requires at minimum a biodegradable scaffold seeded with either (1) a low density of proliferative iPSC-CM, cardiac fibroblasts, and EC (that can survive by simple media/blood diffusion prior to the development of a proper vasculature) or (2) a high, more-physiologic density of these cell types in a scaffold that includes engineered vascular channels that can provide perfusion in vitro and rapid anastomosis in vivo. Recapitulation of cardiac innervation in engineered patches could be necessary for complete patch integration in vivo, however action potentials in the myocardium are primarily transmitted through the cardiomyocyte syncytium (The prevalence of heart disease throughout the human population and the limited supply of donor hearts has created a need for TEMPs that could be used to regenerate myocardial infarct regions or in reconstructive surgeries in CHD patients. We think that an yncytium . Therefoin vitro TEMP, we postulate that a more complex TEMP that also recapitulates the endocardium and epicardium is the most promising approach for heart regeneration. With any of these strategies, the rate of TEMP integration in the host heart needs to exceed the degradation rate of the scaffold to prevent patch rupture during remodeling. In addition, the scaffold and its degradation products need to be tolerated by the host immune system but should also be considered an immunomodulatory tool that can be leveraged for improved healing and integration. Maintaining the viability of implanted iPSC-cardiomyocytes also remains a challenge that must be addressed prior to clinical translation. The inclusion of an endocardium in the patch, optimizing the maturation level of the cardiomyocytes, and modulating the host immune response are all potential strategies for increasing iPSC-CM viability and electrical integration after implantation.In addition to these minimum requirements of an Tissue engineered myocardium represents an important step toward the cure of heart disease and would also be a significant milestone as the field moves toward the eventual engineering of a whole bioartificial heart. Furthermore, the considerations, challenges, and advancements reviewed herein are translatable to many different tissue engineering endeavors, but especially to other cardiovascular applications including tissue engineered heart valves and large vessels.in vitro and in situ. MV was the lead author on section Harnessing the Immune System in Cardiac Tissue Engineering. All authors contributed to the article and approved the submitted version.DJ, EV, MV, and JJ contributed equally to conceptualization of the work. DJ was responsible for manuscript organization, figure development, and primary authorship. EV was the lead author on section Vascularization of Cardiac Patches The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Serosurvey results for Crimean-Congo hemorrhagic fever virus antibodies in dromedary camels in Algeria indicate that the pathogen is circulating endemically in desertic areas, despite the hostile environment. Thus, dromedaries are suitable sentinels for detecting human risk for Crimean-Congo hemorrhagic fever in desertic areas. Orthonairovirus that causes a potentially fatal hemorrhagic systemic disease in humans, Crimean-Congo hemorrhagic fever (CCHF). The virus is sustained in the ecosystem through wild and domestic animals, which act as tick amplification hosts and are asymptomatic (Crimean Congo hemorrhagic fever virus (CCHFV) is a tickborne Camelus dromedarius) has increased . We obtained data on risk factors associated with the individual animals  and management  and evaluated their effect on CCHFV seropositivity with a mixed-effect logistic regression model with herd as a random effect, using R software . We also collected data with regard to patterns of movements  for grazing. To evaluate the characteristics of the environment in which the dromedaries were reared, we created a buffer area around each herd , and obtained the features of the land cover : Biskra, El Oued, Touggourt, and Ouaregla. We tested samples for CCHFV antibodies by using a commercial kit , and herd-level seroprevalence was 95.7%  . Odds of,<1 year of age were seropositive indicates intense recent CCHFV circulation in the area. Traditional and semitraditional breeding systems increased the likelihood of CCHFV seropositivity because of the increased probability of exposure to CCHFV-infected ticks. Traditionally, dromedaries have been reared in constant movement across large pastoral areas in the Sahara desert, but nomadism is being replaced by transhumance , especially in the northeastern Saharan region of Algeria  was similar to that reported in other countries of North Africa (.Attempts to map the distribution of CCHF risk have indicated that the areas at risk in Africa were basically restricted to the sub-Saharan region, where CCHF was associated with the presence of shrub or grassland (