RNA-binding proteins (RBPs) are a class of proteins known for their diverse roles in RNA biogenesis, from regulating transcriptional processes in the nucleus to facilitating translation in the cytoplasm. With higher demand for RNA metabolism in the nervous system, RBP misregulation has been linked to a wide range of neurological and neurodegenerative diseases. One of the emerging RBPs implicated in neuronal function and neurodegeneration is splicing factor proline- and glutamine-rich (SFPQ). SFPQ is a ubiquitous and abundant RBP that plays multiple regulatory roles in the nucleus such as paraspeckle formation, DNA damage repair, and various transcriptional regulation processes. An increasing number of studies have demonstrated the nuclear and also cytoplasmic roles of SFPQ in neurons, particularly in post-transcriptional regulation and RNA granule formation. Not surprisingly, the misregulation of SFPQ has been linked to pathological features shown by other neurodegenerative disease-associated RBPs such as aberrant RNA splicing, cytoplasmic mislocalization, and aggregation. In this review, we discuss recent findings on the roles of SFPQ with a particular focus on those in neuronal development and homeostasis as well as its implications in neurodegenerative diseases. Near identical DNA is present in every cell of an individual organism, yet it is the presence of protein factors and regulatory RNAs in transcriptional and post-transcriptional processing that are vital for producing the temporal and spatial cellular diversity observed . There aDrosophila behavior/human splicing (DBHS) protein family, a highly conserved group of nuclear proteins exclusively found in the animal kingdom . T. TMapt g protein  [53].sfpq mutant embryos while no loss of motoneurons was observed in the brain or in the spinal cord, indicating that SFPQ has specific roles in the differentiation of certain neuronal cell types [From a broader perspective, an earlier study of neurogenesis in zebrafish found that SFPQ is important for the survival and differentiation of neuronal cells . Zebrafill types .sfpq was discovered which was rescued by microinjecting human sfpq mRNA [Although SFPQ is found primarily in the nucleus, a small subset of the total cellular pool of SFPQ has been observed in the cytoplasm of motor axons and shown to drive axon maturation and connectivity . Using afpq mRNA . The autIn another study, colocalization of SFPQ/NONO with another abundant RBP, HERMES , and the stress granule component G3BP1 were observed when neuronal differentiation was induced in retinal ganglion cells, resulting in the formation of cytoplasmic neuronal granules . Colocallaminb2 and bclw in dorsal root ganglion sensory neurons to support axon survival [laminb2 and bclw mRNA from the nucleus to the axon by RNA transport granules. LaminB2 and Bclw proteins are then translated for the use of maintaining axonal survival and functions. When SFPQ was knocked down, the protein expression level of LaminB2 and Bclw in the axon decreased, leading to axon degeneration. This indicates the function of SFPQ in regulating the level of laminb2 and bclw mRNA in the axon for translation and in turn, supporting axonal survival [Similarly, SFPQ was also found to interact and guide multiple axonal mRNAs such as survival . It has survival .More recently, it has been demonstrated that a complex containing RNA and SFPQ directly interacts with a tetrameric kinesin complex containing the motor, KIF5A, and the adaptor, KLC1 , furtherCollectively, these data strongly indicate that SFPQ plays important roles in the nucleus and axon of neurons, and that the balance in the nucleocytoplasmic distribution of SFPQ is critical for the development and maintenance of neuronal integrity and function.Not surprisingly, due to the emerging physiological roles of SFPQ in neuronal development and homeostasis as described above, an increasing number of recent literature has demonstrated the implications of SFPQ in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) frontotemporal lobar degeneration (FTLD), and Alzheimer’s disease (AD) ,62,63,64The cytoplasmic mislocalization and aggregation of RBPs have been emerging as new hallmarks of neurodegenerative diseases ,4,69. ThThe molecular mechanisms by which the nuclear pool of SFPQ is mislocalized to the cytoplasm and forms aggregates remain to be defined. However, several lines of evidence suggest that aberrant interactions of SFPQ with other misregulated or mutated proteins cause these pathological features. Interestingly, most of these proteins are neurodegenerative disease-implicated proteins such as tau, TDP-43, and FUS. Overexpression of pathological tau mutant (P301L) previously identified in familial cases of FTLD promotes cytoplasmic accumulation and aggregation of SFPQ . The famAltered zinc homeostasis has also been proposed as a potential mechanism of the cytoplasmic accumulation and aggregation of SFPQ . AlteredAlthough whether loss of the nuclear pool of SFPQ is a cause or merely an effect of the progression of the diseases is yet to be defined, given the predominant presence of SFPQ in the nucleus and the important nuclear roles of SFPQ in many aspects of RNA biogenesis and the maintenance of genome stability, imbalance in the nucleocytoplasmic distribution of SFPQ is likely to contribute to the onset and/or progression of the diseases by loss-of-function mechanisms . In addition, SFPQ was shown to bind extensively to its retained intron, which leads to nuclear loss and cytoplasmic accumulation of SFPQ. These data led to the proposal that intron retention of the sfpq transcript and nuclear loss of SFPQ are general molecular hallmarks of familial and sporadic ALS [sfpq transcript, which promotes the mislocalization of FUS to the cytoplasm [sfpq transcripts and the interaction of SFPQ and FUS with the retained intron was proposed as an underlying mechanism of mislocalization of SFPQ and FUS in ALS [Interestingly, aberrant RNA splicing of the d in ALS ,75. Abnoadic ALS . In a foS in ALS ,75.Stress granules are another type of membraneless organelles governed by liquid–liquid phase separation . Stress Many lines of evidence point to cytoplasmic accumulation of SFPQ as an emerging hallmark of neurodegenerative diseases. As mentioned previously, nucleus-to-cytoplasmic redistribution of SFPQ is most likely to cause loss of nuclear function. Whether the cytoplasmic aggregates of SFPQ found in the neurodegenerative diseases confer gain-of-function in the form of cytotoxicity is an intriguing possibility.Recent findings on the role of SFPQ and its implications in neurodegenerative diseases are reminiscent of TDP-43 in many ways. Both SFPQ and TDP-43 are RNA- and DNA-binding proteins and play multiple roles in RNA biogenesis and the maintenance of genome stability. A recent finding on the involvement of TDP-43 in DNA damage repair  further The role of SFPQ, in concert with FUS, in maintaining the isoform ratio of tau, a primary component of neurofibrillary tangles in the neurodegenerative diseases, further interweaves the intricate network of SFPQ with other neurodegenerative disease-linked RBPs. However, the precise molecular mechanisms that coordinate these complicated networks spatially and temporally are yet to be elucidated. Thus, further understanding of the precise mechanisms underpinning the interactions of SFPQ and other RBPs may also reveal the molecular mechanisms underlying the onset and progression of neurodegenerative diseases. Pathological protein aggregation manifested as neurofibrillary “tangles” is a hallmark of a number of neurodegenerative diseases including ALS and AD. SFPQ, as presented in this review, participates in the intricate network with many other known neurodegenerative disease-linked RBPs and tau. Given the complex regulatory roles of SFPQ through interactions with a wide array of interaction partners including DNA, RNA, and proteins, finding ways to “untangle” these interactions and navigate through the intricate regulatory network of SFPQ may present future diagnostic and/or therapeutic avenues for neurogenerative diseases.


This article explains the time-series data for sensitivity of water-energy nexus to Dez Dam operation located at Dez basin in the southeast of Iran for a period of 54 years (648 months) from October 1964 to September 2018. The utilized data included outflow of the turbine, reservoir inflow, reservoir volume, evaporation, precipitation, spillway, total outflow of the reservoir, elevation, power generation and demand. In this article, operation of Dez Dam is examined for 54 hydrologic years (1964–2018), considering reducing the full supply level (FSL) gradually from its current value to the minimum possible value, increasing the minimum operating level (MOL) gradually to the maximum possible level and operating the Dam at a constant operating level (COL). Also, the concept of water-energy productivity (WEP), defined as the amount of energy produced per unit of water lost in the process, is proposed to measure water-energy nexus (WEN) to changing Dez Dam operation policy. Analysis of the WEN in the context of Dez Dam operation is imperative for improving decision making in the quest for efficient resource use and management. Specifications table•Data on the outflow of the turbine, reservoir inflow, reservoir volume, evaporation, precipitation, and spillway, total outflow of the reservoir, elevation, power generation and demand in Dez Dam provides an overview of the operation of the dam between 1964 and 2018.•These datasets can be used to analyse the water resources status and hydropower generated in the Dez reservoir operation.•The dataset will be beneficial for modelling purposes, relating to Dez Dam.•The analysis obtained by water-energy productivity (WEP) and water-energy nexus (WEN) can be used by other researchers for comparison.•Other researchers can employ the WEP and WEN indices in other dams and reservoirs with certainty.1In this article, the water-energy productivity (WEP) index is defined in order to perform a suitable surface water resources management. In this regard, new Dez Dam operation policies were suggested herein based on three elevation criteria, namely full supply level (FSL), minimum operating level (MOL), and constant operating level (COL), for the time-series datasets. The time-series dataset of Dez Dam includes outflow of the turbine, reservoir inflow, reservoir volume, evaporation, precipitation, spillway, a total outflow of the reservoir, elevation, power generation and demand for the period of 54 years 1964–2018). The used datasets are shown in 964–2018.2The Dez reservoir is located in the Zagros Mountains in the southwest Iran and was created by the construction in 1963 of Dez Dam with a height of 203 m. An underground power house contains eight 65 MWIn this article, at first, the years of operation were divided into three categories based on the SPIeters BCM [1], [2]3v is the volumetric reliability index, Val-is the vulnerability index, Res is the resilience index, SI is the sustainability index t is the demand of Dez reservoir in period t, Ret is the release from Dez reservoir in period t, NDef is the number of times Det>Ret and Deft is the deficit of Dez Dam downstream demand in period t.Performance criteria are used to evaluate water management policies and enable the comparison of alternative policies. Probability-based performance criteria include time-based and volumetric reliability, resilience, vulnerability and sustainability indices All analyses of this data article for water-energy nexus are presented in The authors declare that they have no known competing financial interests or personal relationships which have, or could be perceived to have, influenced the work reported in this article.


Patients with cancer often carry the dual burden of the cancer itself and other co-existing medical conditions. The problems associated with comorbidities among elderly cancer patients are more prominent compared with younger patients. This study aimed to identify common cancer-related comorbidities in elderly patients through routinely collected hospital discharge data and to use association rules to analyze the prevalence and patterns of these comorbidities in elderly cancer patients at different cancer sites. We collected the discharge data of 80,574 patients who were diagnosed with cancers of the esophagus, stomach, colorectum, liver, lung, female breast, cervix, and thyroid between 2016 and 2018. The same number of non-cancer patients were randomly selected as the control group and matched with the case group by age and gender. The results showed that cardiovascular diseases, metabolic diseases, digestive diseases, and anemia were the most common comorbidities in elderly patients with cancer. The comorbidity patterns differed based on the cancer site. Elderly patients with liver cancer had the highest risk of comorbidities, followed by lung cancer, gastrointestinal cancer, thyroid cancer, and reproductive cancer. For example, elderly patients with liver cancer had the higher risk of the comorbid infectious and digestive diseases, whereas patients with lung cancer had the higher risk of the comorbid respiratory system diseases. The findings can assist clinicians in diagnosing comorbidities and contribute to the allocation of medical resources. The incidence of cancer  is rising rapidly worldwide due to the aging population . Cancer Many population-based surveys and clinical studies have attempted to explore the prevalence of comorbidities and the impact of comorbidities on health care or survival outcomes, such as identifying the comorbidity patterns of mental diseases ,9, and aWith the development and advances in information technology, the emergence of electronic medical record (EMR) systems has made it possible to use clinical information for disease relationship mining. Hospital discharge data, as a type of administrative data derived from EMR, are becoming one of the available data sources for assessing disease comorbidities ,20, withIn this study, we used hospital discharge data derived from 16 tertiary hospitals in northeast China between 2016 and 2018 to identify important cancer-related comorbidities and estimate the prevalence and patterns of these comorbidities among elderly cancer patients with diverse cancer sites.The 10th revision of the International Classification of Diseases (ICD-10)  is used The hospital discharge medical records included the following data: demographic, such as age and gender; disease diagnosis; and medication. The diagnostic data consisted of one primary diagnosis and up to 15 secondary diagnoses, which were coded by trained coders using ICD 10. We used demographic and diagnostic data to analyze the co-morbid relationships to cancers. To ensure data quality, we only included the medical records of patients from tertiary hospitals. Ethical approval to conduct this study was obtained from the Ethics Committee of the School of Public Health at Jilin University  .p-value was ≤ 0.01.The characteristics of patients were summarized using frequency distributions and proportions. We used quartiles to describe the number of comorbidities in patients, presented as median (interquartile range (IQR)). The prevalence ratios (PRs) and 95% confidence intervals (CIs) for categories of co-morbid diseases were calculated, which were based on the categories of ICD 10. Distributions of categories of co-morbid diseases were compared for cancer and non-cancer patients using chi-square tests. Differences were considered significant if the We adopted the Apriori algorithm, which is the best-known ARM algorithm to extract and analyze the patterns of liver cancer comorbidities. The Apriori algorithm is a frequent itemset algorithm for mining association rules. The association rules are evaluated by support  and confidence (the number of occurrences of disease A co-occurring with disease B). The formulas for support and confidence are presented below.The basic premise of the algorithm is to first find all frequency sets, the frequency of which is at least as frequent as the pre-defined minimum support, then generate strong association rules from the frequency sets that satisfy the minimum support and minimum confidence. The advantage of the Apriori algorithm is that the structure is simple, easy to understand, and there is no complicated derivation, which greatly improves the efficiency of the algorithm. The result of the algorithm is a list of patterns between two sets of diseases in the form of “X→Y,” which indicates that if disease X exists, disease Y co-exists. Although each pattern is directed with an arrow, it does not mean causation between diseases, but only represents co-occurrences. To avoid confusion, we ignored the directions of the patterns, and considered all diseases in set X and Y to be associated. Herein, support > 0.01 and confidence > 0.5 were used according to performance of validation diseases.As a group, the cancer patients most often had three comorbidities  and the prevalence of comorbidities tended to be higher in the cancer groups compared to the controls . Patients with liver  and lung cancers  were more likely to have higher levels of comorbidities than patients with other cancers. Females with digestive system cancers had more comorbidities than males . Overall, the number of comorbidities increases with age in patients with cancer. Specifically, we observed that with age, the number of comorbidities in patients with thyroid cancer increases .Overall, cancers were strongly associated with cardiovascular diseases and metabolic syndrome in elderly patients, such as diabetes (E11), glycoprotein metabolism disorder (E77), mineral metabolism disorder (E83), disorder of fluids and electrolytes and acid-base balance (E87), hypertension (I10), angina pectoris (I20), chronic ischemic heart disease (I25), and heart failure (I50). In addition to cardiovascular and metabolic diseases, anemia (D64), and digestive system diseases , other diseases of the liver (K76), esophagitis (K20), and gastritis and duodenitis (K29)) were common comorbidities in elderly patients with cancer, especially with respect to liver, stomach, and colorectal cancers.Liver cancer involved the largest number of types of co-morbid diseases and association rules, with a total of 31 diseases and 96 rules. The categories of these diseases were as follows: infectious diseases; blood and hematopoietic organ diseases; metabolic diseases; cardiovascular diseases; respiratory diseases; digestive system diseases; genitourinary system diseases; and symptoms, signs, and ill-defined conditions. Among the categories of disease, the rule with the highest degree of support was chronic viral hepatitis (B18) and liver cirrhosis (K74) . Although the types of comorbid diseases involved in lung cancer were less than liver cancer, the types of comorbid diseases involved in lung cancer were greater in number than other cancers (17 diseases and 24 rules). The categories of these diseases included metabolic, cardiovascular, respiratory, digestive, and reproductive system diseases. The rule with the highest degree of support was chronic ischemic heart disease (I25) and heart failure (I50) .In addition to cardiovascular and metabolic diseases, common comorbidities of stomach and colorectal cancers were digestive tract inflammation, including esophagitis (K20), gastritis, and duodenitis (K29), while the common comorbidities of esophagus cancer were pneumonia (J18) and pleural effusion (J94). Cervix and breast cancers, cancers of the female reproductive system, had fewer types of comorbidities (mainly common cardiovascular and metabolic diseases).This study was conducted to analyze the association between various types of cancers and comorbid diseases. Diagnostic data used in this study were collected from hospital discharge medical records distributed throughout Jilin province, providing data from a diverse population to comprehensively examine and characterize wide-ranging patterns of comorbidities. We used ARM to identify common comorbidities and comorbidity patterns in patients with cancer. These influential comorbidities could be targeted for specific intervention and/or screening.The results of the high PRs and support for blood system diseases and digestive system diseases showed a strong association between blood and digestive system diseases and cancer, and there was a higher risk of comorbidities in cancer patients than non-cancer patients. Anemia is a common issue in cancer patients, which has several possible causes and contributing mechanisms. Anemia may be the result of the cancer itself, cancer treatment, blood losses, hemolysis or inflammatory cytokines associated with chronic disease . For exaARM analysis showed that cardiovascular and metabolic diseases have a high degree of support. In addition, ARM analysis showed high support rules between cardiovascular and metabolic diseases and each type of cancer, which are consistent with other research results ,36,37. COur study has also shown that different cancer sites have different comorbidity patterns. The study found that liver and lung cancers had the most types and rules of complications, followed by gastrointestinal cancers, such as esophagus, gastric, and colorectal cancers. In contrast, cervical and breast cancer, cancers of the female reproductive system, had fewer comorbidities, which is in agreement with published results . TherefoThere were several limitations to this study. We can only identify diseases that were coded during hospitalization, and there is limited information about the onset of comorbidities, so we cannot determine the precedence or causality of comorbidities. Moreover, the threshold set of association rules is empirical, and the results may vary depending on the selected threshold. Due to space limitations, only rules and comorbidities with high reliability levels were analyzed. Therefore, we will explore the mechanisms underlying comorbidities and the rules of occurrence and development of comorbidity patterns in more detail in subsequent studies.This study used ARM from hospital discharge data to identify an extensive list of important comorbidities in cancer patients. Our work demonstrates how clinically derived data can be used to identify cancer-related comorbidities and the ARM algorithm can be used to analyze the comorbidities associated with cancer. This method may be widely applied to exploring other chronic disease-related comorbidities. From the overall pattern of comorbidities, cardiovascular disease, metabolic disease, anemia, and digestive system disease were the most common comorbidities in elderly patients with cancer. Studies have also shown that different cancer sites have different comorbidity patterns compared with other cancer sites. Elderly patients with liver cancer face the highest risk of comorbidities. These results can provide references for the clinical diagnosis and active prevention of cancer comorbidities, and play a positive role in improving the quality of life of patients with cancer comorbidities.


There is a complex interrelation between epilepsy and cardiac pathology, with both acute and long-term effects of seizures on the regulation of the cardiac rhythm and on the heart functioning. A specific issue is the potential relation between these cardiac manifestations and the risk of Sudden and Unexpected Death in Epilepsy (SUDEP), with unclear respective role of centrally-control ictal changes, long-term epilepsy-related dysregulation of the neurovegetative control and direct effects on the heart function. In the present review, we detailed available data about ictal cardiac changes, along with interictal cardiac manifestations associated with long-term functional and structural alterations of the heart. Pathophysiological mechanisms of these cardiac changes are discussed, with a specific focus on central mechanisms and the investigation of a possible deregulation of the central control of autonomic functions in addition to the role of catecholamine and hypoxemia on heart. Since the description of the first ictal asystole more than 100 years ago . Epileps- The first corresponds to the issue of sudden unexpected death in patients with epilepsy (SUDEP). Among the causes of premature deaths in patients with epilepsy, SUDEP represents a major cause, especially in young adults with uncontrolled seizures with an incidence of about 0.5%/year of uncontrolled epilepsy . SUDEP i- The second aspect is the development of seizure detection devices, especially in order to alert the patients' caregivers and improve their safety. Because of the close relationship between seizures and changes in heart rate, cardiac monitoring has been proposed as a variable of choice for optimizing the detection rate of these devices .Several reviews of the literature have analyzed the relationship between heart and epilepsy. Some have focused on ictal or interictal cardiac changes –12. ReceIn this review, the characteristics of ictal and interictal cardiac manifestations will be successively detailed. We will focus more particularly on their respective physiopathology, especially on central mechanisms with the investigation of a possible deregulation of the central control of autonomic functions, studied in functional imaging and using intracranial stimulations/recordings, in addition to the role of catecholamine and hypoxemia on heart which have already been reviewed elsewhere , 14. TheTachycardia is the most common ictal cardiac manifestation. It is reported in 82% of patients on average, with some intra-individual variability, since not all seizures in a patient with ictal tachycardia will necessarily lead to tachycardia .In the literature, changes in heart rate during seizures correspond on average to an increase of 30 bpm or more than 50% compared to the interictal heart rate. They mainly occur in the pre-ictal period or within 30 s after the beginning of the seizure, the maximal heart rate being achieved for a majority of seizures within the first 60 s , 16. HowThe percentage of seizures associated with a change in heart rate appears to be similar for generalized tonic-clonic seizures (64%) and for focal seizures (71%), although it is likely that the magnitude of the change is increased as the focal seizure progresses to bilateral tonic-clonic seizure , 19. In Seizures with bradycardia or ictal asystole are much rarer. Ictal asystole, defined as a sinusal pause of at least 3 s occurring during a seizure, usually has a duration of <60 s, and is spontaneously reversible –27. TheyOther cardiac arrhythmias and conduction abnormalities, during or after seizures, have been reported in patients with drug-resistant focal epilepsy. Atrioventricular block, atrial fibrillation, supraventricular tachycardia, atrial, or ventricular premature depolarisations, ventricular fibrillation, and QT interval shortening or prolongation can thus be observed , 18.Myocardial ischemia can be caused by seizures, especially in patients with cardiovascular risk factors. Up to 40% of seizures could be associated with ST segment depression . HoweverIt has been suggested both in experimental models and in patients, that recurrence of seizures can progressively lead to cardiac fibrosis, potentially through catecholaminergic toxicity . CompareMore recently, it has also been shown that repetition of seizures can alter the expression of cardiac ion channels. Epilepsy-related alterations in the cardiac expression of sodium (Nav1.1/1.5), potassium (Kv4.2/4.3), calcium (NCX1), and cationic (HCN2/4) channels have thus been reported in animal models . It remaHRV is the change in the time interval between two heart beats. HRV reflects the balance between sympathetic and parasympathetic activity of the autonomic nervous system. HRV is thus an index of activity of the neurovegetative system, whose decrease is a strong predictor of sudden death in patients with heart disease . OverallIn addition, many studies have examined peri-ictal changes in HRV , 54. TheThe mechanisms underlying the emergence of these cardiac alterations remain poorly understood and several hypotheses need to be considered. These hypotheses may coexist in the same patients, interacting with each other.Some of the most important integrative control centers for autonomic nervous system functions are located in the brainstem , 56. HowSome studies suggested the possibility of a lateralization of insular cortex in terms of cardiac function, the right insula being more involved in sympathetic regulation, and the left one in parasympathetic cardiac regulation [see , 68 for Very few studies have investigated the effects of cortical stimulation on heart rate in humans. Electrical stimulation of limbic structures, especially the amygdala and peri-amygdaloid pyriform cortex, have been reported to produce autonomic changes, including cardiovascular responses, mediated by either sympathetic or parasympathetic pathways . AutonomLikewise, Catenoix et al.  reportedSympathetic or parasympathetic ictal changes could so result from direct activation by epileptic discharge of the central autonomic network , whose aSeveral ion channel genes whose mutations are involved in cardiac arrhythmias are also expressed in the brain. For example, the SCN5A gene, whose mutation is associated with long QT syndrome, is also expressed in the brain and is associated with epilepsy . Some caA growing body of evidence points to a genetic susceptibility to cardiorespiratory and autonomic dysfunction in epilepsy. In an analysis of the entire exome sequencing of 61 SUDEP cases, mutations known to cause long QT syndrome were found in 7% of cases and an additional 15% had candidate variants in potentially predisposing genes to malignant cardiac arrhythmias . SimilarSeveral anti-seizure drugs have been associated with conduction abnormalities or arrhythmias. This has been particularly reported with sodium channel blockers , includiThe effect of vagus nerve stimulation (VNS) on autonomic function remains uncertain. Heart changes associated with VNS are rare. Few cases of VNS-induced bradycardia have been reported. In addition, data on the alterations in parasympathetic tone of the cardiovascular system induced by VNS are contradictory .Finally, while the data concerning the relationship between some antiepileptic treatments, in particular enzyme inducers, and the destabilization of lipid metabolism are numerous , the reaEpilepsy-related cardiac dysfunction may be associated with increased risk of premature mortality, because of a relation either with the risk of SUDEP or with the risk of heart diseases. As discussed in details by Verrier et al. the issue of long-term risk of heart diseases might be predominant in terms of incidence and should deserve a specific attention . This riThe data suggesting that the ictal cardiac dysfunction plays a key leading role in the initiation of the cascade of events that lead to SUDEP are limited. As discussed above, the possibility that the main event is a serious heart rhythm disorder seems unlikely or may represent a minority of SUDEP , 27. Alt2 (Accordingly, an important aspect might be the interrelations between the central regulation of respiratory function and the one of neurovegetative functions, including the central regulation of cardiac rhythm. Brain areas involved in these regulations are highly connected to each other, both at the cortical level and in the brainstem, and each of them is partly regulated by the other. Brain regions involved in the regulation of the arterial pressure as well as in breathing control thus overlap with the Central Autonomic Network involved in the regulation of heart rhythm, both at the cortical level and in the brainstem. Direct electrical cortical stimulation of the subcallosal neocortex resulted in consistent decreases in systolic blood pressure . The lat2 . In this2 . In gene2 , 33. In 2 , the cor2 . Further2 . In pati2  as well 2 .Despite these preliminary data, the hypothesis of a leading role of post-ictal central neurovegetative breakdown in the SUDEP requires additional evidence. In addition, the exact relationship between these potential peri-ictal alterations of the Central Autonomic Network, long-term alterations of respiration and long-term alteration of cardiac regulation, especially HRV, remains an open question. Whether or not the risk of severe of post-ictal neurovegetative breakdown, and eventually SUDEP, might be higher in patients with combined alterations of respiratory and cardiac controls is unknown. Better understanding how these issues interact with each other and if they share pathophysiological mechanisms might be of key importance for unraveling SUDEP biomarker with greater predictive value than those currently available , a critiIdentification of interictal cardiac changes should allow the prevention, early detection, and possible treatment of cardiac co-morbidities. It could also guide the choice of anti-seizures drugs according to the patient profile, in order to avoid the appearance or worsening of arrhythmia or cardiac conduction disorders. An EKG should therefore be performed in all patient with newly-diagnosed epilepsy, especially to exclude long-QT syndrome, but it should then be reprocessed regularly in the follow up. Some studies have suggested the interest of prolonged routine EKG recordings .Similarly, identification of patients with severe ictal heart rate changes is important. Although ictal asystole are typically self-limiting events, they can expose to severe injuries. Considering the risk of seizure-related traumatisms and the risk of recurrence, aggressive treatment, including pacemaker implantation, should be discussed if seizure freedom cannot be achieved . BecauseOver the past 10 years, there has been a growing interest in the potential applications of mobile health technologies for seizure detection, with the objective of faster caregivers' intervention and decreased risk of seizure-related injuries. Basically, three physiological variables can be used for non-EEG based seizure detection: detection of body movements, eye movements, and seizure-related modification of vegetative functions, including the cardiac rhythm . While dBeyond detecting ictal tachycardia to alert caregivers about the occurrence of a seizure, an additional question will be how these devices can be used to detect post-ictal arrythmia and/or asystole. Such approach might be used to alert patients family or the rescue services of a severe post-ictal arrythmia with high risk of immediate SUDEP, especially in patients with frequent nocturnal convulsive seizures and who sleep alone .Much progress has been made in recent years in the characterization of ictal and interictal cardiac manifestations in epilepsy. Although their pathophysiology remains debated, improving knowledge could lead us to improve the care of our patients. Their identification should allow the prevention and possible treatment of cardiac co-morbidities, and also guide the choice of anti-epileptic treatments, in order to prevent the appearance or worsening of conduction or rhythm cardiac disorders. In addition, monitoring EKG and HRV, which are biomarkers easy to record and measure, could allow the development of increasingly precise non-invasive seizure detection tools for monitoring and possibly for the early treatment of seizures. However, a key remains to better understand the exact relation between these cardiac manifestations and the risk of SUDEP. Further studies are required to decipher the respective role of centrally-control ictal changes, long-term dysregulation and direct effects on the heart function.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.SR received consultant and/or speaker fees from EISAI, UCB Pharma, Livanova, GW Pharma, Arvelles therapeutics, Idiorsia. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


With increasing environmental and ecological concerns due to the use of petroleum-based chemicals and products, the development of novel materials that combine high efficiency, low prices, and minimum environmental impacts is of great value. In this scenario, nanocellulose appears as a remarkable alternative, since it presents outstanding features such as renewability, biocompatibility, high specific surface area, low density, high elastic modulus, dimensional stability, low thermal expansion coefficient, outstanding reinforcing potential, hydrogen-bonding capacity and eco-friendliness . A concise background of cellulose, its structural organization, and the nomenclature of cellulosic nanomaterials has been given. The various experimental approaches used to produce nanocellulose as well as their advantages and shortcomings have been discussed. Some emerging applications based on nanocellulose such as nanocomposites, Pickering emulsifiers, wood adhesives, wastewater treatment, and biomedical have been broadly presented. Despite the interesting achievement in the field, it is claimed that further research activities need to be carried out to fill the gaps through the practical transition from laboratory to industrial scales, the decrease of the energy- and time-consumption, as well as the optimization of the production process.The first review paper provided a comprehensive overview on the recent researches in the production, modification, and emerging application of nanocellulose, especially cellulose nanocrystals, with a special focus on the reports published within the past 3 years . It is revealed that functionalized nanocellulose can be used as an alternative to the conventional petroleum-based electronics. However, the main challenge that should be overcome in the future, to fully exploit the potential of nanocellulose and integrate it within materials into society and commerce, is the combination of features such as flexibility, conductivity, luminescence, low environmentally impact, and acceptable cost.The second review paper discussed the historical development, the fabrication, and functionalization methods of nanocellulose. The current stage and the prospects of the nanocellulose-based flexible energy and hybrid electronic component and devices has been deeply investigated , polylactic acid (PLA), and polybutylene succinate (PBS) for food packaging applications was also published by Beyene et al.). The authors demonstrated that 20% of xylan can be transformed into furfural through the hydrothermal treatment, which can also assist the hydrolysis process to generate cellulose nanocrystals with significant yield improvement.The topic of integrated processes in biorefinery, which allows converting biomass into value-added products with maximum energy and material recovery, has attracted considerable interest. To this end, one of the original research papers of this special issue focused on the development of a new biorefinery strategy that introduced the hydrothermal treatment of wood pulp prior to acid hydrolysis -oxidized cellulose (TOC) dispersed in water and disintegrated with a magnetic stirrer or high-pressure homogenizer under various conditions. It is revealed that the fibrillated TOC/water dispersions with a controllable degree of fibrillation allowed obtaining TEMPO-oxidized cellulose nanonetwork films with versatile optical, porous, and mechanical features as well as low oxygen permeability.Another interesting research work carried out by Butylina et al. investigated the effect of both PVA and CNC on the characteristics of composite hydrogels prepared by the freeze-traw method. It is proved that the use of 10% of CNC provided a more dense structure with excellent mechanical performance and high-water content, which are considered as crucial features in medical applications such as artificial tissue engineering.Despite the employment of poly (PVA) hydrogels in several applications and their commercial availability, the investigation of such aerogels supplemented with cellulose nanocrystals (CNC) prepared by the freeze-thrawing method is still within current research focus. In summary, the present special issue advances not only our understanding of the emerging and important role of nanocellulose in various fields but also challenges and future research directions to fully exploit its fascinating properties in practical ways.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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 composition and functioning of the gut microbiota, the complex population of microorganisms residing in the intestine, is strongly affected by endogenous and exogenous factors, among which diet is key. Important perturbations of the microbiota have been observed to contribute to disease risk, as in the case of neurological disorders, inflammatory bowel disease, obesity, diabetes, cardiovascular disease, among others. Although mechanisms are not fully clarified, nutrients interacting with the microbiota are thought to affect host metabolism, immune response or disrupt the protective functions of the intestinal barrier. Similarly, key intermediaries, whose presence may be strongly influenced by dietary habits, sustain the communication along the gut-brain-axis, influencing brain functions in the same way as the brain influences gut activity. Due to the role of diet in the modulation of the microbiota, its composition is of high interest in inherited errors of metabolism (IEMs) and may reveal an appealing therapeutic target. In IEMs, for example in phenylketonuria (PKU), since part of the therapeutic intervention is based on chronic or life-long tailored dietetic regimens, important variations of the microbial diversity or relative abundance have been observed. A holistic approach, including a healthy composition of the microbiota, is recommended to modulate host metabolism and affected neurological functions. Gut microbiota is defined as the complex population of microorganisms residing in the intestine with the highest concentrations being found in the colon . In the A summary of the influence of food constituents as well as different dietary approaches may have on the microbiota follows.Clostridium, Enterococcus, Lactobacillus, and Ruminococcus genera) represent up to 60% of the gut microbiota, the Bacteroidetes (such as Bacteroides and Prevotella) represent up to 15%, with all other species represented in a smaller proportion [The gut microbiota features hallmark characteristics throughout the different life phases, starting with a relatively simple microbial composition to mature with an increased microbiota complexity associated to genetic as well as environmental and physiological influences, such as nutrition, lifestyle, hormonal changes, immunity, and the microbiome-gut-brain axis crosstalk. In humans, microbial communities also seem to vary substantially due to geographic location . The trioportion ,4,5.Prevotella has been shown to be mostly anti-inflammatory and protective [Bacteroides to have pro-inflammatory effects and more often associated to increased risk of metabolic syndrome and other diseases, and the genus Ruminococcus to be further explored as its role in human health is less defined [Among the most studied microbial genera in the human gut, the genus otective , the gen defined .A factor to take into account is the role of some xenobiotics able to trigger gut microbiome toxicity. Among the most well-known are antibiotics, with numerous non-antibiotic drugs being tested recently too . Short-tOf interest is the case of artificial sweeteners, food products generally considered safe because they are poorly metabolized by the human body. The microbiota, though, are very active in the process of biotransformation and some of these products may be actively metabolized and give rise to toxic species ,12,13. FAlthough it is difficult to disentangle the complexity of the relationship of microbiota with the human body and its metabolism, changes in microbial metabolites, diversity loss, and interference in energy metabolism could be considered among the most important disturbances that may impact host health via multiple host–microbiota axes. Not all the disturbances are necessarily negative; but if they are, they can potentially lead to increased disease risks .More data sustain the hypothesis that environmentally-induced perturbations are potentially linked to elevated disease risks ,21. AdveThe way nutrients interact with the microbiota can be direct, by providing, or not, the necessary dietary constituents for the growth of certain microorganisms over others, or indirect by affecting host metabolism and immune response or by disrupting protective functions of the intestinal barrier, for example, prompting dysbiosis, and so contributing to inflammatory processes .Looking into the quality and composition of the diet, metagenomic and metabolomic analysis studies have shown differences in the microbiota composition as a result of a trade-off between protein fermentation and degradation in protein-rich diets as opposed to carbohydrate fermentation and AA biosynthesis in plant-based diets ,33. FurtPreclinically, in mice fed a high-fat or a high-fat/high-sugar ”Western” diet, a decrease in Bacteroidetes levels and an increase in Firmicutes and Proteobacteria has been shown to be dose-dependent ,36,37. TRuminococcus gnavus has been associated to a pro-inflammatory effect in light of the production of a pro-inflammatory polysaccharide in patients with Chron’s disease [Clostridia of the Firmicutes phylum have been thoroughly studied as they produce several toxic substances such as phenol, indole, and p-cresol able to reduce the growth of lactic acid bacteria [Clostridia, Clostridium difficile is well characterised as it produces toxins A and B, which in turn induce potent pro-inflammatory signalling in the human body [Faecalibacterium prausnitzii is an example of a marker of gut health in light of immunosuppressive features of the short-chain fatty acids (SCFA) it produces [Modifications in the relative abundance of genera in the human gut may be associated with perturbations correlated to the specific effects of the bacteria metabolism. For example,  disease . Bacteribacteria . Among Cman body . On the produces .Furthermore, the relative abundance of microbial species is of interest. For example, the balance between Bacteroidetes and Firmicutes is an important marker for obesity and higher BMI. A decreased Bacteroidetes:Firmicutes ratio has a strong negative correlation with BMI , possiblDespite interesting research results, in man, the multitude of variables interfering with their lives can have synergistic or opposing outcomes on the gut microbiome, making it difficult to anticipate the net effect of dietary interventions on the microbiota downstream on the human host. Nevertheless, deficiencies of some micronutrients have been found to trigger distinct patterns of microbiota structural alterations in humans, mice, rats, and piglets. Noteworthy examples include iron ,47,48,49The research is always providing more data clarifying the role of nutrition in modulating the microenvironment, but a key factor to always be taken into account remains the inter-individual variability, determined by person-specific responses,  and depeA summary is reported in As this review is focused on patients with phenylketonuria (PKU) who need to heavily modify their dietary regimens in order to reduce intake of phenylalanine (Phe), it seems of value to evaluate the respective roles of proteins, carbohydrates, and lipids in the modulation of the microbiota. Patients with PKU receive a long, ideally life-long, low-protein diet, compensated by the regular supplementation of Phe-free amino acids (AAs), and may receive an excess of low-protein carbohydrates and lipids.Gut microbiota can be modified by dietary carbohydrates, and carbohydrates have a role in the bacterial metabolism. Depending on the type of diet administered, the gut microbiota is modified with bacteria species resulting more or less abundantly as a response to the dietary regimen. Similarly, complex polysaccharides or non-digestible carbohydrates  can be processed by the gut microbiota supporting their digestion or using indigestible carbohydrates as a source of energy for their own metabolism ,70.SCFAs, small organic monocarboxylic acids with a chain length of up to six carbons atoms, such as lactate, acetate, propionate, and butyrate, produced by the microbiota via carbohydrate fermentation, may have beneficial effects, positively modulating carbohydrate and lipid metabolism, energy homeostasis, intestinal barrier function, mucosal immune homeostasis, and inflammatory signal inhibition in the host ,59,63. However, their effects have also been found to contribute to enhanced energy harvest in obese humans and ob/ob genetically obese mice, suggesting unwanted implications in obesity status . Data obBifidobacterium, Roseburia, and Faecalibacterium, associated with positive metabolic effects [The ratio and source of dietary fat are equally important to intestinal microbiota modifications . The con effects . Analogo effects  or incre effects . While g effects ,76. Amon effects .Lactobacilli and Bifidobacteria supplementation (50 billion cfu/day) significantly reduced bodyweight, BMI, waist circumference, and waist-to-height ratio in free-living overweight/obese subjects, with females benefiting more than male participants. Greatest weight losses together with decreases in small dense LDL-C levels were observed in hypercholesterolemic participants [Another exploratory experience, a placebo-controlled, randomized, double-blind study showed that six months (but not three months) of icipants .Literature reports that some metabolites of AAs such as ammonia, amines, phenol and p-cresol are detrimental for the colonic mucosa at high concentrations ,80,81 buDifferent studies have highlighted the role of single AAs on gut microbiota and consequently on intestine performance or health. Glutamate, glutamine, and aspartate are the major oxidative fuels of the intestine. New evidence shows that arginine activates the mTOR signalling pathway in the small intestine, while glycine, used to synthesize glutathione in the small intestine, is considered a powerful cytoprotectant. Furthermore, the major end products of methionine and cysteine metabolism, glutathione, homocysteine, and taurine, play important roles in the intestinal immune and anti-oxidative responses. Threonine is highly utilized by the gut and is particularly important for mucin synthesis and maintenance of gut barrier integrity . Of inteLactobacillus and short-chain fatty acid concentration, expression of T-helper type 2 cytokines and Mucin-4 increased when compared with free AA supplementation [Based on the observation that in pigs a moderate reduction of dietary protein levels (≤4%), compensated by the supplementation of essential AAs, reduces the proportions of harmful bacteria and protein fermentation without damaging the growth performance of pigs, Wang H. et al. compared the effects of casein hydrolysate and free AA supplementations together with a low-protein diet. Their data show that in the casein hydrolysate group the abundance of potentially pathogenic bacteria was reduced while entation . Another pre-clinical study in a streptozotocin-induced type 2 diabetes mouse model suggests that the addition of glycomacropeptide (GMP) hydrolysate to a high-fat diet contributes to an anti-diabetic effect by recovering the muscle insulin sensitivity and by modulating the microbiome. The latter has been found to present an increased ratio of Bacteroidetes/Firmicutes, suggesting that GMP may exert its antidiabetic effects via regulating the integral structure of gut microbiota .Bifidobacterium and Ruminococcus from the Ruminococcaceae family), increased with protein reduction, although the overall microbial composition did not significantly change. While the addition of free AAs allowed observing of growth rates and metabolic performance of formula-fed infants more similarly to those of breast-fed infants, it resulted in being insufficient to reverse the accelerated growth and the insulin-inducing high BCAA phenotype, typically observed in formula-fed monkey new-borns [A very recent study in newborn rhesus monkeys showed the role of adding free AAs in formulas of new-borns whom, differently from those who were breast-fed, are known to exhibit more rapid weight gain, a different faecal microbial profile, as well as elevated serum insulin, insulin growth factor 1, and branched chain AAs (BCAAs) levels. The removal of proteins and the addition of free AAs, in an effort to provide food more similar to breast milk, profoundly suppressed formula intake, lowered weight gain, and improved serum insulin concentrations. Levels of faecal microbes known for their ability to utilize complex carbohydrates , is in its infancy as regards the understanding of the involved mechanisms and the number of clinical studies. The gut microbiota can communicate with the CNS by means of five different communication routes: the neuroanatomical pathway, the neuroendocrine-hypothalamic–pituitary–adrenal axis pathway, the immune system, the gut microbiota metabolism pathway, and the intestinal mucosal barrier and blood-brain barrier . The floImmune cells  and enteric glial cells (EGCs) constantly sense microbial-associated molecules produced at gut level. In response to these stimuli generated by the microbial population, neuro-modulatory molecules targeting the enteric nerves can be secreted locally. Once the enteric nerves are stimulated, they can, in turn, affect the brain and the spinal cord by means of vagal transmission. When molecules or stimuli reach the CNS, neurons, microglia, and astrocytes respond by changing their transcriptional program, either supporting or inhibiting pathological conditions. Increasing knowledge is shedding light on the mechanisms underlying microbiome-gut-brain axis in different pathologies, including neuropsychiatric disorders or neurodegenerative and metabolic diseases ,96,97.Lactobacillus reuteri and L. rhamnosus) improve the enteric nervous system and vagus nerve activations [L farciminis, L. Plantarum, and L. fermentum) can produce a neurotransmitter, nitric oxide, associated with control of the intestinal transit [At gastrointestinal level, the autonomic nervous system is known to regulate gut motility and permeability, secretion of bile acids, bicarbonates, and mucus, as well as mucosal immunity . Moreoveivations ,100 whil transit ,102.One of the most studied topics in gut microbiota modulation is the role of SCFAs, released by the microbiota in the intestine as the main products of the anaerobic fermentation of indigestible dietary fibres and resistant starch. SCFAs can be systemically distributed and cross the blood-brain-barrier where they seem to have numerous properties, including neuroactive functions. The exact mechanisms by which SCFAs exert their effects are largely unknown but several animal studies have shown an influence on key neurological and behavioural processes that may be involved in neurodevelopmental and neurodegenerative disorders ,106,107.Despite the complex pathophysiology of mood disorders, there are studies highlighting the participation of the gut microbiota in the severity of these diseases . For exaIntestinal microbiota represents an essential bioreactor that converts dietary substrates into metabolites with a crucial role in a variety of physiological processes. SCFAs are the most abundant products of microbial fermentation, but neurotransmitters (for example γ-aminobutyric acid and serotonin), choline, phenol derivatives, and toxins are also produced . A bottoTherefore, the diet has a role, especially when taking dietary extremes (e.g. a Mediterranean diet vs. a Western-style diet) into account, in the way the gut-brain axis works. Key intermediaries, more or less also present based on the dietary habits, sustain the communication along the gut-brain axis. The microbiota, producing metabolites such as serotonin/5-hydroxytryptamine, GABA, glutamate, Phe, Trp, tyrosine (Tyr), carnosine, SCFAs, threonine, alanine, lysine, glycine, serine, aspartic acid, ammonia, and gut hormone/incretins, may influence brain functions as well as brain influences on gut activity. In addition, the gut microbiota has the ability to regulate the barrier integrity (both within the gut and at the blood brain barrier), and partial nutrient absorption at the mucosal surface .A great deal of attention has been placed on the potential contribution of the microbiota to disease pathogenesis and clinical manifestations, making it an appealing therapeutic target for treatment of selected diseases. For example, in case of metabolic syndrome, a group of co-associated diseases including obesity, insulin resistance, type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease, the research is currently focusing not only on the analysis of bacterial community composition and how they associate with the disease, but is also trying to elucidate the molecular pathways and metabolites activated and produced by the microbial community, to understand what their effects on manifestations related to metabolic syndrome could be . The obsPrebiotics may support the positive action of probiotics , the latAlthough more data are necessary before they can be fully understood and successfully used, there seem to be fairly strong indications that this approach may be beneficial . As an eLoss of microbial diversity represents the first step toward an altered microbial environment, promoting host susceptibility to diseases . Indeed,Lactobacillus, Bifidobacterium, and other select taxa, or both, into the diet not only mediates improvements to body weight and adiposity but exerts other positive effects on glycaemic control, systemic inflammation, and energy intake. It is necessary, though, to carefully study how these therapeutic approaches work in non-healthy populations, as indicated by some studies suggesting that certain bacterial species of these same genera may be ineffective if not deleterious for obese patients [Green et al.  very recpatients .Among the microbiota roles, the ability to regulate the functionality and maturation of the host’s neuroimmune system ,146 is kIt therefore remains important to continue studying specific patient populations, especially in presence of diseases such as the inherited errors of metabolism (IEMs), where often a modified dietary regimen needs to be followed for many years, if not life-long, with numerous consequences. Initial assessments of these disorders have been conducted, and discussed below, helping to increase the know-how that will ultimately allow clinicians to personalise the use of pre and probiotics to the benefit of the patients.As concerns IEMs, the last few years have seen increasing research data being published on the influence of the dietary regimen on microbiota, due to the fact that at least a part of the therapeutic intervention in patients with these disorders occurs by means of specifically tailored dietetic regimens.These diseases, which share the absent or deficient activity of a given enzyme, show high genetic ad epigenetic heterogeneity and also show different responses among patients with the same genotype. In untreated phenylketonuria (PKU) and in propionic and methylmalonic acidaemia, for instance, the neurological and behavioural impairment are highly variable, while liver disease is commonly developed in tyrosinemia type 1 and urea cycle disorders . DespiteAnother aspect that needs to be taken into account in IEMs is the susceptibility of the central nervous system and the liver due to their high metabolic rate . A few pConsidering the high diversity of IEMs and the relative scarcity of patients in each type of condition, literature on the role of microbiota in these diseases is infrequent for the rarest types. In aminoacidopathies, the majority of the data are available in PKU, while limited data have been published in tyrosinemia and alkaptonuria , classicIn type I nitisinone-treated tyrosinemia patients, a perturbation of the indole metabolism associated with high levels of 4-hydroxyphenylpyruvate has been shown to be directly responsible for the promotion of the indole-pyruvate pathway via the Trp metabolism. Despite the fact that the influence of indolic compounds on human cellular function has not been well described, this class of compounds is especially important in bacterial function and signalling, making perturbations of this pathway potentially interfering with the human microbiome, and consequently the patient .Eubacterium coprostanoligenes group and underrepresentation of the Alistipes, Family XIII UCG-001, and Parabacteroides genera, which have been associated, among other factors, to the diet and vitamin B supplementation [Classical homocystinuria (HCU) is characterized by increased plasma levels of total homocysteine and methionine and part of its treatment consists of supplementation of B vitamins, essential AAs, and a dietary regimen aimed at restricting methionine intake. As dysbiosis has been described in other inborn errors of metabolism, interest in this topic promoted conduction of clinical study in HCU patients on dietary treatment. Among other results, this study indicated that patients with HCU had overrepresentation of the entation .In propionic and methylmalonic acidaemias, the gut microbiota significantly contributes to the production of propionic acid ,181 a meAnother example of interference of microbiota with metabolism is represented by carnitine, widely supplemented to patients with organic acidaemias and primary carnitine uptake deficiency . BecauseVeillonellaceae families, while the beneficial genera Faecalibacterium and Oscillospira were significantly reduced. SCFA quantification revealed a significant increase of faecal acetate and propionate in GSD subjects, whose beneficial role was probably reduced due to unbalanced bacterial interactions [Similarly, in glycogen-storage diseases (GSD-Ia and Ib), a recent publication reported the results of a study, where the gut microbiota of 9 GSD-I subjects and 12 healthy controls was compared. The analyses revealed a significant biodiversity reduction in the GSD group compared to the healthy control group highlighting profound differences of the respective gut microbiota. GSD subjects were characterized by an increase in the relative abundance of Enterobacteriaceae and ractions .We performed a search of the literature in the PubMed and Google Scholar databases to identify articles related to “phenylketonuria” and “microbiota”/“microbiome”, executed on 10 May 2020. Due to the scarcity of literature published, all articles were included in this review with the exception of duplicates. A total of 13 eligible articles  were identified and reported.So far, the role of microbiota has been studied with more depth in PKU than in any other IEM. A handful of pre-clinical works have been published both to shed light on mechanisms involving the microbiota in PKU animal models and to describe how approaches to the microbiota my benefit patients with PKU.Lactobacillus and Bifidobacterium populations in mice in as little as three days after treatment, the study, conducted in PKU (enu2Pah) and wild-type mice, evaluated GMP as a prebiotic by characterizing caecal and faecal microbiota populations, SCFA production and immune responses. Considering that changes in caecal and faecal microbiota are primarily diet-dependent, the introduction of GMP into the diet was associated with a reduction in Proteobacteria, genera Desulfovibrio, in both wild-type and PKU mice. The genus Desulfovibrio, associated with production of hydrogen sulphate, is a cytotoxic compound found at higher levels in patients with ulcerative colitis [The first study to start analysing how microbiota may be modulated in PKU was published in 2015 by Sawin E.A. et al. , to desc colitis . Further colitis .4) presence, due to the existence of BH4-producing bacteria. GTP cyclohydrolase 1-deficient hyperphenylalaninaemia-1 (hph-1) mice were compared to wild-type controls for the presence of intestinal BH4-producing bacteria measuring 6-pyruvoyltetrahydropterin synthase (PTPS-2), an enzyme only present in BH4-generating bacteria. Adult wild-type mice and all-age hph-1 mice presented faecal material containing PTPS-2 mRNA, an indication of the presence of BH4-generating bacteria. In cultured human faecal samples, the PTPS-2-producing bacteria were identified as belonging to the Actinobacteria phylum. In hph-1 mice, Aldercreutzia equolifaciens and Microbacterium schleiferi were associated with bacterial production of BH4 [More recently, another pre-clinical study investigated if microbiota could influence tetrahydrobiopterin  or lactose. Differently, lactose fermentation promoted Proteobacteria growth, indicating that, depending on the substrate, influences on the relative abundance of gut microbial species may occur and in particular that the commercially available GMP was positively associated with the growth of health-related taxa in healthy subjects [Another study analysed the influence on the microbiota of GMP-based products when used in the artificial colon model, growing faecal material from healthy and frail older (non-PKU) subjects. The commercially available GMP-based product shown to sustain the growth of subjects .Anabaena variabilis, a filamentous cyanobacterium, has been cloned into a vector to be expressed by Lactobacillus reuteri. Following in vitro confirmation that the Lactobacillus expressed a functional enzyme, the genetically modified bacteria have been tested in vivo in homozygous PKU mice. Reduced blood Phe levels were observed already after 3 to 4 days of treatment with the probiotic, and in other 2 experiments showed to maintain the Phe-lowering effect after 7 or 14 days of continued probiotic administration [Other approaches consider the possibility to provide the gut with genetically engineered microbes able to degrade some of the ingested Phe prior to absorption, acting as a probiotic. The gene coding for the enzyme Phe lyase from stration .Escherichia coli Nissle has been engineered to express gene encoding Phe-metabolizing enzymes once in the mammalian gut, utilizing different metabolic pathways that produce harmless compounds including trans-cinnamic acid, further metabolized in the liver and excreted as hippurate in the urine. Tests have been conducted in Pahenu2/enu2 PKU mice to observe that the engineered bacteria could be associated with a reduced blood Phe concentration of 38% compared with wild type controls, irrespective of protein intake. The engineered E. coli has also been tested in healthy monkeys, where it resulted in being able to counteract the physiological Phe increase, following an oral Phe dietary challenge [With an analogous aim, hallenge .enu2-/enu2-) has been used to assess if E. coli Nissle expressing PAL2  could significantly reduce serum Phe concentrations 24 h after probiotic gavage. The study revealed up to 50% reduction in serum Phe levels, but this was dependant on strain design and extent of hyperphenylalaninaemia [The murine model of PKU  or an increase of others  when compared to that of healthy individuals. The study results suggest that in patients as well as in matched controls, the differences in the microbiota composition between patients and their matched controls may be ascribed to different dietary habits, such as the percentage of calories deriving from carbohydrates and lipids, the percentage of proteins and AAs coming from products of high biological value, and the intake of selenium, in addition to different Phe circulating levels. The authors suggest that key influencers of a different microbial species abundance in the guts of patients with PKU and healthy subjects could be due to either the disorder, in light of the different plasma Phe levels that appear to have contributed significantly to shifts in the gut microbiota, to the modified dietary habits needed to control Phe blood levels in patients with PKU [One of the first studies to assess the relative abundance of microbial species in the gut of very young patients (mean age: 4.24 years) with PKU, showed a reduced abundance of certain bacteria  were more abundant in subjects with mild hyperphenylalaninaemias, while Blautia, Clostridium (Lachnospiraceae family), and Lachnospiraceae (other) were significantly more abundant in children with PKU. Interestingly, correlations with dietary intake showed that the significantly higher presence of Faecalibacterium spp. in subjects with mild hyperphenylalaninaemia negatively correlated with both soluble and insoluble fibre intake, as well as with glycaemic index and glycaemic load. Similarly, the Ruminococcaceae family, more abundant in subjects with mild hyperphenylalaninaemia, negatively correlated with glycaemic index and soluble fibres, while Lachnospiraceae (other) genus correlated positively with these two nutritional parameters. Furthermore, Oscillospira was found to positively relate to energy assumption and carbohydrates, while Roseburia resulted in being negatively correlated with soluble fibres. Such results, that in part differ from previously reported observations in PKU patients, have been suggested to be related not only to the quantity of consumed carbohydrates, these being quite abundant in the typical low-protein regimen of PKU patients, but also to their quality, affecting, for example, the glycaemic index and insulin resistance. Gene sequencing also revealed that Ruminococcus bromii, a starch degrader and a non-butyrate-forming member of the Ruminococcaceae, was the indicator species in PKU subjects, indicating a shift towards a less healthy profile in the Firmicutes phylum. Blautia spp., known to exert a proinflammatory effect on gut mucosa by inducing cytokine secretion, were also significantly more abundant in patients with PKU than in patients with hyperphenylalaninaemia. These results indicate the need to better investigate gut biodiversity in children and patients with PKU with the objective of modulating the consumption of pre and probiotics adapted to the modified dietary schemes necessary for the management of PKU [A follow-up of the above-reported study measured different parameters among which a more in-depth evaluation of the gut microbial composition, which was confirmed to be different based on the various dietary regimens of the two study populations. While in both groups Firmicutes and Bacteroidetes were the relatively most abundant phyla, t of PKU .E. coli presence in guts of normal subjects versus children with PKU, where these bacteria were not found. In addition to the obvious need of confirmation, this result is aligned with those measuring differences in the relative abundance of microbial species in the gut of patients with PKU [Another group analysed the gut microbial biodiversity in patients with PKU and, besides the limitations of the study mainly based on the extremely low number of patients and inadequate technology for complete faecal analyses, showed a significant difference of with PKU .Detailed information on the role of microbiota in IEMs is scarce, given the rarity of these diseases as well as the presence of subclasses within the same IEM. These few studies normally have a small number of participants, making interpretation complex.Another aspect to be considered is that the microbiota is mainly influenced by diet, but in IEMs, diet overload or restrictions are part of most common treatments, making the identification of an adequate control group very difficult.Overall interpretation of data is extremely intricate in a complex environment such as the microbiota, not only influenced by numerous environmental factors, but where the metabolic genetic defect may also affect the microbiome. At this stage is still not possible to discern if a condition observed in patients  reflects genetic or diet effect.It is without doubt that the condition of the microbiota for human beings is a key aspect to consider for the wellbeing of healthy subjects and for patients. Unfortunately, its complexity has not allowed clarification of all its roles, effects, and interactions yet. If on one side some “functional” roles of the microbiota are highly conserved, such as the contribution to the production of cofactors and vitamins, the influence on the carbohydrate metabolism, and the aromatic AA and ATP synthesis ,203, allIn general terms it is known that a dysbiosis, an impairment of the microbiota favouring an abnormal growth of some microbial species over other ones or a reduced microbial diversity resulting in diminished abundance of some important species, has the potential to affect the health of human subjects. The presence and the quantity of microbial species in the human gut interact with the body because bacteria metabolize food and drugs and because metabolites are released by microbial metabolism. These metabolites are then distributed via blood circulation to the different body organs with the potential to exert positive or negative effects. To be able to proactively modulate the microbiota it is mandatory to continue analysing data and gaining precise understanding, for example assessing the metabolome. Some indicators of how microbiota may be predictive of human diseases have already been defined. For example, elevated TMAO levels seem to be predictive of cardiovascular problems in subjects with cardiovascular history ,206,207 In patients with IEMs the balance of the microbiota may be at higher risk due to the underlying disease and the very frequent need or obligation to observe a special dietary regimen, devoid of those elements or nutrients that the patient is not able to metabolize to reduce the risk of accumulating toxic compounds. In fact, patients with IEMs have a higher risk than the healthy population of modifying their metabolism and physiology with the ultimate result of affecting some pathways and processes in their bodies .Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 for 30 days where anxiety and stress response were reduced and mood was improved [Bifidobacterium bifidum, Bifidobacterium lactis, Lactobacillus acidophilus, Lactobacillus brevis, Lactobacillus casei, Lactobacillus salivarius, and Lactococcus lactis) for 4 weeks showed that negative thoughts associated with sad mood were reduced [Among the various metabolic and functional changes that a modified microbiota may sustain, the implications on the gut-brain axis are particularly relevant when subjects are obliged to observe restricted/modified diets over many years or life-long. Being a two-way communication pattern, stressful situations affecting the brain may affect the gut microbiome via the hypothalamic-pituitary-adrenal axis, with consequences on the immune activity or bowel function , while aimproved . Similar reduced .Another factor not to forget is the opportunity or the necessity, in some of the IEMs, to also treat patients pharmacologically. For example, in propionic and methylmalonic acidaemias metronidazole has been used for many years with the intent of reducing the intestinal bacteria responsible for the production of propionate . ResearcSpecific knowledge of the effects of microbiota both on system-wide or organ-specific metabolism will be more and more helpful to therapeutically approach IEMs. Measurement of faecal samples represents an easy technique to start evaluating how microbiota are able to influence certain pathways of metabolism, primarily that of SCFAs, heterocyclic amine, and bile acids ,219,220.The implementation of analytical approaches, such as metabolomics able to reveal more comprehensive metabolic signatures, it will be possible to intervene with precision on the therapeutic approach of IEMs, taking into account, among others, the role of diet and the microbial influences on host metabolism.As much as these initial results warrant further research and demonstrations, there may be opportunities to intervene with probiotics to modulate the wellbeing of patients with IEMs, and PKU in particular. As PKU is one of the most studied IEMs and still finds in the dietary approach a consistent, if not unique, portion of the therapeutic treatment, the angle of the microbiota composition and modulation should be taken in high consideration in the holistic approach to this disorder. In these patients the modified diet followed to minimize the consumption of Phe could create unbalances in the ratio of Firmicutes /Bacteriodetes, a factor that has been associated with an increase of BMI in human subjects and, dangerously, to childhood obesity. Coupled with chronic reduced consumption of AAs, often not compensated enough by protein substitutes, the microbiota of patients with PKU may result in importantly modified, shifting towards a microbial composition potentially favouring a less efficient glycaemic control, increased insulin resistance, and weight gain.Clostridiaceae, Erysipelotrichaceae and Lachnospiraceae families, Clostridiales class, Coprococcus, Dorea, Lachnospira, Odoribacter, Ruminococcus and Veillonella genera than in control subjects. On the contrary, bacteria of the genera Akkermansia and Prevotella and the Peptostreptococcaceae family were more represented in the PKU group. Interestingly, the Phylogenetic Investigation of Communities by Reconstruction of Unobserved States analysis done on the samples, indicated which could be the functional prediction of such a significantly modified microbiota, as measured in the PKU subjects. In fact, up to 23 bacterial functions resulted in being underrepresented in the PKU group, with potential consequences on starch and sucrose metabolism, glycolysis/gluconeogenesis, as well as Phe, Tyr, Trp, valine, leucine, and isoleucine biosynthesis. Of the overrepresented species in PKU subjects, 26 were related to lipopolysaccharide biosynthesis proteins and to glutathione metabolism. The authors imply that one of the strongest factors at the basis of these modifications is the higher levels of Phe in the blood of PKU subjects vs. the controls, although many other environmental factors need to be taken into account to justify the observed differences. Of interest is certainly the observation that the functional prediction model seems to corroborate the connection between higher carbohydrate and lower lipid intake of the PKU young children with the microbial composition, in turn associated with modification of starch and glucose metabolism. As an impaired energy harvesting capacity could potentially lead to overweight and obesity, such factors should already be taken into account in PKU subjects experiencing an unbalanced diet since the first years of their lives.The few studies that analysed the composition of the microbiota in PKU patients confirm the observation that a chronically modified diet influences the microbiota composition. In very young children (mean age 4.2 years of age) with PKU, de Oliveira F. et al.  showed tF. prausnitzii and Roseburia spp. and of the lactate-producing Lactobacillus spp. As the different diets followed by patients with PKU and MHP subjects do not seem to support the observed differences in SCFA concentrations, the authors suggest the microbiota, related to the reduced abundance of F. prausnitzii and Roseburia spp., as primarily involved in this variation. In addition, the measurement of the glycaemic index and load showing significantly increased values in PKU patients could be the basis of the modified gut microbial composition by providing a different substrate, although this cannot be considered the only cause, as the disease itself could be a direct cause for the observed differences in the microbial population. In larger patient PKU and MHP populations, Bassanini G. et al. [Veillonellaceae significantly depleted in these patients. Furthermore, Faecalibacterium and Ruminococcaceae (other) were significantly more abundant in MHP children, while Blautia, Clostridium (of the Lachnospiraceae family), Lachnospiraceae (other), and other species of the Firmicutes phylum were significantly increased in the PKU subjects when compared with the MHP controls. These changes once again indicate that the changes in the species’ presence as well as their relative abundance were modified in PKU patients with respect to subjects following a regular diet. Consequences can influence the host metabolism, like for example, facing a chronic lower SCFA content, especially of butyrate, due to the relatively reduced abundance of the butyrate-producing species, while hosting more samples of other genera  that have been associated with proinflammatory effects on the gut mucosa. Another aspect to take into consideration is the response of the Firmicutes phylum when evaluating daily glycaemic index and glycaemic load. The negative correlation between F. prausnitzii with the two indexes could be related especially to the quality of the carbohydrates. Fast-absorbed carbohydrates retain a high glycaemic index and seem to be correlated with a reduction of F. prausnitzii concentration in subjects at risk of metabolic syndrome, making an informed and careful composition of the low-protein foods an aspect potentially ameliorating the quality of foods available for this patient population.In children of a median of 8.7 years old, Verduci E. et al.  evaluate. et al.  corrobor. et al.  study thThe interest in the effects of food has encouraged research to shed light on the role of pre and probiotics for patients with IEMs, particularly PKU. A few strategies have been assessed over the years in order to modulate the intestinal microbiota in patients with PKU, starting with the addition of prebiotic oligosaccharides in infant formula that helped maintain a predominant concentration of bifidobacteria and reduce the pH of stools, two factors associated with reduced risk of infection in healthy breast-fed infants and therefore potentially favourable for PKU patients .E. coli and Vibrio cholerae [Desulfovibrio, a sulfate-metabolizing bacterium, in favour of increases in the Bacteroidetes or Firmicutes phyla, and was also associated with increased levels of SCFAs as well as anti-inflammatory effects [Coprococcus and Dorea, if compared with samples whose medium was not enriched with GMP, seems to be a favourable signal, given the association of the presence of these species to resistance to pathobiont colonisation [In this field, the research on the features of the GMP polypeptide has spanned in different directions to find that GMP can bind and inactivate toxins of cholerae , inhibitcholerae , enhancecholerae , increascholerae  and decrcholerae , and actcholerae ,227. Amocholerae ,229,230,cholerae ,232,233, effects . Interesnisation . As muchnisation , could cIn general, the approach to the dietary regimen for patients with PKU can be enriched with different considerations, in addition to the obvious control of Phe intake, to positively affect the way AAs are absorbed, the consequences of the diet composition and AA kinetics on the gut:brain axis pathways and the relative composition of the microbiota .In addition to these approaches possible with specific modifications in the composition or production process of the products used in PKU, other approaches have been taken in order to further improve the control of the disorder and the wellbeing of patients. E. coli Nissle has been extensively studied in animal models for its positive features and persistence in conditions of low microbial diversity, a factor linked to a variety of pathological or disease-related situations, also making it a good candidate as a vector for Phe-metabolizing PAL genome [Lactobacillus reuteri [E. coli Nissle [Aside from the pharmacological approaches, there is a wealth of research aiming at using specific species of bacteria as pre or probiotics, or utilizing the bacteria as vectors of Phe hydroxylase (PAH) or Phe lyase (PAL) to be able to give the patient the possibility to metabolize Phe and reduce or eliminate dependence on the life-long low-protein diet. As a probiotic, L genome . Lactoba reuteri  and agaii Nissle  have beeIn conclusion, the role of microbiota is continuously under scrutiny to better understand how its modulation may support educated approaches to improvement of the wellbeing of patients with IEMs. A holistic approach to the disorder looks at the variety of factors influencing the quality of life, and ultimately the health, of patients, and could strongly benefit from a personalized approach based on the knowledge about how components of the diet or concomitant drugs may modulate the microbiota and how the microbiota may in turn influence host metabolisms and neurological functions. The modified and reduced microbial diversity has been associated to a reduction in the production of beneficial SCFAs and butyrate and an increased release of pro-inflammatory molecules. In order to reduce imbalances, viable approaches, as in the healthy population, patients with IEMs, and particularly PKU, may use an improvement of quality of diet. Further clinical studies on pre, pro, and postbiotics in IEMs to create a microbial environment that facilitates the management of the disorder and improves quality of life are required. Other approaches, mainly pharmacological and genetic engineering, add additional weapons to the treatment of IEMs that could, in the future, reduce the differences between patients with IEMs and healthy subjects.


Intraneural ganglion cysts are benign soft-tissue masses located in the epineurium of peripheral nerves. They originate from nearby joint connections via articular branches. Traumatic events seem to play a role in their pathogenesis as well. Clinical manifestations include pain over the area of the cyst, palpable tender mass, hypoesthesia, and muscle weakness depending on the affected nerve. Our case highlights an uncommon clinical manifestation of this entity with acute foot drop, as the primary symptom, without any previous traumatic event, enriching by this way the current diagnostic thinking process of clinical physicians. We report a case of a 42-year-old military officer who presented to our emergency department with acute foot drop that appeared during a march. Initially, the common peroneal palsy was misdiagnosed as L5-S1 disc herniation, but investigation with lumbar MRI scan led to rejection of our primary diagnosis. After performing EMG of the lower extremity and knee MRI, an intraneural ganglion cyst of the common peroneal nerve was diagnosed. Patient was treated with surgical decompression of the cyst, followed by ligation and complete resection of the articular branch, as well as disarticulation of the superior tibiofibular joint. At a twelve-month follow-up, the patient showed significant functional recovery. This is, to the best of our knowledge, the first case of intraneural ganglion cyst manifested with an acute complete foot drop without a clear prior traumatic event. We underline the need for a high index of suspicion when dealing with cases of acute peroneal palsy without any accompanying symptoms. Intraneural ganglion cysts represent rare benign cystic lesions formed within the epineurium of peripheral nerves, near joints. The most common site affected is the common peroneal nerve and its branches, while similar cysts of the ulnar, sciatic, and tibial nerves have also been reported , 2.Patients usually experience pain, numbness, hypoesthesia, and muscle weakness along the distribution of the affected nerve. Positive Tinel's sign and a palpable tender mass around the area of the ganglion cyst are also common. The onset of symptoms can be gradual or, less commonly, acute, usually exacerbated by a previous traumatic event .The exact etiology of this condition remains unknown. Spinner et al. proposed the unifying articular theory, which highlights the key role of the articular branch in the pathogenesis of an endoneural ganglion cyst . AccordiThis study was conducted in accordance with the ethical standards of the institutional review board of our hospital and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards .A 42-year-old male presented to the emergency department of our military hospital with reported mild low back pain, associated with numbness in his right leg below the knee, and ipsilateral complete foot drop that occurred during a military march. The onset of neurological symptoms was acute, without any previous symptoms, reaching immediately its full intensity and was perceived by the patient as dragging of the foot. The patient had no history of lumbar spine disease. No traumatic event was reported during the march.Physical examination of the right lower extremity showed negative Lasegue's sign and straight leg raise test and hypoesthesia in the lateral aspect of the leg and dorsal aspect of the foot. Foot dorsiflexion and eversion and large toe dorsiflexion were severely impaired . There were no clinical signs of muscle atrophy on the anterior and lateral compartments of the leg. Physical examination of the contralateral lower extremity was normal. Knee and lumbar X-rays were normal.Our initial therapeutic approach included rest, NSAIDs, painkillers, and corticosteroid intramuscular injections. The patient was admitted to our clinic under observation status, and lumbar spine MRI scan was ordered; however, results did not correspond to the patient's symptomatology . MoreoveFollowing negative lumbar spine MRI results, a second more thorough physical examination was conducted, which revealed positive Tinel's sign in the area of the fibular neck, shifting diagnostic thinking process towards peripheral neuropathy. Subsequent EMG and NCS showed decreased conduction velocity and amplitude in the common peroneal nerve around the area of the popliteal fossa. Furthermore, knee MRI showed a multilobulated lesion in the area around the fibular head, in close proximity to the common peroneal nerve .Surgical exploration under loop magnification was decided. The common peroneal nerve was identified and followed to its bifurcation. Common and deep peroneal nerves appeared oedematous . The artPostoperatively, the patient was treated with a foot drop polyethylene splint and physiotherapy. Histological examination confirmed our diagnosis of an endoneural ganglion cyst . At a 3-Intraneural ganglion cyst cases reported in the literature are rare. The most frequent site of occurrence is reported to be the common peroneal nerve, followed by the ulnar and tibial nerves . AlthougCommon symptomatology of an endoneural ganglion cyst of the common peroneal nerve includes pain over the fibular head, with or without swelling, positive Tinel's sign, and paresthesia over the lateral surface of the tibia and dorsum of the foot. Some patients may present with gradual or acute weakness of the muscles located in the anterior and lateral compartments of the leg. Muscle denervation and atrophy have also been described , 13–16. MRI and/or ultrasound serve as useful tools of the diagnostic process. On ultrasonography, an endoneural ganglion cyst appears as a large well-circumscribed hypoechogenic lesion , while oUltrasonography is less time consuming than MRI and may be of value when guided percutaneous aspiration is decided, but it fails to illustrate the relation of the cyst with the neighboring anatomical structures as well as the articular connection and, unless a specialized radiologist in musculoskeletal ultrasonography is available or MRI is contraindicated, intraneural ganglion cysts are best imaged with magnetic resonance .Standard treatment of intraneural ganglion cysts is surgical excision of the ganglion and nerve decompression. An alternative minimally invasive treatment is decompression by percutaneous aspiration of the ganglion under ultrasound guidance, with or without corticosteroid injection . Both thThis article demonstrates a rare case of an acute foot drop caused by an intraneural ganglion cyst. To the best of our knowledge, this is the first case of an intraneural ganglion cyst resulting in an acute foot drop without a prior traumatic event. Our hypothesis is that of an existing asymptomatic intraneural ganglion cyst that deteriorated past the asymptomatic threshold point during the walk, possibly via an indirect mechanism, as proposed by Spinner et al. . AlthougIntraneural ganglion cysts, although infrequent, are well established in the literature and should be considered in the differential diagnosis of peripheral mononeuropathy, in order to avoid diagnostic pitfalls. Early diagnosis and surgical treatment with open decompression and concurrent address of the articular branch are of paramount importance to obtain positive outcome and minimize recurrence risk.


Our objective in the present study is to scrutinize the flow of aqueous based nanofluid comprising single and multi-walled carbon nanotubes (CNTs) past a vertical cone encapsulated in a permeable medium with solutal stratification. Moreover, the novelty of the problem is raised by the inclusion of the gyrotactic microorganisms effect combined with entropy generation, chemical reaction, and thermal radiation. The coupled differential equations are attained from the partial differential equations with the help of the similarity transformation technique. The set of conservation equations supported by the associated boundary conditions are solved numerically with the bvp4c MATLAB function. The influence of numerous parameters on the allied distributions is scrutinized, and the fallouts are portrayed graphically in the analysis. The physical quantities of interest including the skin friction coefficient and the rate of heat and mass transfers are evaluated versus essential parameters, and their outcomes are demonstrated in tabulated form. For both types of CNTs, it is witnessed that the velocity of the fluid is decreased for larger values of the magnetic and suction parameters. Moreover, the value of the skin friction coefficient drops versus the augmented bioconvection Rayleigh number. To corroborate the authenticity of the presented model, the obtained results (under some constraints) are compared with an already published paper, and excellent harmony is achieved in this regard. Nanofluid, characterized by copious attractive features, including outstanding chemical and mechanical steadiness, significant improvement in thermal conductivity, etc. , is founCNTs are the hexagonal structure of carbon atoms that are rolled in a cylindrical shape. Carbon nanotubes possess unique features like corrosion resistance, high thermal conductivity, and exceptional strength . Owing tThe aforementioned literature review reveals that abundant articles are available addressing the topic of nanofluid. But this subject gets narrower once we talk about nanofluid flow over a cone with nanotubes inserted into it. Furthermore, this exploration becomes unique when the above-mentioned characteristics are supported by entropy generation and gyrotactic microorganisms see . The numLet us assume a 2D aqueous fluid flow amalgamated with carbon nanotubes past a vertical cone in an absorbent media. The analysis is accompanied by solutal stratification, chemical reaction, and entropy generation see .x-axis past the cone surface. Along the y-axis, a magnetic field with strength 0B is enforced. The fluid is an aqueous based nanofluid containing both types of CNTs, whose thermo-physical characteristics are defined in The flow of the fluid is along the with the corresponding boundary conditionsThe hypothetical relations are characterized as follows:In the aforementioned equations, the dimensionless parameters are given by:The physically essential quantities, i.e., the skin friction, rate of heat and mass transfers, and local density of motile microorganisms, are appended below:The aforementioned physical quantities in dimensionless form are appraised as follows:The entropy generation of the presented model is specified as follows:i) HFI (heat transfer irreversibility), (ii) FFI (fluid friction irreversibility), and (iii) diffusion irreversibility. The entropy generation In Equation (19), entropy is comprised of three terms, namely  fluid past a cone erected vertically is discussed numerically. The analysis is performed in the presence of motile organisms with solutal stratification in spongy media. Furthermore, the attributes of thermal radiation and chemical species are explored in the presence of entropy generation. The main outcomes of the analysis are: