The digestive system has an innate monitoring and defense capacity, which allows the recognition and elimination of different dangerous substances. The complex analysis of the intestinal content comprises the cross-interactions between the epithelial cells, the enteroendocrine cells, the neural tissue and the cellular defense mechanisms. The enteric nervous system, also called "the enteric brain" or "the second brain" is the only neuronal network outside the central nervous system capable of autonomous reflex activity. The enteric nervous system activity is mostly independent of the central nervous system, but not in all aspects. In fact, even the enteral reflexes are a consequence of the bidirectional intestine-brain relation. The central nervous and enteric nervous systems are coupled through the sympathetic and parasympathetic branches of the autonomic nervous system. The gastrointestinal functions are regulated due to the interaction between the intrinsic neurons within the gastrointestinal wall and the extrinsic neurons outside the gastrointestinal tract. Here we provide an overview of the important role of the enteric brain in defensive behavior, as well as its structural and functional particularities that make it a special organ. All theThe IN are interposed between the IAN and the MN or SN, forming multisynaptic pathways that control the peristalsis .There are two types of motoneurons: excitatory and inhibitory. The branches of the excitatory neurons are projected either nearby or rostrally to the circular muscular layer, while the branches of the inhibitory neurons are distributed caudally from the circular muscular layer. The dominant neurotransmitters secreted by excitatory MN are acetylcholine and substance P, while the inhibitory neurons are vasoactive intestinal polypeptide (VIP) and nitric oxide (NO) .The EGC have laminar prolongations that wrap the surface of the ENS cells. Secondary to the release of cytokines in the gut, EGC secrete interleukins and express surface antigens (MHC class II) , supportThe gut also contains a special type of cells called the interstitial cells of Cajal. These cells are found between the nerve endings and smooth muscle cells  25]. Th. Th25]. The EEC, less than 1% of the gut cells, represent the largest endocrine organ of the human body, playing an important role in enteral information processing and transmission . The EECThe EEC communicate with the nervous system directly, chemically, and indirectly. The EEC have specialized basal processes with the role of hormones releasing and direct connection with the nerves, named neuropods , 38. TheThe direct connections between the EEC and the neurons suggest the double function of EEC, one that occurs at the top of the cell, the chemosensitizing function, and a second, conversion of this information in an electrical one at the cell base .The EEC represent a very important reservoir of chemical signals, with local and remote (including CNS) effects. The EEC are stimulated by the motor fibers of the ENS and transmit information to the extrinsic afferents belonging to ANS.The EEC respond to various substances that exist in the intestinal lumen, from nutrients to toxic products. The EEC represent the first level of intestinal information integration and the first step in the activation of neuronal networks that transmit the information to various cerebral structures –42. BesiThe EEC secrete a huge number of hormones that play a role in modulating appetite. These substances influence both the appetite and the metabolic control centers, as well as the pathways involved in the development of specific behaviors and memory .e.g., CNS) targets through their release into the bloodstream [According to the structure and location in the gastrointestinal mucosa, EEC are classified as opened and closed types. The open type EEC have a bottleneck shape and an apical luminal extension covered by microvilli. The microvilli have the role of directly detecting intestinal content. The closed type EEC do not have microvilli, do not reach the gut's content, and are found nearby the basal membrane. They are indirectly stimulated by the intestinal content via neural or humoral paths , 48. Botodstream , 49.The EEC release more than 30 peptides, most regulating the physiological processes related to digestion. The balance between orexigenic and satiety signals is particularly important in the early phase of digestion when the orexigenic signals are decreasing and the satiety rising, as well as at the start of the interdigestive phase when this situation is reversed .The most studied peptides produced by EEC are motilin and ghrelin, released through the interdigestive time and cholecystokinin (CCK), glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide- 1 (GLP-1) and peptide YY (PYY) released after food intake . The mosThe enteric MN are either excitatory or inhibitory to gut muscle . The excIn the myenteric plexus, there are two types of SM: cholinergic neurons and non-cholinergic neurons that use VIP or similar peptides as principal neurotransmitters. A small group of cholinergic neurons sends projections to the mucosa and the local blood vessels . The nonThe intrinsic afferent neurons (IAN) are also named intrinsic primary afferent neurons or primary enteric afferent neurons. IAN could be considered a distinct class because they have characteristic electrophysiological properties. These types of neurons are present in both plexi , represeThe interneurons are ascending  and descending . The IN appear crucial in controlling and coordinating intestinal activity. Distinct from the MN that have very short projections, less than 16 mm, the IN project up to 68 mm .There are three types of descending IN: ChAT/NOS/VIP positive , ChAT/SOM positive (which has a role in the transport of migrating myoelectric complexes) and ChAT/5-HT positive (regulates the secretomotor functions) , 89.The direct innervation of the digestive tract is realized by parasympathetic and noradrenergic endings . ParasymThere are five types of extrinsic sensory neurons: neurons with intraganglionic laminar endings (IGLEs), mucosal afferents, muscular–mucosal afferents, intramuscular arrays (IMAs), and vascular afferents .IGLEs are found in the capsule of ganglia from the myenteric plexus . They arIMAs are mechanoreceptors activated by stretch . They arMuscular–mucosal afferents are activated by mucosal stroking or stretch .The mucosal afferents do not go through the epithelial layer, and they are indirectly activated by the signals released by the epithelial cell, mainly by the EEC . The fibThere are four extrinsic sensory pathways: the vagal sensory innervation, the sensory innervation provided by the thoracolumbar and lumbosacral dorsal root ganglia, as well as viscero-fugal pathways .The vagal branches transmit information related to the physiological status of the gut, while the sympathetic thoracolumbar tracts convey information related to pain and gastrointestinal discomfort .The concept of "enteric brain" is developed in relation with the description of complex functions such as gut defense, anticipative-defense behavior or visceral metaphors. The enteric nervous system relies on the same nervous cell type and neurotransmitters/neuromodulators found in the central nervous system, being named by some authors "the second brain". This "second brain", in communication with the central nervous system, is involved in the etiopathogenesis of certain diseases, the control of interoceptive awareness and emotional well-being, and the behaviors associated with recompense, disposition, apprehension, stress and memory.


Nuss procedure has become the treatment of choice in pectus excavatum mainly because of the excellent functional and cosmetic results. Despite the good results, several complications have been reported. The aim of this study is to describe a case of thoracic outlet syndrome (TOS) after Nuss procedure and review the management of such rare complication. A 15-year-old boy otherwise healthy was submitted to Nuss procedure, with no perioperative complications. Two-weeks later, the patient complained of right-hand paresthesia, progressive weakness of the right arm and coldness. After imaging and electromyography, TOS diagnosis was established. Removal of the bar was proposed but refused by the patient. Conservative management with rehabilitation exercising and nerve nourishing was initiated. At 7 months, the patient recovered arm and hand function. Abrupt structural changes of thoracic cavity with marked elevation of the upper chest induce nerve and vascular compression arousing a TOS and should be acknowledged as one potential complication of Nuss procedure. Conservative management can be an alternative treatment to bar removal, showing good results on functional recovery in early stages of compression. Pectus excavatum (PE) is the most common chest wall deformity affecting ∼1 to 8 per 1,000 live births.Herein, we describe an unusual complication after PE correction by Nuss technique related to the marked structural change of the thoracic cavity induced by the elevation of the depressed thorax.A 15-year-old boy was referred to pediatric surgery consultation with symptomatic chest wall deformity. A severe PE deformity with a Haller index of 4 (correction index of 36.5%) on the thoracic computed tomography was documented . SurgicArterial Doppler ultrasonography confirmed compression of subclavian artery on costoclavicular space only in orthostatic position. Electromyogram findings corroborated the radicular lesion of C8-T1.After establishing thoracic outlet syndrome (TOS) diagnosis, removal of the thoracic bar was proposed. Since both the patient and the parents were highly satisfied with the esthetic result of the procedure, they refused to undo the procedure and asked for other therapeutic solutions. Conservative management was offered, and the patient underwent rehabilitation exercises and nerve nourishing therapy was given with supplementation with vitamin B1. The rehabilitation program included progressive strengthening of the shoulder girdle to achieve normal position of the scapula and humeral head control and escalating ranges of arm abduction. Cervical mobilization for scalene triangle release and sensory re-education of the right upper limb were also performed.Progressive recovery of muscle function was observed and the patient became asymptomatic. He recovered total arm and hand muscular function at 7-month follow-up.Described by Nuss in 1987, minimally invasive technique for PE correction was presented as an appealing alternative to the standard open repair.TOS is also a rare encountered complication of Nuss procedure.TOS is defined by a symptom complex that comprises pain, paresthesia, weakness, and discomfort of the upper limb aggravated by some movements.Herein, we report a case of a rare complication after Nuss procedure in an adolescent because of the acute structural changes in the thoracic wall. As previously described, the osseous shape alteration after the procedure probably cause narrowing of the space between the first rib and the clavicle. This leads to compression of the subclavian artery causing transient symptoms of acute ischemia, reverted by alteration of the arm positioning. Others have also described this rare complication .TOS treatment choice is highly controversial and depends whether there is a predominant vascular or nerve compression and the duration and evolution of symptoms.According to Nagasao et al,Being Nuss technique the actual state of the art in the treatment of PE, surgeons must be aware of this complication to its early recognition and treatment, preventing irreversible nerve damage. Although the existing literature is scarce, conservative treatment showed good outcomes while maintaining the final aspect of the thoracic wall. In the authors' opinion, it should be considered the first line of treatment in TOS post-Nuss. Progressive neuromuscular deficits or intractable symptoms should incite bar removal.


Dear Editor,The management of neurosurgical patients during the coronavirus disease 2019 pandemic requires special considerations like precautions to be taken during emergency airway access in case of deterioration in neurological status, caring for critically ill patients, protecting health care workers from exposure during the surgery, and post-operative recovery stage. Through this review, we aim to provide evidence-based recommendations and expert opinions for anaesthesiologists caring for neurosurgical practices during the coronavirus disease 2019 pandemic with a focus on preparedness and good clinical neuroanaesthesia practice. Neurological symptoms like dizziness, headache, loss of sense of smell and taste, encephalopathy, and altered mental status have also been found to be common in patients with COVID-19. There have been many reports about acute ischemic stroke also being one of the common presentations of patients suffering from COVID-19. These patients may often come for endovascular treatment or open surgeries.The most common clinical manifestations of COVID-19 have been described as fever, respiratory symptoms, myalgia, and fatigue. Patients with positive history or temperature >38˚C are then sent for real-time quantitative fluorescence polymerase chain reaction test and COVID-19-specific IgM and IgG antibody test. If found positive, these patients are admitted to the COVID-dedicated isolation rooms in the hospital which are suitable for droplet and contact precautions as recommended.The goals of COVID-19 testing specific neurosurgical patients are (a) to protect health care workers by ensuring the use of appropriate personal protective equipment (PPE) and (b) to prevent other post-operative patients from contracting the infection in the recovery room. As our hospital is surrounded by many containment zones that form the major source of our patients, we perform a preliminary temperature check and ask for a verbal history of cough or fever as part of the screening policy set by our municipal health authorities and the Indian Council of Medical Research.Irrespective of the COVID status of the patient, the preanesthesia evaluation of all patients is done by the neuroanesthesiologist wearing full PPE. A distance of 2 m is maintained during the interaction and the patient is made to wear a surgical mask throughout. History about specific neurological symptoms related to COVID like hypogeusia and hyposmia are elicited along with other common symptoms like headache, vomiting, loss of motor or sensory power, and vision disturbances. Complete neurological examination is done . Cough and gag reflex are not elicited while checking for cranial nerve (CN) IX and X. Special attention is paid to the function of CN I (sense of smell). In the general examination of other systems, special attention is given to inspection of the respiratory system for respiratory rate and signs of respiratory distress if any. Auscultation of all respiratory zones is performed thoroughly. Pre-operative oxygen saturation of every patient is noted during pre-operative anaesthesia evaluation. Among the pre-operative tests, chest x-ray of every patient is reviewed, or lung CT if available. In our hospital, general anaesthesia is the anaesthesia of choice for neurosurgical procedures. We use an aerosol protection box described by Tseng and Lai for intubation and extubation around the head of the patient after explaining it to him. Patients are pre-oxygenated using nasal cannula. Rapid sequence induction is followed for every patient to prevent bag-mask ventilation as it can cause aerosolization of the virus. The most experienced anaesthetist does the intubation using a videolaryngoscope to avoid direct exposure to airway and to maintain distance between the operator’s face and the patient’s face to reduce the risk of contamination. Once the endotracheal tube is inserted, it is clamped till the circuit is attached as per advice to reduce aerosol particle dispersion. Heat and moisture exchanger (HME) filters are used between facemask and breathing circuits. Maintenance of anaesthesia is done using total intravenous anaesthesia to reduce the risk of contamination of the vaporizers. Depth of anaesthesia is maintained to prevent any bucking and accidental disconnection of the tube. The aerosol box is used again during the time of extubation. Patient’s airway is thoroughly suctioned using a closed suction system. Lignocaine 1.5 mg kg-1 IV is given prior to extubation to the patient to reduce extubation response and cough. After extubation, the patients’ mouth is again covered with a surgical mask.Minimum number of operating room (OR) personnel required are allowed inside the theater, and everyone has to strictly wear PPE for every case. The patient is wheeled inside once all preparations are completely done wearing a 3 ply surgical mask and a disposable sheet covering his body. All monitors are done as per American Society of Anesthesiology (ASA) standards of monitoring.Following surgery, the soda-lime utilized for the surgery is discarded. Disposable single-use equipment is decontaminated and sterilized. Surfaces of all medical devices are cleaned with ammonium chloride. The OR is then cleaned with sodium hypochlorite 1000 ppm and treated with hydrogen peroxide.Emergency pituitary surgeries such as adenomas presenting with visual symptoms are approached transcranially instead of transnasally or transorally to reduce risk of viral transmission as the virus is highly colonized in the oral and nasal cavity.Usage of drills increases the risk of aerosol contamination of the theater milieu. Thus, all craniotomies in our institute are currently done using Gigli saw and Hudson’s brace. During the procedure, the scrub nurse irrigates the surgical site to reduce aerosol formation. As the COVID-19 pandemic continues to progress throughout the world, neuroanaesthesiologists should educate themselves of the various difficulties related to patient care during the pandemic and they should continue to update their knowledge, practice, and skills to provide a safe environment for the patient as well as fellow health care workers.


Esophago-respiratory fistula (ERF) refers to the formation of a pathological connection between the esophagus and respiratory tract. Acquired ERF is a rare but life-threatening diagnosis in adults. We describe a 79-year-old male who was admitted with an inhalation smoke injury. He was diagnosed with ERF by endoscopic visualization and sampling of the hyaline cartilage within the wall of the esophagus. Percutaneous endoscopic gastrostomy placement and conservative measures were effective in the management of ERF. Esophago-respiratory fistula (ERF) refers to the formation of a pathological connection between the esophagus and respiratory tract. Although rare in adults, it can cause significant morbidity and mortality in patients , 2. Malith day of admission, the patient developed acute melena and anemia while on a heparin drip for atrial fibrillation. Vitals were remarkable for hypotension and tachycardia, and his hemoglobin level was 6.5 g/dL. Esophagogastroduodenoscopy (EGD) was remarkable for a midesophageal ulcer and associated mucosal tear surrounded by granulation tissue. On the anterior wall of the esophagus, there was a yellow-tan foreign body that appeared to be embedded onto the esophageal wall  tube was placed the following day. Eventually, the pathology of the foreign body samples revealed fragments of hyaline cartilage, similar to that found in the tracheobronchial tree, which was concerning for ERF. Chest CT scan without contrast showed a narrowed left mainstem bronchus abutting the esophagus with foci of suspected extraluminal air along the left lateral margin of the esophagus . This waThe fistula had either resolved by the time of bronchoscopy or was too small to be visible during the procedure. The follow-up chest CT scan 11 days after stent placement no longer visualized the previously seen foci of air between the esophagus and left mainstem bronchi.Acquired ERF is a rare but life-threatening diagnosis in adults . A studyAlthough the initial symptoms of ERF can be insignificant, a delayed diagnosis can lead to severe complications such as pneumonia, life-threatening hemoptysis, and respiratory failure , 6, 15. The goal of treatment of ERF is to prevent severe complications and optimize nutritional status . SurgicaIn summary, we present a case of ERF due to inhalation burn injury, which was diagnosed by endoscopic visualization and sampling of hyaline cartilage within the wall of the esophagus. The most likely cause of ERF was inflammation and irritation of the bronchial mucosa secondary to smoke inhalation. PEG placement and conservative measures were effective in the management and healing of ERF. As in our case, the collaboration between pulmonology and gastroenterology services is essential for the diagnosis and management of this condition.


By combining the molecular perturbation design with the kinase inhibition likelihood analysis and similarity assessments, we showed that the proposed molecular design strategy can produce novel valid molecules and transform known inhibitors of different kinase families into potential chemical probes of the SRC kinase with excellent physicochemical profiles and high similarity to the known SRC kinase drugs. The results of our study suggest that task-specific manipulation of a biased latent space may be an important direction for more effective task-oriented and target-specific autonomous chemical design models.In the current study, we introduce an integrative machine learning strategy for the autonomous molecular design of protein kinase inhibitors using variational autoencoders and a novel cluster-based perturbation approach for exploration of the chemical latent space. The proposed strategy combines autoencoder-based embedding of small molecules with a cluster-based perturbation approach for efficient navigation of the latent space and a feature-based kinase inhibition likelihood classifier that guides optimization of the molecular properties and targeted molecular design. In the proposed generative approach, molecules sharing similar structures tend to cluster in the latent space, and interpolating between two molecules in the latent space enables smooth changes in the molecular structures and properties. The results demonstrated that the proposed strategy can efficiently explore the latent space of small molecules and kinase inhibitors along interpretable directions to guide the generation of novel family-specific kinase molecules that display a significant scaffold diversity and optimal biochemical properties. Through assessment of the latent-based and chemical feature-based binary and multiclass classifiers, we developed a robust probabilistic evaluator of kinase inhibition likelihood that is specifically tailored to guide the molecular design of novel SRC kinase molecules. The generated molecules originating from LCK and ABL1 kinase inhibitors yielded ~40% of novel and valid SRC kinase compounds with high kinase inhibition likelihood probability values ( The recent advances in machine learning (ML) have driven the design of new expert systems and automated workflows capable of modeling complex chemical and biological phenomena ,2,3,4,5.Generative adversarial networks (GAN) represent another class of ML approaches successfully applied for de novo molecular design ,16,17,18Generative-based ML models that enable the generation of a three-dimensional (3D) representation of small molecules have also received considerable attention for their unique advantages and potential to explicitly design drug-like molecules in a target-conditioning manner . A novelML models have been actively deployed to help in the discovery of novel inhibitors targeting protein kinases, which are important oncology targets ,37. The The design of novel and selective chemical probes to interrogate kinase functions remains a considerable challenge. The objective of the current investigation is the development and validation of an integrated ML approach for the autonomous molecular design of chemical probes for protein kinase target-specific tasks. Proto-oncogene tyrosine-protein kinase SRC (short for sarcoma) is a non-receptor tyrosine kinase protein that plays a vital role in regulating diverse cellular processes and is frequently overexpressed in various cancers . We deveWe began by introducing the proposed ML model and describing the components and main stages of the generative molecular design pipeline . The appMany well-established and large datasets of generic small molecules and specialized collections of kinase inhibitors were utilized in the development of the generative approach presented in our study. The employed databases of small molecules and drug-like inhibitors included DrugBank (DrugBank Release Version 5.1.9) , BindingAn adaptation of the ChemVAE approach  was usedAfter evaluating the optimal parameters, we examined each stage of the generative learning process and monitored the number of produced valid molecules when the chemical transformation was initiated from different kinase families . SeveralUsing ChemVAE, the training sets of GDB-17 molecules and kinase inhibitors were encoded into a 196-dimensional vectorial representation in the continuous latent space. The 196-dimensional vectors representing these molecules were then fed through principal component analysis (PCA) to facilitate visualization and analysis of the latent space in two dimensions . For theUsing PCA decomposition of the latent space, we analyzed differences in the organization of the latent landscapes for small molecules and the kinase molecules. The two-dimensional latent space plots and heatmaps based on PCA were constructed to visualize and analyze densities of the regions in the latent space . StrikinBy visualizing the latent space of kinase inhibitors targeting different families, we also detected signs of the partial overlap in the latent space representation while showing that some regions of their latent space may be more family-specific. One of the focal observations of our experiments was the fact that the SRC kinase inhibitors and ABL1 kinase inhibitors were organized into distinct clusters in the latent space C. This aPCA allowed to reduce the dimensionality of the dataset while still preserving most of the variance by creating a new feature space based on the top eigenvectors. By computing the percentage of variance explained by the individual principal components (PCs), we found that a significant amount of variance in the data samples and the topology of the latent space landscape could be accounted for by the first two PCs . We obseThe minimum standard deviation values were in the range of 0.65–0.86, while the maximum standard deviation values were within 1.29–1.63 . The SRCUsing Random Forest (RF) architectures, we developed and compared several different ML classifiers of the kinase inhibition likelihood for the generated molecules. The models were constructed using the training set of kinase molecules from 10 kinase families combined with a set of GDB-17 small molecules. The binary and multiclass kinase inhibition likelihood classifiers were developed using both the latent space and chemical feature-based representations of the molecules. The binary classification models considered all kinase families (except for the target SRC kinase family) together with the dataset of GDB-17 molecules and assigned them a target value of 0, while the SRC kinase inhibitors were assigned a target value of 1. The multiclass classification models assigned each of the considered kinase families a different target variable value, with the goal to identify the differences between family-specific kinase inhibitors.The binary latent space classification model was trained using the coordinates of each molecule in the latent space, where each molecule was represented by a total of 197 feature variables (196 latent space dimension variables and one classification variable). While there were distinct clusters of molecules within the latent space, a substantial number of features for each molecule, when converted to its latent space coordinates, decreased the overall accuracy . The conThe latent space-based and chemical feature multiclass models considered the kinase inhibitors of different protein kinase families as distinct categories by assigning each class of the kinase inhibitors a different target variable value. The analysis of these classifiers indicated that the number of classification variables lowered the accuracy of the models in their predictions of the target values . InteresThe receiving operating characteristic (ROC) graph was used to evaluate the performance of the classifier that differentiated the kinase inhibitors from small molecules. The AUC of the model showed that the coverage of variation within the dataset was ~97% and that the model could accurately distinguish both classes of the non-SRC molecules and the SRC kinase inhibitors with a high level of certainty A. To ideWe developed a cluster-based perturbation approach to facilitate targeted sampling of the latent space. In this model, molecules were first clustered into groups in a non-biased manner allowing molecules with comparable properties to assemble into clusters. Accordingly, it was assumed that the molecules clustered within respective clusters would be characterized by specific molecular and chemical properties. To transform these molecules, we then invoked a controllable step of cluster-based perturbation. Using the centroid of each cluster as the representative of the properties, we navigated every data point in the cluster closer to the centroid by optimizing a set of parameters. Using this strategy, a cluster-based perturbation sampling explored the latent space along controllable directions yielding a diverse set of novel molecules featuring various molecular scaffolds. The generated molecules were then evaluated using the kinase inhibition likelihood classifier, and when the output probability was greater than 70%, the respective molecules were designated as SRC kinase-like inhibitors. During the cluster-based perturbation stage of the generative design process, 1000 encoded molecules from each of the 10 kinase families were selected and processed through the pipeline to assess the quality of the predicted molecules and obtain the optimal parameters for the perturbation protocol. These parameters included the number of clusters, a scaling factor for the centroid-based targeted perturbation, and a noise level for a perturbation step . Using tAfter the perturbation step was executed, the perturbed vector was decoded using the ChemVAE network. During this stage, the probabilistic neural network performed 500 decoding attempts of the latent variable into a valid SMILES, each time subjecting the resulting molecules to a validity check via chemical property computations  includinTo illustrate the output of the generative pipeline, we compiled a list of several generated SRC-like kinase molecules that originated from the inhibitors of different kinase families. The presented molecules were characterized by the high kinase inhibition likelihood and a considerable similarity to the existing SRC kinase inhibitors . We notiIn the post-processing analysis, we examined whether novel SRC-like molecules could be generated by the chemical transformation process initiated from the inhibitors of different kinase families. According to this analysis, the perturbation-based molecular generation process that started from the inhibitors of LCK and EGFR kinases yielded a higher percentage of molecules (~19–23%) as compared to the MAPK14 and FLT3 families, which produced only 5–7% of novel valid molecules A. When oTo evaluate similarity between the generated molecules and known SRC kinase inhibitors, we also examined the distribution of the generated molecules with the high Tanimoto similarity coefficient . Our anaTo summarize, a combination of the cluster decomposition and perturbation-based exploration of the latent space allowed for the generation of novel molecules with a high similarity to the experimentally known SRC kinase inhibitors via chemical transformation of the kinase inhibitors from different families.To evaluate the properties of the generated molecules with a high similarity to the known SRC inhibitors, we calculated three different drug-like metrics: QED, logP, and SAS values for the produced molecules, with a specific focus on novel compounds originating from the inhibitors of ABL1, LCK, and EGFR kinases . For comIn addition, we conducted an analysis of the main physicochemical properties of the generated molecules with a high kinase inhibition likelihood . The disWe also performed a comparative analysis of the drug-like properties averaged over generated molecules including QED, SAS, and LogP for classes of produced molecules that were characterized by a high similarity to the known SRC kinase inhibitors A–C as weA more complete description of the generated molecules is presented in the https://github.com/kassabry/Perturbation_Experiment (accessed on 27 August 2022). The GitHub site provides detailed documentation and a guide of the deposited information and software. The deep learning frameworks were supported by the TensorFlow backend and python tools such as NumPy, SciPy, pandas, and scikitlearn ) corresponding to small molecules from a variety of domains, with the following atoms  [For the training datasets of small molecules, we employed a fraction of the GDB-17 database version  ,51. For r, P, I)  and (b) r, P, I) . The kinThe perturbation approach was implemented by using a combination of K-means clustering  and pertThe scaling factor To observe how noise would affect the generation yield of novel compounds, we evaluated six distinct levels of noise, from level 5 to 30 in increments of five. We observed that a noise level of 5 contributed to a greater generation yield of valid molecules as compared to noise levels of 10 and above. At a noise level of 10, there was less generation yield than at a lower noise value. When using noise level 15 and above, the generation yield was low. Due to the extensive alteration in the continuous latent space, adding random noise to already perturbed data points could cause additional changes in the chemical and molecular features of the encoded compounds, which results in low density areas of decoding potential and reduced yield of valid novel molecules. After evaluating and optimizing every parameter that is involved in the targeted perturbation protocol, we found that a 3-cluster-based split, a scaling factor of 0.8 for the centroid-based perturbation, and a noise level of 5.0 were the optimal set of parameters to guarantee a sufficiently high generation yield of valid and novel molecules.After perturbation step was executed, the perturbed vector was decoded using the chemical VAE network. We imposed validity constraints on the created molecules by filtering out any latent locations that had a 0% decode validity. The probabilistic chemical VAE neural network attempted to decode the latent variable into a valid SMILES string 500 times, each time feeding the molecule into RDKit  computathttps://github.com/kassabry/Perturbation_Experiment (accessed on 27 August 2022). The GitHub repository contains the framework and code for molecular transformations of kinase inhibitors using generative learning methodologies and targeted perturbation modeling. The GitHub site provides detailed documentation and guide of the deposited information and software. The deep learning frameworks are supported by the TensorFlow backend [All scripts, software, and models used in the development and experiments are available in the GitHub site  backend  and pythThe Random Forest classification method  is used For chemical feature-based classifier, 20 chemical features are considered for each molecule during training and testing: the number of rings, the exact molecular weight, the number of rotatable bonds, the fraction of carbon Sp3 atoms, the Hall–Kier alpha value, the Labute ASA value, the number of aliphatic carbocycles, the number of aliphatic heterocycles, the number of aliphatic rings, the number of amide bonds, the number of aromatic carbocycles, the number of aromatic heterocycles, the number of aromatic rings, the number of stereocenters, the number of bridgehead atoms, the number of H-bond acceptors, the number of H-bond donors, the QED value, the SAS value, and the logP value. The resulting score in the Random Forest model’s output represents the probability or likelihood that a molecule can be deemed a kinase inhibitor. Values closer to 0 indicate that the molecule has a low kinase inhibition likelihood, whereas values closer to 1 indicate that the molecules have a high kinase inhibition likelihood.To assess the performance of each model, accuracy, recall, precision and F1 scores were calculated to measure the performance of classification models. These parameters are defined as followsAn F-score is a measure of precision and recall and is often used in binary classification problems. Precision is defined as the amount of positive samples the model predicts correctly (true positives) divided by the true positives plus the false positives. Recall is defined as true positives divided by true positives plus false negatives. The model performance is evaluated using the receiver operating characteristic area under the curve. The receiver operating curve (ROC) is a graph where sensitivity is plotted as a function of 1-specificity. The area under the ROC is denoted AUC. A reliable and valid AUC estimate can be interpreted as the probability that the classifier will assign a higher score to a randomly chosen positive example than to a randomly chosen negative example.p > 0.75) and high similarity values (Tanimoto coefficient > 0.6).In this work, we proposed an integrated ML approach for controllable molecule manipulation and an efficient perturbation strategy to improve the steerability and interpretability of the generative models. The results of this study showed that the proposed method allowed for an efficient exploration of the latent space along interpretable directions guiding the generation of novel SRC family-specific kinase molecules featuring scaffold diversity and optimized drug-like biochemical properties. A robust chemical feature-based machine learning predictor of the kinase inhibition likelihood was developed to aid in the perturbation-based transformation of small molecules. By combining molecular perturbation design with the kinase inhibition likelihood analysis and similarity assessments, we demonstrated that the proposed strategy allowed for morphing of the kinase inhibitors into novel chemical probes of the SRC kinase that exhibit desirable ranges for all included chemical properties and display a high similarity to the known potent SRC kinase inhibitors. The central finding of this study revealed that the integration of cluster partitioning and perturbation-based exploration of the latent space allows for the generation of novel kinase molecules with a high similarity to the experimentally known SRC kinase inhibitors via chemical transformation of the kinase inhibitors from different families. Furthermore, the generated molecular output originating from LCK and ABL1 kinase inhibitors yielded ~40% of novel and valid kinase compounds with kinase inhibition likelihood probability values (Although the proposed perturbation-based approach was robust and showed promise in the generation of novel valid molecules and the “interpretable transformation” of kinase molecules towards family-specific kinase probes, there is a significant room for improvement in this approach and related models. Our analysis suggested that one of the important lines for the improvement of the interpretable and target-oriented molecular design approaches would be retraining and adapting the variational autoencoder to use the wealth and diversity of the existing kinase inhibitors with different levels of activity, binding affinity, and selectivity. Since the ChemVAE model is not specifically trained on kinase molecules, the retraining of the deep neural network using the vast space of kinase inhibitors could potentially lead to a more accurate and granular latent space representation of the kinase space, thus enabling a more accurate and robust navigation of the kinase latent landscapes.An important problem associated with generative learning is the “black box” nature of neural networks, which often hinders the interpretability of predictions preventing us from explicitly discerning what specific property or properties are primarily harnessed to generate output. Despite the ability to generate molecules with desired properties, it is often difficult to understand the generation process and the chemical rules that govern the generation process with previous methods. Through assessment of the latent-based and chemical feature-based binary and multiclass classifiers, we developed a robust probabilistic evaluator of kinase inhibition likelihood that is specifically tailored to predict novel SRC kinase inhibitors. The approach leveraged the learned latent space landscapes to achieve controllable generation by accepting/rejecting sampled molecules based on a robust feature-engineered classifier. Another potential avenue for future improvement would also include the incorporation of three-dimensional features and diverse experimental data on kinase molecules into VAE models by adding an additional embedding scheme so that the topological and biological information of molecules can also be embedded and contribute to clustering and the subsequent perturbation navigation stage of the design process. While exploring the chemical space with unbiased pretrained autoencoder generative models becomes a dominant theme in many applications of deep molecular design models, the results of our study suggested that task-specific manipulation of a biased latent space may be an important future direction for more effective task-oriented and target-specific autonomous chemical design models.


Since the initial discovery of surface-enhanced Raman scattering (SERS) and surface-enhanced fluorescence (SEF), these techniques have shown huge potential for applications in biomedicine, biotechnology, and optical sensors. Both methods rely on the high electromagnetic fields created at locations on the surface of plasmonic metal nanoparticles, depending on the geometry of the nanoparticles, their surface features, and the specific location of analyte molecules. Lately, ZnO-based nanostructures have been exploited especially as SERS substrates showing high enhancement factors and increased charge transfer effect. Additionally, applications focused on enhancing the fluorescence of analyte molecules as well as on tuning the photoluminescence properties of ZnO nanostructures through combination with metal nanoparticles. This review covers the major recent results of ZnO-based nanostructures used for fluorescence and Raman signal enhancement. The broad range of ZnO and ZnO–metal nanostructures synthesis methods are discussed, highlighting low-cost methods and the recyclability of ZnO-based nanosubstrates. Also, the SERS signal enhancement by ZnO-based nanostructures and the influences of lattice defects on the SERS signal are described. The photoluminescence enhancement of ZnO in the presence of noble metal nanoparticles and the molecular fluorescence enhancement in the presence of ZnO alone and in combination with metal nanoparticles are also reviewed. Over the last decades, ZnO-based nanomaterials have been extensively used in the industry and investigated in various application fields such as optoelectronics, biomedicine, agriculture, food, and cosmetics –3. The wHybrid nanomaterials can be obtained by combining ZnO with metal NPs, thus integrating the material properties of both components and resulting in new and enhanced properties that are not obtainable from the single component nanoparticles. Recent studies showed that ZnO properties can be tuned and improved when combined with metal nanoparticles, resulting in enhanced photoactivity of Au-decorated ZnO nanocrystals for photoelectrochemical water splitting , improveThe electromagnetic (EM) enhancement in surface-enhanced Raman scattering (SERS) appears due to the enhanced local electric field that is generated when localized surface plasmon resonances (LSPRs) are excited by light incident on noble metal nanostructures. Besides this field enhancement, the excitation of the collective oscillations of the conduction electrons in metallic NPs results in strong absorption and scattering of light in the visible range of the electromagnetic spectrum. Moreover, even larger EM field enhancement can be obtained in noble metal NPs through the creation of “hot spots”, small gaps between NPs (less than 10 nm), due to interparticle EM coupling under the incident light. Similarly, large field enhancements can arise around sharp tips and edges on the rough surface of NPs. The EM enhancement effects on semiconductor nanostructures, however, are significantly inferior to those on noble metals since the LSPR is centred in the near-infrared in the case of the conduction band (CB) and in the UV region in the case of the valence band (VB) . TherefoThis review article seeks to present the fabrication methods and applications of zinc oxide nanostructures enhancing the photoluminescence emission or the Raman signal of analyte molecules. First, we focus on a wide range of synthesis methods of ZnO nanostructures and nanocomposites based on ZnO and noble metals. Second, the Raman enhancing capabilities and advantages of ZnO-based nanostructures as SERS substrates are discussed. Last, we focus on methods for enhancement of ZnO photoluminescence by noble metal nanoparticles and the enhancement of molecular fluorescence by ZnO alone and by ZnO–metal hybrid nanoparticles. Moreover, we consider the physical phenomena governing both the Raman and fluorescence enhancement using ZnO nanostructures.Among the exhaustive list of available physical and chemical methods used for obtaining ZnO nanoparticles, solution synthesis methods such as sol–gel , chemicaThe polyol method offers good control of the shape and size of the synthesized products, accompanied by a uniform granulomere distribution, relatively low reaction temperature, and a reaction time of the order of minutes. Also, the used polyols are environmentally harmless and biocompatible. The method has several particularities due to the involved polyols, such as high boiling point (up to 320 °C) and dielectric constant, the solubility of simple metal salt precursors, and coordinating properties for surface functionalization preventing agglomeration . The ZnOVarious morphologies including nanoworms, nanowires, and nanorods with excellent crystallinity were also obtained using the solvothermal method . AccordiThe simplicity and environmentally friendly conditions involved in the hydrothermal synthesis of ZnO make it an attractive growth method, widely used in recent years. A comprehensive review indicating the morphology of ZnO nanostructures grown using this method is given in . Success2, for SPR-based substrates has gained increased attention in recent years due to important advantages that they offer, for example, good recyclability, long-term use, and cost effectiveness. For ultrasensitive detection of molecules, however, the SERS performance of standalone semiconductor substrates is too weak. Therefore, the development of hybrid nanomaterials based on semiconductors decorated with noble metals, or vice versa, has been proposed. These hybrid nanostructures show enhanced optical and electronic properties due to the coupling between the noble metal and the semiconductor 34], the 6G peaks . The hig6 (before) to 108 (after hydrogenation)  st st7 and study in  found a Another motivating advantage of the ZnO-based plasmonic substrates refers to their recyclability. A renewable substrate is obtained when target molecules adsorbed on it can be fully removed and the substrate reused. Since metal-based SERS substrates are disposable after being used, the photocatalytic property of ZnO would ensure reduced consumption of resources and costs when used as a SERS substrate. The self-cleaning ability of ZnO alone or ZnO–noble metal-based nanostructured substrates has been shown under UV or visible irradiation via the photocatalytic degradation of the organic molecules attached to the substrate ,34,53. FIt appears that the photocatalytic degradation depends on the geometrical configuration of the ZnO–metal nanocomposites, as well as the energy of the incident light . MoreoveZnO nanostructures usually present two emission bands, namely a narrow UV band assigned to exciton recombination  with a m2 NPs with Zn, using 4-MBA as analyte.Xue et al.  and LibiZnO nanomaterials present a wide bandgap of (3.3–3.7 eV) and a high excitation binding energy of 60 meV, which gives them promising optoelectronic device applications –85. BeinHence, the ZnO PL is of great interest and its enhancement is also important in order to develop efficient optoelectronic devices. Numerous studies have demonstrated the enhancement of both near band edge (NBE) and defect emissions using ZnO decorated with metallic NPs –93. The Additionally, the features of ZnO nanostructures photoluminescence spectra were shown to depend on the thicknesses of the Au layer. Viter et al. obtained interesting results studying the variation of photoluminescence spectra with the thickness of the Au layer in Au–ZnO thin films. Using a thin layer of Au (5 nm), the strong UV peak emission was enhanced and the visible emission was quenched. In contrast, when using a thick layer of Au (30 nm), the UV emission was drastically reduced, while the visible emission was enhanced .The PL enhancement has been assigned to the localized surface plasmon resonance of metallic nanostructures –100, as ). The green emission is correlated with  vacancies, which capture the electrons from the conduction band turning into a metastable state. The recombination of these captured electrons and the holes in the VB lead to the green emission [ defects capture electrons from the conduction band and their recombination with the holes from VB can result in the green emission that dominates the spectrum at higher Au concentration attached to ZnO NRs. A 7-fold enhancement of ZnO defect emission was demonstrated for Au–ZnO nanocomposites obtained through a simple photoreduction method and has been assigned to the surface plasmon oscillations of Au and the electron capture by the single ionized oxygen vacancies in ZnO [Besides the UV emission enhancement of ZnO NPs by metal NPs, the presence of metal could also enhance the green emission. The green emission enhancement of Au-decorated ZnO NRs was observed for a higher concentration of Au, which increased single ionized oxygen vacancies  and nanorod arrays by . DiffereA 10-fold fluorescence enhancement was detected for Cy5, rhodamine 6G, and fluorescein placed on a nanoscaled ZnO film  Figure –c. The fThe use of ZnO nanosubstrates for enhanced biomedical detection has received great attention due to their optical properties and other great advantages. Early detection of disease markers and the measurement of specific protein concentrations is a key tool in clinical medicine because it can provide a better diagnostic tool. Fluorescence is also broadly used in biotechnology as a sensitive detection method for different molecules. For all of these applications, high fluorescence quantum yield, photostability, and brightness of the used fluorescent molecules are essential. The values of quantum yield and lifetime could be influenced by non-radiative decay rates, which result from changes in the environment of the fluorophores, fluorescence quenching, or fluorescence resonance energy transfer (FRET) ,116. EngFewer studies investigated the enhancement of fluorescence in ZnO–metal nanocomposites and further research is still needed to explore this direction. Core–shell metal–ZnO nanocomposites have shown new exciting properties and even metal-enhanced fluorescence for dyes mixed with the NPs.  demonstr−6 and 10−5 M of both the fluorophores and ZnO NPs [Considering the fluorescence enhancing properties of ZnO NPs, FRET studies have been carried out as well. FRET, which is a non-radiative process based on the energy transfer between an excited state donor and a ground state acceptor, can be manipulated using NPs, since it depends on a number of parameters including fluorescence lifetime and quantum yield of the donor molecule. The FRET effect has been investigated between two dyes, fluorescein, and rhodamine 6G, in the presence of ZnO nanostructures. An increase of FRET (69%) in the presence of ZnO flower-shaped NPs was observed for concentrations between 10 ZnO NPs . The ZnO ZnO NPs .The promising characteristics of ZnO nanomaterials have recently propelled their investigation for a wide range of applications in optical sensors and optoelectronic devices. This review focused on their applications in surface-enhanced Raman spectroscopy and surface-enhanced fluorescence, two powerful analytical tools based on nanosensors for the sensitive detection of chemical and biological molecules. ZnO alone has presented appealing enhancing abilities in fluorescence-based detection applications. However, in the case of SERS, the performance is still moderate. An attractive solution for improving the sensing capabilities of ZnO nanostructures relies on the development of hybrid nanomaterials based on ZnO and metal nanoparticles. In this manner, the optical properties of ZnO can be improved and adjusted according to the targeted application due to the excitation of localized surface plasmon resonances. ZnO nanostructures can be designed into various controlled morphologies and sizes owing to the advancement in fabrication techniques. Moreover, facile and low-cost synthesis methods can be adapted for large-scale production. The fabrication techniques employed to develop ordered hybrid nanostructured substrates range from more expensive and laborious ones to more cost-efficient and simple ones. The main challenge of fabrication methods relies in the simultaneous development of ordered ZnO nanostructures with sufficient metal coverage and in the creation of “hot spots” at the surface of ZnO nanoparticles required for the amplification of the Raman signal. Therefore, the current demand of metal–semiconductor nanocomposites for nanoscale sensor devices requires the development of more facile and versatile synthesis routes that can yield the required fabrication and performance conditions.The ZnO–metal nanomaterials have shown increased SERS activity compared to ZnO alone or metal-based nanosubstrates. The performance enhancement requires the existence of both electromagnetic and charge transfer enhancements, which can be accomplished by the controlled tuning of the surface plasmon band of the nanosubstrate to the visible region and ensuring efficient interaction of the semiconductor and/or noble metals with the analytes. All of these are essentially contributing to the SERS enhancement. Despite some of the current fabrication challenges and still limited sensing applications, the recently obtained enhancement factors indicate that ZnO-based nanosubstrates are able to achieve high selectivity and ultrahigh sensitivity. Moreover, several encouraging properties of ZnO, such as biocompatibility and self-cleaning, have yet to be further researched. ZnO-based substrates show a photocatalytic potential to degrade the organic molecules attached to their surface and ensure the reproduction of the Raman signal after being cleaned. By incorporating metal NPs, the photocatalytic performance can be enhanced, thus, ensuring economic and environmental advantages.The strong luminescence of ZnO has guaranteed its exploitation for optoelectronic devices, namely light-emitting diodes. Recent research on the fluorescence enhancing capabilities of combined ZnO–metal nanostructures, however, has resulted in contradictory results. Therefore, further studies are needed in order to properly control the fabricated ZnO–metal nanomaterials and correlate the developed nanostructures with the observed fluorescence enhancement and/or quenching. Additionally, clarification of the governing mechanisms is required.Furthermore, ZnO nanostructures showed promising capabilities for SEF applications. The use of ZnO NPs as substrates for fluorescence enhancement is an alternative to overcome the shortages of metal-based substrates, such as fabrication cost and susceptibility to fluorescence quenching. Additional advantages include a high capacity for multiplex detection as well as the fact that the fluorescence enhancement does not seem to depend on the distance between fluorophores and the surface of ZnO substrates, as it happens with metal nanostructures. Nevertheless, SEF applications of ZnO and ZnO–metal nanostructures have been limited and additional studies are needed to elucidate the fluorescence enhancing capabilities and to properly clarify the responsible mechanism.


The rectal prolapse is defined as the concentric protrusion of full or partial thickness of the rectum or rectosigmoid via the anus. This is an increasing clinical concern that is usually found in old female patients.A 39-year-old male patient was referred due to an un-reduceable rectal projection from a week ago. The primary endeavor for reduction of the projection under sedation and after local mannitol treatment at the operation room was unsuccessful, so surgical resection and reduction were planned for the patient.Management of rectal prolapse has always been one of the challenges of colorectal surgery. For patients with incarcerated prolapse manual reduction under sedation is used. If the reduction is unsuccessful, surgical procedures are used. •The rectal prolapse is defined as the concentric protrusion of full or partial thickness of the rectum or rectosigmoid via the anus.•Management of rectal prolapse has always been one of the challenges of colorectal surgery.•Giant rectal prolapse defined as segment of rectosigmoid larger than 10 cm in length. Complet2A 39-year-old male patient was referred to the surgery department of Shahid Madani Hospital in Alborz province in Iran via ambulance due to an un-reduceable rectal projection. The patient had a history of chronic constipation and opium addiction. Also, he noted previous episodes of rectal projection which were reduced to their origin via manipulation. The patient had a negative drug and other medical histories. The current state has been initiated a week ago and progressed till referring. Physical examination revealed an awake and oriented patient, which was not ill or toxic. He was not feverish and did not note any nausea or vomiting. The gas pass and defecation were not impaired. Full-thickness projection of the rectum, with an ulcerative surface and purulent secretions, was notable . The pri3Our patient was a young man with a history of opium addiction and chronic constipation for years which full-thickness rectal projection brought him to the emergency department. Due to primary failure in reducing the rectal prolapse and incarceration, the patient was a candidate for surgical management; altemeier rectosigmoidectomy with an ileal diversional loop.According to the latest version of the World Society of Emergency Surgery and the American Association for the Surgery of Trauma (WSES- AAST) guideline, the management of uncomplicated, non-strangulated cases of rectal prolapse, should be initiated with non-operative procedures including submucosal epinephrine or hyaluronidase administration, rectal insertion of hypertonic dextrose or mannitol treated gauze, and elastic band wrapping, in a mildly sedated patient with Trendelenburg position ; as we h4In-time surgical management after primary failure in the non-operative management of complete rectal prolapse warrants an acceptable clinical course with minimum perioperative complications and excellent short time surgical outcomes.This is a case report paper.There was no funding in this research.All authors had same contribution on this work.There are no conflicts of interest.1.Name of the registry:2.Unique Identifying number or registration ID:3.Hyperlink to your specific registration (must be publicly accessible and will be checked):The corresponding author is Dr. Javad zebarjadi bagherpour who accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.Informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.Not commissioned, externally peer-reviewed.


Relativistic collisionless shocks are considered responsible for particle energization mechanisms leading to particle acceleration. While electron energization in shock front region of electron/ion collisionless shocks are the most studied, the mechanism of electron energization in interaction with self-generated magnetic vortices (MVs) in the upstream region is still unclear. We investigate electron energization mechanism in the upstream region of electron/ion relativistic collisionless shocks, using two dimensional particle-in-cell (PIC) simulations. We discuss mechanism of electron energization which takes place in the upstream region of the shock, where the counter stream particles interact with incoming flow. The energy gain of electrons happens during their interaction with evolving fields of self-generated magnetic vortices in this region. Three Fermi-like electron energization scenarios are discussed. Stochastic acceleration of electrons in interaction with fields of MV leads to anisotropic heating of fast electrons due to diffusion in the momentum space of electrons and, finally, synergetic effect of evolving fields of MVs leads to the formation of a power-law tail of supra-thermal particles. These observations as well as numerical simulations of unmagnetized relativistic collisionless shocks have shown the evidence of electron energization in shock front along with electron energization in the upstream region of the electron/ion shock7. While electron energization in shock front region of collisionless shocks are the most commonly studied, electron energization in other large-scale regions of the shocks (e.g. in the upstream region) is of great interest. The focus of this study is on electron energization and acceleration mechanism during interaction with self-generated magnetic vortices in the upstream of relativistic collisionless electron/ion shocks with no external magnetic field.Collisionless shocks are unique phenomena in space and astrophysical plasma environment such as supernova remnants, gamma-ray bursts, active galactic nuclei, and binary systems. One of the key features in astrophysical collisionless shocks is particle acceleration.The energized particles either escape the acceleration region and become Cosmic Rays (CR), and/or they interact with ambient backgrounds to produce high energy photons. The spectrum of the radiation emitted by high energy particles from indirect observations and by measurements of CR and gamma-ray bursts (GRBs) spectra show evidences of non-thermal particle acceleration generated by collisionless shocks13. A first phase of magnetic field amplification due to Weibel instability happens in the shock front region15. A simultaneous stage of magnetic field growth happens due to development of Weibel instability driven by particles moving ahead of shock front, i.e counter streams, and the incoming cold plasma streams. Counter stream electron flow are electrons that are either reflected off shock transition region or escaped interaction with shock transition region. In addition to Weibel instability, Biermann battery16 induced by nonparallel temperature and plasma density gradients, leads to generation of spontaneous nonlinear magnetic modes such as monopole and dipole vortices (see e.g.18).Collisionless shocks are believed to be mediated by Weibel instability which leads to fast growth of magnetic field at small scales, plasma isotropization and particle energization at later times19. The early stage of the interaction involves the generation of quasi-linear elongated MVs, which subsequently merge to form circularly shaped MVs (bubble). Localized regions of the strong magnetic field in the form of magnetic dipole vortices upstream of the shock were observed in the simulations developed during the nonlinear evolution of the electron and ion filaments.Recently we demonstrated that magnetic vortices (MVs) can self-consistently emerge in the upstream of electron/ion collisionless shocks with no external magnetic field19. The MV’s magnetic (and electric) fields grow, and their longitudinal size shrink as they move towards shock front after formation. Considerable part of ion kinetic energy is finally converted into the thermal energy  are stochastic particle acceleration and acceleration by direct electric fields. These acceleration processes develop not only at shocks, but in reconnection events30. In this paper, we focus on electron energization processes, which takes place not in the shock front, but in the upstream region of the shock, where the counter stream particles interact with incoming flow. The energy gain of electrons happens only during interaction of electrons with evolving fields of MVs. The MVs annihilate before reaching the shock front19. We identified three scenarios of Fermi-like electron energization and correspondingly three group of energized electrons in interaction with evolving fields of self-generated magnetic vortices in the upstream region of the shock. First and second scenarios correspond to energization of counter stream electrons. These electrons move towards overlapping region, where the cold fresh incoming flows meet the counterstream flows. These electrons can gain significant amount of energy through kick-like stochastic energization process31, where particles receive kicks due to interaction with evolving MV fields with steep gradients. The third scenario identified in our simulations is energization of incoming electron flow. The incoming electrons can trap in the fields of MVs in the very early stage of their formation. They move with MV towards shock front region and leave MVs in their final stage of MV, while gaining energy in the process of stochastic acceleration in evolving fields of MV.Most previous works investigated electron energization in interaction with magnetic structure in shock front regionTracking a large number of energized electrons from the non-thermal tail of the energy spectrum shows that particles in this region are directly accelerated by the large inductive transverse and longitudinal electric fields of the evolving MVs in this region. The evolution of energy distribution for the upstream region shows a power-law tail of supra-thermal particles, which saturates rather quickly after the shock forms and stay stable with power law index of The paper is organized as follows: simulation set-up is the first section, followed by self-generated MVs formation mechanism in the upstream, MV structure and non-thermal electron tail formation in the upstream. Then we present scenarios of electron energization in interaction with self-generated MVs. The last section includes discussion and conclusion.In this section, we present the results of a 2D PIC simulation of the formation and evolution of MWs, as well as the electron energization in a collisionless electron-ion shock.32. The code was modified to minimize noise properties of numerical instabilities, by using third-order shaped particles and current smoothing. A rectangular simulation box in the e and m denote the charge and mass of electron, and z) direction. The left boundary is reflecting for particles and fields. Simulation stops when counterstream particles reach the right boundary of the simulation domain. Therefore, no particle leaves the domain during simulation. Fresh flow of electrons and ions enter the domain continuously from the right boundary. Each computational cell is initialized with 16 macro-particles: 8 electrons and 8 ions. We assume that initially the electron-ion  plasma beam with the mass ratio x-axis direction). To reduce the computational effort, the initial contact point of the two counter-propagating streams is modeled as a reflecting wall at 6. The simulation is performed in the reflecting wall frame, where the downstream  plasma behind the shock has a vanishing average flow velocity. All densities (electron and ion) and fields (electric and magnetic) are expressed in dimensionless units as The two-dimensional (2D) version of the relativistic parallel particle-in-cell (PIC) code VLPL is usedz-dimension) and the color plot of the normalized transverse magnetic field . The interaction of counter stream flow with cold incoming flow leads to electron Weibel instability. However, due to thermal spread, the growth rate of electron Weibel instability is low as compared to that for cold beam plasma  is not steep (z) is of the order of inverse dipole size 16) is an order of magnitude less than magnetic field growth rate of Weibel instability. Note 2D kinetic simulation describes all the causes of MV generation, including the Biermann battery mechanism.The upstream region of the shock is characterized by nonparallel temperature and density gradients, driving the Biermann battery mechanism. Since the electron temperature gradient . The energy spectra, averaged over a box enclosing MV, is shown in Fig. 38 and Fermi-like acceleration type40. The power law index revealed in the simulation, As we mentioned above electron energization (acceleration and heating) in the upstream of relativistic collisionless ion/electron shocks is governed by stochastic diffusion. In the absence of binary collisions its role plays particles interaction with EM fields of magnetic vortices. Such effective collisions enable particle acceleration to ultra-relativistic energies via a Fermi-like acceleration mechanism which is similar to acceleration at the front of shock wave, but it results from particle scattering in the interaction process with magnetic fluctuations (self-generated magnetic vortices). This stochastic process of acceleration and heating is characterized by the existence of non-thermal tail of the electron distribution function and considerable part of kinetic energy carried by the non-thermal particles. A power law distribution of accelerated electrons for electron-ion collisionless shock with no external field has been revealed in 2D and 3D PIC simulations with indexes being in the interval range In the following, we will discuss electron energization scenarios in interaction with MVs resulting in energized electron tail in electron energy distribution in Figs. see Fig. d,e. Enersee Fig.  averagedWe start with the first type of electron energization mechanism: a typical counter stream electron moving along entclass1pt{minimax, showing the energy gain and return of electron during this process. The evolution of total energy and work done by the electric field components is plotted in Fig. x), showing the return of these electrons while gaining a large amount of energy. We can see that electrons interacting with nonlinear stage of MV, where fluctuating fields reach their largest magnitude, gain more energy than the electrons interacting with MV at earlier times, when the fields are still growing. Figure As the electron passes the center of the MV and moves towards the negative lobe of longitudinal electric field of the dipole, it loses a fraction of its energy and finally, the electron leaves the MV at its final stage with energy gain of more than an order of magnitude larger than its original energy and moves towards the shock region. A typical trajectory of such energetic electron from the tail of the energy spectrum is illustrated in Fig. x which shows some energy gain for electron before leaving MV. Figure The second type of energized electrons are the pre-accelerated counter stream electrons moving toward the upstream of the shock Fig. e–h. Thesentclass1pt{minimaThe third type of energetic electrons from the tail of the energy spectrum are the incoming electron flow. The incoming electron enters the upstream of the shock and quickly traps in the electric field of MV during linear stage of MV formation. The longitudinal electric field of MV traps the electron, so the electron moves with MV towards shock transition region. At the same time, fluctuating electric and magnetic fields of MV grow significantly. The trapped electron reflects from one lobe to the other due to transverse magnetic Lorentz force. Its energy oscillates rapidly between 15 and 28. Balikhin et al. 28 studied stochastic acceleration of electrons in fairly steep gradients of electrostatic and magnetic fields. In the indicated case, the transition to stochastic dynamics happens in the regular structure of the EM field. However, the structure of the MV fields are more complex and nonstationary , meanwhile electron dynamics is strongly relativistic.We never observed incoming electrons returning to the upstream for obvious reason: the incoming electron flow has mostly longitudinal momentum, therefore the longitudinal force of 19. The fields of MVs grow as they move toward shock region. Electron energization happens as the electrons (counter-stream and incoming flow) interact with electric fields of MVs in the upstream. Three Fermi-like scenarios of stochastic electron energization were discussed: large fields of MVs can return counter stream electrons towards shock, meanwhile electrons gain significant amount of energy during interaction with electric fields of MV. The second energization mechanism happens when counter stream electrons receive a kick during interaction with MVs due to Lorentz force. The electrons gain energy while being kicked (kick-acceleration) due to sharp electric field gradient. The energized electrons continue moving towards overlapping region. The third scenario is energization of incoming cold flow of electrons. Incoming electron flow can trap in the electric field of the MV in its linear stage. The electrons move with MV as fields of MV grow and finally leave MV while gaining energy as MV annihilates. These electron energization processes happen on time scale of MV formation and evolution and does not require long times as it is needed in shock front. Note that ‘kick’ electron acceleration means particle stochastic dynamics in the fields characterized by the sharp gradients of combined electric and magnetic fields of MV. Electrons accelerated in the process of interaction with the MVs are potentially able to become more energetic by multiple shock front crossings, i.e., Fermi acceleration mechanism in shock front.We studied the process of electron energization in interaction with MVs in the upstream of electron/ion shock using 2D PIC simulations. MVs are self-consistently generated in the upstream of electron/ion collisionless shockStochastic acceleration results in generation of non-thermal particles that form a power law spectrum. The energy of non-thermal electrons from the tail of spectrum changes with time due to stochastic character of Fermi-like electron acceleration in electric and magnetic fields of evolving MV. After the shock is formed, the upstream forms and expands, a power-law of supra-thermal particles is formed, which saturates rather quickly by In reality, magnetic vortices are three dimensional entities, where the current flow will be along its central axis and electron current flows around the cavity and forms a spheroidal or ellipsoidal shell. It is expected that magnetic vortices would be self-generated in the upstream of electron/ion shocks. However, due to the additional degree of freedom, MV lifetime might be shorter than the 2D calculations which can potentially change accelerated electron population in interaction with the MVs.25.The focus of our work is on electron energization in the process of interaction with MVs. We consider the described dynamics as a new interesting stage of electron energization to be very important for formation of non-thermal spectra of particles, since the electron acceleration strongly correlates with the growth and dissipation of MVs. We believe these electrons are potentially able to become more energetic in the process of multiple crossing of the shock wave front at long stages of interaction due to the Fermi process44. Energy transfer from fast ion flow to electromagnetic fields and fast particles (electrons and ions), at a time scale much shorter than electron-ion collisional energy exchange time can be modelled in laboratory conditions. Simulations are scalable to astrophysical conditions with the plasma densities of the order of a few particles per cm45. Reaching the collisionless regime also allows the instability dynamics to be described by dimensionless parameters and scaled between laboratory and astrophysical systems.It is worth mentioning that high power laser facilities provide a unique opportunity for laboratory experiments using plasma flows driven by high energy laser systems which opens a new era in astrophysics and space exploration. Laboratory experiments open the door to investigate the electron-ion sub-relativistic and relativistic collisionless shocks, magnetic field generation and amplification, magnetic reconnection, and particle acceleration in a short temporal and limited spatial scale via laser-plasma interactionsSupplementary Information 1.Supplementary Information 2.Supplementary Information 3.Supplementary Information 4.


Thoracic endovascular aortic repair (TEVAR) is a commonly performed operation for patients with type B aortic dissection (TBAD). The goal of TEVAR is to cover the proximal entry tear between the true lumen (TL) and the false lumen (FL) with an endograft to induce FL thrombosis, allow for aortic healing, and decrease the risk of aortic aneurysm and rupture. While TEVAR has shown promising outcomes, it can also result in devastating complications including stroke, spinal cord ischemia resulting in paralysis, as well as long-term heart failure, so treatment remains controversial. Similarly, the biomechanical impact of aortic endograft implantation and the hemodynamic impact of endograft design parameters such as length are not well-understood. In this study, a fluid-structure interaction (FSI) computational fluid dynamics (CFD) approach was used based on the immersed boundary and Lattice–Boltzmann method to investigate the association between the endograft length and hemodynamic variables inside the TL and FL. The physiological accuracy of the model was evaluated by comparing simulation results with the true pressure waveform measurements taken during a live TEVAR operation for TBAD. The results demonstrate a non-linear trend towards increased FL flow reversal as the endograft length increases but also increased left ventricular pulsatile workload. These findings suggest a medium-length endograft may be optimal by achieving FL flow reversal and thus FL thrombosis, while minimizing the extra load on the left ventricle. These results also verify that a reduction in heart rate with medical therapy contributes favorably to FL flow reversal. To solve the pressure and flow fields in the fluid domain, a single-relaxation-time (SRT) incompressible LBM was used as an efficient solver of Navier–Stokes equations . In suchAt the interface of the aortic and septal wall with the fluid, the IB algorithm was used, and the bounce-back boundary condition was used for modeling the fluid flow at the interface of the rigid boundary (endograft). A source term was considered  to satistum wall , which iFor the same geometrical configuration, the material parameter which affects the deformation of the vessel wall governed by al model . Figure The LV was modeled as a time-varying compliance model coupled with the aorta. The extension tube outflow boundary model was used for the truncated vasculature at the outlet of our 3-D FSI solver. At the inlet, the pressure In Clinically, actility   events . The parhe aorta .The D2Q9 velocity model is applied in the LBM with the sound speed Axisymmetric LBM is implemented in this study using an incompressible D2Q9 BGK model. In pseudo-Cartesian coordinates rdinates . For calequation :ρν . For spaThe pulsatile power (Reverse Flow Index (RFI) is calculated to quantify the flow reversal as a measure to predict thrombose formation, following the works done by Birjiniuk et al. . RFI is To quantify nt zones  at each Data from a TBAD patient undergoing TEVAR was studied and utilized to examine the physiological accuracy of our model. The participant was provided with written informed consent and all protocols were approved by the Keck Medical Center of the University of Southern California (USC) Institutional Review Board. The dissection started distal to the origin of the left subclavian artery and extended to the infrarenal aorta and the TEVAR endograft extended from proximal to the left subclavian to the mid-descending thoracic aorta. The entire patient’s aorta was imaged before and after the TEVAR with computed tomography angiography (CTA) with 1 mm slices, and illustrative images in the axial and sagittal planes are shown in A sample pressure inside the TL and FL at zone 4 is shown in e the FL . SimilarIn this study, we investigated clinically relevant hemodynamic patterns inside the TL and FL after endovascular repair using a physiologically accurate idealized model of TBAD. Our results suggest that: 1) There is a non-linear trend towards increased FL flow reversal as the endograft length increases but with an increased LV workload, 2) at a given heart cardiac output, lower HR enhances FL flow reversal and recirculation independent of the endograft length, and 3) at a given HR, a reduced LV contractility enhances FL flow reversal and reduces the systolic blood pressure.in vivo results with our simulation. We utilized FSI computational model of the coupled LV-aorta system to gain insight on the biomechanical behavior of blood flow in type B dissection following TEVAR. Numerous computational models, both patient-specific and lumped parameter  are avaiThe first novel finding in this study is related to examining the impact of endograft-aortic compliance mismatch on LV power requirement which is a global hemodynamic metric of the cardiovascular system. The replacement of highly elastic native aorta with non-compliant endograft reduces compliance and alters the aortic wave dynamics. This alteration has been shown to translate into additional workload on the LV, eventually inducing adaptive hypertrophy . HoweverCurrent understanding indicates that increased FL flow reversal enhances thrombosis, and patients exhibiting reversed flows within the FL may be more likely to develop complete FL thrombosis ; this isAlthough many TBAD patients undergo surgical aortic repair, medical therapy remains an essential part of their treatment. The primary objective of this pharmacological therapy is the reduction of the rate of rise of systolic aortic pressure . Beta-blThis study has certain limitations that should be considered. The dissection model used in this study is constructed based on average physiological values in TBAD patients and is based on a simplified  model of TBAD. This model is limited by the number of tears considered in the septum model as well as the exclusion of aortic branches and the aortic arch. While the geometry of TBAD can be very complex due to tortuosity, irregularities of luminal diameter along the dissection, multiple fenestrations in the septum wall and partial FL thrombosis, our model is intended to contribute to the understanding of the hemodynamics in TBAD independent of each individual. This generic model is ideal to provide insights on the impact of one parameter at a time  while controlling all other parameters. We also utilized Newtonian flow assumption for the fluid in this study. This assumption is still conventionally used in both experimental and CFD studies in large arteries . HoweverThe present study provides a comprehensive analysis of the role of endograft length on both global and local hemodynamic variables in TBAD anatomy. The computational model used here illustrates the amplitude and the form of the septum displacement in TBAD , 9. The


The inner ear, which consists of the cochlea and vestibular systems, is a morphologically complex sensory organ. Hair cells (HC), which serve as inner ear sensory cells, are critical for the transduction of mechanical stimulus into auditory and balance signals in the inner ear. After inner ear injury, auditory abnormalities and balance disorders are major consequences. Promoting hair cell regeneration is one of the most promising strategies to address hearing loss and vestibular dysfunction. Exploring the mechanism of inner ear development provides a practical venue to understand the regeneration process of functional hair cells.Chen J. et al. focused on the greater epithelial ridge (GER) cells that solely present during cochlear development, and profiled the gene expression landscape of the rat's cochlear basal membrane  to categorize major subtypes of GER cells. The authors documented the trans-differentiation of different GER subtypes to inner (IHC) and outer hair cells (OHC) by trajectory analysis. They also elucidated the key regulatory genes and signaling pathways during trans-differentiation, which is instrumental for future research on HC regeneration. Another study about the organ of Corti (OoC) in the present special topic conducted by Liu et al. dug into the connexin26 (Cx26) protein, which is encoded by the GJB2 gene. The study demonstrated that Cx26 is involved in the maturation of the cytoskeleton during the earlier postnatal development of the OoC. In addition, the polymerization of G-actin into F-actin is prevented in Cx26 knock-down (KD) mice. This study elucidated an underlying mechanism of the OoC deformity caused by Cx26 downregulation. Given that GJB2 mutation is one of the most common etiologies of hereditary deafness, the work is particularly noteworthy.Six articles were included in this topic regarding inner ear development. With regard to cochlear development, a pseudo-temporal analysis of single-cell RNA sequencing done by Chen B.-J. et al. described the role of Rab11a, a small G protein, in the formation of the polarity of cilia, thus revealing that Rab11a is essential to the normal development of cilia, as well as the intraflagellar transport. Another investigation conducted by Yan et al. explored the role of BAIAP2L2, a component of the row 2 complex in stereocilia, which was found to cause degeneration of the mechanotransducing stereocilia in cochlear hair cells when inactivated. Surprisingly, such degeneration was not found in the vestibular HC stereocilia, considering the unaffected morphology, the intact development and function of the vestibule, which might be explained by the differential dependency of CAPZB2 localization on BAIAI2L2 in cochlear and vestibular HCs. Thus, the comparative approach focusing on the phenotypic difference between vestibular and cochlear HC development could provide insights into their development, as well as regeneration.As to vestibular development, three articles were included in this topic focusing on the development of vestibular HCs and the formation of the vestibular flat epithelium. He et al. uncovered the role of epithelial-mesenchymal transition (EMT) in this process. Upregulated mesenchymal cell markers in the vestibular FE compared to the normal utricle and robust cell proliferation were observed, which was consistent with GO and DEG analyses following a microarray analysis. The transcriptome features provided by this research provide the foundation for future studies in novel intervention strategies for FE.Degeneration of the vestibular sensory epithelium leads to the formation of flat epithelium (FE) with unclear pathogenesis. Guo et al. found that in the earlier stages of auditory development, under the regulation of autophagy, ribbon synaptic refinement and the pruning of SGN fiber occur and are closely associated with the morphological and functional maturation of ribbon synapses. Further evidence pertaining to IHC functionalities is required to validate the conclusion on inner ear development.Except for HC development, as the first and extremely important synaptic structures formed between IHCs and spiral ganglion neurons (SGN), ribbon synaptic maturity was also included in the topic. The study by Vestibular and cochlear HCs and SGNs are the major objectives of inner ear regeneration. Based on the past inner ear developmental research, three reviews and original articles were also included in our topic.in vitro, Li et al. hypothesized that the integral cochlear structure helps maintain the overall inner ear architecture and improve the sensory epithelium survival in culture. To test the hypothesis, they induced trans-differentiation of adult supporting cells to HC-like cells (HCLCs) after HC degeneration by overexpression of Atoh1 in adult mouse cochlear culture with the (surrounding) bone intact. Furthermore, HCLC-neuron connections were observed, proving the feasibility of culturing adult inner ear tissues for future research in regeneration, HC-neuron pathways, and inner ear drug screening.To expand the knowledge relating to HC regeneration in adult cochlear explant culture, which is complementary to inner ear organoids to study the inner ear Huang et al. summarized the development of human vestibular hair cells during the entire embryonic stage and the latest research on human vestibular hair cell regeneration. The regenerative potential of human vestibular HC and the application of gene therapy in this field were discussed. The author also pointed out the limitations of current studies and future directions, including some important problems such as how to regenerate and maintain mature and functional HCs, which are imminent issues to resolve in order to propel the field of regeneration of inner ear sensory epithelium, whether in vestibular or cochlear.Regeneration of vestibular HC is critical due to its vulnerability to ototoxic drugs and virus infection and limited restorative capacity after damage. Wang et al. reviewed the recent advances in research of SGN regeneration including exogenous stem cell transplantation and endogenous glial cell reprogramming. In sum, SGN regeneration is facing a similar challenge to HC regeneration. Considering the progress of synaptic junction formation and the regeneration of hair cells and spiral ganglion neurons, inner ear regeneration is becoming a promising field in otology.Another review about regeneration in our topic is about the SGN, which is a vital component in sensorineural hearing loss. SGNs are the primary neurons that relay sound signals from the inner ear to the brainstem, however, it is vulnerable to noise and ototoxic drugs. Degeneration of SGNs causes irreversible sensorineural hearing loss (SNHL) and cannot be rescued effectively because of their lack of regenerative potential. Du et al. found that shikonin reduced the ouabain-induced auditory nerve damage and increase the expression of Nrf2 and its downstream molecules HO-1 and NQO1. Shikonin treatment enhanced the antioxidant capacity of SGNs and spiral ganglion Schwann cells, promoted cell proliferation, and inhibited apoptosis by activating the Nrf2/antioxidant response elements signal pathway, thereby testifying it as a candidate therapeutic drug for neurological deafness.In addition to the development and regeneration of the inner ear, this topic also included a study about the protective effect of shikonin, a pigment isolated from traditional Chinese herbal medicine, on spiral ganglion cells. Overall, this topic, with ten papers encompassing various subjects in the area of inner ear development, revealed the promising potential of this research interest and promoted the progress of this lesser-known research direction.DR, HS, and HL designed the literature. HS and BC co-authored the manuscript and reviewed previous research. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.