The voltammetric electrochemical sensing method combined with biosensors and multi-sensor systems can quickly, accurately, and reliably analyze the concentration of the main analyte and the overall characteristics of complex samples. Simultaneously, the high-dimensional voltammogram contains the rich electrochemical features of the detected substances. Chemometric methods are important tools for mining valuable information from voltammetric data. Chemometrics can aid voltammetric biosensor calibration and multi-element detection in complex matrix conditions. This review introduces the voltammetric analysis techniques commonly used in the research of voltammetric biosensor and electronic tongues. Then, the research on optimizing voltammetric biosensor results using classical chemometrics is summarized. At the same time, the incorporation of machine learning and deep learning has brought new opportunities to further improve the detection performance of biosensors in complex samples. Finally, smartphones connected with miniaturized voltammetric biosensors and chemometric methods provide a high-quality portable analysis platform that shows great potential in point-of-care testing. The field of biosensing is in a phase of rapid development, and biosensing assisted by chemometric methods has been gradually introduced to various areas of research. The most common use of voltammetric biosensing is in the the detection of target analytes . The IntVoltammetry, which has good sensitivity, detection speed, reliability and accuracy, is one of the most widely used electrochemical techniques in biosensing ,16,17,18The purpose of this review is to show the potential of chemometric methods in biosensing research using voltammetry sensors through an introduction of classical chemometric methods as a tool to solve the limiting problems in biosensing analysis using voltammetry. At the same time, this review stimulates researchers’ interest in using deep learning methods for voltammetric data analysis. Finally, it is envisioned that this review will encourage researchers to combine the advantages of voltammetric analysis and chemometrics in the field of biosensing to develop more smartphone-mediated electrochemical platforms with on-site decision-making capabilities.Voltammetry is generally used in standard three-electrode system . It applies a certain form of potential to cause the oxidation and reduction reaction of electroactive substances on a working electrode, then samples the response current within the time range . Cyclic Cyclic voltammetry is the most widely used electrochemical technique, which applies a scanning potential of a triangular waveform to a working electrode to detect a generated current A1. PotenA voltammetric analysis reflects the chemical properties of analytes from different perspectives using functions of potential, current and time. The voltammogram records the current curves of the oxidation and reduction processes of the electroactive species in the analyte and the working electrode at a specific potential. The response current characteristics such as peak value, peak width and peak potential of the voltammetric curve present the electrochemical properties of an analyte. In addition, the response curves also contain redundant information about the solution matrix. The ability of chemometric methods to handle multivariate data offers the possibility to parse more meaningful information from voltammograms.Chemometric tools can obtain reasonable analytical results from voltammetric data to improve the performance of voltammetric sensors in biosensing ,54. On oChemometrics is defined as a chemical discipline that uses mathematics, statistics and formal logic to provide a vast number of tools for the analysis of voltammetric data ,57,59. A●Exploratory analysis of the data to obtain the relationship between the data.●Qualitative analysis of target analytes to deal with the classification and discrimination of samples.●Quantitative prediction of analytes to achieve the determination of indicators of interest for analytes.Research papers published in the field of biosensing in recent years have shown a strong interest in deep learning models ,62,63,64Validation of method performance and evaluation of effects are also important parts of data processing. Due to the strict requirements in the fields of sensing equipment, experimental process and data measurement, a voltammetric sensing data set often has a small amount of data and uneven samples. In the case of limited samples for analysis, careful consideration should be given to the correctness of method application to establish meaningful correlations between voltammetric biosensor responses and analytical parameters. At the same time, appropriate and reasonable validation strategies were provided for the data processing methods to evaluate the reliability of the models in practice and to avoid inadvertent formation of biased results during data processing and model use.Principal Component Analysis (PCA) is one of the most effective and popular analytical tools for data exploration. It reveals the underlying relationships and structure of data in an unsupervised manner, in the absence of prior information about the data ,70,71. PThe score plots and loading plots obtained by PCA are used to show the sample distribution in relation to the study parameters and the contribution of different sensors to the principal components. Coral Salvo-Comino et al. compared the performance of silver nanowires and silver nanoparticles as platforms for immobilizing specific enzymes by scoring and loading plots drawn by PCA  72]. Di. Di72]. PCA enables exploratory studies of sensor performance and analyte parameters. Medina-Plaza et al. immobilized glucose oxidase or tyrosinase on electrodes of six different materials and used PCA to evaluate the ability of an electrode array to identify five grape juices . ThroughPCA can assign samples with similar characteristics to the same cluster according to the inherent properties of the sample data, which exhibits the characteristics of clustering. Strictly speaking, PCA is not a classification method, but it can assist in the judgment of the quality of sample data with class prior information. When there are meaningful clusters in the score plot, it is a reasonable choice to use supervised pattern recognition methods. Class-modeling techniques can supervise the establishment of classification rules to provide qualitative answers to questions according to the needs of the target task. K-Nearby (K-NN), Linear Discriminant Analysis (LDA), Quadratic Discriminant Analysis (QDA) and Partial Least Squares Discriminant Analysis (PLS-DA) are all widely used classical classification methods ,75,76. TApetrei et al. used a screen-printed electrode array and cyclic voltammetry based on six electroactive compounds and nanomaterials to monitor the water quality of the Danube for pH, resistivity, turbidity, total dissolved solids, iron content and nitrate ions parameters . An expl2, ZnO, TiO2, Bi2O3) modified nickel foam electrodes [It is worth noting that more learning methods for machine classification modeling, such as decision tree (DT) and support vector machine (SVM), have been added to chemometrics, which continue to promote the development of biosensing data analysis. It also provides new strategies for solving quantitative descriptive problems ,82,83. Nectrodes . The priQuantitative predictions of analyte indicators can be obtained by processing data from voltammetric sensor systems using multivariate calibration methods. Partial least squares (PLS), a classic statistical regression model, provides an effective way for quantitative prediction . Unlike Cristina Garcia-Cabezon et al. used biosensor arrays and PLS to analyze phenolic content in the residues (seeds and peels) of eight grape winemaking species . Figure The PLS method has shown high efficiency for high-dimensional variable processing. Clara Pérez-Ràfols et al. used a voltammetric tongue composed of four screen-printed electrodes modified with different materials to detect Cd(II), Pb(II), Tl(I), In(III), Zn(II) and Bi(III) for multivariate analysis of very complex mixtures of metal ions . In ordePLS has good scalability for different task requirements. Dionisia Ortiz-Aguayo et al. used a voltammetric sensor array composed of three different screen-printed electrodes modified by graphite, cobalt(II) phthalocyanine and palladium. Characteristic voltammograms for heroin, morphine, codeine, caffeine and paracetamol were extracted using SWV . Next, aPLS is a very general method that can provide an efficient and stable solution to complex forecasting problems. However, there are a large number of nonlinear factors between predictors and response variables in practical biosensing applications, and classical PLS is weak for modeling data with nonlinear information characteristics. In contrast, artificial neural network (ANN) is a flexible nonlinear model . ANNs arANN provides help for the analysis of signal dissimilarity and improves the qualitative resolution of complex signals. A more accurate type identification is achieved, and a rough estimate of the concentration is proposed. Zhou et al. demonstrated the simultaneous determination of catechol and quinone in municipal solid waste compost using a tyrosinase-based biosensor array and differential pulse voltammetry . The resCurrently, deep learning shows great potential in many fields. Deep learning models can effectively deal with the complex and high-dimensional data obtained from voltammetric biosensors. They use a multi-layered structure to sequentially extract multi-level features of the source data that reflect the patterns contained in the data. Using these patterns, deep learning models can be well applied to prediction tasks. In the face of different data forms and domain requirements, they have evolved various typical architectures. Convolutional Neural Network (CNN) is one of the most popular deep learning models ,93. SimiDue to its strong data description ability and relatively strong adaptability to new problems, deep learning models gradually enter the field of data processing for voltammetric tongues as a chemometric tool with excellent performance. Yuan et al. proposed an automatic feature extraction strategy based on a convolutional neural network in an electronic tongue system for tea classification . Since eThere are potential pitfalls regarding the use of deep learning models, especially in voltammetric datasets, which often have a small amount of data formed from limited samples. It is necessary to establish effective model verification for deep learning models. A common verification method is to divide the data set into training subsets and verification subsets. The training subset is used in the training process of the model, and the validation subset is used to evaluate the predictive ability of the model. At the same time, the data for the validation subset should remain independent. In small data sets, cross-validation is often used to evaluate model performance. Although this validation method is widely used, it is easy to make mistakes in adjusting the model on the results of the validation set, making researchers overly optimistic about the predictive ability of the model . A suggeThe combination of chemometric methods and voltammetric biosensors is widely used in food analysis, environmental monitoring, medical and health diagnosis. The small size of the voltammetric biosensor, the simplicity of the voltammetric analysis method and the flexibility of the chemometric method are ideal to obtain the target result from the information obtained by the voltammetric biosensor, for the simple operation and quick analysis of the results in various fields. POCT provides the premise . In partHealth-related biomolecular assays can provide reference for disease prevention and diagnosis, and POCT devices play an important role. Daizong Ji et al. designed a smartphone-based voltammetry system for trace detection of ascorbic acid, dopamine, and uric acid using nanomaterial-modified electrodes and differential pulse voltammetry . A smart2 = 0.92). Meanwhile, the study demonstrates a monitoring system consisting of a portable electrochemical detection device and a decision-making unit based on an iOS platform application and an IoT-based cloud server that shares the results via the Internet  provide the premise for POCT. Chemometric methods perform a decision-making analysis of the acquired voltammetric data, providing meaningful results for the detection of target analytes. There are reasons to believe that functional devices with mobile computing and multiple connectivity methods represented by smartphones can become the key to the combination of portable electrochemical analysis platforms and chemometric methods. It is expected that an intelligent platform for on-site detection and analysis using voltammetric biosensing systems can be applied in the fields of food industry, environmental monitoring and medical health.Biosensing research has been growing exponentially with the aid of chemometrics. Chemometric tools have shown impressive results both in helping biosensors perform high-resolution detection of multicomponent solutions with matrix effects and in parsing effective information from high-dimensional data generated by bioelectronic tongues. At the same time, the advantages of chemometrics combined with voltammetric-based biosensing have led to the development of point-of-care detection systems that are more accurate, easier to use, and capable of decision making. The current practice of chemometric methods in voltammetric biosensing research provides confidence for more explorations in the future. Here, the status quo is summarized and future directions are as follows:


Obstruction ofthe mainstem or proximal lobar bronchus is a rare condition in intrauterine life andin neonates, in whom it causes respiratory difficulties. Such obstruction usuallyresults in severe, lethal conditions. The live birth of a neonate with bronchial atresia who thriveswith the anatomical repercussions of the malformation and survives the surgicaltreatment after birth is even more uncommon, only one case having beendescribed.Bronchial atresia is a rare condition characterized by the absence of communicationbetween the distal bronchi and proximal airway and can affect any segment of thebronchial tract. The severity of malformation is related to the site of obstructionof the proximal airways. Segmental obstruction affects a small volume of the lungsand is usually related to late incidental diagnosis in children andadultsUltrasound is the gold-standard method for the diagnosis of bronchial atresia.However, in late pregnancy, polyhydramnios is common due to bronchialatresia-induced mediastinal deviation, which limits the accuracy of ultrasound.Magnetic resonance imaging (MRI) can be a helpful method, adding informationregarding the spatial relationship between the enlarged affected lung and theadjacent organs and overcoming the limitations imposed by the increased quantity ofamniotic fluid..Images can also be acquired in three-dimensional (3D) sequences, which makes itpossible to segment regions of interest for the planning of surgical interventionsand for the counseling of parents. The 3D images acquired can be exported toexternal software, which can make them more comprehensible by better demonstratingthe spatial relationships between malformations and the surrounding organs andtissues. Here, wepresent a case of right-sided mainstem bronchial atresia in which the images fromprenatal MRI and postnatal computed tomography (CT) were used in order todemonstrate the capacity of a compressed lung to grow over the course of apregnancy. The images presented . The files were then transferred to the MeshLabprogram, version 2021.07 , which was used forsurface reconstruction and texture mapping, as previously described. Using varioustechniques, we have demonstrated impressive development of the normal lung in a caseof mainstem bronchial atresia. The software employed here allows clinical MRI and CTimages to be reconstructed in 3D, and the results graphically demonstrate thecapacity of the fetal lungs to develop during the second half of pregnancy evenunder pronounced compression and in severe conditions such as bronchial atresia.The growth of congenital pulmonary malformations normally peaks around 25 weeks ofgestation


In the past, different human disorders were described by scientists from the perspective of either environmental factors or just by genetically related mechanisms. The rise in epigenetic studies and its modifications, i.e., heritable alterations in gene expression without changes in DNA sequences, have now been confirmed in diseases. Modifications namely, DNA methylation, posttranslational histone modifications, and non-coding RNAs have led to a better understanding of the coaction between epigenetic alterations and human pathologies. Melatonin is a widely-produced indoleamine regulator molecule that influences numerous biological functions within many cell types. Concerning its broad spectrum of actions, melatonin should be investigated much more for its contribution to the upstream and downstream mechanistic regulation of epigenetic modifications in diseases. It is, therefore, necessary to fill the existing gaps concerning corresponding processes associated with melatonin with the physiological abnormalities brought by epigenetic modifications. This review outlines the findings on melatonin’s action on epigenetic regulation in human diseases including neurodegenerative diseases, diabetes, cancer, and cardiovascular diseases. It summarizes the ability of melatonin to act on molecules such as proteins and RNAs which affect the development and progression of diseases. Epigenetics can be redefined as any biological process that changes the genetic expression and activity minus alteration of the DNA sequence resulting in cellular modifications . There aHistone modification is a post-translational process involving gene expression alterations through the small protein ‘tails’ from the nucleosomes. The covalent addition of these histone proteins including methylation, phosphorylation, sumoylation, acetylation, and ubiquitylation, have all been shown to be responsible for the epigenetic modifications . Aberrat6-adenosine, 5-methylcytosine, pseudouridine, and N1-methyladenosine). The microRNA (miRNA) has been a notorious contributor to diseases when it binds to specific sites associated with the translation of mRNA, inhibiting the process. For instance, when binding occurs at the 3’ untranslated regions of mRNA, the actions of mRNA are suppressed  and RNA methylation  hormone largely synthesized by the pineal gland and can also be found in small quantities in organs such as the retina, lens, gut, bone marrow, skin, and other solid organs with multifunctional facets . BecauseFavorable evidence has premised an antagonistic relationship between melatonin and insulin secretions observed in diabetic patients. Studies have demonstrated that the action of beta cells of the pancreas is suppressed by melatonin and vice versa . That isIn the study of cancer, melatonin has exhibited positive results in the prevention and improvement of this disease. The vast knowledge of the hallmarks of cancer has expedited the understanding and development of different mechanisms involved in the treatment of cancer by melatonin. Mechanisms range from, targeting DNA repair, increasing the cytotoxicity of chemotherapy drugs, scavenging free radicals, and inhibiting tumor growth and metastasis . StudiesBased on the vast effects of melatonin on a variety of diseases, it is worth pondering the deep reason for the diverse functions and the common impression in these conditions. Regulation of epigenetic modification by melatonin seems to be the reasonable answer to the question. Yet, the study of the interaction between melatonin and epigenetics in human pathology is still in its infancy. There is no coherent and consistent picture to summarize the relativity of epigenetic modifications by melatonin currently. Therefore, we intend to narrow the gap by unraveling potential markers on the connections between previous and current work on the basic mechanisms involving epigenetic changes as a result of effects imparted by melatonin (both endogenous and exogenous) in pursuit of treatment of pathologies across the clinical spectrum. The information collated herein serves to account for the prospective formulation of ideas on melatonin’s function in alleviating various diseases. Furthermore, as a quick response guide, we have summarized in For years, the aging brain has directly been linked with manifestations of neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson's disease (PD). These were characterized by anomalies in the synthesis of proteins and a conglomeration of misfolded proteins as a result of altered signaling pathways by epigenetic manipulations . These dDrosophila model showed how both knockdown and overexpression of HDACs resulted in long-term memory impairment in a specific way (Histone deacetylation (HDACs), one of the many epigenetic mechanisms now identified as playing a significant role in long-term potential and memory formation has been linked with memory and cognitive processes in the hippocampus and prefrontal cortex in Alzheimer’s disease. An experiment conducted on a ific way . By targific way . Moreoveific way . In the ific way . Thus, iDe novo methylation and DNA methyltransferases (DNMTs) are critical in neurological function and behavior  has been widely used in studies including but not limited to, impaired learning and cognitive functions which are related to neurodegenerative diseases such as Parkinsonism and Alzheimer’s. Abnormal regulation in phosphorylation of histone proteins modification by the histone enzymes, leading to accumulation of highly phosphorylated tau protein aggregates has been linked with cell growth and activation of gene transcription resulting in a dozen of neurodegenerative diseases including AD . The kinAdditionally, phosphorylation of H3K14 and H3K9 have been demonstrated to cause activation of transcriptional regulation , and enhThe generation of the amyloid precursor protein initiates the development of the pathogenic peptides of Aβ, in the AD brain. Immunohistochemical analysis of the hippocampus and the frontal cortex revealed remarkable reductions in amyloid-beta deposition as a result of long-term treatment of melatonin through ERK phosphorylation and activation of transcription factors including CREB which in turn upregulates the ADAM 10 transactivation, causing a reduction in the generation of amyloid- β peptides .Collectively, these results show that further exploration of the role of melatonin enhanced transcriptional activation of these genes by their complementary proteins, together with the establishment of the connection between phosphorylated protein kinases and histone phosphorylation could give a deeper understanding and shade more light on the fate of the neuronal cells in the context of gene transcription and modulation of chromatin state and the pursuit of design and development of neurological therapeutics.PD is a neurological disorder due to cytoplasmic aggregation of the α-synuclein protein within the neurons, jointly with the inadequate or loss of dopamine in the neurons in the regions of substantia nigra, resulting in motor and non-motor manifestations such as bradykinesia, tremor, rigidity, instability of the posture, random-eye movement, sleep behavioral disorder, cognitive impairments and autonomic dysfunction . EpigeneThe biological effects of melatonin regarding PD are vastly widespread. Studies have demonstrated its neuroprotective effects in improving both motor and non-motor impairments experienced by PD patients . MelatonEpigenetic regulation of specific genes by HDACs through impairment of histone acetylation has been attributed to PD, accomplished through inhibitors of HDACs whose effects could lead to increased histone acetylation and transcription of genes that encode specific neurotrophic factors or via a reduction in the accumulation of neurotoxic proteins (such as α-synuclein) causing a neuroprotective effect . A good DNA hypomethylation of the α-synuclein has been reported as a pathogenic substrate attributed to the development of Lewy bodies diseases such as PD. One such study, a cohort survey, showed how all PD subjects exhibited significant hypomethylation of the a-synuclein compared to the controls suggesting a possible nexus between a-synuclein, promoter hypomethylation, and the risk of PD . PreviouType 1 diabetes (T1D) also known as insulin-dependent diabetes mellitus is an autoimmune condition characterized by inflammatory responses due to the influx of immune response cells in the pancreas, leading to the destruction of insulin-producing beta cells . InteracThough inadequately studied, the association between miRNAs and immune cells has been established in T1D. Studies have found that dysregulation of expressed miRNAs which correlates with immune cells such as T cells and B lymphocytes was linked to the onset of T1D and that these miRNAs when manipulated to participate in the preservation of cells of the pancreas as reviewed by Mohammad The importance of melatonin in immune cells has been established through modulation of responses of pancreatic cells whereby melatonin exerted beneficial effects in type 1 diabetes through suppression of T cell proliferation in the islets . Wu Guo P300 has further been investigated in Type 2 diabetes through different epigenetic modulated mechanisms to that of T1D. P300 protein has been implicated in insulin secretion patterns in the beta cells of the pancreas. Overwhelming evidence shows activation of p38 MAPK in insulin-releasing cells causes a damaging effect on the beta cells. Natalia in vivo and in vitro studies  protein levels, increasing the binding sites available for phosphorylation to the transcription factors . These fCardiac fibrosis is a common manifestation of chronically stressed myocardial tissues characterized by abnormal thickening of the valves of the heart due to the proliferation of the fibroblasts . The funStrides have been made in the interest of employing epigenetic therapies to arrest myocardial fibrotic degeneration through stimulation of human cardiac fibroblasts to suppress or express pro-fibrotic protein genes which have the effect of modulating DNA-methylating genes such as DNMT1 and DNMT3a/3b . ActivatThe protective effects of melatonin have been previously investigated, effectively alleviating cardiac fibroblast-induced cardiac fibrosis via inhibition of mitochondrial oxidative injury and regulation of SIRT3-mediated SOD2 deacetylation . MelatonBig strides have been made in understanding melatonin-induced epigenetics on cardiac fibrosis and towards the identification of therapeutic targets. One such study conducted by in vivo and in vitro studies have suggested possible epigenomic-related mechanisms underlying the etiology of hypertension. Unusual activation of RAAS by the associated genes has been previously reported to cause an increase in blood pressure  alongside pressure . Angiotepressure . Moreovepressure . Similarpressure . Elsewhepressure  and hypopressure  both ledpressure . MiR-27apressure .ace2, agt, and agtra1 genes. Additionally, melatonin attenuated hypertension through suppression of the renin-angiotensin system  led to an increase in the expression of PDCD4 and a decrease in expression of IGFR1 proteins . ChangesMiR-200 family is a target molecule in the pathology of heart failure. Angiotensin II a well-known pro-inflammatory regulator has been implicated in cardiac dysfunction of a failing heart through its association with reactive oxygen species (ROS)  and phosAtherosclerosis is a condition characterized by the buildup of plaques from cholesterol, deposited on the inner walls of the endothelium, causing stenosis and heart attack, and sometimes death . Endothe−/− mice. They found out that at high doses, melatonin was able to cause significant stabilization of atherosclerotic plaque. They further explained this occurrence to be caused by melatonin-induced Akt phosphorylation of the specificity protein 1 (Sp1), which cleaved to the promoter site and elevated the expression of the PH4alpha-1 gene. The PH4alpha-1 gene has been associated with the formation of a major component of the extracellular matrix known as 4- hydroxyproline in collagens (Increasing the fibrous content through collagen synthesis is the basic idea of stabilizing atherosclerotic plaque. Recently, ollagens . Sp1 is ollagens . Earlierollagens . Additioollagens . An incrollagens . This reollagens . Computaollagens . This piollagens , which cDifferent experimental reports have deduced molecular pathways involving inflammatory processes leading to atherosclerosis . The rolThe concept of aging and growing old seems not to go down well with many people; some people believe once they grow old, they might lose their worth, good looks, or importance in society. For a long period, several factors majorly environmental stimuli had been attributed to aging. In recent decades, scientists have been able to demonstrate that aging is hugely dependent and associated with genetic and epigenetic pathways which influence lifespan. Senescence involves a prolonged condition requiring the adaptation of the cell to a stressful microenvironment initiated by a deep epigenetic reconditioning response resulting in irreparable DNA damage. For instance, when mitochondrial DNA methylation was examined during the senescence period, a study concluded that hypomethylation of the mitochondrial CpG region was directly linked to cellular senescence as a result of oxidative stress . LikewisMelatonin has been used substantially in many vital life processes, and its secretion and circulation decline gradually over time. For instance, Lahiri postulated that the levels of melatonin in the serum decreased significantly with age, in body tissues including the heart , and thaMelatonin has a broad spectrum of functions that are not well understood due to the vast effects mediated by its receptors MT1 and MT2. The expression of these receptors in different peripheral body cells insinuates that melatonin may associate and affect cellular functions ubiquitously in a fashion related to circadian rhythm. The characteristic rhythm of secretion of melatonin by the pineal gland is known to decline in an aged and/or diseased state . AlthougDespite the well-collated information on the benefits of melatonin, there are inadequacies due to poor investigations on the subject. The nexus between melatonin and melatonin receptors in specific organs is not clearly explained. This is to say, the signaling routes by which melatonin regulates the epigenetic process, require further investigation. Secondly, we could not decipher how the action of melatonin affects different cells. For instance, in cancer, melatonin is seen doing the exact opposite of what is known of non-cancer cells . It is wClinical trials on the safety and efficacy of melatonin in the field of medicine demonstrate low toxicity with a wide range of doses . Doses uThe regulatory interaction of melatonin and epigenetics has so far been studied under the conditions of early development. The study of miRNAs interaction with melatonin, though in its infancy, has elicited huge interest in the research field. The signaling pathway of melatonin can be affected by miRNAs, as numerous diseases display alterations in levels and the general composition of miRNAs indicating their importance in the pathology of diseases. Pointing out, the beneficial role of melatonin has been reported in atherosclerosis in elevated levels of miR-29b , neoplasThere are but a handful of studies demonstrating the mechanism by which melatonin influences epigenetic processes. Herein, we have highlighted the effects of melatonin on histone modification, DNA methylation, and non-coding RNAs and summarized its significance in alleviating aberrant regulations often leading to diseases. Several other proteins which directly regulate epigenetic modifications causing mutation or functionality loss have resulted in a series of human disorders. This has enabled a precedential focus on the transcription factors and miRNAs in the quest to unlock the mystery behind their association with diseases and melatonin action on them. This, therefore, provides exciting prospects about melatonin as an oscillator of the epigenetic gene in human diseases, and great potential in the development of “epigenetic therapies” as an adjuvant and/or alternative treatment to the currently available therapies.


EGFR) exon 19 deletion mutations, and one lesion had the L858R mutation. After first-generation EGFR–tyrosine kinase inhibitor (TKI) treatment, the three lesions all showed a good response until disease progression. After the corresponding drug treatments were given based on the different drug resistance mechanisms, good responsiveness was shown in each lessions. This case suggests that in the treatment of SMPLC, it is necessary to learn the molecular-biological information of each lesion due to the differences thereof, and a targeted treatment regimen should be developed on this basis.Non-small-cell lung cancer (NSCLC) is the most common cancer in the world. In recent years, the incidence of synchronous multiple primary lung cancer (SMPLC) has gradually increased. Surgery is the preferred method to treat these patients. The management of SMPLC patients who cannot tolerate surgical treatment is controversial. We report a rare case in which a 70-year-old Chinese woman with no history of smoking had three primary lung adenocarcinoma lesions. Two lesions had epidermal growth factor receptor ( Lung cancer is the cancer with the highest mortality rate in the world. With the advancement of modern medical technology, the 2-year survival rate of patients with non-small-cell lung cancer (NSCLC) has increased from 34% to 42% . With thEGFR) mutations in SMPLC patients is high  can play a role in the diagnosis and treatment of these patients. However, the identities of the driver genes between individual tumors in SMPLC patients can differ by 72.0-92.1% . The middle lobe of right lung had adenocarcinoma (acinar growth) with EGFR exon 19 deletion mutation (L2). The lower lobe of the right lung had adenocarcinoma (solid) accompanied by point mutation of EGFR exon 21, L858R (L3). The patient started oral icotinib 125 mg Q8H treatment on June 15, 2018, and the three cancer lesions all showed persistent good responses  and the right middle lobe (L2) lesions had responded well to osimertinib, and the efficacy was evaluated as a partial response  was punctured again, and peripheral venous blood of the patient was collected for NGS detection. Rebiopsy of the L1 tumor showed adenocarcinoma, And the L1 tumor tissue and peripheral venous blood tests all suggested The management of SMPLC should be based on the judgment of a multidisciplinary team, Surgical approach is the first choice recommended by the American College of Chest Physicians for those with SMPLC . ReportsEGFR gene is the most common driver gene mutated in lung adenocarcinoma.EGFR-TKI is the preferred treatment for inoperable lung adenocarcinoma patients with EGFR mutations  mutation, the lesion in the middle lobe of the lung carried the EGFR 19Del-074PLA mutation, and the lesion in the lower lobe of the right lung carried the EGFR 21L858R mutation. After first-generation EGFR-TKI treatment, two lesions showed two different secondary drug resistance mechanisms. The lesions in the left upper lobe showed the T790M mutation, while the lesions in the right lower lobe showed MET amplification. At the same time, only T790M was detected by two NGS tests based on circulating tumor DNA (ctDNA), but not MET-amplification. The left upper lobe lesions showed a good response to osimertinib, while the right lower lobe lesions did not. After MET amplification was found in the right lower lobe lesion, savolitinib was added to oral osimertinib. The three lesions of the patient showed good responsiveness and tolerability.Here, we report a rare case of three primary lung adenocarcinoma lesions, each with an independent driver gene mutation. The left upper lobe lesion carried the CtDNA has emerged as an appealing approach that permits the minimally invasive genotyping of NSCLC . After tThis is the first case report of SMPLC showing different drug resistance mechanisms after receiving first-generation EGFR-TKI treatment. This study provides novel ideas and experience for the diagnosis and treatment of SMPLC patients who cannot undergo surgical resection. Due to the differences in molecular biology of SMPLC, NGS technology should be utilized whenever possible to detect the molecular biology of patients’ lesions in order to guide their treatment.At the same time, each lesion may also have different mechanisms of drug resistance to targeted therapy drugs. For such patients with multiple independent lesions, the lesions should be biopsied again if possible after the emergence of drug resistance to clarify the mechanism of drug resistance and to guide the targeted treatment. The application scenarios of ctDNA-based NGS detection need to be further studied.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.SX: Conceptualization, data curation, writing - original draft. QL: Conceptualization, funding acquisition, writing - review & editing.This work was supported by Medical science research project of Hebei province (Grant No. 20201076), the program of the government funding Clinical Excellence of Hebei province (2019Grant No. 139), and the program of the government funding Clinical Excellence of Hebei province (2022Grant No. 126).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.


This particular topic of the journal has received numerous submissions but considering the focus of this special topic and the quality of the articles, only few of these were ultimately published including three comprehensive reviews, one mini review and three original articles. Out of many complications of diabetes mellitus, diabetic retinopathy is one of the leading causes of diabetes-associated blindness in the industrial world (Chang et al. thoroughly discussed the roles of several non-coding RNAs such as microRNAs, lncRNAs and cricRNAs, involved in the gene expression as well as other biological processes in the development of novel therapeutics for diabetic retinopathy, which may help in developing novel therapeutics for diabetic retinopathy. The involvement of microRNAs has been further observed in one of the original studies published under this topic, where Guan et al. reported the upregulation of miR-199a-5p in the placenta of patients with gestational diabetes mellitus. On the other hand, while approximately 50% of people with diabetes are undiagnosed, diagnosing the disease at an early or a prediabetic stage can make a big difference in preventing or delaying the development of T2D. Applications of newly identified biomarkers may make a considerable difference in the diagnosis of prediabetes and ultimately preventing the rapidly growing prevalence of T2D. This has been widely discussed in the mini review published on this topic by Luis et al. As mentioned above, novel antidiabetic compounds are being identified either from the natural or synthetic origin, when a number of factors may limit the propagation of plants with potential antidiabetic phytochemicals for the viable production of antidiabetic drugs. Ali et al. not only elaborated on the recent progress of antidiabetic phytoconstituents but also their cellular mechanisms, and clinical outcomes as well as micropropagation methods of plants using callus culture and nano-elicitation strategies, which may help in the viable production of antidiabetic medicines from phytochemicals. Lastly, many medicines for different diseases have been developed via modulating the activities of cell membrane channels and gene expressions. It has been shown by Lu et al. in one of the original studies on this topic that Cisapride, a stomach-intestinal motility drug, may play a crucial role in reducing diabetes-associated hyperglycemia and hyperinsulinemia by modulating the expression of KCNH6, a potassium channel protein. This has not only been confirmed by in vitro experiments but also by using KCNH6 knockout mice. There is also another original study where the roles of D-Chiro-Inositol on hepatic insulin resistance has been investigated by Cheng et al., when Li et al. comprehensively reviewed the roles of pyroptosis, particularly mediated by the NLPR3, in the progression of T2D. In a world, all these reviews and original studies will contribute significantly to create better strategies for the development of novel anti-diabetic medicines by using molecular targets in the following years.Considering the rapidly growing prevalence of diabetes around the world  and gradal world . Chang e


Serine proteases are heavily present in the gastrointestinal tract where they are essential in numerous physiological processes. An imbalance in the proteolytic activity is a central mechanism underlying abdominal pain in irritable bowel syndrome (IBS). Therefore, protease inhibitors are emerging as a promising therapeutic tool to manage abdominal pain in this functional gastrointestinal disorder. With this review, we provide an up-to-date overview of the implications of serine proteases in the development of abdominal pain in IBS, along with a critical assessment of the current developments and prospects of protease inhibitors as a therapeutic tool. In particular, we highlight the current knowledge gap concerning the identity of dysregulated serine proteases that are released by the rectal mucosa of IBS patients. Finally, we suggest a workflow with state-of-the-art techniques that will help address the knowledge gap, guiding future research towards the development of more effective and selective protease inhibitors to manage abdominal pain in IBS. Irritable bowel syndrome (IBS) is a highly prevalent disorder of the gut-brain axis affecting 4% of the world population . Also acThe symptoms of IBS are likely a manifestation of several contributing mechanisms, as depicted in Proteases are enzymes that hydrolyze peptide bonds, which can result not only in the inactivation of the target but also in the activation of signaling molecules and receptors. In the gastrointestinal tract, while proteases are best known for their role in food digestion, they are now emerging as pivotal mediators of increased intestinal epithelial permeability and visceral pain . Among tProteases can modulate visceral pain through several mechanisms as illustrated in Evidence from pre-clinical studies has indicated that proteases can promote VHS in mice via PAR2-mediated sensitization of TRPA1 and TRPV4. Intracolonic administration of PAR2 activating peptide causes visceral hyperalgesia in wild-type mice, but not in TRPA1 knock-out mice, suggesting that TRPA1 is needed to mediate PAR2-induced hyperalgesia . AdditioProteases can also convert molecules that are active on pain pathways. Bradykinin for example, a potent proinflammatory mediator, is generated through cleavage of kininogens by kallikreins, which are serine proteases, and can induce hyperalgesia via TRPV1 and TRPA1 sensitization . The conin situ zymography, is expressed by the intestinal epithelium and upregulated in IBS  and cysteine proteases (papain and cathepsin B), but not thrombin, elastase, or chymotrypsin. This inhibitor was used by Rolland-Fourcade et al. to demonstrate that lipopolysaccharide-stimulation of intestinal epithelial cells results in basolateral release of trypsin-like proteases . APC-366This indicates that drugability is a critical aspect that requires a lot of attention. For compound UAMC-00050 the efficacy decreased when given locally via an enema versus intraperitoneal injection . Plasma The two major factors hampering the development of specific protease inhibitors are the superficial identification of overactive serine proteases in this disorder, as well as the limited mapping of substrate preferences of relevant proteases. Activity-based probes (ABPs) provide a solution for the first obstacle. The reactive group of the probe binds specifically and irreversibly to the proteases of interest. This allows identification of the bound proteases by mass spectrometry after affinity-based purification. The use of these probes is slowly increasing in the field of inflammatory and functional bowel diseases, which can only be encouraged further . To tack10) and diverse pool of substrates is phage display technology (HyCoSuL has proven to be a valuable tool to study protease substrate preference, however, it is limited to the amino acid residues N-terminal to the cleavage site . Internachnology . Random chnology . A beautchnology . By applCombining target identification via ABPs and inhibitor design via HyCoSuL should provide a reliable and accessible toolbox to design highly specific protease inhibitors for the management of abdominal pain in IBS . TestingThe investigation of protease dysregulation in gastrointestinal diseases, and more specifically in VHS and IBS, has definitely increased in recent years, bringing protease inhibition to the forefront of one of the most promising novel therapeutic strategies to explore. However, three important factors need to be addressed to advance serine protease inhibitors as a treatment for VHS in IBS. The first is the limited knowledge of the targets. The dysregulated proteases need to be characterized unambiguously and on a patient level, an endeavor that can be achieved with activity-based probes. Secondly, as underlined in this review, proteases have many important physiological roles and any inhibition will have to be carefully targeted to limit side effects. Accurate mapping of substrate specificities of the proteases of interest with a technique like HyCoSuL will facilitate and accelerate the development of highly specific serine protease inhibitors. The third and final limiting factor is that the current oral bioavailability of serine protease inhibitors is poor and improvement of formulations favoring local delivery should be prioritized to give the inhibitors a higher chance to succeed in clinical trials for IBS.


Specular highlights detection and removal in images is a fundamental yet non-trivial problem of interest. Most modern techniques proposed are inadequate at dealing with real-world images taken under uncontrolled conditions with the presence of complex textures, multiple objects, and bright colours, resulting in reduced accuracy and false positives. To detect specular pixels in a wide variety of real-world images independent of the number, colour, or type of illuminating source, we propose an efficient Specular Segmentation (SpecSeg) network based on the U-net architecture that is expeditious to train on nominal-sized datasets. The proposed network can detect pixels strongly affected by specular highlights with a high degree of precision, as shown by comparison with the state-of-the-art methods. The technique proposed is trained on publicly available datasets and tested using a large selection of real-world images with highly encouraging results. Regions with specular reflections in an image are generally unwanted yet mostly unavoidable features. This is why the problem of specular highlight detection is challenging and has been an area of progressive research for both traditional photography and digital imaging since the beginning. Specular reflections are extremely hard to avoid in real-world conditions since they depend on several factors, including variables related to the illuminating source as well as the target object in the scene. These factors include azimuthal, zenith orientations of the illuminating source and the object as the primary factor in the presence of specular highlight, alongside factors such as the material of the surfaces interacting with the light. In most natural-world conditions, one or more of these factors are uncontrollable, which makes the presence of specular reflections impossible to avoid. Specular highlights are a highly informative feature and have an essential role in image processing and computer graphics. Specular reflections are essential for human vision as they provide powerful visual cues about the shape of the objects, the material of the object, and the location of the illuminating light source. However, apart from specific applications, specular reflection is generally considered an undesirable feature in the image processing domain, causing loss of chromatic and textural information that is often vital to applications .d, s stand for the diffuse (body) and specular (interface) components, respectively, c is the spectral power distribution, While there are several physical models for the definition of specular reflections in images, the most prominent one is the Dichromatic Reflection Model (DRM) proposed by Shafer et al. . They prThe DRM model is valid for inhomogeneous materials only , which aIn digital imaging, the requirement of detecting the occurrence of specular reflections and identifying all the corresponding affected pixels accurately becomes an essential yet formidable task. The affected specular pixels have to be segmented before any processing algorithm can be used to remove the specularity and mitigate the undesirable effects of the reflection. As the DRM model is an ill-posed problem with more unknown than known variables, accurately segmenting and detecting specular pixels in an image is challenging. A single image does not provide enough information regarding the physical orientation of the light source or the surface orientation required to calculate the surface normals about which light is specularly reflected. Since specular pixels are generally represented by the brightest pixels in an area, they are hard to differentiate from lighter colours in the scene. This is further accentuated with the presence of large brightly-lit regions, such as the sky, or the presence of any light source directly in the image. Similarly, pixels nearing the colour of the light source are hard to differentiate from specular reflections, thus making the accurate segmentation of specular pixels a highly arduous task. Furthermore, since the strength of the illumination is captured as pixel intensity, specular pixels are represented by higher intensity values, often near or fully saturated values  to simplify all chromaticity-based methods. It is further assumed that each segmented cluster has uniform diffuse chromaticity. While being very helpful for modelling the problem of specular highlight, these and other assumptions do not reflect real-world images’ randomness and limit the generalisation and applicability of methods.Since most limitations are not considered for deep learning-based methods, it is quite clear that modern state-of-the-art methods are significantly more robust and can cater to a much more comprehensive range of images. However, limitations are enhanced in the presence of outdoor images, which have both strong illumination and inter-reflections in an uncontrolled and often stochastic environment. Outdoor environments have illumination from the sun as an omnidirectional light source, causing light to bounce off in often undesirable directions and strength. Strong light sources also result in more significant specular regions in images, which makes the regions easily visible but also easily confused with the objects in the scene, as well as causing a significant loss of information in the area, which hinders the recovery of colour and other information in the affected region.As already detailed in the preceding section, accurate detection and segmentation of specular pixels from real-world images have significant implications in various fields. This work intends to fill the research gap and add to the current state of the art in specular highlight segmentation. To achieve this, we propose a specular highlight segmentation network that is simple to model, fast to train, and works on images used in the literature as well as a wide variety of general real-world images. Most state-of-the-art deep learning models are structurally complex, with a complex organisation of deep hidden layers and innovative, unique features such as attention and other methods. Secondly, due to their complex design, they require a significant time to train and fine-tune due to there being many hyperparameters in the model and deep neural network layer structure. This, in turn, causes significant hindrances in research and development due to unoptimised training times required while expected nominal results are not achieved. Furthermore, complex and deep networks also mandate the utilisation of expensive and powerful hardware, consuming much power while training and re-training. We avoid both these pitfalls by our proposed Specular Highlight Segmentation Network (SpecSeg Network for short), based on the proven U-net model, which is a highly reliable yet straightforward model that was initially proposed for medical segmentation . Our expSince its inception, U-Net has proven to be a breakthrough for segmentation tasks and has been instrumental in paving the way for developing a more advanced encoder–decoder style of network. The network is named after the U-shape of the hidden layers, combining an encoder–decoder arrangement for downsampling the input to a bottleneck and upsampling again to an output image, with convolution, activation, and pooling operations between its successive hidden layers. Skip connections allow the network to propagate context information from higher resolution layers to the decoder’s generated outputs and significantly affect the quality and accuracy of the Unet output . By parsSpecSeg comprises five encoder blocks and four decoder blocks based on the classical U-net pattern, and each path from the encoder is passed to the decoder via a skip connection. Each encoder block consists of two 2D convolutional layers with filters r et al.  propose r et al.  that theAn incremental dropout of networks , and theThe decoder block mostly mirrors the encoder block setup defined above with a few notable changes. Firstly the decoder performs an upscaling operation. This is done using 2D transpose convolutional layers with filters Thus the overall U-net structure takes batches of 16 images of resolution For deep learning problems, loss functions depend profoundly on the problem being solved and are often tailored to the task at hand. For specular highlight segmentation, we selected a linear combination of Dice similarity coefficient (DSC)  and Focap is the ground truth, Dice similarity coefficient (DSC) is a spatial overlap index developed to measure the pixel-level similarity between two images, where one is generally the binary mask image. DSC loss function has values in the range of 0–1. Lower values indicate minimum spatial overlap between two sets of binary segmentation results, whereas larger values nearing 1 indicate increasing overlap, where 1 represents 100% complete overlap. The dice similarity coefficient has been widely adopted in biomedical segmentation problems where manually annotated lesions or cancerous cell datasets are available to train segmentation algorithms. Mathematically, the dice similarity loss (fined as .(2)LDicFocal loss  addresseBy adding the losses mentioned above, we can create a total loss that calculates the true positive segmented pixels and enables the network to focus on the misclassified samples of the training dataset. The dice loss maximises the overlap between predicted and actual labels, whereas the focal loss addresses class imbalance by reducing the effect of biased or skewed classification on the predicted results. The total loss function is defined as a linear combination of both the Dice loss and Focal loss and is used for backpropagating over all learnable parameters.SpecSeg network is implemented using Tensorflow 2.8’s sequential API as it provides easy and high-performance execution of the relatively straightforward network. SpecSeg is optimised using ADAM optimiser with  network . All tra network  and SHIQ network . The datThe results of segmenting specular highlights using SpecSeg network on the Whu-Specular dataset  are showThe quantitative results of the testing done on the datasets used are presented in Outdoor conditions present the most significant and extreme challenge for any specular highlight detection network. The presence of a bright sky and strong sunlight in unpredictable imaging conditions and scene contents present the biggest failure challenges for all algorithms. The proposed SpecSeg network was tested on acquired outdoor images taken on a clear and bright sunny day. Some of the segmentation results are presented in Visually comparing with the manually annotated masks in Owing to several challenges, as discussed in One of the most significant caveats of deep learning is the significantly staggeringly large times required for training the networks. To compare training time with the other methods, our proposed network was trained on the Whu-specular training dataset for 200 epochs for a mere 40 min on a P100 . In comparison, the SHDNet achieved its results after training for 100 epochs in 80 h on a GTX-1080Ti . This significantly reduces training time without the need for additional computational power to achieve comparable segmentation results. For training and inference comparison, Fu et al.  trained In order to test the proposed network, an in-depth ablation study was carried out by varying different aspects of the network. As shown by the performance comparison in The proposed losses combined with batch normalisation and LRelu activation give the best results for PSNR, MSE, Dice, and S-measure scores, whereas the SSIM score is lower only by a negligible amount. Using Leaky ReLU activation gives the overall best scores as it avoids the vanishing gradient problem. The combination of dice and focal losses appear to converge successfully towards the best results on the test dataset. All ablation tests were carried out on the same hardware and did not see any change in training time.A deep-learning-based method for segmenting specular highlights from single images was presented. The proposed network is significantly fast to train with limited images and accurately detects specular reflections in real-world images with no restriction on illumination conditions for image acquisition. The novelty of the proposed method is the customisation and tailoring of an established architecture for the accurate detection of specular highlights that have not been applied to the segmentation of specular highlights to real-world images in the prior literature. Furthermore, the proposed network’s training time requirement and inference performance are significantly better than other competing networks trained and tested on comparable hardware. The segmented specular highlights are comparable with state-of-the-art specular detection methods provided in the literature. Unfortunately, as most competing methods do not provide their implementations or pre-trained weights, direct retraining or testing on custom datasets is impossible. We also show that the proposed network can detect specular highlights in outdoor images taken under extremely bright conditions, with good results. To our knowledge, no other prior work has presented a specular highlight detection network that works on indoor and outdoor images with reasonably accurate results on both conditions. The proposed methods can further be improved by possibly incorporating self-attention methods to improve the robustness of the learned specular features. In the future, we intend to improve the inference process’s accuracy and implement recovery of the affected textural information for dovetailing into advanced pipelines for specular highlight mitigation. We also intend to further improve the results on outdoor images by acquiring more extensive amounts of outdoor data with specular highlights using polarimetric cameras and training SpecSeg for improved segmentation results.


The tumor was resected using the translabyrinthine approach and was pathologically confirmed as schwannoma based on the surgical specimen.Preoperative audiogram and vestibular test findings and MRI images.Preoperatively, pure-tone audiogram showed progressive sensorineural hearing loss only on the affected side. The video head impulse test and vestibular evoked myogenic potential test showed vestibular dysfunction on the affected ear. Immediate gadolinium-enhanced T1-weighted MRI revealed an enhanced region in the vestibule. Meanwhile, magnetic resonance cisternography showed a filling defect. Delayed 3D-FLAIR MRI revealed a signal void in the scala media of the cochlea indicative of cochlear hydrops, and a strong signal in the perilymph at the basal cochlea suggestive of impaired blood–labyrinthine barrier.Delayed 3D-FLAIR MRI is useful in diagnosing concurrent ILSs and endolymphatic hydrops. Intralabyrinthine schwannomas (ILSs) are a rare clinical entity, and they arise from the distal branches of the vestibular and cochlear nerves within the membranous labyrinth , 2. The A woman in her 30's visited our department due to hyperacusis in the right ear. Audiogram showed almost normal hearing level . The patvia 3D-FLAIR MRI and ILS diagnosed via pathological examination of surgical specimen. To the best of our knowledge, there are only two studies describing endolymphatic hydrops diagnosed via delayed 3D-FLAIR MRI in patients with ILS   of patients  for the publication of any potentially identifiable images or data included in this article.KN conceived the idea of the study and drafted the original manuscript. All authors reviewed the manuscript draft, revised its intellectual content critically and approved the final version of the manuscript for publication.The study was supported by JSPS KAKENHI Grant Number 22H03239.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.


Metoposaurus krasiejowensis from the Krasiejów locality, southern Poland.Neoplasms are common across the animal kingdom and seem to be a feature plesiomorphic for metazoans, related with an increase in somatic complexity. The fossil record of cancer complements our knowledge of the origin of neoplasms and vulnerability of various vertebrate taxa. Here, we document the first undoubted record of primary malignant bone tumour in a Mesozoic non-amniote. The diagnosed osteosarcoma developed in the vertebral intercentrum of a temnospondyl amphibian, A wide array of data collected from gross anatomy, histology, and microstructure of the affected intercentrum reveals the tumour growth dynamics and pathophysiological aspects of the neoplasm formation on the histological level. The pathological process almost exclusively pertains to the periosteal part of the bone composed from a highly vascularised tissue with lamellar matrix. The unorganised arrangement of osteocyte lacunae observed in the tissue is characteristic for bone tissue types connected with static osteogenesis, and not for lamellar bone. The neoplastic bone mimics on the structural level the fast growing fibrolamellar bone, but on the histological level develops through a novel ossification type. The physiological process of bone remodelling inside the endochondral domain continued uninterrupted across the pathology of the periosteal part.Based on the results, we discuss our case study’s consistence with the Tissue Organization Field Theory of tumorigenesis, which locates the causes of neoplastic transformations in disorders of tissue architecture.The online version contains supplementary material available at 10.1186/s12862-022-02098-3. Investigating the pathogenesis and tumour growth dynamics in non-human animals promotes understanding of neoplasm biology and indirectly helps to develop treatment strategies for cancer in humans. Veterinary and comparative oncology document the current occurrences of neoplasms in various taxa. Examination of the occurrence of neoplastic diseases in various extinct taxa across the Phanerozoic supplements this current state of knowledge with respect to the mechanisms of tumour development in an evolutionary perspective, as well as documents the somatic vulnerability of extinct animals to neoplasms. The fossil record, although limited mainly to hard tissues, provides an exceptional insight into the tumorigenesis across the animal kingdom in the evolutionary time.Occurrences of cancer were documented in extinct amniotes—in a Late Permian-Early Triassic therapsid , a MiddlMetoposaurus krasiejowensis Sulej 2002 .Additional file 7. Close-ups of osteocytes lacunae in the neoplasm-affected part of vertebral intercentrum showing their subspherical shapes.


The most significant features for clinical diagnosis of schizotypal personality disorder (SPD) are cognitive-perceptual and disorganized symptoms. Experimental study of visual perceptual processes is important to elucidate the psychological mechanisms of cognitive-perceptual impairment in SPD.To research the performance of visual perceptual tasks in SPD.Series I and II presented the subjects with visual perceptual tasks with different types of instructions . The Wechsler Adult Intelligence Scale (WAIS-R) was also administered. The participants were 39 SPD patients, 36 obsessive-compulsive personality disorder (OCPD) patients , and 102 healthy controls.p < 0.01). With visual perceptual cues in Series II, patients with SPD had the same number of correct answers as controls, whereas OCPD patients had the same number of correct answers as controls with verbal cues in Series I. SPD patients had significantly lower scores in most verbal and nonverbal WAIS-R subtests in comparison with controls. SPD patients differed from OCPD patients in that they had lower scores in the “Information” (p < 0.05) and “Comprehension” (p < 0.05) subtests.SPD patients had a significantly lower number of correct answers in conditions of vague instruction and verbal cues in Series I of a visual-perceptual task in comparison with healthy subjects (With visual-perceptual cues, SPD patients were able to achieve normative results in the performance of visual-perceptual tasks, whereas patients with OCPD demonstrated lower productivity. In SPD patients, the basic impairments were associated with difficulties in inhibition of peculiar responses, stability of a subjective manner of performance and inability to revise it, low orientation to the model, and slipping into subjective associations with the stimuli. Psychiatric research on cognitive deficits in schizophrenia and in non-psychotic disorders within the schizophrenia spectrum is considered to be a promising approach for understanding mental dysfunction . SchizotCognitive dysfunction is an essential line of modern clinical and psychological research into schizophrenia-spectrum disorders as one of the levels of the disease . MoreoveClinicians suggest that the most significant clinical diagnostic criteria for SPD are cognitive-perceptual  and bizarreness, disorganized criteria  . A distiPsychological studies on visual perceptual processes in SPD focus on several different aspects. The neuropsychological approach describes dysfunction of spatial working memory , executiExperimental studies of perception in patients with SPD have shown intact early visual perceptual processes and heightened mental imagery , which pSocial cognition is a significant facet of visual perceptual processing. Patients with SPD were characterized by empathic dysfunction with regard to others’ negative feelings, which was associated with lower indices of social support . It is iThe cultural-historical approach discusses the systemic structure of mental activity in schizotypal disorders, and the significant role of culture in accepting cognitive-perceptual symptoms of SPD as normative experiences . This apTherefore, SPD is characterized by destabilization of mental activity in situations of social interaction , which iThus, the investigation of visual perceptual functions in SPD requires the development of a particular methodological approach that explores the processes of mental activity in an expanded form. This approach is based on the close relationship between cognitive performance, and emotional and personality features. It includes methods that allow the researcher to vary the emotional intensity of stimuli, increase the degree of uncertainty, change instructions for tasks, and use different manners of stimulus presentation. Such an organization of an experiment is more sensitive and informative with regard to the structure of mental activity and the specific characteristics of executive functions of patients with SPD. Based on the principle of cognitive-affective unity, this approach proved its effectiveness in the investigation of hysterical personality disorder .The study of interdependence, different aspects of cognitive performance, emotional and personality features, represents an integrative approach to the interpretation of experimental data. This methodology allows us to overcome limitations of the description of cognitive impairment in personality disorder at the level of separate phenomena  and provThe crucial role of the cognitive-perceptual and disorganization criteria of SPD identified in clinical studies, as well as the significance of special conditions of manifestation of cognitive disturbances  indicate the prospects for psychological study of strategies for solving visual perceptual tasks for better understanding of the psychological mechanisms of cognitive impairment in SPD. The inconsistency of visual perceptual productivity, and the ability to find solutions corresponding to the norm differentiate SPD from schizophrenia. These peculiarities of visual perceptual processes in SPD align with the cognitive functions in personality disorders. At the same time, it is important to create conditions in which discrepancies among different types of severe personality disorders  could be revealed. In our experimental study, we elaborated the conditions of different degrees of uncertainty, social regulation of answers, and complexity of stimuli to detect which is more sensitive in SPD patients. We have proposed that inconsistency of cognitive functioning productivity in SPD is manifested in steady alteration of conditions and the necessity to find new ways to adapt. These manifestations are differentiated from those in other severe personality disorders .This study aimed to research the performance of visual perceptual tasks in patients with SPD, their ability to create and use compensatory strategies, conditions of normative performance and manifestation of impairments, and their severity.The clinical groups comprised 39 patients with SPD (F21.8 in ICD-10) aged 18–55  and 36 patients with obsessive-compulsive personality disorder aged 18–56 . The clinical comparison group (OCPD) is more severe than other types of personality disorders. This allows for comparability of results of cognitive tests in patients with SPD and OCPD, to elucidate similarities and differences in psychological mechanisms of performance of visual perceptual tasks in SPD and other personality disorders.p = 0.02) (Table 1). All patients were examined before the treatment.The control group consisted of 102 healthy individuals between the ages of 18 and 54. Patients were recruited from mental health clinics in Moscow . They were consulted by psychiatrists and signed an informed consent agreement. Patients with personality disorders and normal controls had an equivalent educational level, except in the group of patients with OCPD, who generally had higher education . The embedded figures of Witkin and Goldstein  were useThree types of instructions were used. The first one was vague ( “Do you think this figure is in a complex one?” ) and was presented after the first simple figure had been shown alongside the first complex figure in Series I. The second instruction provided verbal clues about the criteria for correct answers: “Every simple figure is not necessarily embedded within every complex one, but if you find a simple figure, it should be the same as the one in the model”. This verbal clue was presented before a demonstration of the second complex figure in Series I. The third instruction involved visual perceptual cues in Series II, when one of the two simultaneously presented complex figures could be considered as a corrector for the answers. Thus, the procedure provides the opportunity to moderate uncertainty of stimuli and experimental conditions.The analysis of performance of visual perceptual tasks included the number of correct answers in the different types of instructions.To analyze different aspects of the cognitive functions of patients with SPD, the study included the WAIS-R test , with six verbal and five performance subtests .Statistical significance was ascertained by Student’s t-test for comparing independent groups, the Spearman rank correlation coefficient, a two-way 3×3 factorial analysis of variance, and Fisher’s exact test to compare categorical variables.Visual Perceptual Tasks in Patients with Schizotypal Personality Disorder, Healthy Subjects, and Patients with Obsessive-Compulsive Personality Disorder.Figure 1 shows the values of the correct answers for the different types of instructions. The data shows that all subjects had the smallest number of answers when the key figure was presented with “vague” instructions. However, the healthy individuals had significantly more correct answers with “vague” instructions compared to the patients with personality disorders (Table 3). Patients with SPD had significantly fewer correct answers with verbal cues in comparison with the healthy subjects (Table 3). OCPD patients had intermediate outcomes with verbal cues, with more right answers than SPD patients and less than the healthy controls, without significant differences with either the SPD patients or healthy subjects . This result indicates the possibility of increasing the productivity of performance of visual perceptual tasks by patients with OCPD at the level of standard indicators, when the degree of uncertainty of the stimulus was reduced.Table 3). SPD patients had no significant differences in the number of correct answers in comparison with the controls . Patients with OCPD had significantly fewer correct answers with visual perceptual cues in comparison with healthy individuals (Table 3).In Series II, with visual perceptual cues, there was an equal percentage of healthy subjects who found the key figures and of those who could not. The same was observed in patients with SPD, with slightly more patients who found the key figures in the pair of complex figures , the “Picture Completion” (p ≤ .01), and the “Block Design” (p ≤ .01). Patients with SPD managed to fill in the same number of digits on the Digit Symbol subtest as the healthy subjects in the allotted time, but they displayed differences in the quality of writing of the symbols. The patients more often had a change in the slope or character size, an incorrect alignment of lines in the symbol, or extra lines.To further illuminate the performance of visual perceptual tasks, nonverbal WAIS-R subtests were analyzed for patients with SPD in comparison with healthy subjects. The lower scores in the Block Design subtest in patients with SPD was associated with difficulty analyzing parts within the whole, when this was required to compare the results of their performance with an externally provided sample.Patients with SPD had lower productivity in the Picture Completion subtest because of a tendency to focus on insignificant, peculiar aspects of the stimuli.An important characteristic of the cognitive processes of patients with SPD was the significantly lower score on WAIS-R verbal subtests. Analysis of performance of verbal tasks by patients with SPD allowed us to elucidate the general psychological mechanisms, which can also determine the impairment of visual perceptual processes in SPD.p ≤ .01), Comprehension (p ≤ .01), Arithmetic (p ≤ .05), Digit Span (p ≤ .05), and Vocabulary (p ≤ .05) verbal subtests.Patients with SPD differed statistically from healthy subjects in the performance of the Information . In some cases, the answers of patients with SPD included both egocentric solutions and standard social criteria. When conveying the figurative meaning of non-frequent expressions, SPD patients tended to resort to magical meanings combined with situation-based generalizations. It should be noted that the patients could give the correct answers in tasks where they were asked to explain the figurative meaning of common proverbs and expressions, which suggests the ability of these patients to operate with conventionalized abstract meaning.Patients with SPD had lower scores on the Arithmetic subtest in comparison with healthy subjects, which can be explained by the former’s inconsistent productivity in counting operations. These patients, when faced with difficulties in tasks with one-phase counting, did not attempt to find an answer. More rarely, patients with SPD expressed unwillingness to count. By contrast, the patients performed well on easy tasks on the Arithmetic subtest with two-phase counting, and obtained additional points for speed in these tasks. In the most complicated tasks of the Arithmetic subtest, patients with SPD easily substituted a correct description of the necessary actions, thereby avoiding counting operations.Comparison of Performance on the Wechsler Adult Intelligence Scale (WAIS-R) in Patients with OCPD and Healthy SubjectsTable 4 shows a significant difference between the WAIS-R performance by patients with OCPD and healthy individuals only in the Digit Span verbal subtest (p ≤ .01). However, in nonverbal subtests, the results of patients with OCPD were significantly lower than with healthy subjects (in the Digit Symbol (p ≤ .05), in the Picture Completion (p ≤ .01) and in the Block Design (p ≤ .01) subtests).The lower scores on the Digit Span subtest were associated with a shift of patients’ attention from the instruction for the task to thoughts of failure, greater doubts about one’s own performance, abilities, etc. Patients with OCPD demonstrated on the Digit Symbol subtest the intention to accurately imitate the symbols specified by the instruction, which led to an excessive focus of attention on verifying the result. They also corrected their mistakes, which slowed their performance. Preoccupation with details made the patients with OCPD take a long time searching for answers in the Picture Completion subtest, going beyond the time allocated to each item.Patients with OCPD gave a detailed analysis of the parts that presented difficulties when synthesizing them into a whole, were unable to revise their work method, doubted the correctness of the process, and often canceled the correct answers, which reduced their productivity in the Block Design nonverbal subtest.p ≤ .05) and Comprehension (p ≤ .05) verbal subtests. Analysis of the performance of nonverbal subtests by patients with different types of personality disorders revealed no significant differences.Patients with OCPD had significantly higher scores than patients with SPD on the Information  and scores on the Object Assembly subtest .In patients with SPD there were significant positive correlations between the number of correct answers under the condition of visual perceptual cues, and the Sum of Performance scores , and the adaptive ability of patients with OCPD. The latter were able to develop their own effective criteria based on the verbal cue  in searching for the key figures embedded in the complex ones.In the performance of Series II tasks with visual perceptual cues, the situation is the opposite. SPD patients could switch their attention to the second figure and treat it as a corrector to their own solutions, so, they had standard results, whereas patients with OCPD demonstrated a significant decrease in performance of visual perceptual tasks when two complex figures are presented simultaneously. These findings indicate the abilities of patients with SPD to find a new way of adapting when the conditions of performance were changed and to follow it effectively. This corresponds to the fact that patients with SPD had no discrepancies with normative indicators when working on nonverbal tasks with visually presented social context (the Picture Arrangement subtest) and concrete content (the Object Assembly subtest). This fact suggests that patients with SPD had no decrease in social regulation of activity in case of direct visual support of the social context. At the same time, patients with SPD display lower productivity in verbal tasks associated with a social context. Therefore, among nonverbal tasks, the performance of tasks with abstract visual perceptual information is the most sensitive to impairments in patients with SPD. This result is consistent with the significant role of cognitive-perceptual criteria for diagnosis of SPD identified in clinical studies .The decline in most cognitive parameters of the Wechsler Adult Intelligence Scale in patients with SPD corresponds to data from meta-analyses of cognitive impairment in schizophrenia spectrum disorder  and suggSPD patients’ inconsistent productivity in performing verbal tasks was caused by difficulties in inhibiting subjectively significant responses when socio-deterministic formal criteria were available for making judgments; the stability of a subjective manner of performance and inability to revise it; vagueness in definition of concepts; and slipping into subjective associations with the stimuli. OCPD patients are characterized by relatively intact ability to solve verbal tasks, as evidenced by lower scores than normative on only one of the verbal subtests.Although patients with SPD and OCPD did not differ significantly in their scores on nonverbal tasks, the qualitative analysis revealed the principal differences in the psychological mechanisms of their impairments. In SPD patients, the lower scores on nonverbal subtests were a result of low orientation toward the model, ease of subjective transformation of the targets, and impairment of the selectivity of cognitive processes. The latter is specific for patients with schizophrenic spectrum disorders. This impairment is characterized by a tendency to rely on insignificant, bizarre, unusual attributes of concepts . The lowFor healthy subjects and patients with OCPD, there was no association in Series I and Series II between productivity in performing visual perceptual tasks under conditions of different instructions, and the parameters on the intelligence scale, whereas in SPD patients, the productivity of the search for figures under condition of visual perceptual cues was associated with nonverbal subtests and the integrative performance score.The patients with SPD had more severe cognitive impairment than the OCPD patients. The former had lower productivity in performance of verbal and nonverbal tasks. Patients with OCPD had difficulties only in the performance of nonverbal tasks, whereas in verbal tasks they had scores corresponding to the normative.It is important to note the specific mechanisms of impaired cognitive functioning in SPD. The basic impairment in these patients was associated with difficulties in inhibition of bizarre responses, stability of the subjective manner of performance and inability to revise it, low orientation to the model, and slipping into subjective associations with the stimuli. In OCPD it was associated with a shift of patients’ attention from the instruction about the task to thoughts of failure, strengthening of doubts, and excessive focus on checking one’s performance.Varying the degree of uncertainty of the visual perceptual tasks with abstract stimuli made it possible to reveal the specific compensatory strategies of patients with SPD, which help to increase the productivity of the performance. So, under the condition of visual perceptual cues, these patients could achieve normative results, whereas patients with OCPD demonstrated lower productivity. These facts also suggest that the performance of visual perceptual tasks in patients with SPD is characterized by inconsistent productivity and the availability of compensatory strategies that increase the performance to normative levels.This experimental study has some clinical implications. First, these findings broaden the pathopsychological picture of impairments of visual perceptual processes and compensatory strategies of patients with SPD. Second, it should be useful for differential diagnostics of severe personality disorders, SPD, and other schizophrenia-spectrum disorders. Furthermore, these results contribute to addressing complex issues of social and daily-life adaptation, occupational activity, and productivity of SPD patients.The current study had several limitations that should be addressed in future research. First, it might be informative to compare the results of cognitive tasks of patients with SPD and schizophrenic patients (pseudoneurotic type), to discuss specific and general impairment of cognitive productivity in schizophrenia-spectrum disorders. Second, it would be promising to discuss the duration of clinical symptoms and their association with the change or intactness of cognitive productivity in the performance of the visual perceptual tasks in patients with SPD.