During the reproduction of animals and lower plants, one sperm cell usually outcompetes the rivals to fertilize a single egg cell. But in flowering plants, two sperm cells fertilize the two adjacent dimorphic female gametes, the egg and central cell, respectively, to initiate the embryo and endosperm within a seed. The endosperm nourishes the embryo development and is also the major source of nutrition in cereals for humankind. Central cell as one of the key innovations of flowering plants is the biggest cell in the multicellular haploid female gametophyte (embryo sac). The embryo sac differentiates from the meiotic products through successive events of nuclear divisions, cellularization, and cell specification. Nowadays, accumulating lines of evidence are raveling multiple roles of the central cell rather than only the endosperm precursor. In this review, we summarize the current understanding on its cell fate specification, intercellular communication, and evolution. We also highlight some key unsolved questions for the further studies in this field. Unlike that in animals where the haploid spores generated by meiosis directly differentiate into functional gametes, in plants the haploid spores undergo additional mitosis to produce multicellular gametophytes. In lower plants, like the Bryophyte, gametophytes are dominant of their life cycles and unusually free-living, whereas in seed plants (gymnosperms and angiosperms), the gametophytes are structurally reduced and develop within the sporophytic sexual organs. In flowering plants (angiosperms), the female gametophytes are developmentally reduced to a miniature structure with only a few cells embedded within layers of sporophytic ovular tissues. In contrast to the gametophyte-dominant species and sporophyte-dominant gymnosperms, the emergence of an additional female gamete, the central cell, is a critical innovation of sexual reproduction and a hallmark of angiosperms. Fertilization of both the egg and the central cell, known as double fertilization, produces the embryo and endosperm, respectively, within the seed coat. Besides acting as the endosperm precursor, the central cell also undertakes important roles during embryo sac development and function. This review outlines recent advances in our understanding of the central cell with focuses on cell specification, cell-to-cell communication, and evolution.Amborella trichopoda, a single extant species, forms a unique Amborella-type embryo sac that contains three synergid cells due to an extra cell division of one of the micropylar cells  was initiated at the tip of each nucellus . Throughar cells . Anotherar cells . Other tar cells . All thear cells . It is uar cells . Given tDuring the female gametophyte development, positional cues, hormones, and coordinated cell-to-cell communication have been proposed to orchestrate the establishment of embryo sac polarity and development . A plethIn contrast to other gametophytic cells, the central cell is characterized by its central position and large volume, including a large central vacuole at the chalazal end, two polar nuclei, cytoplasm and organelles that are inherited from the developing syncytial gametophyte. The polar nuclei fuse before fertilization in Arabidopsis, but after fertilization in cereals . Hence, GAMETOPHYTIC FACTOR2 (GFA2) encodes a mitochondrial chaperone that is required for the outer membrane fusion of polar nuclei (ATP/ADP translocator 2 (AAC2) results in unfused polar nuclei and persistent antipodal cells , CLOTHO (CLO/GFA1), and ATROPOS (ATO) encode core spliceosomal components and are initially expressed throughout the female gametophyte. Defect of these genes causes the switch of the synergids and central cells to the fate of egg cells  mutant of the putative plant ortholog of the Inner Centromere Protein (INCENP), produces additional egg cells at the expense of the accessory synergid cells and is defective in central cell differentiation , a DNA glycosylase that is required for DNA demethylation in the central cell, as well as the determination of central cell and endosperm development  components in the central cell . DisruptAt epigenetic regulation level, the central cell is drastically distinct from the egg cell. The EAR motif-containing repressors suppress target gene expression through chromatin modification of regulatory regions by histone deacetylation, often via forming complex with co-repressor TPL and histone deacetylases. In central cell of Arabidopsis and rice, locus-specific and active DNA demethylation contribute to the maternal chromosome hypomethylation in the endosperm . The replis, clo, and ato mutants, the central cell and egg cell identities are misspecified  that are expressed specifically in the egg cell, but not in the central cell (tetraspore (tes) mutant has suggested that polyspermy block exists in egg, but not in central cell , like Cycads, Gnetales, and Gingko, the surrounding gametohpytic cells take the role of endosperm function to nourish the embryo. The female gametophyte undergoes numerous rounds of mitosis to produce a coenocytic cell with approximately thousands of free nuclei . At matuThe evolution of the endosperm in flowering plants has been discussed for years . One sceWelwitschia, only the egg nucleus is fertilized since the second sperm nuclei does not enter the egg cell and degenerates (Gnetum and Ephedra, the two sister nuclei of the egg cell fused with the two sister sperm nuclei, respectively (Welwitschia (Although no fertilization-based endosperm was generated in gymnosperms, some comparison has been made between gymnosperms Gnetales and angiosperms . In Gnetenerates . In Gnetectively . Howeverwitschia . After fNowadays, we have a more comprehensive understanding of the cell specification and intercellular signaling of central cell in molecular and evolutionary aspects. The active involvement of central cell in diverse aspect of fertilization points to an emerging importance of this non-heritable female gamete. Experimental evidence is still limited for the full understanding of this mysterious cell. Although with the studies in the past two decades, the identification of the key components and their functional connectivity remains the major hurdle in understanding of central cell function and evolution. The central cell is enriched in secreted peptides, but most of them have yet to be functionally characterized as the conventional T-DNA and gene knock-down approaches are powerless in these highly redundant and sequence-diverged gene families. In addition, the relaxation of the gene silencing machinery activates the transposable elements and a large number of genes that would make the reverse genetic study laborious. With the dawn of innovative strategies in experimental techniques, such as single-cell transcriptome and epitranscriptome, gene editing technology and increase of sequenced species, we can expect a more comprehensive understanding on central cell specification, fertilization, and coordination with the surrounding cells, as well as how the central cell helps to shape the flowering plants’ overwhelming predominance on earth.H-JL and W-CY wrote the manuscript. Both 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.


Driving cessation is a major life transition in late life, and can affect the quality of social life in older adults. The present study aims to systematically review the literature on how driving cessation affects social participation among older adults in the US. The study selection followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Extant literature published from 1990 to 2019 that examined driving cessation and social participation or social engagement among older adults in the US was searched using eight search engines: PsycINFO, CINAHL, SocIndex, AgeLine, MedLine, Scopus, Transportation Research Board Publication Index, and Cochrane Library. Quantitative studies that met the inclusion criteria were reviewed. The assessment of methodological quality was also conducted for included studies. In total, seven studies met the inclusion criteria. Six of the included studies found significant relationships between driving cessation and at least one domain of social participation, such as volunteering, employment, leisure-time activities, and the frequency of contacts. However, the measures of social participation were inconsistent across studies, which might explain that no effects of driving cessation were found on the structure of social network, such as contacts with friends and extended family. There is a need to assist older adults in successfully transitioning to driving cessation and maintaining the social participation. The overall quality of included studies is moderate based on the assessment of risk of bias and confounding.


Atherosclerosis is an inflammatory disease of large and medium-sized arteries, characterized by the growth of atherosclerotic lesions (plaques). These plaques often develop at inner curvatures of arteries, branchpoints, and bifurcations, where the endothelial wall shear stress is low and oscillatory. In conjunction with other processes such as lipid deposition, biomechanical factors lead to local vascular inflammation and plaque growth. There is also evidence that low and oscillatory shear stress contribute to arterial remodeling, entailing a loss in arterial elasticity and, therefore, an increased pulse-wave velocity. Although altered shear stress profiles, elasticity and inflammation are closely intertwined and critical for plaque growth, preclinical and clinical investigations for atherosclerosis mostly focus on the investigation of one of these parameters only due to the experimental limitations. However, cardiovascular magnetic resonance imaging (MRI) has been demonstrated to be a potent tool which can be used to provide insights into a large range of biological parameters in one experimental session. It enables the evaluation of the dynamic process of atherosclerotic lesion formation without the need for harmful radiation. Flow-sensitive MRI provides the assessment of hemodynamic parameters such as wall shear stress and pulse wave velocity which may replace invasive and radiation-based techniques for imaging of the vascular function and the characterization of early plaque development. In combination with inflammation imaging, the analyses and correlations of these parameters could not only significantly advance basic preclinical investigations of atherosclerotic lesion formation and progression, but also the diagnostic clinical evaluation for early identification of high-risk plaques, which are prone to rupture. In this review, we summarize the key applications of magnetic resonance imaging for the evaluation of plaque characteristics through flow sensitive and morphological measurements. The simultaneous measurements of functional and structural parameters will further preclinical research on atherosclerosis and has the potential to fundamentally improve the detection of inflammation and vulnerable plaques in patients. Atherosclerosis is a chronic, inflammatory disease of the vessel wall, characterized by intimal lesions (atherosclerotic plaques) in the vascular system. Rupture or erosion of these plaques can trigger disease such as myocardial infarction and stroke, the major causes of morbidity and mortality worldwide. Plaque development is driven by the intimal accumulation of leukocytes. Early endothelial dysfunction and lipid deposition trigger the recruitment of inflammatory cells and foam cell formation within intimal atherosclerotic plaques. In addition to monocytes/macrophages, also other immune cells, including T and B cells, contribute to the cellular plaque infiltrate. Increasing evidence supports a critical role of inflammation and the immune system in atherosclerosis in preclinical mouse models of atherosclerosis and in patients, as reviewed in detail in ,2,3,4. C18F-fluorocholine (18F-FCH), a strong correlation was found between the uptake of the tracer and the macrophage infiltration, as revealed by histological analysis of carotid endarterectomy specimens . . 141]. T−/− mice ), the 3DAtherosclerosis is a chronic disease, initiated and modulated by blood flow characteristics, inflammatory processes in the vessel wall, and vessel wall elasticity. Low shear stress has been shown to promote arterial inflammation in multiple cell types to promote lesion formation and plaque vulnerability; the role of oscillatory shear stress seems more complex. Arterial wall stiffening is regulated by inflammatory processes and may in addition contribute to the inflammatory load. Moreover, WSS and PWV are intertwined in the regulation of biological processes in atherosclerosis. How these parameters correlate with disease and plaque vulnerability, however, remains to be defined. In this regard, MRI as a non-invasive technique—which does not use ionizing radiation—can be used to gather information on physical properties of flow and vessel wall properties. As we discussed here, cardiovascular MRI can already enable simultaneous measurements of flow-related parameters such as pulse wave velocity and wall shear stress. In the future, efforts should be made to further develop and improve the tools for the detection of inflammation. The analyses of these parameters in one measurement could significantly advance basic preclinical investigations of atherosclerotic lesion formation and progression, but also the diagnostic clinical evaluation of plaque characteristics to aid the early detection of culprit lesions which require therapy.


Medical imaging can be categorized broadly into applied science or more narrowly into imaging science. As applied science, it encompasses the middle ground between basic science and engineering technology, where a definite practical end is in mind, and where the approach may lead to new discoveries in basic science as well. As imaging science, it explores the nature of visualization.More specifically, medical imaging visualizes the inner world of the human body noninvasively. Its primary objective is to delineate the structures and map the functions of organs and tissues, based on the principles of physics, mathematics, engineering, computer science, physiology and biology.Due to the complexities of the human body and the associated signals generation and detection, the tasks of delineating the structures and mapping the functions of the organs and tissues can be very challenging. Modeling or simplifying the complexities to visualize the major attributes of the structures and functions is a commonly adapted strategy. While all models reported in the literature are wrong in terms of describing or representing the complexities, they are very useful and have been contributing to the accumulation of current knowledges about our living body in various conditions.This special issue calls for papers which would provide some innovative (revolutionary) ideas or models for simplifying the complexities with some preliminary demonstrations and would furthermore provide some insightful discussions about the impacts on and possible future directions of the corresponding fields. The ten papers presented in this special issue can be summarized accordingly.Computed tomography (CT) is now a widely used imaging modality for screening and diagnosis, emergency medicine, image-guided interventions and monitoring of therapeutic responses because of its excellent capabilities of delineating the structures of the organs and tissues and mapping the contrast material dynamic distributions through the tissues . HoweverFor tomographic image reconstruction of a continuous region from limited number of projections around the region, sparse-view problem always exists unless the number of the projections goes to infinity . The proThe beauty of tomographic image reconstruction from projections is seen from the art of filtered back-projection (FBP) reconstruction, which is so far a mathematically-exact solution of the reconstruction in the absence of data noise. However, when the data counts are limited, for example for low-dose CT , modelinPositron emission tomography (PET) has many attractive properties as a functional imaging modality to map the tissue heterogeneity at the molecular level, thus called molecular imaging modality . While tThe above four papers focus on image reconstruction, where the ultimate goal is to bring as much information as possible into the reconstructed images to achieve a desired clinical task. For medical diagnosis, imaging the tissue heterogeneity is probably the most important task, because the heterogeneity is a footprint of lesion evolution and ecology, and an indicator of lesion progress and response to intervention –11. The In the following five papers of this special issue, the focus is shifted from image reconstruction to image processing toward computer-aided detection (CADe) and CADx of abnormalities. As noted in refs. , 15, a lSince the report of radiomics as an integrated lesion descriptor, including image features, experts’ text descriptions and lesion genetics , many raAs mentioned above in the paper of Gao, Shi, Cao, et al., tissue texture patterns effectively represent the tissue heterogeneity and, therefore, are considered as imaging biomarkers. Many texture descriptors  are also investigated within the radiomics framework. Robustness of texture descriptors is an important research topic as shown by the work of Cattell, Chen, and Huang. The paper of Cao, Pomeroy, Gao, et al. takes the gray-level co-occurrence (GLCM) texture descriptor as an example to explore the possible causes of the variations, and provides a solution to minimize the variations by adaptive machine learning. More importantly, this paper of Cao, Pomeroy, Gao, et al. takes the GLCM as a texture image and explores the multiscale texture sampling opportunity in a similar manner as multiscale image analysis.As mentioned above, imaging the tissue heterogeneity is probably the most important task in medical diagnosis, image-guided intervention, and treatment response quantification –14. ThusLung cancer remains the leading cause of cancer-related deaths. Detecting the lung nodules, the precursor of lung cancer, is the primary consideration to prevent and treat the disease early. Currently the task of detecting the nodules is performed by low-dose CT (LdCT) scanning, followed by radiologists’ interpretation of the reconstructed LdCT chest images. Artificial intelligence (AI) has been traditionally applied to the reconstructed images to mimic the experts’ interpretation. During the image reconstruction processing from acquired raw data to chest images, additional variables may be introduced, which can compromise the detection task. Therefore, a logic strategy to accomplish the detection task is taking the AI-enabled learning during the entire process from the raw data to the reconstructed images. The paper of Gao, Tan, Liang, et al. presents such a logic strategy, which has shown significant improvement over the traditional reconstructed image-focused approaches.In summary, the ten papers in this special issue cover a wide range of modeling strategies to address the complexity in medical diagnosis, image-guided intervention, and treatment response quantification, which is usually impossible to solve without innovative modeling strategy.


A 71 year-old male with a history of multiple excisions of an initial Clark's level V melanoma of the breast followed by combined radiation and interferon treatment, as well as a recurrence, 3 years later, of a BRAF-positive tumor of the shoulder, with subsequent therapy with dabrafenib and trametinib, presented again with progressive intracardiac masses causing significant right ventricular outflow obstruction. Additionally, the patient complained of dyspnea and fatigue on exertion, thus he was scheduled for surgical resection. What is the epidemiology of cardiac metastatic melanoma?What is the pathophysiology of cardiac metastatic melanoma?What is the most adequate imaging technique for the diagnosis?What are the insights, pitfalls, aims and impact of the surgical treatment?What is new in the melanoma treatment?Is there a therapeutic algorithm?ante-mortem. This discrepancy between ante- and post-mortem manifestations may be attributed to the variability or lack in clinical signs. Cardiac metastases are usually clinically silent and only 20-30% of the patients develop impaired cardiac function. Cardiac manifestations in general occur late in the course of the disease, when there is already a widespread dissemination of the tumor to several organs (Question A).Melanoma has the highest propensity for cardiac metastases among malignant tumors. In the largest autopsy series of metastatic melanoma reported, more than 60% of the cases showed cardiac involvement. On the contrary, metastases of the primary tumor are found only in less than 2% of patients Cardiac metastatic melanoma occurs primarily via hematologic dissemination anywhere in the heart, invading the walls of all 4 cardiac chambers, with the right atrium being the most frequently affected. They mostly involve the pericardium and myocardium appearing with multifocal lesions, while the endocardium is rarely affected. Solitary metastases from melanoma in a cardiac chamber is uncommon, thus anecdotally reported. Especially when the tumor is localized in the left chambers, a possible patent foramen ovale should be ruled out through a transesophageal echocardiograph (Question B).Currently, the gold standard for diagnostic imaging is positron emission tomography-computed tomography (PET-CT), which can be used concomitantly with magnetic resonance imaging (MRI) of the brain and CT of the chest, abdomen, and pelvis . One of ex-vivo resection and autotransplantation. The aim of the surgical procedures should be a complete resection of all masses with tumor-free margins, when technically/anatomically feasible, followed by accurate anatomic reconstruction. Despite few reports presenting complete resection of metastatic melanoma from both atria and ventricles with survival up to one year, it is difficult to estimate the overall morbidity and mortality related to the resection of cardiac melanoma metastases, due to the lack of longitudinal data in the current literature (Question D).Regarding the surgical techniques, these are determined by the anatomic site and extent of the tumor growth and anecdotally have even employed Despite the dismal prognosis in standard chemotherapies with 5-year survival rates of 5-10%, the introduction of BRAF- and MEK-targeted therapies and immune checkpoint inhibitors in 2011 resulted in significant better outcomes. In a recent published pooled analysis of extended survival data from two trials (COMBI-d and COMBI-v) evaluating patients not previously treated with unresectable or metastatic melanoma and a BRAF V600E or V600K mutation, who had received BRAF inhibitor dabrafenib plus MEK inhibitor trametinib, the estimated overall survival and 5-year progression-free survival were 34% and 19%, respectively (Question E).The management of cardiac metastatic melanoma should be individualized according to the characteristics of the patient and the tumor. In asymptomatic patients with solitary cardiac metastasis, if complete surgical resection to clean the margins seems feasible and removal would render them in a status of a non-evident disease, surgery is a reasonable first choice therapeutical option. On the other hand, in case of multiple and/or invading tumors, or further systemic disease dissemination, not amenable to complete resection, especially in cases positive for BRAF mutation, then BRAF, MEK, and immune checkpoint inhibitors should be considered as first-line therapy.Regarding symptomatic patients, the following conditions are to be mentioned:In cases with solitary or disseminated symptomatic, but not acute life-threatening and BRAF mutation positive metastases, treatments with targeted inhibitors showed a high response rate with a short median response time. Subsequently, this may result either in regression of symptomatic lesions and/or in converting previously unresectable lesions into surgically removable ones.Highly symptomatic patients with hemodynamic failure should undergo urgent surgical complete resection with clear margins, if feasible (Question F).th postoperative day and was referred for further immunotherapy with PD-1-inhibitor pembrolizumab. Unfortunately, the patient died suddenly due to an unknown cause, shortly after receiving the first treatment cycle on the 42nd postoperative day-9.In the case presented, the indication for surgical intervention was justified, as there was no clear evidence of further spread of the disease, the patient had cardiac symptoms and there was an intention for treatment escalation with immunotherapy. Under cardiopulmonary bypass, the tumor in the right ventricle was approached through a vertical incision extending from the lower mid portion of the anterior wall to the outflow tract. In addition to the resection of multiple tumor masses from the right atrium, ventricle and outflow tract with sizes of approximately 15, 40 and 70 mm respectively, stabilization of the tricuspid valve was performed using a fixation stitch. The resulting ventricular wall defect was repaired with a bovine pericardial patch . The patEarly diagnosis of cardiac involvement in patients suffering from malignant melanoma is crucial.The development and introduction of new systemic therapies and the timely appropriate integration of surgery in the therapeutic scheme may be beneficial to the outcome, especially in cases with isolated lesions.The prognosis for metastatic melanoma remains poor, enabling to surgery predominantly only a palliative role.


Many lower gastrointestinal diseases are associated with altered mechanical movement and deformation of the large intestine, i.e., the colon and rectum. The leading reason for patients’ visits to gastrointestinal clinics is visceral pain, which is reliably evoked by mechanical distension rather than non-mechanical stimuli such as inflammation or heating. The macroscopic biomechanics of the large intestine were characterized by mechanical tests and the microscopic by imaging the load-bearing constituents, i.e., intestinal collagen and muscle fibers. Regions with high mechanical stresses in the large intestine (submucosa and muscularis propria) coincide with locations of submucosal and myenteric neural plexuses, indicating a functional interaction between intestinal structural biomechanics and enteric neurons. In this review, we systematically summarized experimental evidence on the macro- and micro-scale biomechanics of the colon and rectum in both health and disease. We reviewed the heterogeneous mechanical properties of the colon and rectum and surveyed the imaging methods applied to characterize collagen fibers in the intestinal wall. We also discussed the presence of extrinsic and intrinsic neural tissues within different layers of the colon and rectum. This review provides a foundation for further advancements in intestinal biomechanics by synergistically studying the interplay between tissue biomechanics and enteric neurons. The large intestine refers to the segment of the gastrointestinal (GI) tract distal from the Ileocecal valve to the anal verge, consisting of ascending, transverse, descending, sigmoidal colon and the rectum. The physiological functions of the large intestine include absorbing water, moving waste residue down the GI tract, and temporary fecal storage, all of which involve mechanical movement and deformation of the tubular GI structure. Pathophysiological conditions in the large intestine are often associated with the malfunction of intestinal biomechanics, including changes in gut motility and muscle activities : mucosa, submucosa, muscularis propria , and serosa. Nonetheless, most studies did not consider this through-thickness heterogeneity when characterizing the macroscopic biomechanics of the colon and rectum. An array of conventional mechanical testing methods have been applied to characterize the macroscopic mechanical features of the large intestine, including uniaxial tensile stretch ,17,18, bThe microscale mechanics of the large intestine can correlate to the content and morphology of collagen and muscle fibers within the wall tissue, which provides structural support to almost all soft biological tissues . IntestiMany GI disorders in the large intestine are poorly managed in the clinics. Especially, chronic visceral pain is the cardinal complaint of patients with IBS that affects up to 20% of the U.S . populatThe large intestine extends approximately 150 to 180 cm in adults and consists of mostly the colon and rectum. Compared to the small intestine, the colon is larger in diameter, mainly fixed in position, and plays a very limited role in nutrient absorption. The main functions of the colon are to push the waste content down the GI tract by coordinated wave-like mechanical movement , absorb water to form solid feces, and send them to the rectum, which is the distal six inches of the GI tract. The large intestine is also host to a significant amount of bacteria, archaea and fungi, i.e., the intestinal microbiota, which perform a host of useful functions such as fermenting unused energy substrates, training the immune system, and producing vitamins and hormones, etc. The rectum’s main functions are continence and defecation, i.e., temporarily storing feces and expelling feces out of the body, respectively. As shown in The mucosa is the inner lining of the colon and rectum, consisting of a thin layer of epithelium, a connective tissue layer , and a thin layer of muscle (muscularis mucosa). Lack of a prominent role for nutrient absorption by the large intestine has resulted in the absence of the villi structure in the mucosa, i.e., small, folded components that greatly enhance the intraluminal surface area of the small intestine. The epithelium in the large intestine “sinks” into large cylindrical structures, i.e., the crypts  that extThe submucosa is a fibrous connective tissue layer that surrounds the mucosa. It contains major branches of blood and lymph vessels supplying the large intestine. It has a high concentration of lymphocytes, fibroblasts, and mast cells. In addition, the submucosa hosts one of the two major enteric neural plexuses, i.e., the submucosa plexus that regulates the configuration of the luminal surface, controls glandular secretions, alters electrolyte and water transport, and regulates local blood flow. We recently reported the concentrated presence of thick collagen fibers within the submucosa via second harmonic generation imaging , which pThe muscularis propria consists of two layers of smooth muscle: an inner circular muscle layer and an outer longitudinal muscle layer. Between these two muscular layers is the myenteric plexus, one of the two major enteric neural plexuses. The ganglia in the myenteric plexus are more prominent than their submucosal counterpart. The myenteric plexus receives projections from preganglionic parasympathetic fibers as well as postganglionic sympathetic fibers . The myeThe serosa is the outermost layer of the intestinal wall and is composed of a continuous sheet of squamous epithelia cells, the mesothelium . It reprThe macroscale biomechanics of the large intestine was characterized mostly by uniaxial and biaxial extension and luminal inflation, and to a lesser extent by compression, shear, and indentation tests. Biaxial tensile stretch and luminal inflation best match the mechanical conditions in vivo. These conventional means were extensively implemented for studying the esophagus and small intestine. Despite the prevalence of lower-GI disorders and the importance of large intestine biomechanics in those disorders, the body of literature devoted to studying the macroscale biomechanics of the large intestine is smaller than those for the upper GI tract. In In the longitudinal direction, the large intestine changes its geometry slightly, gradually decreases in diameter and increases in thickness from the proximal to distal regions. Radially, the large intestine is heterogeneous showing four major layers see . In addiMost mechanical tests were conducted on the distal portion of the large intestine, especially the sigmoidal colon and rectum. The passive mechanical properties, i.e., in the absence of muscle activities, were systematically characterized at four different locations along the rat large intestine by two independent studies, both of which reported the highest mechanical stiffness in the transverse colon ,60. FromIn mouse distal colon and rectum, we systematically studied the longitudinally heterogeneous behaviors in pre-stress, tissue stiffness, viscoelasticity, and anatomic thickness . We repoThe layered structure of the intestinal wall strongly indicates heterogeneous biomechanical properties through the thickness of the wall, i.e., along the radial direction. Most biomechanical studies considered the colon as a homogeneous membrane and carried out the tests on the whole colorectal wall. Egorov et al.  conducteUnlike the tubular organs such as the blood vessels that are usually axisymmetric along the central axis, the presence of mesentery along one side of the colorectum makes it a nonhomogeneous tissue additionally in the circumferential direction. Moreover, the distribution of LSN sensory endings in the circumferential direction is not homogeneous and is only concentrated close to the mesentery . In humaThe colorectum can be considered as a thin-walled cylinder in which the longitudinal and circumferential directions form a planar surface. As reported by several studies ,22,26,32The macroscopic mechanical characterization was also conducted on colon and rectum from patients with lower GI disorders or in animal disease models. Increased colon stiffness was reported in most inflammatory bowel disease conditions  with a fThe microscale networked collagen fibers form the major load-bearing skeleton for many biological tissues, e.g., skin , tendon As mentioned previously, the intestine from lumen to the outside is composed of four main layers: mucosa, submucosa, muscularis propria, and serosa. Other than our recent study , there aMucosa: Most studies on intestinal collagen have focused on the pathology of the mucosa to detect or differentiate various intestinal diseases such as cancer ,81,84,93Submucosa: A few studies have focused on this intestinal layer to assess its morphology, fibers angle, and collagen content in healthy ,74,75,80Muscularis propria: The collagen fibers in the two muscular layers are generally characterized by chromatic or immuno-staining studies on thin tissue sections. Our SHG study through the thickness of the colon and rectum allows direct comparison of relevant collagen contents in the muscle layers as compared to other intestinal layers . CompareSerosa: the serosal layer as a connective tissue membrane is also rich in collagen , but itsThe majority of the studies in The macro- and micro-scale biomechanics of the colon and rectum have significant implications in lower GI disorders. Various mechanical behaviors of the colon and rectum are altered in disease conditions, including gut motility and muscle activities, tissue structure and compliance, luminal shear flow, and voluntary muscle controls. The macroscale biomechanics of the colon and rectum were systematically characterized by conventional test methods for soft biological tissues, revealing the large intestine’s hyperelastic and viscoelastic material properties similar to other fiber-reinforced biological tissues. The large intestine varies in diameter and thickness from proximal to distal regions, consists of four major layers in the wall, and is circumferentially unsymmetrical due to the mesenteric attachment along one side of the intestine. These anatomical features also correlate with heterogeneous biomechanical properties along the longitudinal, radial, and circumferential directions of the tubular large intestine. The large intestine is stiffest in the middle segment, i.e., the transverse colon, and more compliant at either the proximal or the distal ends, i.e., the proximal colon and rectum. Increased rectal compliance facilitates fecal storage, while increased compliance in the proximal colon allows better mechanical coupling with the ilium, the most distensible segment of the small intestine. Overall, the large intestine is stiffer longitudinally than circumferentially, reducing elongation during physiological distension and peristalsis to allow the intestine to maintain position. Through the wall thickness, the submucosa and the muscularis propria are the major load-bearing structures whereas the mucosa and serosa have no significant stiffness. Along the circumferential direction, regions close to the mesentery are mechanically softer than regions away from the mesentery as suggested by the concentrated distribution of sacs or pockets in the mesenteric region of the colon in patients with diverticular diseases.The microscale biomechanics of the large intestine is reflected by the contents, morphology, and orientation of collagen fibers in different layers of the large intestine. Collagen is concentrated in the submucosa and serosa whereas the content in the muscularis propria and mucosa is significantly lower. In addition, collagen fibers in the submucosa have the largest average diameter and consist of two groups of fibers oriented approximately ±30° along the longitudinal direction to form a tight-knit network. This microstructure of collagen fibers in the submucosa indicates its load-bearing roles to support substantial mechanical loads. Despite low contents of collagen fibers, muscularis propria showed a mechanical stiffness comparable to the submucosal/mucosal composite, and its load-bearing role is likely provided by the thick muscle bundles in the circular and longitudinal muscle layers. Extrinsic and intrinsic neural innervations concentrate in the submucosa and muscularis propria, which are focal regions of high mechanical stresses during physiological intestinal distension and peristalsis. The nociceptor-like nerve endings in the submucosa strongly indicate their critical roles in detecting tissue-injurious mechanical stimuli by evoking pain from the colon and rectum. In addition, changes in collagen content and morphology in intestinal mucosa can potentially be a marker for many lower GI disorders.Recent years have seen significant progress in our biomechanical understanding of the large intestine in both health and diseases, especially from recent applications of the SHG imaging to characterizing the collagen fibers in intestinal tissues. Further advancement in the field of intestinal biomechanics will likely take place in close association with knowledge of neural innervations of the large intestine, which plays critical roles in an array of mechanical events in the large intestine like peristalsis, smooth muscle tone, and mechano-nociception. The fact that the load-bearing region of the large intestine (submucosa and muscularis propria) correlates with the concentrated distribution of intestinal neuronal tissues is likely not a coincidence. Understanding the synergistic interplay between the intestinal biomechanics and neurophysiology will advance our mechanistic understandings of various lower GI disorders in which biomechanical factors play critical roles. In addition, accelerated application of SHG detection of collagen contents and morphology in the intestinal mucosa will likely reveal changes in the microscale mechanics in various lower GI disorders. Future studies will likely extend the detection beyond the mucosal layer to reveal changes in collagen of deeper layers of the large intestine. Last, the integration of multimodal experimental evidence by multiscale computational simulation of both the intestinal tissue biomechanics and the encoding of neuronal tissues in the intestinal wall will likely drive theoretical hypotheses about various lower GI disorders to help elucidate their etiology.


Daniar OsmonovJ Sex Med. 2020 Feb;17(2):210-237.Guidelines for Male Sexual Dysfunction recognize penile prosthesis implantation as the third line treatment for erectile dysfunction (ED). Given the invasive and essentially irreversible nature of penile prosthesis implantation (PPI) surgery, counseling regarding short- and long-term postoperative expectations is essential .Since the beginning of the penile prosthesis implantation, multiple modifications have been made which has lead to decreased postoperative infection and mechanical failure and increased rigidity, durability, and patient satisfaction ,3.Currently, the preferred type of penile implant in developed countries is the inflatable one. In certain regions of the world (like Brazil), the malleable penile prosthesis is the penile implant of choice for ED, certainly because of economic reasons (no insurance coverage) , but proIn this recent publication, the European Society for Sexual Medicine (ESSM) warns that a majority of the studies published on PPI deal with clinical or technical aspects of surgery, but not with associated factors, such as the patients’ and partners’ expectations, comorbidities, and social profiles. Over the last decades, a number of articles have described the expectations of both patients and their partners, the influence of the patients’ comorbidities, as well as a variety of social aspects in association with penile prosthesis. But most publications derived from single center, retrospective studies with low patient numbers and limited follow-up.There is a need for appropriate patient selection and counseling with any surgical procedure, particularly when quality of life and satisfaction are the primary objectives of treatment. Despite the unavoidable nature of complications in general, the ability to discriminate appropriate surgical candidates remains completely within the control of the surgeon .The satisfaction of the patient and the partner is the most important end point of PPI. It is increasingly relevant to assess the psychosocial status of the couple and to inform them about the procedure to avoid unrealistic expectations .Satisfaction with IPP is influenced by many factors, which can be categorized into three distinct patient care stages: preoperative, intraoperative, and postoperative. There are several techniques described in each patient care stage to improve perceived penile length including preoperative counseling and correct penile length measuring, preoperative penile stretching, the use of adjuvant surgical procedures, and postoperative penile rehabilitation .The CURSED  assessment of preoperative expectations can help to identify high- risk patients, a challenging subset of patients that may be at increased risk of postoperative dissatisfaction. Character traits of those difficult patients include obsessive/ compulsive tendencies, unrealistic expectations, those seeking multiple surgical options, feelings of entitlement, patients in denial of their prior erectile/sexual function and current disease status, or those with other psychiatric disorders .This ESSM position statement provides relevant recommendations on optimization of patient outcome by patient selection, and individualized peri- and intra-operative management. The article clarifies the multiple aspects of PPI surgery, offering an evidence-based clinical framework to guide patient-tailored management of ED. Influence of comorbidities and social circumstances like smoking, obesity, aging, H.I.V., organ transplantation, spinal cord injury, Peyronie disease and diabetes; The importance of a thoroughly discussion on expected post-operative outcomes with both partners prior to PPI surgery, including possible complications and their management; The impact of length, girth, and implant type on satisfaction; And even IPP in transgender gender, are all addressed during this nice review.According to ESSM, the influence of cultural and social factors related to the aging process and a shift in the expression of sexuality due to increased life expectancy, as well as improvement of quality of life over the last decade, increases the role of sexual medicine.The authors concluded that standardized methods for assessment of patient and partner expectations have not been established resulting in heterogeneous study types that evaluate different outcomes and have a low (<3) level of evidence. Many studies used validated scoring systems, such as EDITS or IIEF. However, these have not necessarily been developed specifically for the evaluation of penile implant outcomes. Validated scoring systems for PPI surgery include the Quality of Life and Sexuality with Penile Prosthesis .And their final message stresses the need for larger prospective multicentric epidemiological studies that should be initiated and ideally supported by international societies.


The load on drive elements under extreme pressure conditions is significantly larger than that used in machine tools. When operating under a heavy load for a long period, large deformation and severe wear between the ball and the track are more likely to occur. To reduce wear, the most fundamental solution is to improve the surface properties of the material. Moreover, heat treatment is the most effective method to improve the surface properties of materials, thereby achieving wear resistance and low friction. It is necessary to develop a new heat treatment technology for wear resistance in extreme pressure conditions. Therefore, this study conducted experiments using a reciprocating friction tester. The responses of electrical contact resistance and the friction coefficient were measured synchronously to investigate wear resistance and low friction of the alloy steels after the induction heat treatment. Then, the results were compared and verified with low-carbon alloy steel after the traditional carburizing heat treatment. The experimental results show that the application of new induction heat treatment technology can not only improve the performance of drive components, but also save time and energy, and streamline the production process of the drive components. Therefore, the results of these wear analyses confirm that the induction heat treatment mode can replace the traditional carburizing heat treatment mode for drive elements. Due to the advancement of science and technology, the fields of machine tools and precision machinery are moving towards high precision, high speed, high load, long life, and automation. Hence, there are considerable requirements for product quality, dimensional accuracy, and service life. At the present, drive elements play crucial roles in precision machinery, and they must have low-friction and antiwear properties ,2,3. DueAfter long-term operation of mechanical components, the problem of poor dimensional accuracy due to wear arises, and long-term accumulation causes mechanical damage and failure. As a result, the improvement of material surface engineering is an important topic to ensure the wear resistance life of drive elements ,13. RegaAfter basic heat treatment, such as quenching and tempering, the overall material properties are improved . Then, tBased on the author’s previous related results , a serieA reciprocating friction tester with measuring systems, shown in The ball was made of the high-carbon chromium alloy steel (ϕ6.35 mm). Furthermore, the cylinder specimens were made of low-carbon alloy steel or high-carbon chromium alloy steel. The contents (wt %) are given in The experimental conditions are shown in The variation of electrical contact resistance for the B3 specimen is shown in The variation of the friction coefficient for the B3 specimen is shown in The average friction coefficient of the four specimens is shown in The optical microscopes images of the worn surface of the cylinder specimens after sliding the ball against the four cylinder materials are shown in The wear depths of the cylinder specimen for a ball sliding against the four cylinder materials are shown in Based on the above experimental results of electrical contact resistance, friction coefficient, optical microscope images, and wear depth, it can be seen that the changes of the four characteristics correspond to each other. The greater the friction coefficient, the higher the oscillation frequency of the electrical contact resistance, and the faster the “generation” and “elimination” of wear particles, resulting in more serious wear.For the accuracy of the experiment, all of the cylinder specimens were subjected to three reproducibility experiments. The average wear depth result is shown in The experimental results of electrical contact resistance, friction coefficient, optical microscope images, and wear depth showed correspondence to each other. These results allowed comprehensive evaluation of tribological performance.All of the alloy steels after induction heat treatment showed less abrasion than the low-carbon alloy steel after the traditional carburizing heat treatment. Moreover, better abrasion resistance was obtained by adding cryogenic treatment.To protect the tool life in long-term processing, the experimental results prove that the heat treatment process with higher temperature tempering is acceptable.The induction high-carbon chromium alloy steel can obtain the dual advantages of antiwear and low friction properties. This not only saves a significant amount of electrical energy, but also simplifies the manufacturing process of the transmission element production line due to the reduced heat treatment time.The online induction heat treatment mode after proper material processing can replace the nonproduction line-based traditional carburizing heat treatment mode.The tribology properties of alloy steels after induction heat treatment and low-carbon alloy steel after traditional carburizing heat treatment were investigated and compared. The conclusions are as follows:


Recycling waste into new materials and energy is becoming a major challenge in the context of the future circular economy, calling for advanced methods of waste treatment. For instance, microbially-mediated anaerobic digestion is widely used for conversion of sewage sludge into biomethane, fertilizers and other products, yet the efficiency of microbial digestion is limited by the occurrence of antibiotics in sludges, originating from drug consumption for human and animal health. Here we present antibiotic levels in Chinese wastewater, then we review the effects of antibiotics on hydrolysis, acidogenesis and methanogenesis, with focus on macrolides, tetracyclines, β-lactams and antibiotic mixtures. We detail effects of antibiotics on fermentative bacteria and methanogenic archaea. Most results display adverse effects of antibiotics on anaerobic digestion, yet some antibiotics promote hydrolysis, acidogenesis and methanogenesis. Antibiotics are widely used to treat human and animal diseases, yet the overuse of antibiotics is inducing issues of pollution, development of antibiotic resistance by pathogenic bacteria, and inhibition of engineered microbial processes such as anaerobic digestion of wastewater. The global consumption of antimicrobials in livestock production was estimated at more than 63 thousand tons in 2010, and is projected to rise to 105 thousand tons by 2030 . In the Anaerobic digestion involves processes during which microorganisms breakdown biodegradable organic material in the absence of oxygen . DigestiThe efficiency of anaerobic digestion is reduced by the presence of antibiotics and antibiotic residues, which inhibit the microbial community and activity, thus further limiting the efficiency of the entire anaerobic digestion system . AccordiAt present, antibiotics are mainly used in hospitals and livestock farms . ResiduaMicrobes transform complex organic substances into methane through anaerobic digestion, which is the primary way of anaerobic mineralization of organics. The process of biomethane production from macromolecular organic carbon involves a variety of microbes, mainly fermenting bacteria and methanogenic archaea. The accumulation of antibiotics dissolved in wastewater into sludge can affect the microbial community associated with each stage of anaerobic digestion . SpecialThe hydrolysis stage is considered as the main rate-limiting step of anaerobic digestion . During β-lactams, an absence of effect on organic degradation has been shown for cefalexin.Gamma-proteobacteria and Rhodobacter declined. Overall, some macrolides and tetracyclines inhibit clearly hydrolysis and acidification, and more investigations are needed to confirm other isolated findings.Erythromycin’s long-term action inhibits microbial growth, reduces hydrolysis rate, blocks substrate storage, and accelerates endogenous respiration . In contA study showed that roxithromycin macrolide and sulfamethoxazole increased the production of VFAs in anaerobic fermentation of waste activated sludge, which is explained by affecting microbial diversity and disruption of extracellular polymeric substances . On the The antibiotic concentration is a factor controlling effects on acidogenesis. For example, a high concentration of tylosin inhibited propionate and butyrate metabolisms during the anaerobic fermentation process of pig manure . By contBacteria having hydrolysis and acidification functions play an important role in the early stage of anaerobic digestion, in which these microbes convert larger molecules of organic matter in sludge into simple smaller molecules and then into VFAs, and consequently affect the overall efficiency of anaerobic digestion. In the last ten years, researchers focused on interaction between antibiotics and fermentative microbes. Some mechanisms of antibiotics affecting anaerobic fermentation have been elucidated. For example, macrolides and tetracyclines are inhibitors of protein synthesis in bacteria , inhibitSyntrophobacter, thus indirectly inhibited Methanosaeta by high propionate concentrations and low pH, resulting in the long-term reactor failure , oxyterramycin significantly inhibited propionate oxidizing bacteria, and shown significantly lower degradation rate of propionate than that of the control group without antibiotics . Howeverβ-lactam inhibitors can inhibit the synthesis of cell wall murein by inhibiting penicillin-binding protein, which can cause bacterial cell wall defects . β-lacta2 reduction, acetate dismutation, and methylotrophic methanogenesis. First, about the two-thirds of biomethane production is explained by acetoclastic methanogenesis in natural environments. However, in H2 upgrading/ammonia inhibited AD system, methane production is mainly from hydrogenotrophic methanogenesis pathway. For acetoclastic methanogenesis, methanogens oxidize carboxyl groups to CO2 and generate reducing forces to reduce methyl carbon to methane   . Overall methane ; this prMacrolides mainly include roxithromycin, erythromycin and tylosin. Methanoseata, Methanofastidiosum, and Methanolinea The presence of antibiotics generally lead to the accumulation of VFAs in the anaerobic fermentation system. However, different types of antibiotics or even different antibiotics of the same type have different influences on the anaerobic digestion process, the methane-production capacity, and the related microbial community.(2)Besides the type of antibiotics, the concentrations, the duration of action, and the temperature of the anaerobic digestion system altogether considered to be the key factors affecting the effects of antibiotics on anaerobic digestion and methane production.(3)The short-term and long-term effects of antibiotics show certain differences. Short-term experiments may be difficult to accurately reflect the potential effects of antibiotics on complex microbial consortia due to the lack of microbial adaptation. Short-term experiments ignore the long-term effects on the growth of anaerobic microbes and the adaptability of microbes to antibiotics. Thus, long-term observation and comprehensive analysis are to be given topmost priority. In the later stage of the anaerobic digestion reaction, some antibiotics lose their bacteriostatic effects. The possible reasons for such happenings are as follows: (1). the hydrolysis reaction of antibiotics is natural to occur; (2). bacteria and methanogens have developed tolerance to specific concentrations of antibiotics.Antibiotics in sludge are generally not present alone, they are usually accompanied by other antibiotics. However, current research mainly focuses on a single antibiotic and its inhibition effect on anaerobic digestion. The lack of exploration and summary of mixed antibiotics’ impact on the anaerobic digestion system results in an incomprehensive knowledge on the joint effect of multiple antibiotics. Thus, it may not be instructive to practice under anaerobic conditions for wastewater and/or diverse antibiotic-enriched sludge treatment.The effects of single or multiple antibiotics on anaerobic digestion of sludge depend not only on the antibiotics themselves but also on the sludge substrates, the microbial community composition, the biological and non-biological degradation of antibiotics, and the adsorption of antibiotics. These factors need to be further evaluated and will be the focus of future research. As environmental pollutants, ARGs require to be comprehensively studied in anaerobic fermentative environments, which is indispensable to characterize the impact of antibiotics. In contrast, the current techniques can only cultivate a small proportion of the anaerobic fermentative system members, which severely restrained our knowledge of the bacterial meta-resistome in various environments. Moreover, it wasn’t yet well documented the distribution of ARGs and antibiotic-producers and the effects of antibiotics on anaerobic digestion.As a non-culture-based method, metagenomics becomes a vital tool to comprehend the bacterial communities sufficiently. Various omics techniques are more and more applied in understanding the effect of antibiotics on microbial communities, synthesizing new antimicrobial compounds, and analyzing the antibiotic resistance genes’ distribution in different anaerobic systems. For example, functional metagenomics can be applied in identifying novel antibiotic resistance genes, and descriptive metagenomics can be used for analyzing the composition of the microbial communities and catching the proportion of known antibiotic resistance genes . FurtherLX, YW, ZL, PK, JL, DF, QY, and FL collected the data. LX, EL, PK, and DF analyzed the data and wrote this manuscript. 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.


Background and objectives: A deeper comprehension of the role that environmental risk factors play in the development of adolescent Bipolar Disorder (BD), as well as in the evolution of high-risk states for BD, may entangle further prevention and treatment advances. The present systematic review is aimed at critically summarizing evidence about the role that environmental risk factors play in the development of BD in adolescence and their interaction with BD high-risk states. Materials and Methods: MEDLINE/Pubmed, Scopus and Web of Science datasets were systematically searched until 4 September 2020. Original studies that reported information about the role of environmental risk factors in the development of BD during adolescence, or assessing their influence on the development of psychopathology in high-risk states for BD, were considered for inclusion. Two blind researchers performed title/abstract, full-text screening, and hand-screening of relevant references. The risk of bias was assessed by means of the Newcastle-Ottawa Scale. Results: Fourteen studies were included in the review. Negative stressful life events, particularly sexual and physical abuse, but also emotional mistreatment, were associated with more severe psychopathology in adolescents with BD, as well as with higher risk for developing mood disorders in BD offspring. Similar findings were detected for familial environment-related features, such as parental rejection and low perceived care, while no univocal results were found when analyzing familial functioning. Conclusions: The present systematic review confirmed the relevant role that environmental risk factors, particularly negative stressful live events and family-related features, play in the development of BD psychopathology during adolescence. Future studies are expected to clarify possible further environmental factors that may be implicated in the development of BD during youth that may serve as target of prevention and early treatment strategies. Bipolar disorder (BD) represents a serious mental illness affecting the global functioning of subjects at different ages. The prevalence of early-onset BD, defined by the onset occurring before the age of 18, significantly increased during the last years, despite being considered a rare clinical entity in the past . The corThe development of BD is strongly influenced by genetic factors, as demonstrated by twin and family studies underlining the presence of an inheritable component up to 58% . NonetheThe better identification of potentially modifiable risk factors for the development of BD in adolescence represents a crucial issue in the context of a better understanding of the disorder, also due to its severe clinical presentation and to its implications in terms of illness course and overall burden. In addition, a deeper comprehension of the role that environmental risk factors play in the evolution of high-risk states for BD may entangle prevention and treatment advances. Therefore, the aim of the present systematic review is to critically summarize the evidence about the role of environmental risk factors in the development of BD during adolescence and their interaction with high-risk states for BD.The present review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement .A systematic search of the electronic databases MEDLINE/PubMed, Scopus and Web of Science was conducted from inception to 4 September 2020, using the following search string: ((((bipolar disorder [MeSH Terms]) AND (bipolar disorder)) AND (adolescen*)) AND (environment)) AND (risk factor*).Two blind investigators (GM and PMB) performed the literature search, title/abstract screening, full-text review. The obtained references were cross-checked and the reference list of selected articles was screened in order to search for additional literature. Discrepancies were resolved through consensus. A third investigator was consulted (AT) whenever a final decision could not be made.Observational studies investigating the role of environmental risk factors in the development of BD during adolescence were included in the present review. In addition, we included papers reporting information about the influence of the environment on specific aspects of BD in adolescence. Reports assessing the interplay between environmental risk factors and the development of psychopathology in high-risk states for BD, namely first-degree relatives of subjects affected by BD, were also included. Studies considering parents affected by non-BD mood disorders were not included, unless they served as control group. No language restriction was applied. Grey literature was included if sufficient information was provided. Articles presenting only an opinion or hypothesis without empirical investigation, retrospective studies, reviews, letters to the editor, and case reports were excluded. Studies reporting data about genetic risk factors and peripheral biomarkers were not deemed eligible for the present review, as well as interventional studies and research focusing on BD as a possible risk factor for other disorders.Whenever different papers referring to overlapping samples were analyzed, more than one paper was considered for inclusion if relevant information was provided for the aims of the present review. Reports investigating the development of psychiatric disorders among high-risk adolescent populations were included only if reporting information about the development of mood disorders, particularly BD, or psychopathological features possibly connected to the development of BD.Two blind researchers performed data extraction (LA and FB). In order to address the objectives of the review, the following information was extracted from the included papers: First author name, year and country of publication, analyzed period of time, study sample, study methodology, analyzed risk factors, and results.The quality of the evidence provided by eligible studies was assessed by the two independent researchers (GM and PMB). The Newcastle-Ottawa Scale was employed for risk of bias assessment in cohort studies, considering the selection of the study groups, the comparability and the outcome assessment . As for The search initially yielded 304 records. Among these, 78 were identified as duplicates and were subsequently excluded. After performing the title and abstract screening, 15 papers were deemed eligible for further evaluation. The full text examination led to the final selection of 9 papers. The hand search of references led to the inclusion of 5 further records. The final selection led to the inclusion of 14 papers in the present review . Although, no significant differences were detected when comparing BD youths to those affected by depression and anxiety. In this population, psychiatric comorbidities, namely conduct disorders, anxiety disorders, Attention Deficit and Hyperactivity Disorder (ADHD), and Oppositive Defiant Disorder (ODD), were associated with the total number of negative live events at the binomial regression model . In the One of the selected studies investigated the association between suicidal ideation and family environment in a sample of BD youths, where the prevalence of suicidal ideation resulted to be 36%. The study dedicated particular attention to familial cohesion (the level of warmth and intimacy between family members), adaptability (the ability of the family to change in response to stressful situations), conflicts, familial stressful events and familial psychiatric history . CurrentIn a population of BD offspring considered as genetically high-risk subjects, family environment was analyzed as a possible risk factor influencing illness trajectories, in absence of significant differences in family cohesion, parental care, and parental overprotection among the high-risk subjects and controls . In the Preliminary results from a prospective high-risk cohort study outlined the development of a mood disorder during adolescence in 27% BD offspring from the analyzed population . The relStudies included in the present review showed a relatively low risk of bias as measured by the two versions of the Newcastle-Ottawa Scale see . When asThe present systematic review assessed the influence of non-genetic risk factors in the context of adolescent BD, not only focusing on populations of subjects with full-blown presentation of the disorders, but also considering the interplay between environmental and hereditary load in the possible evolutions of high-risk states for BD in adolescence. The identification of risk factors, during early stages of BD and in high-risk states presents several implications, due to the pleomorphic nature of such conditions and to the higher efficacy that the early administration of psychiatric treatments may demonstrate ,41,42. TNegative stressful life events appeared to be strongly related to the development of mood disorders during the follow-up of BD high-risk populations ,37,39, eDue to the already-mentioned overall high severity of BD when presenting during early stages of life , the ideFurther studies focusing on the role of traumatic experiences in the development of BD may also present implications in consideration of the frequent comorbidity between BD and PTSD. In fact, the two disorders were also demonstrated to share common genetic heritage that two may be mediated by a variant of the Brain-Derived Neurotrophic Factor (BDNF), with possible epigenetic mechanisms that could act as response to traumatic and stressful life events . SimilarThe role of family functioning was controversial according to reports included in the present review, influencing specific features of BD in adolescence, e.g., suicidal ideation, rather than the development of the disorder . This fiSurprisingly, only few risk factors were considered in the included studies. Although medical comorbidities may play a less significant role in younger populations, the shared pathophysiological pathways leading to both mental and physical illnesses and the decrease of life expectancy caused by the medical burden in BD subjects claim further research also in youth samples ,64. A grTo our best knowledge, the present review presents the first effort to systematically summarize the evidence about environmental risk factors in youths affected by BD and high-risk populations, in the attempt to enhance knowledge in this still under-studied area of investigation. Potential strengths of this report include the use of a systematic methodology following PRISMA guidelines, the inclusion of studies considering not only full-blown BD, but also high-risk populations, and the methodological validity of most of the assessed studies. Despite this, the present review presents limitations. First, the different study designs and the heterogenous populations in terms of age limited the possibility of inter-study comparisons. Small sample sizes in some of the included studies represented a further limitation to the generalizability of findings. As for outcome assessment, we did not select studies on the basis of specific instruments, e.g., semi-structured interviews, thus including reports evaluating symptoms by means of auto-administered tools that may increase subjectivity of findings. Furthermore, the indirect exclusion of subjects that may present with unipolar depressive disorders during adolescence did not allow crucial issues in adolescent BD to be assessed, such as antidepressant use and the unipolar-bipolar conversion.The present systematic review confirmed the relevant role that environmental risk factors play in the development of BD psychopathology, with particular attention to adolescent and high-risk populations. Although the function of negative stressful life events and family-related factors appeared to be crucial, future studies should hopefully better stratify risks related to the above-mentioned determinants, as well as possible further environmental factors that may be implicated in the development of BD during youth. The better identification of the complex pathogenetic pathways that lead to full-blown manifestations of BD may help targeting preventing strategies and thus contribute to the modification of unfavorable illness outcomes.


Due to numerous links between trimethylamine-N-oxide (TMAO) and various disorders and diseases, this topic is very popular and is often taken up by researchers. TMAO is a low molecular weight compound that belongs to the class of amine oxides. It is formed by the process of oxidation of trimethylamine (TMA) by the hepatic flavin monooxygenases (FMO1 and FMO3). TMAO is mainly formed from nutritional substrates from the metabolism of phosphatidylcholine/choline, carnitine, betaine, dimethylglycine, and ergothioneine by intestinal microflora in the colon. Its level is determined by many factors, such as age, gender, diet, intestinal microflora composition, kidney function, and also liver flavin monooxygenase activity. Many studies report a positive relationship between the level of TMAO concentration and the development of various diseases, such as cardiovascular diseases and cardiorenal disorders, including atherosclerosis, hypertension, ischemic stroke, atrial fibrillation, heart failure, acute myocardial infarction, and chronic kidney disease, and also diabetes mellitus, metabolic syndrome, cancers , as well as neurological disorders. In this review, we have summarized the current knowledge on the effects of TMAO on human health, the relationship between TMAO and intestinal microbiota, the role of TMAO in different diseases, and current analytical techniques used in TMAO determination in body fluids.  TMAO is an oxidized form of trimethylamine (TMA)  is a dietary component that belongs to the class of amine oxides with the formula . One ofal., 2020). Accordal., 2020; Sarma aal., 2020). The aim of this review was to summarize the current state of knowledge about TMAO, biological properties, metabolic pathways, and essential metabolism nutrients which act as precursors of TMAO. The importance of TMAO metabolism and its role in human health are also highlighted. We provided and discussed the potential relationships between TMAO and intestinal microbiota. Attention was also paid to the potential contribution of intestinal microbiota-derived production of TMAO from the metabolism of nutrients, which has been associated with an increased risk of major adverse disorders in humans. Then we presented the potential role of TMAO in the etiology of various diseases, and the possible mechanisms that could explain their association. Finally, we analyzed the current analytical techniques which are used in TMAO determination in biological fluids.TMA is formed from the dietary compounds present in the diet, which is then immediately absorbed and converted into TMA by various enzymes , and fish  is oxidized to TMAO, which is transported to the tissues for accumulation as an osmolyte or, more frequently, cleared by kidneys , which The intestinal microbiota is shaped from birth and plays a key role in the immune system. One of the main functions of the intestinal microbiota is to form systemic immunity and maintain immune homeostasis. Factors affecting the intestinal microbiota are diet, type of labor, antibiotic use during infancy, and age, because the composition of the intestinal microbiota changes with age.Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Fusobacteria and Verrucomicrobia are the dominant phyla, with Firmicutes and Bacteroidetes accounting for over 90 % of the gut bacteria . An incues, 2020). Bacterher, 2018).Firmicutes to Bacteroidetes demonstrating a greater response to the dietary precursor of TMAO which suggests that the production of TMAO may be a function of individual differences in the intestinal microbiota . Studieher, 2018). The prher, 2018).Understanding the role of human intestinal microbiota has led to the identification of a large number of metabolites which are produced in the gut. These metabolites may play a role in human health and possible diseases. One of these is TMAO, whose elevated concentration increases the risk of developing renal failure, diabetes mellitus, heart failure, atherosclerosis, hypertension, metabolic syndrome, dyslipidemia which may lead to serious cardiovascular events  suggestAcinetobacter can convert lecithin and carnitine into TMAO. Analysis of fecal specimens suggested that participants with enriched bacteria of the genus Prevotella, as a result of a high-fat diet, were characterized by higher levels of TMAO compared to participants with the enrichment of the genus Bacteroides .Akkermansia mucinophilia in colon biopsies and concentration levels of TMAO . As it al., 2019).Firmicutes and Proteobacteria, which are capable of producing TMA. The strains of these bacteria show an increased proportion in patients with HF. This indicates that changes in intestinal microbiota may affect TMAO levels by regulating TMA synthesis in the intestines . HF causes changes in the composition of the intestinal microflora, which may affect the circulating levels of TMAO in human body. Researchers suggested intestinal strains, such as al., 2021).As we know, many factors influence the level of TMAO concentration in the human body. Such factors include gender, diet, gut microbiome composition, and kidney function. Unfortunately, there is no clear answer if gender can have an influence on TMAO concentrations. Some studies indicate a relationship between gender and metabolite concentration in a healthy study group . HigherGriffin et al. (2019) examineIn another study, Van Hecke and colleagues (2016) examineMoreover, the high-salt diet is indicated as a cardiovascular risk factor. High salt intake increases the level of TMAO concentration in plasma, which is associated with the reduction of urinary TMAO excretion . MoreovSome studies indicate that fish intake would contribute to the increased production of TMAO. In the research conducted by Lenz et al. (2004) the proOne of the metabolites produced by the intestinal microflora is TMAO. Researchers pay a lot of attention to the intestinal microbiome because of its possible role as a promoter of chronic diseases, cancers and even neurological disorders . IntestUntil now, high concentrations of TMAO have been combined with the development of atherosclerosis, which is one of the major causes of CVD. Increased concentrations of TMAO and also TMAO precursor in plasma have been observed in participants at risk of CVD . The liResearch conducted by Wilson et al.  indicIn research conducted by He et al. (2020) 451 peoSchneider et al. (2020) analyzeTMAO is linked to impaired renal function. In patients with compromised renal function absorbed from the intestine, TMA and TMAO may accumulate. Elevated levels of TMAO in patients with an impaired renal function may result from higher production or reduced clearance. Elevated levels of TMAO may be associated with type 2 diabetes (T2D) or atherosclerosis mediated renal dysfunction. This reduces the excretion of TMAO, thus increasing the levels of plasma TMAO . It meaResearchers observed that levels of TMAO increased along with the body mass index, visceral adiposity index and fatty liver index in metabolic syndrome. The levels of TMAO concentration in the serum with values ≥ 8. 74 µM may be considered predictive of metabolic syndrome .A correlation between increased TMAO levels and neurological disorders has been also hypothesized, but the role of TMAO in the central nervous system (CNS) has not been fully explored. Due to the importance of TMAO as a mediator of inflammatory processes, the possible participation of this compound in the etiology of neurological disorders is presumed. In the literature, there are very few studies demonstrating the relationship between brain disease and TMAO levels. The research conducted by Liu and Huang (2015) suggest1H-NMR). Table 1Various methods have been established to demonstrate TMAO and its related metabolites in body fluids . The analytical methods often used are chromatographic techniques, including liquid chromatography-mass spectrometry (LC-MS), high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), ultra-performance liquid chromatography-mass spectrometry (UPLC-MS), liquid chromatography/differential ion mobility spectrometry tandem mass spectrometry (HPLC/DMS-MS/MS), stable-isotope dilution-hydrophilic interaction liquid chromatography-time of flight mass spectrometry with multiple reaction monitoring (LC-ToF-MRM), gas chromatography-mass spectrometry (GC-MS), and also spectroscopic techniques such as proton nuclear magnetic resonance spectroscopy (In conclusion, experimental findings constantly suggest that there is a potential link between the metabolites produced by the gut flora and the risk factors for diseases. Production of TMA and TMAO relies on intestinal microbiota, and also on host genetics, co-metabolism, and diet. To broaden our knowledge on nutrient metabolism and the ways diet may influence health, the research on the relationship between TMAO and intestinal microflora should be continued. If it was possible to fully exploit the potential of TMAO, it could become a new therapeutic target for improving the outcomes of patients. A better understanding of the specific role of bacteria in regulating the levels of TMAO concentration and their mechanism and reaction to dietary modulation, in combination with the factors determining the TMAO concentration is essential and necessary before the potential benefits of TMAO manipulation may be realized under the selected disease conditions.The authors declare no conflict of interest.


Tanystropheus hydroides is well-known, but observations of skull morphology were previously limited due to compression of the known specimens. Here we provide a detailed description of the skull of PIMUZ T 2790, including a partial endocast and endosseous labyrinth, based on synchrotron microtomographic data, and compare its morphology to that of other early Archosauromorpha. In many features, such as the wide and flattened snout and the configuration of the temporal and palatal regions, Tanystropheus hydroides differs strongly from other early archosauromorphs. The braincase possesses a combination of derived archosaur traits, such as the presence of a laterosphenoid and the ossification of the lateral wall of the braincase, but also differs from archosauriforms in the morphology of the ventral ramus of the opisthotic, the horizontal orientation of the parabasisphenoid, and the absence of a clearly defined crista prootica. Tanystropheus hydroides was a ram-feeder that likely caught its prey through a laterally directed snapping bite. Although the cranial morphology of other archosauromorph lineages is relatively well-represented, the skulls of most tanystropheid taxa remain poorly understood due to compressed and often fragmentary specimens. The recent descriptions of the skulls of Macrocnemus bassanii and now Tanystropheus hydroides reveal a large cranial disparity in the clade, reflecting wide ecological diversity, and highlighting the importance of non-archosauriform Archosauromorpha to both terrestrial and aquatic ecosystems during the Triassic.The postcranial morphology of the extremely long-necked  Protorosaurus speneri, Prolacerta broomi, the herbivorous Rhynchosauria and Allokotosauria, and the long-necked Tanystropheidae (Macrocnemus bassanii and Langobardisaurus pandolfii), largely aquatic (Tanytrachelos ahynis and Tanystropheus hydroides), and possibly even fully marine  taxa  taxa . The clais) taxa . Due to Macrocnemus bassanii and Amotosaurus rotfeldensis, to the ‘fish-trap’ type dentition of Tanystropheus hydroides, to the partially tricuspid dentition of Tanystropheus longobardicus and Langobardisaurus pandolfii  has recently revealed the cranial morphology of the tanystropheid taxa ructions . This haopheidae . In contpredator . FurtherThe aim of this study is to describe the skull and preserved cervical vertebrae of PIMUZ T 2790 in high detail based on the SRµCT data. This represents the most complete and detailed cranial description of any tanystropheid to date and expands our understanding of early archosauromorph cranial diversity and evolution.). The specimen was discovered in 1952 at the Punkt 902 locality of the Besano Formation (formerly Grenzbitumenzone), which is of latest Anisian to earliest Ladinian age . The skull of PIMUZ T 2790 is dorsoventrally compressed and most elements have become disarticulated and overlap each other, hampering observation of their morphology and the overall configuration of the skull , the elements were digitally positioned in their perceived in-vivo positions, thus ‘re-assembling’ the skull . The resulting data were segmented using Mimics Research v19.0 . and Italy (Lombardy).HorizonBesano Formation, Anisian-Ladinian boundary, Middle Triassic.DiagnosisTanystropheus hydroides can be distinguished from other Tanystropheus species based on the following combination of characters (autapomorphies among Triassic archosauromorphs indicated by an asterisk): premaxilla lacking a postnarial process; single cusped marginal dentition; dentary tooth piercing through a foramen in the maxilla*; depression on the dorsal surface of the nasals; straight suture between frontals; fused parietals; conspicuously hooked dorsal quadrate head; wide and anteriorly rounded vomers with a single row of large recurved teeth along its outer margin*; edentulous palatine and pterygoid; dentary bearing a distinct ventral keel at its anterior end*; a maximum total length of over 5 m.The following diagnosis has also been presented in RemarksTanystropheus hydroides  were referred to ydroides . Specimeydroides , was alsydroides . Due to tropheus , we mainmporally . Since te contra .Tanystropheus hydroides, which are all largely or completely flattened. Most of the bones are preserved underneath the two large plate-like frontals, which have been displaced somewhat posteriorly from the mandibular rami, premaxillae and maxillae, and as such protected the bones underneath from breakage and distortion. The length of the skull is 138 mm .Even though the skull of PIMUZ T 2790 is dorsoventrally compacted, most of the bones still preserve a three-dimensional morphology with only certain bones being somewhat deformed . This isPremaxillaTanystropheus longobardicus . The prefrontal would have formed the anterodorsal margin of the orbit. The remaining edges of the prefrontal are broken and poorly preserved. They are very likely incomplete, in part because the element was crushed over the left surangular. The prefrontal was orientated in the ‘re-assembled’ skull based on the position of this bone in PIMUZ T 2819, which is in partial articulation  were possibly fused , Protorosaurus speneri , and in some specimens of Prolacerta broomi (e.g. BP/1/471) and Proterosuchus spp. (e.g. SAM-PK-K10603). From PIMUZ T 2819 it can be inferred that the pineal foramen was completely enclosed by the parietals on their anterior portion in Tanystropheus hydroides (figure 4B of Tanytrachelos ahynis (NMS G.2017.11.1), Prolacerta broomi (BP/1/5880), Proterosuchus fergusi (BP/1/3993), and Teyujagua paradoxa , whereas relatively large-sized taxa with a widely different diet  show a similar morphology.Among non-archosauriform archosauromorphs fused parietals also occur in mus spp. , Trilophuettneri , Euparkeparadoxa  is positfrontals . The larosuchids . The larPostfrontalTanystropheus hydroides had previously been identified in PIMUZ T 2819  and similar to that of Macrocnemus bassanii  was recently re-interpreted based on the shape of the postorbital in Tanystropheus hydroides  and Pectodens zhenyuensis (IVPP-V18578). In none of these taxa does this process connect to the quadrate or quadratojugal, and the presence of a complete infratemporal bar is considered a synapomorphy of Archosauriformes , Pectodens zhenyuensis (IVPP-V18578), and Jesairosaurus lehmani (ZAR 06). The postorbital bar of Azendohsaurus madagaskarensis appears to be somewhat wider than that seen in most archosauromorphs, but less so than in the abovementioned taxa  on the specimen lateral to the posterior part of the right mandibular ramus . Howeverbardicus . The antriformes . Trilophis taxon . The ascis taxon  and 6A. is taxon  and 6A. ned taxa . In contSquamosalMacrocnemus bassanii, the anterior portion of the squamosal can be distinguished into a discrete anterior process, which articulates with the posterior process of the postorbital, and a ventral process which is located directly anterior to the quadrate  and possibly Protorosaurus speneri . The combined shape of the exoccipitals and the basioccipital gave the condyle a hemispherical shape , Dinocephalosaurus orientalis (IVPP-V13767), and Pectodens zhenyuensis (IVPP-V18578) among early archosauromorphs. The squamosal does not possess a separate ventral process and the posterior margin of the infratemporal fenestra was formed by the anterolateral margin of the quadrate and the quadratojugal. The horizontally orientated posterior process of the jugal formed the ventral margin of the fenestra but did not connect to any bone posteriorly and therefore the infratemporal fenestra was open ventrally.The infratemporal fenestra is relatively small in he skull  and 6A. ChoanaThe palatal region is only partially preserved in PIMUZ T 2790 , but theSuborbital fenestraBecause our identification of the ectopterygoid is tentative, we are not able to confidently interpret the shape of the suborbital fenestra. It was likely framed by the palatine, ectopterygoid, pterygoid, and maxilla  and 6C. Posttemporal fenestraTanystropheus hydroides .In addition to the skull, PIMUZ T 2790 preserves cervical vertebrae one through eight . Of thesydroides , as wellydroides  and 32. Atlas-axis complexThe atlas-axis complex is preserved but disarticulated in PIMUZ T 2790, and consists of the atlas pleurocentrum, atlas intercentrum, two atlantal neural arches, axis intercentrum, and axis. The atlas pleurocentrum and intercentrum are preserved in between the axis ventrally and right postorbital dorsally. The right atlantal neural arch is located above the left quadrate and below the left frontal and squamosal, whereas the left atlantal neural arch is preserved underneath the right squamosal and the anterior end of the axis. Anterior to the atlas pleurocentrum and intercentrum, the axis intercentrum is preserved between the right posterolateral process of the fused parietals dorsally and the anterior part of the neural spine of the axis ventrally.Macrocnemus bassanii, Trilophosaurus buettneri, and Azendohsaurus madagaskarensis  were tightly bunched in the majority of known specimens  connecting the hyobranchial apparatus to the pectoral girdle retracts this apparatus, which creates a negative pressure within the buccal cavity (Suction feeding in vertebrates can be inferred from skeletal adaptations of the hyobranchial apparatus. The contraction of muscles (e.g. the l cavity . The appTanystropheus hydroides specimens PIMUZ T 2819 and SNSB-BSPG 1953 XV 2. This slightly curved bone is comparatively thin (measurements provided on page 44 of Tanystropheus hydroides. Furthermore, the ‘fish-trap’ dentition seems to preclude the possibility of suction feeding in Tanystropheus hydroides, since the elongate fangs would interfere with the prey item entering the buccal cavity.No elements of the hyobranchial apparatus are preserved in PIMUZ T 2790. However, ceratobranchial I is known from Tanystropheus longobardicus specimens PIMUZ T 2791, PIMUZ T 2484 (both in Tanystropheus longobardicus specimen PIMUZ T 3901, directly posterior to the left lower jaw (see figure 2B of Tanystropheus hydroides, an ossified hyoid corpus was likely not present in Tanystropheus longobardicus. The apparent absence of an ossified hyoid corpus and the lack of robust hyobranchial rods therefore indicate that both species of Tanystropheus were not suction feeders.Hyobranchial elements were previously also identified in  both in , and MSN both in . We wereSalt glandsTanystropheus hydroides, but the large space of confluent external nares could have facilitated such a gland. This is also the case in Triassic sauropterygians such as Nothosaurus marchicus (Tanystropheus specimens, both of Tanystropheus hydroides and Tanystropheus longobardicus, limits the observation of this trait and therefore nothing can be said unambiguously about the presence of salt glands in Tanystropheus currently.A tetrapod spending large amounts of time in a marine environment needs to excrete excess salt from its body. This is achieved by salt glands. Salt glands are generally located within the nasal or orbital cavities (an overview is provided in archicus . HoweverTanystropheus hydroides, and highlights that the configuration of the skull is entirely unique among archosauromorphs and adapted for a lifestyle as an aquatic ambush predator. The external nares are confluent and positioned on the dorsal surface of the snout. As in Tanystropheus longobardicus, but in contrast to other archosauromorphs, the frontals are wide across the interorbital region and form most of the dorsal margin of the orbit. The postorbital region is characterized by dorsally directed supratemporal fenestrae, laterally facing supratemporal fossae of the parietals, a dorsoventrally tall squamosal, and dorsally hooked quadrate. The braincase is characterized by several derived archosaur traits, such as the presence of a laterosphenoid, and the ossification of the lateral wall of the braincase by a connection between the prootics and parabasisphenoid. However, the braincase differs from more derived archosauriforms in the morphology of the ventral ramus of the opisthotic, the horizontal orientation of the parabasisphenoid, and the lack of a clearly defined crista prootica. There is no indication of pneumatization in the braincase of Tanystropheus hydroides. The flocculus was pronounced. The cochlear duct of the endosseous labyrinth is well-developed, indicating advanced auditory capabilities in Tanystropheus hydroides. The configuration of the palate is distinct from other archosauromorphs, including Tanystropheus longobardicus, but possibly resembles in some respects the poorly known palatal region of the marine archosauromorph Dinocephalosaurus orientalis. The marginal dentition is also comparable to that of Dinocephalosaurus orientalis and forms a clear indication of a piscivorous diet. The skull of Tanystropheus hydroides possessed an unusual articulation between the quadrate and squamosal and, together with the sliding contact between the quadrate and pterygoid, provided the osteological potential to retract the quadrate posteriorly. The dentition, as well as the morphology of the hyoid apparatus, indicates that Tanystropheus hydroides was clearly not a suction feeder but likely employed a laterally directed snapping bite like certain sauropterygians. The lower jaw of Tanystropheus hydroides allows for the reinterpretation of the mandible of Tanystropheus longobardicus, specifically with regards to the splenial, surangular, angular and prearticular.The detailed morphological study of the SRµCT data presented here provides much additional information on the skull and anterior cervical region of Tanystropheus hydroides and Tanystropheus longobardicus from the Besano Formation of Monte San Giorgio, thus indicating niche partitioning within the genus (Tanystropheus species and other tanystropheid taxa such as Macrocnemus bassanii as revealed in this study provides a clear indication of the ecomorphological diversity of Tanystropheidae, which was previously only marginally understood.The SRµCT data of PIMUZ T 2790 previously revealed the taxonomic and ecomorphological distinction between he genus . Further