Purpose: The composition and the metabolic activity of the gut microbiota of breastfed and formula-fed infants has been the focus of several studies over the last two decades. Gene sequencing techniques and metabolomics in biological samples have led to expansion of our knowledge in this field. A more thorough comprehension of the metabolic role of the intestinal microbiota could assist and expedite the development of optimal feeding strategies. The aim of this systematic review is to present available data regarding the effect of the feed type on the infantile intestinal microbiota  by DNA-sequencing and metabolome analysis of neonatal stool. Methods: A systematic search of the literature in PubMed was attempted to establish relevant studies. Randomized controlled trials studying the diversity and composition of gut microbiota and metabolites of infants that received different types of feed were included. The study subjects were infants/neonates born at term or preterm receiving either breast, donor, or formula milk. Formula could be either classic or fortified with probiotics, prebiotics, or both. The included trials compared the differences on metagenomics and metabolomics of infantile stool, aiming at investigating the beneficial effects of fortification of formula with synbiotics. Results: Out of 1452 papers identified by the initial search, seven were selected for inclusion, following screening for eligibility. Eligibility was determined by closer examination for relevance of the title, abstract, and subsequent full text. The results of these studies mostly support that the feed type modulates the microbiome composition. In terms of the alpha-diversity, no significant difference exists between the feeding groups, whereas significant differences were noted with regards to beta-diversity in breastfed and formula-fed infants. As for the microbial composition, the studies revealed different populations in the formula-fed group compared to the breastfed group at the phylum and genus level. Bifidobacteria supplementation of infant formula did not seem to change the proportions of Bifidobacterial sequences during the first year of life. Another finding according to the studies is that the pH of fecal samples in breastfed as well as prebiotic-supplemented formula-fed infants. was significantly lower than that of formula-fed infants. Infant milk formula with a mixture of prebiotics (GOS/FOS oligosaccharides) was shown to be capable of selectively stimulating the growth of Bifidobacteria with analogous changes in fecal pH and short-chain fatty acid content in fully formula-fed infants. Conclusions: Overall, there is evidence to support that feed type modulates the infants’ microbiome constitution. The impact of feeding on term and preterm microbiota could have potential benefits on intestinal functionality, immune system, and metabolism, and probably pursuing the host for life. Breast milk is the most appropriate source of nutrition for infants. In addition to normal nutrients, such as fats, proteins, carbohydrates, vitamins, and minerals, breast milk carries many more biologically active molecules, including growth factors, cytokines, antimicrobial substances, and immune-enhancing components. The dietary advantages of breastfeeding and its defense against infection have been well demonstrated ,2.When breast milk is not available, formula milk will substitute. Many efforts have attempted to create a formula as close as possible to breast milk’s composition, aiming at optimizing the infant’s growth and development .Over the last few years, it has become clear that crucial imprinting events are modulated in early-life by nutrition, which contributes to potentially long-lasting effects for the infant . These eThe composition and the metabolic activity of the gut microbiota of breastfed and formula-fed infants has been the focus of several studies over the last two decades.Gene sequencing techniques, and metabolomics in biological samples, such as breast milk, urine, or stool, have led to expansion of our knowledge in this field. The capacity to bring to light the identities, activities, and functionalities of the gut microbiota is an instrument of utmost importance.Several authors reported that fecal samples of breastfed infants consist of higher amounts of Bifidobacteria and Lactobacilli, while they contain lower levels of potential pathogens compared to that of formula-fed infants. Furthermore, breastfed newborns carry a more stable and invariable microbial population when compared to the formula-fed ones , which aA more thorough comprehension of the metabolic role of the intestinal microbiota, and of the profile and dominant participants in the gut microbial population hold considerable promise to assist and expedite the development of optimal feeding strategies . FormulaThe aim of this systematic review is to present available data with an objective, reproducible method of investigation of the effect of the feed type on the infantile intestinal microbiota  by DNA-sequencing and metabolome analysis of neonatal stool. This review also aims to evaluate whether clear differences, depending on feed type, exist, and how robust these findings are.In order to find existing research outcomes that analyze and prove how feed type modulates the infants’ microbiome and metabolome constitution, available studies related to this specific issue were reviewed, and subsequently, the reported results were combined and compared.A systematic literature search via PubMed was attempted and relevant studies were identified. Publications over the last 20 years, were retrieved with the help of combined keywords and was identified original research investigating the differences on the metagenomic and metabolomic profile of feces of infants fed exclusively with breast milk compared to that of infants fed with formula/fortified with synbiotics.No exclusion criteria were applied regarding gestational age or postnatal period of observation of the study populations. Studies and general reviews involving the analysis of biological specimen other than stool were excluded from the assessment. Studies not including an analysis of the metabolites and the composition the intestinal microbiota depending on the feed type were also excluded in the process of the initial screening of the abstracts and papers.The present study was performed in strict accordance with guidelines for meta-analysis. Eligible studies published on PubMed, up to 15 September 2020 (the study data collection time instance) were selected and were considered eligible for a potential inclusion in his systematic review.We selected trials studying the diversity and composition of gut microbiota and metabolites of infants that received different types of feed. The study subjects were infants/neonates born at term or preterm receiving either breast, donor, or formula milk. Formula could be either classic or fortified with probiotics, prebiotics, or both. The time of postnatal observation differed in each study. Infant stool was the biological specimen investigated. Trials compared the differences on metagenomics and metabolomics of infantile stool, aiming at investigating the beneficial effects of fortification of formula with synbiotics. Primary outcome measures were the identification of microbial composition and metabolites in the gut and the recognition of any differences on the population and metabolic activity depending on the feed type. Secondary outcome measures were the fecal pH, SCFA (short-chain fatty acids), lactate, and occasionally growth-anthropometrics and stool characteristics.The search query was formulated according to the PICO framework ,14. PICOThe query was issued to the PubMed database using the advanced search builder, which allows the issuing of handwritten questions. The individual parts of the query were used for specific searches: the combination with the AND operator of the above components resulted in the final query , which rThe procedure that was followed for selecting the relevant literature is summarized in In the course of the systematic assessment, study data were reviewed, whenever possible, in relation to gestational age and number of groups of the participants, feed type, techniques used for analyzing the specimens, and differences reported in the composition and metabolic consequences between the infants.A table of data extraction was developed to ensure that the same information and variables were primarily collected from the included studies, including the type of intervention, study subjects, follow-up duration, applied methods, and the reported outcomes of the studies. The collected information was subsequently checked by the same two authors that performed the review of the papers.With regards to the risk of bias in the individual studies and the overall quality of the body of evidence, we followed the GRADE approach  more de.A total of seven studies, including five randomized controlled trials; one prospective, observational cohort study; and one secondary analysis of data from a prospective exploratory study, were distinguished for inclusion in the review. The studies that were excluded were those not relevant mainly because they used different biological specimens or the study population other than neonates. A search of PubMed databases was conducted that provided a total of 1452 outcomes at first. Of these, 1366 studies were excluded because after reviewing the titles, these papers appeared not to be as relevant. Sixty-six additional studies were also excluded because after reviewing the abstracts, it appeared that these papers evidently did not meet the criteria. The full text of the remaining 20 citations was studied in more detail. It turned out that 13 studies failed to meet the inclusion criteria, as described, because they examined the metabolome in urine, or milk samples, or the studies were not conducted on humans. Seven studies met the inclusion criteria in terms of participants, type of intervention, and aim of the study, thus were included in the systematic review.The duration of the intervention was variable from during the first month of life to 24 months of age. Although one study lasted for 24 months, ultimately the observation was only close during the first 12 months, with only some of the participants attending the 2-y follow-up. The included studies involved variable sizes of populations. For the study subjects, the main inclusion criteria entailed term and preterm neonates and infants, fed with either breast milk or formula milk (standard or supplemented); the intervention always occurred after obtaining parental consent before study entry. Three of the trials were multicentric. In all studies, the primary outcome was gut microbial patterns associated with feed type and in one study, the primary outcome was SIgA. All studies evaluated confounding factors, including the effect of gestational age, the mode of delivery, use of antibiotics, pathology of the mother, and the presence of co-morbidities. Secondary and additional outcomes were fecal pH, SCFA (short-chain fatty acids), lactate, and also growth-anthropometrics and stool characteristics in some articles. The timing of outcome measures was variable and could include monthly evaluations and sampling for a year, or evaluations every two weeks for one month.Exclusion criteria included congenital abnormalities, surgery, maternal chronic illness, and antibiotics received either by the infants or the mothers.Breastfed infants comprised the control group. The specimen used in all studies was frozen stool samples; storage conditions in relation to storage temperature and storage time length before analysis of fecal samples varied. Fluorescent in situ hybridization (FISH) was used for bacterial detection in two studies, 16S rRNA sequencing was used in another two studies, and three studies used 16S rRNA gene amplified by PCR in analyzing the samples.Different reference databases were used for the assignment of taxonomy, such as QIIME , UPARSE, Greengenes 16S rRNA gene database, as well as alpha diversity indices (Chao1 and Shannon), beta diversity (UNIFRAC and Bray–Curtis), and statistical methods to analyze possible discrepancies between study population or controls concerning their gut microbial community properties, with non-parametric multivariate statistical tests, such as PERMANOVA .More specifically, in one study, two groups of infants fed infant formula with GOS/FOS and a control group fed with standard formula were placed in a randomized, double blind, placebo controlled intervention study. Simultaneously, a breastfed group was evaluated. At study onset and after 4 and 6 weeks, fecal samples were collected and studied for the amount of Bifidobacteria, as well as biochemical factors, such as pH, short chain fatty acids, and lactate.The second study included preterm newborns that were enlisted at birth and followed up for 30 days. Infants were classified into six groups . Stool samples were collected every day during the first month of life.The next study included infants that were observed from birth to 12 months postnatally and they were separated into three groups: breastfed, standard formula-fed, and fortified-formula-fed (probiotics).In the next study that was included, the impact of an infant fermented formula also containing a mixture of prebiotics was studied in healthy term infants. Three experimental formulas either containing a combination of bioactive compounds (FERM) and prebiotic oligosaccharides (FERM/scGOS/lcFOS), prebiotic oligosaccharides (scGOS/lcFOS), or the bioactive compounds (FERM) were compared to a standard control formula. As a reference, healthy term infants who received breast milk exclusively during the first six months of life were surveyed.In the other study, the purpose was to explore the differences on the initial composition and gene expression of gut bacteria depending on the feed type in moderate late-preterm infants. The two groups included babies feeding with maternal milk and those feeding with formula.The next study evaluated the impact of infant feed type from birth until 12 months of life depending on the duration of breastfeeding and the timing of formula introduction. Infants were classified into three groups: the exclusively breastfed group, infants who had been only fed with formula and infants who were on mixed feeding (both with breast milk and formula) prior to their stool sample.The last study had the objective to assess the impact of donor human milk upon preterm intestinal microbiota. The population was neonates with gestational age < 32 weeks and with a birth weight ≤ 1500 g. Neonates were classified in three groups according to feeding practices consisting of their maternal milk, donor human milk, or formula.All the studies included analyzed gut microbiota composition and metabolites of neonatal stool samples and compared the differences between different groups depending on the feed type.Although the studies were similar regarding the data and the outcomes presented, a meta-analysis was not performed as evaluation showed it would increase the risk of bias. The studies that are presented show discrepancies in the size of the population or the structure of the methods and results The use of different analysis, design, and time-points of assessment causes difficulties combining the data using a statistical process and the individual research outcomes cannot be combined quantitatively. The analysis was limited to a systematic qualitative review; the outcomes and characteristics of the separate studies are reported in a descriptive form .The results of these studies are mostly in line with the main findings that the feed type modulates the microbiome composition.Bifidobacteria does not affect intestinal a- and b-diversity to a significant extent.In terms of the intrasample bacterial richness and diversity , little or no significant difference exists between the feeding groups, whereas with regards to the intersample, microbial variations (beta-diversity) in breastfed and formula-fed infants were significantly different. In three studies, the bacterial abundance and diversity proved lower in breastfed infants vs. formula-fed infants ,21,22. OFirmicutes was the predominant bacterial phylum in the majority of infants of both breastfed and formula-fed groups, although in one study on preterm infants significantly higher relative abundance of Firmicutes was noticed in formula-fed group compared to breastfed group.As for the dominant phyla that comprise the gut microbiome, the studies revealed that Escherichia and Clostridium and the family of Enterobacteriaceae seem to be more present in the formula-fed groups. Among the breastfed infants higher abundance of Bifidobacteriaceae was observed, mostly in term, and lower abundance of Clostridiaceae [Bifidobacterium and Lactobacillus  between breastfed and formula-fed groups. The main health-relevant genera in all groups are Bifidobacterium and Lactobacillus.In terms of genus, the idiaceae ,19,20,22idiaceae , no diffBifidobacterium and Lactobacillus species relative to other species was higher in the breastfed group in comparison to other groups. Propionibacterium on the other hand, as reported by Wang et al. [Bacteroides and one Blautia species [Bifidobacteria significantly weakened the relative abundance of Bacteroidaceae at 1 month of age, but these differences largely disappeared at 3 months, supporting the overall finding of the study that bifidobacterial intervention does not show any long-term aftermath on fecal microbiome.Li et al.  showed tg et al. , had rem species ,18,22. BBifidobacteria supplementation of infant formula also did not seem to change the proportions of bifidobacterial sequences during the first year of life. Such an intervention is therefore unlikely to compensate for differences in microbiota composition observed between breast- and formula feeding as the supplementation with Bifidobacteria alone was inadequate in altering the microbial populations and the stool metabolite profile over a longer period of time in this study [is study .Bifidobacteria in the prebiotic-supplemented (GOS/FOS oligosaccharides) formula group and the standard-formula group were similar, after 6 weeks the percentage of Bifidobacteria increased in the prebiotic-supplemented formula group compared to the standard formula group.Knol et al.  reportedAnother factor that appeared to play a role in affecting neonatal gut microbiome is the acidity of the gut, resulting from nutritional sources. According to the studies, the pH of fecal samples in breastfed, as well as prebiotic-supplemented formula-fed infants was significantly lower than that of formula-fed infants ,20,21.Bifidobacteria with analogous changes in fecal pH and short-chain fatty acid content in fully formula-fed infants. This study demonstrates the enhanced growth of Bifidobacteria and a related impact on metabolic activity in infants with an already formed gut microflora associated with conventional milk formula. Microbial enzymatic decomposition of non-digestible carbohydrates and proteins in the colon causes a decreased luminar pH mainly attributed to the generation of short-chain fatty acids and lactate.Knol et al.  demonstrBifidobacteria in the prebiotic-supplemented formula-fed group compared to the standard group. The production of acetic acid and lactic acid has been attributed to Bifidobacteria and lactic acid bacteria in the colon of breastfed infants [The short-chain fatty acid (SCFA) pattern of infants in the prebiotic-supplemented formula-fed infants, approximates the pattern of the short-chain fatty acids of breastfed infants. High levels of acetate, and low levels of propionate and butyrate appeared to arise following feeding a standard formula or breast milk. The distinct SCFA profile that appeared between the groups of infants fed the prebiotic mixture and those fed the standard formula, is an indication that the composition of the microflora differs between the two groups. This was consistent with the finding of a higher percentage of  infants .Bifidobacterium was remarkably, positively related to specific metabolites, such as L-proline, D(–)-arginine, DL-threonine, while there was a negative correlation to creatine, capric acid, and taurine. An increase in proline seemed to result from a relatively large community of Bifidobacterium. Specific metabolites were also associated with Lactobacillus, Bacteroides, or Klebsiella. The amino acid metabolic pathway was more related to breastfed infants supporting that the amino acid synthesis pathways are increased in the microbiota of these infants. Compared with the breastfed group, the mixed- and formula-fed groups were more related to fatty acid biosynthesis and biosynthesis of unsaturated fatty acid [The findings of Li et al.  supportetty acid . On the tty acid  reportedBéghin et al.  reportedEnterobacteria acid resistance mechanisms, and L-fucose utilization functions were upregulated in breastfed infants, and at the same time a decreased expression of genes related to the methionine and valine degradation functions was observed compared to the formula group. This analysis used different gene ontology databases  to find differential gene expression. The metatranscriptome data were analyzed and the reads that are involved in biological processes  were obtained. There were genes differentially expressed depending on the feed type. Finally, Béghin et al. [Wang et al. , using fn et al.  showed tOverall, there is evidence to support that feed type modulates an infant’s microbiome constitution. The impact of feeding on term and preterm microbiota could have potential benefits on intestinal functionality, immune system, and metabolism, and probably pursuing the host for life.In terms of the supplementation of the infant formulas, the included intervention studies showed that although Bifidobacteria-supplemented formula initially modulates the infant intestinal microbiome, this effect is not longstanding as it was observed that the Bifidobacteria ingested from formula failed to continue to remain in the infant intestinal system over time and the persistent colonization beyond intervention failed in all feeding groups.Furthermore, providing a formula enriched with prebiotic GOS/FOS oligosaccharides to formula-fed infants with an established intestinal microflora results in an increased proportion of Bifidobacteria in the stools. This alteration of the intestinal bacterial communities has an impact on stool characteristics, such as a reduction in stool pH and a SCFA pattern containing a higher proportion of acetate and a lower proportion of propionate. The alterations induced by the addition of prebiotic oligosaccharides to infant formula lead the intestinal flora and its metabolic activity closer to that of breastfed infants.This study has some limitations: (a) the included studies are not of optimal quality, due to their design (cohort studies) or other issues, such as no blinding or randomization reporting, though there are not many studies available; and (b) we searched a single database (PubMed), though a subsequent search in additional databases (Scopus and Google Scholar) did not produce more results.In conclusion, these data provide a better understanding of the shaping of the gut microbiome in term and preterm infants depending on the feed type, which can be a valuable tool in the effort to improve infant formulas. They also open channels to explore the links between the gut microbiome–metabolome for biomarker detection and to identify important areas for future research.


In a recent definition , which have led to an improved understanding of the neural correlates of motivation-cognition interaction mechanisms. Specifically, these methods have suggested the critical role played by dopaminergic modulation of both cortical and subcortical structures, especially the prefrontal cortex, the anterior cingulate and the parietal cortex  effects on cognitive performance. Likewise, Crawford et al. suggest the importance of considering the type of incentive, in that they found robust effects of both monetary and liquid incentives on cognitive performance and self-reported affect and motivation, but weaker motivational and affective effects for social incentives. A number of papers compared motivation-cognition interactions among younger and older adults. Interestingly, Jang et al. provided evidence for the demotivating/distracting effects of loss incentives, respectively, in the two age-groups. Bowen et al. also tested both younger and older adults, but focused on reward anticipation, to demonstrate that these incentives bolster memory in a relatively automatic, rather than strategic, fashion. In contrast, Di Rosa et al. highlight the role of anxiety among both age groups, in producing potential distracting effects of reward motivational incentives. Le et al. utilized functional neuroimaging (fMRI) to examine the neural basis of aging effects on reward motivation, observing clear evidence of age-related reductions in activity in a rewarded Go/NoGo task, that mediated the observed behavioral changes. Zhuang et al. focused on intra-individual variability, demonstrating that hormonal changes during the menstrual cycle influenced impulsivity and both activity and connectivity in frontostriatal circuits. Schiff et al. also examined intra-individual variability, finding a significant effect of fasting on the motivational modulation, by food-reward stimuli, of attentional and cognitive control mechanisms. Taken together, this first set of papers demonstrate the need to consider variables that have previously received less attention in motivation studies, such as the kind of motivational incentive being , inter-individual variability in psychological variables such as trait anxiety, and as well non-psychological intra-individual variables, such as hormonal levels or the hours from the last meal. Additionally, these papers clearly show the importance of investigating how aging can impact these mechanisms, since younger and older adults have been found to respond differently to different kinds of incentive manipulations.A first section of papers presents new research on healthy participants. Many of these papers yield important new insights into the nature of motivation-cognition interactions. Chami et al. the researchers demonstrated the efficacy of food-specific inhibitory control training, in patients with bulimia nervosa and binge eating disorder, using an innovative paradigm based on principles related to motivation-cognitive control interaction mechanisms. In Cardi et al. the researchers analyzed the role of motivation in a self-help intervention for patients with anorexia nervosa, showing its role in predicting drop-outs, alliance with the therapist, psychological distress and the ability to change. Two studies provided new evidence on motivation-cognition mechanisms in schizophrenia. Kreis et al. reported the presence of a reduced effort investment in patients with schizophrenia, but also indicated the lack of a direct link between objective and subjective measures of effort. ten Velden Hegelstad et al. did not find any relation between motivation and memory performance in patients with psychosis, suggesting that the primary deficit may be cognitive rather than motivational in nature. Taken together, these two works clearly indicate the need to additional investigate this clinical condition, and moreover highlight the need of further investigation about the feasibility of using subjective vs. objective measures of effort. Last but not least, two original contributions concern the study of patients with mild cognitive impairment (MCI) and with Alzheimer's disease (AD). Using resting state fMRI, Wang et al. examined the effect of a music-based intervention on the intrinsic connectivity of the auditory and the reward neural systems, reporting on the presence of dysfunctional within and between-network connectivity in AD patients, when compared with individual with MCI and with healthy controls. Yin et al. analyzed data from the Chinese Longitudinal Healthy Longevity Survey, reporting a significant association between social support and rewarding activities, like children's visit, in reducing the risk of cognitive impairment among older adults.A second set of papers illustrate the utility of applying motivation-cognition interaction models to the study of clinical populations. Two studies were conducted on eating disorders. In To conclude, we are pleased to note that the Special Research Topic offers a diverse set of fourteen engaging papers, each of which addresses in its own way the theme of this issue: Motivation-Cognition interaction. We thank the Frontiers in Psychology Editorial team for their commitment to the project over the past months, the many reviewers who kindly helped us, the researchers whose work is published here and, most importantly, the participants who took part in their studies.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


We discuss emerging views on the complexity of signals controlling the onset of biological shapes and functions, from the nanoarchitectonics arising from supramolecular interactions, to the cellular/multicellular tissue level, and up to the unfolding of complex anatomy. We highlight the fundamental role of physical forces in cellular decisions, stressing the intriguing similarities in early morphogenesis, tissue regeneration, and oncogenic drift. Compelling evidence is presented, showing that biological patterns are strongly embedded in the vibrational nature of the physical energies that permeate the entire universe. We describe biological dynamics as informational processes at which physics and chemistry converge, with nanomechanical motions, and electromagnetic waves, including light, forming an ensemble of vibrations, acting as a sort of control software for molecular patterning. Biomolecular recognition is approached within the establishment of coherent synchronizations among signaling players, whose physical nature can be equated to oscillators tending to the coherent synchronization of their vibrational modes. Cytoskeletal elements are now emerging as senders and receivers of physical signals, “shaping” biological identity from the cellular to the tissue/organ levels. We finally discuss the perspective of exploiting the diffusive features of physical energies to afford in situ stem/somatic cell reprogramming, and tissue regeneration, without stem cell transplantation. Increasing and compelling experimental evidence show that biology is fashioned and regulated not only by chemical signaling, but even by multifaceted physical energies, including mechanical waves, electric patterning and gradients, as well as electromagnetic radiation, which also includes light.A major challenge that has always and long badgered scientists of multiple disciplines is trying to decipher the mechanisms underlying the causal relationship between chemical/molecular patterning at cellular level, and the timely construction and unfolding of the variegated shapes that comprise organs and tissues, up to the specification of entire individuals.Within this context, many fundamental questions either remain unsolved, or are addressed in such a way that only scratches the surface of a largely unexplored territory.How is information originated and fashioned from the molecular to the cellular and intercellular level, up to the point of defining the nanotopography, the micro-, and then the macro-anatomy of a given tissue/organ system?Many of the processes that have been essential to build up and complete embryogenesis do not cease after birth, but they are timely resumed throughout the entire lifespan. Are these processes essential to maintain the biological identity at the cellular- and the larger anatomical-scale level? In the affirmative, how are they intertwined with the adulthood unfolding of our biology? Alternatively, but perhaps not mutually exclusively, are the anatomy and the biology of an adult individual originated through an afterbirth chronobiology of self-organizing embryonic processes?Why are some of these embryonic-like patterns overexpressed throughout diseased, degenerative, or cancer states?How can we interpret, and deploy at the therapeutic level, the finding that cancer entails relevant embryogenetic traits, and the observation that tissue regeneration itself may drift towards tumorigenesis, using common pathways in both embryogenesis and cancer? In addition, at what/up to which level does normal coherent tissue regeneration avoid such drift, while making use of the same or similar armamentarium?What about the increasing evidence that degenerative diseases, affecting organs with highly specified anatomical diversities and functions, are nevertheless sharing an astonishing superimposable molecular misfolding? Highly diversified tissues nonetheless show a trans-organ nature in the way they are affected by similar molecular derangement(s). This applies, for instance, to the presence of similar misfolded proteins in the brains of subjects with neurodegenerative states and in patients affected with cardiac amyloidotic failure, or cardiac Tau-pathies.Overall, how are non-local, long-range communicating patterns established outside the neurally mediated connection(s)?The physical dynamics of molecular folding;The establishment of nano-architectonics using supra-interactions;The biomolecular recognition and signal propagation afforded through the dynamics of molecular synchronization and swarming.At a very general level, when trying to reconnect our biology to the universe in which we are immersed and are part of, we cannot avoid thinking about ourselves as a part of the vibratory nature of the universe itself. If we start thinking this way, and looking at the scientific evidence that may corroborate or neglect the approach of seeing biology with the eyes of physics, we will indeed find mounting evidence that physical forces are essential in the orchestration of living organisms. A number of interrelated processes can be deciphered with this approach, including:In all these processes, the inherent underlying mechanism at the physical level may be viewed as a form of vibration. Sophisticated tools, including atomic force microscopy (AFM) ,2,3,4, sA single peptide molecule can be viewed as an array of repetitive helix–loop–helix domains. These modules are intrinsically oscillatory, with the helix acting as a spring (oscillator) and the loops as inter-oscillator linkers. However, these springs are highly polarized, with arrays of positively charged amino groups (such as those in lysine and arginine) and negatively charged carboxyl groups (such as those in aspartate and glutamate). As a result, the helices in a peptide are far from behaving like a pure mechanical oscillator, but they act, rather, as an electromechanical oscillator, harboring features of interacting chemically and physically with other similar helix–loop–helix molecules. Seeing these molecules as electro-mechanical actuators implies that their mechanical oscillation is also capable of generating an electric field with radiation characteristics. Moreover, a consistent number of signaling molecules include, with their vibrational features, the capability of absorbing and emitting light within defined domain spectra, therefore being deemed “chromophores”. The list of these molecules is remarkably increasing, and includes flavins, flavoproteins, and cytochromes ,13,14,15It is conceivable that nanomechanical and electromagnetic oscillations will coexist as intimately connected features in these cellular actuators, since mechanical waves will hardly separate from the generation of electric oscillations and electromagnetic radiations. Conversely, the exposure of these cellular actuators  to an electromagnetic field or light will produce mechanical oscillations . CompounThe physical properties of signaling molecules intrinsically embed mechanical and electromagnetic patterning, as a whole, in an inseparable nanoworld of physical forces;As a consequence, we prefer referring to vibrations as an “inclusive term”, symbolizing the oneness in the way the same forces may emerge from, and be sensed by, cellular molecules;Such physical characteristics are fashioned to be expressed as, and consequently, respond to, precise signatures.These observations strongly suggest that:−1, and (iii) persisting motions within the under-damped modes. The occurrence of these persisting motions indicates that damping and intermode coupling are both weaker than previously assumed, and suggest that, like violin strings or pipes of an organ, cellular molecules can vibrate in different patterns within our cells [The function of cellular proteins is tightly related to their dynamic flexibility and specific structural changes. These changes have long been known to be essential in the establishment of cellular communication and fate decisions. Nevertheless, only recently, owing to the use of THz-NFM, has it been possible to infer that flexibility and structural changes occur as a precise pattern of vibrations, and that such vibrations are organized as (i) long-range modes, (ii) under-damped modes, existing for frequencies greater than 10 cmur cells .A logical consequence of these findings is also that the signaling features of molecules involve the capability to both express and respond to precise vibrational signatures.Consonant with this expectation, innovative approaches have been developed that are based upon the exploitation of vibrational features of molecules to afford further characterization of their properties under both physiological and diseased states. One of these approaches is the resonant recognition model (RRM) . The RRMAnother advantage of the use of RRM is the chance of developing novel peptides with unprecedented spectral features and bioactivities .Interestingly, the spectral signatures predicted by RRM for resonance frequencies of tubulin have been verified and supported by experimental evidence ,35. In fA major challenge in the biophysical interpretation of cellular dynamics is moving from the analysis of single-molecule vibrations to the dissection of complex collective behaviors on a vibrational basis. How can biomolecular recognition patterning within an interactome be figured in terms of multiple interacting vibrational signatures?Answering these questions has been made possible by the increasing understanding of the physics behind the structure and function of the cytoskeleton, with particular emphasis on cellular microtubuli. It is now evident that these elements form a complex vibrational network involving the generation of concerted electromechanical waves, where mechanical vibrations  and mechIn addition to their mechanical properties, microtubuli have been found to exhibit sophisticated electric signaling features. The possibility that these elements emit high-frequency electric fields with radiation characteristics had been initially postulated on theoretical basis by Havelka and coworkers . SubsequCompelling evidence for previously unexpected features of microtubuli came from the discovery that they even entail multi-level memory-switching properties. By the aid of sophisticated STM analyses, the formation of these memory states has been found to involve vibrational  modes that control protein arrangement symmetry related to the conducting state written within the nanowire structure of the microtubule. These features were found to enable a single microtubule to store and process about 500 distinct bits, with 2-pA resolution, creating a random access memory analogue of the flash memory switch used in a computer chip .Microtubuli have attracted even more interest from the physicist community, as their structures share some similarities with photosynthetic antenna complexes, particularly in the ordered arrangement of photoactive molecules with large transition dipole moments. The analysis of tryptophan molecules, the amino acid building block of microtubules with the largest transition dipole strength, has been conducted by taking their positions and dipole orientations from realistic models capable of reproducing tubulin experimental spectra, and using a Hamiltonian widely employed in quantum optics to describe light–matter interactions. This approach showed that such molecules, arranged in their native microtubule configuration, exhibit a superradiant lowest exciton state, which represents an excitation fully extended on the chromophore lattice . TheoretAn overall picture emerges where the microtubular network, and more generally, the cytoskeleton, can be regarded as a complex “bioelectronic circuit”, capable of generating a continuous flow of information fashioned as a multitude of self-organizing vibrations, emerging and diffusing as short- and long-range mechanical/electromagnetic (including light) oscillatory patterns. This bioelectronic circuit is also the context where biomolecular recognition and further information is generated. In fact, the extremely high speed and coordinated tuning of molecular interplay at the basis of complex cellular decisions, including the orchestration of stem cell fate, cannot be solely explained by the diffusion and collision of molecules within the aqueous intracellular environment. A number of interrelated observations argue against a diffusive model in the scaling-up of information by interacting molecules: (i) the establishment of free-diffusion trajectories will be minutely disturbed by the continuous motion of cytoskeletal elements; (ii) the cellular interior is continuously remodeled by motions of a great number of subcellular organelles; (iii) continuous fluid perturbations are generated by a hive of nanovesicles (exosomes) moving along cytoskeletal tracks from their multiple sites of fabrication and “refinement” up to the cell surface, where they are released to contribute paracrine and autocrine signaling; (iv) the microtubular network is also the tracking system for highly polarized motions of molecular motors, which will increase the density of intracellular trafficking and hamper diffusive mechanisms; (v) the formation of tunneling nanotubes, now emerging as an additional tool of physical intercellular communication, involves remarkable contribution by cytoskeletal elements and further traffic crowding; and (vi) the synthesis and accumulation of a wide variety of intracellular glycosaminoglycans, such as hyaluronans, impart the features of a non-homogeneous aqueous gel, dynamically modifying its composition and diffusive properties in response to cell metabolism.Taking into account these considerations, a biomolecular recognition based upon diffusive mechanisms and lock-and-key interactions among molecules appears to be highly unlikely, entrusted to an extreme degree of randomness and unpredictability.A reliable alternative view of biomolecular recognition and its role in the emergence of biological information may result from translating the vibrational properties of individual molecules/oscillators into the collective behavior of multiple oscillators placed and moving within the context of a visco-elastic microtubular network. Signaling proteins can be equated to a crowd of oscillators using molecular motors to move along the microtubular net.An important characteristic in microtubule networks is the establishment of synchronization patterns, as well as the exhibition of a collective behavior. Synchronization is a self-organization modality which manifests in a wide variety of natural as well as manufactured technological systems, ranging from excitable cells  to coupled lasers, metallic rods, and robots. The finding that simple mixtures of microtubules, kinesin clusters, and a bundling agent assemble into spontaneously oscillating structures suggests that self-organized vibration modes may emerge as a generic feature of internally driven bundles . SynthetAnother form of self-organization is the swarming of insects, flocking of birds, or schooling of fish, where a collective behavior emerges as the movement of a multitude of individuals through space without significant change in their internal state(s) . PioneerThese discoveries have brought to the fore a previously unsuspected universality of synchronization and swarming, as the modality through which individual oscillators may converge into a collective behavioral network.Increasing experimental evidence is now indicating that signaling molecules may not only exploit their individual function, but even recognize each other and establish informational networks through specific vibrational patterning. Structural vibrations steer protein structure to functional intermediate states, as has been shown by anisotropic terahertz microscopy and simplified versions of this technique, revealing specific vibrational protein signatures with remarkable functional implications . These aAn analysis of collective motions in the DNA-binding domain (DBD) of wild-type, mutant, and rescued mutant forms of p53 indicated that similar defined low-frequency vibration patterns could be detected in the wild-type and rescued mutants . The mutOn this basis, signaling peptides can be regarded as a multitude of oscillatory devices using molecular machines (such as kinesin motor proteins) to move along the microtubular net, with the microtubules acting themselves as multi-level connectors affording efficient phase synchronization between multiple oscillators. Although coherent synchronization and chaotic behavior have long been deemed as mutually exclusive in a network of similar/identical oscillators, there is now evidence that chimeric states may spontaneously ensue from contention among antagonistic synchronization patterning within oscillators joining a hierarchical web .f) were placed on two swings, freely moving in a plane. Within one subset, the oscillators became strongly coupled by the motion of the swing they were bound to. Increases in f resulted in increased momentum transfer to the swing, which led to stronger coupling between oscillators (metronomes). Upon the increase of the coupling within the same subset, a single swing underwent a transition phase, from a chaotic to a coherent (synchronized) state. In this system, self-organization was controlled by elementary ubiquitous mechanics found in many natural and artificial technological systems [Martens et al. have devised non-local coupling in a hierarchical network encompassing two subsets of oscillators, with each subset embedding strongly coupled oscillators, but with a weaker coupling strength between the two subsets. Identical metronomes with a given oscillatory frequency , carrying on her shoulder some precious cargo full of information , gently walking on an elastic wire (the microtubule). On a collective scale, we may think of an ensemble of dancers moving through a network of these nanowires. Recall the metronome experiments of Martens and coworkers : each siThis means that it is easier for these metronomes to achieve a synchronous state, and while they will remain individual, each element of the network will become aware of what is occurring in the system as a whole because of its interconnectivity. This entire approach uses tenets from nanomechanics, electromagnetism, and quantum field theory, since it aims at taking a glimpse at how multiple patterns can share information. We are becoming aware that microtubuli within the cell behave as migrating oscillatory tracks, and that their “dancing” is associated with a remarkable generation of electric fields, spreading information across the cells, and trespassing the cell boundaries. Further dissection and understanding of these dynamics will very likely provide novel cues for reinterpreting cell-to-cell communication.Like a symphony, in the cellular orchestra we may envision multiple coherent domains, each with a population of oscillators synchronized on specific frequencies, waveforms, and/or pause intervals. An additional level of self-organization may be achieved through the swarming of multiple coherent domains, each retaining their internal state of synchronization while migrating across the cell.The capability of cells to act as both senders and receivers of physical signaling discloses the chance to exploit completely new actions at biomedical level. One possibility is to reprogram stem cells and enhance their rescuing potential without relying upon the use of cumbersome chemistry, or viral vector-mediated gene transfer, an approach which is still not readily envisionable in clinical practice. The strategies of modulating stem cell biology with electromagnetic fields ,70,71,72Comprehensive review analyses, focusing on the rescue of damaged tissues by the aid of physical energies, also including the use of shock waves and photobiomodulation, can be found in ,78,79.The diffusive features of electromagnetic and mechanical waves would allow the efficient reprogramming and modulation of stem cell biology in places where the stem cells already reside—in all tissues of the human body. We believe that targeting stem cells with a physical stimulation in vivo will pave the way for an unprecedented approach in regenerative medicine, avoiding cell or tissue transplantation, and providing tissue regeneration by directly boosting the multilineage and paracrine repertoire of tissue-resident stem cells. This will basically lead to enhancing our inherent self-healing potential. The recent discovery of multilineage-differentiating stress-enduring (MUSE) cells, an SSEA-3(+) pluripotent, tissue-resident stem cell population within human mesenchymal stem cells (hMSCs) ,81,82, mConsidering what we have discussed above, cells may be equated to a fractal component of a living organism, being “traversed” by mechanical and electromagnetic vibrations that self-organize in both local and non-local dynamics, similar to what occurs in the universe we are a part of. Within each cell, the cytoskeleton may be considered as a bioelectronic circuit capable of sending and receiving oscillatory patterns in the form of mechanical and electromagnetic radiation. The local and non-local transmission of oscillations and traveling waves, the assembly of stable and migrating intracellular domains, the homeostatic control in bioelectric circuitries, and the role of electromagnetic fields in the control of gene expression and cell fate ,72,73,74Any tissue/organ is a highly integrated multi-cellular ensemble where different cell types merge to create defined architectures that, at the embryo level, proceed in the hierarchical definition of the cranial–caudal axis. Intriguingly, tissue regeneration recapitulates multiple hallmarks of embryonic development, repurposing lineage-specific profiles to re-initiate morphogenesis and tissue rescue . This obWhile, in referring to the structure–function relationship, we often think in terms of multi-component/multi-task target functions, biology has brought us the notion of one-component/multiple-task target functions. As an example of the first category, we may include the seven helices G-protein-coupled receptors, where multiple components  afford multiple tasks and interact with multiple targets in the related signaling cascades. An example of the second category is provided by tyrosine kinase receptors, or serine-threonine kinase receptors, with their monomeric G-proteins exemplifying a system in which one or a few elements control cascades of multiple protein kinases and, therefore, their related downstream signaling. Other such examples include many so-called pleiotropic agents that act as a single-component, affecting the structure and function of a wide variety of signaling players. To this end, DNA has been reported to have remarkable characteristics of an electromagnetic fractal cavity resonator, which can interact with the electromagnetic fields over a wide range of frequencies .Using the lattice details of human DNA, the radiation of DNA has been modeled as a helical antenna, with the DNA structure resonating with electromagnetic waves at 34 GHz, with a positive gain of 1.7 dBi . Based uWhile the spreading of mechanical oscillations in the cytoskeleton may be assumed as a relatively short-range spreading phenomenon, the diffusion of electromagnetic (light included) waves through the cytoskeletal elements may be envisioned as a long-range disseminating phenomenon, theoretically circulating through an entire organism.Considering cell biology in the light of software- and hardware-like dynamics may provide deeper understanding and control of developmental as well as regenerative pathways, and may place diseased states, such as degenerative diseases and cancer, within the context of an unplugging of the cellular hardware from the network of physical energies organized as a cellular software.With the advancement of technologies, and in particular with the progress in the field of optics, understood as the ability to interact with the dual, mass/wave nature of light, research studies, even in the biological field, have launched into a new era that is not determined by chemistry alone. There is more and more evidence, at first only corroborated by observation and intuition, that there are phenomena, which we now know are related to quantum physics, that are capable of governing the biological and biochemical mechanisms of cells in particular, and whole individuals in general. In nature, quantum mechanisms are used in practically all fields in which matter must interact with light: photosynthesis, for example, exploits the now well-studied phenomena of tunneling and entanglement to produce energy, and manages to do so in what was once thought to be a “forbidden” field to quantum effects, that is, a living and hot system ,97,98. IAmong the main players in this field, we find cryptochromes, proteins for which the name itself suggests the complex and mysterious nature of their action. It has been discovered that these proteins, involved in essentially all the interaction processes with electromagnetic waves, are fundamental for collecting the signal and translating it into a classic “voltage-dependent” or “chemical-dependent” pathway ,104,105.Even more intriguingly, light-sensitive melanopsin neurons are located in the retina, and are tightly involved in the regulation of cognitive and mood functions in response to defined light patterning in mice . MoreoveThe term bioelectricity points at the capability of living cells, tissues, and organisms to endogenously generate electric fields, with the potential to affect biological/functional dynamics. This field of enquiry grew progressively and has spread since the first studies, published in 1791 by Luigi Galvani in “De Viribus Electricitatis in motu musculari”, and Galvani’s subsequent discovery that a twitch can be elicited by placing a muscle in contact with a deviating cut sciatic nerve without the supply of metal electricity ,113,114.Following these pioneering studies, a fundamental breakthrough in the history of bioelectricity was marked by the relentless work of Harold Saxton Burr in the early 20th century (from 1916 up to the late 1950s). His studies were published in extremely relevant journals, including the Proceedings of National Academy of Sciences USA and Science. Burr developed an accurate millivoltmeter , and wasIn addition to reporting further citations of studies from the monumental scientific production of Dr. Burr, we believe that some excerpts taken from his “Blueprint for Immortality, The Electric Patterns of Life”, first published in 1972 , will he“Electro-dynamic fields are invisible and intangible; and it is hard to visualize them. But a crude analogy may help to show what the fields of life—L-fields for short—do and why they are so important. Most people who have taken high school science will remember that if iron filings are scattered on a card held over a magnet, they will arrange themselves in the pattern of the ‘lines of force’ of the magnet’s field. And if the filings are thrown away and fresh ones scattered on the card, the new filings will assume the same pattern as the old. Something like this happens in the human body. Its molecules and cells are constantly being torn apart and rebuilt with fresh material from the food we eat. But, thanks to the controlling L-fields, the new molecules and cells are rebuilt as before and arrange themselves in the same pattern as the old ones” .Burr had a clear vision of the needs for novel tools and strategies to investigate novel fields and falsify or confirm a remarkable paradigm shift, as the chance of reinterpreting cellular and organ dynamics through the hypothesis that field physics, more than particle physics, may help with navigating the largely unexplored territory of morphogenetic signaling under normal and diseased states..The feelings of Dr. Burr, while discovering this new landscape, are well expressed in other excerpts from his work:.Burr had also provocatively hypothesized that living organisms possessed a global bioelectric field orchestrating and/or emerging from more localized fields and acting as a sort of electrodynamic representation of smaller-scale components  of the whole body itself, thus setting the basis for future studies aiming at verifying or falsifying such a hypothesis. .A major outcome from Dr. Burr’s work was laying the basis for a transdisciplinary effort in science, fostering the needs for cooperation among committed “researchers” in apparently different disciplines, such as the arts, philosophy, and religion, always aiming at taking a glimpse from the merging of different viewpoints.This transdisciplinary endeavor is now being propelled by the merging of cellular and developmental biology studies with the most advanced applications in computer science and artificial intelligence (AI), coupled with the development and availability of novel probes designed for the 3D imaging of electric microcurrents at both the single-cell and tissue levels.di-4-ANEPPS, a fast-responding, ratiometric, voltage-sensitive probe, revealing electric field changes as a shift in its fluorescence spectrum emission [Addressing the intracellular electric fluxes by the aid of a patch or voltage clamp merely allows for the assessment of electric dynamics at the cellular membrane level, which only accounts for about 0.1% of the cell volume. The availability of E-PEBBLEs , nanosized voltmeters that can diffuse throughout the entire cell volume, is currently providing a novel landscape based upon the 3D profiling of electric fields in living cells and tissues ,133. E-Pemission ,133. Notemission ,133. Theemission ,135. Theemission ,135. Theemission ,137; cells in vitro, as well as in in vivo settings, to afford remarkable modulation of cell behavior, as well as tissue patterning and rescue. Thus, the chance of exploiting the diffusive features of physical energies to modulate and control cell biology in situ is opening the perspective of reprogramming tissue-resident stem and somatic cells, to afford a reverse remodeling of injured tissues without the need for cell or tissue transplantation. In our opinion, significant progress along this line of study may be achieved by the combinatorial use of sophisticated technologies, including AFM, STM, and HSI, coupled with confocal microscopy analyses, to decipher the defined vibrational signatures resulting from the merging of the nanomechanical and electric/electromagnetic levels of cellular activities. We are currently working to extract specific signaling information from these types of recordings, then modulating targeted (stem) cell dynamics through the release of the acquired mechanical and electromagnetic (including light) signals by the aid of ad hoc-designed multifrequency transducers. This is a complex and difficult task, requiring a transdisciplinary approach and the convergence of scientists with different backgrounds and competences. We hope that these efforts will boost the chance among the scientific community of using mechanical vibrations, bioelectricity, and electromagnetic radiation (including light) to develop innovative approaches in the control of epigenetics, tissue morphogenesis, and regeneration, even paving the way for offering additional tools in the handling of oncogenesis and metastatic spreading.The progressive growth of a transdisciplinary endeavor and of cooperation within a new generation of scientists, as well as the availability of targeted funding programs, may hopefully provide further unfolding in this field.


Cutis Laxa is a rare connective tissue disease featuring inelastic and saggy skin. It is thought that plastic surgery might be the most effective treatment, while the previous pieces of literature on the surgical treatment for Cutis Laxa complained of the recurrence. We report a patient of Congenital Cutis Laxa who has received systematic and sequential treatment based on plastic surgery. The patient is content with the effect of treatment, and there are no signs of recurrence after 5 months. By referring to relevant pieces of literature, we evaluate the clinical manifestations and diagnosis of the disease. A multi-step, systematic, and sequential treatment is recommended for the treatment of Congenital Cutis Laxa. Cutis Laxa (CL) is a group of rare connective tissue diseases characterized by lack of skin elasticity, sagging, with or without variable systemic involvement. CL manifests in acquired and congenital forms. Acquired Cutis Laxa usually occurs in early adulthood , 2, whilA 26-year-old man was admitted to hospital for being conscious of facial skin inelastic and saggy over the 26 years. The patient complained of systemic skin relaxation from 3 days after birth, especially the middle and lower parts of the face, as shown in The patient is the second child and full-term spontaneous delivery. His mother denied the history of toxic radiation exposure during pregnancy and childbirth. The patient's parents and sister were in good health, and the parents denied close marriage. The patient had been operated on the inguinal hernia at the age of 6 years old, and post-operative scar was not obvious. The patient denied having family history of hereditary diseases and infectious diseases.The skin of the whole body is inelastic and saggy, especially the middle and lower parts of the face, with external canthus ptosis, nasal tip collapse, long and soft earlobes and the lower part folding, philtrum shallow, deep nasolabial sulcus, and ptosis of labial angle, showing a typical “hound-dog” appearance feature.Fibrinogen, 1.88 g/L . No abnormalities were found in liver, gallbladder, pancreas, spleen, and kidney. The heart structure was roughly normal.There was neutrophil infiltration around small vessels in the dermis of skin tissue. Elastic fiber staining showed that elastic fibers were reduced and broken. Elastic fiber (+).Ectopic gastric mucosa of esophagus. Reflux esophagitis. Esophageal Iscan staining, non-atrophic gastritis with erosion (HP infection).One mutation of ELN gene was found, and the associated disease was autosomal dominant Cutis Laxa type 1 (OMIM: 123700). The related clinical features are skin relaxation and hernia.Congenital Cutis Laxa.Complete relevant examinations and exclude surgical contraindications. The surgical was performed under general anesthesia. Design surgical incision from the front of the tragus to behind the auricle. After finishing routine disinfection and setting sterile towels, use 2% lidocaine, saline, and epinephrine to swell and infiltration anesthetize the operative region. After several minutes, incise skin to superficial fascia along the marked surgical incision. Along the superficial musculo-aponeurotic system (SMAS), the dissection is done towards the midline, up to the zygomatic arch and cheeks. After completing hemostasis, remove 2-cm skin within the incision line, and repair a skin edge. Use 5-0 PDSII to do the local intermittent suture in the SMAS layer, and use 5-0 PDSII intermittent suture subcutaneously, 6-0 single-silk nylon suture closed skin for the surgical incision area. Disinfect the incision with saline and alcohol in sequence, then cover with sterile dressings. The excision tissue was set for pathology. The patient has used scar cream and worn pressure masks for at least 1 month, and then received 755-nm non-ablative fractionated laser therapy and dietary guidance. The patient is content with the effect of treatment, and there are no signs of recurrence after 5 months, as shown in As a rare connective tissue disease, Cutis Laxa is characterized as loose skins with decreased resilience and elasticity, and with or without systemic involvement. CL manifests in acquired and congenital forms. Acquired Cutis Laxa , 2 showsThe major pathological manifestations of CCL are absence or significant reduction of elastic fibers in the dermis layer and residual fragments of elastic fibers after elastin staining , as showIt is highly important to grasp the surgical indications of CCL and should be fully checked before treatment to exclude contraindications and to differentially diagnose from other hyperelasticity diseases, which have poor skin healing, such as Ehlers-Danlos syndrome or Hutchinson-Gilford progeria syndrome . Ehlers-There is a small number of pieces of research on the treatment of CCL, and the existing treatment methods include plastic surgery, laser , intraleWe developed a multi-step diagnosis and treatment plan for our patient to carry out a systematic and sequential treatment. Before operation, the patient must complete relevant examinations, including abdominal ultrasound and cardiac ultrasound, to exclude surgical contraindications. And then we communicated with the patient about the risks during the operation and the high possibility of recurrence. What is more, psychological counseling may be of great help for the patient. After the operation, we followed up the patient regularly and instructed him to use scar cream and wear pressure masks to reduce scar hyperplasia. Moreover, laser therapy and dietary guidance in an outpatient clinic were recommended. Cho  proved tIn summary, we recommend systematic and sequential treatment based on plastic surgery for the treatment of CCL. Although multiple surgeries may be required, the social and psychological benefits need to be considered, and early surgical intervention is recommended. Due to the small number of cases and the lack of long-term follow-up, the accuracy of systematic and sequential approach selection and patient prognostic evaluation need to be further studied and demonstrated.The original contributions presented in the study are included in the article/Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.YK performed the majority of the writing. FC reviewed the literature and contributed to manuscript drafting. HR and FC were responsible for the revision of the manuscript for important intellectual content. SM analyzed and interpreted the pathology findings. YK and SM made the literature review. All authors issued final approval for the version to be submitted.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Our results provide new insight on the tolerance of marine meio- and macrofaunal taxa to the extreme conditions generated by hydrothermal vent emissions in shallow-water ecosystems.Ocean acidification is causing major changes in marine ecosystems, with varying levels of impact depending on the region and habitat investigated. Here, we report noticeable changes in both meio- and macrobenthic assemblages at shallow hydrothermal vents located in the Mediterranean Sea. In general, the areas impacted by the vent fluids showed decrease in the abundance of several taxa and a shift in community composition, but with a clear biomass reduction evident only for macrofauna. CO2-vents, resulting in water acidification phenomena and the creation of an acidified benthic environment. Here, we report the results of a study conducted at three sites located at ca. 16, 40, and 80 m of depth, and characterized by CO2 emissions to assess the effects of acidification on meio- and macrobenthic assemblages. Acidification caused significant changes in both meio- and macrofaunal assemblages, with a clear decrease in terms of abundance and a shift in community composition. A noticeable reduction in biomass was observed only for macrofauna. The most sensitive meiofaunal taxa were kinorhynchs and turbellarians that disappeared at the CO2 sites, while the abundance of halacarids and ostracods increased, possibly as a result of the larger food availability and the lower predatory pressures by the sensitive meiofaunal and macrofaunal taxa. Sediment acidification also causes the disappearance of more sensitive macrofaunal taxa, such as gastropods, and the increase in tolerant taxa such as oligochaetes. We conclude that the effects of shallow CO2-vents result in the progressive simplification of community structure and biodiversity loss due to the disappearance of the most sensitive meio- and macrofaunal taxa.The Aeolian Islands (Mediterranean Sea) host a unique hydrothermal system called the “Smoking Land” due to the presence of over 200 volcanic CO Some ofspecific . Amphipo studies .The emission areas are therefore drivers that shape the structure of macrofaunal assemblages  and theiBoth DistLM models for meiofauna and macrofauna showed that food availability  were crucial driving forces of community composition. Sediments surrounding the sites with vent emissions exhibit a relative high concentration of the most labile compounds of the organic matter, especially proteins, and a preferential accumulation of phytopigments. The larger availability of high-quality food sources could explain the higher abundance and diversity of meiofauna generally observed in the present study. At the same time, the increased food availability can offset reductions in calcification and growth associated with acidification in corals and mussels ,85,86,872 emissions from shallow hydrothermal vents of the Aeolian Islands on both meio- and macrofaunal assemblages at both shallow and deep sites. However, while acidification impacted directly on highly sensitive meio- and macrofaunal taxa, the decrease in other taxa may be caused by the effect of vent emissions on food availability. Kinorhynchs and turbellarians, for instance, disappeared at low-pH sites. Other cascade effects may be due to altered top-down interactions. Among macrofauna, calcifying organisms, especially gastropods, appeared more sensitive than amphipods and brittle stars to acidification. Finally, the polychaetes response to low pH varied from species to species.Our results show a clear impact of COThe results of this study indicate that the effects of fluid vents and related acidification cannot be easily predicted as the response of the different components of the benthic system (even within the same size class) may vary drastically. Further studies are needed to fully elucidate the complex physiological mechanisms allowing a different tolerance of the benthic species and the cascade ecological effects due to the disappearance of some taxa and the altered food availability.