They constitute important components in the human diet, acting as nutraceutical compounds with antioxidant, chemopreventive, antimitotic, neuroprotective, cardioprotective, and anti-inflammatory activities. Several phenylpropanoids are considered high-value biochemicals employed in the production of fragrances, pharmaceuticals and biopolymers  functional characterization of genes involved in the phenylpropanoid metabolism and its coordination with physiological processes; and (4) biotechnological approaches to exploit the economic, medicinal, and nutraceutical potential of phenylpropanoids.This Research Topic aimed to gather recent findings in all aspects of phenylpropanoid metabolism gained by means of systems biology approaches and the utilization of biotechnology to exploit the economic, medicinal and nutraceutical potential of phenylpropanoids. The topic is organized into four sections: (1) structural, molecular and computational approaches toward unraveling the biosynthetic pathways involved in synthesis of diverse phenylpropanoid-derived metabolites; (2) discovery of genes and/or gene networks involved in distinct aspects of phenylpropanoid metabolism Delli-Ponti et al. (in this volume) have reviewed how gene expression and co-expression networks can be used as tools to uncover specialized metabolism biosynthetic pathways. Also using a computational approach, Elder et al. (in this volume) have applied density functional theory (DFT) calculations to evaluate the thermodynamics of coupling modes and subsequent rearomatization reactions between coniferyl alcohol and hydroxystilbene glucosides, which has been detected as a natural monomer in the bark lignin of Norway spruce.The chemical diversity of phenylpropanoids results from the modification and amplification of a set of core structures derived from the shikimate pathway. A vast array of regulatory proteins, biosynthetic enzymes, oxidases and other genes are recruited to produce the various classes of phenolic metabolites. Additionally, many phenylpropanoids are specific to just one or a few plant species, underscoring the complexity of phenylpropanoid biosynthesis and the need for comprehensive characterization studies in diverse species that expand our knowledge base beyond traditional model plant and crop species. Structural, molecular and computational approaches have been applied to identify genes, enzymes and metabolites involved in the biosynthesis of phenylpropanoids in different plants. Du et al. (in this volume). Lignin is a phenolic polymer important for plant growth and development but it is also considered a major bottleneck to the efficient conversion of plant biomass into downstream products. Rosado et al. (in this volume) have reported an in-depth characterization of the structural characteristics of lignins present in rice husks and straw, which are agricultural by-products that can be used to produce chemicals and materials in biorefineries. To identify the timing and key parameters of cell wall recalcitrance across different switchgrass genotypes, Saha et al. (in this volume) measured cell wall composition and phenylpropanoid/lignin biosynthesis gene expression in three switchgrass genotypes representing lowland and upland ecotypes. Yao et al. (in this volume) reviewed recent progress in defining the lignin biosynthetic pathway in lycophytes, monilophytes, gymnosperms, and angiosperms, and integrated new insights on major transcriptional regulators. In another study with evolutionary implications, Rencoret et al. (in this volume) structurally characterized the lignin-like fractions isolated from several ancestral plants, including those from moss, lycophyte, horsetail, fern, cycad, and gnetophyte species. Blaschek and Pesquet (in this volume) provided an overview of the differences and similarities in the structures, reaction mechanisms, substrate specificities, and functional roles between phenoloxidases. Because grasses are able to synthesize phenylpropanoids from either phenylalanine (Phe) or tyrosine (Tyr), Simpson et al. (in this volume) employed 13C isotopic-labeled precursors and mass spectrometry-based metabolomics to determine the downstream metabolites derived exclusively from Phe and Tyr in sorghum. Several phenylpropanoids show bioactivity that might influence plant growth and development or might be beneficial for human health. El Houari et al. (in this volume) reviewed reports describing altered accumulation of bioactive phenylpropanoids (or phenylpropanoid-derived metabolites) as the causal factor for observed phenotypes of lignin mutants in Arabidopsis. Cappellini et al. (in this volume) reviewed the recent progress in understanding the anthocyanin biosynthetic pathway in plants, with special emphasis on the differences in molecular mechanisms between monocot and dicot plants, and discuss the biological activities of anthocyanins as beneficial components of the human diet. Similar to anthocyanins, tannins form another group of phenolic compounds with beneficial effects on human health. Wang et al. (in this volume) performed a genome-wide analysis of the tannase gene family to identify candidate genes responsible for tannin metabolism in three nut tree species in the Juglandaceae family: walnut, pecan, and Chinese hickory.The biosynthesis of phenylpropanoids is often triggered by environmental stimuli. To this end, the effect of chilling treatment on the accumulation of phenylpropanoids and on antioxidant activity in seedlings of two rice varieties (contrasting for chilling tolerance) was studied by Tang et al. (in this volume) leveraged single-molecule real-time sequencing technology to elucidate flavonoid synthetic pathways in blueberries. Their transcriptome analyses led to the discovery of a R2R3 MYB transcription factor that can positively regulate anthocyanin synthesis in fruits. 5-aminolevulinic acid (ALA) is a plant growth regulator that induces fruit coloration and thereby finds potential applications in modern fruit production. A transcriptome study by Zheng et al. (this volume) identified the differentially expressed genes associated with ALA-induced anthocyanin accumulation in apple, including two R2R3-MYB transcription factors involved in flavonoid accumulation. A study by Aničić et al. (this volume) investigated flavonoid metabolism during fruit development in rockrose, a traditional medicinal plant rich in bioactive phenylpropanoids, using comparative metabolomic and transcriptomic approaches. This work highlights correlations between expression patterns of biosynthetic genes and the content of proanthocyanidins. Phenolic compounds are modulated by biotic and abiotic stresses, and a study by Laoué et al. (in this volume) used quantitative trait locus (QTL) mapping and RNA-Seq to explore the complex polygenic network underlying the constitutive production of specific stilbenoids, flavonoids, and lignans in white spruce. Understanding the formation of secondary cell walls (SCWs) and their lignification has important agro-industrial applications. Hixson et al. (this volume), by undertaking an integrated analysis of the metabolome, transcriptome, and proteome of Arabidopsis lines mutated in arogenate dehydratase genes, exposed the involvement of novel proteins and additional post-transcriptional and translational processes that govern phenylpropanoid/lignin biosynthesis. As a proxy to study SCW formation in the bioenergy crop sugarcane, Simões et al. (this volume) established a lignifying cell culture system that they probed with transcriptomic and metabolomic analyses to illuminate the molecular mechanisms involved in this differentiation process, leading to the discovery of regulatory modules that control SCW deposition.The identification of genes and transcriptional networks responsible for specific accumulation patterns of phenylpropanoids during a physiological development process or a stress response is essential to elucidate and harness the fine regulatory mechanisms involved in these patterns. Recent advancements in omics technologies enable integrated approaches to unravel these mechanisms at the transcriptomic, proteomic, and metabolomic levels. These studies provide platforms to guide future research on improving crops for human health and wellness. Chen et al. (in this issue) identified two non-selective uridine diphosphate (UDP) glycosyltransferases (UGTs) from Isatis indigotica Fort. that catalyze the addition of a sugar molecule onto several structurally diverse lignin acceptor substrates. Shi et al. (in this issue) sought to explore the transcriptional regulatory mechanisms of anthocyanin and proanthocyanidin biosynthesis in Chinese bayberry, of which the fruit is considered an important dietary source of natural antioxidants. They identified a MrMYB6 gene that is highly upregulated during the latter stages of fruit development and determined it is a negative regulator of anthocyanin and proanthocyanidins through formation of a complex with two transcription factors, bHLH and WD40. Busche et al. (in this issue) carried out a study five 2-oxoglutarate-dependent dioxygenases involved in the formation of the flavonoid aglycon in banana (Musa): flavanone 3-hydroxylase, flavonol synthase and anthocyanidin synthase. Biochemical analysis of several recombinant candidate proteins showed that MusaF3H1 and MusaF3H2 act as flavanone 3-hydroxylases, MusaFLS1 and MusaFLS3 both function as flavonol synthases, and MusaANS has anthocyanidin synthase activity. Elucidating the activity of these genes will facilitate the development of bananas with higher nutritional value. Hydroxycinnamoyl acid amides, such as clovamide, are phenylpropanoid metabolites that play roles in protecting plants from biotic and abiotic stresses. Sullivan and Knollenberg (this issue) identified, cloned and biochemically characterized a hydroxycinnamoyl-CoA:L-DOPA hydroxycinnamoyl transferase (HDT) from red clover that is capable of synthesizing clovamide and related hydroxycinnamoyl amides in vitro. Characterization of this enzyme activity expands our knowledge of the poorly characterized family of BAHD hydroxycinnamoyl-CoA transferase enzymes and will aid in future studies aimed at understanding the molecular basis of substrate specificity within this important family.The phenylpropanoid pathway in plants plays a major role in the synthesis of a wide variety of secondary metabolites. Metabolites originating from this pathway are frequently involved in plant structure or chemical signaling and defense, including flavonoids, lignins, hydroxycinnamic esters, flavonoids, anthocyanins and tannins. Dietary flavonoids, anthocyanins, proanthocyanidins, hydroxycinnamoyl acid amides and lignans are bioactive compounds that have been shown to exhibit multiple health promoting and antioxidant activities. Lignans are plant secondary metabolites composed of a core scaffold that is formed by two or more phenylpropanoid units that can adopt a spectrum of different structural forms. Lin et al. (in this issue) provide direct evidence that two key enzymes involved in monolignol biosynthesis, 4-Coumaric acid:CoA ligase (4CL) and 4-hydroxycinnamoylCoA:shikimic acid hydroxycinnamoyl transferase, form a Ptr4CL-PtrHCT complex in Populus trichocarpa and its formation is a potential mechanism to modulate metabolic flux during secondary cell wall synthesis. The brown midrib (bmr) phenotype found across several C4 grasses has been critical for identifying mutants compromised in lignin synthesis. Tetreault et al. (in this issue) used a combined bulk segregant analysis (BSA) and next-generation sequencing (NGA) approach to show that bmr30 encodes a chalcone isomerase (CHI) and is involved in synthesis of the flavonoid tricin and not a monolignol. In Populus species, lignin can also be further modified by acylation with p-hydroxybenzoate. Zhao et al. (in this issue) used wild type (WT), lignin p-hydroxybenzoate deficient, and p-hydroxybenzoate overproduction plants to investigate the role of this modification in the response of plants to gravitropic/mechanical stress. They showed that lignin-bound p-hydroxybenzoate content increased during tension wood formation. This increase is correlated with a significant induction of expression of a gene encoding a BAHD family acyltransferase, namely, p-hydroxybenzoyl CoA: monolignol p-hydroxybenzoyltransferase 1 (PtrPHBMT1) whose gene product preferentially conjugates p-hydroxybenzoate to S-lignin monomer sinapyl alcohol.Lignin is a heterogeneous phenolic polymer that is highly abundant in the secondary cell walls of all land plants and is composed of three major monolignol subunits: 4-hydroxyphenyl (H), guaiacyl (G), and syringyl (S). The monolignol building blocks of lignin are synthesized by enzymes acting in concert that catalyze sequential reactions. Ferreira and Antunes (this volume) reviewed current progress on synthetic biology and highlighted the application of biosensors for re-engineering and autonomously controlling plant phenylpropanoid metabolism. Lam et al. (this volume) reviewed the understanding and bioengineering of the biosynthesis of tricin, a type of plant flavonoid that is an essential plant defense chemical and a promising nutraceutical. Sullivan et al. (this volume) established a de novo hydroxycinnamoyl-malate ester biosynthetic pathway in alfalfa via heterologous expression of a red clover gene and enhanced alfalfa post-harvest protein protection. A transcriptomic study of transgenic tomato plants by Zhao et al. (this volume) defined a GATA transcription factor mediating the co-regulation of drought stress response and phenylpropanoid biosynthesis. Genetic, biochemical and physiological studies from Lee et al. (this volume) found that Arabidopsis needs optimal anthocyanin content for better growth under high nitrate and high salt conditions. A study by Roldan et al. (this volume) using transgenic white clover with high levels of foliar condensed tannins discovered that condensed tannins bind to forage proteins to reduce anthropogenic greenhouse gas emission. Huber et al. (this volume) chemoenzymatically synthesized a series of new phenylpropanoid derivatives and studied their structures and biological effects. Using qualitative and quantitative phytochemical analyses, Gampe et al. (this volume) demonstrated that Ononis hairy root cultures produce isoflavonoids with less chemical divergence and in higher quantity, suggesting a promising system for large-scale isoflavonoid production.Plant phenylpropanoids and their derivatives are essential for plant growth, stress responses, and health benefits for humans. A comprehensive understanding of the biosynthetic mechanisms and transcriptional regulatory network(s) of phenylpropanoid metabolism in various plant species is central for developing biotechnological approaches to produce economically desirable traits and products. Additionally, advancements in synthetic biology and biosensor technology illuminate the potential of real-time control of phenylpropanoid metabolism in the future. Systems biology and biotechnology have largely contributed to enhance our understanding on the molecular mechanisms underlying the biosynthesis of phenylpropanoids in plants, as well as to manipulate the phenylpropanoid metabolism to exploit its economic, medicinal and nutraceutical potential. Articles in this volume further contribute to these goals, covering different aspects and branches of the pathway. Novel insights and exciting biotechnological strategies involving the phenylpropanoid pathway are expected in the years to come.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.IC is indebted to Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) for the Research Grant No. 2019/25587-0 and to Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) for the research fellowship 302927/2018-2. MX is supported by the U.S. Department of Energy, Office of Science, Office of Biological and Environmental Research, as part of the Quantitative Plant Science Initiative at Brookhaven National Laboratory. BU is supported by the Center for Bioenergy Innovation (CBI), a U.S. Department of Energy Bioenergy Research Center supported by the Office of Biological, Environmental Research in the DOE Office of Science.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.


The encapsulation of seeds in hard coats and fruit walls (pericarp layers) fulfils protective and dispersal functions in many plant families. In angiosperms, packaging structures possess a remarkable range of different morphologies and functionalities, as illustrated by thermo and hygro‐responsive seed pods and appendages, as well as mechanically strong and water‐impermeable shells. Key to these different functionalities are characteristic structural arrangements and chemical modifications of the underlying sclerenchymatous tissues. Although many ecological aspects of hard seed encapsulation have been well documented, a detailed understanding of the relationship between tissue structure and function only recently started to emerge, especially in the context of environmentally driven fruit opening and seed dispersal (responsive encapsulations) and the outstanding durability of some seed coats and indehiscent fruits (static encapsulations). In this review, we focus on the tissue properties of these two systems, with particular consideration of water interactions, mechanical resistance, and force generation. Common principles, as well as unique adaptations, are discussed in different plant species. Understanding how plants integrate a broad range of functions and properties for seed protection during storage and dispersal plays a central role for seed conservation, population dynamics, and plant‐based material developments. In fruits and seeds, tissue hardening is often a result of lignification, but hard secondary cell walls may also consist mainly of polysaccharides. A good example are the hard, nonlignified endosperm cell walls in many palm seeds – for example, date palm (Phoenix dactylifera) or the tagua nut (Phytelephas macrocarpa) – which serve simultaneously as storage and protective tissues  against physical, chemical, and biological damage Fig. . In hardBertholletia excelsa; Sonego et al., Ibicella lutea; Horbens et al., Hamamelis mollis; Poppinga et al., Based on their performance, we classify sclerenchymatous encapsulations as either static, meaning dimensionally stable and indehiscent , Proteaceae  and woody cones in the Pinaceae (e.g. Pinus spp.) and Cupressaceae (e.g. Sequoiadendron giganteum), which may all reduce seed loss or damage from granivores, desiccation, and fire  die and typically dry together with the embyro(s) inside. After this point, seed viability depends strongly on the hydration level. Therefore, a major function of many hard encapsulation tissues is to retain a low moisture content inside the seed. A low seed moisture content may increase the desiccation tolerance of the embryo and induces dormancy in a large number of species Werker, . In addiet al., et al., et al., et al., et al., et al., et al., et al., et al., In static encapsulations, waterproofing may only be beneficial until conditions are suitable for germination. As germination requires water uptake by the embryo (imbibition), all covering layers play a central regulatory role in this step Fig. . In addiet al.  represents a unique adaptation for epizoochorous dispersal via trample‐burrs. The tissue is entirely fibrous  for separation and are often simply realized by means of a locally reduced tissue and cell wall thickness, and/or lignification gaps . This i, et al. , known a, et al.  and dry  et al., . These p et al., , for exawns Fig.  that alset al., et al., Aethionema arabicum), which consequently show different modes of dispersal and different levels of physical dormancy , plants develop follicles (responsive systems) with different valve curvatures along a climatic gradient, which results in higher levels of serotiny and higher opening temperatures in drier regions , four genes related to the flavonoid metabolism and seven peroxidases and thio/peroxiredoxins have been associated with differential dormancy along an aridity gradient  have far‐reaching consequences for dispersal, protection, and germination. They may occur within the lifetime of an individual  and eastern black walnut (J. nigra). In both species, the seed is surrounded by an ellipsoidal hard shell and partly separated by a septum. However, the septum in J. regia is thin and mechanically insignificant, whereas in J. nigra it is extremely thick and reinforces the shell internally . Interestingly, they also occur in many species of the palm family (Arecaceae); for example, in the Borneo giant fan palm , the Bismarck palm (Bismarckia nobilis), and in Eugeissona palms (Eugeissona spp.) . Shell geometry is particularly important to resist shell cracking by granivores via compression loading, for example. Owing to a higher rigidity, small spherical shells are more advantageous than elongated shells of similar size and thickness (Huss et al., et al., et al., et al., et al., Hard encapsulations for seed protection and dispersal are morphologically extremely diverse. On a general basis, the functionality of packaging structures arises from characteristic modifications of the tissues surrounding the embryo. Despite large genetic and ecological differences, many encapsulations share rather common features, such as predetermined breaking points, employment of fibres for force generation, and the incorporation of flavonoids for long‐term storage and protection. However, many questions still remain open. In the context of cell shapes, for example, it is unclear why 3D puzzle sclereids are rather rare in static structures despite their high strength (Huss


Oxytocin is widely used for induction and augmentation of labour, particularly in low- and middle-income countries (LMICs). In this systematic review and meta-analysis, we examined the effect of intra-partum Oxytocin use on neonatal encephalopathy.The protocol for this study was registered with PROSPERO (ID: CRD42020165049). We searched Medline, Embase and Web of Science Core Collection databases for papers published between January 1970 and May 2021. We considered all studies involving term and near-term (≥36 weeks’ gestation) primigravidae and multiparous women. We included all randomised, quasi-randomised clinical trials, retrospective studies and non-randomised prospective studies reporting intra-partum Oxytocin administration for induction and/or augmentation of labour. Our primary outcome was neonatal encephalopathy. Risk of bias was assessed in non-randomised studies using the Risk Of Bias In Non-randomised Studies of Interventions (ROBINS-I) tool. The RoB 2.0 tool was used for randomised studies. A Mantel-Haenszel statistical method and random effects analysis model were used for meta-analysis. Odds ratios were used to determine effect measure and reported with 95% confidence intervals.p < 0.00001).We included data from seven studies  of which 3 took place in high-income countries (HICs) and 4 in LMICs. The pooled data included a total of 24,208 women giving birth at or after 36 weeks; 7642 had intra-partum Oxytocin for induction and/or augmentation of labour, and 16,566 did not receive intra-partum Oxytocin. Oxytocin use was associated with an increased prevalence of neonatal encephalopathy (Odds Ratio 2.19, 95% CI 1.58 to 3.04; Intra-partum Oxytocin may increase the risk of neonatal encephalopathy. Future clinical trials of uterotonics should include neonatal encephalopathy as a key outcome.The online version contains supplementary material available at 10.1186/s12884-021-04216-3. Clinical administration of exogenous Oxytocin is the most common way to induce and augment labour as it increases the frequency, duration and strength of uterine contractions . Recent Intra-partum Oxytocin administration has been shown to reduce the mean duration in labour in several clinical trials . This isImproper use and administration of high doses of Oxytocin has been found to precede perinatal sentinel events such as uterine rupture, cord prolapse or placental abruption as a result of uterine hyperstimulation, leading to fetal asphyxia . InapproThe protocol for this study was registered with PROSPERO (ID: CRD42020165049). Any amendment or modification to the original protocol during the course of the review was submitted to PROSPERO. The Cochrane handbook for systematic reviews of interventions was used to frame this review. One investigator (CB) searched the published literature between January 1970 to May 2021 on Medline (Ovid), Embase (Ovid) and Web of Science Core Collection  databases to access relevant studies. The years were limited to 1970 to reflect current clinical practice as much as possible to allow the translation of findings. We searched for the concepts (1) encephalopathy/HIE, (2) oxytocin/uterotonic, expanded with risk factors and intrapartum injections/treatment/intervention/management/surveillance to find papers not explicitly mentioning oxytocin and (3) newborn infants/newborn infant diseases and obstetric, using controlled terms (i.e. MeSH-terms in MEDLINE) and words in title and abstract. , quasi RCTs, non-randomised prospective cohort studies and retrospective studies reporting intrapartum use of Oxytocin.Primigravidae and multiparous women giving birth at or after 36 weeks’ gestation.Intra-partum Oxytocin for induction (continuous and discontinuous) and augmentation of labour through intravenous and intramuscular routes at all doses. We excluded studies where Oxytocin was used after the delivery of the baby for prevention of post-partum bleed.Women who did not receive Oxytocin or any other uterotonic drug during labour.Babies with signs of neonatal encephalopathy following Oxytocin administration during labour. Neonatal encephalopathy was defined as the need for prolonged resuscitation at 5 min of age and/or a 5-min Apgar score < 7  or lack of crying by 5 min of age for babies born at home.2 index. An I2 value of size 0–40% was considered a low, 30–60% as moderate, 50–90% as substantial and 75–100% as considerable heterogeneity according to the Cochrane Handbook [2 index. A Chi2 test was conducted to determine subgroup differences. Lastly, the overall effect was presented using a Z-test. All statistical analyses were performed on the RevMan V.5.1.4 software.Raw data was extracted from the selected studies on Excel spreadsheets by two independent investigators (CB/MM) and cross-checked by a third investigator (PM). Any disagreement during study selection or data extraction and analysis were resolved by consensus or by involving a senior reviewer when no consensus was reached. Risk of bias was assessed for each study by one investigator (CB) using the Risk Of Bias In Non-randomised Studies of Interventions (ROBINS-I) tool, which evaluates risk of bias in estimates of the effectiveness or safety (benefit or harm) of an intervention. The RoB 2.0 tool was used to assess the risk of bias of randomised studies. Grading of Recommendations, Assessment, Development and Evaluations (GRADE) was used to assess certainty in the body of evidence. A Mantel-Haenszel statistical method and random effects analysis model were used for meta-analysis. Odds ratios were used to determine effect measure and reported with 95% confidence intervals. Heterogeneity between studies was assessed to determine variability in the data using the IWe identified seven studies following full text screening, of which one had its data collected during a previous community-based cluster randomised controlled trial. These seven studies included neonatal encephalopathy as an outcome, of which 6 were case controls and 1 was a cluster randomised trial –17 , asphyxiated infants (Apgar score of < 6 at 1 min) with no sign of encephalopathy (n = 1 study) or term infants with a Thompson score < 3 (n = 1 study). Data from the remaining study compared women with no injections during labour and women with injections during labour. Three of the included studies were undertaken in HICs, 4 in LMIC settings and all reported Oxytocin use and the prevalence of neonatal encephalopathy in newborns (Supplementary Table Inclusion criteria for participants in selected studies were comparable: (1) a gestational age of at least 36 weeks with 2) a classification of the baby into mild, moderate or severe neonatal encephalopathy according to Sarnat scoring and (3) administration of Oxytocin for induction and/or augmentation of labour. Studies compared neonatal encephalopathy infants with term infants with no sign of encephalopathy at birth . The Committee defines neonatal encephalopathy as a clinically defined syndrome of disturbed neurological function within the first week of life in term infants , manifested by difficulty initiating and maintaining respiration, depression of tone and reflexes, subnormal level of consciousness, and often, seizures. Upon further reading, we established that the PMMRC defines moderate and severe neonatal encephalopathy as Sarnat stages 2 and 3 [Two of the studies, however, did not use Sarnat scoring to determine neonatal encephalopathy severityis et al  assessednn et al  employedny et al  considerFarquhar  et al de 2 and 3 .Risk of bias was evaluated for 6 studies using the ROBINS-I tool, which is used in observational studies comparing health effects of interventions. The RoB 2.0 tool was used to assess for of bias of the cluster-randomised study. Selected studies ranged from low to severe risk of bias due to confounding domain and co-interventions, as these were not assessing specifically the effect of Oxytocin on neonatal outcomes  [Ellis et al, Futrakul et al, Mullany et al, Tann et al) [Farquhar et al [, Hayes et al [Milsom et al [, Ellis et al [, Futrakul et al [, Mullany et al [Tann et al [Pooled data from HIC studies  –13 revean et al) –17 reporar et al , Hayes ees et al  and Milsis et al , Futrakuul et al , Mullanyny et al  and Tannp = 0.02). Furthermore, the subtotal difference in the onset of neonatal encephalopathy between the Oxytocin  and the Oxytocin-free  groups was significantly different in studies from LMICs . The overall effect combining results from both HICs and LMICs demonstrates a significant difference between the Oxytocin  and Oxytocin-free group  in the onset of neonatal encephalopathy . Subgroup differences analysis (I2) revealed that 72.2% of the variability in effect estimates from both groups is due to subgroup differences rather than sampling error  was available for 158 infants in the Oxytocin group and 175 infants in the Oxytocin-free group in high-income settings. Pooled data from HIC studies showed a significant difference in the subtotal for the onset of neonatal encephalopathy between the Oxytocin  and Oxytocin-free 175/600; 29%) groups . The heterogeneity amongst subgroups was of 44% for HIC studies and 51% for LMIC studies.The included studies had an overall substantial heterogeneity  and LMICs  that included intra-partum Oxytocin use in mothers of term infants with neonatal encephalopathy. Our main finding was an association between Oxytocin use and the onset of neonatal encephalopathy, which was significantly higher in term babies of women induced/augmented with Oxytocin compared to Oxytocin-free women . Moreover, this was found to be even higher in LMICs  compared to HICs . A higher percentage of heterogeneity across LMIC studies may be linked to variability in social environment as well as settings where studies were taking place such as home births in rural areas of southern Nepal [We assessed a total of seven studies from HICs  summary. Supplementary Table 4. Risk of bias for Mullany et al., 2013 (RoB 2.0). Supplementary Table 5. Summary of Findings table (GRADE).


Fueled by advances in computing power, algorithms, and big data, the last decade has witnessed widespread applications of artificial intelligence (AI) in every major field, including medicine and healthcare. Generally speaking, AI is expected to help realize the promise of precision medicine in three major areas: (1) disease prevention, (2) personalized diagnosis, and (3) personalized treatment. In this Research Topic, “Artificial Intelligence for Precision Medicine,” we aim to set up an open stage in the community where breakthrough application examples of AI for precision medicine are presented. We envisage that AI technologies, if applied openly, fairly, robustly, and in close collaboration with human intelligence, will open new doors for effective and personalized healthcare worldwide.Hart et al.- AI-aided diagnosis and early detection of diseases: Chen et al.; Jensen et al.; Mistro et al.; Wang et al.- AI-enhanced treatment and delivery: Barua et al.- Clinical decision support with AI techniques: Luo- Enhancing patient care via AI applications: Zhang et al.- Radiomics and quantitative imaging: Kapelner et al.; Namdar et al.- Bioinformatics for more effective healthcare: Chan et al.- Innovative AI applications for patient safety: Hart et al. developed seven machine learning algorithms based solely on personal health data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), and compared them with 15 practicing physicians in stratifying endometrial cancer risk for 100 women. The results indicate that their random forest model achieves a testing AUC of 0.96, 2.5 times better at identifying above-average risk women with a 2-fold reduction in the false-positive rate. A novel concept named “Statistical Biopsy” was proposed for the first time.In their work, Chen et al. reported their development of a deep-learning convolutional neural network (DCNN) for enhanced organ-at-risk (OAR) segmentation on cone beam computed tomography (CBCT), trained with forty post-operative head and neck cancer patients. The developed DCNN improved CBCT in terms of Hounsfield unit (HU) accuracy, image contrast, and OAR delineation accuracy.Jensen et al. demonstrated that their novel machine learning model can be used to quickly estimate the Pareto set of feasible dose objectives in cancer radiotherapy, which may directly accelerate the treatment planning process and indirectly improve final plan quality by allowing more time for plan refinement. Their model outperforms the existing machine learning techniques by utilizing optimization priorities and output initialization.Using a cohort of 100 prostate cancer patients, Mistro et al. have demonstrated that knowledge models can be effectively used as teaching aid to bring inexperienced planners to a level close to experienced planners in fewer than 2 days. The proposed tutoring system can serve as an essential component in an AI ecosystem that will enable clinical practitioners to use knowledge-based planning effectively and confidently for personalized radiation treatment.As a first attempt, Wang et al. have demonstrated a novel deep learning framework for pancreas stereotactic body radiation therapy (SBRT) planning, which can predict a fluence map for each beam, hence bypassing the lengthy inverse optimization process.Based on 85 training cases and 15 test cases, Barua et al. demonstrated that a Multivariate Functional Principal Component Analysis (MFPCA) approach can be used to characterize the temporal trajectories of mandibular subvolumes receiving radiation. Their work suggests that temporal trajectories of radiomics features derived from sequential pre- and post-RT CT scans correlate with radiotherapy-induced mandibular injury, which may be used to aid in earlier management of osteoradionecrosis, a major side-effect in radiation therapy of oropharyngeal cancer patients.In their work, Luo summarized three major approaches currently employed in predicting cervical cancer outcomes: statistical models, medical images, and machine learning, and discussed some of the challenges in making clinical outcome prediction more accurate, reliable, and practical.In a mini-review, Zhang et al. proposed a transfer learning-based prognostication model for overall survival in pancreatic ductal adenocarcinoma patients. The model achieved the area under the receiver operating characteristic curve (AUC) of 0.81, significantly higher than that of the traditional radiomics model of 0.54. Their result suggests that transfer learning-based models may significantly improve prognostic performance in typical small sample size medical imaging studies.Kapelner et al. introduced and discussed a novel R package called “Personalized Treatment Evaluator (PTE)” developed by them. They combined randomized comparative/controlled trial (RCT) data with a statistical model of the response to estimate outcomes under different treatment allocation protocols. Their PTE package can be used to evaluate personalization models in medicine as well as fields outside of medicine.To evaluate the overall effectiveness of personalized medicine, Namdar et al. presented first a comprehensive review of AUC metric, and then proposed a modified version of AUC that takes confidence of the model into account and incorporated AUC into Binary Cross Entropy (BCE) loss function. They demonstrated the validity of the new concept on MNIST, prostate MRI, and brain MRI datasets.In their paper, Chan et al. discussed and summarized the various applications of machine learning approaches in machine-specific and patient-specific quality assurance (QA), a key component in safeguarding patient safety during the radiation treatment of cancer patients.In a review paper, Precision medicine is an evolving healthcare approach focused on tailoring medical decisions, treatments, practices, and products to individual patients based on their genetic, environmental, lifestyle, and other factors. In this Research Topic, eleven teams reported promising results from their experience in applying AI for precision medicine. Moving forward, we anticipate that more work needs to be done to eliminate biases in the AI models and make these models interpretable, therefore ultimately achieving the promise of precision medicine, i.e., delivering the right treatment to the right patient at the right time.JD drafted the editorial. JD, TH, EC, JC, and FE-S revised and approved the final version. All authors contributed to the article and approved the submitted version.Research reported in this publication was supported by the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health under Award Number R01EB022589, by the National Science Foundation under Award Number DMS 1918925, by the National Cancer Institute under Award Number 21X130F, and by the Department of Energy under Award Number DE-SC0021655 to JD. EC was supported by the grant NSF 19-500 under Award Number DMS 1918925 and 1922843 in years 2019-2022.The content is solely the responsibility of the authors and does not necessarily represent the official views of those institutions.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.


A study of natively iodinated bovine thyroglobulin demonstrates that structural details of biologically important chemical reactions can now be visualized by electron cryo-microscopy. Its circulation regulates metabolism and many other fundamental processes, including neuronal tissue growth (Caravalho & Dupuy, 2017Acta Cryst. D (Kim et al., 2021et al., 1989et al., 2020in vivo conditions and those made available under the in vitro conditions of iodination assays (Coscia et al., 2020et al. did not observe the presence of mono-iodinated tyrosine residues in the bovine TG structure. Similarly, biochemical assays performed by Coscia et al. did not reveal the presence of T3, the active form of thyroxine hormone. Hence, direct synthesis of T3 still needs to be demonstrated. The bovine TG structure exposes another interesting issue potentially related to the regulation of the redox potential of thyroid follicles. TG structures contain numerous cysteine residues, many of which are present in the cysteine-rich thyroglobulin type domains. In the human TG structure, all cysteine residues are linked by disulfide bonds. Due to the limiting resolution of density maps, this conclusion was often only supported by their proximity. In contrast, the bovine TG structure contains cysteine residues not involved in disulfide bridges despite their proximity, as described by Kim et al.In the cryo-EM structure of bovine TG from natural sources presented in this issue of et al., 1985et al., 1999et al., 1996et al., 2020et al. stated, the bovine TG material at first also appeared unstable on the grids. They hypothesized that the instability was caused by the interactions at the solvent–air interface and that a small addition of detergent already successfully applied in other studies (Noble et al., 2018et al., 2019et al. is a triumph of sample preparation and the maturation of electron cryo-microscopy. The structure demonstrates that structural details of biologically important chemical reactions can now be visualized by electron cryo-microscopy.Although TG has been extensively studied, its three-dimensional structure could not be determined for decades. Isolation of purified TG (Heidelberger & Palmer, 1933


Inspired by how the human brain works, neurocomputing algorithms, including deep learning, reinforcement learning, and neurodynamic optimization, have achieved tremendous success in various applications across many domains, e.g., visual object tracking, speech recognition, human-level control, text understanding, and real-time optimization.Various types of intelligent equipment and hardware devices have been developed to implement neurocomputing models for engineering systems. Deep learning has been employed for industrial robotic applications, including stereo reconstruction, object pose recognition, and product quality check. With the advent of the Internet of Things and edge computing devices, deep reinforcement learning has become popular in the predictive maintenance of engineering equipment. Embedded convolutional neural networks are widely utilized for autonomous vehicle control. The success of applying neurocomputing approaches and related hardware implementations in different engineering domains, such as intelligent manufacturing, energy internet, and smart healthcare, has proven the potential of employing neurocomputing for solving real problems in various engineering fields.In recent years advances in sensor and data storage technologies have enabled the accumulation of a large amount of data from engineering systems. Driven by big data generated from engineering systems, neurocomputing, and its hardware implementation will continually transform engineering systems into more intelligent forms.This Research Topic aims to provide a forum for researchers to present the latest research on applications of neurocomputing algorithms and neurocomputing-based hardware in engineering systems. It brings together 14 high quality papers reporting on the latest applications of neurocomputing in transportation, manufacturing, biomedical engineering, electrical engineering, and knowledge management.Self-Triggered Consensus of Vehicle Platoon System With Time-Varying Topology,” Wang et al. designed a secure event-triggered controller considering the safe distance for the vehicle platoon system. Based on the new event-triggered function, a more energy efficient self-triggered control strategy was developed by using the Taylor formula. The new self-triggered control strategy could avoid continuous calculation and measurement of vehicles.In the paper entitled “Industrial Control Malicious Traffic Anomaly Detection System Based on Deep Autoencoder” by Wang et al. proposes a method of detecting abnormal traffic in industrial control networks based on autoencoder technology. The Kullback–Leibler divergence was added to the loss function of the proposed model to improve the ability of feature extraction and the ability to recover raw data. The gas pipeline dataset was used to verify the performance of the proposed method.The paper on “Data-Driven Hybrid Equivalent Dynamic Modeling of Multiple Photovoltaic Power Stations Based on Ensemble Gated Recurrent Unit” Long et al. report on a data-driven hybrid equivalent model for the dynamic response process of the multiple PV power stations. The data-driven hybrid equivalent model contained the simple equivalent model and data-driven error correction model. The simulation results validated the super-performance of the proposed model both in response speed and accuracy.In a contribution on “Sun et al. contribute a paper on “AutoPath: Image-Specific Inference for 3D Segmentation,” which introduces AutoPath, an image-specific inference approach for more efficient 3D segmentations. The proposed AutoPath dynamically selected enabled residual blocks regarding different input images during inference, thus effectively reducing total computation without degrading segmentation performance. Experimental results on a liver CT dataset showed that the proposed approach not only provided an efficient inference procedure but also attained satisfactory segmentation performance.Boosting Knowledge Base Automatically via Few-Shot Relation Classification” by Pang et al. investigated a fully automatic method to train a relation classification model which facilitates to boost the knowledge base. In the proposed method, various multiple instance learning methods were incorporated into the classic prototypical networks, reducing sentence-level noises.A paper on “Gu et al.'s article “Investigating the Impact of the Missing Significant Objects in Scene Recognition Using Multivariate Pattern Analysis” adopted multivariate pattern analysis to explore the object-scene association in scene recognition when different amounts of significant objects were masked. The analysis results suggested that the lateral occipital complex was sensitive to the loss of significant objects and mainly involved in scene recognition by the object-scene semantic association.Machine Learning Models to Predict Primary Sites of Metastatic Cervical Carcinoma From Unknown Primary,” Lu et al. conducted a series of bioinformatics analyses based on a dataset from The Cancer Genome Atlas (TCGA) RNA-Seq data of squamous cancer and TCGA Pan-Cancer data. Three machine learning models, random forest, neural networks, and support vector machine, were developed to explore potentially effective tools to distinguish these squamous cancers.In the paper “A Manufacturing-Oriented Intelligent Vision System Based on Deep Neural Network for Object Recognition and 6D Pose Estimation” Liang et al. present a new two-stage intelligent vision system based on a deep neural network with RGB-D image inputs for object recognition and 6D pose estimation. A dense-connected network fusing multi-scale features was first built to segment the objects from the background. The 2D pixels and 3D points in cropped object regions were then fed into a pose estimation network to make object pose predictions based on the fusion of color and geometry features.In their contribution examining “Artificial Intelligence-Based Application to Explore Inhibitors of Neurodegenerative Diseases” by Deng et al. explores an integrated new approach for finding lead compounds that inhibit galectin-3, by combining universal artificial intelligence algorithms with traditional drug screening methods. Manifold artificial intelligence algorithms were performed to validate the docking results and further screen compounds.The paper titled “Energy Investment Risk Assessment for Nations Via Seq2seq Model” Liang et al. propose a sequence to sequence model to evaluate the energy investment risk of 50 countries. Bi-long-short term memory was used as an encoder to process the historical statistics in the proposed method.In their “A Relational Adaptive Neural Model for Joint Entity and Relation Extraction” by Duan et al. describes a relational-adaptive entity relation joint extraction model based on multi-head self-attention and densely connected graph convolution network. In the model, the multi-head attention mechanism was specifically used to assign weights to multiple relation types among entities to ensure that the probability space of multiple relations was not mutually exclusive.The paper on “Classification of Metastatic and Non-Metastatic Thoracic Lymph Nodes in Lung Cancer Patients Based on Dielectric Properties Using Adaptive Probabilistic Neural Networks” by Lu et al. proposes a classifier to identify metastatic and non-metastatic thoracic lymph nodes in lung cancer patients based on dielectric properties. Compared with the other methods, the proposed classifier achieved a higher classification accuracy based on dielectric property data collected from lung cancer patients.An article on the “Xiang et al.'s contribution on the “Prediction of Dangerous Driving Behavior Based on Vehicle Motion State and Passenger Feeling Using Cloud Model and Elman Neural Network” presentes a new method for dangerous driving behavior prediction using a hybrid model consisting of cloud model and Elman neural network based on vehicle motion state estimation and passenger's subjective feeling scores.A New Way of Airline Traffic Prediction Based on GCN-LSTM” by Yu employed graph convolutional neural network and long short memory network to construct an airline traffic prediction system with short-term prediction ability.The paper titled “These successful applications of neurocomputing in various domains demonstrate the significant potential of applying neurocomputing approaches to solving complex engineering problems. With the help of big data and increasing computing power, neurocomputing will play a vital role in future engineering systems.LW wrote the manuscript. ZZ, ZS, and CH edited the manuscript. All authors contributed to the article and approved the submitted version.This work was supported in part by the National Natural Science Foundation of China under Grant 62002016, in part by the Guangdong Basic and Applied Basic Research Foundation under Grants 2020A1515110431 and 2019A1515111165, and in part by the Fundamental Research Funds for the Central Universities and the Youth Teacher International Exchange & Growth Program under Grant QNXM20210037.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.


The 2021 Nobel Prize in Physiology or Medicine honors the discoveries of the temperature or mechanically activated channels, whose structural studies provided insights of channel gating at atomic level. Using capsaicin, a natural pungent agent that induces pain in our skin similar to that induced by heat, David Julius identified the TRPV1 ion channel as a heat-activated nociceptor in the peripheral nervous terminus  Unexpectedly, the atomic structures of these channels were all determined by single-particle cryo-electron microscopy (cryo-EM), a structure determination technique that does not require crystallization but, instead, images individual biological molecules embedded in a thin layer of vitreous ice using an electron microscope followed by extensive computational image analysis (Cheng, 2018et al., 2013et al., 2013et al., 2016Interestingly, progress in structural studies of TRPV1 and the technological developments and advancements of single-particle cryo-EM were tightly entwined. With the methodological breakthroughs in single-particle cryo-EM, the first structure of TRPV1 was determined in 2013 (Cao etc. These exogenous stimuli generate pain that serve as a warning signal for avoidance. TRPV1 activation can also be modulated by endogenous stimuli, such as extracellular protons generated by tissue acidosis associated with inflammation. Potentiation of TRPV1 by extracellular protons causes heat hypersensitivity. Without the restriction of crystallization, single-particle cryo-EM not only enabled atomic structure determination of TRPV1 (see Fig. 1et al., 2013et al., 2016et al., 2021As a polymodal signal detector, TRPV1 can be activated by exogenous stimuli, such as heat, capsaicin, plant toxins and peptide toxins from spider et al., 2015et al., 2019et al., 2018As for Piezo1/2, soon after its initial discovery, structural biology had entered this new era of single-particle cryo-EM. As such, structural studies of Piezo channels were carried out exclusively using this method and comprehensive structural studies have progressed rather rapidly (Ge The major goals of structural biology go beyond knowing the atomic structures of these channels and what they look like, but address the harder questions of how they work to generate physiological responses. In this regard, there are still many unanswered questions concerning these channels. Among them, the mechanisms of temperature activation, such as TRPV1 by heat or TRPM8 by cold, and the mechanism of mechanosensing by Piezos, remain among the most pressing unanswered questions. Recognition of the Nobel Prize not only honors the seminal discoveries of these channels, but also stimulates excitement among structural biologists to continue pursuing these burning questions.


Sci., 2020, DOI: 10.1039/d0sc04044d.Correction for ‘Direct synthesis of the organic and Ge free Al containing BOG zeolite (ITQ-47) and its application for transformation of biomass derived molecules’ by Qintong Huang  In the original manuscript, the affiliations of authors Anmin Zheng and Avelino Corma were displayed incorrectly. The corrected affiliations are as displayed above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.


Alzheimer's disease (AD) is a complex neurodegenerative disease, affecting a significant part of the population. The majority of AD cases occur in the elderly with a typical age of onset of the disease above 65 years. AD presents a major burden for the healthcare system and since population is rapidly aging, the burden of the disease will increase in the future. However, no effective drug treatment for a full-blown disease has been developed to date. The genetic background of AD is extensively studied; numerous genome-wide association studies (GWAS) identified significant genes associated with increased risk of AD development. This review summarizes more than 100 risk loci. Many of them may serve as biomarkers of AD progression, even in the preclinical stage of the disease. Furthermore, we used GWAS data to identify key pathways of AD pathogenesis: cellular processes, metabolic processes, biological regulation, localization, transport, regulation of cellular processes, and neurological system processes. Gene clustering into molecular pathways can provide background for identification of novel molecular targets and may support the development of tailored and personalized treatment of AD. Alzheimer's disease (AD) is a progressive neurodegenerative disorder, affecting the cerebral cortex and hippocampus in human brain , presenilin-1 (PSEN1), and presenilin-2 (PSEN2) are associated with early-onset AD (EOAD), developing in fourth or fifth decade of life  can be observed already 15–20 years prior to the onset of the clinical symptoms  and meta-analyses combining multiple GWAS dataset (n = 21) in AD risk evaluation were included (n = 16) were analyzed separately (n = 13) combined identified genotype alterations in GWAS and meta-analyses with changes in AD-related biomarkers  enrichment analysis was performed, using Cytoscape plug-in ClueGO . This toIn our dataset of genes related to AD risk, we observed significant enrichment for four major GO biological process categories: cellular process, metabolic process, biological regulation, and localization .APP, PSEN1, and PSEN2 genes result in overproduction of the hydrophobic Aβ40 and Aβ42 peptides, leading to aggregation and formation of insoluble plaques  family that includes PS1 and PS2  have increased risk for early development of memory impairment  E4 allele (APOE4), which is associated with more extensive Aβ deposition is considered a major risk factor for LOAD  and rs7412 (p.Arg158Cys) define polymorphic alleles APOE2, APOE3, and APOE4 that encode three respective protein variants: apoE2 , apoE3 , and apoE4  , followed by APOE4 (5–35%) and APOE2 allele (1–5%)  gene were associated with AD. PICALM rs3851179 was associated with decreased AD risk  rs744373 SNP was associated with risk for LOAD  was associated with AD  family  were linked to AD. Rs11136000 was associated with decreased risk for AD  or increased (rs9331888) risk for AD  were associated with AD and type 2 diabetes (T2D), indicating potential shared molecular pathways between the diseases /proton (H+) exchanger in the Golgi, important in maintenance of homeostasis  cluster encodes a family of cell surface proteins that participate in the regulation of calcium signaling  and was shown to considerably increase AD risk , important for tau phosphorylation and NFT formation in CNS . Rs1466662 within this DCHS2 was associated with AD  is a gene, encoding for poliovirus receptor 2, immunoglobulin expressed in neuronal cell tissues, that is important in T-cell activation  were identified as novel AD related risk alleles  forms one of the primary pores via which proteins can readily enter the mitochondria. The TOMM40 gene is the only gene identified in genetic studies to date that presumably contributes to LOAD-related mitochondria dysfunction   locus, contributing to the diverse and specific Ig forming in the adaptive immunity  and blood plasma biomarker levels can predict neurodegenerative changes in AD progression and memory decline and are often used in clinical diagnostics. Except for their diagnostic potential, biomarkers can be applied in studies of AD molecular mechanisms and could be used to monitor the biochemical effects of potential disease intervention  linked to molecular pathways identified in this review  were associated with CSF Aβ and tau levels , important mediator of immune system, were associated with CSF Aβ and tau levels , were associated with LOAD protein expression in CSF [271]. Furthermore, association of rs2228145 with CSF and serum IL6R levels revealed the effect on age of onset in AD [171]. GLIS3 rs514716 association with CSF Aβ and tau levels was observed  were associated with CSF levels of ACE gene product  and APOE-containing lipoproteins  that were associated with CSF Aβ levels in AD subjects  gene, is important enhancer of immune response  encodes ATIP3, inhibitor of extracellular signal-regulated kinase 2 (ERK2) and cell proliferation. Similarly, rs3092960 within CCR2 encoding for CCL2 receptor was also associated with significant levels of CCR2 protein in CSF  were associated with CCRL2 protein expression in CSF as well  were associated with biomarker levels, with rs573521 being the best predictor of MMP3 protein expression in CSF in LOAD  as a novel AD-related locus (Zhong et al., BCAM was associated with CSF levels of phosphorylated tau181 and Aβ42 (Huang et al., BCAM is a gene encoding Lutheran blood group glycoprotein, an immunoglobulin important in laminin recognition (Parsons et al., ARHGAP24 rs111882035 was associated with memory tests outcomes in MCI individuals (Chung et al., ARHGAP24 is important in actin cytoskeleton remodeling and specifically suppresses Rac1 and Cdc42 activity (Lavelin and Geiger, Although not enriched in GO analysis, many other genes were manually annotated cellular processes and are also summarized in Genes and key SNPs, involved in biological regulation, associated with biomarkers in GWAS and their meta-analyses, are summarized in CD1A polymorphisms: rs16840041, rs2269714, and rs2269715 were associated with increased plasma neurofilament light level, a potential protein biomarker for AD (Wang et al., Three ATP6V1H rs1481950 was associated with higher CSF BACE activity (Hu et al., Additionally, one biomarker associated gene was manually annotated to biological regulation . A polymGenes and key SNPs, involved in localization, associated with biomarkers in GWAS and their meta-analyses, are summarized in GRIN2B rs10845840 was reported as a risk loci for AD, associated with temporal lobe atrophy (Stein et al., GRIN2B encodes the NR2B subunit of NMDA receptor that mediates a Ca2+ dependent synaptic transmission in the CNS (Hu et al., MAPT rs242557 was associated with plasma tau levels (Chen et al., MAPT encodes for tau, the prominent component of NFTs. H2 haplotype is associated with MAPT expression and LOAD risk (Allen et al., BCHE rs509208 with PET imaging of cortical Aβ in AD subjects was revealed (Ramanan et al., Genes and key SNPs, involved in neurological system process, GO term specific for biomarker gene set, are summarized in Among all AD related biomarker loci, obtained from GWAS and meta-analyses that were not enriched in GO analysis, additional 18 were manually annotated.The remaining seven genes could not be associated with any of the seven main enriched pathways, even though they were linked biomarker changes in AD GWAS and meta-analysis. Although some of them were linked to a specific function in the literature, they have not been annotated with any of the GO terms. Genes and key SNPs with no known function associated with AD biomarkers in GWAS and meta-analyses are summarized in CCDC134 rs7364180 was associated with CSF Aβ levels in AD subjects (Kim et al., CCDC134 is a proliferation promoting molecule, driving cytokine-like activation of CD8+ T-cells (Huang et al., ECRG4 rs34487851 was observed (Chung et al., ECRG4 encodes a peptide hormone that is involved in NFT formation, age-related senescence of precursor cells in the CNS and activation of microglia and peripheral mononuclear leukocytes (Kujuro et al., FRA10AC1 as a novel risk locus (Li et al., FRA10AC1 gene are potential cause of folate-sensitive fragile site FRA10A expression (Sarafidou et al., LUZP2 was also proposed as a novel AD risk locus as rs7943454 was associated with higher plasma neurofilament light levels (Li et al., LUZP2 gene (Stepanov et al., ZNF804B, is not known yet, a ZNF804B rs73705514 was associated with memory tests outcomes in MCI individuals (Chung et al., Alzheimer's disease is the most prevalent neurodegenerative disorder worldwide. A lot of research focuses on the identification of genetic factors that may contribute to the development and progression of the disease. Numerous GWASs and meta-analyses reported different genetic factors associated with AD risk or biomarker levels. A cumulative effect of small but significant contributions of numerous genetic factors can at least in part elucidate the LOAD progression. The pathogenic processes in AD may be influenced on a personalized basis by a combination of variants in key genes and pathways. Apart from serving as a hallmark of the disease, polymorphisms in various genes might help in early diagnostics and prediction of disease progression. Integration of genetic factors and biomarker status may increase the predictive value of diagnostic or prognostic models.Through the GO analysis we compiled a list of the most enriched pathways, associated with AD pathology. Among four GO parental categories in AD risk gene set, immune response, APP metabolism, cholesterol metabolism, endocytosis and biological regulation on different levels can be exposed as important AD related biological processes. Furthermore, enrichment analysis on smaller AD biomarker gene set pinpointed three additional parental categories. Besides neurodegeneration, numerous research evidence link AD with neuroinflammation, lipid metabolism as well as receptor mediated endocytosis, supporting scientific background of our analysis. Several identified genes were associated with more than one biologic process, represented in various GO categories. The intersection of different biological processes creates a complex interconnected network, suggesting multi-pathway approach in AD genetic background evaluation is needed. Additionally, manual annotation of genes that were not associated with the most significant pathways in GO analysis, could help to elucidate their function in AD pathogenesis.This comprehensive summary of genetic variants identified by GWAS studies and their meta-analyses can also provide background for identification of novel molecular targets, and the results may be important for development of personalized medicine. However, GWAS and meta-analyses cannot explain the molecular mechanisms of the contribution of a novel susceptibility locus to the overall genetic risk. Therefore, our compiled and annotated results may serve as a basis for the functional studies of pathophysiological mechanisms of risk genes, identified on a genome-wide scale. Furthermore, better characterization of risk genes functions could enable the stratification of AD patients according to the main molecular mechanisms of pathogenesis, supporting development of tailored and personalized treatment of the disease.The original contributions presented in the study are included in the article/DV performed literature search and gene enrichment analysis. DV, KG, and VD participated in writing and editing of manuscript. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The development of bioactive biomaterials is an important component in the general field of tissue engineering, specifically for the success of tissue repair and regeneration approaches . BioactiEngineered bioactive materials involve conventional biomaterials, such as bioactive glasses and ceramics, as well as biopolymers based on proteins. Polysaccharides and biomoleculecontaining biomaterials . In receSprio et al. reviewed the application of biomorphic transformations to obtain nanostructured 3-D bioceramics. Yanmei Tang et al. reviewed the advances of polydopamine nanoparticles in tissue engineering applications, including the repair of bone, cartilage, skin, heart, and nerve. Fujian Zhao et al. reported tantalum-gelatin methacryloyl-bioactive glass (Ta-GelMA-BG) scaffolds which could enhance osteointegration at the early stage of implantation. Haiping Lu et al. developed Ag and MSCs-derived exosomes-contained PCL scaffold for regulating immune cells and MSCs proliferation and differentiation. Haiping Lu et al. introduced the broad application of β-TCP in tissue engineering and discussed different approaches to enhance and customize β-TCP scaffolds, including physical modification.This Research Topic is the second part on the “Multifunctional Bioactive Nanomaterials for Tissue Regeneration” series, which includes several papers demonstrating the main advances of multifunctional nanomaterials in tissue engineering. In this topic, Multifunctional Bioactive Nanomaterials for Tissue Regeneration Part 2” will contribute to inspire future developments of advanced bioactive nanomaterials for regenerative medicine to close the gap between research and clinical applications.The editors hope that the current topic “


In last few decades, organic materials  including polymers have received much attention for their potential applications in electronics, because they have outstanding advantages such as high processibility, mechanical flexibility, and low weight. Extensive research efforts have thus been devoted to the development and advancement of organic materials for various applications, covering a wide range from molecular design to device-fabrication methods. In addition, it has been recognized that surfaces and interfaces play a crucial role in the operation and performance of the devices. For instance, various interactions at organic–metal interfaces are of great importance in organic epitaxy, and also have a strong correlation with intermolecular structures and their electronic properties.In this context, the main focus of this Special Issue was collecting scientific contributions addressing surface and interface engineering with organic materials, and related applications. The diversity of contributions presented in this Special Issue exhibits the potential of organic materials in a variety of applications that are not limited to the fabrication of organic devices. This Special Issue contains eight featured original research papers as regards nanoarchitecture based on organic elements , physicaIn the contributed article entitled “Investigation on the Adsorption-Interaction Mechanism of Pb(II) at Surface of Silk Fibroin Protein-Derived Hybrid Nanoflower Adsorbent” , Xiang LByung Soo Hwang et al. provided an outlook for the development of stimuli-responsive functional materials through their study of gelation behaviors of hydrogels in the contributed article entitled “Thermogelling Behaviors of Aqueous Poly(N-Isopropylacrylamide-co-2-Hydroxyethyl Methacrylate) Microgel–Silica Nano-particle Composite Dispersions” [Peng Xiao et al. presented a facile method for the fabrication of liquid metal electrodes using polydimethylsiloxane, and also demonstrated solar-blind photodetection via surface exfoliation in a series of contributed articles entitled “Fabrication of a Flexible Photodetector Based on a Liquid Eutectic Gallium Indium” , and “FlIn the contributed article entitled “Crack-Assisted Charge Injection into Solvent-Free Liquid Organic Semiconductors via Local Electric Field Enhancement” , Ju-HyunIn the contributed article entitled “Cesium Doping for Performance Improvement of Lead(II)-acetate-Based Perovskite Solar Cells” , Min-SeoHyeok Jo Jeong et al. reported the sigmoidal concentration dependence of electrical conductivity of poly:poly(styrene sulfonate) processed with linear glycol-based additives in the contributed article entitled “Sigmoidal Dependence of Electrical Conductivity of Thin PEDOT:PSS Films on Concentration of Linear Glycols as a Processing Additive” . It was In the contributed article entitled “The Methods and Experiments of Shape Measurement for Off-Axis Conic Aspheric Surface” , Shijie Materials. I am personally grateful to Ms. Freda Zhang, Managing Editor of this Special Issue.In conclusion, the contributed articles in this Special Issue demonstrate relevant progress and the potential of organic materials in a variety of applications. I wish to thank and acknowledge all the authors for their priceless contributions and the editorial members of


The bladder exstrophy–epispadias complex (BEEC) is an abdominal midline malformation comprising a spectrum of congenital genitourinary abnormalities of the abdominal wall, pelvis, urinary tract, genitalia, anus, and spine. The vast majority of BEEC cases are classified as non-syndromic and the etiology of this malformation is still unknown. This review presents the current knowledge on this multifactorial disorder, including phenotypic and anatomical characterization, epidemiology, proposed developmental mechanisms, existing animal models, and implicated genetic and environmental components. Congenital anomalies of the lower urinary tract (CALUT) are a group of birth defects of the ureter, bladder, and urethra, which includes bladder exstrophy–epispadias complex . BEEC is an abdominal midline malformation comprising a spectrum of congenital genitourinary abnormalities of the abdominal wall, pelvis, urinary tract, genitalia, anus, and spine . The sevEpispadias is rare, with incidences of one in 101,000 live births in males and one in 1,300,000 in females ,8. CBE hEpispadias is generally diagnosed at birth, although its presentation is dependent on severity and sex. It consists of a dorsal located ectopic urethral meatus as a result of non-closure of the urethral plate during embryological development . In bothCBE presents as a protrusion of the urinary bladder through a defect on the infraumbilical abdomen, in association with a diastasis of the pubic symphysis with distally divergent rectus abdominis muscles A 3]. Pu. Pu3]. PCE is a major birth defect in which the bladder is widely open on the infraumbilical abdominal wall and is separated into two distinct halves. It is often associated with omphalocele, separated pubic bones, short-gut syndrome, and other malformations, including talipes and spina bifida B 1,11].,11.1,11]The vast majority of BEEC cases are non-syndromic, however, a number of cases have been reported whereby BEEC has also been associated with various other syndromes, malformations, and congenital diseases . There aThe majority of individuals affected by BEEC have no positive family history of BEEC. However, even though familial occurrence is rare, 30 multiplex families have been described ,19,20,21n = 28) and triplets (n = 2), including monozygotic (n = 20), dizygotic (n = 3), trizygotic (n = 2), and unknown zygosity (n = 5). Of the CE anomalies within the 20 monozygotic twins, 9 were concordant and 11 were discordant. The higher incidence of CE in monozygotic twins compared to dizygotic twins could suggest a possible genetic contribution to the occurrence of these anomalies. Fullerton et al., 2017 [Reutter et al., 2007  reportedl., 2017  reportedThere is an extensive history of successful disease gene discovery made through the characterization of individuals with chromosomal abnormalities. These chromosomal changes provided a shortcut to identify relevant chromosomal loci for positional cloning approaches before next generation sequencing techniques transformed disease gene discovery over the past decade. Translocations disrupting disease-associated genes and deletions harboring the causative gene led to some of the earliest disease gene identifications in the last century.Cytogenetic analyses have identified a number of chromosomal anomalies in individuals with BEEC, summarized in Multiple autosomal chromosome anomalies have been reported in association with BEEC. Zaki et al., 2012  identifiBoyadjiev et al., 2005  identifiEl-Hattab et al., 2010  reportedThauvin-Robinet et al., 2004  reportedA study undertaken by Harrison et al., 2014  of 17 feDraaken et al., 2010  performeFrom a cohort of 244 BEEC cases, Lundin et al., 2010  reportedA comparison of eight previously reported 22q11.21 duplications in individuals with CBE revealed a 414 kb “phenocritical” region, encompassing 10 candidate protein coding genes . Within In contrast to the potential high penetrance effect of chromosomal changes, candidate and genome wide association studies (GWAS) investigate the contribution of more common variants, conferring a smaller effect size. Both association study approaches seek to genotype large cohorts of individuals with BEEC and compare allele frequencies of SNPs in these against ethnically matched controls.p = 0.026, odds ratio (OR) = 18.33) whereas a four-base-pair insertion was associated with an increased risk in non-Caucasian patients OR = 4.58. Using luciferase assays, they showed a consistent statistically significant reduction in transcriptional efficiencies of the promotor sequences containing indel polymorphisms, suggesting that indel polymorphism of the deltaNp63 promoter leads to a reduction in p63 expression which could potentially lead to BEEC.To date, only a small number of candidate gene association studies have been undertaken, the first of those by Wilkins et al., 2012  to invesReutter et al., 2014  conductep = 2.22 × 10−8). Meta-analysis of rs6874700 from this study and the previous study by Draaken et al., 2015 [p = 9.2 × 10−19). Analysis of ISL1-expressing cells by a lineage tracer mouse model showed ISL1-expressing cells in mouse model in the urinary tract E10.5 and distributed in the bladder E15.5. In zebrafish larvae, staged 48 HPF ISL1 expression was detected in a small region of the developing pronephros. This association together with functional studies in mouse embryos and zebrafish larvae suggest ISL1 as an important susceptibility gene for CBE and as a regulator of urinary tract development.Draaken et al., 2015  performeThe lack of large multiplex families has made traditional positional cloning approaches to disease gene discovery incredibly challenging in BEEC. Ludwig et al., 2009  conducteThe introduction of exome and genome sequencing technologies and large sequence variant databases in healthy controls have opened opportunities to determine the effects of rare variants that may be enriched in individuals with BEEC. Reutter et al., 2016  were theThe application of array-based, GWAS, and next generation sequencing techniques in large BEEC cohorts has helped to identify putative disease-causing genes and chromosomal regions in the human genome for both Mendelian and multifactorial BEEC. Functional analysis of embryonic pathways provides a better understanding of the molecular biological mechanisms underlying normal, urorectal, and genitourinary malformations within the embryology of the human urogenital system.It is reasonable to propose that both inherited and de novo highly penetrant variants could be relevant to the etiology of BEEC as they have been shown for many genetically heterogeneous congenital birth defects such as congenital heart disease.New approaches such as gene and pathway enrichment analyses of high-impact de novo variants from whole exome or whole genome data in parent-offspring trios will likely aid in the identification of novel genes and/or pathways to better understand the underlying genetic mechanisms of BEEC, and the potential to use these data to develop therapeutic approaches to help children affected by this devastating congenital disorder.


Mental health problems early in life can negatively impact educational attainment, which in turn have negative long-term effects on health, social and economic opportunities. Our aims were to: (i) estimate the impacts of different types of psychiatric conditions on educational outcomes and (ii) to estimate the proportion of adverse educational outcomes which can be attributed to psychiatric conditions.N = 2511) were from a school-based community cohort of Brazilian children and adolescents aged 6–14 years enriched for high family risk of psychiatric conditions. We examined the impact of fear- , distress-  and externalising-related conditions  on grade repetition, dropout, age-grade distortion, literacy performance and bullying perpetration, 3 years later. Psychiatric conditions were ascertained by psychiatrists, using the Development and Well-Being Behaviour Assessment. Propensity score and inverse probability weighting were used to adjust for potential confounders, including comorbidity, and sample attrition. We calculated the population attributable risk percentages to estimate the proportion of adverse educational outcomes in the population which could be attributed to psychiatric conditions. Analyses were conducted separately for males and females.Participants (p < 0.05) and grade repetition , respectively. Externalising conditions were associated with grade repetition in males  and females , as well as age-grade distortion in males  and females . Externalising conditions were also associated with lower literacy levels  and bullying perpetration  in females. If all externalising conditions were prevented or treated, we estimate that 5.0 and 4.8% of grade repetition would not have occurred in females and males, respectively, as well as 10.2  and 5.3%  of age-grade distortion cases and 11.4% of female bullying perpetration.Fear and distress conditions in males were associated with school dropout (odds ratio (OR) = 2.76; 95% confidence interval (CI) = 1.06, 7.22; The study provides evidence of the negative impact of psychiatric conditions on educational outcomes in a large Brazilian cohort. Externalising conditions had the broadest and most robust negative impacts on education and these were particularly harmful to females which are likely to limit future socio-economic opportunities. The global prevalence of these conditions in young people is around 13.4%  on a range of educational indicators beyond attainment  in young males and females separately, while implementing robust adjustment for confounders  and a random subsample based on all eligible children (n = 958). These families (n = 2511) were selected for full household assessment by lay interviewers (parent interview) and trained psychologists (child interview) at baseline (6–14 years) and at follow-up . Participation was associated with higher maternal education, socioeconomic group (SEG), living in Porto Alegre, and anxiety-related conditions at baseline  and 3-year follow-up (2013–2014) data from the Brazilian High-Risk Cohort Study for Psychiatric Conditions (BHRCS), a large school-based community cohort enriched for high family risk for psychiatric conditions , University of São Paulo and Federal University of Rio Grande do Sul ethics committees. Written informed consent was obtained from parents and participants that were able to read, write and clearly understand the written consent.et al., et al., Current psychiatric conditions were assessed at baseline using parent-report on the Brazilian–Portuguese version of the Development and Well-being Assessment (DAWBA)  were excluded due to divergent literature as to which broad group they might belong.Based on previous literature . Age-grade distortion was calculated for participants reporting grade repetition, dropout or expulsion since baseline, but still enrolled in education. For these participants, age-grade distortion was measured in years and calculated by subtracting the participant's current age from the expected age range for the current school grade. For example, if a child was 12–13 years and enrolled in 5th grade (expected age 10–11 years), we estimated an age-grade distortion of 2 years. For subjects not currently enrolled in school but reporting grade repetition or dropout since baseline, to be conservative, we attributed the value of 1 year.et al., Reading and writing literacy was measured via the School Performance Test (‘Teste de Desempenho Escolar’ – TDE) ; intelligence (IQ); study site  and the dummy comorbidity variable described above.SEG was assessed using the classification from the ‘Associação Brasileira de Empresas de Pesquisa’ (Brazilian Association of Research Companies) ABEP, . ClassifIQ was assessed by trained psychologists with the vocabulary and block design subtests of the Wechsler Intelligence Scale for Children, 3rd edition – WISC-III .We estimated the impact of baseline psychiatric conditions on educational outcomes at 3-year follow-up using unadjusted and adjusted regression models and using schools as the primary sampling units. Maternal education, any anxiety condition and study site predicted response at follow-up in the present sample , based on weighted predicted probabilities from regression models. ‘Punaf’ generates estimates based on two scenarios: first, using predicted probabilities from the model and second, if all participants did not have a psychiatric condition. The ratio of predicted prevalence estimates from the two scenarios was then used to calculate PARPs. As we aimed to generalise to the Brazilian population, we included an additional sampling weight for PARP calculations. This sampling weight fully accounted for the family liability oversampling (see sample description). The methods and results can be found in the Supplemental material in Martel et al.  due to psychiatric condition category. Estimated PARPs can be interpreted as a percentage of adverse educational outcomes in the total population attributable to psychiatric conditions . The PARP was computed using l et al. . This alFor educational outcomes, we used data from the National Institute of Educational Studies and Research database to estimate the number of Brazilians to which PARPs would translate. Details of estimates are described in online Supplementary material.Potential confounders were adequately balanced (standardised mean difference <0.2) between weighted groups following application of PSWs .Among males, fear-related conditions were associated with higher odds of school dropout, and distress-related conditions were associated with higher odds of grade repetition . ExternaComorbidity between fear-, distress- and externalising-related condition categories was included as a covariate in regression models and associated estimates are presented in online Supplementary Tables S6a to S8b. Females with a comorbid condition in addition to fear-related or distress-related condition had higher odds for school dropout and age-grade distortion, respectively (online Supplementary Tables S5a and S6a). Males with fear-related or distress-related conditions who met criteria for at least one other condition category had higher odds of bullying perpetration and low literacy levels respectively (online Supplementary Tables S5b and S6b).Applying school participation estimates for 2014 in Brazil, described in online Supplementary material (p. 3), we estimate that for the Brazilian population, 154 000 cases of grade repetition , 591 000 cases of age-grade distortions  and 236 000 cases of bullying perpetration  would have been avoided if externalising conditions were prevented or treated. As hypothesised, some differences according to gender were found, et al., et al., et al., Psychiatric conditions can have multiple short- and long-term impacts on individuals and society  were more likely to experience school dropout and grade repetition, respectively. This further increases the gender disparity already experienced by males who have lower educational attainment than females OECD, . Previouet al., et al., et al., et al., To contextualise the population impact of psychiatric conditions, we calculated PARPs for each educational indicator. Previous research has estimated that up to 10.2% of early school termination could be attributed to psychiatric conditions (Vander Stoep et al., et al., et al., As a practical application of our estimates, we consider the case of ADHD in Brazil. Among those with ADHD, it is estimated that only 20% receive medication treatment (Mattos et al., et al., This study has some limitations. First, cohort participants came from two large urban areas and thus findings are more generalisable to urban areas, where more than 80% of the Brazilian population lives OECD, . TherefoIn conclusion, the current study estimated the impact of psychiatric conditions on educational outcomes, including examining different condition categories with several widely used educational indicators. The United Nation Sustainable Development Goals recognise education as ‘one of the most powerful vehicles for sustainable development’. Our findings provide support that treatment and prevention of psychiatric conditions could prevent around 4.9% of grade repetition and 7.7% of age-grade distortion in males and females, and 11.4% of bullying perpetration behaviour and low literacy performance in females with prior externalising-related conditions. Thus, policies which encourage early intervention and collaboration between education and health sectors to support the mental health of schoolchildren can have profound consequences for lifetime opportunities and socioeconomic well-being.


Retinal vein occlusion (RVO) is a differential diagnosis for Coats’ disease due to retinal arterial Leber’s aneurysms. Occasionally, RVO shows a Coats-like appearance. The differential diagnosis between Coats’ disease and RVO is essential for clinical therapy, especially for those obsolete RVOs with collateral vessels and without retinal hemorrhage. In this case report, we describe and discuss the imaging characteristics of bilateral RVO-simulated Coats’ disease with tortuous retinal arterioles and its prognosis after anti-vascular endothelial growth factor therapy, which will be beneficial for its definite diagnosis and aid further investigation. Coats’ disease was first reported in 1908 as an ocular disorder with retinal telangiectasis and massive intraretinal and subretinal exudation . RetinalA 52-year-old woman was presented to the ophthalmology department of First Hospital of China Medical University complaining of blurred vision in her left eye for two months. She had amedical history of hypertension and no diabetes. The best-corrected visual acuity was 60/60 in her right eye and 15/60 in her left, and the intraocular pressure was 17mmHg in both eyes. Slight cataracts were found in both eyes, and other anterior segment examinations were normal. Wide-field fundus imaging showed bilateral tortuous retinal arterioles with retinal hemorrhage, as well as tortuous and dilated retinal veins in the supratemporal quadrant. Heavy hard exudates were found in the macula of the left eye. The middle phase of fluorescein angiography revealed numerous miliary aneurysms in both eyes and patchy, blocked fluorescence in the left eye. Peripheral fluorescein angiography demonstrated the “fishing net” appearance of retinal capillaries and non-perfusion regions in both eyes . Multico4 and Schatz et al [Herein, we described a bilateral branch RVO with a Coats-like appearance and tortuous retinal arterioles. Hypertension may be a risk factorfor RVO. In contrast to reports by Scimecaetaltz et al , no secotz et al , which iFamilial retinal arteriolar tortuosity is characterized by tortuosity of the second- and third-order retinal arterioles . Khan etIn conclusion, this was the first report of bilateral RVO-simulated Coats’ disease with tortuous retinal arterioles. A definitive diagnosis is crucial for further investigation and treatment.


Proteins as molecular machines have dynamic structures sampling various conformational states, which determine their functionality, ligand binding, and allosteric properties. Allosteric communication as an intrinsic property of proteins  simulations, elastic network models (ENM), hybrid and integrated methods, and protein structure networks (PSN).Khan et al., performed an integrated computational study on the estrogen receptor alfa (ERα), which have been observed to be recurrent in metastatic breast cancer patients. The impact of experimentally-reported ERα polymorphisms was studied using techniques such as mCSM stability and binding affinity analysis  has become a promising therapeutic approach in cancer immunotherapy. In Liu et al.'s work, the binding features of PD-1 with Nivolumab, a humanized IgG4 antibody approved by the US FDA, were investigated using MD simulations. The computational analysis suggested that the N-terminal loop of PD-1 serves as an important gatekeeper for the anti-PD-1 antibody binding, which might be a potential target for anti-PD-1 antibody design.MD simulation is the most popular computational method used in complementing experimental techniques as it captures the behavior of proteins in full atomistic detail for understanding binding and allosteric events  complex was generated as a potential therapeutic target for inflammatory bowel disease. Eight “hot spots” residues and six potential binding sites at the OSM-OSMR interface were predicted using computational alanine scanning and FTMap , and identified potential key binding sites. Besides, some possible tunnel pathways of the inhibitors in these CYP51-inhibitor complexes were proposed. Using MD simulations, Du et al. gave a detailed analysis of thermostability factors of barley limit dextrinase, including eight salt-bridges.In the brief research report by Dudas et al. used the hybrid MDeNM    enzyme and its allosteric properties. In particular, large fluctuations of the N-terminal domain and its allosteric role were discussed in the context of infectious disease treatment.Normal mode analysis based on ENM facilitates the study of protein dynamics and allosteric effects in a high-throughput manner   as the case study. Based on available experimental structures conformationally most variable region of HA was identified as a potential target for diverse ligands. Furthermore, the empirical contact potentials including an ENM-based entropy term were found successful in ranking the free energies of peptide/proteins designed against HA.Halder et al., gave a thorough presentation on the network-dynamical systemic approach to protein function. In addition, their work highlighted the advantages of the side-chain network analysis in studying subtle conformational changes with an emphasis related to allostery. Gosu et al., used PSN to study the MD ensemble of Myeloid differentiating factor 88 (Myd88) and AlloSigMA  that could serve as a potential binding site. Yan et al. designed the ANCA webserver for constructing and analyzing PSN for interpretation of functional residues and allosteric regulation.Topological description of protein structures has become a popular tool to quantify protein structures and dynamics  is a technique that measures the thermodynamics of binding reactions and reaction kinetics. The review by 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.