Editorial on the Research TopicHearing Loss: Mechanisms and PreventionHearing Loss: Mechanisms and Prevention has encompassed 34 contributions from experts who are dedicated to recent advances in the mechanisms and prevention of hearing loss in ways of hair cell damage and prevention, spiral ganglion cell development and inherited hearing loss in animal models and patients, as well as a range of novel treatment approaches for hearing loss.Hearing loss, which is often referred as an “invisible disability,” is one of the most common sensory impairments worldwide. The prevalence of hearing loss is high and it is estimated that 20 percent of the world’s population is affected by hearing loss to some degree in 2021 according to the WHO report. The resulting consequences are significant burdens to the economy and society. There are numerous contributing factors to hearing loss, such as noise exposure, congenital, infectious, traumatic, and immune-mediated causes and the severity of hearing loss is always related with age. To develop preventative and treatment strategies specific to the underlying causes, it is crucial to understand the pathophysiology of these contributing factors. This Frontiers Research Topic entitled Sun et al. identified that the G protein-coupled receptor 125 is expressed in multiple cell types dynamically in the developing and mature cochlea in mice. Stereocilia play an important role in hearing and balancing sensation. Du et al. investigated the role of the Rho GTPase cell division cycle 42 in mice and reported it as a vital regulator in stereocilia development of cochlear hair cells. In recent decades, new technologies have emerged in inner ear research which help researchers reveal the development of hair cells. As such, single-cell sequencing technology is a powerful tool for analyzing gene expression variations across different cell types, and it has also been proven to be useful in inner ear research. Wu et al. reviewed recent applications of single-cell sequencing in inner ear research, covering from identifying unknown cell subtypes, discovering novel cell markers, to revealing dynamic signaling pathways during development. Meanwhile, by using single-cell RNA sequencing analysis, Chen et al. Identified different cell subtypes in the greater epithelial ridge cells in the cochlear duct related to their degeneration during postnatal development in rats. During P1 and P7 rats, five cell clusters reduced significantly while four clusters, enriched with genes associated with the degeneration of the greater epithelial ridge cells, had high similarity in gene expression patterns and biological properties. Besides utilizing single-cell sequencing technique, Wu et al. from a different group developed a 3D imaging technique for the three-dimensional examination of the microstructure of the full thickness of the tympanic membranes in mice. With this imaging technique, they discovered the 3D form of the elastic and collagen network, as well as the close spatial relationships between the elastic fibers and the elongated fibroblasts in the tympanic membranes, which provides important information for hair cell development.Hair cells are most important part in sound conduction and balancing sensation. Their development is tightly correlated with the function of cochlea. To reveal cochlear development and hearing, Liu et al. reported excessive accumulation of calcium due to acoustic overexpression and slow clearance around the presynaptic ribbon might lead to disruption of calcium homeostasis by compared the consequences of noise-induced cochlea synaptopathy of C57BL/6J and CBA/CaJ mice. The susceptibility of noise-induced cochlear synaptopathy in CBA mice is caused by mitochondrial dysfunction of inner hair cells. Xiao et al. investigated the molecular behavior of high-mobility group box 1 (HMGB1) in the cochlea following noise exposure both in mice and in vitro and reported that HMGB1 has a possible negative effect on cellular lifespan indicated by the higher cell viability observed in the HMGB1 knocked-down mice after stimulation with H2O2. In addition to resolving the intrinsic cause of noise-induced hearing loss, researchers are also working on the approaches to protecting noise-induced damge. The use of FK506 (tacrolimus) to treat noise-induced hair cell loss and noise-induced hearing loss (NIHL) has been applied clinically and He et al. identified the downstream mechanisms of FK506-attenuated NIHL. They found that FK506 treatment not only inhibits calcineurin activity to attenuate moderate-noise-induced outer hair cell loss and hearing loss, but also inhibits reactive oxygen species and activates autophagy. Badash et al. demonstrated that endolympahtic hydrops are correlated with noise-induced cochlear synaptopathy by exposing live CBA/CaJ mice to various noise intensities and using optical coherence tomography to measure endolymph volume. Liang et al. also found a positive role sirtuin-3 in protecting cochlear hair cells against noise-induced damage via the superoxide dismutase 2/reactive oxygen species signaling pathway. Many different factors are also involved in the development of hair cells and contribute to hearing loss. Ding et al. identified that the ototoxicity of 2-hydoxypropyl-beta-cyclodextrin (HPβCD) spread from the high-frequency base towords the low-frequency apex of the cochlea from P3 to P28 and the HPβCD-induced outer hair cell (OHC) death is correlated with the upregulation of prestin in OHCs. In addition, 4–6 weeks post-HPβCD treatment, there is a second, massive wave of degeneration involving inner hair cells, pillar cells, auditory nerve fibers and spiral ganglion neurons. An interesting effect of caffeine in cochlear hair cells was identified by Tang et al. They showed that caffeine induces autophagy and apoptosis in auditory hair cells via the SGK1/HIF-1ɑ pathway, which suggests overdoes of caffeine may lead to hearing impairment. Gong et al. described the importance of claudin h in morphogenesis and auditory function of the hair cells. Zebrafish with deficiency of claudin h have significant reduction of otic vesicle size and loss of utricle otolith and loss of hair cells in neuromasts caused by the deficiency of claudin h can be rescued by claudin h mRNA in zebrafish. Tu et al. demonstrated that the deficiency of small muscle protein, x-linked (SMPX) causes stereocilia degeneration in cochlea and progressive hearing loss using an Smpx null mouse model by CRISPR-Cas9 technique. Kwesi et al. presented a study of effect of high jugular bulb (HJB) on the hearing loss in patients with large vestibular aqueduct syndrome (LVAS). LVAS patients with concurrent HJB show higher air conduction thresholds.A great effort has been made to study the cause of hair cell damage and the approaches to protecting them. Noise can induce cochlear hair cell damage and it is the most common cause of hearing impairment. Noise-induced hearing loss involves different mechanisms and pathways. Li et al. Although hearing loss can be caused by various factors, new approaches to treating hearing loss are emerging. Dong et al. revealed the positive function of optic atrophy1 (OPA1) in hearing by examining the ability of OPA1 to protect against cisplatin-induced cochlear cell death both in vitro and in vivo. They showed overexpression of OPA1 prevented cisplatin-induced ototxicity, which suggests a possible role of OPA in ototoxicity and/or mitochondria-associated cochlear damage. It has been demonstrated before that neither N-acetylcysteine nor dexamethasone can protect hair cells from oxidative stress when at ineffective concentrations, but Bai et al. reported when these two drugs combine together, they show a better therapeutic effect both ex vivo and in clinical patients. Chen et al. developed a stable and effective to deliver dexamethasone (DEX) via an electrode coated with polycaprolactone. This device maintains stabilityof DEX concentration for more than 9 months and shows promising application in cochlear implantation. New technologies are also making contributions to treatment of hearing loss, such as stem cell-based therapies as reviewed in He et al. and nanoparticle treatment as reviewed by Huang et al. In the prior review, they fully described the ways of inducing the differentiation of stem cells, the implantation operation and regulation of exogenous stem cells after implanted into the inner ear, and elaborated the relevant inner ear signal pathways and the clinical applications of new materials. In the latter review, they summarized recent developments challenges of nanoparticles in diagnostics and treatment of hearing loss.Apart from cochlear hair cell damage, hearing loss can also relate several neurological disorders, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and autism spectrum disorder, as thoroughly reviewed in Sun et al. explored the regulatory mechanisms of atrial natriuretic peptide (ANP) underlying functional properties of auditory neurons in vitro and reported that ANP could support and attract neurite outgrowth of sprial ganglion neurons (SGN) and possesses a high capacity to improve neuronal survival of SGNs against glutamate-induced excitotoxicity via triggering the natrieretic peptide receptors-A/cGMP/PKG pathway. Ma et al. indicated that the expression levels of vesicle transporter protein 3, glutamate/aspartate transporter protein, and Na+/K+-ATPase ɑ1 are disrupted in spiral ganglion cells in mice after noise exposure, suggesting that disruption of glutamate release and uptake-related protein expression may exacerbate the occurrence of synaptopathy. Some gene mutations are also participated in the development of spiral ganglion neurons. Qiu et al. investigated the pathological role of mutant ATP6V1B2 in the auditory system with transgenic mice carrying c.1516 C > T (p.Arg506∗) in Atp6v1b2, Atp6v1b2Arg506∗/Arg506∗. They showed the transgenic mice have hidden hearing loss at early stages and developed late-onset hearing loss. The degeneration of spiral ganglion neurons are induced by apoptosis activated by lysosomal dysfunction and the subsequent blockade of autophagic flux, which then further impairs the hearing. Meanwhile, scientists are searching for potential approaches to protecting spiral ganglion neurons. Wang et al. described a transgenic mice with tumor necrosis factor 2/4 double knockout show the attenuation of spiral ganglion neuron degeneration by the differential regulation of some core molecules. Chen et al. explored a way to reprogram cochlear Sox2+ glial cells into functional spiral ganglion neurons by induction of small molecules. In the field of regeneration research of spiral ganglion neurons in the inner ear, utilization of specific genetic tool of animal models is a common research approach. For example, a specific spiral ganglion neuron damage approach is described by Hu et al. They generated a strain of transgenic mice exhibiting inducible SGN-specific Cre activity in the inner ear which may serve as a valuable SGN damage model.Spiral ganglion neurons are bipolar neurons connecting the primary auditory receptor cells, the hair cells, with the auditory brain stem. Their development and protection are highly linked with the auditory system. Xu et al. identified a spontaneous mutation of coiled-coil domain-containing 154 gene as a new osteopetrosis-related gene can induce congenital deafness. In porcrine model, Ren et al. studied the population statistics, hearing phenotype, and pathological changes of congenital single-sided deafness (CSSD) which is highly resembled with human non-syndromic CSSD disease. The deaf cochlear of this strain show cochlear-saccular degeneration. In vitro, Wen et al. investigated the mechanisms of Waardenburg syndrome (WS) by inducing an iPSC line derived from a WS patient with SOX10 mutation. The induced cells differentiated into neural crest cells (NCCs) and SOX10 deficiency had a significant impact on the gene expression patterns throughout NCC development in the iPSC model. In children, Liang et al. identified 18 new potential genes associated with congenital deafness and 87 potential new genes associated with otitis media by using a network-based method incorporating a random walk with restart algorithm, as well as a protein-protein interaction framework. In patients, Wang et al. reported a phenotypic heterogeneity of post-lingual and/or milder hearing loss with the GJB2 c.235delC homozygous mutation. Zhu et al. reported a compound heterozygous variant of the OTOF gene in familial temperature-sensitive auditory neuropathy and the auditory neuropathy can be diagnosed by the presence of cochlear microphonics with absent or markedly abnormal auditory brainstem responses (ABRs). Wang et al. further demonstrated the significance of genetic testing for auditory neuropathy patients with p.E818K in the ATP1A3 gene. All these findings have made contributions to a genetic understanding of inherited deafness and provide novel biomarkers for clinical screening.Although various environmental insults can cause damage to hair cells and spiral ganglion neurons, inherited factors will also lead to hearing loss verified both in animal models and clinical patients. In mice, In conclusion, the collection of research articles and reviews presented in this Research Topic provides a comprehensive set of information on the factors attributing to hair cell development, the mechanisms of hair cell damage and the approaches to protect them, as well as spiral ganglion neuron development and protection and genes involved in the inherited hearing loss. Most importantly, there are various new potential treatment approaches to hearing loss. Together, the achievements included in this Research Topic make huge contributions to further understand the underlying causes of hearing loss and may facilitate the development of novel therapies to treat hearing loss in the near future.


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Escherichia coli and Saccharomyces cerevisiae, over the past few years, oleaginous yeasts that naturally accumulate high-content lipids have been directly used or genetically modified for producing diverse bioproducts, although early trials on the commercial production of microbial oil date back to World War I. This Research Topic concentrates on the advancement of bioengineering of oleaginous yeasts, including Yarrowia lipolytica and Rhodosporidium (Rhodotorula) toruloides, for producing biofuels and bioproducts, with particular emphasis on the establishment of synthetic biology tools and novel engineering strategies.The current Research Topic provides an effective communication platform, collecting both original research articles and review papers examining explorations of the mechanism for lipid accumulation, biotechnological applications, and metabolic engineering efforts related to oleaginous fungi including the non-conventional yeasts. Microbes have been harnessed for the production of hydrocarbon with a high-energy density as “drop-in” fuels, renewable chemicals, and value-added compounds. In addition to the commonly used model organisms such as Y. lipolytica   biological engineering cycle for strains development and improvement. The sets of molecular biology toolbox have been established for the genetic manipulation of non-conventional yeasts Y. lipolytica has been engineered for producing microbial lipid with a titer of 99 g L−1 and a rate of 1.2 g/L/ h , the oleaginous yeast Y. lipolytica, NADPH to support lipid biosynthesis was primarily generated from the oxidative pentose phosphate pathway (PPP) when glucose was used as a carbon source, this resulted in carbon loss as released CO2 for the biosynthesis of the end product (Wasylenko et al., Y. lipolytica, different synthetic pathways were engineered in yeast cytosol to convert glycolytic NADH into NADPH (Qiao et al., Y. lipolytica (Markham et al., Y. lipolytica (Xu et al., Aspergillus terreus in Y. lipolytica (Zhao et al., Y. lipolytica (Larroude et al., To construct the productive cell factories of oleaginous microorganisms, some novel metabolic engineering strategies including engineering central carbon metabolism and pathway compartmentalization have been employed. In the oleaginous yeast XX wrote the manuscript. YX and JQ provided comments and helped with the revision of the manuscript. All the authors approved the submission of this 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 interest in utilizing food-derived compounds therapeutically has been rising. With the growing prevalence of systematic chronic inflammation (SCI), efforts to find treatments that do not result in the side effects of current anti-inflammatory drugs are underway. Bioactive peptides (BAPs) are a particularly promising class of compounds for the treatment of SCI, and the abundance of high-quality seafood processing byproducts (SPB) makes it a favorable material to derive anti-inflammatory BAPs. Recent research into the structural properties of anti-inflammatory BAPs has found a few key tendencies including they tend to be short and of low molecular weight (LMW), have an overall positive charge, contain hydrophobic amino acids (AAs), and be rich in radical scavenging AAs. SPB-derived anti-inflammatory BAPs have been observed to work via inhibition of the NF-κB and MAPK pathways by disrupting the phosphorylation of IκBα and one or more kinases , respectively. Radical scavenging capacity has also been shown to play a significant role in the efficacy of SPB-derived anti-inflammatory BAPs. To determine if SPB-derived BAPs can serve as an effective treatment for SCI it will be important to understand their properties and mechanisms of action, and this review highlights such findings in recent research. Food has been used as a therapeutic treatment of diseases for millennia, however the discourse surrounding the role that food and food-derived compounds play in human health has been reinvigorated of late . Recent Systemic chronic inflammation (SCI) is one of the greatest challenges to human health and wellbeing in the 21st century . SCI proSeafood processing byproducts (SPB) are an ideal candidate to derive useful biomolecules and have already garnered attention in the fields of nutrition, medicine, and cosmetics ,11. A laBAPs are small, liberated protein fragments, around 2-20 amino acid (AA) bases long. The small size and exposed AA side chains of BAPs enable ready interaction with other molecules ,21,22. BThe properties of anti-inflammatory protein products and the mechanisms by which they act are intrinsically linked. A better understanding of how BAPs structural properties and mechanisms are connected will be required to harness their potential in the coming years. This review provides a resource in which properties and mechanisms of fish- and shellfish-derived anti-inflammatory protein products are discussed based on the recent evidence. Previous work by Chakrabarti et al., Bechaux et al., Venkatraman et al., Cal et al., Chalamaiah et al., Olsen et al., Daliri et al., La Manna et al., Zamora-Sillero et al., Nongonierma et al., Urakova et al., Guha et al., and Zhu et al. have expounded on aspects of marine-derived bioactive compounds ,32,33,34Inflammation is an important biological mechanism that promotes healing and resolution in cases of infection and injury . FurtherPancreatic cancer, for instance, can be initiated by DNA damage resulting from inflammation and the associated increase in reactive oxygen and nitrogen species . SCI proNSAIDs are a common treatment for inflammation, both chronic and acute. While NSAIDs are an invaluable tool in combating inflammation, problems arise when used to treat chronic inflammation over long periods of time, the risk of associated gastric bleeding, ulceration, renal failure, and a myriad of other side effects can occur ,25,40. AA number of broad trends have been observed in the structure of anti-inflammatory peptides. Anti-inflammatory BAPs tend to be positively charged, have hydrophobic AA residues, be rich in antioxidative AAs, and be short, of low molecular weight (LMW) peptides  34]. N-. N-34]. Anti-inflammatory peptides tend to have an overall positive charge, and contain an abundance of positively charged AAs such as arginine, lysine, and histidine, particularly in the N- and/or C-terminal positions ,44,45,462+ signaling, which plays a central role in NF-κB signaling and cytokine production . NS. NS43]. NF-κB is a family of inducible transcription factors that contribute to an immune and inflammatory response. NF-κB is a large biochemical pathway that stimulates the production of numerous cytokines and chemokines that can be easily measured via a multitude of methods, both in vivo and in vitro . NF-κB iThe canonical pathway for NF-κB activation relies upon the phosphorylation and subsequent degradation of the subunit IκBα by IκB, which then allows for nuclear translocation of NF-κB ,61,63. ACOX-2 stimulates the conversion of arachidonic acid into prostaglandins, and is the target of most NSAIDs . ProstagIL-1β and IL-6 are cytokines that are upregulated during inflammation. IL-1β deregulation is implicated in inflammation related pain as well as many of the numerous chronic inflammation-related diseases previously mentioned . IL-6 upActivation of MAPK is another notable cellular process under inflammation. MAPK is a highly conserved pathway integral to numerous cellular functions including cell proliferation, differentiation, and inflammatory response ,79. MAPKTNF-α is cytokine produced by macrophage cells during inflammation and is both an activator of inflammatory pathways and a product of inflammation. TNF-α expression is regulated by both MAPK and NF-κB pathways. Research by Gao et al.  indicateOxidative stress and inflammation are intimately connected. Reactive oxygen species and reactive nitrogen species (RNS) are ubiquitous in the body and regulate cellular function when at healthy levels ,70. HoweChronic inflammation is one of the preeminent threats to the human health in the 21st century, in fact over 50% of deaths worldwide are attributable to diseases associated with chronic inflammation . It is i


Circular RNA (circRNA) is a novel class of single-stranded RNAs with a closed loop structure. The majority of circRNAs are formed by a back-splicing process in pre-mRNA splicing. Their expression is dynamically regulated and shows spatiotemporal patterns among cell types, tissues and developmental stages. CircRNAs have important biological functions in many physiological processes, and their aberrant expression is implicated in many human diseases. Due to their high stability, circRNAs are becoming promising biomarkers in many human diseases, such as cardiovascular diseases, autoimmune diseases and human cancers. In this review, we focus on the translational potential of using human blood circRNAs as liquid biopsy biomarkers for human diseases. We highlight their abundant expression, essential biological functions and significant correlations to human diseases in various components of peripheral blood, including whole blood, blood cells and extracellular vesicles. In addition, we summarize the current knowledge of blood circRNA biomarkers for disease diagnosis or prognosis. EGFR) gene was used to guide the response of EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC) patients, which was approved by the FDA in clinical practice  are a group of endogenous noncoding RNA molecules Chen, . They weDue to the importance of liquid biopsy biomarkers in precision medicine  is covalently joined with an upstream 3-prime ss Fig.  Li et a. There aWith the rapid application of high-throughput RNA-sequencing (RNA-seq) technology  , is the first circRNA that was discovered to function as an RBP sponge  at the promoter region of their parental genes and enhances their transcription  and cyclin-dependent kinase inhibitor 1 (p21), which facilitates the inhibition of CDK2 by p21, thus blocking cell cycle progression  modification of circRNAs , such as BodyMap dataset, we observed tissue-specific circRNA expression in all 11 rat tissues, which may be closely related to the physiological functions of those tissues  patients after surgery  in adipose-secreted exosomes was found to regulate deubiquitination via the suppression of miR-34a and the activation of deubiquitination-related USP7 in plasma samples of hepatocellular carcinoma (HCC) patients, which could reduce DNA damage and promote HCC cell growth  patients and 55 normal subjects. They found that serum exosomal circFLI1 levels were significantly higher in SCLC patients, especially in SCLC patients with distant metastasis  under normal conditions  and identified circRasGEF1B as a conserved positive regulator of the LPS response  and lung cancer patients (Huang et al., hsa_circ_001937 had good discriminative power with an AUC of 0.873. After anti-TB treatment, the expression level of hsa_circ_001937 was significantly decreased compared to that of healthy controls. These results suggest that PBMC hsa_circ_001937 may be a TB diagnostic biomarker (Huang et al., circ_0000798 expression in PBMCs of HCC patients, which was associated with poor overall survival (Lei et al., circ_0000798 expression could distinguish HCC patients from healthy controls with an AUC of up to 0.703. The authors suggested that PBMC circ_0000798 has potential as a blood biomarker for HCC diagnosis and prognosis (Lei et al., , hsa_circ_0057762 and hsa_circ_0003090, that can differentiate children with SLE from healthy controls (Li et al., hsa_circ_0054633 in peripheral whole blood as a sensitive and specific diagnostic biomarker for prediabetes and T2DM (Zhao et al., With increasing knowledge of blood cell circRNAs and their function, many circRNAs in blood cells or whole blood have been proposed as liquid biopsy biomarkers for human diseases Fig. C Aufier. For insThe high stability, abundance and spatiotemporal specific expression of blood circRNAs make them ideal biomarkers for liquid biopsy. In the past several years, many studies have shown that blood circRNAs, both cell-free blood circRNAs and circRNAs in blood cells, have great potential as biomarkers of many human diseases in liquid biopsy. A biomarker with broad clinical application must have demonstrated analytical validity, clinical validity and clinical utility (Byron et al.,


N- and N,N′-alkyl indigo derivatives’ by Daniela Pinheiro et al., Chem. Sci., 2020, DOI: 10.1039/d0sc04958a.Correction for ‘Deep in blue with green chemistry: influence of solvent and chain length on the behaviour of  The authors regret that incorrect compound names and values are reported in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.


We have read the study by Jerjes-Sánchez et al with interestCould you detail how many of your PA-VTE developed left-sided extensive iliofemoral DVTs?Chan et al performed a systematic review in 124 patients with PA-DVT in which 84 (88%) of the known 96 patients, for which the side was known to be affected, were reported to have left-sided DVT; 87 (71%) of the 122 DVTs were restricted to the proximal veins, without distal calf vein involvement, and 64% 56/87) were iliofemoral DVTs, concluding that if larger studies confirmed such findings, these could positively impact our understanding of pathophysiology and derivation of diagnostic algorithms in PA-VTE.6/87 wereWax et al performed a retrospective care series in four women with MTS, describing diverse clinical scenarios; previous ischemic stroke from presumed paradoxical emboli, chronic LE venous congestion treated prepregnancy with stenting, previous history of iliofemoral DVT treated with catheter-directed thrombolysis, anticoagulation and stenting, and active third trimester acute iliofemoral DVT. The first three patients received thromboprophylaxis doses of anticoagulation, while the fourth one was fully anticoagulated.DeStephano et al described successful pharmacomechanical percutaneous thrombectomies in three patients with extensive iliac DVTs in pregnancy from MTS, concluding that endovascular interventions may play an important role in carefully selected patients, reducing thrombotic burden, and decreasing long-term complications like postthrombotic syndrome.Regarding MTS and pregnancy, evidence suggests that MTS confers an anatomic predisposition to DVTs as vein compression leads to endothelial damage and subsequent buildup of elastin and collagen and stagnant blood flow.Should societal clinical practice guidelines  consider including MTS as a strong preexisting risk factor for the development of PA-VTE?Given the paucity of data regarding MTS during pregnancy and postpartum in the form of case reports and case series,


Imaging technology is being recognized as an important tool for breaking through the bottleneck of drug development as it is able to provide great insights into the morphology or functionality of pharmacological models, including cell, tissue, and animal. Imaging has several advantages compared to traditional evaluation methods, which include high spatiotemporal resolution, imaging sensitivity, and tissue specificity. In addition, imaging can be utilized to determine the gene expression, metabolism of various substances, cancer detection, drug development, as well as other fields.Imaging technology includes both microscopic and macroscopic imaging scales, and encompasses fluorescence-based microscopy , Raman-bFang et al. systemically summarized the recent advances that have been made in the development of noninvasive imaging and radiotherapy agents for the different molecular subtypes of breast cancer in preclinical studies in their study, “Theranostics for the different molecular subtypes of breast cancer.” The researchers provided a conceptual examination of recent or current original articles that were published within the last decade in the field of preclinical breast cancer nuclear imaging. Data were extracted from the PubMed database and filtered according to the key words “breast cancer,” “preclinical,” “PET/SPECT,” and “targeted imaging.” In order to help guide future investigations of novel theranostic agents, they listed different imaging agents and cell lines that were tested in preclinical studies. They think molecular imaging can help with diagnosis, staging, guiding treatment, and predicting response to corresponding targeted therapy. The review of Zeng et al. which was titled “Treatment coherent Raman scattering microscopy in oncology pharmacokinetic research” highlighted coherent Raman scattering (CRS) microscopy as a novel emerging platform to facilitate oncology pharmacokinetic research. It would be of great importance to develop label-free optical microscopy that is able to assess stability and dissolution of drugs in the solid state, and uptake, distribution, interaction, and excretion of anticancer drug nanocarriers in a biological environment. Therefore, they summarized the recent technical advances and applications of CRS microscopy in the field of anticancer drug pharmacokinetics at the single cell level, drug stability and dissolution in the solid state, as well as the activities of anticancer drug nanocarriers in single cells. According to their review, there are several reasons to believe that CRS microscopy with label-free, chemically selective, high temporospatial resolution, and highly sensitive imaging can offer novel opportunities for investigation of anticancer drugs.Two review articles demonstrated the role of one imaging technology in the treatment of cancer. in vitro studies. Zhang et al. in the article “Metabolic reprogramming of sulfur in hepatocellular carcinoma and sulfane sulfur-triggered anti-cancer strategy” uncovered reprogramming of sulfur metabolism in hepatocellular carcinoma (HCC) and were able to provide a potential therapeutic strategy for HCC by donating sulfane sulfurs. Herein, the cell imaging assay was carried out to support their hypothesis. Their findings suggest that application of sulfane sulfurs may be an effective therapeutic strategy, particularly for HCC tumor cells that have reprogrammed the sulfur metabolism. Jin et al. in their article “Hirsutella sinensis fungus regulates CD8 + T cell exhaustion through involvement of T-Bet/Eomes in the tumor microenvironment” have provided insights into the application of Hirsutella sinensis fungus (HSF) in a tumor immune treatment. Their study demonstrated that HSF exerts antitumor effects mainly by reducing the expression of immune checkpoints by inhibiting T-bet in T cells, which lowers Tex cell production in the tumor microenvironment. Additionally, HSF could promote the Eomes expression in order to enhance T cell function. In vivo imaging technology was utilized to evaluate the effects of HSF on various tumor mouse models. Their findings were able to provide novel insights into the effect of HSF on tumor immune responses.In order to explore a novel strategy of cancer treatment, imaging technology can be applied across several in vivo evaluation of drugs. Xu et al. in their article “Bioluminescence imaging-based assessment of the anti-triple-negative breast cancer and NF-Kappa B pathway inhibition activity of britanin” were able to evaluate the anti–breast cancer activity of britanin. Their results demonstrated that britanin induces apoptosis via inhibition of the NF-κB pathways. The bioluminescence imaging screening system is useful for accelerating application of britanin in the antitumor field, which provides a useful tool for evaluating the efficacy of phytochemicals in inhibiting cancer cell proliferation in animal models. Zhan et al. in their article “in vivo improvement of synergistic chemotherapy in esophageal cancerConstruction of biocompatible dual-drug loaded complicated nanoparticles for ” developed a doxorubicin and β-elemene–loaded mesoporous silica nanoparticle system to exert inhibitory effects in esophageal cancer treatment. Fluorescence images were applied in order to validate efficacy of the combination therapy in vivo. Zhang et al. in their article “Terphenyllin suppresses orthotopic pancreatic tumor growth and prevents metastasis in mice” reported a novel marine-derived natural product terphenyllin with potent anti-pancreatic cancer (PC) activity. Herein, terphenyllin was found to significantly suppress PC cell growth and metastasis in vitro and in vivo. Terphenyllin induced PC cell apoptosis by increasing the expression of proapoptotic proteins and decreasing the expression of antiapoptotic proteins. The Panc1-Luc cell lines were utilized to develop an orthotopic mouse model, which may be able to closely mimic the original situation in human PC patients and may be better able to predict the therapeutic efficacy of the test compound. The in vivo imaging technique demonstrated significant inhibitory effects of terphenyllin on tumor growth. Their results reveal the therapeutic potential of terphenyllin in PC, which can help provide a basis for further developing this natural compound as an anticancer therapeutic agent.Imaging technology was a powerful tool for the Li et al.’s “Manganese-based targeted nanoparticles for postoperative gastric cancer monitoring via magnetic resonance imaging,” an Mn-based contrast agent for MRI was synthesized to provide accurate evaluation of therapeutic effects and guide treatment strategy adjustment over time. A series of in vitro and in vivo imaging experiments were employed to assess the characters of Mn3O4@PEG-RGD NPs. Their results indicated that Mn3O4@PEG-RGD NPs likely have a great potential for the MRI postoperative monitoring of gastric cancer and give an appropriate strategy for following chemotherapy. Xu et al. in their research “in vitro anticancer activity of fullerenol-foxorubicin conjugates alpha 3 function by colchicineSynthesis, characterization, cellular uptake, and s” designed and synthesized the fuller enol (FU)-DOX conjugates and folic acid (FA)-grafted FU-DOX conjugates in order to improve the selectivity and activity of DOX in cancer cells. They synthesized DOX and FU conjugates (FU-DOX) through the use of the acid-sensitive hydrazone bond and were further modified by FA in order to obtain FA-FU-DOX conjugates for improving tumor-targeting effects. In their study, fluorescent microscopy was utilized to monitor cellular uptake. Indeed, FA-FU-DOX conjugates may optimize the safety and efficacy profile of DOX. Zhou et al. also wrote another review article “pH-Sensitive and long-circulation nanoparticles for near-infrared fluorescence imaging-monitored and chemo-photothermal synergistic treatment against gastric cancer” which reported photothermal–chemotherapy combined nanoparticles (PCC NPs) that have functions of chemo-photothermal synergistic therapy and continuous imaging for gastric cancer. The PCC NPs consisted of dopamine, poloxamer, DOX, and IR-820 via π–π stacking and demonstrated good biocompatibility both in vitro and in vivo. Their study can offer a novel postoperative treatment for gastric cancer.The integrated diagnosis and treatment of nanoparticles will provide precise information for a cancer treatment strategy. In Zhao et al. in their article “Accuracy of endoscopic diagnosis of helicobacter pylori based on the Kyoto classification of gastritis: a multicenter study” provided evidence of clinical accuracy and robustness of the Kyoto classification of gastritis in the Chinese population. Furthermore, they discovered that the reappearance of two indicators (unclear atrophy boundary and unclear atrophy boundary) in atrophic mucosa could help sufficiently determine the presence of Helicobacter pylori (H. pylori) infection on an endoscopic basis. Their prospective and multicenter study was based on 650 Chinese patients. In order to prevent the occurrence and development of gastric cancer (GC) early on, their study offered an important novel finding for screening of early GC based on the close relationship between H. pylori and GC.Moreover, imaging technology also plays a significant role in a clinical anticancer medication strategy. in vitro, evaluating in vivo anticancer effects, and benefiting the clinical diagnosis. These articles provide deep insights into methodology and applications of imaging technology. We believe that imaging technology would be increasingly welcome in oncology pharmacological research.In conclusion, a collection of 11 articles contributed to this research topic, which covers two reviews and nine research articles. It is important to note that these published articles cover a wide spectrum of applications of imaging technology in oncology pharmacological research, which includes exploring a novel anticancer chemotherapy strategy


Matricaria chamomilla, commonly known as chamomile, and one of the most popular medicinal plants in the world. Thanks to a high content of phenolic compounds and essential oils, preparations from chamomile flowers demonstrate a number of pharmacological effects, including antioxidant, anti-inflammatory, antimicrobial and sedative actions as well as improving gastrointestinal function. Several recent studies have shown certain positive effects of chamomile preparations in the prevention of obesity and complications of diabetes. These effects were associated with modulation of signaling pathways involving the AMP-activated protein kinase, NF-κB, Nrf2 and PPARγ transcription factors. However, the potential of chamomile in the management of obesity seems to be underestimated. This review summarizes current data on the use of chamomile and its individual components  to treat obesity and related metabolic disorders in cell and animal models and in human studies. Special attention is paid to molecular mechanisms that can be involved in the anti-obesity effects of chamomile preparations. Limitation of chamomile usage is also analyzed. Obesity is an increasing health concern related to many metabolic disorders, including metabolic syndrome, diabetes type 2 and cardiovascular diseases. Many studies suggest that herbal products can be useful dietary supplements for weight management due to the presence of numerous biologically active compounds, including antioxidant polyphenols that can counteract obesity-related oxidative stress. In this review we focus on  AMPK 5' adenosine monophosphate-activated protein kinaseAP-1 activator protein-1FOXO1 forkhead box O protein 1GLUT-4 glucose transporter type 4HFD high fat dietFFAs free fatty acidsLDL low density lipoproteinsNF-κB nuclear factor-κBNrf2 nuclear factor erythroid 2 related factor 2PPARγ peroxisome proliferator-activated receptor gammaROS reactive oxygen speciesSTZ streptozotocinTAG triacylglyceridesTNFα tumor necrosis factor alphast century . Intensal., 2017; Kanda eal., 2017; Matsudaal., 2017; Catryssal., 2017; Bayliakal., 2017). Metaboal., 2017; Laclausal., 2017; Saklayeal., 2017). Global anti-obesity strategies are focused on dietary and lifestyle changes, i.e., change the energy balance so that calories spent prevail over calories consumed along with an increase in physical activity . NaturaMatricaria chamomilla (synonym: Matricaria recutita), commonly known as chamomile, is one of the most popular medicinal plants in the world  and phenolic compounds - phenolic acids, coumarins and flavonoids . Preparal., 2011; Europeaal., 2011), and coal., 2000; McKay aal., 2000; Haghi eal., 2000). In vitro and in vivo studies have shown that polyphenols have protective effects against oxidative stress-related diseases, including metabolic syndrome and obesity . In linal., 2006, 2020) an) an(7) Anta, 2012). It seeSeveral human clinical trials have confirmed the effectiveness of chamomile tea in the improvement of inflammatory markers, lipid profile and insulin resistance in patients with type 2 diabetes , and thgenerally recognized as safe) list of the United States Food and Drug Administration (FDA), which means a substance added to food is considered safe by experts . Howeveal., 2010; Benito al., 2010; Europeaal., 2010), and thal., 2001; Paulsenal., 2001). Chamomal., 2001), rhinital., 2001) and eyeal., 2001). In addal., 2001; Europeaal., 2001; Nakagawal., 2001). Peopleal., 2001). Sesquial., 2001) and coual., 2001) are conal., 2001). Due to chamomile mild sedative effects , long-tSince chamomile essential oils and phenolic compounds possess a strong antibacterial activity, the oral consumption of chamomile preparations at high concentrations can affect gut microbiota composition. In this, context, both beneficial and undesirable gut bacteria can undergo qualitative and quantitative changes resulting in health adverse effects such as gastrointestinal problems. However, future clinical studies on this issue are needed. At high concentrations, plant phenols exert pro-oxidant activity ; therefChamomile flowers contain a wide range of polyphenolic compounds and essential oils that possess various biological activities including antioxidant, anti-inflammatory and energy metabolism modulating effects. Due to these properties chamomile preparations can be effectively used for obesity prevention and treatment. Whole chamomile extract seems to be more effective than isolated individual components since the latter show some differences in cellular and protein targets and together may demonstrate synergetic effects. More research is needed to establish the molecular mechanisms of action of chamomile preparations. In particular, there is a need to further explore the involvement of PPARγ and Nrf2 signaling pathways because these were found to play dual roles in obesity demonstrating both anti-obesity and obesity-promoting effects  to VIL and a grant from National Research Foundation of Ukraine (#2020.02/0118) to MMB.The authors declare that they have no conflict of interest.Maria M. Bayliak provided idea and design of the article, prepared figures and tables, performed review and editing; provided funding acquisition; Tetiana R. Dmytriv collected literature, wrote the original draft and prepared figures; Antonina V. Melnychuk and Nadia V. Strilets collected literature and wrote the original draft; Kenneth B. Storey performed review and editing and provided valuable discussion; Volodymyr I. Lushchak performed analysis, review and editing the manuscript, provided funding acquisition. All authors read and approved the final manuscript.


Endogen (DAMPs) . Upon PA et al.) .Nucleic Acid-Associated Inflammation” by Roca Suarez et al., as well as Xu et al.Given the central role of PRRs in the control of invading pathogens and endogenous threats, it is not surprising that genetic or etiological alterations of inflammation foster a wide range of human pathologies. Underscoring this concept, the persistent dysregulation of nucleic acid-associated inflammatory pathways has been associated with the development of chronic liver diseases. The two main etiology agents that are linked with these liver pathologies are hepatitis B virus (HBV) and hepatitis virus C (HPC). These viruses have distinct genomes and viral life cycles but can both repress innate anti-viral defenses through common mechanisms. These strategies are being discussed in our Research Topic “via comparative analyses of innate immune responses, from biological models (zebrafish and mouse) to human. This underscores the existence of tissue- and species- specificities, and is discussed in six reviews of the Research Topic which cover various aspects, ranging from the role of transposable elements to the limitations of in vivo models and provides cues towards the development of high content therapeutic strategies in relevant physiological models .Innate immunity largely relies on the recognition of evolutionarily conserved structures that can be identified Santa et al. and by Kumar give a comprehensive overview of the regulatory circuitries of nucleic acid-sensing pathways.However, despite major advances in the field of innate immunity to identify the pathways involved in the onset of cytokine production in response to immune-stimulatory nucleic acids, there are still many open questions. Specifically, how these signalling pathways are regulated in respect to various nucleic acid substrates and tissue insults. In this special Research Topic, key opinion leaders in the field offer an overview of (1) the major molecular and cellular aspects of nucleic acid sensing across species; (2) the complexity of innate and adaptive immune responses and their key role in the maintenance of tissue homeostasis; and (3) the intricate connections between deregulated nucleic acid sensing machinery and human disease. For instance, reviews by Constanzo et al. and by Taffoni et al.Even though nucleic acid-associated inflammation is the first line of defense of the host, activation of innate immunity is not always guaranteed. Indeed, microbes and malignant cells have developed a variety of strategies to prevent inflammation, in order to counteract the host response or escape the induction of anti-tumor immunity . SupportHemphill et al. from this Research Topic is discussing the therapeutic potential of the three-prime repair exonuclease 1 (TREX1) targeting as a novel immunotherapy strategy against cancer.Regulating abnormal nucleic acid sensing is emerging as a potent strategy against inflammatory diseases. Thus, PRRs and their downstream effectors have become attractive targets for the identification of biomarkers and the development of therapeutic agents with broad-range efficacy against inflammatory disorders. Review by Nucleic Acid-Associated Inflammation focuses on one specific aspect of nucleic acid sensing, encompassing signaling, regulation, interspecies specificities, and pathology relevance. The Research Topic is equally addressed to expert investigators who may wish to extend their knowledge on inflammation, innate and nucleic acid immunity, and to newcomers to this exciting and quickly progressing field of investigation.In conclusion, each one of the reviews and articles presented in All authors wrote the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.In Vivo Investigation (EMERG’IN DOI: 10.15454/90CK-Y371). DO is supported by the Lundbeck Foundation (R335-2019-2138), a young talented cancer researcher grant from Kræftens Bekæmpelse (R279-A16218), the Brødrene Hartman Fond, the Hørslev Fond, the fabrikant Einer Willumsens mindelegat, and the Eva og Henry Fraenkels Mindefond. VT is supported by an LSHTM/Wellcome Institutional Strategic Support Fund (ISSF) Fellowship (204928/Z/16/Z). CV-B is supported by a startup grant from the Dept. of Radiation Oncology at Weill Cornell Medicine  and by WCM Prostate Cancer SPORE Development Research Program Award. EV is supported by ANRS (ECTZ104527), LabEx HepSYS (ANR-10-LAB-28), and the French National Research Agency (ANR-21-CE15-0035-01).NL is supported by the European Research Council , “LA LIGUE pour la recherche contre le cancer” and the “Agence Nationale de Recherche sur le SIDA et les Hépatites virales” (ANRS: ECTZ117448). CL is supported by the EU INFRAIA project VetBioNet (EU H2020 project 731014) and received institutional support from INRAE. The INRAE Infectiology of Fishes and Rodents Facility  belongs to the National Distributed Research Infrastructure for the Control of Animal and Zoonotic Emerging Infectious Diseases through 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.


Moreover, since 2013, 12 different in vivo inhibition of TASK-1 in rats with A293 at 10 mg/kg/day induced the development of significant early signs of PAH, with abnormal elevation of right ventricular systolic pressure (RVSP), abnormal pulmonary vascular cell proliferation, pulmonary vessel remodeling, and lung inflammation  in a porcine model of persistent AF was associated with an increase in pulmonary arterial pressure (Wiedmann et al., + currents, and the in vitro and in vivo selective TASK1 inhibition reduces the T cell proliferation and cytokine production (Meuth et al., In line with these results, Wiedmann et al., found that chronic in vivo pharmacological inhibition of TASK-1 should be extremely managed in treated-patients with AF.For all these physiological role played by TASK-1 in several tissues, the Based on these results, one can hypothesize that A293 may induce PAH and right ventricular dysfunction in humans. Given the long history of drug-induced PAH [anorexigens (Montani et al., HL, DM, and FA drafted the manuscript. All authors reviewed and revised the final version and approved manuscript submission.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.


Biomedicines journal. The mechanisms of HDL modifications and their functional implications was exhaustively reviewed by Márquez et al. [Epidemiological studies have shown that low levels of plasma high-density lipoprotein cholesterol (HDL-C) are associated with increased atherosclerotic cardiovascular disease (CVD). However, accumulating experimental evidence has challenged this epidemiologic notion in the last decade, since HDL-C-raising strategies failed to confer increased cardioprotection in subjects at high risk for cardiovascular disease ,2. Thus,z et al. . Other sz et al.  and subjz et al. , which iz et al. .Beyond the predictive value of compositional and functional properties of HDL, a retrospective study also revealed the role of low HDL-C in predicting the risk of developing coronary artery ectasia in healthy subjects . In lineThe clinical significance of HDL changes in composition or function do not only relate to atherosclerosis. Dysfunctional HDL has also been associated with other diseases, including cognitive impairment ,11 and aRecent findings from epidemiological studies suggest an inverse relationship between HDL-cholesterol (HDL-C) and Alzheimer’s disease (AD). In the context of neurological disabilities, accumulating experimental evidence supports an HDL-mediated protection against memory deficits, neuroinflammation, and endothelial dysfunction . HoweverApart from traditionally assigned cardioprotective favorable functions of HDL , accumulating data suggest that HDL is also involved in host defence as part of immune system (reviewed in ). In linAn impaired insulin signaling is frequently associated with NAFLD and increased risk of cardiovascular disease . Plasma Finally, the work reported by Cedó et al.  was a clIn summary, studies published in this Special Issue provided clinical evidence of the usefulness of alterations in HDL composition and function in a wide spectra of diseases and helped define novel targets for the diagnosis/prognosis/therapeutics of cardiovascular/neurological/autoimmune diseases.


There has been recent debate regarding the efficacy of electroconvulsive therapy in the treatment of depression. This has been based on narrative reviews that contradict existing systematic reviews and meta-analyses. In this special article, we highlight the mistakes that occur when interpreting evidence using narrative reviews, as opposed to conventional systematic reviews and meta-analyses. For example, a group of mental health professionals, patients and relatives recently wrote to the Chair of the Care Quality Commission (CQC) in the UK, stating: ‘Given the high risk of permanent memory loss and the small mortality risk, the longstanding failure to determine whether or not ECT works means that its use should be immediately suspended until a series of well designed, randomised, placebo controlled studies have investigated whether there really are any significant benefits against which the proven significant risks can be weighed’ Read, . Calls hv. simulated ECT (sECT) for treatment of depression , and RCTs comparing different forms of ECT and pairwise and network meta-analyses of these trials.Briefly, clinical trial evidence for ECT in depression can be divided into original placebo-controlled (sECT) RCTs, further RCTs assessing ECT Ten ECT-sECT RCTs for depression have been published (summarised in n = 294), remission rates were significantly higher for ECT v. rTMS  with a significantly more pronounced reduction of depressive symptoms in the ECT group    and remission . Neither review found a significant difference in discontinuation between groups. Whilst this illustrates improved trial design (contemporary ECT modes and active comparators), these trials usually lack blinding of participants.The original ECT-sECT RCTs, conducted between the 1950s and mid-1980s, would not meet contemporary standards of evidence-based medicine (EBM) . Numerous additional modern RCTs have assessed the efficacy of ECT against non-pharmacological interventions such as rTMS. In a systematic review and meta-analysis comparing ECT with rTMS   of persistent and, for some, permanent brain dysfunction, primarily evidenced in the form of retrograde and anterograde amnesia, and the evidence of a slight but significant increased risk of death, the cost-benefit analysis for ECT is so poor that its use cannot be scientifically justified.’et al., et al., These bold claims directly contradict evidence available at the time, as well as recently published reviews  states only five of ten studies were statistically significant. Such vote-counting is a flawed method of research synthesis, and acknowledged as misleading  (see I2 = 0) and non-significant . This effect size is comparable to that reported by the UK ECT group, −0.91 (95% CI −1.27 to −0.54) derived from six trials.Given the lack of reporting of an effect size across all included trials, we conducted our own meta-analysis of trials included in the narrative review. Read and Bentall suggested Ulett et al.  be exclu63]) see . Heteroget al. , and cognitive impairment in depression is recognised in MDD  ; the study was powered based on this measure, which showed a statistically significant improved outcome with real ECT  is discouraged’. The failure to employ any standardised assessment of quality critically undermines both any objectivity and ability to draw conclusions about quality – especially as many such scales exist that are standardised, reliable and widely employed. As noted decades ago, Greenland  and Begg and Mazumdar Kendall's τ  were non-significant. The funnel plot however showed some visual asymmetry and a trim and fill analysis suggested three potentially missing studies – adjusting the effect size downward from −0.85 to −0.68.Meta-analyses of small underpowered trials can exaggerate effect sizes  . This has implications for their general criticism of past meta-analyses, where they argue, ‘All five of the meta-analyses claim that ECT is effective for depression but, as we have seen, they are all of a poor standard, not least because none of them pay sufficient attention to the quality of the papers on which they base this claim.’ The current analysis suggests at least two possibilities: either study quality is not a key driver of effect size in sECT trials or the Read et al. assessment of study quality fails to capture relevant quality differences.Importantly, meta-regression showed the Read et al.  quality et al.  in trials where previous ECT was unknown or unreported (−1.13 [95% CI −1.50 to −0.76]) rather than those reporting previous treatment with ECT (−0.67 [95% CI −0.97 to −0.37]) . Hence, trials where patients previously received ECT did not bias in favour of the ECT arm through patients being ‘unblinded’. It is also worth noting that significant differences demonstrated when comparing different modes of ECT in contemporary trials  would likely not be consistent with contemporary standards yet are still of high enough standard to contribute to the evidence base. Second, it represents a misunderstanding of principles of EBM that both Read and Bentall  and Readet al.  focus exet al., (et al., et al., et al., et al., Read et al.,  fail to  et al.,  and non-v. sECT and has significant effects on patient safety that merit a public enquiry. Examining their evidence, we have identified numerous substantial problems that stem from these narrative reviews having inherent biases and major methodological shortcomings. We would suggest those concerned with interpreting evidence continue to use conventional standardised methods of systematic review and meta-analysis where possible and that policy decisions must continue to be based on this level of evidence.Recent calls for banning ECT are based on selective narrative reviews written by authors who suggest ECT does not have efficacy et al.'s empirical arguments, moving beyond disagreement is crucial. We therefore advocate for modern trials to optimise ECT side-effect monitoring, and studies to elucidate the mechanism of action of one of the most effective treatments we have in Psychiatry.Whilst we cannot agree with most of Read


Editorial on the Research TopicAdvances in Molecular Docking and Structure-Based ModellingThe three-dimensional (3D) structures of proteins form the structural framework of their functions. Having access to the structure allows scientists to better apprehend molecular details of protein functions; it is also crucial for protein engineering, e.g., to modify and optimize an enzyme for a certain biochemical reaction; or for designing new and improved drug molecules based on the structure of the target protein. Structures are also needed to investigate how proteins interact; a vast majority of the protein-protein interface residues are involved in extensive intra-protein interactions apart from inter-protein interactions .https://www.rcsb.org)  , and thephaFold2 , it is ein silico methodologies are often complex, have limitations, and the results must be associated with appropriate statistical and quality measures. The objective of this Research Topic was to bring together various contributions based on cutting-edge computational methodologies; these include computational analysis of structures and complexes with developments and applications that integrate docking and molecular dynamics approaches, and complex experimental data such as cryogenic electron microscopy (cryo-EM).These ab-initio. The first work by Olek and Joseph dealt with the quality of models obtained by cryo-EM. In fact, the final atomic model is often incomplete or contains regions where atomic positions are less reliable or incorrectly built. They presented a software tool for the validation of the backbone trace of atomic models built in the cryo-EM maps. They use the false discovery rate analysis to segregate molecular signals from the background and show how this approach can properly complement current measures Olek and Joseph. Launay et al. tackled the challenging question of scoring in protein–protein docking. They explored several ways to perform consensus-based rescoring. They showed that rescoring performs worse than the traditional physics-based evaluation but the two complement each other and can be used in combination .Two articles underline the importance of new computational approaches for evaluating atomic models derived from experimental data or built Pitard et al. studied the interaction of calmodumin (CaM) with the bacterial virulence factor, Edema Factor (EF). The system is of great interest as orthosteric and allosteric ligands have been proposed to inhibit EF activity. Using state-of-the art MD simulations, they underlined the presence of cavities at the interface between EF and CaM that could be linked to allosteric events Pitard et al.; Tang et al. combined molecular modelling and MDs to apprehend new mechanistic insights into the exciting CRISPR-Cas9 system in the DNA cleavage state. Their results provide useful guidance for engineering new CRISPR-Cas9 editing systems with improved specificity Tang et al.; Kumari et al. look at the Farnesoid X receptor (FXR) that is essential in regulating the network of genes involved in maintaining bile acid and lipid homeostasis. MDs of FXR with or without cofactors allowed a precise description of critical residue positioning during conformational changes that explain FXR activation state underlying main differences between bound and unbound forms Kumari et al.; Ghoula et al. analysed the multi domain ceramide transfer protein (CERT) implicated in the transport of ceramide from the endoplasmic reticulum to the Golgi and plays a major role in sphingolipid metabolism. Combining docking and MD simulations, the binding affinity of 14 ligands was tested. This study suggests a novel inhibitory mechanism of CERT for limonoid compounds involving the stabilization of the sub-domain interface and could help in developing new and potentially more selective inhibitors of this transporter Ghoula et al.Classical approaches such as molecular dynamics (MD) are useful to apprehend new biological systems. In this field, Gheyouche et al. applied different approaches to model the structure of RHOA-ARHGEF1 complex and they further analysed the protein-protein interface. They refined the models using MD simulations and highlighted the importance of data-driven human inspection. The modelled RHOA-ARHGEF1 interface will be extremely useful for the design of inhibitors targeting this protein-protein interaction (PPI). Gheyouche et al. Similarly, Pal et al. look at systems of economic interest. They have characterized, using molecular docking, immune response molecules of duck protein TLR3, TLR7, and RIGI and predicted to have potent antiviral activities against different identified strains of Avian influenza Pal et al.; Gobinath et al. combined experiments and docking approaches in COVID research. They have screened and proposed new indole derivatives on the famous spike glycoprotein of SARS-CoV-2 Gobinath et al.As previously mentioned, experimental 3D structures or structural models are crucial for the design of new drug molecules. Chakraborti et al. looked at the infectious pathogen with a serious global impact: Mycobacterium tuberculosis. There is a constant need to search for novel therapeutic strategies because of the emergence of multidrug-resistant tuberculosis (MDR-TB). Universal stress protein  is a perfect target in this field. A library of 1.9 million compounds was subjected to virtual screening, which led to the selection of 2,000 hits through an enrichment process, then 22 potential binders of Rv1636 were prioritized for experimental validations where two compounds of natural origin showed promising binding affinities Chakraborti et al.; Vedithi et al. looked at the proteome of Mycobacterium leprae. They presented a large set of computational approaches to unravel new potential druggable targets Vedithi et al.At a larger-scale, Souza et al. presented innovative approaches to perform high-throughput ligand-protein docking calculations by using coarse-grained molecular dynamics simulations, based on the most recent version of the Martini force field. Their approach, characterized by excellent computational efficiency, offers a level of accuracy comparable to all-atom simulations Souza et al.; Jiang et al. looked at the Interaction of leukocyte integrin macrophage-1 antigen (Mac-1) to platelet glycoprotein Ibα (GPIbα) implicated in haemostasis and inflammatory responses. They performed a series of “ramp-clamp” steered molecular dynamics (SMD) simulations and compared the results with single molecular AFM measures. The concordance in the results underlined the importance of such approach to understand the platelet–leukocyte interaction in haemostasis and inflammatory responses under mechano- and microenvironments Jiang et al.Finally, This special issue is dedicated to the loving memory of Prof. Narayanaswamy Srinivasan who left us too soon on the third of September 2021 . As a pa


The maintenance of genomic stability in multicellular organisms relies on the DNA damage response (DDR). The DDR encompasses several interconnected pathways that cooperate to ensure the repair of genomic lesions. Besides their repair functions, several DDR proteins have emerged as involved in the onset of inflammatory responses. In particular, several actors of the DDR have been reported to elicit innate immune activation upon detection of cytosolic pathological nucleic acids. Conversely, pattern recognition receptors (PRRs), initially described as dedicated to the detection of cytosolic immune-stimulatory nucleic acids, have been found to regulate DDR. Thus, although initially described as operating in specific subcellular localizations, actors of the DDR and nucleic acid immune sensors may be involved in interconnected pathways, likely influencing the efficiency of one another. Within this mini review, we discuss evidences for the crosstalk between PRRs and actors of the DDR. For this purpose, we mainly focus on cyclic GMP-AMP (cGAMP) synthetase (cGAS) and Interferon Gamma Inducible Protein 16 (IFI16), as major PRRs involved in the detection of aberrant nucleic acid species, and components of the DNA-dependent protein kinase (DNA-PK) complex, involved in the repair of double strand breaks that were recently described to qualify as potential PRRs. Finally, we discuss how the crosstalk between DDR and nucleic acid-associated Interferon responses cooperate for the fine-tuning of innate immune activation, and therefore dictate pathological outcomes. Understanding the molecular determinants of such cooperation will be paramount to the design of future therapeutic approaches. Innate immunity, the first line of host defense, is classically triggered in response to pathogen infection or local lesions to promote infection clearance or wound-healing processes. The activation of innate immune responses vastly relies on pattern-recognition receptors (PRRs) that detect danger associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs). Upon recognition of PAMPs or DAMPs, PRRs trigger signaling cascades leading to the production of soluble mediators, such as type I Interferons, cytokines and chemokines. Pathogen-derived nucleic acids constitute major PAMPs that are detected by a vast array of PRRs that operate in specific subcellular localizations. In recent years, self-nucleic acids, originating from replication stress , DNA or A plethora of cytosolic nucleic acid sensors have been described to participate in triggering Interferon responses. Such receptors notably include the ubiquitous DNA-dependent activator of Interferon regulatory factors (DAI) , AIM2 77, 8, IntHowever, there is emerging evidence for an intricate signaling network beyond the cGAS-STING cascade, which cannot be overlooked in therapeutic strategies aiming to boost STING activation. Of particular importance is the fact that cGAS and STING have been both described as involved in genotoxic stress response and to participate to the maintenance of genomic integrity. Furthermore, the DNA-PK complex, which is best known for its function in non-homologous end-joining (NHEJ)-mediated repair of dsDNA breaks (DSB), has been shown to serve as an alternative route to stimulate type I Interferon production –21. In pmini review, we discuss this interconnection between DNA repair mechanisms and nucleic acid immunity, by focusing on the cGAS and IFI16 receptors and the way in which they control STING activation. While several DNA repair proteins have been involved in the fine tuning of inflammatory responses , “LA LIGUE pour la recherche contre le cancer” and the “Agence Nationale de Recherche sur le SIDA et les Hépatites virales” (ANRS). CT was supported by Merck Sharp and Dohme Avenir (MSD-Avenir – GnoSTic) program, followed by an ANRS fellowship (ECTZ119088). JM was supported by a “Conventions Industrielles de Formation par la Recherche” (CIFRE) fellowship from the “Agence Nationale de Recherche Technologie” (ANRT). AS is supported by the ERC-PoC DIM-CrIC (893772). IV was supported by the European Research Council (637763) followed by the Prix Roger PROPICE pour la recherche sur le cancer du pancréas of the Fondation pour la Recherche Médicale . HC is supported by a PhD Fellowship from “La Ligue contre le cancer” (TAGQ21108). We acknowledge the SIRIC Montpellier Cancer Grant INCa_Inserm_DGOS_12553 for support.JM was employed by Azelead.The remaining 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.


Vaccines entitled “Influenza Virus and Vaccine Development”. This Special Issue collects one review and seven research papers that cover multiple aspects of influenza vaccine development, including the development of candidate vaccine virus (CVV) and master donor viruses for generating high growth reassortants, new vaccines and adjuvants, assay evaluation and vaccine safety. These investigations provide a wealth of experience and lessons from recent influenza pandemics, which can also be applied to current COVID-19 vaccine development.While the scientific community has been focusing on combating novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is responsible for the current COVID-19 pandemic, we also want to draw your attention to this Special Issue of The review article by Rockman, Laurie and Barr , highligFour other manuscripts in this Special Issue report how novel vaccines can increase the strength and breadth of immune responses beyond the traditional HA response in animal or clinical studies. Bazhan et al.  describeIn this Special Issue, Carnell et al.  focused The paper by Ambati et al.  investigWe sincerely hope these lessons learned from past and current influenza research will benefit the ongoing battle against the COVID-19 pandemic.


Matrix nanocomposites are high performance materials possessing unusual features along with unique design possibilities. Due to extraordinary thermophysical characteristic contained by these matrix nanocomposites materials they are useful in several areas ranging from packaging to biomedical applications. Being an environment friendly, utilization of nanocomposites offer new technological opportunities for several sectors of aerospace, automotive, electronics and biotechnology. In this regards, current pagination is devoted to analyze thermal features of viscous fluid flow between orthogonally rotating disks with inclusion of metallic matrix nanocomposite (MMNC) and ceramic matrix nanocomposites (CMNC) materials. Morphological aspects of these nanomaterials on flow and heat transfer characteristics has been investigated on hybrid viscous fluid flow. Mathematical structuring of problem along with empirical relations for nanocomposites materials are formulated in the form of partial differential equations and later on converted into ordinary differential expressions by using suitable variables. Solution of constructed coupled differential system is found by collaboration of Runge–Kutta and shooting methods. Variation in skin friction coefficient at lower and upper walls of disks along with measurement about heat transfer rate are calculated against governing physical parameters. Impact of flow concerning variables on axial, radial components of velocity and temperature distribution are also evaluated. Contour plots are also drawn to explore heat and thermal profiles. Comparison and critical analysis of MMNc and CMNc have been presented at lower and upper porous disks. Our computed analysis indicates that hybrid nanofluids show significant influence as compared to simple nanofluids with the permutation of the different shape factors. Initially, nanofluids are considered as single phase flows but it is experimentally proved that consideration of nanoliquid as two phase compositions is much more beneficial. Yamada et al.2 discussed the combined two or more than two organic and inorganic constituents at nanoscale which are obliged in polymers. This idea executed hybridization of nanoparticles with different organic/inorganic compositions. The hybridization of base fluid with multiply structured nanoparticles change dynamics of industrial world3.With advancement in technology modern thermal management systems like central processing units in computers, light emitting diodes, transistor, solar collectors, audio amplifiers and so forth requires liquids with improved thermal conductivity. Since, ordinary fluids are unable to meet desired requirements for advanced industrial and technological procedures so insertion of nanoparticles in poorly conducting ordinary liquids are managed. The appropriate mixture of nanoparticles in specified ratios has generated exceptional thermal performance of weak thermalized systems. The concept of addition of nanoparticles was inaugurated by Choi and Eastman2, Aluminum Oxide (Al2O3) because of fact that they provide strong wear resistance and compressive power. In addition, majority volume of matrix metal composites are filled by a ceramic such as nitrides, oxides, silicides and borides. To gain optimized usage and evoking of precise nanoscopic features the ceramics as well as metallic elements are uniformly distributed. Zeeshan et al.4 investigated influence of morphological aspects of nanoparticles by varying shape on features of fluid floating across a spinning disk. Ahmad et al.5 depicted magnetized nano squeezed flow between two parallel disks along with consideration of viscous dissipation and multi natured hybrid particles. Haq et al.6 inserted Manganese-Zinc ferrite and Cobalt ferrite in viscous fluid flow between parallel disks and adumbrated enhancement in thermal conductance. Heat transfer features by inducting platelet, cylinder, and brick-shaped copper nanoparticles in water was studied by Khan et al.7. Hajabdollahi et al.8 examined morphometric aspects of (Al2O3) nanoparticles by considering platelets, spherical, cylindrical shapes, and bricks shapes on performance of tube heat exchangers. Kucharik et al.9 discussed absorption of metallic particles in water for formation of colloidal substances used in heat transfer diffusion processes in lasers. Ghozatloo et al.10 analyzed experimentally about dynamics of insertion of gold nanoparticles in water and ethylene glycol and build comparative framework regarding affectivity of particles against viscosity variant base liquids.From advent of twenty-first century a new findings in nanotechnology is discovered which is the concept of matrix nanocomposites materials. It is a two phase material with one phase consisting of solid material and other phase is nanometer sized particles. Nanomaterials are lightweight, highly strength full, sustainable, elevated temperature strengthened, corrosion resisted can be used in a wide variety of applications, e.g. aerospace, automotive, biomedical engineering etc. On basis of such mechanical, electrical, thermal, optical, electrochemical and catalytic features nanocomposites are characterized in to ceramic/metal matrix nanocomposites. MMNC is the material which composes of metal matrix distributed in concrete, ceramic, or organic substances. The reinforcement and distribution of matrix material into nano-scale particles which generates remarkable improvement in mechanical properties of formed composition. In metal matrix composites metals like copper, magnesium, and aluminum are capitalized as base metal. Since, base materials are metal which have stiffness and strength so MMNC is obliged in aviation, aerospace, defensive weapons and other areas. The most widely used reinforcements in matrix nanocomposites are Silicon Carbide (SiC), TiO11 investigated unsteady squeezing flow and upsurge in convective motion of fluid molecules bounded between two parallel disks. Mochizuki et al.12 conducted experimental analysis the mount in thermal conductivity of viscous fluid flowing between two parallel heated disks rotated radially. Characteristics of hall current on hybridized nanoliquid flow across spinning disk was demonstrated by Acharya et al.13. Bhattacharyya et al.14 examined enhancement in heat transfer properties of viscous liquid between two coaxial disks by adding carbon nanotubes. Bhat et al.15 analyzed heat transfer in flow through addition of nanostructures in a porous disk by employing tangential slip level constraint at boundary. Maskeen et al.16 established hybridized nano fluid flow with combination of alumina and copper particles under impact of Lorentz magnetic field. Ghaffar et al.17 numerically studied heat transfer in incompressible flow of fluid between two orthogonally passing coaxial porous disks with interaction of ferromagnetic nanoparticles.Heat is form of energy that arises due to temperature difference. Heat transfer with in flow procedures has received several applications like in electric power production, vehicle propulsion and climate control devices, home heating, and cooling appliances and so many. Heat transmits during the flow by the way of conduction, convection, and radiation. Generally, heat transfer in fluid arises due to convective motion of liquid molecules and enhanced is done by uplifting thermal conductivity of liquid. Researchers have experimentally discovered that this is executed by adding nanoparticles. This experimentation is proved to be successful when cooling and heating of domestic appliance like refrigerator, coils and electrical device is raised by nanoparticles inclusion. Chamkha et al.18 used hybridization of Titanium dioxide with Silicon Carbide in heavy water limited between moveable disks under effect of vertical magnetic field. Use of hybrid nanofluid during treatment of cancer patients was disclosed by Hayat et al.19. Enhancement in thermal transfer by using hybrid nanoliquid during industrial procedures was explained by Hussein et al.20. Devi et al.21 examined hydromagnetic hybrid nano-liquid (Cu-Al2O3/water) for raise in temperature and heat transfer up gradation in liquid flowing in permeable flow domain. Sarkar et al.22 evaluated optimistic impact of hybridization of nanoparticles for enhancing temperature profile. Sundar et al.23 provided comparative analysis regarding heat transfer features attained with addition of ordinary and hybridized nanoparticles.In recent years some inconsistencies in reported results regarding heat transfer rate with addition of nanoparticles is found. So, researchers have tried to use hybridized nanofluid which is engineered suspension of dissimilar nanoparticles in mixture or in composite form. This idea has further improved heat transfer and pressure drop characteristics and removed disadvantages of individual suspension. With the formation of hybridized nanofluids a better thermal network containing synergistic effect of nanomaterials is attained. In this regard several studies is available in literature like Behnam et al.24 analyzed MHD flow and its practical appliance in multiple sectors. The field of magneto hydrodynamics was introduced by Alfven et al.25. Emad et al.26 demonstrated analytical and numerical treatment about hybrid magnetic nano material in porous stretching/shrinking medium. Ghadikolaei et al.27 analyzed heat transfer features of electrical conducting hybridized nano liquid (TiO2-Cu) in water by varying shape of nanoparticles. Hayat et al.28 explored magnetically effected fluid flowing between two parallel spinning disks by using analytical approach. Ahmad et al.29 explored impact of magnetic field on asymmetric flow of fluid and found decrease in momentum profile. Rashidi et al.30 magnetic flow of viscous fluid by interpreting impact of it on thermal conductivity. Raddya et al.31 explored impact of magnetic field on nano-liquid flow in rotating frame and found reduction in velocity against Hartmann number. Mliki et al.32 demonstrated convective flow of nano fluid under appliance of MHD in an enclosure by examining thermo physical features. Turkyilmazoglu et al.33 explicated heat transfer features of magnetized viscous fluid flow generated by spinning disks. Some recent literature about flow characteristics of fluid under appliance of magnetic field in different physical configurations is enclosed in38. Sheikholeslami et al.39 aimed to investigate hot gas flow inside inner pipe and operating fluid in the annulus region filled with nanoparticles composed of CuO. Wang et al.40 analyzed utilization of hybrid nanofluid in solar photovoltaic system using the spectral beam splitting technology. Chuanpan et al.41 described a high-efficiency sensing system working with carbon nanofibers and discussed it efficiency by varying shape and amount of fibers. Guo et al.42 founded application hybridized nano based materials in environmental protection. Yun et al.43 determined degradation performance of nano-TiO2 as a coating material used in roads and bridge construction. Sheikholeslami & Farshad44 discussed the solar collector system with turbulater effect for hybrid nanoparticles. Hybrid nanofluid is useful to increase the exergy efficiency of solar system and produces higher overall efficiency45.Magneto hydrodynamics describe flow behavior of moving conducting liquid which in turns polarized it. Impact of magnetic field is evaluated in industrial processes like fuel industry, electric generators, nuclear plants, aerodynamics, crystal production and so forth. Tamim et al.To the best of the author’s knowledge there has been a scarcity in research regarding analysis of morphology effect of hybrid nanofluids coupled with matrix metal and ceramic matrix nanocomposites on thermo physical features of fluid flow between two orthogonally placed porous disks. Mathematical modeling in the form of partial differential equations is developed by considering shape and size of different (MMNC) and (CMNC). Later on, attained PDE’s are converted into ODE’s by using appropriate variables. Solution of intricate coupled differential system is attained by implementing Runge–Kutta and shooting method jointly. Impact of involved dimensionless parameters on associated profiles is adorned.2-Cu/water nanoparticles between two orthogonally moving porous coaxial disk in the presence of the external magnetic field applied in z-direction. The diameter of boundary disks is 2r. The physical model takes in a cylindrical coordinate system Let us consider an incompressible, viscous, laminar, unsteady, 2D flow of hybrid nanofluid containing TiOmentclass2pt{minim46HNfd).Law of conservation of mass, momentum, and energy are as follows referred to Kashif et al.Thermophysical properties of  is defined in Hybrid nanofluid effective heat capacitance is denoted byHNfd), and3O4), second (Al2O3), third (TiO2) and fourth (Cu) NP’s (n1 and n2) based on thermal conductivity of (HNfd). The thermal conductivity of copper nanoparticles is high than titanium oxide.HNfd) The thermal conductivity of hybrid nano fluid of specific size and shape factor of NP’s is described as underFor boundary situations the flow state is:Here, Following similarity variables are usedAssociated boundary conditionsR = Here, α = R, and consider the case following Majdalani et al.50 when α is a constant, Finally, we set F = Boundary conditions at lower and upper wall of channelSkin friction and Nusselt number at both porous walls are computed coefficients which are of engineering interest are computed in this section.The The calculation at the lower and upper disk for heat transfer rate (Nusselt numbers) Since attained couple system of ODEs manipulated in Eqs.  and 29)29) are iIn a shooting method, the missing initial condition at the initial point of the Interval is assumed, and the DE is then integrated numerically as an initial value problem. The accuracy of the assumed missing initial condition is then checked by comparing the calculated value of the dependent variable at the terminal point with its given value here. If a difference exist, another value of the missing initial condition must be assumed and the process is repeated. This process is continued until the agreement between the calculated and the given condition. For this purpose, given below Table An extensive representation of non-linear coupled system of ordinary differential equations along with coefficients possessing features of matrix composite materials and hybrid nano fluidPutting values of Eq. , Eq. 2323, Eq. , Eq. 2525, Eq.  and Eq. in Eqs. We followed the RK methodology with the inclusion of shooting methods for the solution purpose of the existing flow model. The following replacement remain ingredient to start the process:First, transform the model system of ODEs Eq.  and Eq. in the fBy interchanging, embedded in Eq. , the folConsequently, the initial condition are:46. Table This section is presented to elaborate the impact of flow concerning equations like expansion/contraction ratio parameter entclass1pt{minimamentclasspt{minimaentclass1pt{minimaR was seen in Fig. R.Figure entclass1pt{minimamentclasspt{minimamentclasspt{minimaIn this study numerical analysis of MHD hybrid nanofluids flows through porous surfaces is adumbrated. Thermophysical features of metallic and ceramic-metallic nanocomposites are combined with hybrid nanofluid. Evaluation about shape, size factors and particle volume fraction on velocity, temperature profile is executed. Numerical and graphical consequences are gained regarding skin friction coefficient and Nusselt number. n = 5.7 shows good results in MMNC than shape factors at both porous walls.Nusselt number atMagnetic parameters have a significant effect on skin friction and Nusselt number for hybrid flow.In absence of injection/suction all governing parameters at lower porous surface show good performance as compared to upper surface.R indicate better results as compared to nanofluids.Hybrid nanofluids under the effect of M and For the contracting case Nusselt and skin friction coefficients for hybrid nanofluid show significant results.Increase in volume fraction thermal boundary layer thickness increases but permeable Reynold number reduces thermal boundary layer thickness.Some key findings are itemized as below


Chemical signals are routinely propagated through biomacromolecules to modulate the structure of active sites and protein-protein interfaces. However, our understanding of the fundamental mechanisms coupling disparate regions of proteins is limited by the lack of accurate, atomic resolution information on their intrinsic dynamics. Indeed, the pathways most critical to chemical information flow are often intimately linked with the conformational ensembles populated by biomolecules, and spatially distant from traditional catalytic or ligand binding sites. A “holy grail” of biophysical chemistry has been to understand, at the molecular level, how ligand binding information is transmitted through a protein matrix to induce a functional response. Though a majority of information about dynamically-driven biological function comes from lower molecular weight proteins, an exploding number of studies have taken advantage of advances in spectroscopy, electron microscopy, and molecular simulations to synergistically map dynamic pathways that underlie long-range communication in multidomain systems.de novo spatial and temporal regulation of protein function. The articles in this Research Topic tackle this knowledge gap by reporting on the structural and dynamic components that govern intra- and inter-domain crosstalk.The advantage of visualizing the solution ensembles of large biomolecules lies in the potential to leverage flexible hotspots for drug discovery or Redzic et al. demonstrated an intricate link between micro-millisecond protein dynamics and allostery in biliverdin reductase β (BLVRB). Strikingly, evolutionary differences in amino acid sequence distal to the catalytic site induce a substantial variability in molecular motions that work in concert to regulate BLVRB function. A thermodynamic and kinetic investigation by Dubrow et al. offers insight into the role of protein motions in organizing biomolecular interfaces. Through site-directed mutagenesis, this work captures the per-residue impact on conformational selection during the binding transition state of influenza A nonstructural protein 1 and human p85β. The allosteric interactions of cholesterol with the chemokine receptor CCR3, critical to immune cell trafficking, is characterized by van Aalst and Wylie with circular dichroism and fluorescence polarization. The authors identified cholesterol as a critical mediator of substrate binding and receptor activation that drives signal transduction in GTPase assays. Cole and Igumenova used NMR spectroscopy to explore the interplay between Cd2+, Zn2+ and the conserved homology 1 (C1) zinc finger domain of protein kinase C, revealing the atomistic structural and thermodynamic properties of the C1 coordination sphere that facilitate competition between divalent metals.Purslow et al. highlighted the influence of protein dynamics on the activity of bacterial phosphotransferase Enzyme I by dissecting the contributions of active site flexibility to enzymatic turnover, most notably through the rotameric equilibrium of the catalytic His. Another elegant NMR relaxation study, performed by Zeng et al., revealed an RNA-driven disorder-to-order transition in the N-terminus of a bacterial RNase P, which serves as a dynamic checkpoint to ensure substrate alignment and enzyme activation. Baudin et al. reported an NMR structural study of the SERPINE1 mRNA binding protein (SERBP1), revealing SERBP1 to be intrinsically disordered but capable of sampling several compact conformations. The authors further define its RNA binding preferences and propensity for liquid-liquid phase separation, providing seminal molecular details of its mechanism.In another study, Le et al. carried out a novel structural study of the SpeG N-acetyltransferase, defining the structural basis for an allosteric mechanism that is unique within this enzyme family. This work implicates a dynamic loop, along with several β-strands, as mediators of enzyme activity and lays the foundation for expanded structure-function studies of SpeG. Long-range allostery in α-tryptophan synthase (αTS) is shown by D’Amico et al. to involve networks of flexible residues that propagate ∼25 Å chemical signals. Here, a novel role for surface-exposed residues in modulating dynamic crosstalk in αTS is revealed by NMR and molecular simulations. Skeens et al. and Cui and Lisi explored the intrinsic dynamics of cytokines as a driver for promiscuous and non-overlapping functions. Site-directed mutagenesis, novel structural engineering, and receptor binding demonstrated an intimate link between multi-timescale conformational dynamics and several biological activities.in silico predictions. For instance, Raniolo and Limongelli combined quantum-mechanics and free-energy calculations to improve standard ligand parametrization, allowing enhanced sampling (Funnel-Metadynamics) simulations of the paradigmatic benzamidine/trypsin molecular binding system that elegantly reproduced the high-resolution crystallographic ligand binding mode, providing a very accurate description of the binding mechanism. Hajrediniand and Ghose, instead, showed how enhanced sampling MD simulations could provide insight into the structural mediating role of a conserved “catalytic” residue that inactivates two distantly related kinase families, i.e., bacterial tyrosine and shikimate kinases.The computational works contributing to this Research Topic covered various flavors and challenges of modern atomistic simulations, demonstrating the benefits of obtaining information with atomistic resolution that can be directly compared with experimental evidence and highlighting the potential of Estarellas et al. computationally assessed changes in the structural and dynamical properties of distinct isoforms of the adenosine monophosphate-activated protein kinase complexes. The comprehensive analysis of molecular dynamics simulations, also involving network theory tools, enabled characterization of key molecular factors that mediated activation of pan-activator PF-739, identifying distinctive features that correlate with the affinities of different isoforms. Massi and Morgan also combined molecular dynamics simulations with network analysis to show that substrate specificity in the enzymatic activity of the oligosaccharyltransferase of Campylobacter lari is regulated by modulation of dynamic allosteric pathways. Finally, Pacini et al. provided a perspective on the future challenges of network theory calculations aimed at elucidating the link between the information encoded in protein primary sequences, their dynamics and functions. Jernigan and Kumar proposed, instead, the use of elastic network models to infer the dynamics of a variety of proteins (with known bound and unbound structures) by observing the transfer of fluctuations among distant regions upon binding of an allosteric ligand.Frontiers in Molecular Biosciences highlights once more the power of combining computational and experimental approaches to characterize protein allostery with atomic resolution. We expect that further strengthening and exploiting such synergy will be instrumental toward a complete dissection of the structure/dynamics/function relationship in proteins and the development of predictive tools to identify allosteric networks and hot spots for drug design.Overall, the collection of manuscripts selected for this special issue of


However, few studies integrate genetic, epigenetic, social, and environmental determinants of early life phenotypes to understand their links with diseases in later life. In this Mancilla et al. reviewed the literature to examine health inequality within the context of social epigenomics. Sasaki et al. investigated the effect of sample handling on DNA methylation profiles. Candelo et al. investigated a possible association between Zika virus infection and cyclin-dependent kinase 5 regulatory subunit-associated protein 2 (CDK5RAP2) mutation. Le et al. investigated the mechanisms linking assisted reproductive technology (ART) to cholesterol metabolic and respiratory disorders later in life. Xu et al. investigated the use of maternal serum human leukocyte antigen-G (sHLA-G) to detect prenatal chromosomal abnormalities. Ferreira and Dantas Junior reported a case study of a neonate with Beare-Stevenson Syndrome whose father had Congenital Bilateral Absence of the Vas Deferens (CBAVD). Luo et al. presented a whole exome sequencing study of Joubert Syndrome (JBTS), a type of ciliopathies.This topical collection presents original research, review articles, and case studies on a scope of exposures and health outcomes spanning the pre-natal period through adulthood. Future studies integrating a spectrum of genetic and epigenetic studies along with relevant exposures  have a potential to inform mechanisms that underlie the associations between maternal phenotypes, birth outcomes, and offspring adult diseases.