Plants are a remarkable source of high-value specialized metabolites having significant physiological and ecological functions. Genes responsible for synthesizing specialized metabolites are often clustered together for a coordinated expression, which is commonly observed in bacteria and filamentous fungi. Similar to prokaryotic gene clustering, plants do have gene clusters encoding enzymes involved in the biosynthesis of specialized metabolites. More than 20 gene clusters involved in the biosynthesis of diverse metabolites have been identified across the plant kingdom. Recent studies demonstrate that gene clusters are evolved through gene duplications and neofunctionalization of primary metabolic pathway genes. Often, these clusters are tightly regulated at nucleosome level. The prevalence of gene clusters related to specialized metabolites offers an attractive possibility of an untapped source of highly useful biomolecules. Accordingly, the identification and functional characterization of novel biosynthetic pathways in plants need to be worked out. In this review, we summarize insights into the evolution of gene clusters and discuss the organization and importance of specific gene clusters in the biosynthesis of specialized metabolites. Regulatory mechanisms which operate in some of the important gene clusters have also been briefly described. Finally, we highlight the importance of gene clusters to develop future metabolic engineering or synthetic biology strategies for the heterologous production of novel metabolites. Plants produce an array of specialized metabolites to evade biotic and abiotic stressors. Therefore, the production of specialized metabolites is influenced by various environmental cues. These metabolites have been extensively employed in preparing herbal formulations for human health care. For instance, specialized metabolites, such as vincristine, vinblastine, paclitaxel, and curcumin, are recognized as effective inhibitors of cell proliferation and being used in cancer therapeutics  and major histocompatibility complexes (MHCs), which exist as clusters in animals and are expressed in a synchronized manner  involved in the biosynthesis of hydroxamic acid 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one (DIMBOA), it was assumed that secondary metabolite-producing genes occur randomly in the plant genome  of clusters in fungi, which is absent in plants  contributed significantly to the understanding of cluster organization, and these findings could aid in developing metabolic engineering/synthetic biology strategies for overproducing these compounds in heterologous production platforms  regions spanning around oxidosqualene cyclases (OSCs are key enzymes involved in sterol biosynthesis in plants) and identified that clade II OSCs were surrounded by cytochrome P450s (CYP450s) and acyltransferase genes possibly indicating the cluster organization. These GNs were found to be in highly dynamic chromosomal regions and lacked synteny toward the regions originated from whole genome duplication (WGD) in Brassicaceae, depicting an independent mode of evolution. Interestingly, functional characterization of GNs together with OSC in different species revealed that these putative clusters are equipped with a similar set of genes, even though they exhibited a diverse spatial and temporal expression  are required for producing thalianin, which might have occurred through a chromosomal inversion event, but in A. lyrata five genes  are responsible for epithalianin production  and euphol, respectively  and Solanum tuberosum (potato) through a duplication event from the common ancestor. Similar orthologous clusters have been identified in eggplant and pepper. In pepper, few genes for SGA biosynthesis underwent deletions during the course of evolution, and as a result pepper plant produces steroidal saponins instead of SGAs  responsible for the production of medium-chain acyl sugars. These genes might have evolved through the insertion and segmental duplication events that occurred in a common ancestor before divergence , and this cluster has been reported to have evolved independently . They are considered to share a common ancestry, even though other members of Papilionoideae lost this cluster during the course of evolution as an adaptive strategy toward specific environmental niche  provided conclusive evidence about the co-occurrence of betalain pigment-producing genes on a specific chromosome, but in spinach (Spinacia oleracea) and quiona (Chenopodium quinoa) additional copies of the genes were found to exist. This could be due to tandem gene duplication mechanisms , Sad2 genes in oat avenacin cluster are recruited from sterol metabolism, and novel functions were acquired subsequently  and dicots  and GAME8 genes of SGA biosynthesis are found to be located away from the cluster in both tomato and potato  and tetrahydroprotoberberine N-methyltransferase (TNMT) genes of noscapine biosynthesis are known to lack a clustered arrangement due to their additional functions in sanguinarine biosynthesis  involved in the production of thalianin  are located away from the thalianol cluster  and marneral  clusters initiate metabolite bioproduction in Arabidopsis by converting 2,3-oxidosqualene, a branch point intermediate to a different set of metabolites. THAS and MRN1 belong to the clade II OSC of Arabidopsis, and other enzymes belonging to this clade are also found to be flanked and are co-expressed  gene is similar to cycloartenol synthase (has a role in sterol precursor production) and mediate the conversion of 2,3-oxidosqualene into β-amyrin  gene of the cucurbitacin cluster catalyzes the first step to produce cucurbitadienol, and Bi is known to be highly conserved across cucurbits  in L. japonicus, encodes an unusual OSC to produce dihydro-lupeol along with a relatively lower amounts of β-amyrin  that divert the flux of primary metabolites to synthesize the cluster-specific specialized metabolites. For instance, OSC of thalianol (Ricinus communis are involved in the diversion of geranylgeranyl pyrophosphate (GGPP) pool from the primary metabolism to the synthesis of casbene oxidases  share an analogy with the enzymes of gibberellin biosynthesis ] of maize diverts the flux of indole-3-glycerol phosphate from tryptophan synthesis to indole for the biosynthesis of benzoxazinoids, and Bx1 is considered to have evolved independently in monocots through duplication and neofunctionalization , which catalyzes the conversion of amino acids  into respective oximes . These oximes are subsequently converted to linamarin and lotaustralin  to impart nitrogen into the steroidal backbone - reticuline biosynthesis, which is the precursor for the biosynthesis of benzylisoquinoline alkaloids (BIA). On the other hand, P. somniferum methyltransferase 1 (PSMT1) and (S)- to (R)-reticuline (STORR) mediate the committed step in noscapine and thebaine biosynthesis, and these two genes are found to be arranged in proximity within their respective clusters  and CYP71 clan (CYP705 family) exist as pairs in both thalianol and marneral clusters, and it has been observed that TTC/CYP71 pairs are duplicated from a single founder cluster and then both clusters independently recruited another CYP71 family genes, which include THAH of thailanol, marneral oxidase (MRO) of marneral clusters to complete the cluster organization , a key metabolite involved in modulating microbiome of the Arabidopsis roots , short-chain alcohol dehydrogenases, transaminases, and decarboxylases . CYP450sL. japonicus catalyzes the final steps of converting dihydro lupeol to 20-hydroxy-betulinic acid, and this enzyme is found to be phylogenetically similar to MRO  of marneral cluster belonging to CYP71 clan CYP450s  accounts for the bioproduction of cucurbitadienol and its further conversion to cucurbitacin C (CuC) in Cucumis sativus  do not produce CuC due to non-functional CYP88L2, instead they produce cucurbitacin B (CuB) and cucurbitacin E (CuE) through the catalytic activity of CYP87D20 and CYP81Q59, respectively  by CPS2, then two kauerene synthase like genes (KSL6 and KSL7) produce ent-isokaurene and ent-cassadiene from ent-CDP, which are the immediate precursors for oryzalides and phytocassanes, respectively , kaurene synthase like (KSL4), CYP99 family (CYP99A2/CYP99A3) genes, and dehydrogenase (OsMAS), which are collectively involved in the production of momilactone  has a combination of diterpene synthase genes with CYP450s of CPY71 clan (TPS/CYP71). GGPP is converted into R. communis perform the conserved step reaction by oxidizing casbene and neocembrene at the fifth position, and the oxidation of the fifth carbon atom is conserved among the casbene-derived metabolites distributed across Euphorbiaceae  on the seventh chromosome of rice while OsTPS28 converts GGPP to casbene and the other two CYP450s converts casbene to 5,10-diketo-casbene  encoding enzymes of the first two steps of avenacin biosynthesis  of maize involved in DIMBOA biosynthesis are of monophyletic origin and homologous genes were not observed in other monocots other than Bx2  genome assembly led to the identification of TPS-TPS, TPS-BAHD acyltransferases, and TPS-CYP450 gene pairs, which are found to be induced upon stress conditions  as the acyl donor  and the mutants of asaat1 exhibited susceptibility to pathogenic Gaeumannomyces sp. , respectively  encodes a unique vacuolar glycosyl hydrolase 1 (GH1), and the final addition of glucose moiety is known to occur in the vacuole, although an activity of glycosyl transferases is predominant in the cytosol as well , which is essential for its antimicrobial activity  of α-tomatine gene cluster adds tetrasaccharide moieties  to tomatidine for the formation of α-tomatine  glycosylate them to avoid auto toxicity and store these biomolecules in the vacuole, while during defense response β-glucosidase cleaves sugar molecule and activates the function  compared to wild type , bitter leaf (Bl), and bitter root (Br), and the expression of these TFs is specific to fruits, leaves, and roots, respectively. These regulators can strongly bind to the promoter regions of nine cucurbitacin biosynthesis genes and influence the biosynthesis of CuC, CuB, and CuE ] is found to regulate SGA bioproduction. While the overexpression of GAME9 leads to increased levels of α-tomatine, α-chaconine, the knockout of GAME9 activity reversed the expression of SGA biosynthetic genes  of GAME9 in wild and domesticated Solanum species. In the wild species, GAME9135A exhibited a strong binding affinity to GAME7 and GAME17 gene promoters  transcription factors (TFs) related to cucurbitacin biosynthesis have been identified in cucurbits, OsTGAP1 has been identified along with its possible role in momilactone biosynthesis, and it has been shown that the overexpression of OsTGAP1 significantly enhanced metabolite accumulation  and histone 2 variant H2A.Z chromatin signatures regulated by sick with RSC/Rat1 (SWR) complex-mediated chromatin remodeling  severely affected the formation of root epidermis, implicating the biosynthesis and accumulation of specific intermediates of specialized metabolites is cytotoxic to the plant , are known to activate protein kinase C- (PKC-) mediated signaling, which is involved in repolarizing cardiac muscle cells, and could be used for treating cardiovascular disorders (Jiang et al., in silico approaches, including cluster predicting tools, such as PhytoClust, plantiSMASH, ClusterFinder, and ClustScan to name a few, have accelerated the discovery of diverse metabolic pathway-related gene clusters in plants (Chavali and Rhee, The biosynthesis of specialized metabolites in plants underpins many traits of ecological, pharmaceutical, and agronomic importance. However, plant-derived products have not gained importance till the recent times due to the domination by synthetic chemical analogs. Recent era has evidenced the emergence of plant-based natural compounds as the potential alternatives against synthetic counterparts in both agricultural and pharmaceutical sectors. Furthermore, advances in the omics approach led to the identification of plant metabolic gene clusters involved in the biosynthesis of terpenoids, alkaloids, benzoxazinoids, and cyanogenic glycosides, that have several applications. Novel findings from several studies shed light on developing sustainable metabolic engineering strategies for the overproduction of some of these specialized metabolites to meet market demands. In this regard, Artemisia annua by downregulating the expression of β-caryophyllene synthase gene to increase the bioproduction of artemisinin (Lv et al., Primarily, the biosynthetic pathways of plant specialized metabolism are complex with several gene cascades, enzymatic reactions, and compartmentalized intermediates and or end products. Hence, a thorough understanding of the pathway dynamics is necessary to develop a strategy for heterologous metabolite production. For instance, the introduction of 12 artemisinin biosynthetic genes into tobacco chloroplasts severely affected the growth of the plant (Saxena et al., Escherichia coli and yeast, is another promising approach for overproducing target metabolites by synthetic biology (Pyne et al., Santalum album. In addition, opoids were successfully produced in yeast through the introduction of morphine biosynthesis genes (Galanie et al., in silico analysis, the availability of robust functional genomic tools, and the knowledge about metabolic gene clusters could shed light into new directions in synthetic biology research at an accelerated level. The present scenario in this area of research holds a great promise to translate the basic knowledge of plant metabolism into tangible benefits for agricultural and pharmaceutical applications.The use of robust microbial hosts, such as RB, SRK, and AS wrote the manuscript. RS revised it. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.


Background: Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease with diverse clinical manifestations. Although most of the SLE-associated loci are located in regulatory regions, there is a lack of global information about transcription factor (TFs) activities, the mode of regulation of the TFs, or the cell or sample-specific regulatory circuits. The aim of this work is to decipher TFs implicated in SLE. Methods: In order to decipher regulatory mechanisms in SLE, we have inferred TF activities from transcriptomic data for almost all human TFs, defined clusters of SLE patients based on the estimated TF activities and analyzed the differential activity patterns among SLE and healthy samples in two different cohorts. The Transcription Factor activity matrix was used to stratify SLE patients and define sets of TFs with statistically significant differential activity among the disease and control samples. Results: TF activities were able to identify two main subgroups of patients characterized by distinct neutrophil-to-lymphocyte ratio (NLR), with consistent patterns in two independent datasets—one from pediatric patients and other from adults. Furthermore, after contrasting all subgroups of patients and controls, we obtained a significant and robust list of 14 TFs implicated in the dysregulation of SLE by different mechanisms and pathways. Among them, well-known regulators of SLE, such as STAT or IRF, were found, but others suggest new pathways that might have important roles in SLE. Conclusions: These results provide a foundation to comprehend the regulatory mechanism underlying SLE and the established regulatory factors behind SLE heterogeneity that could be potential therapeutic targets. Systemic Lupus Erythematosus (SLE) is a complex and multisystemic autoimmune disease characterized by the production of autoantibodies leading to chronic inflammation and organ damage. SLE is very heterogeneous, with possible affliction in almost any organ and diverse clinical manifestations including skin rashes, arthritis and renal failure . SLE is With the development of genomics technologies, our knowledge about the pathogenesis of SLE and the underlying molecular mechanisms has significantly increased. In this context, Genome Wide Association Studies (GWAS) have been widely used to identify novel susceptibility genes in SLE, with more than 60 loci found to be associated with the disease , includiDeciphering TF activity can provide models of regulatory mechanisms to explain the observed changes in gene expression patterns. During the last few years, different studies have shown that TF activity can be inferred from the expression levels of its targeted genes, known as TF-regulon . This apIn this work, we have systematically analyzed the TFs activity patterns of almost all known human TF-regulons in two gene expression cohorts of SLE patients and control samples. We first estimated the activity of TFs for each sample using DoRothEA , a curatWe used two independent gene expression datasets, one from adult and another from pediatric SLE patients, as previously described . The pedRaw data files were downloaded from Gene Expression Omnibus (GEO) (GSE65391 and GSE121239). For the adult dataset, Affymetrix Cel files were used and background correction and normalization were performed with rma function from affy R package. Normalized values of the pediatric dataset were downloaded from GEO series GSE65391 using the R package GEOquery. Sample processing pipeline is described in the original publication . Then, fTranscription factor activity from the two independent cohorts was estimated using DoRothEA, a curated database of transcription factor-target gene interactions. The methodology is described in detail in ,17. BrieHierarchical clustering analysis (using Euclidean distance and average agglomerative method) and principal component analysis were applied to the TFs activity matrix in order to establish sets of samples with similar TF activity patterns. To define the number of clusters for each dataset we used Calinski and Harabasz index implemented in the R package NbClust.The TFs activity matrix was also used to analyze differential activity between SLE and healthy controls in each dataset. We performed this analysis using linear models implemented in limma R package. Transcription factors with False Discovery Rate (FDR) < 0.05 were considered statistically significant for further analysis.Gene Set Enrichment Analysis (GSEA) was applied with the list ranked by the t value of the differentially expressed genes between SLE and healthy controls and the target genes of each TF in order to obtain the leading-edge subsets for each TF. These subsets are the gene lists that contribute the most to the enrichment score, and they are the most differentially expressed target genes for every TF. Functional enrichment analysis was performed using the Enrichr webtool. In order to identify drugs that target the significant TFs we queried the CLUE database . We downFor statistical analysis among clinical variables  between the SLE groups obtained by subgroup identification the Mann–Whitney U test was used.SLE is a very heterogeneous disease and there is consistent evidence about differences in global gene expression programs among different SLE patients. In order to evaluate if TFs activity patterns can reveal SLE subgroups, we first performed clustering analysis of SLE samples in both datasets.p =1.76 × 10−4 and Pediatric: p < 0.0001 1.33 × 10−12) and neutrophil percentages (Adults: p = 1.96 × 10−4 and Pediatric: p < 0.0001) in each group . On the other hand, the cluster 2 samples showed similar NLR values to the healthy individuals (Adults: p = 0.6441 and Pediatric: p = 0.8143)  B.Taken together, these results show that activity patterns of TF-regulons can distinguish between two main groups of SLE patients that are characterized by differences in neutrophil/lymphocyte proportions. In addition, there is clear evidence of the shared transcription activity patterns between SLE patients enriched in lymphocyte proportions and the healthy controls.In order to establish the set of TFs operating in SLE we first performed a differential activity analysis of all SLE against healthy samples. We found a set of 49 TFs that showed significant differential activity between SLE and healthy samples in both datasets . NeverthTherefore, we compared each SLE cluster independently against healthy samples in order to identify TFs that consistently showed differential activity with respect to healthy individuals. This analysis revealed a set of 96 and 60 TFs in cluster 1 and cluster 2, respectively, for the adult dataset, and 135 and 57 TFs in cluster 1 and 2, respectively, for the pediatric set. Sixty-nine TFs in cluster 1 overlapped in both sets  while 21We next evaluated which was the set of target genes whose expression contributed more to the activity signal of the 14 TFs defined in the analysis. To this end, a GSEA was carried out to identify the leading-edge subset of target genes most differentially expressed between SLE clusters and healthy samples for each TF. This analysis yielded a total of 44 target genes B. In thiSystemic lupus erythematosus is a complex and heterogeneous disease with limited diagnosis and treatment options. Despite research efforts and clinical trials that have been conducted to establish new treatments, only belimumab, a monoclonal antibody against B cell-activating factor (BAFF), has been approved in the last few decades . TherefoIn this work we have inferred the TF activities for most human TFs using gene expression levels of SLE patients with active status of the disease in two different cohorts. First, the unsupervised clustering analysis of the activity matrix revealed a two-cluster structure in both datasets, characterized mainly by differences in the neutrophil and lymphocyte proportions. Our molecular classification and clinical characterization are coherent with previous works that stratified SLE or systemic autoimmune diseases in which different proportions of neutrophils and lymphocytes were associated with different groups ,10,11. IAfter comparing TF activities from SLE and healthy samples, we defined 49 TFs with significant differential activity. A detailed analysis revealed that some of them could be biased by the heterogeneity of cell population in SLE samples, which is remarkable for the TFs MYC, RFX5, RFXAP and RFXANK. RFX5, RFXANK and RFXAP, that act as enhancers of the gene expression of the Major Histocompatibility Class II genes (MHC II) . These aDue to the observed heterogeneity in TF activities of SLE patients, we decided to compare TF activities of each cluster with healthy samples in order to obtain consistent and unbiased regulation patterns across all SLE patients. From these analyses we established 14 TFs that were consistently activated or repressed in SLE.Those with greater activity in SLE were STAT1, STAT2, IRF1, IRF3, NFATC1, PPARD, E2F2 and GATA4. As expected, this set contains transcription factors that are well-known in the context of SLE pathogenesis including STAT1, STAT2, IRF1 and IRF3 which are activators of interferon genes ,36. The NFATC1 is overexpressed in lupus-prone MRL/lpr mice activating the calcium/NF-AT pathway . MoreoveMice deficient in Ppard develop Lupus-like autoimmunity with increased production of autoantibodies and abnormal apoptotic cell clearance . There aThe rest of the significant TFs had lower activity in SLE than in controls: SMAD1, ARNTL, WT1, RELB, SPIB and TCF7L2. SMAD1, along with other genes involved in the BMP/Smad signaling pathway, is repressed through NF-κB signaling pathway in bone marrow-derived mesenchymal stem cells (BMMSCs) from SLE patients . On the Lupus nephritis is one of the most severe manifestations of SLE, characterized by the inflammation of the kidneys and the loss of podocytes . WT1 is SPIB belongs to the ETS family of TFs and promotes the development of plasmacytoid dendritic cells (pDC), the major producers of type I interferon and is involved in the development of germinal center B cells . HoweverAlthough many of the TFs associated with SLE patients have been previously described, in this work we described the stratification of SLE patients into two subgroups based on global TF activity profiles, which are characterized by differences in the neutrophil and lymphocyte proportions. In addition, we identified 14 significant and robust TFs across SLE patients. These results reveal regulation mechanisms regarding SLE heterogeneity, which might be possible therapeutic targets. The groups observed here are consistent with previous findings  and can


Reactive oxygen species (ROS) are generally small, short-lived and highly reactive molecules, initially thought to be a pathological role in the cell. A growing amount of evidence in recent years argues for ROS functioning as a signaling intermediate to facilitate cellular adaptation in response to pathophysiological stress through the regulation of autophagy. Autophagy is an essential cellular process that plays a crucial role in recycling cellular components and damaged organelles to eliminate sources of ROS in response to various stress conditions. A large number of studies have shown that DNA damage response (DDR) transducer ataxia-telangiectasia mutated (ATM) protein can also be activated by ROS, and its downstream signaling pathway is involved in autophagy regulation. This review aims at providing novel insight into the regulatory mechanism of ATM activated by ROS and its molecular basis for inducing autophagy, and revealing a new function that ATM can not only maintain genome homeostasis in the nucleus, but also as a ROS sensor trigger autophagy to maintain cellular homeostasis in the cytoplasm. Since the 1940s, the traditional view of ROS has been thought that their production is unregulated, and their targets within the cell are random. These damaged and oxidized biomolecules are considered as potential factors leading to a series of pathologies, including neurodegenerative diseases, carcinogenesis, atherosclerosis and the aging process ATM protein is an evolutionarily highly conserved serine/threonine protein kinase that is the core component of the DNA repair system and is activated to promote the homologous recombination (HR) repair pathway when DNA double-strand breaks Here, we focus on the regulatory mechanism of ATM activated by ROS and its molecular basis for inducing autophagy, and revealing a new function that ATM can not only maintain genome homeostasis in the nucleus, but also as a ROS sensor trigger autophagy to maintain cellular homeostasis in the cytoplasm.2•-), hydroxyl radical (HO•), hydrogen peroxide (H2O2), peroxynitrite (OONO-) and others ROS are generally small, short-lived and highly reactive molecules initially thought to play a pathological role in the cell. In addition to increasing the oxidative environment and thus irreversibly changing organelles and intracellular substances, such as protein, DNA and lipid, ROS also trigger important signaling events. Members of ROS mainly include the superoxide  and peroxisomes (as involved in the metabolism of long-chain fatty acids (LCFA)) In order to maintain cellular redox homeostasis, cells have evolved the antioxidant systems to eliminate reactive oxygen species, which can be divided into enzyme system and non-enzyme system. The enzyme system mainly consisted of various antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), while the non-enzyme system mainly consisted of glutathione (GSH), anti-apoptotic factor Bcl-2 and vitamin C/E. The antioxidant system can decrease the level of ROS and maintain the redox balance For many years, the traditional view of ROS has been that their production is unregulated, and their targets within the cell are random. Biomolecules damaged by excessive ROS including intracellular lipid, protein and DNA accumulate in the cell. These damaged and oxidized biomolecules are considered as potential factors leading to a series of pathologies, including neurodegenerative diseases, carcinogenesis, atherosclerosis and the aging process It is realized that reactive oxygen species are not only harmful to cells produced under pathological conditions, but also important molecules involved in signal transduction under physiological conditions. An emerging concept is redox control of protein-protein interactions. Signal transduction via proteins containing redox-sensitive cysteine residues is now a well-established concept. More and more evidence suggested that ROS can cause reversible posttranslational protein modifications to regulate signaling pathways. One of the earliest observations supporting the role of ROS in signal transduction is that the increase in tyrosine phosphorylation that occurs after growth factor stimulation  is dependent on the burst of ROS generation ROS gives us a more subversive understanding that ROS appear to be induced in response to pathophysiological stress and function as a signaling intermediate to facilitate cellular adaptation to this stress, such as regulation of autophagyATM protein is an evolutionarily highly conserved serine/threonine protein kinase originally identified for its key role in the DDR. In mammals, three protein kinases, ATM, ATR and DNA-PKCs, are the most upstream of DDR. When DNA damage occurs, they can be recruited by the corresponding protein complex to activate at the DNA damage site, performing the function of repairing DNA damage. After activation, ATM, ATR and DNA-PKcs can phosphorylate a large number of downstream proteins, which are phosphorylated and activated at Ser/Thr-Glu motifs or other sites to promote DNA repair ATM is activated by different mechanisms under DDR and ROS conditions. In mammalian cells, ATM initially appears as an inactive, noncovalently bound dimer form and is transformed into an active monomer after DNA damage However, because the ROS environment can prevent MRN from binding to damaged DNA sites, when cells are exposed to the ROS environment, the ATM activation pathway triggered by DSB is inhibited. As a result, ATM pathway activation can not only depend on autophosphorylation on Ser-1981, but also evolved an activation mode independent of the autophosphorylation of the MRN complex/Ser-1981. When the generated ROS rises to a certain threshold, some specific enzymes such as prdx2, Trx1 can chemically modify the cysteine residues on ATM to form intermolecular disulfide bonds at cys-2991, which can activate ATM. When this disulfide bond was mutated, the level of ATM activated by ROS decreased, but the MRN complex activation pathway was unaffected, suggesting the two activation pathways of ATM do not overlap. The fact that the activation pathway of ATM by ROS was inhibited upon addition of the reducing agent NAC, whereas the stimulation pathway through the MRN complex was unaffected, indirectly argues for the notion that ROS are able to activate ATM independently of the MRN complex. In this case, the activated ATM is not a monomer, but a covalent dimer linked in disulfide bonds ATM is capable of providing protection to cells under oxidative stress. In this case, activated ATM phosphorylates HSP27, binds and activates glucose-6-phosphate dehydrogenase (G6PD), alters metabolic pathways, converts glycolysis to the pentose phosphate pathway (PPP), and enhances the function of PPPUnlike ATM, ATR is activated by error events that occur during transcription and replication, particularly in ssDNA breaks. Replicating protein A (RPA) can recruit ATR to the site of DNA damage and promote ATR binding to the interacting protein ATRIP, enable the ATR-ATRIP complex to integrate into the damaged DNANutrient deficiencies and metabolic fluctuations will increase the production of ROS in cells, which can threaten cell integrity through oxidizing cellular components such as lipids, proteins, and DNA. Cells can prevent damage caused by oxidative stress by up-regulating antioxidants. However, glucose starvation promotes the enhancement of β-oxidation of fatty acids in mitochondria, and is accompanied by the generation of a large amount of ROS. At the same time, it inhibits the pentose phosphate pathway, resulting in a decrease in NADPH and GSH production, and down-regulating the antioxidant effect A growing body of evidence in recent years demonstrates oxidative stress acting as the meeting point of these stimuli, with ROS as the main intracellular signal transducers initiating autophagy Autophagy is an evolutionarily highly conserved important process for the degradation and recycling of intracellular substances in eukaryotes. During this process, some damaged proteins or organelles are encapsulated by autophagic vesicles with a double-layer membrane structure, and then sent to lysosomes for degradation and recycling. Autophagy is largely considered non-specifically mediate the bulk degradation of cytosolic components in response to acute stress. However, a grouping body of evidence suggests that autophagy selectively mediates removal of specific targets such as damaged or excess organelles (mitochondria and peroxisome) under oxidative stress. Mitophagy and pexophagy have been proposed to reduce the potential oxidative damage caused by mitochondrial or peroxisome defects 2O2 exposure, particularly through oxidation of ATM cysteine residue (C2991)2O2 or doxorubicin and endogenous ROS such as menadione or phenylethylisothiocyanate), cytoplasmic ATM acts as an ROS sensor and activates the tuberous sclerosis 2 (TSC2) tumor suppressor via the Liver kinase B1 (LKB1) / Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway to repress mammalian target of rapamycin complex 1 (mTORC1) and induce autophagy. Upon activation by ROS in the cytoplasm, ATM phosphorylates LKB1 at the same site of LKB1 that Sapkota et al found to be phosphorylated by ATM in response to DNA damage. The difference is that under DNA damage conditions, AMPK activation cannot be triggered 2O2 (disappearance of ATP deprivation). Under these conditions, the activation of the ATM/CHK2 pathway indicates that this pathway is a more sensitive signaling pathway for detecting redox disturbances caused by changes in metabolic pathways ROS has been widely reported as autophagy in the early inducers of nutrient deficiency. However, the question that still needs to be considered is how oxidative stress can crosstalk with autophagic machinery to initiate autophagy. Indeed, ATM has been proposed as being activated upon Hesidue C2919. In rMitophagy is a selective process that can remove damaged mitochondria. The damaged mitochondria are phagocytized by phagosomes, and then autophagosomes are formed and be degraded. Studies have found that S-nitrosolation can inhibit mitochondrial phagocytosis and promote cell aging through the modification of cysteine residues2O2. ROS-activated ATM can phosphorylate Ser141 of PEX5, making PEX5 monoubiquitination at Lys209. During the formation of autophagosomes, one side of PEX5, which is monoubiquitinated, is recognized by SQSTM1 and binds to SQSTM1 or neighbor of Brca1 gene (NBR1) receptor proteins through the ubiquitin binding domain, while the other side binds to the newly formed LC3B on the phagocytic membrane to target phagocytic peroxisomes. However, the induction of PEX5 pseudo-phosphorylated mutations did not induce pexophagy, indicating that ROS-activated ATM activation is necessary for PEX5-induced pexophagy Peroxisome is a highly metabolizing organelle, where many important intracellular reactions take place. In these reactions, D-amino acid metabolism and peroxisomal β-oxidation can generate a large amount of ROS Deng research group made interesting discoveries in this direction. When mitochondria are damaged by carbonyl cyanide m-chlorophenyl hydrazone (CCCP) or antimycin and oligomycin (AO), ATM translocates to mitochondria in a BRCA1-dependent manner and activates AMPK, which provides a link for the recruitment of DRP1 and BRCA1 to mitochondria. These findings indicate that the BRCA1-ATM-AMPK-DRP1 signal axis plays an important role in regulating mitochondrial fission and mitophagy Senescence means that the cell enters a stagnant state of survival in which the cell does not divide but is still active. Cell senescence is a complex biological process. Among several possible hypotheses, Mitochondrial radical theory has been widely recognized. In mitochondria, the excessive production of ROS is related to the stimulation during cell aging. When cells are senescent, the intracellular ROS level will increase ATM is an important protein kinase in the cellular senescence signal cascade. Cell senescence is closely related to the DDR pathway and ROS pathway of ATM. However, the function of ATM/DDR pathway is different from that of ROS in aging process, and these two pathways play roles in different aging stages It has been reported that in breast cancer cell models, the use of anti-cancer drugs can trigger the cellular senescence mechanism and can also cause an increase in ROS levels Ataxia-telangiectasia (A-T) is an uncommon autosomal recessive genetic disease that involves defects in the nervous system and immune system. Its pathogenic gene was discovered by Savitsky et al. and named it ATM Drebrin (DBN) is a protein that regulates cytoskeleton in the process of neuronal cell development. It can coordinate the stability of actin filaments, participate in the formation and stability of synapses, and is widely mentioned in the research of Alzheimer's disease. The stability of DBN is regulated by phosphorylation and ubiquitination, and phosphorylation can enhance protein stability. Because the metabolism of neuron cells is very active, the cells can produce a higher level of reactive oxygen species, and then activated ATM can phosphorylate DBN in ser-647, which has a promoting effect on improving the stability of DBN protein, thereby enhancing the stability of synapses, which helps to reduce the occurrence of nervous system diseases In addition, ATM contributes to the growth, maturation and stabilization of astrocytes and protects neurons under conditions of oxidative stress. In ATM-/- astrocytes, extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) are activated, leading to the up-regulation of cyclin-dependent kinase inhibitor p16 and inhibiting the proliferation of astrocytes, which makes the cells showed obvious growth defects and early death. However, N-Acetyl-L-cysteine (NAC) can inhibit these phenotypes, which indicates that these phenotypes are probably caused by ROS A growing number of studies have shown that ATM plays an important role in inhibiting the inflammatory response. In neutrophils and dendritic cells, the burst of ROS can activate ATM, inhibit the production of pro-inflammatory factors such as IL-23, and reduce the level of cell inflammation Multiple evidences indicate that ROS is an alarm signal released by cells to activate autophagy under a variety of metabolic stresses. On the one hand, autophagy can provide cells with energy, and on the other hand, autophagy can eliminate damaged biological macromolecules and organelles (such as mitochondria) to reduce further oxidative stress damage. Therefore, the autophagy activated by ROS plays a vital role in maintaining the homeostasis of cells under stress conditions. Although a large number of possible mechanisms have been reported to be involved in ROS-induced autophagy, few mechanisms directly link the perception of ROS signals and the autophagy machinery. ATM is one of the few candidate proteins. ATM can not only maintain genome homeostasis in the nucleus, but also as a ROS sensor trigger autophagy to maintain cellular homeostasis in the cytoplasm. Nevertheless, the precise mechanism of how ATM participates in selective autophagy remains to be further revealed.So far, it has been reported that ATM is involved in a variety of oxidative stress-related diseases, and these diseases is closely related to autophagy. Whether ATM-mediated autophagy is involved in these diseases, and what role it plays remains to be further explored. Although ROS scavengers can effectively reduce cellular ROS levels, they are usually ineffective in improving cardiovascular disease and sometimes even more harmful. This may be due to the different effects of ROS at different stages of the disease. It might become a new treatment strategy that activating ATM-mediated protective mitophagy to improve the outcome of ischemic diseases. ATM can be directly activated by ROS, but only a small part of the various functions performed by ROS have been revealed in the ATM dependent manner. Whether ATM is widely involved in the life activities of ROS will be a new topic in ATM research.


The vast majority of deaths due to breast cancer are attributed to metastasis and its associated relapse,3, which typically transpires in patients ~5-20 years after their initial diagnosis. Although metastasis is the most lethal characteristic of breast cancer, our understanding of the molecular mechanisms that govern this event remains incomplete, a stark reality reinforced by the finding that diagnosis of distant-stage disease has remained unchanged over the course of the last two decades.Breast cancer remains the most common malignancy and most frequent cause of cancer-related death in women, a devasting reality that annually claims more than 600,000 lives across the globe. Breast cancers most frequently disseminate to the brain, bone, and liver, doing so by undergoing a distinct sequence of events that involve: (1) local invasion through the epithelial basement membrane and migration through stromal connective tissue; (2) intravasation into blood or lymphatic vessels to facilitate dissemination; and (3) extravasation and infiltration into tissue parenchyma, followed by eventual colonization of secondary organ sites,8,9. Importantly, the rapid development of powerful new technologies and models to study breast cancer metastasis has greatly expanded our appreciation of the complexities associated with this last frontier of cancer biology. This Special Issue on Breast Cancer Metastasis is a compendium of 17 review articles, 13 original articles, and 3 case reports that collectively cover a wide spectrum of topics associated with the development and treatment of breast cancer metastases. Among the review topics presented herein are thought-provoking discussions on the potential impact of estrogen disrupting agents and ESR1 mutations to engage the metastatic cascade, as well as eloquent analyses of how fluidity and plasticity within the hierarchy of normal and malignant stems cells drives breast cancer development and metastatic progression. Similarly, Robinson et al. provide an elegant perspective on how alternations in telomere maintenance mechanisms influence the metastatic evolution of breast cancer stem cells. Likewise, thoughtful discussions on the regulation of epithelial-mesenchymal transition (EMT) programs and carcinoma plasticity also extend into new arenas of: (1) epigenetic modification of histones by lysine-specific demethylase (LSD1 or KDM1A); (2) spatiotemporal control of the translatome coupled to EMT by aberrant expression and activation of hnRNP E1; and (3) mRNA splicing factors and their essential contribution to the acquisition of EMT and metastatic phenotypes. Along these lines, Maisel and Schroeder present an intriguing and comprehensive discourse on how defects in retrograde trafficking of cytokine and growth factor receptors contribute to the acquisition of metastatic phenotypes in breast cancer.The metastatic cascade is a highly complex and inefficient process subject to regulation by a host of intrinsic and extrinsic cellular mechanisms,20. Indeed, the mysteries of metastatic dormancy have been identified as one of the ten most critical research gaps and translational priorities needed to be solved to alleviate breast cancer. Herein, the paradoxical role of autophagy in both suppressing and promoting breast cancer development and metastatic progression is discussed, particularly its importance in maintaining dormancy-associated phenotypes in disseminated breast cancer cells. Gooding et al. highlight the far-reaching impact of the noncoding genome and the long noncoding RNA BORG in regulating breast cancer metastasis, chemoresistance, and disease recurrence during metastatic dormancy. Not to be forgotten are the essential functions of the tumor microenvironment in regulating breast cancer biology and metastatic progression. Indeed, the therapeutic potential of disrupting breast cancer cell communication with stromal factors and cryptic peptides is presented, as are intriguing discussions of how: (1) involution in the postpartum mammary gland engenders a pro-metastatic microenvironment reminiscent of those found in their tumorigenic counterparts; and (2) stress and inflammatory signals disrupt neuronal circuitry, thereby contributing to brain metastasis by breast cancers.Science and medicine currently lack the knowledge to understand how disseminated breast cancers escape clinical detection by remaining dormant for years before reemerging as chemoresistant and incurable secondary tumorset al. present a comprehensive review comparing active vs. passive treatment strategies to alleviate breast cancer metastasis to the brain, while dos Santos et al. offer an equally far-reaching review on the molecular mechanisms underlying photodynamic therapy and its potential to treat metastatic disease. Additionally, the clinical utility of monitoring circulating tumor cellsas a measure of disease progression and therapeutic effectiveness is also discussed.This Special Issue also considers the translational and clinical aspects of therapeutic targeting metastatic breast cancers. Indeed, Kamal Finally, it is our hope that these timely and topical reviews will prove to be intellectually stimulating and highly thought-provoking. Likewise, we invite you to explore the 13 original articles and 3 case reports, which dovetail topically with the aforementioned reviews.


We oxidized gallium-based liquid metal that exhibited excellent wetting behavior on the surface of the composites to enable patterning of the electrodes by a facile stencil printing. The fluidic behavior of the liquid metal electrode and modulated dielectric properties of the composite ( Dielectric elastomers classified as electroactive polymers can convert electrical energy to mechanical energy in response to strain. They are typically fabricated by dispersing conductive fillers in an insulating polymer matrix in order to enhance the dielectric properties of the polymer ,2,3,4. CIn order to fabricate various deformable electronic devices out of these dielectric elastomers, competent electrodes need to be fabricated which can comply with the deformability of the soft dielectric layer without compensating factors such as connectivity, softness, and stretchability. Common materials used as electrodes include copper tapes, silver pastes, carbon pastes, and elastomers with highly loaded conductive fillers which are limited by their deformability or prolonged fabrication process. In lieu of them, gallium based liquid metal alloys can be utilized as soft and stretchable electrodes. Gallium and its alloys have drawn tremendous attention in the field of stretchable electronics due to their metallic conductivity, fluidity, and reconfigurability ,33,34,35In this work, by utilizing the unique features of the liquid metal electrode and the dielectric elastomer, we fabricated a soft and stretchable capacitive sensor. Polydimethylsiloxane (PDMS) has been widely used to fabricate dielectric elastomers by adding fillers such as graphene oxide , functioGraphite nanofibers  used as fillers were obtained from Carbon Nano-material Technology Co., LTD., Pohang, Korea. The matrix polymer used is polydimethylsiloxane . Chloroform used to disperse GNF and dilute PDMS was purchased from Samchun Chemicals, Seoul, Korea. Eutectic Gallium Indium alloy  used for electrode preparation was purchased from Indium Corporation, Clinton, New York, USA. All materials used in this work were used without any further refinement.Various solvent-based ultrasonication techniques to prepare homogenously dispersed composites have been reported previously ,61,62,63Oxidized EGaIn to be used as electrodes was prepared by stirring 20 g of EGaIn in a glass vial using magnetic stirrer at 200 rpm till the viscosity attained retarded the rotation of the stirrer (around 50 min) . Figure σdc) of the samples were measured using KEYSIGHT 34461A benchtop multimeter  using the formula [d is the thickness of the sample, A is the surface area, and pR is the resistance across the thickness.All capacitance related values were measured at room temperature using GWINSTEK 6200A precision LCR meter . For all the dielectric related measurements, five values were recorded at each frequency points and their average values and standard errors were plotted. The thickness of the films was measured using a digital thickness gauge. Scanning electron microscopy images and optical microscopy images were obtained using Supra 40 VP  and CX23 , respectively. All contact angle measurements were carried out using goniometer SEO-Phoenix 300 . DC conductivity  or dielectric constant (k) which is generally expressed as a complex value [D) which is given by the formula in Equation (3)δ is mathematically defined as the angle between the voltage and charging current, also known as loss angle [The polarizability of a dielectric material is governed by its relative permittivity  effect originating in the insulator-conductor interface [D remained significantly low. At lower frequencies, the value of k increased sharply from 10 wt % of the GNF along with high increase in dissipation factor xf is the weight fraction of the GNF in PGNC, fc is the percolation threshold (cf > xf) and s is critical exponent in the insulating region [k were observed to be increased with the increase in weight percent of the GNF in PGNC in accordance with Equation (4)  . Theoreteratures ,73,74. Tk is inversely proportional to temperature as predicted by Equation (5) involving a temperature dependent function P(T) [0k is the dielectric constant of fillers at P(T) = 1. The function P(T) can be represented by Arrhenius equation as shown in Equation (6)E refers to the vibrational activation energy of the carbon ions and k value [Furthermore, the effect of temperature on the dielectric constant of PGNC was also studied by subjecting PGNC@6wt % the GNF to different temperatures. As shown in ion P(T) (5)k=k0/ k value .A detailed comparison of some of the previously reported dielectric constant values of PDMS by incorporating different fillers at their respective concentrations of usage is shown in −3 Pa.s), but presence of the oxide skin imparts viscoelastic properties to the material [Gallium based liquid metals, especially EGaIn, have attracted great interest as conducting elements for application in soft and stretchable electronics due to their remarkable properties such as “infinite” stretchability, metallic conductivity, and fluidity near room temperature ,81,82,83material . The shematerial ,86. Thismaterial ,88. Priomaterial . Using tmaterial . Based oC is the parallel plate capacitance value, k is the dielectric constant of the dielectric layer, A is the effective area between the electrodes, and d is the thickness of the dielectric layer. The gauge factor of the device, which is defined as the slope of the relative capacitance change upon stretching, was found to be 0.7488 ± 0.0085  electrode patterned capacitive strain sensor with PDMS/graphite nanofiber composite (PGNC) as dielectric material. The dielectric properties of pure PDMS were enhanced by homogeneous dispersion of graphite nanofibers as fillers in the PDMS matrix. EGaIn was highly oxidized by magnetic stirring, which showed excellent wetting characteristics on PGNC and imparted suitable rheology for stencil printing of liquid metal electrodes on either surface of PGNC. The synergistic combination of enhanced dielectric properties of the soft and stretchable composite and the characteristic stretchability and viscoelasticity of the patterned electrodes enabled fabrication of soft and stretchable capacitive sensors that were used to sense and monitor various human motions, including finger movements and hand gesticulations, owing to capacitance changes induced by different degrees of deformation of the sensor. A combination of ease in fabrication, deformability and applicability establishes the versatility of the soft and stretchable sensor which can further prove competency in conformal, wearable, and stretchable electronics and soft robotics.


COVID-19 patients normally experience mild cold-like symptoms that progress from the early viral response phase through the lung phase to the hyper-inflammation phase. Acute respiratory distress syndrome (ARDS) characterizes the most critical stage of the illness with progressive respiratory failure. Hypoxemia is the most dangerous and challenging problem. We suggest an inductive study approach to postulate a hypothesis and synthesis of supporting evidence as a trial to resolve hypoxia in patients with COVID-19 by increasing the volume of fetal hemoglobin which has a high affinity for oxygen using methods for hypothesis related research evidence synthesis.We recommend involving umbilical cord fetal blood transfusion or the use of hydroxyl urea as a clinical trial on COVID-19 patients and also for all other types of ARDS to determine its efficacy in correction of hypoxemia, controlling progression of the disease, and increasing survival rate. In December 2019, a sudden public health incident (the corona virus disease [COVID-19] epidemic) occurred in Wuhan, China .Mortality are as high as 46% in critically ill patients requiring intensive care unit admission and oxygen therapy [Many hypotheses have explained hypoxemia in COVID-19 patients, such as hyperimmune reaction to viral infection and cytokine storm that leads to serious lung tissue and alveolar damage or even direct viral insult .A dysregulated immune system whose cells penetrate and destroy several organs, including the lungs, kidneys, and heart, is a hyper-inflammatory storm. SARS-CoV-2 is now generally known to induce aberrant T lymphocyte activation and macrophage activation, resulting in a “cytokine storm.”The dysregulated immune system destroys the endothelium and stimulates blood clotting, allowing micro and macro blood clots to form hyper-coagulability (increased clotting). Blood supply is affected by these blood clots.Extreme hypoxemia  and waiting for the cytokine fire to burn itself out simply does not work .There is more than one type of hemoglobin. In adults, Hb A or adult hemoglobin is the main hemoglobin in the blood, but there is another type of hemoglobin called fetal hemoglobin. Fetal hemoglobin  is the main oxygen carrier protein in the human fetus. Hemoglobin F is found in fetal red blood cells (f cells) and is involved in transporting oxygen from the mother’s bloodstream to fetal organs and tissues. It is produced at around 6 weeks of pregnancy . HemogloAt birth, hemoglobin F accounts for 50–95% of the infant’s hemoglobin and at around 6 months after birth, hemoglobin A becomes the predominant type. Levels of hemoglobin F gradually decrease and reach adult levels  usually within 1 year of life [The four hemes, which are the oxygen-binding parts of hemoglobin, are similar between hemoglobin F and other types of hemoglobin, including hemoglobin A. Thus, the key feature that allows hemoglobin F to bind more strongly to oxygen is by having γ subunits . In fact, some naturally existing molecules in our body can bind to hemoglobin and change its binding affinity for oxygen. One of the molecules is 2,3-bisphosphoglycerate  and it enhances hemoglobin’s ability to release oxygen . 2,3-BPGIn an interesting study, the therapeutic effect of two different doses of GBT1118 (a compound that enhances the oxygen affinity of hemoglobin) was evaluated in a murine model of acute lung injury induced by intratracheal lipopolysaccharides (LPS) instillation 24 h before exposure to 5% or 10% hypoxia in mice. GBT1118 administration to mice greatly improved the oxygen affinity of hemoglobin. Compared with mice receiving vehicle control, mice treated with GBT1118 had significantly lower mortality after LPS + 5% hypoxia  and had decreased severity of illness. Mice treated with GBT1118 showed a sustained significant increase in SpO2 over 4 h of hypoxia exposure. GBT1118 did not attenuate lung inflammation or even affect alveolar-capillary barrier permeability which means increasing survival and decreasing mortality by its ability to increase oxygen affinity to hemoglobin only .Some people have hereditary high amount of fetal hemoglobin and this condition is called hereditary persistence of fetal hemoglobin (HPFH), and it is found that people with hemoglobinopathies like sickle cell anemia or beta-thalassemia attributed with high amount of fetal hemoglobin become mostly asymptomatic or have mild symptoms , 14.So, the rational of this hypothesis is that we need to increase fetal hemoglobin which has high affinity to oxygen in COVID-19 patients so we can overcome hypoxia and desaturation that cause more tissue damage and lead to cardiac arrest—as in cases with happy hypoxia which have happened widely in COVID-19 patients—thus, we buy time for the patient’s immunity to overcome the virus.(A)The volume of umbilical cord blood varies from 50 to 140 ml with a mean of 85 ml rich in fetal hemoglobin, the average percentage is 85.5% with a range from 79 to 91%. Cord blood is currently used safely with people suffering from varying stages and grades of malignancy, thalassemia major, aplastic anemia, systemic lupus erythematosus, chronic renal failure, rheumatoid arthritis, ankylosing spondylitis, and a geriatric group of patients with benign prostatic hypertrophy after following the precautions of standard blood transfusion protocol. All have tolerated the procedure without any immunological or non-immunological reactions .(B)Hydroxyurea has been used for a long time in the treatment of myeloproliferative diseases, reducing vaso-occlusive crisis, acute chest syndrome and transfusion requirements by increasing fetal hemoglobin (Hb F) in patients with sickle cell disease, thus minimizing hemoglobin S polymerization and clinical complications .We can accomplish that by two ways: (A) injecting fetal blood from umbilical cord of newly born infants which is rich with fetal hemoglobin directly to patient, or (B) giving the patient hydroxyurea which raises F cells and fetal hemoglobin.The precise mechanism of action is not yet clear, but it appears that hydroxycarbamide increases nitric oxide levels, causing soluble guanylyl cyclase activation with a resultant rise in cyclic GMP, and the activation of gamma globin gene expression and subsequent gamma chain synthesis necessary for fetal hemoglobin (Hb F) production . Hydroxyurea also suppresses the development of bone marrow granulocytes that have a mild immunosuppressive effect, particularly at vascular sites where blood flow is obstructed by sickle cells, so it is used in cases of thrombocytosis and leukocytosis associated with a higher risk of thrombosis , 18.Indeed, maximal increments in F reticulocytes are attained at 10 or 11 days after the start of hydroxyurea treatment in patients with sickle cell anemia , 20, indF cell tests also indicate maximum changes within 14–21 days .Although many empirical therapeutic options have been introduced on several operational recommendations, including existing and new generation of antivirals, steroids, anticoagulants, and supportive management; however, the optimal management strategy for severe COVID-19 remains unclear and the degree of illness varies, ranging from asymptomatic to fulminant and fatal. While treatment of the virus itself is certainly desired, management of hypoxia which is one of the primary causes that leads to multiple organ injuries and death in COVID-19 patients may be the clue to improve the survival. High oxygen therapy has adverse toxic effect.To provide a clearer understanding of how increasing fetal hemoglobin directly affects the outcomes in patients with fulminant COVID-19.A)Site of study: this study will be conducted in COVID-19 isolated intensive care units.B)Ethical approval and consent to participate: approval will be obtained from Institutional Review Board (IRB). Written informed consent will be signed by all patients or their first-degree relatives after discussing the study design including the procedure.C)Sample size: a pilot study.D)Study design: prospective randomized controlled clinical trial.A written informed consent will be signed from all patients or their first degree relatives after discussing the study design including the procedure.# Control group: patients will receive standard investigations and treatment protocol for COVID-19.# Protocol group: patients with trial of increasing the amount of fetal hemoglobin besides receiving standard protocol.E)Hypoxia with respiratory distressHypoxia (need noninvasive or invasive ventilatory support)Refractory hypoxemia> 50% involvement of the lung parenchyma on chest imaging.Inclusion criteria: admitted COVID-19 patients to the ICU with the following clinical criteria:F)Exclusion criteria: no exclusionG)The primary outcome of this study will be 30 days or discharge survival of selected patients. This will be defined as survival to hospital discharge or to 30 days if the patient remained in the hospital.Secondary clinical outcomes will include level of hypoxemia before and after intervention, oxygen perfusion parameters, certain medication usage , investigations (rate of CT scanning), ventilator days and length of ICU stay, ICU readmission rates, and cost-effectiveness.Study outcomesDeteriorating hypoxic patients with fulminant COVID-19 will be divided randomly into two groups:This hypothesis concentrates on one and the main dangerous morbidity that occurs in COVID-19 patients which is hypoxia, and we offer a solution by increasing fetal hemoglobin in the critical patients as a trial to impact the course of the disease and minimize the morbidity especially in moderate and sever cases who suffer from desaturation until suppression of the immune dysregulation and avoidance of the impending death. Accordingly, we explicitly recommend involving fetal blood in umbilical cord for transfusion and the use of hydroxyurea in a clinical trial on COVID-19 patients and also all other types of ARDS to determine its efficacy in controlling progression of the disease and increasing survival rate.


Mitosis ensures genome integrity by mediating precise segregation of the duplicated genetic material. Segregation of subcellular organelles during mitosis also needs to be tightly coordinated in order to warrant their proper inheritance and cellular homeostasis. The inheritance of mitochondria, a powerhouse of the cell, is tightly regulated in order to meet the high energy demand to fuel the mitotic machinery. Mitochondria are highly dynamic organelles, which undergo events of fission, fusion and transport during different cell cycle stages. Importantly, during mitosis several kinases phosphorylate the key mitochondrial factors and drive fragmentation of mitochondria to allow for their efficient distribution and inheritance to two daughter cells. Recent evidence suggests that mitochondrial fission can also actively contribute to the regulation of mitotic progression. This review aims at summarizing established and emerging concepts about the complex regulatory networks which couple crucial mitotic factors and events to mitochondrial dynamics and which could be implicated in human disease. Mitosis is a fundamental process in eukaryotes which ensures genome integrity by elegantly coordinating the segregation of duplicated chromosomes in order to give rise to genetically identical daughter cells . MitosisBona fide remodeling and distribution of subcellular organelles during cell division is equally critical for maintaining the fidelity of the genome and cellular homeostasis as recently discussed by de novo, it is important to gain deep insights into the molecular mechanisms governing the inheritance of preexisting organelles in each cell division in order to prevent mitochondrial damage and detrimental consequences on cell physiology.However, energy production is not the sole function of mitochondria, since they have evolved as critical regulators of various cellular processes including metabolism, apoptosis, calcium buffering and cell division. Given that mitochondria cannot be formed Mitochondria constantly undergo dynamic remodeling of their network through fusion and fission events along with cytoskeleton-based transport, revealing a complexicity behind their distinct shapes in response to different stimuli . MitochoMFN2, OPA1, MIEF1, DNM1L, and MFF) are causally linked to severe neurodegenerative diseases extensively discussed in the literature (RHOT1 (the gene encoding Miro1 protein) and they are linked to decreased endoplasmic reticulum-mitochondrial contact sites and impaired calcium homeostasis in fibroblasts from Parkinson’s disease (PD) patients , a major cell division kinase which controls the transition from G2 phase into mitosis . InteresMoreover, yeast studies revealed that CDK1 directly phosphorylates the translocate precursor tom6 specifically during G2/M transition, stimulating the assembly of the protein import channel tom40 . This phFurthermore, CDK1-Cyclin B1 phosphorylates DRP1 on Ser 616 to stimulate its mitochondrial fission activity specifically in mitosis . This moAnother example of communication between mitochondria and the mitotic phosphorylation machinery is the recruitment of the mitotic kinase monopolar spindle (MPS1) to the mitochondrial compartment through its binding to the voltage dependent anion channel protein (VDAC1) . MPS1 isCDH1 control, which mediates the ubiquitylation and subsequent proteasomal degradation of DRP1 by binding to its destruction box (D-box) motif , a major NADPH-producing enzyme in mitochondria, thus indirectly enhancing the production of reactive oxygen species (ROS) during mitosis, although the exact mechanism is not yet clear (The anaphase-promoting complex/cyclosome (APC/C) is the E3 ubiquitin ligase and the central mediator of the ubiquitin-dependent degradation of dozens of substrates during mitotic exit through the coordinated actions of its co-activators CDC20 and CDH1 . As suchx) motif . Moreove network . Finallyet clear .CDH1 expression, although the exact mechanism is not yet known (Sentrin specific protease 5 (SENP5) is a sumo protease with essential roles in mitosis and its depletion leads to cytokinesis failure . Transloet known . Finallyet known . The autet known . Regardiet known , then OP2+ levels after x-irradiation and is partially responsible for the induction of mitotic catastrophe in mouse breast cancer cells  and the E3 ubiquitin ligase PARKIN. While, the PINK/PARKIN pathway has mostly been studied for its involvement in Parkinson disease and in mitochondrial quality control through mitophagy, several lines of evidence have proven that PINK/PARKIN activation has also prominent roles in driving mitochondrial dynamics by activating pro-fission and inactivating pro-fusion proteins, research that is described in detail in the recent review article .2+ uniporter (MCU) on Ser 57 by AMPK is vital for boosting Ca2+ import and therefore ATP production in mitochondria specifically during mitosis  is an actin-based motor protein whose protein stability and mitochondrial recruitment depends on its binding and interaction with the mitochondrial transmembrane proteins Miro . Myo19 dIn contrast to studies supporting that mitochondrial trafficking during cell division is mediated through microtubule- and/or actin-based active transport, some evidence also demonstrates the existence of a passive model for mitochondrial positioning and inheritance . The autA recent scientific breakthrough study challenged our view on how actin filaments interact with mitochondria to ensure their equal partitioning during symmetrical cell division, proving that this is far from a passive process but rather depends on multiple, parallel coordinated events . The autDefective mitochondrial dynamics either due to fission/fusion imbalance or due to deregulated transport leads to mitochondrial dysfunction and as a consequence to numerous pathological conditions and human disorders, extensively summarized in the review articles . HoweverDJ-1/PARK7  which is linked to loss of function mutations in the BLM gene . Both fiBLM gene , furtherAttacking the mitotic machinery of tumor cells through the chemotherapeutic use of mitotic kinase inhibitors and microtubule poisonous agents is a classical anti-cancer strategy, with nonetheless serious side effects and toxicity in patients and is often prone to failure in clinical trials . AccumulThe crossroads of mitotic mitochondrial fission often converge on DRP1-based pathways, suggesting DRP1 as an attractive target for combined anti-cancer strategies . Large-sConclusively, identification of new therapeutic targets and intervention strategies based on the crosstalk between the mitotic and the mitochondrial network will potentially prove beneficial in the battle against aneuploidy and aggressive tumor phenotypes.The mitochondrial network is subjected to dramatic morphological changes during cell cycle transitions. Mitochondria transform from interconnected structures during interphase to highly fragmented ones during mitosis and they need to reestablish an elongated network for the next cell cycle . The recThe signaling pathways mediating the communication between mitochondria and kinetochore represent a research line that certainly warrants further investigation. Major SAC components such as MPS1, HEC3 and BUB3 have been reported to partially localize at mitochondria but their function there remains unknown . MoreoveTraditionally, the prevailing dogma is that mitosis is a cellular process with high energy demands and that functional mitochondria are required to provide sufficient ATP amounts to fuel the mitotic machinery . A recenFor many years it was thought that cell fate is determined during mitosis, but whether and how this can be coupled to mitochondrial dynamics regulation remained unknown . A recenSince the interactions between mitochondrial dynamics and mitochondrial DNA (mtDNA) integrity and inheritance are tightly interconnected, it is highly possible that deregulation of any of these processes at any stage of the cell cycle can lead to mitochondrial dysfunction and consequently to mitochondria-related diseases. Given the indisputable role of mtDNA mutations in a wide variety of diseases, it is important to consider that there are fundamental differences in the types of mtDNA mutations and in the mtDNA replication models between mitotic and post-mitotic cells. More specifically, in mitotic tissues and cells there is a tendency for both strict and relaxed mtDNA replication alongside with a predisposition for accumulating mtDNA point mutations, whereas in post-mitotic tissues and cells, relaxed mtDNA replication and mtDNA deletions predominate . AnotherUnbalanced mitochondrial dynamics are often associated with embryonically lethal or severely abnormal developmental phenotypes . These pEP and IS: conceptualization, writing, review and editing.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.


Cytokines are key mediators of cellular communication and regulators of biological advents. The timing, quantity and localization of cytokines are key features in producing specific biological outcomes, and thus have been thoroughly studied and reviewed while continuing to be a focus of the cytokine biology community. Due to the complexity of cellular signaling and multitude of factors that can affect signaling outcomes, systemic level studies of cytokines are ongoing. Despite their small size, cytokines can exhibit structurally promiscuous and dynamic behavior that plays an equally important role in biological activity. In this review using case studies, we highlight the recent insight gained from observing cytokines through a molecular lens and how this may complement a system-level understanding of cytokine biology, explain diversity of downstream signaling events, and inform therapeutic and experimental development. Cytokines are small signaling proteins that serve as effectors of immunity and require spatial or temporal expression to regulate biological outcomes . Cytokinin vitro (. from bench to bedside), it is clear that having thorough understanding of the mechanisms driving cytokine function is crucial. One factor that complicates structure-function investigations of cytokines, and the establishment of general rules that govern their function, is the fact that these proteins exert a great deal of their influence under conditions of disease, which are more difficult to mimic in structural characterizations. In this Review, we discuss current efforts to define the mechanisms of cytokines at the “residue level,” where changes in atomic structure or conformational dynamics of the protein yields information relevant to physiological scenarios. We highlight case studies of cytokines with emerging diverse roles, while also showcasing experimental and theoretical approaches for understanding cytokine biochemistry. Though we cannot comprehensively discuss every avenue of investigation in this Review  is implicated in a wide range of disease states, where elevated MIF levels are markers for tumorigenesis , sepsis in vivo, but also regulates tautomerase enzymatic activity (Efforts to understand MIF at the molecular level have focused on 1) studies of mutations that affect its structure and function, 2) studies of signaling within its homotrimeric structure, and 3) studies of interactions between MIF and drug-like molecules . Site-diactivity  through activity . The facactivity , presentGranulocyte macrophage colony-stimulating factor (GMCSF) is involved in myelopoiesis , immunomThe GMCSF structure has been studied by X-ray crystallography , and mor. a microenvironment at neutral pH mimicking only circulating GMCSF), the resulting biochemical outcomes would not have captured its high affinity state for heparin and a gap in our understanding of its mechanism(s) would remain. Put another way, if GMCSF is expressed in high quantities in acidic environments and in the presence of high heparin concentrations, a measurable amount of biological activity presumed to be related to the GMCSF concentration would likely not correlate with its expected activity-to-quantity ratio.Atomic level studies of GMCSF mapped a clinically-relevant interaction to reveal the binding site and the biophysical factors that influence its accessibility to ligands. This work also reinforced an important aspect of cytokine biochemistry that is intimately tied to the hypothesized dynamic mechanisms of action; the utility of conducting biophysical studies in regimes beyond those of “ideal” conditions. In this case, if GMCSF were only characterized based on its presence in a certain niche . One subclass, the interleukin (IL)-1 family, comprises 11 pro- and anti-inflammatory cytokines that have abnormal expression profiles in many autoimmune diseases , which p disease .Several groups have explored the biophysical aspects of these structures in order to understand how IL-1s transduce signals throughout the cell. One example is the computational approach taken by Ozbabakan et al to map the structural postures of IL-1, IL-1R1 and IL-1RAP as well as downstream signaling proteins (such as MYD88 and TOLLIP) when previously identified oncogenic SNPs cause changes in amino acid residues . This st+ cells, including regulatory T-cells (TReg) and lymphocytes. IL-2 has been used in both agonistic and antagonistic contexts for immunotherapies, including 1) low-dose efforts to increase TReg cell counts in autoimmunity, chronic inflammatory conditions and graft rejection  hejection . Effortsvia allosteric activation as shown by Sgourakis and coworkers (μs-ms) relevant to enzyme catalysis, ligand binding, and allostery  cell populations  protein dynamics that toggle active conformations of cytokines are a driver of functional promiscuity, 2) the cellular or chemical environment modulates cytokine structure and interactions with specific binding partners, and 3) despite their small size, mechanisms of cytokine regulation can be driven by principles of allostery and concerted motion.


Radiotherapy is recognized globally as a mainstay of treatment in most solid tumors and is essential in both curative and palliative settings. Ionizing radiation is frequently combined with surgery, either preoperatively or postoperatively, and with systemic chemotherapy. Recent advances in imaging have enabled precise targeting of solid lesions yet substantial intratumoral heterogeneity means that treatment planning and monitoring remains a clinical challenge as therapy response can take weeks to manifest on conventional imaging and early indications of progression can be misleading. Photoacoustic imaging (PAI) is an emerging modality for molecular imaging of cancer, enabling non-invasive assessment of endogenous tissue chromophores with optical contrast at unprecedented spatio-temporal resolution. Preclinical studies in mouse models have shown that PAI could be used to assess response to radiotherapy and chemoradiotherapy based on changes in the tumor vascular architecture and blood oxygen saturation, which are closely linked to tumor hypoxia. Given the strong relationship between hypoxia and radio-resistance, PAI assessment of the tumor microenvironment has the potential to be applied longitudinally during radiotherapy to detect resistance at much earlier time-points than currently achieved by size measurements and tailor treatments based on tumor oxygen availability and vascular heterogeneity. Here, we review the current state-of-the-art in PAI in the context of radiotherapy research. Based on these studies, we identify promising applications of PAI in radiation oncology and discuss the future potential and outstanding challenges in the development of translational PAI biomarkers of early response to radiotherapy. External X-ray beam radiotherapy (EBRT) is a common and effective treatment for many solid tumors, used as a standalone method or in combination with other treatments, from first line to palliative setting . DependiResponse to EBRT is typically assessed by the response evaluation criteria in solid tumors (RECIST)  and its Radiobiological response is strongly influenced by hypoxia, or oxygen starvation, in solid tumors , 20. The18FMISO) in positron emission tomography (PET) can map tumor hypoxia and adjust dose escalation  and deoxyhemoglobin (Hb) in tumors at high spatio-temporal resolution (2) and blood oxygen saturation (sO2 = HbO2/THb). sO2 measured with PAI has been shown to correlate with tumor hypoxia, using ex vivo histology as the reference standard (2 (Photoacoustic imaging (PAI) is a clinically emerging localized imaging modality that enables affordable, real-time interrogation of oxyhemoglobin  (Dynamic contrast-enhanced (DCE)-PAI has also been assessed as a marker of radiation response  using ex2 (ΔsO2) , 45, whi2 (ΔsO2) . PAI usi2 (ΔsO2) , to imag2 (ΔsO2)  and uppe2 (ΔsO2)  in 3D, a2 (ΔsO2) , 75.in vivo  depths  depths , or in w) depths , 50. PAIfication . Althougfication , the oveIntratumoral heterogeneity complicates treatments in radiation oncology. The presence of focal hypoxia is clinically associated with cellular heterogeneity, genomic instability , 79, pooLocal tumor control with EBRT can be improved in patients with well-oxygenated tumors . The abi2 can inform on the heterogeneity of tumor hypoxia at ~200 µm resolution  and breast cancers. Ultrasound is already recommended in H&N cancer to detect and delineate thyroid masses or tumors arising in the neck, and to identify local adenopathy in lymph nodes of the neck  before ESince both H&N and breast cancers are widely treated with EBRT, PAI-based assessment of radiation response is already being investigated in registered and recruiting clinical trials on H&N cancer . Nonetheless, the introduction of PAI to escalate dose to hypoxic regions in EBRT requires image co-registration between handheld PAI and planning CT, and would also benefit from co-registration of PAI between fractions to observe local differences in oxygenation. Ultrasound has been investigated for inter-fraction motion management in radiotherapy  and fusiHealthy skin toxicity is a common side effect of radiation, namely, acute dermatitis, burns and inflammation , and als2 distribution have been shown to precede clinical symptoms, detectable with cutaneous blood flow measurements  scoring criteria is limited to the subjective visual assessment of visible clinical signs over weeks . For earurements  and charcroscopy , diffusecroscopy , and difcroscopy , 125. Sicroscopy .2 change between measurements taken before and after salivary stimulation post-EBRT was associated with radiation-induced salivary gland toxicity in a murine model assessed with macroscopic PAI  was later acquired by CYBERDYNE Inc. and research support from iThera Medical GmbH, both vendors of photoacoustic imaging equipment. MT would like to disclose that he is currently employed at Merck & Co.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This selective review aims to summarize the recent advances in understanding the neuromolecular underpinnings of biased cognition in depressive disorder. We begin by considering the cognitive correlates of depressed mood and the key brain systems implicated in its development. We then review the core findings across two domains of biased cognitive function in depression: pessimistic judgment bias and abnormal response to negative feedback. In considering their underlying substrates, we focus on the neurochemical mechanisms identified by genetic, molecular and pharmacological challenge studies. We conclude by discussing experimental approaches to the treatment of depression, which are derived largely from an improved understanding of its cognitive substrates. Depression is the leading cause of disability in the 21st century, affecting an estimated 350 million people worldwide [One of the most important yet still underappreciated symptoms of depression is aberrant cognition. Indeed, cognitive problems have been included in the diagnostic criteria for mood disorders, and according to the Diagnostic and Statistical Manual (DSM 5), the specific criteria for depression include a reduced ability to concentrate, disturbed memory and indecisiveness . These cThe symptomatology of depression suggests a processing bias toward negative aspects of the environment. Indeed, depressed individuals are more likely to recall negative autobiographical memories, and when they do recall positive experiences, they are overly general and lacking in detail . IndividAmong the brain regions that have been most commonly implicated in the biased cognition associated with depression are the ventromedial (vlPFC) and orbitofrontal (OFC) cortices . It has This selective minireview aims to summarize recent advances in understanding the neuromolecular underpinnings of biased cognition in depressive disorder. We begin by reviewing the core findings across two domains of biased cognitive function in depression: pessimistic judgment bias and abnormal response to negative feedback. In considering their underlying substrates, we focus on the neurochemical mechanisms identified by genetic, molecular and pharmacological challenge studies. We conclude by discussing potential experimental approaches to the treatment of depression, which are derived largely from an improved understanding of its cognitive substrates.This term refers to the tendency to overestimate the likelihood of experiencing negative events while underestimating the likelihood of positive events . This atThe two major cognitive theories of depression, Seligman’s learned helplessness theory ,21 and BAlthough the theoretical rationale and experimental evidence regarding the association between pessimistic judgment bias and depression are relatively strong, information about the neuromolecular background of this interaction is still meager and requires elucidation.2 receptor antagonist haloperidol [One of the promising neuromolecular candidates involved in the regulation of expectations about future outcomes is dopamine (DA), a key neuromodulator in reward learning and reward-seeking behavior both in humans  and in aoperidol . The effoperidol , it has operidol .1A autoreceptors in the raphe nuclei [The second key neurotransmitter implicated in cognitive judgment bias is serotonin (5-HT). Although in the abovementioned study by Sharot and colleagues , adminise nuclei ,40. Accoe nuclei ,42,43,44e nuclei . In 2013e nuclei . These re nuclei , who deme nuclei . A studye nuclei  demonstre nuclei .Along with DA and 5-HT, noradrenaline (NA) is the third neurotransmitter involved in mediating optimistic and pessimistic biases. In preclinical studies using animal models, administration of drugs boosting NA neurotransmission consistently biases cognitive judgment toward pessimism. In the study by Rygula and colleagues in 2014, the NA reuptake blocker desipramine at all tested doses rendered the rats pessimistic . A studyAlthough judgment bias was initially seen mainly as a derivative of a current affective state, which depends on the environment to which an individual is exposed, rather than a phenotypic trait, recent research unequivocally demonstrated that optimism and pessimism can be considered stable and enduring phenotypic traits ,50,51,52While the involvement of individual genes in the development of cognitive distortions and depression has not been widely proven, there are reports of the role of 5-HT transporter (SERT) polymorphisms in the development of depression, suggesting their important role in shaping cognitive biases associated with this disorder. Indeed, individuals carrying the short allele of the SERT gene are characterized by negative cognitive bias, as they tend to display enhanced attention toward negative information and interpret ambiguous stimuli in a more pessimistic way ,56. Alth1 receptor expression were more optimistic, while chicks with higher serotonin 5-HT2A receptor expression tended to be less optimistic. These results further suggested the involvement of monoaminergic systems in cognitive judgment bias.A recent study by Boddington and collaborators suggested that individual differences in biased cognition can be partially explained by variations in brain gene expression . They anTaken together, although the mechanisms contributing to biased judgment in depression remain poorly understood, the majority of the studies conducted to date point to a common neuromolecular and cellular background of emotional regulation and cognitive judgment bias. This background includes various alterations in the function of the monoaminergic system function in the brain and associated physiological and cellular processes, such as a proinflammatory profile, variability in serotonergic and dopaminergic gene expression, or altered telomerase activity  “Go” pathway. On the contrary, DA depletion  switches the balance toward higher sensitivity of dopamine D2 receptors and leads to activation of the (indirect) “No-Go” pathway. Therefore, activation of dopamine D1 receptors improves learning from positive feedback, while activation of dopamine D2 receptors improves learning from negative feedback.As proposed by Frank and O’reilley  and supp2 receptor gene, associated with striatal dopamine D2 receptor function, predicted the degree to which participants learned to avoid choices that had been probabilistically associated with negative outcomes; and the Val/Met polymorphism of the catechol-O-methyltransferase (COMT) gene, associated with prefrontal cortical DA function, predicted participants’ ability to rapidly adapt behavior on a trial-to-trial basis. A specific role of another dopamine D2 receptor gene polymorphism (DRD2-TAQ-IA) in feedback-based learning in a human neuroimaging paradigm was demonstrated in 2007 by Klein and colleagues [2 receptor densities learned to avoid actions with negative consequences less efficiently than those without the allele. In the latter, the A1 subjects demonstrated an impaired ability to sustain a newly rewarded response after a reversal of the stimulus-reward contingency in the PRL task and showed a generally decreased tendency to stick with a rewarded response.Research by Cools and collaborators  revealedlleagues  and in 2lleagues . In the 2C [2C receptor antagonist SB 242084 reduced sensitivity to positive feedback, while administration of the serotonin 5-HT2C receptor agonist WAY 163909 resulted in changes associated with increased sensitivity to positive feedback and decreased sensitivity to negative feedback. It has been proposed that oversensitivity to negative feedback associated with low levels of tonic 5-HT could represent either enhanced prediction error signals, brought about by an increased signal-to-noise ratio of phasic 5-HT bursts [A growing number of studies have also implicated 5-HT in the modulation of sensitivity to feedback. Published reports suggest that increasing 5-HT transmission leads to a reduced sensitivity to aversive outcomes, whereas decreasing 5-HT transmission, by way of either acute tryptophan depletion, presynaptic receptor stimulation or upregulation of SERT, leads to an increased sensitivity to aversive outcomes (reviewed by ). In the2C . In the T bursts , or atteT bursts .In 2017, Rychlik and colleagues reported the role of glutamatergic neurotransmission in mediating sensitivity to feedback . In thisRecent research with a pharmacogenetic model of reduced neurogenesis and a translationally relevant PRL paradigm demonstrated novel functions for adult-born neurons in sensitivity to rewards and negative feedback . In thatA study by Vaselic and colleagues revealed that reward processing and learning can be influenced by the sex hormone estradiol, which increases sensitivity to positive feedback and that these effects can be partially modulated by striatal DA transporter (DAT1) genes and personality traits related to reward sensitivity . SimilarThe studies by Bryce and Floresco  and DietTo summarize this section, key components of the neuromolecular puzzle constituting sensitivity to feedback include components of the dopaminergic, serotonergic and glutamatergic neurotransmitter systems, as well as sex and stress hormones and alterations in neurogenesis .Contemporary pharmacological treatment strategies for depressive disorder are directed at drugs that block the reuptake of 5-HT (the SSRIs) and/or NA (the SNRIs) from the extracellular space, which is thought to enhance the neural activity of these systems over time. Although clinical evidence clearly shows that the beneficial effects of these drugs occur with prolonged (min. 4–6 weeks) treatment, this delay in antidepressant action seems to be counterintuitive, as the molecular, cellular and chemical effects occur very quickly after a drug is administered, and recent studies have demonstrated that beneficial effects on biased cognition are evident even after the first dose. The cognitive neuropsychological theory of antidepressant action ,108 was The aforementioned advances in studying neuromolecular correlates of biased cognition in depression are both exciting and timely. We are sure that the next few years will see exciting discoveries emerge from a new focus on this level of inquiry. This progress must evolve from the collection of experimental data from various brain areas and neural networks through the integration of a biologically grounded theoretical framework with deeply analogous animal research using the newest neuromolecular techniques to human cognitive neuroscience and clinical psychiatry. Indeed, current single-cell genomic technology already allows us to obtain new molecular mechanistic insights from the brains of depressed patients. Other emerging techniques include transcranial focused ultrasound/radiation methods. These approaches can be improved by combining them with the molecular mechanisms suggested in our manuscript. It seems also crucial to combine the levels of inquiry tackling at the same time molecular mechanisms and whole circuits. When seeking a better understanding of the neuromolecular background of cognitive biases in depression, we need to actively commit to synergy.