DNA markers improved the productivity and accuracy of classical plant breeding by means of marker-assisted selection (MAS). The enormous number of quantitative trait loci (QTLs) mapping read for different plant species have given a plenitude of molecular marker-gene associations.In this review, we have discussed the positive aspects of molecular marker-assisted selection and its precise applications in plant breeding programmes. Molecular marker-assisted selection has considerably shortened the time for new crop varieties to be brought to the market. To explore the information about DNA markers, many reviews have been published in the last few decades; all these reviews were intended by plant breeders to obtain information on molecular genetics. In this review, we intended to be a synopsis of recent developments of DNA markers and their application in plant breeding programmes and devoted to early breeders with little or no knowledge about the DNA markers. The progress made in molecular plant breeding, plant genetics, genomics selection, and editing of genome contributed to the comprehensive understanding of DNA markers and provides several proofs on the genetic diversity available in crop plants and greatly complemented plant breeding devices.MAS has revolutionized the process of plant breeding with acceleration and accuracy, which is continuously empowering plant breeders around the world. The advent of the Green Revolution in the 1960s brought a step change in the potential yield of wheat and rice and is credited with avoiding severe food crises . To meetA molecular marker in association with a genetic map linked to a gene or quantitative trait loci (QTLs) of agronomic interest;Molecular markers are tightly associated with the QTLs or major genes;Sufficient recombination between the molecular markers that are associated with desirable traits and the rest of the genome; andA possible analysis method of a large number of individuals in a time and cost-effective manner.A fruitful utilization of molecular markers to help breeding systems depends on a few elements:Most of the fruitful utilization of MAS examined beneath depends on this class of molecular markers. The gene located on a particular region of the chromosome can be shown by one or more QTLs. In this situation, genomic regions to be chosen are frequently chromosome fragments; it is in this manner best either to have two polymorphic markers flanking the targeted QTL or potentially at least one marker inside the QTL genomic region. A few models identified with the two methodologies for the introgression of QTLs into various genetic systems are discussed below. Until now, MAS has been demonstrated to be powerful for generally basic characteristics that are controlled by few genes, and a few examples are given in this review on the benefits and on the effective use of MAS for this class of traits. For progressively complex traits, it has been proven that MAS is not to be more effective; a few reasons in the premise of these challenges, a few instances of fruitful utilization of MAS for quantitative characteristics, and points of view for expanding the effectiveness of MAS for QTLs are talked about. The basic procedure of molecular marker-assisted selection is presented in Fig. There are five fundamental contemplations for the utilization of DNA markers in MAS: reliability; quality and quantity of required DNA; amount and nature of DNA required; specialized methodology for marker examination; the level of polymorphism; and cost , 12.Markers ought to be firmly connected to the target loci, ideally under a 5-cm distance of genes. The utilization of flanking markers or intragenic markers will significantly build the reliability of the markers to foresee the phenotype.Some marker strategies require enormous sums and a high calibre of DNA, which may some of the time be hard to get by and by, and this adds to the expense of the system.The degree of effortlessness and the time required for the procedure are basic contemplations. High-throughput, straightforward, and snappy techniques are exceptionally attractive.Ideally, the marker ought to be profoundly polymorphic in the breeding material (for example it should separate between various genotypes), particularly in the central breeding material.The cost of DNA markers should be affordable. This infers the test ought to be modest, easy to understand, and simple to apply for effective screening of enormous samples/populations. The cost-effectiveness of the molecular marker assay should be considered to ensure the plausibility of the molecular marker-assisted selection. Sequence tagged site (STS), Simple sequence repeats (SSRs), single nucleotide polymorphism (SNP), or sequence characterized amplified region (SCAR) markers that are gotten from an explicit DNA sequence of markers (for example limitation piece length polymorphisms: RFLPs) that are connected to a quality or quantitative attribute locus (QTL) are likewise amazingly helpful for MAS [2015].Nature of gene action (dominant or co-dominant markers);Detection methods of molecular markers (PCR based molecular markers or hybridbased molecular markers);Transmission mode of molecular markers .DNA or molecular markers are classified in different groups on the basis of:DNA or molecular markers have been developed in various kinds and all these have applied successfully in breeding and genetic activities in different agricultural crops throughout the world. In this review, brief information has provided that is related to molecular markers based on the detection methods of molecular markers. Comparisons of the important characteristics of the most used molecular markers are given in Table Molecular markers are sequences of nucleotides and can be explored through the polymorphisms present between the nucleotide sequences of various people. Deletions, insertions, gene mutation, duplication, and translocation of these nucleotide sequences are the basis of polymorphisms among the population; however, they do not really influence the function of genes. A perfect DNA marker ought to be co-predominant, uniformly distributed, genome, more and having the capacity to recognize a more significant level of polymorphism.DNA markers, conventional, or first-generation RFLPs, require the utilization of a properly labelled DNA probe for the selection of the specific genes of interest from the digestion of DNA samples and then, by hybridization. RFLP was the primary molecular marker strategy and the main marker framework dependent on hybridization. People of the same species show polymorphisms because of insertions/deletions (known as InDels), gene mutations, duplications, translocations, and inversions. The isolation of pure DNA from the target is the primary step in the RFLP strategy. This DNA is blended in through the cutting enzymes (restriction endonucleases) which are isolated from the target such as bacteria, human cells, etc. and a specific function of restriction enzymes identify specific nucleotide sequences along the DNA strand, and therefore they cut DNA at specific loci (acknowledgment destinations). These outcomes are an immense number of segments with various lengths.Molecular markers based on PCR techniques do not require a probe hybridization step. PCR-based markers are atomic markers that do not require the hybridization step. Their improvement has prompted the disclosure of a few valuable and simple to screen new generation markers, for example random amplified polymorphic DNA(RAPD), amplified fragment length polymorphism(AFLP), microsatellite or SSRs, SNP, RAMP, SRAP, ISSR, SCAR, expressed sequence tagged (EST), and so forth . Being PSometimes, DNA sequences change their position in the genome and may insert into the coding regions of the genome. Such mobile DNA sequences are called transposable elements (TE). These transposable elements have been found in maize during the study of the genome by Barbara McClintock in 1950 and considered that they are present in the eukaryotic genomes at a larger scale (Bourgeois and Boissinot ). BeforeRetrotransposon microsatellite amplification polymorphism (REMAP) is also a more important marker based on retrotransposons and commonly used to evaluate the genetic diversity of individuals of the population. The protocol for utilization of REMAP is just like IRAP, although SSRs (microsatellites) are used in conjunction with specified markers of LTE at the time of PCR cycling . The priRetrotransposon-based insertion polymorphism (RBIP) technique is used to investigate the presence or absence of sequences of retrotransposons present in the genome. In this technique, amplification of DNA is accomplished with the help of a primer having 3′ and 5′ end regions that are flanking the retrotransposon insertion site. Insertion sequences in retrotransposons are identified through the development of a primer from the LTR region. The information of nucleotide sequences along the flanking region of the retrotransposon insertion site is required in the RBIP technique, and the result of this technique in typing of a single locus compared to other molecular markers based on retrotransposons . Like otInter-SINE amplified polymorphism is based on retrotransposons having none of the LTR region and the technique has developed , designeThere are limitation factors are LTR sequences must be known during utilizing retrotransposons as molecular markers. The technique inter-primer binding site (iPBS) was created by Kalendar et al.  to overcSeveral genes in animals and plants are involved in defence mechanisms and some specific sequences of these genes act as markers, so they are called resistance gene markers . Before Resistance gene analogue polymorphism (RGAP) employs uncut genomic DNA as a PCR template and degenerate primers for conserved regions of R genes to screen for R genes and RGAs . Over a Several biological responses of plants to biotic and abiotic factors during growth and developmental processes may regulate due to the expression of genes. Several methods have been evolved for getting an insight into these biological responses of plants and lead to the generation of markers based on polymerase chain reaction (PCR-based markers). Fingerprinting markers are based on the amplification of a subset of fragments prepared from RNA or DNA. The techniques summed up here depend on the transcription of a specific region of the genome that is most likely functional. Recently, Rustogi and Gupta  reviewedEndogenous noncoding small RNAs consisting of 20–24 nucleotides are ubiquitous in eukaryotic genomes, where they play important regulatory roles Gui et al.  and theySequencing of cDNA creates a lot of data, presently accessible in open information databases. Expressed sequences tags (ESTs) are short regions of transcribed sequences that are typically read in a direction and provide a precise way of gene expression analysis and assist in detecting genetic diversity. When changed over to cDNA, the expressed genes can be sequenced in two ways, delivering 5′ and 3′ ESTs. The last fall more frequently inside untranslated regions (UTRs), while 5′ ESTs are related to protein coding. Numerous accessible bioinformatics apparatuses  permit tExploiting the genomic components, a novel group of markers has been created, here named targeted fingerprinting markers (TFMs). They are defined as multi-locus markers, produced in a semi-arbitrary and targeted way at different regions of the genome, and apparently compared to polymorphic sites of any gene or gene-related area regardless of their capacity. This implies the marker systems assembled here are (gene)-targeted markers which do not really yield fingerprints engaged with phenotypic mutations. TFM markers will in general combine the advantageous features of different techniques, highlights of a few essential procedures, while likewise the integration of several methods to identify genetic discontinuities or distinctiveness. Fingerprints are created in a semi-arbitrary way, because of the incorporation of normal features of the plant genome, banding designs are delivered to unknown yet targets sites. This empowers the entire genome distribution and preferable reproducibility can be accomplished with a specific primer design or even with a changed PCR protocol. Exploiting the basic genomic features makes TFM procedures effectively adaptable between numerous life forms and gives options in contrast to past AAD markers.Gossypium L.) promoter regions.The promoter regions that facilitate the transcription of a gene are located too close to a particular gene ; along tThis technique, developed by Desmarais et al. , resemblThe second technique, called targeted region amplified polymorphism (TRAP) and developed by Hu and Vick , is likeSome of the transcribed regions of molecular markers within the genome could have applications in genotyping of plants as they unmask the polymorphism that is related directly to the function of genes. Start codon targeted polymorphism (SCoT), a novel system of marker, gets popularity quickly after being described by Collard and Mackill . The SCoConserved region amplification polymorphism (CoRAP) by Wang et al.  is a tecThe advantages of MAS described below may have a deep impact on crop plant breeding in the future and may change the crop plant breeding paradigm . In thisSeeds from different strains are to be often mixed because of difficulties in handling many seed samples that are utilized between and within plant breeding programmes. Markers may be utilized in conferring the actual identity of plant individuals. High-level genetic purity and their maintenance are more important in the production of cereal hybrids to exploit heterosis. In hybrid rice, SSR and STS markers were used to confirm purity, which was considerably simpler than the standard “grow-out tests” that involve growing the plant to maturity and assessing morphological and floral characteristics .It was reported from a hybrid of maize and sorghum that molecular or DNA markers have been used to define a heterotic group that may be used in the exploitation of heterosis (hybrid vigour). The hybrid line is developed for the utilization in producing superior hybrids and this developmental process of the line is more time consuming and more expensive. Unfortunately, it is not yet possible to predict the exact level of heterosis based on DNA marker data, although there have been reports of assigning parental lines to the proper heterotic groups . The abiDistinguishing proof of movement in allele frequencies inside the genome can be significant data for breeders since it makes them aware of screening explicit alleles or haplotypes and can be utilized to configuration proper breeding procedures . DifferePlant breeding programmes are greatly depending on the high level of diversity in the genetic material in attaining progress in the selection process. Expansion of the genetic base of the core breeding material needs the identification of various strains for hybridization with elite cultivars . NumerouIntrogression essentially implies the transfer of a particularly desirable trait from one plant species to another with the help of hybridization and frequent backcrossing. Hospital F. 2009 , charactSome time ago, the primary study about the evolution of species or characters was dependent completely on geographical conditions and morphological variation among the populations. The development of various techniques in molecular biology offers more information to the genetic makeup of an organism. Nowadays, a large number of molecular markers are required for phylogeny to get information about evolution and used to reconstruct the genetic map of an individual. Due to the simplicity and stability in genetic makeup, the molecular study of chloroplasts has extended the information about the phylogeny of an individual and make them perfect markers.Markers can be used in backcross breeding at three phases of frontal area, recombinant, and foundation determinations. At the main phase of forefront choice, markers are utilized to select the desirable trait. The utilization of markers here is strong because a few qualities have relentless phenotypic selection methods or passive alleles whose impact could have been suppressed by the dominant genes. The recombinant selection is the second stage which includes selecting backcross offspring with the character and firmly connected flanking markers, so linkage drag can be decreased. The third stage is referred to as the selection of background and it includes selecting backcross descendants (for example offspring previously selected for the desirable traits) utilizing the background markers. In any case, the background markers must not be firmly connected to markers yet ought to be perfect rice markers , 76. ThiThe procedure of integrating multiple genes at the same time or quantitative trait loci into a single genotype is known as pyramiding . PyramidCommon DNA markers like restriction fragment length polymorphism (RFLP), randomly amplified polymorphic DNA (RAPD), and simple sequence repeats (SSRs) have aided in the mapping and association studies that led to the uncovering of genes of interest. These DNA markers, on the other hand, are produced at random from polymorphic locations in the genome, and some can be found far away from the gene of interest, suggesting that they are not related to the phenotype. Therefore, such random DNA markers can be replaced with functional markers  created using polymorphic regions within genes that produce phenotypic trait variation . FunctioArabidopsis plants [Targeted induced local lesions in the genome (TILLING) is a non-transgenic technique of reverse genetics and is applicable to most crop plants. TILLING was developed by McCallum in 1990 during the study of understanding the functioning of two genes in s plants . TILLINGs plants . Later, Virus-induced gene silencing (VIGS) is a virus-mediated methodology that is used to exploit an RNA-mediated defence mechanism. After the synthesis of siRNA, its base pairs guide the complex of RNase in that condition in which it targets a specific single-stranded RNA that appears just like the dsRNA molecules . Double-Various crop plant has improved due to the utilization of CRISPR genome editing technique . The newO. sativa spp. indica and O. sativa spp. japonica varieties and 446 wild rice accessions (Oryza rufipogon) were collected and sequenced with low genome coverage [O. rufipogon accessions for leaf sheath colour and tiller angle, which would have stronger mapping power owing to a higher level of genetic diversity in the wild species. Moreover, the GWAS was performed based on the microarray-based genotyping approach. In total, 413 diverse accessions of O. sativa were genotyped at 44,100 SNP variants and phenotyped for 34 traits, and the result showed the complex genetic architecture of the traits in rice. In maize, the genetic architecture of flowering time, leaf angle, leaf size, and disease resistance traits were dissected by conducting linkage mapping and GWAS jointly in the NAM panel, and multiple related candidate genes were identified [Genomic-wide association studies (GWAS) take full advantage of ancient recombination event to identify the genetic loci underlying traits at a relatively high resolution. GWAS methodology became well established in human genetic during a decade of great effort. With the rapid development of sequencing technologies and computational methods, GWAS are now becoming a powerful tool for detecting natural variation underlying complex traits in cops . GWAS incoverage . A high-entified –169. Theentified . A totalRNA-sequencing (RNA-seq)-based genotyping retrieves genotypes from RNA-seq data. Despite the great variation in genome size for different crops, there are no significant changes in the number of genes or total gene size. Because most repetitive regions are ignored, performing transcriptome sequencing for SNP calling rather than whole-genome resequencing is quite cost efficient. For example, a recent study genotyped many SNPs and expression of QTL (eQTL) mapping simultaneously . It woulGenetic mapping of major genes and quantitative trait loci (QTLs) for many important agricultural traits is increasing the intention of biotechnology with the conventional breeding process. Exploitation of the information derived from the map position of traits with agronomical importance and of the linked molecular markers can be achieved through marker-assisted selection (MAS) of the traits during the breeding process. However, empirical applications of this procedure have been shown that the success of MAS depends on several factors, including the genetic base of the traits, the number of individuals that can be analysed, and the genetic background in which the target gene must be transferred. MAS for simply inherited traits are gaining increasing importance in breeding programmes, allowing acceleration of the breeding process. Traits related to disease resistance to pathogens and to the quality of some crop products are offering some important examples of a possible routinary application of MAS. For more complex traits, like yield and abiotic stress tolerance, several constraints have determined severe limitations on efficient utilization of MAS in plant breeding, even if there are a few successful applications in improving quantitative traits. Recent advances in genotyping technologies together with comparative and functional genomics approaches are providing a useful tool for the selection of genotypes with superior agronomical performances.Although some investigations provided examples on the practical application of MAS to increase yield, it is becoming clear that an integrated approach involving traditional methods of agricultural improvement  and a coOryza rufipogon have recently been extensively studied by using advanced BC populations [O. rufipogon had a beneficial effect for yield and yield components in the recipient rice elite cultivars. The lower percentage reported in the second study may be explained by a higher genetic similarity between the elite line and O. rufipogon at the yield QTL alleles or by the fact that in this cross the elite cultivar may have more favourable alleles at most of the identified loci. Some of the O. rufipogon yield QTLs identified were linked to any deleterious negative QTLs and would directly be useful to develop breeding materials. In several different instances, the O. rufipogon alleles showed the same effects in different genetic background and environment, supporting the stability of these yield QTLs. A thousand grain weight (TGW) QTL has recently been identified on chromosome 6 by using BC inbred line derived from a cross between the high-yield rice japonica cv. Nipponbare and the low-yield indica cv. Kasalath [QTL alleles for yield components traits derived from the wild rice relative ulations . In thesulations  and 33% ulations  of the QKasalath . The QTLMarker-mediated backcrossing is a selection scheme used in maize to monitor the transfer of favourable allele at QTLs (foreground selection) and to hasten the return to the recipient genotype in the remainder of the genome (background selection) . A similar approach of marker-mediated backcrossing has been used to generate series of maize NILs derived from an elite recipient line (the recurrent line) and an exotic donor line . Marker-CBF1 overexpression induces COR genes and enhances freezing tolerance in Arabidopsis [CBF gene family may regulate the stress. PCR-based markers (a RAPD marker and an STS derived from the sequence of a wheat RFLP mapped in the frost tolerance QTLs region on chromosome 5H) have recently been validated for their ability in assessing frost tolerance level in two sets of winter and spring barley genotypes and in doubled-haploid lines derived from a cross between a highly tolerant and susceptible genotype [OsAOX1a) with two closely linked QTLs (Ctb1 and Ctb2) for low-temperature tolerance of anther at the booting stage mapped to chromosome 4. They found that the allelic variation in molecular mass of AOX isoforms among varieties differing in low-temperature tolerance co-segregate to the presence of the QTL. These results suggest that exploitation of this SNO represent a good tool for MAS of the cold-tolerant QTLs. Ctb1 locus has recently been physically mapped and seven candidate genes for these QTLs have been identified [T. aestivum) recombinant inbred lines, a single locus for Al tolerance (referred to as AltBH) was found on the long arm of chromosome 4D [BH), rye (Alt3), and barley (Alp) [BH, Alt3, and Alp genes are orthologous loci because of the high level of synteny among chromosome 4DL, 4RL, and 4HL and they may share a common function.Besides a requirement for vernalization, overwintering crops also require frost and cold tolerance. Cold tolerance is recognized as having a complex quantitative inheritance, making therefore problematic MAS approach to increase tolerance phenotypic values. Nevertheless, few examples of successful utilization of MAS for improving cold tolerance in cold plants are available. In barley, two tightly linked QTLs for low-temperature tolerance were identified on chromosome 5H ; these Qbidopsis , these rgenotype . These tgenotype  reportedentified . Aluminiosome 4D . A singley (Alp) . Based oMost quality traits show continuous variation and influenced by environmental factors. Notwithstanding, some examples of quality traits, for which MAS is reliable approach for selection, are now available for several important crops including tomato, barley, wheat, cotton, and rice.Lycopersicum pennellii, was characterized [L. pennillii Brix allele increases the glucose (28%) and fructose (18%) content in various genetic backgrounds of cultivated tomato and across different environments, and confer around a 3-fold increase in soluble solid content (up to 15% of the fresh fruit weight). Brix9-2-5 was shown to be partially dominant and independent of fruit weight and yield.Soluble-solids content is of paramount importance for processing tomatoes, because lines with higher sugar content require less energy input during the concentration process. To uncover the molecular basis of the sugar content variation, a QTL for total soluble solids (sugar and acids), named Brix9-2-5, derived from the green fruited tomato species cterized . The genIn China, there is a strong emphasis on improving the quality of indica hybrid rice varieties. “Zhenshan 97”, the female parent of several widely cultivated hybrid, is of poor quality because of its high amylase content (AC), hard gel consistency (GC), low gelatinization temperature (GT), and chalky endosperm. These three traits for cooking and eating quality are controlled by the genomic region containing the Waxy locus. The eating and cooking quality of Zhenshan 97A  has been improved by introgression of the Waxy gene from Mighui 63 (restorer line) . MAS werGlu-Alb and Glu-Dld. SDS-PAGE of seed protein is used for screening wheat lines for glutenin polypeptide profiles. This method is relatively efficient because allelic variation at multiple loci can be assessed in a single gel line. PCR-based molecular markers based on sequence variation of the coding and promoter region of the wheat HMW glutenin gene at the Glu-1 locus have been developed [The most important quality parameters in wheat relate to the physical properties of the dough during bread making, such as extensibility and resistance to extension. These properties depend on the endosperm gluten protein, which comprises two major factors: gliadin and glutenin . Generaleveloped . When teeveloped . These cThe recent progress in the area of plant molecular biology and genomics has the potential to initiate a new “Green Revolution”, which is of vital importance for the development of drastically improved crop germplasm . IncreasGenotypic DNA markers can be obtained from any tissue of crop plants and investigated plants already screened at the seedling stage or even in seeds. Thus, screening and selection can be performed at an early stage for the specific traits that are expressed in the adult plants . Due to the availability of information about the genotype of pre-flowering MAS allows controlling pollination, e.g. in marker-assisted recurrent selection.For traits with complex inheritance, every individual genetic component contributing to the trait can be selected separately. Moreover, multiple characters that would normally be epistatic (i.e. they show a certain positive or negative effect only in combination with each other) can be maintained and ultimately fixed.Molecular markers help in the selection of targeted alleles which are very difficult, more expensive, and/or time consuming in scoring the phenotypes .Selections can be made on a single plant basis where this would not be possible by phenotypic selection. Poor heritability does not pose a problem if the selection is based on marker information.Recessive genes in various crop plants can be maintained without progeny tests required in each generation, as heterozygous and homozygous crop plants can be differentiated with the assistance of codominant markers. During backcrossing, DNA or molecular markers may help minimize the linkage drag around a gene of interest and are important to reduce the generation needed to recover the genetic background of a recurrent parent.The time of choice of parents for crossing DNA markers can also be applied . Here, DNA markers can help in minimizing diversity in genetic makeup, and in this way, they support heterosis exploitation, or they can reduce the diversity in gene complexity build-up in elite inbred germplasm are not to be preserved.The use of molecular or DNA markers for selection and screening of crop plants in a breeding programmes provide many advantages and therefore marker techniques are more attractive to plant breeders.i.Marker-assisted selection methods are more costly. It needs a well-equipped laboratory viz expensive chemicals and equipment’s glassware.ii.The detection of different linked DNA markers , is more time consuming, difficult, and much laborious.iii.Molecular marker-assisted selection requires the trained manpower in handle the sophisticated equipment, DNA isolation, and study of DNA markersiv.The utilization of MAS is very difficult in QTL study due to their cumulative effects, which are greatly affected by environmental factors and genetic background.v.Sometimes, marker-assisted selection (MAS) uses radioisotopes for labelling the DNA, which may lead to serious hazards for health. This is a major disadvantage of markers based on RFLP. However, markers based on PCR are safe in this regard.vi.It has been reported from this study that marker-assisted selection may become least efficient than the selection of phenotypes in the long term.The most recent 30 years have seen a continuous improvement in the molecular marker technique from restriction fragment length polymorphism (RFLP) to single nucleotide polymorphism (SNPs) and the diversity of array technology based on molecular markers. Headways in the sequencing advancements have prompted the improvement of NGS stages that are minimal effort with high throughput. The fundamental purpose for this lies in erroneous phenotyping. Several efforts have been constructed to generate precise, new, and more efficient markers in plant breeding for agricultural importance , but less research has been performed for developing markers in underutilized crops. Other scientific fields such as phylogenetics and molecular ecology have little information about the molecular marker techniques still now. The CRISPR technology has changed plants’ reproducing and hereditary qualities, and analysts are concentrating on altering the genomes of all financially significant plants. The major disadvantage of some methods in MAS is the need for preliminary information of the genome, in some cases, which requires additional and excess time-consuming laboratory work. It can be anticipated that most of the methods discussed in this review article could provide a structured database which could be utilized alone or in a mix with sequence-level characters in specific fields of plant science where they have not yet been used.


The participation of proteasomes in vital cellular and metabolic processes that are involved in tumor growth has made this protease complex an attractive target for cancer treatment. In contrast to ubiquitously available constitutive proteasome, the increased enzymatic activity of immunoproteasome is associated with tumor-infiltrating immune cells, such as antigen-presenting cells and T lymphocytes. In various tumors, an effective anti-tumor immunity is provided through generation of tumor-associated antigens by proteasomes, contributing crucially to cancer eradication by T lymphocytes. The knowledge regarding the role of immunoproteasomes in the communication between tumor cells and infiltrating immune cells is limited. Novel data suggest that the involvement of immunoproteasomes in tumorigenesis is more complex than previously thought. In the intestine, in which diverse signals from commensal bacteria and food can contribute to the onset of chronic inflammation and inflammation-driven cancer, immunoproteasomes exert tumorigenic properties by modulating the expression of pro-inflammatory factors. In contrast, in melanoma and non-small cell lung cancer, the immunoproteasome acts against cancer development by promoting an effective anti-tumor immunity. In this review, we highlight the potential of immunoproteasomes to either contribute to inflammatory signaling and tumor development, or to support anti-cancer immunity. Further, we discuss novel therapeutic options for cancer treatments that are associated with modulating the activity of immunoproteasomes in the tumor microenvironment. The ubiquitin–proteasome system (UPS) has a central role in the selective degradation of intracellular proteins. More than 80% of eukaryotic proteins within a cell are degraded through the UPS to maintain cellular homeostasis and cell viability  and T lymphocytes  infections  and Th1 cells into the microenvironment of solid tumor is a pivotal step in recognizing tumor-associated antigens and in preventing the tumor growth and progression (Ritter and Greten Collectively, tumors have developed many strategies to avoid immune surveillance and to minimize the production of neo-antigens. Hence, a better understanding and a deeper knowledge of multiple interaction between tumor and immune cells in the tumor microenvironment is needed to develop therapeutic strategies for facilitating generation of more immunogenic tumor antigens. This might be achieved by enhancing the activity of immunoproteasomes in both, tumor and immune cells.The flexibility and fine-tuning of the UPS is important for immune cells to adopt to inflammation, viral infections and cancers. It is well known that pro-inflammatory factors such as IFN-γ synergistically induce all three subunits of immunoproteasome to optimize the presentation of antigens on MHC class I molecules. In addition to shaping the T-cell repertoire for CTLs to better recognize tumor antigens, immunoproteasomes also modulate the cytokine production in APCs, T-cell differentiation, and even the secretion of chemokines and other factors by cancer cells. Novel results have revealed that the immunoproteasome is a crucial player in promoting colon tumorigenesis, and thus a potential molecular target for treatment of colorectal cancer. In contrast, the anti-tumorigenic properties of immunoproteasomes have been described for melanoma and other cancer types. Various aspects of proteasomal activities appear to be implicated in the multiple crosstalk of cancers with immune cells. Therefore, a better understanding of the immunoproteasome activity in different cancer types and in the immune cells of tumor microenvironment will be essential for developing targeted therapeutic approaches aiming at improving anti-tumor immunity. The utilization of pharmacological inhibition and modulation of immunoproteasome function in various cancer types, but also in the context of adoptive cell therapy, may shed light on novel therapeutic strategies to halt the progression of malignant neoplastic diseases.


COVID-19 is the disease caused by SARS-CoV-2, one of a large family of coronaviruses. Severe forms of the disease can lead to respiratory failure with multiple organ failure necessitating rehabilitation in both acute and long-term care. With the increasing prevalence of COVID-19 and rehabilitation needs, the African Rehabilitation Network (AFRENET) produced a guidance document to assist in reducing variation in clinical practice among rehabilitation professionals in the Africa Region. This report outlines the process of the guideline development. COVID-19 is the disease caused by SARS-CoV-2, one of a large family of coronaviruses .In Africa, COVID-19 is reported through the WHO AFRO , and the WHO EMRO . The first cases of COVID-19 were confirmed on 14 February 2020 in Egypt, and soon after in Algeria, Nigeria, and Senegal .Although African health systems are growing, there are still many places where health services are inadequate. The COVID-19 pandemic has increased the strain on already fragile health systems with insufficient rehabilitation services across the region also challenged. Many existing rehabilitation services across Africa often suffer from lack of infrastructure and human resources with increased workload for rehabilitation professionals. There are few clinical practice guidelines in rehabilitation that were adapted or contextualized to the region to improve practice. To the best of our knowledge there were no existing guidelines developed, adapted, or contextualized for rehabilitation professionals during this period of COVID-19.As the pandemic grew, rehabilitation professionals took notice of the increasing rehabilitation needs in the region. The African Rehabilitation Network (AFRENET) was formed by a diverse group of rehabilitation professionals in Africa. We thought of innovative ways to mobilize resources and deliver effective services despite the extra burden imposed by COVID-19. With these initiatives and efforts, we created a community of practice involving rehabilitation professionals practicing in Africa, using WhatsApp and Zoom to bring practitioners together from many countries to discuss the important role of rehabilitation in the region during the crisis.One action taken by AFRENET was to develop a set of guidelines for rehabilitation practitioners to improve on the effectiveness of service delivery, decrease costs, prevent avoidable mistakes, and reduce variation in clinical practice in the region. This process was inspired by, and adapted with permission from, a group at McMaster University in Canada who had already published rehabilitation guidelines during the COVID-19 pandemic , and anoReviewing the literature: given the fact that COVID-19 is a new disease of pandemic proportions and data is still evolving, very little was published in the academic literature specifically about COVID-19 and rehabilitation. At that time, we found no academic literature specific to COVID-19 and rehabilitation emanating from the Africa Region. As such we gathered literature that was being shared from professional networks, gray literature, and from academic databases on related topics across the globe. We also identified and adopted guidelines from other settings within the region. All the available data was collected into a Zotero library and made accessible to all members of the rehabilitation professional group.Online discussions: following the group initiative, a draft list of guidelines was developed based on existing literature. A Google document was generated with the drafted guidance document to allow for contributions. There was significant discussion which recognized the diversity, the strengths, and the challenges across the continent. Discussion centered on what was feasible and acceptable within the African context based on existing infrastructure and human resources. Contributors talked about the existence of a very low ratio of health professionals to patients and need to improve practice and quality of care during this period. This lack of health personnel is even more evident among rehabilitation workers such as community-based rehabilitation workers (CBRWs), occupational therapists (OTs), physiotherapists (PTs), speech and language therapists (SLTs) in the continent. Other frontline workers who had firsthand experience or who had participated in developing any form of guidance document related to rehabilitation at the institutional or national level also shared their experiences for discussion on what was most relevant and practical in the region.The authors recognized that the situations in various settings, cities, regions, and countries can be very different based on infrastructure and availability of rehabilitation professionals. We discussed the need for guidelines to be applicable in a variety of settings. For example, there are significant differences between the management of COVID-19 in the better resourced healthcare settings, and the many other African settings where rehabilitation is not fully supported. Social and cultural conditions were also considered where rehabilitation professionals represented and shared their experiences. It was agreed that the document would not replace institutional policies and practices but rather supplement existing efforts and resources put in place to improve client/patient and healthcare professionals´ safety and practice during this period.Consultation with experts: the complete draft guideline for rehabilitation professionals in Africa was then forwarded to experts in guideline development and specialist clinicians in rehabilitation including the team at McMaster University, Ontario, Canada and the Community-based rehabilitation Africa Network, who provided detailed constructive feedback. This feedback was then discussed among the writing group members and integrated into the document.Rehabilitation of patients with COVID-19 in African Settings: Guidance for Community Based Rehabilitation Workers, Physiotherapists, Occupational Therapists, Speech and Language Therapists, and Assistants. The guidelines are available online. Updates of this document will also be posted on these sites when made. The final guidance document is divided into two main sections. The first section is composed of seven interconnected key considerations applicable to all rehabilitation providers. Each of these key considerations is further supported with specific recommendations. The key considerations are: i) assessment of risk and actions to be taken to reduce risk and spread of COVID-19 in rehabilitation settings; ii) working as a team; iii) avoidance of person to person contact as much as possible; iv) anticipation of an increased demand of workforce; v) type of personal protective equipment (PPE) needed for patient contact; vi) inclusion of people with other impairments and disabilities apart from those due to COVID-19; vii) streamlining of documentation procedures.The result was a set of guidelines called The second section is composed of best practice statements for specific rehabilitation providers notably, statements for community-based rehabilitation workers for homes and communities where the present COVID-19 patients are established and where the presence of COVID-19 is unknown. We also provided specific statements for different phases of the rehabilitation process in hospital settings, as well as therapeutic procedures for physiotherapists, occupational therapists, and speech and language therapists.The guidance document was designed to be practical and to meet the need of a diverse group of rehabilitation professionals  in the African context. While clinical practice guidelines have evolved from being opinion-based to evidence-informed with an increasing sophisticated methodology in development , expertsChallenges: from the conception to realization of the guidelines, there were challenges principally due to insufficient availability of rehabilitation professionals with skills on guideline development and COVID-19 disease. This perceived lack of skilled professionals was further compounded by the absence of a well-established international or national guideline development group or manual in the region such as the Scottish Intercollegiate Guideline Network (SIGN) [k (SIGN) . Other fWe report a successful adaptation and contextualization of a clinical practice guideline for rehabilitation professionals working in African settings with patients with or without COVID-19, through the efforts of a small team of dedicated volunteers with variable understanding of developing clinical practice statements and recommendations. We encourage similar efforts and collaboration in rehabilitation within the region.


Stock price prediction is one of the major challenges for investors who participate in the stock markets. Therefore, different methods have been explored by practitioners and academicians to predict stock price movement. Artificial intelligence models are one of the methods that attracted many researchers in the field of financial prediction in the stock market. This study investigates the prediction of the daily stock prices for Commerce International Merchant Bankers (CIMB) using technical indicators in a NARX neural network model. The methodology employs comprehensive parameter trails for different combinations of input variables and different neural network designs. The study seeks to investigate the optimal artificial neural networks (ANN) parameters and settings that enhance the performance of the NARX model. Therefore, extensive parameter trails were studied for various combinations of input variables and NARX neural network configurations. The proposed model is further enhanced by preprocessing and optimising the NARX model's input and output parameers. The prediction performance is assessed based on the mean squared error (MSE), R-squared, and hit rate. The performance of the proposed model is compared with other models, and it is shown that the utilisation of technical indicators with the NARX neural network improves the accuracy of one-step-ahead prediction for CIMB stock in Malaysia. The performance of the proposed model is further improved by optimising the input data and neural network parameters. The improved prediction of stock prices could help investors increase their returns from investment in stock markets. The importance of the stock market to the international economy is undeniable . Stock mWang et al. stated that different arguments had been made between participants in the market about the stock price predictability , with twTwo hypotheses are closely related to the first argument regarding the unlikelihood of correct prediction, namely the Random Walk Hypothesis (RWH) and the Efficient Market Hypothesis (EMH). The RWH was introduced by , who staPrevious studies have attempted to predict the stock price or return movement with varying degrees of success . SurAccurate prediction of the stock market is still a big challenge because of the complexity and stochastic nature of the market data –21. SpecThis paper's main objective is to analyse and compare the performance of the NARX neural network model to the performances of two other models , 27. TheThis study explores the potential improvement in prediction performance by utilising technical variables in NARX models with optimised input data, preprocessing, and model parameter configuration. A comprehensive set of parameter trails for different combinations of input variables and different NARX neural network settings are investigated.The remaining sections of the paper are organised as follows: Forecasting the stock market is made by utilising a variety of prediction models. These forecasting models take technical and fundamental factors into account and as such, fundamental and technical analyses are two methods for forecasting a stock's future direction.The fundamental analysis utilises economic and financial data about the company  to determine the company's intrinsic value . FundameOn the other hand, forecasting stock prices can be accomplished by examining previous price and volume trends . Thus, iResearchers employed various conventional and digital computing prediction models. These models may incorporate different explanatory input variables from the fundamental and technical analysis . The CAPOther structural models can be classified as linear or nonlinear. Linear models include the linear-trend prediction model  and the Some research suggests that nonlinear models might outperform linear models . HoweverSeveral studies have utilised the recent advancements in soft computing techniques and artificial intelligence to improve prediction model performance in forecasting the stock market , 24. SofVarious ANN training algorithms are available, each with its own benefits and drawbacks. Levenberg–Marquardt (LM), Bayesian Regularization (BR), and Scaled Conjugate Gradient (SCG) are three training algorithms that have been utilised successfully for stock market data prediction in prior studies –49.The characteristics of the problem to be solved influence the choice of an ANN model. The feedforward neural network, for example, may not perform well if the input data pattern changes over time. A viable solution is to utilise a recurrent neural network (RNN), in which neurons have additional connections to the prior layer , 51.This study employs a nonlinear autoregressive network with exogenous inputs (NARX), a type of recurrent neural network with high prediction capabilities for time series data. Given that the stock price prediction problem incorporates historical data as well as external variables, the NARX could be a compelling choice for modelling such a problem , 52–57.A comparison of the prediction performance of the NARX model with other neural network models for the Indonesian stock index was carried out by  over a fIn another recent study, Gandhmal and Kumar employed the NARX model to forecast the stock market using some technical indicators as exogenous variables. The NARX model outperformed a regression model, a Deep Belief Network (DBN) model, and a NeuroFuzzy model in terms of MSE and MAPE errors.Moreover, Nikoli et al. (2019) suggest that the NARX model might successfully predict other financial time series data, such as the EUR/USD currency exchange rate. The prediction results can be enhanced further by integrating additional input variables and fine-tuning the NARX model's internal parameters .The main objective of this study is to compare and analyse the performance of an adaptive nonlinear autoregressive exogenous (NARX) neural network model that incorporates lagged pricing and technical indicators with two previously published models , 27. TheThis section discusses the experimental setup, including the model parameters used to perform the experiments. The first step is to collect data on CIMB stock and then compute the technical factors. After that, the data is filtered and normalised during the preprocessing stage. The data is then partitioned into input and test sets, which are then fed into the NARX neural network model.Following that, the prediction model is constructed, and its parameters are adjusted, after which the model is put through a series of trials to determine its performance. Finally, all experiments' output results are saved for further evaluation and comparison. The overall methodology is depicted in The NARX model input data includes the CIMB stock adjusted closing prices and three-day lagged data, as well as six calculated technical variables: momentum, MACD, RSI, oscillator, WPCTR, and CHVOL. For technical factors refer to , an arbind Jan., 2008 to 29th Dec., 2017). Two thousand three hundred thirty-three observations were included in the CIMB stock information dataset (trading days). Each observation included daily data on the lowest and highest prices, the opening and closing prices, and trading volume. Based on this, three subsets of the ten-year dataset were constructed .CIMB stock data was obtained from the Yahoo Finance website for a ten-year period  Momentum (MOM). This indicator recognises price movement in terms of strength and speed by measuring the price (P) change rate. It is calculated by determining the difference between the current and past prices over an n-period.n=12[In the calculation, the frequently adopted value of n=12 is used.(2) Moving Average Convergence Divergence (MACD). Another momentum indicator for trending stock price data is MACD. It depicts the relationship between two stock price moving averages  [verages) . The mac(3) Relative Strength Index (RSI). The relative strength index (RSI) measures the magnitude and velocity of stock price changes [ changes . RSI is (4) On-Balance-Volume (OBV). OBV measures stock momentum by relating volume and stock price changes [ changes . The onb(5) Williams' Percent Range (Williams' %R) or (WPCTR). This technical indicator is used to determine whether or not a stock is oversold or overbought in the market [R is calculated in MATLAB using the willpctr function.e market . The cal(6) Chaikin Volatility (CHVOL). CHVOL is used to compare the spread between a stock's high and low prices by quantifying the volatility based on the changes of the moving average over a specific period. In this study, MATLAB's chaikvolat function was used to calculate CHVOL.After calculating the technical indicators, the data is preprocessed using the smoothing and normalisation transformation techniques to improve the prediction outcomes . The CIMThis study employed a single-layered neural network structure of a nonlinear autoregressive exogenous (NARX) model. The NARX model uses a single hidden layer because single-layer models often give better prediction results and are more practical due to their ability to reduce computation time and reduce the risk of overfitting, which can degrade prediction performance , 61.The following steps describe how the NARX model's parameters were set and optimised in MATLAB.The absence of a systematic method for determining the appropriate quantity of inputs that can affect the learning performance of neural networks is unfortunate . Consequ(1) Data size. CIMB closed price data for  years.(2) Inputs. The model's inputs are CIMB closing price data and exogenous variables , which were combined in arbitrary combinations by adding one variable at a time. No variable switching was performed between exogenous variables, as this would significantly complicate the experiments. Additionally, the model was supplied with lagged data of the CIMB closing price and the exogenous variables. The number of lags varied; both the closing price and exogenous input lags ranged between 0 and 3.(3) Data split. Two datasets were created from the input data. The first 90% of data was utilised as the neural network's input dataset, while the remaining 10% was unknown to the model and was used as a testing dataset and not for training. The 90% input dataset was then split into three segments, 70% training data, 15% testing data, and the remaining 15% was validation data . There is no consensus on the optimal number of hidden neurons although some literature gives rules of thumb that can be utilised as a jumping-off point for experiments. The use of a fixed technique, in which the number of hidden neurons is changed while keeping all other parameters constant, can be used to identify the optimal number of neurons, resulting in the minimization of errors, the prevention of overtraining, and the avoidance of local minima. During the training phase, this study optimised by using a variety of different numbers of neurons. The range of neurons employed in the search for the optimal number of neurons was based on , 62, in Different parameter combinations were tested in order to identify the optimal neural network for the study model in terms of prediction accuracy as measured by mean square error (MSE). Three different training algorithms were used with both the training and testing sets, including the Levenberg–Marquardt algorithm (trainlm), Bayesian Regularization (trainbr), and Scaled Conjugate Gradient (trainscg).The Leveneberg Marquardt algorithm (LM) is a more powerful optimization than the gradient descent , 62. It The random initialization of biases and weights is another issue to consider when designing neural networks, as two networks with identical designs and parameters might generate different results . This issue was addressed in this study by training many networks and picking the one with the lowest mean square error.R2.Moreover, to avoid overfitting, the neural network is first trained on a large part of the data sample and then tested on the remaining, smaller part to see if it can generalise what it learned during training when met with unknown data. After setting the initial model parameters and selecting the optimal number of neurons and neural network, the final model is constructed and prepared for testing with various combinations of exogenous factors and input dataset durations.Three cascading loops were utilised to run the model and test all potential combinations efficiently. The first loop modifies the amount (duration) of data inputs . The second loop is responsible for selecting the training algorithms . Finally, the third loop selects various exogenous variable combinations . In each iteration of these loops, the model is run on the training dataset then the test dataset.R2) [The test data was used to evaluate the model's performance using three widely used performance metrics: mean square error (MSE), hit rate (HR), and R-squared coefficient of determination (R2) , 67 , and MSE is dependent on the data type and order of magnitude and is calculated as follows:Hit rate (HR) measures the prediction accuracy by calculating the percentage of correct movement of the predictions either up or down.R2 (R-squared coefficient of determination) is also used to indicate the prediction accuracy as it measures the percentage of the response variable variation explained by the model [R2 is calculated using the following equation:n denotes the total number of data points, yi denotes the actual output [The he model . R2 is cl output .A total of 72 experiments were conducted to evaluate the developed ANN-NARX model's performance in predicting the CIMB stock closing price, with each experiment incorporating a different combination of data size (duration), exogenous variables , training functions , and the optimal number of neurons. As stated in Tables 2R2) ranged from 97.21% to 99.88%.The model performance results reveal that the proposed model performs remarkably well in predicting the CIMB stock adjusted closing price movement. The model achieved a high hit rate percentage that reaches above 81% with a low average MSE of 0.000618044, which indicates that the average error of the proposed model is as low as The proposed model performed best in terms of hit rate (HR) in experiment 22 (HR = 81.25%), where three years of data were used as input, technical factors  were utilised as exogenous variables, and (trainlm) was used as the training function.As for the training algorithms illustrated in Regarding the number of neurons in the neural network, as indicated in R2 while degrading the average MSE and hit rate.Additionally, Furthermore, it was also noticed that adding more exogenous variables was only helpful when the data duration is longer than a year. However, when a longer duration was paired with more technical indicators, as illustrated by combining Figures As shown in In this study, the problem of stock market prediction is examined for a selected stock on the Malaysian stock exchange. The prediction of the CIMB stock closing price one step ahead was investigated using technical variables in a NARX neural network. The prediction performance was improved by including technical variables as exogenous inputs to the model, preprocessing the input data, and optimising the neural network's input variables and parameters. The model proposed in this study outperformed two other models previously published in the literature in terms of hit rate and MSE.R2.The results suggest that including technical indicators into the NARX neural network model has a high potential for improving prediction performance and is demonstrated by examining performance indicators such as MSE, Hit rate, and In this study, only three training algorithms  were examined. To further improve prediction performance, it may be useful to investigate other widely used training algorithms such as, gradient descent and gradient descent with momentum in future studies.Additionally, this study only considered the use of technical indicators as exogenous variables in the NARX model arbitrarily for only one stock in the Malaysian stock market. In future works, it might be beneficial to optimise the selection of the exogenous variables by using advanced features selection methods such as, deep mining and exploring the use of integrating fundamental factors to improve the prediction for different stocks in the market.


Despite decades of research on the neurobiology of major depressive disorder (MDD), the mechanisms underlying its expression remain unknown. The medial prefrontal cortex (mPFC), a hub region involved in emotional processing and stress response elaboration, is highly impacted in MDD patients and animal models of chronic stress. Recent advances showed alterations in the morphology and activity of mPFC neurons along with profound changes in their transcriptional programs. Studies at the circuitry level highlighted the relevance of deciphering the contributions of the distinct prefrontal circuits in the elaboration of adapted and maladapted behavioral responses in the context of chronic stress. Interestingly, MDD presents a sexual dimorphism, a feature recognized in the molecular field but understudied on the circuit level. This review examines the recent literature and summarizes the contribution of the mPFC circuitry in the expression of MDD in males and females along with the morphological and functional alterations that change the activity of these neuronal circuits in human MDD and animal models of depressive-like behaviors. Recent estimates from the World Health Organization (WHO) revealed that more than 300 million people of all ages suffer from major depressive disorder (MDD) worldwide . DespiteMDD is a highly heterogeneous disorder characterized clinically by the expression of persistent depressed mood, anxiety, anhedonia, cognitive impairments, weight changes, fatigue, feeling of worthlessness, recurrent thoughts of death, and suicidal ideation , p. 5. TA growing body of evidence now suggests that the expression of different symptoms in males and females may results from the alterations of distinct pathways and circuits in the brain with the medial prefrontal cortex (mPFC) acting as a hub structure. For instance, elevated functional connectivity of the mPFC with the posterior cingulate cortex and angular gyrus is associated with rumination while hypoactivation of the ventral striatum associates with the expression of anhedonia . InteresThe hub status of the mPFC is further strengthened by anatomical and functional studies performed in animal models of chronic stress. The mPFC integrates neuronal inputs from several brain regions  and sendConsistent with its crucial role in higher executive functions, the mPFC is more developed in higher order mammals, and exhibit more elaborate behaviors than rodents . In huma2+/calmodulin kinase II (CaMKII)  and GABAergic inhibitory interneurons (10-20%) . Pyramid(CaMKII) . Studies(CaMKII) .The remaining 10–20% are composed of different subtypes of inhibitory interneurons expressing gamma-aminobutyric acid (GABA) as a neurotransmitter . GABA inThe human mPFC is organized in six layers while rodents lack layer IV . PyramidIn return, mPFC neurons send glutamatergic projections to nucleus accumbens (NAc), hippocampus, amygdala, lateral habenula, thalamus and hypothalamus, DRN, VTA, periaqueducal gray (PAG), and LC  and alsoTogether, the cellular diversity of the mPFC following a complex laminar and anatomical distribution is ideally organized to integrate the diverse sensory and emotional information coming from other brain regions and redirect it to other structures to drive behavioral responses to environmental challenges. In the next section of this review, we will elaborate on the morphological and functional consequences of chronic stress that have been described in the mPFC of males and females.Previous studies performed on post-mortem tissue from MDD patients reported several neuroanatomical alterations in the mPFC. For instance, gray matter is reduced in the mPFC of patients suffering from MDD across its different sub-structures . AccordiThese findings in humans have been supported by studies in animal models of chronic stress. For instance, male rats exposed to chronic restraint stress exhibit a 20% reduction of the apical dendritic length and branch number  with a sMore recently, exposure to 21 days of chronic variable stress (CVS) has been shown to induce sex-specific modifications in the dendritic complexity of two distinct pyramidal populations in the mPFC, namely NAc- or VTA-projecting mPFC neurons . Indeed,In addition to the effects mentioned above on pyramidal neurons, alterations in GABAergic interneurons have also been consistently reported in the mPFC of MDD patients. Density and size reduction of GABA interneurons, along with decreased expression of the 67kDa glutamic acid decarboxylase (GAD67) gene expression, have been reported in post-mortem mPFC tissue from MDD patients . In contOverall, the sum of evidence reported here suggests that chronic stress induces a global reorganization of neuronal spine and arborization in the mPFC, disrupting the frontotemporal neuronal network’s integrity differently in males and females . ImportaAt this point, whether chronic stress increases or decreases the E/I balance in the mPFC is still a matter of debate with functional studies that aim at modulating the activity of the mPFC, and report conflicting results. On one hand, studies increasing the excitability of mPFC pyramidal neurons or decreasing the inhibitory tone of GABAergic interneurons suggest that pyramidal hyperactivity in the mPFC associates with the expression of depressive-like behaviors. For instance, asynchronous optogenetic activation of pyramidal neurons in the mPFC was shown to induce the expression of depressive-like behaviors in male rats . PreviouConsistently, the inactivation of GABAergic inhibitory tones in the mPFC has also been shown to promote the expression of depressive-like behaviors. For instance, the acute chemogenetic inhibition of SST-expressing GABAergic interneurons in the PLC triggers anxiety-like behaviors in male and female mice . ChemogeOn the other hand, contrasting findings have been reported where the stimulation of pyramidal neurons in the mPFC has been associated with antidepressant responses. For instance, social withdrawal and anhedonia induced in males after 10 days of social defeat stress were shown to be reversed by optogenetic stimulations of the mPFC  while siTogether, by interfering with the morphological and functional organization of pyramidal and GABAergic neurons in the mPFC, chronic stress interferes with the E/I balance controlling the function of the mPFC. The morphological adaptations observed in pyramidal and interneurons of the mPFC after chronic stress suggest that their ability to integrate and transmit correctly neuronal signals is compromised. This is leading to functional modifications that interfere with the E/I balance. A proper E/I balance assures proper responses to various stimuli received by these neurons. This being said, given the complex integrative role of the mPFC at the circuit level, it is likely that the morphological changes reported above may affect precise neuronal subpopulations that could be defined based on their inputs or outputs  and by dThe mPFC receives various afferences from cortical, subcortical and brainstem areas  which haNeurons from the VTA projecting to the mPFC constitute the mesocortical pathway. The VTA itself, and more importantly, via its projections to the mPFC has been extensively studied for its contribution to aversive stimuli processing . FunctioThe ventral hippocampus (vHIPP) sends dense glutamatergic projections to the mPFC with denser inputs in the vmPFC . This paProjections from the basolateral amygdala (BLA) to the mPFC are also directly involved in the control of anxiety-like behaviors in mice. The mPFC receives excitatory glutamatergic inputs from the BLA targeting dmPFC and vmPFC in layers II/III and V . TraditiThe LC sends dense noradrenergic projections distributed across the mPFC superficial layers I and II/III . The LC Finally, the mediodorsal thalamus (MDT) integrates inputs from various brain regions such as the amygdala, VTA, and DRN and transmits this information to the mPFC . The MDTAs detailed above, the mPFC projects to several brain regions involved in the control of emotions and reward processing . As for Amongst the distinct neuronal circuits emerging from the mPFC, the corticoaccumbal pathway has received considerable interest regarding its involvement in the expression of stress susceptibility or resilience. For instance, the optogenetic acute stimulation of pyramidal mPFC neurons projecting to the NAc was shown to promote anxiety in the open field test in naïve males but did not change the immobility in the forced swim test or the interaction time in the social interaction test . On the The contribution of the mPFC projections to the amygdala, and more specifically to its different nuclei, has also been extensively studied in the context of stress responses. Indeed, optogenetic stimulation of the vmPFC neurons projecting to the basomedial nucleus of the amygdala (BMA) was shown to decrease anxiety-like behaviors with increased time spent in the open arms of the elevated plus-maze in both male and female mice chronically exposed to corticosterone . On the Additionally, mPFC neurons projecting to the dorsal raphe nucleus (DRN) were shown to control specific aspects of social behaviors. Optogenetic inhibition of this pathway decreases social avoidance after CSDS in male mice . AnotherIn consequence, the activation of the mPFC neurons that project to the LC, vHIPP, BLA, and VTA elicits anxiety, while the inhibition of vHIPP-mPFC and BLA-mPFC have anxiolytic effects in rodents . ActivatThe sum of evidence described in this review strongly supports the role of the mPFC as a hub region in the integration and consolidation of emotional responses to chronic stress in males and females . This coNow, another crucial aspect to consider in future studies is the type of stress used to induce anxiety- and depressive-like behaviors in animals, which based on the literature reviewed above, appear to impose distinct changes on the activity of mPFC neurons and circuits. Indeed, stress paradigms involving mainly physical stressors are likely to impact the mPFC circuitry differently than those involving psychosocial stressors . Such diTPB and BL contributed to the literature review and the redaction of the manuscript. Both authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Level of Difficulty: Intermediate.)The authors describe a case of transposition of great arteries with a large atrial septal defect with fusion of tricuspid valve leaflets and severe aortic stenosis. The latter two were likely rheumatic in etiology. The patient’s condition improved after atrial switch and aortic valve replacement surgery. (  A 23-year-old man presented to us because of dyspnea on exertion and bluish discoloration of his lips. He was found to have cyanosis with pandigital and symmetrical clubbing of fingers and an oxygen saturation of 85%. A grade III ejection systolic murmur was heard in the right second intercostal space radiating to the carotids. The patient had received a diagnosis of a “heart defect” in childhood and had been advised to see a specialist. However, being only mildly symptomatic, he never followed up.Echocardiography showed two atria, with a large 36-mm ostium secundum atrial septal defect and bidirectional shunting of blood. The inferior vena cava (IVC) was seen draining into the right-sided morphologic right atrium (RA). The morphologic right ventricle (RV) and left ventricle (LV) were on their respective sides , Video 1Bicuspid aortic valve and RHD are the most likely causes of severe AS in young adults. The typical morphology of the TV, coupled with the high prevalence of RHD in India, made RHD the most likely cause. Primary TV disease in RHD is relatively rare, and the MV is generally affected concomitantly . Such afRV dysfunction is common in uncorrected TGA. The AS compounded this dysfunction. In cases of uncorrected TGA, the LV regresses quickly and cannot support the systemic circulation after 12 years of age. Although there are no clear recommendations for such a scenario, as per the 2018 adult congenital heart disease guidelines, owing to the patient’s age, atrial switch surgery was advised along with aortic valve replacement . On postOur case serves to highlight the rare entity of rheumatic AS in TGA and the peculiarity of tricuspid and aortic valve affection without MV disease in this case of RHD with TGA.The authors have reported that they have no relationships relevant to the contents of this paper to disclose.


Growing evidence has highlighted the interplay between early life environment and long-term consequences in metabolic status and performance of livestock animals. Exposure to stressors, mainly maternal nutrition, during critical developmental windows have been pointed out as the major factor leading to altered metabolic and physiological programming of the bodily systems . Lately,The increasing availability of genomics tools and high throughput technologies has opened new opportunities to untangle the complex relationship between environmental factors, fetal developmental programming, inheritance mechanisms, and long-lasting phenotypic effects. Thus, we aimed to shed light on the genomic basis of fetal developmental programming by collecting up-to-date high-impact research in the field. To this end, this Research Topic focused on analyzing genomic and epigenomic mechanisms responsive to parental and other environmental factors. We brought three Original Research and one Review article together summarizing the recent findings of the impact of maternal nutrition effects on fetal development, offspring performance, and the opportunities for improving livestock production.Foroutan et al. explored the relationship between prenatal nutrition and selection for residual feed intake in beef cattle. The authors provided an overview of the importance of maternal nutrition and its effects on economically important traits, such as health, growth, carcass quality and fertility. Additionally, they highlighted results from multiple omics analyses to shed light on biological pathways and potential candidate markers involved with feed efficiency and prenatal nutrition. The authors concluded that integrating data from different regulatory genomic layers will contribute to our understanding of the genomic basis of complex phenotypes in cattle.To meet the growing demand for food, we need to maximize the production efficiency of livestock species. The review by Copping et al. and Cracco et al.Copping et al. used a 2 Cracco et al. assessed female fertility traits in heifers born to dams that were protein supplemented (whole gestation or only last trimester) or not. Furthermore, the authors explored the interaction of single nucleotide polymorphisms (SNPs) in response to maternal diet with carcass and reproductive traits. Cracco et al. reported three SNPs harbored in genes previously associated with fetal programming. However, no effect of maternal diet on offspring reproductive tract development was observed.The importance of proper maternal dietary protein during the peri and postconceptional period was investigated by Ding et al. uncovers an intriguing perspective of sex-specific differences in offspring heart muscles in response to maternal overnutrition (MO) in sheep. The authors investigated the effects of MO at different time points of gestation on autophagy-associated pathways. They revealed a sexually dimorphic response with more pronounced effects in females regardless of developmental stages.The study by The articles within this Research Topic illustrate the role of maternal nutrition on offspring development and long-term consequences on performance. This improves our knowledge and will help us to design strategies to mitigate the adverse effects of developmental programming. It also highlights the need for further studies to use strategic supplementation to improve the production efficiency in livestock species. We thus hope that this collection fills some of the gaps in knowledge and pave the way for mechanistic studies further elucidating fetal programming.


Background: The Kingdom of Saudi Arabia (KSA) was the first country in the Middle East to adopt the hepatitis B virus (HBV) vaccine. Despite an expanded HBV immunization program and significant progress in HBV prevention in the country, HBV infection is a significant public health burden. This review lists coordinated solutions for healthcare stakeholders, patients, and health authorities to curb HBV and its impact in KSA. It further aims to draw policymakers’ attention to key priorities to bridge HBV care gaps in the country.Methods: As part of the pre-engagement activity, medical experts across KSA were interviewed to gain a preliminary understanding of the current unmet needs in HBV management in the country. Top-recommended action points derived from the pre-engagement activity were discussed. Key priority action points to curb the impact of HBV in KSA were identified.Results: The priority action points together with the challenges and unmet needs in the management and care of HBV in KSA were: (a) establish a national-level registry, (b) implement screening campaigns, (c) improve linkage of care between primary care physicians (PCPs) and specialists, and (d) increase PCP education and awareness.Conclusion: This work is an endeavor to set the stage for a strategic policy framework aimed at eliminating HBV in KSA. The action points/steps for the identified priorities must run parallelly across various regions in KSA, to successfully manage and further eliminate the threat of HBV. Viral hepatitis is the seventh leading cause of death in the world, with hepatitis B virus (HBV) being the most widespread viral hepatitis infection . AccordiAs of 2018, a whopping 290 million people worldwide, accounting for 89% of the global hepatitis B and C-infected population, were unaware that they were infected . ConsequThe Kingdom of Saudi Arabia (KSA) is a high-endemic country for HBV infection in the Middle East. According to the Polaris Observatory, a resource for global HBV and HCV epidemiological data, the 2016 prevalence of HBV for KSA was 2% . AljumahSimilar to the global paradigm, there is a low diagnosis rate of HBV in KSA, with 2019 Polaris Observatory data indicating an HBV diagnosis rate of 7% . In newlIn 2016, HBV caused 1,700 annual deaths  in KSA [The current scenario in KSA demands the implementation of a structured policy framework to combat and eliminate HBV. Therefore, a collaborative workshop involving the Saudi Association for the Study of Liver Diseases and Transplantation (SASLT) and medical experts across KSA was convened to brainstorm on key priorities and action points for HBV management and elimination in KSA that could be highlighted to the Saudi Health Council.The collaborative workshop was presided over by medical experts in the field of hepatology representing both the public and private sectors across KSA. The results of the collaborative workshop were detailed in a call-to-action report, which aims to summarize recommendations and key action points put forth by the medical experts to curb HBV and its impact in KSA through targeted collaborative actions.A previous review article identified the gaps in the hepatitis B care pathway in KSA . Prior tA total of nine out of the twelve participating physicians (75%) responded to the in-depth qualitative survey. Overall, 11 priority discussion points were identified from the pre-engagement survey results. The most favored action points were as follows: implementing screening campaigns (78% response), followed by increasing primary care physicians’ (PCPs) education and awareness on HBV, improving linkage to care between PCPs and specialists, and establishing a national-level patient registry-each with 67% response The HBV disease burden across KSA can be accurately assessed by obtaining prevalence estimates. As there are limited data on current HBV prevalence and mortality in KSA, the medical experts opined that a national-level registry should be created under the Saudi Health Council to include patients from the governmental, semi-governmental, and private sectors. This will help in generating a granular map based on the prevalence and incidence of HBV in various parts of KSA. The medical experts added that there is no need for new epidemiological studies, as a single registry will help in assessing the number of HBV-infected individuals. The national registry should be set up before further action on HBV screening campaigns, to avoid duplication of entries . A single national registry will not only provide data on the number of infected patients but also give insights into the demographics of the infected population. A few medical experts were in favor of conducting a burden-of-disease/cost-of-disease assessment in the country, as clinical and economic assessments would give a concrete message to policymakers on the importance of devising a structured strategy for HBV; however, this recommendation did not reach a consensus.Implement Screening Campaigns (Identify)Implementing an effective, targeted, customized screening program to assess the occurrence of HBV across all age groups is another key priority in the country. The vaccination program for HBV started in KSA in 1989 and reportedly reduced the prevalence to 2% . HoweverImprove PCP Education and Awareness (Educate and Orient)The medical experts acknowledged the importance of PCPs and stated that they are an integral part of the management of HBV in the healthcare framework. Lack of awareness among PCPs about HBV is a major factor resulting in the under-diagnosis of HBV in the country. This can result from a shortage of primary care centers and a lack of training programs for PCPs. Therefore, educating PCPs on HBV and equipping them to ensure a timely, accurate diagnosis of the disease would increase awareness of the HBV referral chain among primary and tertiary care centers. The medical experts further added that there are about 5,000 PCPs in KSA that register HBV patient visits. Hence, educating them will require time; however, it should be done on priority. Additionally, this education initiative would, in turn, reduce the patient load among hepatologists and gastroenterologists.Enhance Linkage to Care From PCPs to Specialists (Link)CHB patients diagnosed at the primary care level and requiring further treatment are directed to specialists. Monitoring of HBV patients directed to specialized care facilities is essential. While PCP education is linked to enhanced diagnosis, the medical experts acknowledged the concern of patients lost to follow-up or patient unwillingness to visit a specialist due to the stigma around HBV disease. Hence, in addition to increasing patient awareness via counseling, the health system needs to be strengthened to improve the link between primary and tertiary care centers.This collaborative workshop gathered recommendations and priority action points from regional medical experts to curb HBV and its impact in KSA. Four priority action points were recommended for HBV care management in KSA. For each of the priorities, specific actions are needed from health partners. While the rapidity of implementation/response in achieving key actions may vary, these action points need to be implemented in a parallel manner rather than sequentially. The key action points identified by the medical experts for moving toward a robust policy framework for the country are presented in Table This document aims to draw the attention of policymakers in KSA to key priorities for bridging gaps in HBV care, set the stage for "going beyond the evidence," and establish the context for a strategic policy framework for addressing HBV in KSA. The medical experts set forth KSA-specific recommendations that are complemental to the WHO 2030 target to eliminate HBV. All the recommendations consider the current evidence and practical healthcare scenario in KSA.Implementing these strategic measures will require a multi-collaborator approach. We sincerely believe that our endeavor will provide a strong message to the Saudi Health Council regarding the need to prioritize a policy framework for the successful elimination of HBV in KSA.


Multiple risk factors such as age, body mass index (BMI), preoperative diagnosis, smoking, diabetes mellitus, malalignment of an implant, and presence of ipsilateral hindfoot fusion have been shown to contribute to failure of total ankle arthroplasty (TAA). However, the exact causes of TAA failure remain uncertain, and various causes can lead to a need for revision surgery. We report a case of early aseptic loosening of the implant following TAA in a patient with severe varus deformity of the ipsilateral knee. Total ankle arthroplasty (TAA) is one of the surgical treatment options for end-stage osteoarthritis of the ankle, and it can decrease pain and improve function . Ankle aWe report a case of a 72-year-old male patient with concurrent osteoarthritis of the ankle and an ipsilateral varus knee in whom TAA was performed, resulting in early aseptic loosening of the implant.2. The patient reported difficulty walking more because of his left ankle pain than his left knee pain, and he had experienced no improvement of his symptoms after receiving medication and injection treatment at another clinic. The physical examination revealed a large effusion and pain with limited range of motion in the left ankle. The osteoarthritic stage of the ankle was Takakura's classification stage 4 [A 72-year-old male patient who complained of serious pain in the left ankle and ipsilateral knee for about five years presented to the clinic in January 2017. He had no systemic musculoskeletal disease or other medical history such as hypertension or diabetes mellitus. He was 159.0 cm in height and 60.0 kg in weight, with a body mass index of 23.7 kg/mAfter considering all the findings, we decided to operate on the painful ankle first and then on the knee three months later. The patient underwent total ankle arthroplasty (TAA) with a Zenith Total Ankle Replacement  . The ankAt three months following the procedure, the patient complained of medial side pain in the left ankle, especially on walking. Clinical examination revealed restriction of movement due to pain and tenderness on the medial side and edema of the ankle. Laboratory studies including a complete blood-cell and differential count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) level were within normal limits, and there was no clinical evidence of infection. Plain radiographs demonstrated a radiolucent line and osteolysis of the medial tibial component . It was At six months postoperative, the patient complained of global pain in the left ankle joint, as well as tenderness and swelling. He reported aggravation of pain when his full body weight was loaded on his left ankle. Plain radiographs demonstrated a progressive radiolucent line and osteolysis of the tibial component. The talar component was not well positioned in the anteroposterior (AP) plane, sitting lateral to the midline . It was The purpose of this report is to emphasize the need to evaluate the function and varus alignment of the knee joint both clinically and radiologically prior to TAA. In elderly patients with severe varus deformity of the knee, performing TKA first before TAA could be beneficial in reduction of the burden on ankle joints.Numerous studies have reported the role of individual patient characteristics and clinical and radiographic factors as risk factors associated with failure of TAA. Such risk factors include age, body mass index (BMI), preoperative diagnosis, smoking, diabetes mellitus, malalignment of the implant, and presence of an ipsilateral hindfoot fusion. Patient age at the time of surgery was predictive of implant failure, and multiple authors have shown a relationship between younger patients and higher failure risk , 9. SchiThe changes in alignment in the proximal tibia can affect the loading conditions within the ankle joint . TherefoOur report represents a case of early failure in a patient with severe varus deformity of the knee following TAA. It demonstrates that it is possible to incorrectly distribute weight loading on the ankle in patients with ipsilateral varus knee deformity, and this might be a cause of early failure. It seems reasonable to evaluate the function and varus alignment of the knee joint both clinically and radiologically prior to TAA.