Tobacco mosaic virus (TMV) was the first virus to be studied in detail and for many years TMV and other tobamoviruses, particularly tomato mosaic virus (ToMV) and tobamoviruses infecting pepper (Capsicum spp.), were serious crop pathogens. By the end of the twentieth and for the first decade of the twenty-first century tobamoviruses were under some degree of control due to introgression of resistance genes into commercial tomato and pepper lines. However, tobamoviruses remained as important models for molecular biology, biotechnology and bio-nanotechnology. Recently, tobamoviruses have again become serious crop pathogens due to the advent of tomato brown rugose fruit virus, which overcomes tomato resistance against TMV and ToMV, and the slow but apparently inexorable worldwide spread of cucumber green mottle mosaic virus, which threatens all cucurbit crops. This review discusses a range of mainly molecular biology-based approaches for protecting crops against tobamoviruses. These include cross-protection (using mild tobamovirus strains to ‘immunize’ plants against severe strains), expressing viral gene products in transgenic plants to inhibit the viral infection cycle, inducing RNA silencing against tobamoviruses by expressing virus-derived RNA sequences in planta or by direct application of double-stranded RNA molecules to non-engineered plants, gene editing of host susceptibility factors, and the transfer and optimization of natural resistance genes.

Peripheral and autonomic neuropathy are common disease manifestations in systemic amyloidosis. Neurofilament light chain (NfL), a neuron-specific biomarker, is released into the blood and cerebrospinal fluid after neuronal damage. This systematic review provides an overview on the value of NfL in early detection of neuropathy, central nervous system involvement, monitoring of neuropathy progression, and treatment effect in systemic amyloidosis. A literature search in PubMed, Embase and Web of Science was performed on 14-02-2024 for studies investigating NfL levels in patients with systemic amyloidosis and transthyretin gene variant (TTRv) carriers. Only studies containing original data were included. Included were twelve full-text articles and six abstracts describing 1604 participants: 298 controls and 1306 TTRv carriers or patients with or without polyneuropathy. Patients with polyneuropathy demonstrated higher NfL levels compared to healthy controls and asymptomatic carriers. Disease onset was marked by rising NfL levels. Following initiation of transthyretin gene-silencer treatment, NfL levels decreased and remained stable over an extended period. NfL is not an outcome biomarker, but an early and sensitive disease process biomarker for neuropathy in systemic amyloidosis. Therefore, NfL has potential to be used for early detection of neuropathy, monitoring treatment effect, and monitoring disease progression in patients with systemic amyloidosis.

Toxoplasmosis is a zoonosis of warm-blooded animals, affecting also humans, caused by Toxo-plasma gondii, an obligate intracellular parasite with a complex biological cycle. Toxoplasmosis is considered a re-emerging zoonosis and an important public health threat, also for the absence, up to now, of efficient vaccines and preventive measures. Sources of transmission to humans are environmental or food-borne, mainly through the consumption of raw and undercooked meat, predominantly of Sus scrofa, considered highly susceptible to T. gondii. Mainly in the last dec-ades, an effective strategy to counter animal infectious diseases was based on the discovery of resistance immuno-genetic markers, possibly to be used for association studies between geno-typic and phenotypic traits and consequently in Marker Assisted Selection. Until now, this gen-otyping approach has never been adopted for T. gondii infection, so this study aimed, for the first time, to fill this gap. In particular, pigs, reared in different farms of Central Italy, were serologically characterized by an ELISA assay performed on diaphragm meat juice. Out of 179 tested animals, 98 resulted seropositive (54.74%), 57 seronegative (31.84%) and 24 doubtful (10.6%), underlining a possible re-emerging diffusion of this protozoan in the investigated areas. Atten-tion was firstly focused on IL-18 gene, encoding for a pro-inflammatory cytokine that plays a key role starting from the upstream steps of the immunity pathway towards T. gondii. A RT-PCR assay followed by Sanger sequencing of IL-18 cDNA was de novo developed. For this interleukin, at this stage, genetic analysis has not highlighted significant polymorphic variations compared to the reference sequence, except for a seropositive animal. However, the outcomes of this pre-liminary innovative study will be investigated in depth analyzing other relevant genetic re-gions and other target genes.

Intratumoral immune cytolytic activity (CYT), measured as the geometric mean of the expression of Granzyme-A (GZMA) and Perforin-1 (PRF1), has emerged as a critical factor in cancer immunotherapy, with significant implications for patient prognosis and treatment outcomes. Here, we review how different immune checkpoint pathways, the composition of Tumor Microenvironment (TME), antigen presentation and metabolic pathways, all regulate CYT. We also discuss the various methods through which CYT can be assessed. The detection and analysis of tumor-infiltrating lymphocytes using flow cytometry or immunohistochemistry provide important information on the immune cell populations within the TME. Gene expression profiling and spatial analysis techniques, such as multiplex immunofluorescence and imaging mass cytometry, allow researchers to study CYT in the context of the TME. We further report the significant clinical implications that CYT has, as its increased levels are associated with positive clinical outcomes and a favorable prognosis. Moreover, CYT can be used as a prognostic biomarker and aid in patient stratification. Measuring CYT through different methods offers promising paths for improving treatment responses. Overall, we highlight that the understanding and modulation of CYT levels is critical for improving cancer immunotherapy. Research into CYT and the factors that influence it has the potential to transform cancer treatment and improve patient outcomes.

We investigated and quantified bacterial accumulation in facemasks used by the general population, using 16S rRNA (Sanger Sequencing), culture and biochemical analysis along with Rose Bengal staining. Additionally, a systematic overview of the literature on face mask contamination was undertaken. We found an average bacterial load of 4.24 × 10⁴ CFU recovered/mask, with a maximum load of 2.85 × 10⁵ CFU. This maximum is 310 times higher than the limit value for contamination of ventilation system outlet surfaces specified by the German standard VDI 6022. Biochemical and molecular identification predominantly found Staphylococcus species (80%), including Staphylococcus aureus, along with endospore-forming Bacillus spp. Literature reports also indicate contamination of masks by bacterial and fungal opportunists of the genera Acinetobacter, Aspergillus, Alternaria, Bacillus, Cadosporium, Candida, Escherichia, Enterobacter, Enterococcus, Klebsiella (including K. pneumoniae), Micrococcus, Microsporum, Mucor, Pseudomonas, Staphylococcus and Streptococcus. Bacterial counts increase linearly with wearing duration, and prolonged use may affect the skin and respiratory microbiomes, promoting consequential eye, skin, oral and airway conditions. These aspects underscore the urgent need for further research and a risk-benefit analysis in respect of mask use, particularly given their unproven efficacy in disrupting the transmission of respiratory viruses and their adverse social consequences.

Transcription factors must scan genomic DNA, recognize the cognate sequence of their control element(s), and bind tightly to them. The DNA recognition process is primarily carried out by their DNA binding domains (DBD), which interact with the cognate site with high affinity and more weakly with any other DNA sequence. DBDs are generally thought to bind to their cognate DNA without changing conformation (lock-and-key). Here we used nuclear magnetic resonance and circular dichroism to investigate the interplay between DNA recognition and DBD conformation in the Engrailed homeodomain (EnHD), as model case for the homeodomain family of eukaryotic DBDs. We found that the conformational ensemble of EnHD is rather flexible and becomes more structured as ionic strength increases following a Debye-Hückel’s dependence. Our analysis indicates that EnHD’s response to ionic strength is mediated by a built-in electrostatic spring-loaded latch that operates as conformational transducer. We also found that, at moderate ionic strengths, EnHD changes conformation upon binding to cognate DNA. This change is of larger amplitude and somewhat orthogonal to the response to ionic strength. As a consequence, very high ionic strengths (e.g. 700 mM) block the electrostatic-spring-loaded latch and binding to cognate DNA becomes lock-and-key. However, the interplay between EnHD conformation and cognate DNA binding is robust across a range of ionic strengths (i.e. 45 to 300 mM) that covers the most physiologically-relevant conditions. Therefore, our results demonstrate the presence of a mechanism for the conformational control of cognate DNA recognition on a eukaryotic DBD. This mechanism can function as a signal transducer that immediately locks the DBD in place upon encountering the cognate site during active DNA scanning. The electrostatic-spring-loaded latch of EnHD can also enable the fine control of DNA recognition in response to local/temporal changes in ionic strength induced by variate physiological processes.

The knowledge of what separates us genetically from our less-evolved relatives is crucial for gaining new biomedical insights about the human-chimpanzee relatedness for the use of appropriate stand-in towards the development of new treatments and diagnostic aids for various ailments. Although the genomes of humans and chimpanzees share 99% similarity, significant differences exist between the two species in their non-coding intronic regions. However, no work has been carried out in the aspects of target prediction concerning the ‘predicted homology’ in their microRNA sequences. Non-coding miRNAs which are post-transcriptional regulators of development, differentiation, growth, and metabolism, harboring the intronic regions may be crucial for expanding the horizons of our understanding. In this study, we proposed to perform the target prediction for the human-chimp miRNA homologs in the PHEX gene of the human X chromosome using various computational tools and databases. We identified a total of 1296 human miRNAs, 46, 957 gene targets, and 30, 563 targets of human and homologous chimp miRNAs respectively. Furthermore, we analysed gene interacting networks to identify the top interacting targets in both the species. Finally, we interpreted the biological importance of top-interacting miRNAs and their targets. The results demonstrated varying levels of multiplicity and cooperativity between the predicted miRNAs and target genes in the two genera. Such miRNAs may be responsible for the dysregulation of gene expression in several signaling pathways.

The rapid expansion of transcriptomics from increased affordability of next-generation sequencing (NGS) technologies generates rocketing amounts of gene expression data across biology and medicine, and notably in cancer research. Concomitantly, many bioinformatics tools were developed to streamline gene expression analysis and quantification. We tested the concordance of NGS RNA sequencing (RNA-seq) analysis outcomes between the two predominant programs for reads alignment, HISAT2 and STAR, and the two most popular programs for quantifying gene expression in NGS experiments, edgeR and DESeq2, using RNA-seq data from a series of breast cancer progression specimens, which include histologically confirmed normal, early neoplasia, ductal carcinoma in situ and infiltrating ductal carcinoma samples microdissected from formalin fixed, paraffin embedded (FFPE) breast tissue blocks. We identified significant differences in aligners’ performance: HISAT2 was prone to misalign reads to retrogene genomic loci, STAR generated more precise alignments, especially for early neoplasia samples. edgeR and DESeq2 produced similar lists of differentially expressed genes in stage comparisons, with edgeR producing more conservative, though shorter, lists of genes. Albeit, Gene Ontology (GO) enrichment analysis revealed no skewness in significant GO categories identified among differentially expressed genes by edgeR vs DESeq2. As transcriptome analysis of archived FFPE samples becomes a vanguard of precision medicine, identification and fine-tuning of bioinformatics tools becomes critical for clinical research. Our results indicate that STAR and edgeR are well-suited tools for differential gene expression analysis from FFPE samples.

The emergence of acquired resistance to EGFR-TKIs is almost inevitable even after a remarkable clinical response. Secondary mutations such as T790M and C797S are responsible for the resistance to 1st/2nd generation (1/2G) TKIs and 3G TKIs, respectively. To overcome both the T790M and C797S mutations, novel 4G EGFR-TKIs are now under early clinical development. In this study, we evaluated the efficacy of a 4G EGFR-TKI in the treatment of lung cancer with EGFR mutation as well as explored resistance mechanisms to a 4G TKI. First, we compared the efficacies of seven TKIs including a 4G TKI, BI4020, against Ba/F3 cell models that simulate resistant tumors after frontline osimertinib treatment failure because of a secondary mutation. We also established acquired re-sistant cells to BI4020 by chronic drug exposure. Ba/F3 cells with an osimertinib-resistant secondary mutation were refractory to all 3G TKIs tested (alflutinib, lazertinib, rezivertinib, almonertinib, and befotertinib). BI4020 inhibited the growth of C797S-positive cells; however it was not effective against L718Q-positive cells. Erlotinib was active against all Ba/F3 cells tested. In the analysis of resistance mechanisms of BI4020 resistant (BIR) cells, none harbored secondary EGFR mutations. HCC827BIR cells had MET gene amplification and were sensitive to a combination of capmatinib (MET-TKI) and BI4020. HCC4006BIR and H1975BIR cells exhibited epithelial to mesenchymal transition. This study suggests that erlotinib may be more suitable than 4G TKIs to overcome sec-ondary mutations after front-line osimertinib. We found that off-target mechanisms that cause re-sistance to earlier generation TKIs will also cause resistance to 4G TKIs.

Migraine is a neurovascular disorder that can be debilitating for individuals and society. Current research focuses on finding effective analgesics and management strategies for migraines by targeting specific receptors and neuropeptides. Nevertheless, the responder rates of recently approved calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) and receptor inhibitors remain around 50 percent. To address the need for novel therapeutic targets, researchers are exploring the potential of another secretin family peptide, pituitary adenylate cyclase-activating polypeptide (PACAP), as a ground-breaking treatment avenue for migraine. Preclinical models have revealed how PACAP affects the trigeminal system, which is implicated in headache disorders. Clinical studies have demonstrated the significance of PACAP in migraine pathophysiology; however, a few clinical trials remain inconclusive: the pituitary adenylate cyclase-activating peptide 1 receptor mAb, AMG 301 showed no benefit for migraine prevention, while the PACAP ligand mAb, Lu AG09222 significantly reduced the number of monthly migraine days over placebo in a phase 2 clinical trial. Meanwhile, another secretin family peptide vasoactive intestinal peptide (VIP) is gaining interest as a potential new target. In light of recent advances in PACAP research, we emphasize the potential of PACAP as a promising target for migraine treatment, highlighting the significance of exploring PACAP as a member of the antimigraine armamentarium, especially for patients who do not respond to or contraindicated to anti-CGRP therapies. By updating our knowledge on PACAP and its unique contribution to migraine pathophysiology, we can pave the way for reinforcing PACAP and other secretin peptides, including VIP, as a novel treatment option for migraines.

A whole-exome capture and next-generation sequencing applied to an 11 y/o patient with a clinical history of congenital hypotonia, generalized motor and cognitive neurodevelopmental delay, severe cognitive deficit, without any identifiable Syndromic pattern, and to her parents, disclosed a de novo heterozygous pathogenic mutation, c.697_699del p.Phe233del (rs786204835)(ACMG classification PS2, PM1, PM2, PP5), harbored in the PURA gene (MIM*600473) (5q31.3), associated to Autosomal Dominant Mental Retardation 31 (MIM # 616158). We used the significant improvement in the accuracy of protein structure prediction recently implemented in AlphaFold that incorporates novel neural network architectures and training procedures based on the evolutionary, physical, and geometric constraints of protein structures. The wild-type (WT) sequence and the mutated one, missing the Phe233, were reconstructed. The predicted local Distance Difference Test (lDDT) for the PURA WT and the PURA-Phe233del showed that the occurrence of the Phe233del affects between 220-320 amino acids. The distortion in the PURA structural confor-mation in the ~5Å surrounding area after the p.Phe233del produces a conspicuous disruption of the repeat III, where the DNA and RNA helix unwinding capability occurs. PURA Protein-DNA Docking corroborated these results in silico Analysis that showed a loss of the contact of the PURA-Phe233del III repeat domain model with the DNA. Together, i) the energetic and stereochemical, ii) the hydropathic indices and polarity surfaces, and iii) the hybrid Quantum Mechanics-Molecular Mechanics (QM-MM) analyses of the PURA molecular models demarcate at the atomic resolution the specific surrounding region affected by these mutations and paves the way for future cell-based functional analysis. To the best of our knowledge, this is the first report of a de novo mutation underpinning a PURA syndrome in a Latin American patient and highlights the importance of predicting the molecular effects in protein structure using artificial intelligence algorithms and molecular and atomic resolution stereochemical analyses.

Streptomyces, being one of the most promising genera due to its ability to synthesize a variety of bioactive secondary metabolites of pharmaceutical interest, here studied in relation to its genomic and metabolomic potential. Coinciding with the increase in sequenced data, mining of bacterial genomes for biosynthetic gene clusters (BGCs) has become a routine component of natural product discovery. Herein, we describe the isolation and characterization of a Streptomyces tendae VITAKN with quorum sensing inhibitory activity (QSI) that was isolated from southern coastal parts of India. The nearly complete genome consists of 8,621,231bp with a GC content of 72.2%. Utilizing the BiG-SCAPE-CORASON platform, a sequence similarity network predicted from this strain was evaluated through sequence similarity analysis with the MIBiG database and existing 3,365 BGCs predicted by antiSMASH analysis of publicly available complete Streptomyces genomes. Crude extract analyzed on LC-HRMS/MS and Global Natural Product Social Molecular Networking (GNPS) online workflow using dereplication resulted in the identification of cyclic dipeptides (2,5-diketopiperazines, DKPs) in the extract, which are known to possess QSI activity. Our results highlight the potential use of genomic mining coupled with LC-HRMS/MS and bionformatic tools (GNPS) as a potent approach for metabolome studies in discovering novel QSI lead compounds. This study also provides the biosynthetic diversity of these BGCs and an assessment of the predicted chemical space yet to be discovered.

All life on Earth uses three integrated molecular systems in which genetic information contained in DNA base sequences is transmitted to ribosomes by RNA and a genetic code, then translated into the amino acid sequences of structural and catalytic proteins. Therefore, the most important point for understanding the origin of life is to determine how such systems could emerge from random processes on the early Earth. In this review, two alternatives are compared: the RNA world hypothesis and the [GADV]-protein world hypothesis. [GADV] refers to four amino acids, Gly [G], Ala [A], Asp [D] and Val [V] that are conserved in the amino acid sequences of many common proteins. Here I will argue that the origins of the three primary processes required for life to begin can be better explained by the GADV hypothesis than the RNA world hypothesis. The GADV hypothesis also incorporates a conversion process by which random polymers can evolve into proteins with ordered sequences.

Keywords: spinal muscular atrophy (SMA); survival of motor neuron 1 (SMN1); SMN2; SMN protein; antisense oligonucleotide (ASO); nusinersen; gene therapy; onasemnogene; risdiplam; small molecule, combination therapy

The hospital indoor environment plays a significant role in shaping the microbial exposures that humans encounter. Resistance to antibiotics is one of the mechanisms employed by bacteria to develop resilience against stress in indoor environments. The extensive usage of antibiotics has been a key factor in driving changes in the ecological function of antibiotic resistance genes (ARGs) and their acquisition by pathogenic bacteria. By integrating the 16S rRNA Illumina sequencing and high throughput-qPCR approaches with water and air dust samples across seven departments at Peking University Shenzhen Hospital, China, this study yielded intriguing findings regarding the department-specific variation, transmission, and correlation of bacteria, ARGs and MGEs within the hospital indoor environment. One notable observation was that the seasonal variation played a vital role in shaping the bacterial composition in the overall hospital indoor environment across seven studied departments. Nevertheless, a similar significant seasonal impact was only observed in the blood test room and emergency departments, rather than in the other five departments. Another intriguing finding was the correlation between ARGs and MGEs abundance. This correlation was evident in the overall hospital indoor environment, which was conversely not found in the emergency, pneumology and gynecology departments. Additionally, while there was no significant relationship that occurred between bacterial communities and ARGs/MGEs within the hospital, the gynecology department demonstrated a close link between bacterial communities and the presence of ARGs/MGEs. Notably, the gynecology department also stood out as an important source of bacteria and ARGs/MGEs for other departments. This study underscores the need for careful surveillance and monitoring of antibiotic resistance, particularly in Legionella spp. in man-made water systems. The findings also show the importance of monitoring and understanding the genetic elements such as Tp614 involved in gene transfer and recombination, as well as their impact on antimicrobial treatment efficacy.

In addition to its use as a food additive, sesame is also very popular in conventional drugs because of its antifungal, anticancer, analgesic, antioxidant, and antiproliferative, vitamin B and E supplier, serum cholesterol and blood pressure-lowering, wound healing potential. In this study, the cytotoxicity, wound healing, and anticancer (antiproliferation) properties of the ex-tract obtained from in vitro cultures of Sesamum orientale L. cv. "Gökova" were investigated using in L929 fibroblast, MCF-7 breast, and A549 lung epithelial cell lines. In our study, the cisplatin was also used as a control group to compare the anticancer efficacy of our plant extract. The IC50 values obtained from cell treatments were 922.73 µg.ml-1 (plant extract) and 33.09 µg.ml-1 (cispla-tin) for A549 µg.ml-1, 1837.07 µg.ml-1 (plant extract) and 19.27 µg.ml-1 (cisplatin) for MCF-7, and 154.70 µg.ml-1 (plant extract) for L929, respectively. The subcytotoxic doses of the treated plant extract provided the healing of artificially created wounds on L929 fibroblast cell cultures within 48 hours. For the evaluation of the anticancer activity, it was also determined that transcriptomic analyzes of BCL-XL gene, which is negatively correlated with apoptotic pathway, and Cas3 and Cas9 genes, which are positively correlated with apoptotic pathway, showed a statistically sig-nificant increase in A549 and MCF-7 cell lines treated with plant extract or cisplatin. In the light of the results obtained from the present study, it was seen that sesame plant extract may have wound healing potential at decreasing doses and anticancer activity potential at increasing dos-es. The present study can be a useful resource for the development of a drug with wound healing and/or antiproliferative potential, with applications to be made in different cell lines in the future.

Rice blast, caused by Magnaporthe oryzae, poses significant threat to rice production. Rice blast susceptibility has been observed in Japanese rice varieties with excellent eating quality. Enhancing blast resistance is essential to ensure minimal use of agricultural chemicals. Two types of blast resistance are observed: true resistance, which is a type of qualitative resistance expressed by a major gene, and field resistance, which is a type of quantitative resistance expressed by multiple micro-acting genes. ‘Resistance collapse’, in which a variety with a true resistance gene becomes diseased by blast fungus races compatible with the resistance gene, has been observed. Varieties carrying blast-resistance genes, such as Pb1 (panicle blast resistance 1), have been developed through DNA marker-assisted selection. In this review, we focus on the Pb1, which expresses strong quantitative resistance to panicle blast and has been widely used in Japan without showing ‘resistance collapse’ for 40 years. Pb1 is an ‘adult plant resistance gene’ that does not exert strong selection pressure on the blast population during the leaf blast stage, thus preventing the selective multiplication of Pb1-compatible blast strains. This epidemiological mechanism prevents ‘resistance collapse’. Interdisciplinary research and breeding are required to sustainably use genes that induce high field resistance.

Early reports demonstrated the presence of cells with stem-like properties in bone marrow, with these cells having both hematopoietic and mesenchymal lineages. Over the years, various investigations have purified and characterized mesenchymal stromal/stem cells (MSCs) from different human tissues as cells with multi-lineage differentiation potential under the appropriate conditions. Due to their appealing characteristics and potential, MSCs are leveraged in many applications including medicine, oncology, bioprinting and as recent as treatment of COVID-19. To date, reports indicate mesenchymal stromal/stem cells have varied differentiation capabilities into different cell types and demonstrate immunomodulating and anti-inflammatory properties. Reports indicate that different MSCs microenvironments or niche and the resulting heterogeneity may influence their behavior and differentiation capacity. The potential clinical applications of mesenchymal stromal/stem cells have led to an avalanche of research reports on their properties and hundreds of clinical trials being undertaken. The future looks bright and promising for mesenchymal stem cell research with many clinical trials under way to prove their utility in many applications and in the clinic. This report provides an update on the potential broader use of mesenchymal stromal/stem cells, review early observations of the presence of these cells in the bone marrow and their magnificent differentiation capabilities and immunomodulation.

Primary open-angle glaucoma (POAG) is a progressive optic neuropathy with a complex, multifactorial aetiology. Raised intraocular pressure (IOP) is the most important clinically modifiable risk factor for POAG. All current pharmacological agents target aqueous hu-mour dynamics to lower IOP. Newer therapeutic agents are required as some patients with POAG show a limited therapeutic response or develop ocular and systemic side ef-fects to topical medication. Elevated IOP in POAG results from cellular and molecular changes in the trabecular meshwork driven by increased levels of transforming growth factor β (TGFβ) in the anterior segment of the eye. Understanding how TGF affects both the structural and functional changes in the outflow pathway and IOP is required to de-velop new glaucoma therapies that target the molecular pathology in the trabecular meshwork. In this study we evaluated the effects of TGF-1 and -2 treatment on miRNA expression in cultured human primary trabecular meshwork cells. Our findings are pre-sented in terms of specific miRNAs (miRNA-centric), but given miRNAs work in net-works to control cellular pathways and processes, a pathway-centric view of miRNA ac-tion is also reported. Evaluating TGF-responsive miRNA expression in trabecular meshwork cells will further our understanding of the important pathways and changes involved in the pathogenesis of glaucoma and could lead to the development of miRNAs as new therapeutic modalities in glaucoma.

Fanconi anemia (FA) patients display an exacerbated risk of oral squamous cell carcinoma (OSCC) and precursor lesions at young ages, mainly at the oral cavity. As patients have defects in DNA repair mechanisms, standard-of-care treatments to OSCC such as radiotherapy and chemotherapy give rise to severe toxicities. New methods for early diagnosis are urgently necessary to allow treatments in early disease stages and achieve better clinical outcomes. We have conducted a prospective, longitudinal study whereby liquid biopsies from sixteen lesion/tumor-free patients were analyzed for the presence of mutations in cancer genes. DNA from saliva and plasma were sequentially collected and deep-sequenced, and the clinical evolution followed during a median time of around 2 years. In 9/16 FA patients we detected mutations in cancer genes (mainly TP53) with molecular allele frequencies (MAF) down to 0.07 %. Importantly, all patients having mutations and clinical follow-up data after mutation detection (n=6) developed oral precursor lesions or OSCC. Lead-time between mutation detection and tumor diagnosis ranged from 23 to 630 days. Strikingly, FA patients without mutations display significantly lower risk of developing precursor lesions or OSCC. Therefore, our diagnostic approach could help to stratify FA patients into risk groups, which would allow closer surveillance for OSCC or precursor lesions.

In the implementation of thermal enhanced oil recovery (TEOR) techniques, the temperature impact on relative permeability in oil - water systems is of special concern. Hence, developing a fast and reliable tool to model the temperature effect on two-phase oil - water relative permeability is still a major challenge for precise studying and evaluation of TEOR processes. To reach the goal of this work, two promising soft-computing algorithms, namely Group Method of Data Handling (GMDH) and Gene Expression Programming (GEP) were employed to develop reliable, accurate, simple and quick to use paradigms to predict the temperature dependency of relative permeability in oil - water systems (K_rw and K_ro). To do so, a large database encompassing wide-ranging temperatures and fluids/rock parameters, including oil and water viscosities, absolute permeability and water saturation, was considered to establish these correlations. Statistical results and graphical analyses disclosed the high degree of accuracy for the proposed correlations in emulating the experimental results. In addition, GEP based correlations were found to be the most consistent with root mean square error (RMSE) values of 0.0284 and 0.0636 for K_rw and K_ro, respectively. Lastly, the comparison of the performances of our correlations against those of the preexisting ones indicated the large superiority of the introduced correlations compared to previously published methods. The findings of this study can help for better understanding and studying the temperature dependency of oil - water relative permeability in thermal enhanced oil recovery processes.

Premature ovarian insufficiency (POI) is a highly prevalent disorder, characterized by the development of menopause before age of 40. Most cases are idiopathic; however, in some women the cause of this condition (e.g. anticancer treatment, genetic disorders, and enzymatic defects) may be identified. Although hormone replacement therapy, the principal therapeutic approach for POI, helps to alleviate the related symptoms, this does not effectively solve the issue of fertility. Assisted reproductive techniques also lack efficacy in these women. Thus, the effective approach to manage the patients with POI is highly warranted. Several mechanisms, associated with POI, have been identified, including lack of FSH receptor functioning, alterations in the apoptosis control, mutations in Sal-like 4 genes, thymulin or basonuclin-1 deficiency etc. The above-mentioned may be good targets for gene therapy in order to correct defects, leading to POI. The goal of this review is to summarize the current experience on the POI studies, that employed gene therapy, and to discuss the possible future directions in this field.

The central promise of personalized medicine is individualized treatments that target molecular mechanisms underlying the physiological changes and symptoms arising from disease. We demonstrate a bioinformatics analysis pipeline as a proof-of-principle to test the feasibility and practicality of comparative transcriptomics to classify two of the most popular in vivo diet-induced models of coronary atherosclerosis, apolipoprotein E null mice and New Zealand White rabbits. Transcriptomics analyses indicate the two models extensively share dysregulated genes albeit with some unique pathways. For instance, while both models have alterations in the mitochondrion, the biochemical pathway analysis revealed, Complex IV in the electron transfer chain is higher in mice, whereas the rest of the electron transfer chain components are higher in the rabbits. Several fatty acids anabolic pathways are expressed higher in mice, whereas fatty acids and lipids degradation pathways are higher in rabbits. This reflects the differences between two translational models of atherosclerosis. This study validates transcriptome analysis as a potential method to precisely identify altered cellular and molecular pathways in atherosclerotic disease, which can be used to individualize treatment even in the absence of genetic data.

BackgroundThe use of antimicrobials to treat food animals may result in antimicrobial residues in foodstuffs of animal origin. The European Medicines Association (EMA) and World Health Organization (WHO) define safe antimicrobial concentrations in food based on acceptable daily intakes (ADIs). It is unknown if ADI doses of antimicrobials in food could influence the antimicrobial susceptibility of human-associated bacteria. ObjectivesThis aim of this study was to evaluate if the consumption of ADI doses of erythromycin could select for erythromycin resistance in a Galleria mellonella model of Streptococcus pneumoniae infection. Methods A chronic model of S. pneumoniae infection in G. mellonella larvae was used for the experiment. Inoculation of larvae with S. pneumoniae was followed by injections of EMA (0.0875 μg/ml) and WHO (0.012 μg/ml) ADI doses of erythromycin proceeded by isolation of S. pneumoniae colonies on selective agar plates. Minimum inhibitory concentrations (MICs) of resistant colonies were measured, and whole genome sequencing (WGS) was performed followed by variant calling to determine the genetic modifications.   Results Exposure to single doses of both EMA and WHO ADI doses of erythromycin resulted in the emergence of erythromycin resistance in S. pneumoniae. Emergent resistance to erythromycin was associated with a mutation in rplA. Conclusion In our in vivo model, even single dose of erythromycin that are classified as acceptable by the WHO and EMA induced significant increases in erythromycin MICs in S. pneumoniae. These results suggest the need to include the induction of antimicrobial resistance (AMR) as a significant criterion for determining ADIs.

New insights into the causes and mechanisms of congenital heart disease (CHD) have been gained through the use of next-generation sequencing. Examination of the whole exome sequence detects detrimental gene variations modifying single or contiguous nucleotides, that are characterised as pathogenicity based on statistical assessments of families. and correlates with congenital heart disease, elevated expression during heart development, and reduction of harmful protein-coding mutations in the general population. Patients with CHD and extracardiac abnormalities enriched for gene classes meeting these criteria. CHDs and extracardiac defects, supporting a common set of pathways in the organogenesis of CHDs. Single-cell transcriptomics data reveal the expression of genes associated with CHD in specific cell lineages, and emerging evidence suggests that genetic variants disrupt multicellular genes essential for cardiogenesis. Metrics and units are being tracked in whole genome sequence studies.

Mesenchymal Stem Cells derived from bone marrow (hBM-MSCs) are utilized in tendon tissue‐engineering protocols while extra-embryonic cord-derived, including from Wharton’s Jelly (hWJ-MSC), are emerging as useful alternatives. To explore the tenogenic responsiveness of hBM-MSCs and hWJ-MSCs to hGDF-5 we supplemented each at doses of 1, 10, and 100 ng/mL and determined proliferation, morphology and time-dependent expression of tenogenic markers. We evaluated expression of Collagen types 1 (COL1A1) and 3 (COL3A1), Decorin (DCN), Scleraxis A (SCX-A), Tenascin-C (TNC) and Tenomodulin (TNMD) noting the earliest and largest increase with 100 ng/mL. With 100 ng/mL, hBM-MSCs showed upregulation of SCX-A (1.7-fold) at day 1, TNC (1.3-fold) and TNMD (12-fold) at Day 8. hWJ-MSCs, at the same dose, showed up-regulation of COL1A1 (3-fold), DCN (2.7-fold), SCX (3.8-fold) and TNC (2.3-fold) after 3 days of culture. hWJ-MSCs also showed larger proliferation rate and marked aggregation into a tubular shaped system at Day 7 (with 100 ng/mL of hGDF-5). Simultaneous to this we explored expression of pro-inflammatory (IL-6, TNF, IL-12A, IL-1β) and anti-inflammatory (IL-10, TGF-β1) cytokines across for both cell types. hBM-MSCs exhibited a better balance of pro-inflammatory and anti-inflammatory cytokines upregulating IL-1β (11-fold) and IL-10 (10-fold) at Day 8; hWJ-MSCs, had a slight expression of IL-12A (1.5-fold) but a greater up-regulation of IL-10 (2.5-fold). Collagen type I and tenomodulin proteins, detected by immunofluorescence, confirming the greater protein expression when 100 ng/mL were supplemented. In the same conditions, both cell types showed specific alignment and shape modification (fibroblast-like) with a Lenght/Width ratio increase at value higher than 1, suggesting their response in activating tenogenic commitment events, and they both potential use in 3D in vitro tissue engineering protocols.

It is known that knockdown of the mitochondrial 18 kDa translocator protein (TSPO) as well as TSPO ligands modulate various functions, including functions related to cancer. To study the ability of TSPO to regulate gene expression regarding such functions, we applied microarray analysis of gene expression to U118MG glioblastoma cells. Within 15 minutes, the classical TSPO ligand PK 11195 induced changes in expression of immediate early genes and transcription factors. These changes also included gene products that are part of the canonical pathway serving to modulate general gene expression. These changes are in accord with reverse transcriptase (RT) real-time -PCR. At the time points of 15, 30, 45, and 60 minutes, as well as 3 and 24 hours of PK 11195 exposure, the functions associated with the changes in gene expression in these glioblastoma cells covered well known TSPO functions. These functions included cell viability, proliferation, differentiation, adhesion, migration, tumorigenesis, and angiogenesis. This was corroborated microscopically for cell migration, cell accumulation, adhesion, and neuronal differentiation. Changes in gene expression at 24 hours of PK 11195 exposure were related to downregulation of tumorigenesis and upregulation of programmed cell death. In the vehicle treated as well as PK 11195 exposed cell cultures, our triple labeling showed intense TSPO labeling in the mitochondria but no TSPO signal in the cell nuclei. Thus, mitochondrial TSPO appears to be part of the mitochondria-to-nucleus signaling pathway for modulation of nuclear gene expression. The novel TSPO ligand 2-Cl-MGV-1 appeared to be very specific regarding modulation of gene expression of immediate early genes and transcription factors.

Remaining service life (RSL) of pavement, as a sign of future pavement performance, has always received growing attention from pavement engineers. The RSL describes the time from the moment of pavement inspection until such a time when a major repair or reconstruction is required. The conventional approach to determining RSL involves using non-destructive tests. These tests, in addition to being costly, interfere with traffic flow and compromise users' safety. In this paper, surface distresses of pavement have been used to estimate the pavement’s RSL in order to eliminate the aforementioned problems and challenges. To implement the proposed theory, 105 flexible pavement segments were taken from Shahrood-Damghan Highway (Highway 44) in Iran. For each pavement segment, the type, severity, and extent of surface damage and pavement condition index (PCI) were determined. The pavement RSL was then estimated using non-destructive tests include Falling Weight Deflectometer (FWD) and Ground Penetrating Radar (GPR). After completing the dataset, the modeling was conducted to predict RSL using three techniques include Support Vector Regression (SVR), Support Vector Regression Optimized by Fruit Fly Optimization Algorithm (SVR-FOA), and Gene Expression Programming (GEP). All three techniques estimated the RSL of the pavement by selecting the PCI as input. The Correlation Coefficient (CC), Nash-Sutcliffe efficiency (NSE), Scattered Index (SI), and Willmott’s Index of agreement (WI) criteria were used to examine the performance of the three techniques adopted in this study. In the end, it was found that GEP with values of 0.874, 0.598, 0.601, and 0.807 for CC, SI, NSE, and WI criteria, respectively, had the highest accuracy in predicting the RSL of pavement.

Microarray gene expression-based detection and classification of medical conditions have been prominent in research studies over the past few decades. However, extracting relevant data from the high-volume microarray gene expression with inherent nonlinearity and inseparable noise components raises significant challenges during data classification and disease detection. So, this paper proposes a two-level strategy involving feature extraction and selection methods before the classification step. The feature extraction step utilizes Short Term Fourier Transform (STFT), and the feature selection step employs Particle Swarm Optimization (PSO) and Harmonic Search (HS) metaheuristic methods. The classifiers employed are Non-Linear Regression, Gaussian Mixture Model, Softmax Discriminant, Naive Bayes, SVM (Linear), SVM (Polynomial), and SVM (RBF). The two-level extracted relevant features are compared with raw data classification results, including Convolutional Neural Network (CNN) Methodology. Among the methods, STFT with PSO feature selection and SVM (RBF) classifier produced the highest accuracy of 94.47%.

Oral squamous cell carcinoma (OSCC) is a highly prevalent and aggressive malignancy, with mortality rates that reach 60%, mainly due to an excessive diagnostic delay. MiRNAs, a class of crucial epigenetic gene-expression regulators, have emerged as potential diagnostic biomarkers, with >200 molecules reported to be dysregulated in OSCC. We had previously established an in silico methodology for the identification of the most disease-specific molecules by bridging genetics and epigenetics. Here, we identified the stage-specific miRNAs that govern the asymptomatic early stages of oral tumorigenesis by exploiting the reverse interplay between miRNA-levels and their target-genes’ expression. Incorporating gene expression data from our group’s experimental hamster model of sequential oral oncogenesis, we bioinformatically detected the miRNAs that simultaneously target/regulate >75% of the genes that are characteristically upregulated or downregulated in the consecutive stages of hyperplasia, dysplasia and early-invasion OSCC, while exhibiting the opposite expressional dysregulation in OSCC-derived tissue and/or saliva specimens. We found that all stages share the downregulation of miR-34a-5p, miR124-3p, and miR-125b-5p, while miR-1-3p is underexpressed in dysplasia and early-invasion. Malignant early-invasion stage is distinguished by the downregulation of miR-147a and the overexpression of miR-155-5p, miR-423-3p and miR-34a-5p. The identification of stage-specific miRNA molecules may facilitate their utilization as biomarkers for presymptomatic OSCC diagnosis.

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive neuromuscular disease prevalent in 1 in 3500 to 5000 males worldwide. As a result of mutations that interrupt the reading frame of the dystrophin gene (DMD), DMD is characterized by a loss of dystrophin protein which leads to decreased muscle membrane integrity, which increases susceptibility to degeneration. CRISPR/Cas9 technology has garnered interest as an avenue for DMD therapy due to its potential for permanent exon skipping, which can restore the disrupted DMD reading frame in DMD and lead to dystrophin restoration. An RNA-guided DNA endonuclease system, CRISPR/Cas9 allows for the targeted editing of specific sequences in the genome. The efficacy and safety of CRISPR/Cas9 as a therapy for DMD has been evaluated by numerous studies in vitro and in vivo, with varying rates of success. Despite the potential of CRISPR/Cas9-mediated gene editing for the long-term treatment of DMD, its translation into the clinic is currently challenged by issues such as off-targeting, immune response activation, and sub-optimal in vivo delivery. Its nature as being mostly a personalized form of therapy also limits applicability to DMD patients, who exhibit a wide spectrum of mutations. This review summarizes the various CRISPR/Cas9 strategies that have been tested in vitro and in vivo for the treatment of DMD. Perspectives on the approach will be provided, and the challenges faced by CRISPR/Cas9 in its road to the clinic will be briefly discussed.

Cancer is a complex and devastating disease that has engaged scientists and researchers for decades. Despite tremendous efforts, previous hypotheses about cancer development have not achieved significant breakthroughs. Evolutionary Cancer Cell Biology (ECCB) is a novel and emerging branch of oncological science that provides an evolutionary perspective on the origin of cancer. It reveals that the cancer genome evolved hundreds of millions of years ago, long before multicellular organisms such as metazoans and humans emerged. ECCB aims to unify all evolutionary insights, hypotheses, and theories into a cohesive framework. It investigates the intricate relationship between cancer genomics and ancient pre-metazoan genes that emerge when normal cells transform into cancer cells. It challenges the conventional wisdom of cancer research by suggesting that cancer could arise through intrinsic cellular mechanisms without genetic alterations and mutations. Furthermore, it postulates that somatic mutations are only secondary, downstream events in the process of oncogenesis.

The vast majority of patients with pancreatic ductal adenocarcinoma (PDAC) suffer cachexia. Although cachexia results from concurrent loss of adipose and muscle tissue, most studies focus on muscle alone. Emerging data demonstrate the prognostic value of fat loss in cachexia. Here we sought to identify the muscle and adipose gene profiles and pathways regulated in cachexia. Matched rectus abdominis muscle and subcutaneous adipose tissue were obtained at surgery from patients with benign conditions (n=11) and patients with PDAC (n=24). Self-reported weight loss and body composition measurements defined cachexia status. Gene profiling was done using Ion proton sequencing. Results were queried against external datasets for validation. 961 DE genes were identified from muscle and 2000 from adipose tissue, demonstrating greater response of adipose than muscle. In addition to known cachexia genes such as FOXO1, novel genes from muscle, including PPP1R8 and AEN correlated with cancer weight loss. All the adipose correlated genes including SCGN and EDR17 are novel for PDAC cachexia. Pathway analysis demonstrated shared pathways but largely non-overlapping genes in both tissues. Age related muscle loss predominantly had a distinct gene profiles compared to cachexia. This analysis of matched, externally validate gene expression points to novel targets in cachexia.

Background: Nodal peripheral T-cell lymphomas (nPTCLs) encompass a heterogeneous group of mature and aggressive lymphoid malignancies, including peripheral T-cell lymphoma, not otherwise specified (PTCL/NOS), angioimmunoblastic T-cell lymphoma (AITL) and anaplastic large cell lymphoma (ALCL) ALK-positive and ALK-negative. Their differential diagnosis and prognosis are an issue in the clinical practice. Accurate biomarkers to refine the different subtypes of nPTCLs and to stratify their prognosis are essential to improve their treatment approach. The aim of this study was to test the prognostic impact of GATA3 gene expression, and its capability to discriminate the different subtypes of nPTCLs. Patients and Methods: From 2000 to 2017, 80 patients with nPTCLs were eligible for GATA3 gene expression analysis that was assessed retrospectively by quantitative real time PCR (qRT-PCR) of neoplastic biopsies in Formalin-Fixed Paraffin-Embedded samples (FFPE). Results: Median age was 49 years old (IqR 34-59), 43/80 (53.7%) were male. Median follow-up was 1.72 years. Of them, 36.3% were classified as PTCL/NOS, 31.2% ALK-negative ALCL, 21.2% ALK-positive ALCL and 11.3% AITL. The majority of cases had advanced stage (III/IV). Two-year estimated overall survival (OS) and progression-free survival (PFS) were 52.2% and 39.5%, respectively. The median GATA3 gene expression level was 0.49% (range 0 – 7.07) in all cohort, it was 0.11% for ALK-positive ALCL, 0.46% for ALK-negative ALCL, 0.86% for PTCL/NOS and 0.67% for AITL. The difference of GATA3 gene expression among distinct variants of nPTCLs was statistically significant (p < 0.001). GATA3 gene expression levels ≥ 0.71% discriminate PTCL/NOS from ALK-negative ALCL and AITL with sensitivity of 62% and specificity of 80.3%. GATA3 gene expression levels ≥ median was associated with poor 2-year OS for PTCL/NOS (46.7% x 21.4%, p=0.04) and for ALK-negative ALCL (85.7% x 54.5%, p=0.04). Conclusion: Despite the relative small and heterogeneous group of patients with nPTCLs, GATA3 gene overexpression may be an important biomarker associated with poor prognosis in PTCL/NOS and ALK-negative ALCL. Moreover it may also discriminate different subtypes of nPTCLs. Further studies with larger series of patients should confirm our findings.

The concept of gray-zone lymphoma (GZL) has been progressively refined since its in-troduction in the literature in 1998. For several years, it was applied to a rather broad spectrum of conditions, posing the problem of the differential diagnosis between any type of Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma, with special reference to primary mediasti-nal forms (PMBL). Officially recognized as a provisional entity in the 4th and revised 4th editions of the WHO Classification of Tumour of Haematopoietic and Lymphoid Tissues with the term “B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lym-phoma and classical Hodgkin lymphoma”, it was limited to tumours, which showed either morphologic features reminiscent of classical HL (CHL) but carrying a complete B-cell pheno-type or conversely provided with a PMBL morphology but revealing CHL phenotypic charac-teristics. The definition of GZL has been further revised in the recently published International Lymphoma Classification and 5th Edition of the WHO Classification of Haemato-lymphoid Tu-mours, which have limited it to mediastinal neoplasms based on emerging molecular evidences. The aim of this review is to critically discuss the issue of GZL, also in the light of the suboptimal response to current therapies.

Fusarium wilt of banana is a devastating disease that has decimated banana production worldwide. Host resistance to Fusarium oxysporum f. sp. cubense (Foc), the causal agent of this disease, is genetically dissected in this study using two Musa acuminata ssp. malaccensis segregating populations segregating for Foc Tropical (TR4) and Subtropical (STR4) race 4 resistance. Marker loci and trait association using 11 SNP-based PCR markers allowed the candidate region to be delimited to a 12.9 cM genetic interval corresponding to a 959 kb region on Chromosome 3 of ‘DH-Pahang’ reference assembly v4. Within this region, there is a cluster of pattern recognition receptors, namely leucine rich repeat ectodomain containing receptor-like protein kinases, cysteine-rich cell wall associated protein kinases, and leaf rust 10 disease-resistance locus receptor-like proteins positioned in an interspersed arrangement. Their transcript levels were rapidly upregulated in the resistant but not in susceptible F2 progenies at the onset of infection. This suggests that one or several of these genes may control resistance at this locus. To confirm the segregation of single-gene resistance, we generated an inter-cross between the resistant parent ‘Ma850’ and a susceptible line ‘Ma848’, to show that the STR4 resistance co-segregated with marker ‘28820’ at this locus. Finally, an informative SNP marker 29730 allowed the locus specific resistance to be assessed in a collection of diploid and polyploid banana plants. Out of the 60 lines screened, 22 lines were predicted to carry resistance at this locus, including lines known to be TR4 resistant, such as ‘Pahang’, ‘SH-3362’, ‘SH-3217’, ‘Ma-ITC0250’, and ‘DH-Pahang/CIRAD 930’. Additional screening in the International Institute for Tropical Agriculture’s collection suggests that the dominant allele is common among in the elite ‘Matooke’ NARITA hybrids, as well as in other triploid or tetraploid hybrids derived from East African highland bananas. Fine-mapping and candidate gene identification will allow characterization of molecular mechanisms underlying TR4 resistance. The markers developed in this study can now aid the marker-assisted selection of TR4 resistance in breeding programs around the world.

There is scientific consensus that organismal aging did not evolve by natural selection (NS) because it lacks individual benefit. Nonetheless it exists, leading to much speculation about its origins, and when the diminishing force of selection begins. Both concepts are based upon two misconceptions; that aging occurs in and of itself and is caused by the declining strength of NS during the reproductive lifespan. Although lacking individual benefit, aging evolved by NS as a tradeoff of survival for reproduction. Based upon regulatory dynamics that participate in this tradeoff, aging begins once reproductive success has been achieved through offspring nurturing. Thereafter, the strength of NS wanes to exponentially accelerate aging, leading to death. Assumptions of the theory are that: (1) a life-long, “holistic” regulatory mechanism whose genic expression is modified epigenetically, originates in ontogenesis; (2) the regulatory mechanism of the last developmental stage becomes redundantly expressed during “morphostasis”, a non-aging, life interval of peak vitality to ensure completion of reproduction through nurturing, and (3) thereafter, loss of regulatory redundancy causes aging which reduces the strength of natural selection and allows accumulation of randomly occurring somatic damage.

Type 1 diabetes affects millions of people globally and requires careful management to avoid serious long-term complications, including heart and kidney disease, stroke, and loss of sight. The present standard-of-care for type 1 diabetes is exogenic insulin substitutional therapy. The most advanced stretegies in this area is the development of hybrid-closed loop system and the producing of long-acting insulins. Progresses in stem cell therapies have started to revolutionize the care of patients with type 1 diabetes; however, significant challenges remain including the limited islets availability, difficulties in maintaining the viability, the heterogeneity within a complex pathology and in patients’ responses to treatment. On the way, a considerable amount of efforts in maximizing the islet transplantation effectiveness by controlling the advantageous of different stem cell approaches. With the availability and the use of big data, the concept of precision medicine is gaining wide attention worldwide and could bring the dream of “presonlaized” therapies as a reality in the near future. Here we review the current range of treatments available as well as recent pre-clinical breakthroughs in the field of personlaized medicine for type 1 diabetes.

The emergence of proteins in the prebiotic world was a watershed event at the origin of life. With their astonishing versatility, the protein enzymes catalyzed crucial biochemical reactions within protocells into more complex biomolecules in diverse metabolic pathways, whereas structural proteins provided strength and permeability in the cell membrane. Five major biochemical innovations followed in succession after availability of various kinds of protein molecules during decoding and translation of mRNAs. These are: (1) the modification of the phospholipid membrane into the plasma membrane; (2) the origin of primitive cytoplasm; (3) primitive gene regulation; (4) the beginnings of the virus world; and (5) the advent of DNA. The creative role of viruses during prebiotic synthesis led to the origin of the DNA world, when DNA replaced mRNA as the major genome of the protocells. With the advent of DNA, replication of information was entirely dissociated from its expression. Because DNA is much more stable than mRNA with more storage capacity, it is a superb archive for information systems in the form of base sequences. DNA progressively took over the replicative storage function of mRNA, leaving the latter for protein synthesis. Genetic information began to flow from DNA to mRNA to protein in a two-step process involving transcription and translation. In the biological stage, DNA replication was central to the binary fission of the first cell, orchestrated by the duplication of genomes and then the division of the parent cell into two identical daughter cells. With the onset of binary fission, the population of primitive cells grew rapidly in the hydrothermal vent environment, undergoing Darwinian evolution and diversification by mutation. The habitat of the earliest fossil record (≥ 3.5 Ga) from the Archean sedimentary rocks of Canada, Greenland, Australia, South Africa, and India offers a new window on the early radiation of microbial life. The development of anoxygenic and then oxygenic photosynthesis from early hyperthermophiles would have allowed life to escape the hydrothermal setting to the mesophilic global ocean.

Objectives: Multicentric Osteolysis, Nodulosis, and Arthropathy (MONA) syndrome is a rare genetic skeletal dysplasia. Its diagnosis can be deceptively similar to childhood-onset genetic skeletal dysplasias and juvenile idiopathic arthritis. We aimed to report the syndrome’s clinical and radiologic features with emphasis on skeletal manifestations. And establish relevant phenotype-genotype correlations. Methods: We evaluated two boys, 4-and-7-years-old with MONA syndrome. Both patients had consanguineous parents. We verified the diagnosis by correlating the outcomes of clinical, radiologic and molecular analysis. We specifically evaluated the craniofacial morphology and clinical and radiographic skeletal abnormalities. We contextualized the resultant phenotype-genotype correlations to publications on MONA and its differential diagnosis. Results: Skeletal manifestations were the presenting symptoms and mostly restricted to hands and feet in terms of fixed extension deformity of the metacarpophalangeal and flexion deformity of the interphalangeal joints with extension deformity of big toes. There were arthritic symptoms in the older patient especially of the wrists and minute pathologic fractures. The skeletal radiographs showed osteopenia/dysplastic changes of hands and feet. Both patients had variants in the matrix metalloproteinase2 gene which conformed to phenotype of previously reported literature in one patient while the other had a novel variant which conformed to MONA phenotype. Craniofacial abnormalities were present. However, minimal extra-skeletal manifestations. Conclusion: Overall, there is an emerging distinctive skeletal pattern of involvement in terms of both clinical and radiographic features. This includes age of onset and location of presenting skeletal manifestations, chronological order of joint affection, longitudinal disease progression, specifics of skeletal radiographic pathology and craniofacial features. Nevertheless, physicians are cautioned against differential diagnosis of similar genetic skeletal dysplasias and juvenile idiopathic arthritis.

Appropriate estimation of soil settlement is of significant importance since it directly influences the performance of building and infrastructures that are built on soil. In particular, the settlement of fine-grained soils is critical because of low permeability and continuous settlement with time. Coefficient of consolidation (Cc) is a key parameter to estimate settlement of fine-grained soil layers. However, estimation of this parameter is time consuming, needs skilled technicians, and specific equipment. In this study, Cc was estimated using several soil parameters such as liquid limit (LL), plastic limit (PL), and initial void ratio (e0). Estimating such parameters in laboratory is straight forward and needs substantially less time and cost compared to conventional tests to estimate Cc such as Oedometer test. This study presents a novel prediction model for Cc of fine-grained soils using gene-expression programming (GEP). GEP is a biologically inspired technique capable of offering closed-form solution for the optimal solution. A database consisted of 108 different data points was used to develop the model. A closed-form equation solution was derived to estimate Cc based on LL, PL, and e0. The performance of developed GEP-based model was evaluated through coefficient of determination (R2), root mean squared error (RMSE), and mean average error (MAE). High R2 and low error values indicated the descent performance of the model. Furthermore, the model was evaluated using the additional performance measures and met all the suggested criteria. Furthermore, the model had a better performance in terms of R2, RMSE, and MAE compared to most of existing models. It is expected that the developed model will decrease the time and cost associate with determining Cc of fine-grained soils.

Appropriate estimation of soil settlement is of significant importance since it directly influences the performance of building and infrastructures that are built on soil. In particular, the settlement of fine-grained soils is critical because of low permeability and continuous settlement with time. Coefficient of consolidation (C_c) is a key parameter to estimate settlement of fine-grained soil layers. However, estimation of this parameter is time consuming, needs skilled technicians, and specific equipment. In this study, C_c was estimated using several soil parameters such as liquid limit (LL), plastic limit (PL), and initial void ratio (e₀). Estimating such parameters in laboratory is straight forward and needs substantially less time and cost compared to conventional tests to estimate C_c such as oedometer test. This study presents a novel prediction model for C_c of fine-grained soils using gene-expression programming (GEP). GEP is a biologically inspired technique capable of offering closed-form solution for the optimal solution. A database consisted of 108 different data points was used to develop the model. A closed-form equation solution was derived to estimate C_c based on LL, PL, and e₀. The performance of developed GEP-based model was evaluated through coefficient of determination (R²), root mean squared error (RMSE), and mean average error (MAE). High R² and low error values indicated the descent performance of the model. Furthermore, the model was evaluated using the additional performance measures and met all the suggested criteria. Furthermore, the model had a better performance in terms of R², RMSE, and MAE compared to most of existing models. It is expected that the developed model will decrease the time and cost associate with determining C_c of fine-grained soils.Keywords: evolutionary model, gene-expression programming (GEP), prediction, soil compression index, estimation, soil engineering, soil informatics, civil engineering, machine learning, data science, big data, soft computing, deep learning, forecasting, subject classification codes, construction informatics, computational intelligence (CI), artificial intelligence (AI), estimation