Recently, selection in pigs has been focused on improving the lean meat content in carcasses; this focus has been most evident in breeds constituting a paternal component in breeding. Such sire-breeds are used to improve the meat quantity of cross-breed pig lines. However, even in one breed, a significant variation in the meatiness level can be observed. In the present study, the comprehensive analysis of genes and microRNA expression profiles in porcine muscle tissue was applied to identify the genetic background of meat content. The comparison was performed between whole gene expression and miRNA profiles of muscle tissue collected from two sire-line pig breeds (Piertain, Hampshire). The RNA-seq approach allowed the identification of 627 and 416 differentially expressed genes (DEGs) between pig groups differing in terms of loin weight between Pietrain and Hampshire breeds, respectively. The comparison of miRNA profiles showed differential expression of 57 microRNAs for Hampshire and 34 miRNAs for Pietrain pigs. Next, 43 genes and 18 miRNAs were selected as differentially expressed in both breeds and potentially related to muscle development. According to Gene Ontology analysis, identified DEGs and microRNAs were involved in the regulation of the cell cycle, fatty acid biosynthesis and regulation of the actin cytoskeleton. The most deregulated pathways dependent on muscle mass were the Hippo signalling pathway connected with the TGF-beta signalling pathway and controlling organ size via the regulation of ubiquitin-mediated proteolysis, cell proliferation and apoptosis. The identified target genes were also involved in pathways such as the FoxO signalling pathway, signalling pathways regulating pluripotency of stem cells and the PI3K-Akt signalling pathway. The obtained results indicate molecular mechanisms controlling porcine muscle growth and development. Identified genes (SOX2, SIRT1, KLF4, PAX6 and genes belonging to the transforming growth factor beta superfamily) could be considered candidate genes for determining muscle mass in pigs.

Esophageal cancer is an extremely deadly tumor that accounts for 5% of all cancer deaths. The two main subtypes of the disease are esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). To date, few studies analyse EAC for transcriptional signatures associated with diagnosis and/or prognosis, while most focus on the analysis of transcriptional profiles of ESCC. In this study, we used single-cell RNA sequencing (scRNA-seq) analysis of CD45+ cells enriched from Tumors and matched Non Tumor tissues from therapy naїve patients to identify all types of immune cells present in tumor immune infiltrate and its transcriptional profile. In addi-tion, we analysed the entire transcriptome in a cohort of 23 patients whose tissue biopsies were taken from Tumors and matched with Non Tumor tissue. The transcriptional signatures we obtained were then used to stratify a large cohort of TCGA EAC patients, demonstrating a strong association with their prognosis, as well as the ability to predict a patient's clinical outcome and better define the prognosis of EAC after surgery. In addition, these features may lead patients to effective therapies including immunotherapy approaches.

RNA polymerase II (RNAPII) frequently transcribes non-protein coding DNA sequences in eukaryotic genomes into long non-coding RNA (lncRNA). Here, we focus on the impact of the act of lncRNA transcription on nearby functional DNA units. Distinct molecular mechanisms linked to the position of lncRNA relative to the coding gene illustrate how non-coding transcription controls gene expression. We review the biological significance of the act of lncRNA transcription on DNA processing, highlighting common themes, such as mediating cellular responses to environmental changes. This review presents the background in chromatin signaling to appreciate examples in different organisms where we can interpret functions of non-coding DNA through the act of RNAPII transcription.

To examine the role of RNA silencing in defense against viroid, a Dicer-like 2 and 4 (DCL2&4)—double knockdown transgenic tomato line 72E was created. The expression of endogenous DCL2 and DCL4 in line 72E decreased to about a half of the empty cassette line EC. When challenged with potato spindle tuber viroid (PSTVd), 72E allowed significantly higher level of PSTVd accumulation early in infection and showed lethal systemic necrosis. The size distribution of PSTVd-derived small RNA was significantly changed: the numbers of 21 and 22 nucleotides (nt) species in line 72E was approximately 66.7% and 5% of those in line EC, respectively. Conversely, the numbers of 24-nt species increased by 1100%. Furthermore, expression of miR398a-3p and miR398 increased 770–868% in the PSTVd-infected 72E, compared to the PSTVd-infected EC. In parallel, superoxide dismutase (SOD1) in PSTVd-infected 72E showed higher expression levels. In concert with miR398a-3p, SOD1 controls detoxification of reactive oxygen species (ROS) generated in cells. Since high levels of ROS production and its scavenging activity were observed in PSTVd-infected 72E, the lack of full-activity of DCLs was thought to have made the plant incapable to control excessive ROS production and thus resulted in to develop lethal systemic necrosis.

Hydroperoxides (ROOH) are known as damaging agents capable of mediating mutation, while a role as signaling agents through oxidation of protein sulfhydryls that can alter cancer-related pathways has gained traction. Glutathione peroxidase 2 (GPX2) is an antioxidant enzyme that reduces ROOH at the expense of glutathione (GSH). GPX2 is noted for a tendency of large in-creases or decreases in expression levels during tumorigenesis that leads to investigators focusing on its role in cancer. However, GPX2 is only one component of multiple enzyme families that metabolize ROOH and GPX2 levels are often very low in the context of these other ROOH reducing activities. Colorectal cancer (CRC) was selected as a case study for examining GPX2 function as colorectal tissues and cancers are sites where GPX2 is highly expressed. A case can be made for a significant impact of changes in expression levels. There is also a link between GPX2 and NADPH oxidase 1 (NOX1) from earlier studies that is seldom addressed and is discussed, presenting data on a unique association in colon and CRC. Tumor-derived cell lines are quite commonly used for pre-clinical studies involving the role of GPX2 in CRC. Generally, selection for this type of work is limited to identifying cell lines based on high and low GPX2 expression with the standard re-search scheme of overexpression in low expressing lines and suppression in high expressing lines to identify impacted pathways. This overlooks CRC subtypes among cell lines involving a wide range of gene expression profiles and a variety of driver mutation differences along with a large difference in GPX2 expression levels. A trend for low and high GPX2 expressing cell lines to segregate into different CRC subclasses, indicated in this report, suggests that choices based solely on GPX2 levels may provide misleading and conflicting results by disregarding other properties of cell lines and failing to factor in differences in potential protein targets of ROOH. CRC and cell line classification schemes are presented here that were intended to assist workers in performing pre-clinical studies but are largely unnoted in work on GPX2 and CRC. Studies are often initiated on the premise that the transition from normal to CRC is associated with up-regulation of GPX2. This is probably correct. However, the source normal cells for CRC could be almost any colon cell type, some with very high GPX2 levels. These factors are addressed in this study.

Gradients of smooth functions with non-independent variables are relevant for exploring complex models and for the optimization of functions subjected to constraints. In this paper, we investigate new and simple approximations and computations of such gradients by making use of independent, central and symmetric variables. Such approximations are well-suited for applications in which the computations of the gradients are too expansive or impossible. The derived upper-bounds of the biases of our approximations do not suffer from the curse of dimensionality for any $2$-smooth function, and theoretically improve the known results. Also, our estimators of such gradients reach the optimal (mean squared error) rate of convergence (i.e., $\mathcal{O}(N^{-1})$) for the same class of functions. Numerical comparisons based on a test case and a high-dimensional PDE model show the efficiency of our approach.

Selective mutism (SM) is an “Anxiety Disorder” characterized by a child’s “persistent inability” to communicate verbally in some (or all) contexts of social life that is associated with other cognitive-affective disorders. Cognitive-behavioural assessment and psychological intervention may be complex to be performed due to both the difficulty to administered standardized neuropsychological batteries (e.g., language-mediated tests) and the difficulty to involve family and teachers in the intervention program, respectively. Here, a single-case study is described in which a female Filipina child with SM underwent a comprehensive neuropsychological assessment and multimodal therapeutical intervention between the ages of 7 to 11 years. More specifically, the psychological intervention included cognitive-behavioral psychotherapy to both improve social-cognitive skills and learning abilities and to reduce anxiety, and speech therapy. Moreover, the parents and teachers were actively involved in the therapeutic process and they were also administered a psycho-education program. After this specific treatment, at the age of 11 years the girl began to verbalize in both therapy and school contexts, although she still was used to adopt non-verbal strategies. A parallel and gradual improvement in communicative-linguistic skills and school learning was also observed. In conclusion, the present report highlights the importance to apply an "integrated and multimodal intervention" to treat SM in children that includes also psycho-education intervention for both parents and teachers.

Assessing observation noise is a critical step in the development of a stochastic model for GNSS navigation and positioning. This process ensures that the statistical properties of the observational data are accurately characterized, leading to more reliable and precise positioning results. Traditionally, the one sigma values for observation noise, 0.3 m for code and 3 mm for carrier phase, alongside elevation-dependent weighting schemes, have been standard. However, these may no longer be suitable due to significant advancements in GNSS systems, receivers, and antennas. Previous research predominantly focused on code type and PPP techniques, often limited by the inability to separately assess observation types across different frequency bands due to ionospheric delay. Furthermore, these studies were generally constrained by limited experimental data. This research advocates for the use of ultra-short baselines to eliminate atmospheric delay and other error sources, providing a detailed assessment of observation noise for various frequency bands, GNSS systems, and receiver & antenna types over an extensive period and across multiple baselines. The findings suggest a need to reconsider traditional one sigma values and elevation-dependent weighting schemes for current applications.

Brain pathological changes impair cognition early in disease etiology. There is an urgent need for understanding aging-linked mechanisms of early memory loss to develop therapeutic strategies and prevent the development of cognitive impairment. Tusc2, also named Fus1, is a mitochondrial-resident protein regulating Ca2+ fluxes to and from mitochondria impacting overall health. We reported that Tusc2-/- female mice develop chronic inflammation and age prematurely, causing age- and gender-dependent spatial memory deficits at 5 m.o. Therefore, we investigated Tusc2-dependent mechanisms of memory impairment in mice, comparing changes in resident and brain-infiltrating immune cells. Interestingly, Tusc2-/- female mice demonstrated proinflammatory increase in astrocytes, IFN-γ expression in CD4+T cells and Granzyme-B in CD8+T cells. We also found fewer FOXP3+ T-regulatory cells and Ly49G+ NK and Ly49G+ NKT cells in female Tusc2-/- brain, suggesting a weakened anti-inflammatory response. Moreover, Tusc2-/- hippocampi exhibited Tusc2- and sex-specific protein changes associated with brain plasticity, including mTOR activation, and Calbindin and CamKII dysregulation affecting intracellular Ca2+ dynamics. Overall, data suggest that dysregulation of Ca2+-dependent processes and proinflammatory brain microenvironment heighten in Tusc2-/- mice could underlie cognitive impairment. Thus, strategies to modulate the brain’s Tusc2-, Ca2+, and mitochondria-dependent pathways should be explored to improve cognitive health.

We consider a Cauchy problem for differential equations in a Hilbert space $X$. The problem is stated in a time interval $I$, which can be finite or infinite. Weuse a fixed point argument for history-dependent operators to prove the unique solvability of the problem. Then, we state and prove convergence criteria for both a general fixed point problem and thecorresponding Cauchy problem. These criteria provide necessary and sufficient conditions on a sequence $\{u_n\}$ which guarantee its convergence to the solution of the corresponding problem, in the space of both continuous and continuously differentiable functions. We then specify our results in the study of a particular differential equation governed by two nonlinear operators. Finally, we provide an application in viscoelasticity and give a mechanical interpretation of the corresponding convergence result.

The integrated stress response is a signaling network comprised of four branches, each of which senses different cellular stressors, converging on the phosphorylation of eIF2α to depress global translation and initiate recovery. One of these branches is composed of GCN2, which senses cellular amino acid insufficiency and participates in the maintenance of amino acid homeostasis. Previous studies have shown that GCN2 is a viable cancer target when amino acid stress is provoked by inhibiting an additional target. In this light, we screened a combination of drugs to identify biologically active compounds which synergize with the GCN2 inhibitor TAP20. First, a panel of 25 compounds was assayed in six cancer cell lines for drug sensitivity. Each compound was then combined with TAP20 at concentrations below their IC50, and the impact on cell growth was assessed. Selected strongly synergistic combinations were further characterised using synergy analyses and matrix-dependent invasion assays. Inhibitors of proteostasis, of the MEK-ERK pathway and pan-CDK inhibitors flavopiridol and seliciclib were found to potently synergize with TAP20 in two of the tested cell lines. Among their common CDK targets is CDK7, which was selectively targeted with THZ-1 and found to synergize with TAP20. Finally, these combinations were found to be partially synergistic when assessed using matrix-dependent invasion assays. However, we found that TAP20 alone was sufficient to restrict invasion at concentrations well below its growth-inhibitory IC50. We conclude that GCN2 can be targeted for treating cancers by polytherapy or even monotherapy.

Two monoclonal antibodies (mAbs) against human epidermal growth factor receptor 2 (HER2), trastuzumab and pertuzumab, were clinically approved. We previously developed a highly sensitive and specific anti-HER2 mAb, H2Mab-139 (mouse IgG1, kappa). In this study, we produced a defucosylated IgG2a version of anti‑HER2 mAb (H2Mab-139-mG2a-f) to enhance ADCC-mediated antitumor activity. H2Mab-139-mG2a-f exhibits a high binding affinity in flow cytometry with the dissociation constant (KD) determined to be 3.9 × 10‑9 M and 7.7 × 10‑9 M against HER2‑overexpressed Chinese hamster ovary (CHO)-K1 (CHO/HER2) and HER2-positive BT-474 cells, respectively. Moreover, we showed that H2Mab-139-mG2a-f exerted ADCC and complement-dependent cytotoxicity against CHO/HER2 and BT-474 cells in vitro and exhibited potent antitumor activities in the xenograft models. These results indicated that H2Mab-139-mG2a-f exerts antitumor effects against HER2-positive human breast cancers and could be useful for an antibody treatment regimen for HER2-positive human cancers.

This paper discusses a passive control issue for Nonlinear Time-Varying (NTV) systems subject to stability and attenuation performance. Based on the modeling approaches of Takagi-Sugeno (T-S) fuzzy model and the Linear Parameter-Varying (LPV) model, a Parameter-Dependent Polynomial Fuzzy (PDPF) model is constructed to represent the NTV systems. According to Parallel Distributed Compensation (PDC) concept, a parameter-dependent polynomial fuzzy controller is built to achieve robust stability and passivity of PDPF model. Furthermore, the passive theory is applied to achieve the performance constraining the disturbance effect on the PDPF systems. To develop the stability criteria, by introducing a parameter-dependent polynomial Lyapunov function, one can derive some stability conditions which belong to the term of Sum-Of-Squares (SOS) form. Based on the Lyapunov function, two stability criteria are proposed to design the corresponding PDPF controller such that the NTV system is robustly stable and passive. Finally, a numerical example is applied to demonstrate the effectiveness of the proposed stability criterion.

Calcium/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) regulates bone remodeling through its effects on osteoblasts and osteoclasts. However, its role in osteocytes, the most abundant bone cell type, and the master regulator of bone remodeling, remains unknown. Here we report that the conditional deletion of CaMKK2 from osteocytes using Dentine matrix protein 1 (Dmp1)-8kb-Cre mice led to enhanced bone mass only in female mice owing to a suppression of osteoclasts. Conditioned media isolated from female CaMKK2-deficient osteocytes inhibited osteoclast formation and function in in vitro assays, indicating a role for osteocyte-secreted factors. Proteomics analysis revealed significantly higher levels of extracellular calpastatin, a specific inhibitor of calcium-dependent cysteine proteases calpains, in female CaMKK2 null osteocyte conditioned media, compared to media from female control osteocytes. Further, exogenously added non-cell permeable recombinant calpastatin domain I elicited a marked, dose-dependent inhibition of female wild-type osteoclasts and depletion of calpastatin from female CaMKK2-deficient osteocyte conditioned media reversed the inhibition of matrix resorption by osteoclasts. Our findings reveal a novel role for extracellular calpastatin in regulating female osteoclast function and unravel a novel CaMKK2-mediated paracrine mechanism of osteoclast regulation by female osteocytes.

The resistance of cancer cell subpopulations, including cancer stem cell (CSC) populations, to apoptosis-inducing chemotherapeutic agents is a key barrier to improved outcomes for cancer patients. The cationic amphiphilic drug hexamethylene amiloride (HMA) has been previously demonstrated to efficiently kill bulk breast cancer cells independent of tumor subtype or species, but acts poorly toward non-transformed cells derived from multiple tissues. Here we demonstrate that HMA is similarly cytotoxic toward breast CSC-related subpopulations that are resistant to conventional chemotherapeutic agents, but poorly cytotoxic toward normal mammary stem cells. HMA inhibits the sphere-forming capacity of FACS-sorted human and mouse mammary CSC-related cells in vitro, specifically kills tumor but not normal mammary organoids ex vivo, and inhibits metastatic outgrowth in vivo, consistent with CSC suppression. Moreover, HMA inhibits viability and sphere formation by lung, colon, pancreatic, brain, liver, prostate and bladder tumor cell lines, suggesting that its effects may be applicable to multiple malignancies. Mechanistically, HMA elicits the permeabilization of the limiting lysosomal membrane, a hallmark feature of the lysosome-dependent cell death pathway. Our observations expose a key vulnerability intrinsic to cancer stem cells, and point to novel strategies for the exploitation of cationic amphiphilic drugs in cancer treatment.

Neurological complications of infection by the mosquito-borne Zika virus (ZIKV) include Guillain-Barré syndrome (GBS), an acute inflammatory demyelinating polyneuritis. GBS was first associated with recent ZIKV epidemics caused by the emergence of ZIKV Asian lineage in South Pacific. Here, we hypothesize that ZIKV-associated GBS relates to a molecular mimicry between viral envelope E (E) protein and neural proteins involved in GBS. Analysis of ZIKV epidemic strains showed that glycan loop (GL) region of the E protein includes an IVNDT motif which is conserved in voltage-dependent L-type calcium channel subunit alpha-1C (Cav1.2) and Heat Shock 70 kDa protein 12A (HSP70 12A). Both VSCC-alpha 1C and HSP70 12A belong to protein families which have been associated with neurological autoimmune diseases in central nervous system. The purpose of our in silico analysis is to point out that IVNDT motif of ZIKV E-GL region should be taken in consideration for the development of safe and effective anti-Zika vaccines by precluding the possibility of adverse neurologic events including autoimmune diseases such as GBS.

We propose an iterative scheme for feature-based positioning using a new weighted dissimilarity measure with the goal of reducing the impact of large errors among the measured or modeled features. The weights are computed from the location-dependent standard deviations of the features and stored as part of the reference fingerprint map (RFM). Spatial filtering and kernel smoothing of the kinematically collected raw data allow efficiently estimating the standard deviations during RFM generation. In the positioning stage, the weights control the contribution of each feature to the dissimilarity measure, which in turn quantifies the difference between the set of online measured features and the fingerprints stored in the RFM. Features with little variability contribute more to the estimated position than features with high variability. Iterations are necessary because the variability depends on the location, and the location is initially unknown when estimating the position. Using real WiFi signal strength data from extended test measurements with ground truth in an office building, we show that the standard deviations of these features vary considerably within the region of interest and are neither simple functions of the signal strength nor of the distances from the corresponding access points. This is the motivation to include the empirical standard deviations in the RFM. We then analyze the deviations of the estimated positions with and without the location-dependent weighting. In the present example the maximum radial positioning error from ground truth are reduced by 40% comparing to kNN without the weighted dissimilarity measure.

This work presents a novel approach to construct surrogate models of parametric Differential Algebraic Equations based on a tensor representation of the solutions. The procedure consists in building simultaneously, for every output of the reference model, an approximation given in tensor-train format. A parsimonious exploration of the parameter space coupled with a compact data representation allows to alleviate the curse of dimensionality. The approach is thus appropriate when many parameters with large domains of variation are involved. The numerical results obtained for a nonlinear elasto-viscoplastic constitutive law show that the constructed surrogate model is sufficiently accurate to enable parametric studies such as the calibration of material coefficients.

The open communication is an exigent need for future power system where the time delay is unavoidable. In order to secure the stability of the grid, the frequency must remain within its limited range which is achieved through the load frequency control. The load frequency control signals are transmitted through communication networks which induces time delay that could destabilize the power systems. So, in order to guarantee the stability the delay margin should be computed. In this paper, we present a new method for calculating the delay margin in load frequency control systems. The transcendental time delay characteristics equation is transformed to frequency dependant equation. The spectral radius is used to find the frequencies at which the roots crosses the imaginary axis. The crossing frequencies are determined through the sweeping test and the binary iteration algorithm. A one-area load frequency control system is chosen as case study. The effectiveness of the proposed method has been proved through comparing with the most recent published methods. The method shows its merit with less conservativeness and less computations. The PI controller gains are preferable to be chosen large to reduce the damping, however, the delay margin decreases with increasing the PI controller gains.

Initial attempts to develop monoclonal antibodies as therapeutics to resolve influenza infections focused mainly on searching for antibodies with the potential to neutralise the virus in vitro with classical haemagglutination inhibition and micro-neutralisation assays. This led to the identification of many antibodies that bind to the head domain of haemagglutinin (HA) which generally have potent neutralisation capabilities that block viral entry or viral membrane fusion. However, this class of antibodies has a narrow breadth of protection in that they are usually strain specific. This led to the emphasis on stalk targeting antibodies which are able to bind a broad range of viral targets that span across different influenza subtypes. Recently, a third class of antibodies targeting the vestigial esterase (VE) domain have been characterised. In this review, we describe the key features of neutralising VE targeting antibodies and compare them with head and stalk class antibodies.

Many systems in nature and laboratories are far from equilibrium and exhibit significant fluc- tuations, invalidating the key assumptions of small fluctuations and short memory time in or near equilibrium. A full knowledge of Probability Distribution Functions (PDFs), especially time- dependent PDFs, becomes essential in understanding far-from-equilibrium processes. We consider a stochastic logistic model with multiplicative noise, which has gamma distributions as stationary PDFs. We numerically solve the transient relaxation problem, and show that as the strength of the stochastic noise increases the time-dependent PDFs increasingly deviate from gamma distributions. For sufficiently strong noise a transition occurs whereby the PDF never reaches a stationary state, but instead forms a peak that becomes ever more narrowly concentrated at the origin. The addition of an arbitrarily small amount of additive noise regularizes these solutions, and re-establishes the existence of stationary solutions. In addition to diagnostic quantities such as mean value, standard deviation, skewness and kurtosis, the transitions between different solutions are analyzed in terms of entropy and information length, the total number of statistically distinguishable states that a system passes through in time.

In this paper, we study the problem of controllability of impulsive neutral evolution integrodifferential equations with state dependent delay in Banach spaces. The main results are completely new and are obtained by using Sadovskii's fixed point theorem, theory of resolvent operators, and an abstract phase space. An example is given to illustrate the theory.

The aim of this study was to identify differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) in the endometrium of individuals with and without EMS during the proliferative (P) and secretory (S) phases of the menstrual cycle. Tissues were obtained from 18 control (CT; P-phase [pCT], n=8; S-phase [sCT], n=13) and 23 EMS patients (P-phase [pEMS], n=13; S-phase [sEMS], n=12). DElncRNAs and DEmRNAs were analyzed using total RNA-sequencing. In P-phase, expression of NONHSAG019742.2 and NONHSAT120701.2 was significantly higher in EMS than control patients, that of while NONHSAG048398.2 and NONHSAG016560.2 was lower in EMS patients. In S-phase, expression of NONHSAT000959.2, NONHSAT203423.1, and NONHSAG053769.2 was significantly increased in EMS patients, while that of NONHSAG012105.2 and NONHSAG020839.2 was lower. In addition, the expression of HSD11B2, THBS1, GPX3, and SHISA6 was similar to that of neighboring lncRNAs in both P- and S-phases. In contrast, ELP3 and NR4A1, respectively, were up- or downregulated in pEMS tissues. In sEMS, expression of LAMB3 and HIF1A was increased, while expression of PAM was reduced. Our findings on lncRNAs and mRNAs encourage not only to explore the potential clinical applications of lncRNAs and mRNAs as prognostic or diagnostic biomarkers for EMS but also to gain valuable insights into its pathogenesis.

Related studies have shown that mitophagy plays a role in the progression of Atherosclerosis (AS). Utilizing GSE43292, GSE100927, and GSE159677 datasets, WGCNA and differential expression analysis identified mitophagy-related module genes and DEGs1, while single-cell analysis screened DEGs2. MR analysis revealed causal AS-linked genes in DEGs1. LASSO and expression validation identified biomarkers, evaluated via ROC curves. Further analyses included GSEA, immune infiltration, ANN, regulatory networks, and drug prediction. Four candidate genes were identified through WGCNA, differential expression analysis and MR analysis. The LASSO analysis identified CD36, IL1RN, and MME as biomarkers, while the MR analysis showed that IL1RN and MME are protective factors and CD36 is a risk factor in AS. The ROC curves disclosed that the ANN model had greater diagnostic power for AS than any other biomarker. The GSEA revealed that the biomarkers were enriched in lysosomes and hematopoietic cell lineage and were significantly positively correlated with monocytes. The regulatory network construct showed that small nucleolar RNA host gene 16 regulates MME via the micro RNAs. This study identified CD36, IL1RN, and MME as biomarkers of mitophagy in AS and indicated that they could be applied in the diagnosis and treatment of this condition.

Gestational Diabetes Mellitus (GDMs) is worldly wide pregnancy complication. Gestational Diabetes can significantly impact the fetus development. However, the effects of high glucose on embryological development post-fertilization are yet to be researched. Danio rerio embryos are great model to study the embryonic development. In this study, the effects on embryological (morphological and genetic) development were examined in the presence of a high glucose environment that mimic the developing fetus in pregnant women with GMD. Fertilized Zebrafish embryos were treated with normal media and high glucose for 5 days from 3 hours post-fertilization(hpf) to 96hpf respectively as control and experimental groups. Morphological changes are recorded with Microscope images. Hatch rate and heart rate are compared between groups in set up time points. RNA-Seq is performed to examine the gene changes in experimental group. Glucose delayed the zebrafish embryo development by slowing the hatch rate about 24 hours. The brain, heart, and tail started showing morphology smaller in the glucose group compared to the control group at 24 hpf. Heart rate is faster in the glucose group compared to the control group on day 2 and 3 with a statistically significant difference. Among zebrafish whole genome, the significantly changed genes are 556 genes up-regulated and 1118 genes down-regulated respectively in high glucose group. The metabolic and Wnt pathways are altered under high glucose condition. These conditions contribute to significant physiological differences that may provide insight on functionality post-embryological development.

It is generally accepted that atherosclerosis is a chronic inflammatory disease. The link between atherosclerosis and other inflammatory diseases such as psoriasis, type 2 diabetes mellitus (T2DM), and rheumatoid arthritis (RA) via metabolic, inflammatory, and immunoregulatory pathways is well established. The aim of our review was to summarize the associations between selected microRNAs (miRs) and long non-coding RNAs (lncRNAs) and atherosclerosis, psoriasis, T2DM, and RA. MicroRNAs are short noncoding RNA molecules involved in cell signaling, intracellular communication, and gene expression. We reviewed the role of miR-146a, miR-210, miR-143, miR-223, miR-126, miR-21, miR-155, miR-145, miR-200, miR-133, miR-135, miR-221, miR-424, and let-7 in atherosclerosis, psoriasis, T2DM, and RA. LncRNAs are RNA transcripts longer than 200 nucleotides that are involved in cellular processes such as apoptosis, metabolism, inflammation, cell differentiation, and proliferation. We evaluated the role of lncRNA-H19, lncRNA-MEG3, lncRNA-UCA1, and lncRNA-XIST in atherosclerosis and psoriasis, T2DM, and RA. Extracellular vesicles (EVs) are a method of intracellular signal transduction. Their function depends on surface expression, cargo, and the cell from which they originate.

Parkinson's disease (PD) stands as the most prevalent degenerative movement disorder, characterized by the loss of dopaminergic neurons in the substantia nigra of the midbrain. In this study, we assessed the transcriptome by analyzing post-mortem mRNA extracted from the substantia nigra of individuals with PD and healthy controls. A total of 16,148 transcripts were identified, with 92 mRNAs displaying differential expression between PD and control groups. Specifically, 33 mRNAs were significantly upregulated, while 59 mRNAs were downregulated in PD compared to controls. The identification of statistically significant signaling pathways, with an adjusted p-value threshold of 0.05, unveiled noteworthy insights. Particularly, enriched categories included cardiac muscle contraction (involving genes such as ATPase Na+/K+ transporting subunit beta 2 (ATP1B2), solute carrier family 8 member A1 (SLC8A1), and cytochrome c oxidase subunit II (COX2)), GABAergic synapse (involving GABA type A receptor-associated protein like 1 (GABARAPL1), G protein subunit beta 5 (GNB5), and solute carrier family 38 member 2 (SLC38A2)), autophagy (involving GABARAPL1 and tumor protein p53-inducible nuclear protein 2 (TP53INP2)), and Fc gamma R-mediated phagocytosis (involving amphiphysin (AMPH)). These findings uncover new pathophysiological dimensions underlying PD, including the involvement of cardiac muscle contraction and specific mitochondrial activity. This knowledge not only contributes to better diagnostic precision but also paves the way for the development of new targeted therapies.Keywords: mRNAs; RNA sequencing; Parkinson’s disease; transcriptome analysis; substantia nigra

Background: We investigated the tumor immune response in gastric cancer patients receiving third line nivolumab monotherapy to identify immune-related biomarkers for better patient se-lection. Methods: Nineteen patients (10 males, median age 67 years) who received nivolumab as a third or later line therapy were enrolled. We analyzed the tumor immune response in durable clinical benefit (DCB) and non-DCB patients. Pre-treatment and early-on-treatment tumor transcriptomes were examined, and gene expression profiles, immunograms, and T cell receptor (TCR) repertoire were analyzed. Results: DCB was observed in 15.8% of patients, with comparable secondary endpoints (ORR, OS, PFS) to previous trials. Individual immunograms showed no significant changes before and ear-ly-on-treatment, nor consistent alterations among DCB cases. The intratumoral immune response was suppressed by previous treatments in most third or later line nivolumab recipients. TCR repertoire analysis revealed newly emerged clonotypes in on-treatment tumors, but clonal re-placement did not impact efficacy. High T cells/Tregs ratios and a low UV radiation response gene signature were linked to DCB and treatment response. Conclusions: This study emphasizes the tumor immune response's importance in nivolumab ef-ficacy for gastric cancer. High T cells/Tregs ratios and specific gene expression signatures show promise as potential biomarkers for treatment response. Larger cohort validation is crucial to optimize immune checkpoint inhibitors in gastric cancer treatment.

Cerebral palsy (CP) is the most common movement disorder in children with a prevalence rang-ing from 1.5 to 4 per 1000 live births. CP is caused by a non-progressive lesion of the developing brain, leading to progressive alterations of the musculoskeletal system, including spasticity, often leading to the development of fixed contractures, necessitating tendon lengthening surgery. Total RNA-sequencing analysis was performed on semitendinosus tendons from diplegic and tetraple-gic CP patients subjected to tendon lengthening surgery compared to control patients undergoing anterior cruciate ligament reconstructive surgery. Tetraplegic CP patients showed increased ex-pression of genes implicated in collagen synthesis and extracellular matrix (ECM) turnover, while only minor changes were observed in diplegic CP patients. In addition, tendons from tetra-plegic CP patients showed an enrichment for upregulated genes involved in vesicle-mediated transport and downregulated genes involved in cytokine and apoptotic signaling. Overall, our results indicate increased ECM turnover with increased net synthesis of collagen in tetraplegic CP patients without activation of inflammatory and apoptotic pathways similar to observations in athletes where ECM remodeling results in increased tendon stiffness and tensile strength. Never-theless, the resulting increased tendon stiffness is an important issue in clinical practice, where surgery is often required to restore joint mobility.

During the recent pandemics of COVID-19, sequencing technics became powerful tool for gaining information about the SARS-CoV-2 virus and using this knowledge in our advantage. Thanks to this advantage, scientists over the world were able to search for emerging variations, watching the virus evolving in real time. Assembly of the virus genomes is crucial part of getting this kind of useful information. In our study, we sequenced 79 samples from nasopharyngeal swabs of COVID-19 patients. Positivity on disease was evaluated by qRT-PCR. By studying assembly success rate, we noticed, that Ct-value of qRT-PCR can predict success of genome assembly and SARS-CoV-2 lineage assignment. In this work we described the relationship between Ct-value and further steps of genome construction and its assignment to specific viral strain.

Obesity has become a global epidemic, contributing to the development of numerous chronic diseases, including diabetes, chronic kidney disease (CKD) and cardiovascular disorders. MicroRNAs (miRNAs) have emerged as key regulators in various biological processes, including metabolism, inflammation, and tissue remodeling, making them pivotal players in obesity-related pathologies. This review aims to provide comprehensive insights into the roles of miRNAs in obesity, with a particular emphasis on their involvement in the pathogenesis of CKD and cardiovascular disorders. We highlight the involvement of specific miRNAs in adipose tissue development, energy homeostasis, inflammation, and insulin resistance, contributing to the pathogenesis of obesity. Moreover, we explore the impact of miRNAs on renal fibrosis, and inflammation, giving clues on their roles in the development and progression of CKD. Additionally, we discuss the influence of miRNAs on endothelial dysfunction, atherosclerosis, and cardiac remodeling, emphasizing their contribution to obesity-related cardiovascular disorders. Understanding the regulatory functions of miRNAs in these interconnected conditions holds promise for improved diagnosis, prognosis, and therapeutic interventions. Indeed, miRNAs are potential diagnostic biomarkers for obesity-related diseases although challenges remain to be elucidated before their clinical translation. Furthermore, we highlight the emerging strategies that target miRNAs as therapeutic interventions to mitigate the detrimental effects of obesity on kidney and cardiovascular health.

The achievement of reproductive competence in male mammals is dependent on the testis. Goat testis’ development and spermatogenesis involve physiological events with high complexity. In the current work, 6 testes were respectively collected from immature, sexually mature and physically mature Qianbei Ma goats (1, 6 and 12 months old, respectively). RNA-Seq was carried out to reveal changes in testis mRNA expression levels in Qianbei Ma goats at various developmental stages, and gene expression profiling at different ages was established. Totally 18 libraries were established for screening genes and pathways associated with testis development and spermatogenic processes. Totally 9,724 upregulated and 4,153 downregulated genes were identified between immature (I) and sexually mature (S) testes; 7 upregulated and 3 downregulated genes were detected between sexually mature (S) and physically mature (P) testes, and approximately 4% of genes were alternately spliced between the I and S groups. Selected genes were verified by qRT-PCR, in agreement with sequencing data indicating their reliability. Those genes have critical functions in various developmental stages of goat testicular development and spermatogenesis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were carried out to evaluate differentially expressed genes (DEGs). GO analysis suggested DEGs were involved in “reproduction process”, “channel activity” and “cell periphery part” between I and S, and in “ion transport process”, “channel activity” and “transporter complex part” between S and P. KEGG analysis indicated that pathways such as “glycerolipid metabolism”, “steroid hormone biosynthesis” and “MAPK signaling pathway” may be involved in testis development and spermatogenesis. Genes including IGF1, TGFB1, TGFBR1 and EGFR may regulate the development of the testis from immature to sexually mature, which may be key candidate genes for the development of goat testis. These findings provide novel insights into goat testicular development and spermatogenesis.

This paper presents results of the experiments performed on a nonconventional and extremely interesting in regard to evolution, creature, the European river lamprey Lampetra fluviatilis (Petromyzontiformes, Cyclostomata), one of the oldest taxa of vertebrates. We present detailed immunocytochemical and electron microscopy analyses of chromosome synapsis, the transcription process, and chromatin dynamics in lamprey prophase I, which is the first time for science. We found that not all chromosomes complete synapsis. Rounded structures were detected in chromatin and in some synaptonemal complexes but their nature could not be determined conclusively. An analysis of RNA polymerase II distribution led to the conclusion that transcriptional reactivation in lamprey prophase I is not associated with the completion of chromosome synapsis. Monomethylated histone H3K4 is localized to meiotic chromatin throughout prophase I, and this pattern has not been previously detected in the animals. Thus, the findings made it possible to identify synaptic and epigenetic patterns specific for this group, and to add new pieces of the puzzle to the discussions of the scientific issues under study. The research on lamprey meiotic chromatin and chromosomal dynamics raises many questions leading to new discoveries.

Human T-lymphotropic virus type 1 (HTLV-1)–associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a slowly progressive spinal cord disorder with no effective treatment. There is much of interest in developing potential biomarkers for predicting the pathogenesis of HAM/TSP disorder. This study used Illumina massive parallel sequencing (MPS) technology to assess the cellular global noncoding RNAome expression profile in HAM/TSP patients (n = 10), asymptomatic HTLV-1 infected carriers (ASP, n = 8), and a second group of healthy controls (n = 5). Using various bioinformatics tools, the sRNA MPS reads were aligned, annotated, and profiled. There were 251 known and 50 potential novel sRNAs among the 402 detected sRNAs in the HAM and ASP groups versus the HC group. Sixty-eight known sRNAs were found to be significantly different between the ASP and HAM groups. In HAM vs ASP subjects, 88 mature miRNAs were downregulated. Three of these miRs (hsa-miR-185-5p, 32-5p, and 192-5p) have the potential to be used as biomarkers for predicting the pathogenesis of HAM/TSP. The top seven deregulated miRS target genes were linked to a variety of biological processes and molecular functions. Relevant reactome pathways to our findings provide a rich source of data and an opportunity to further understand sRNA regulation and function in HTLV-1 pathophysiology.

Rose (Rosa spp.), especially R. hybrida, is one of the most popular ornamental plants in the world and the third largest cut flower crop in Taiwan. Rose mosaic disease (RMD), showing mosaic, line patterns and ringspots on leaves, is a common rose disease caused by complex infection of various viruses. Due to pests and diseases, the rose planting area in Taiwan has been decreasing since 2008; however, no rose virus disease has been reported in the past five decades. In the spring of 2020, rose samples showing RMD-like symptoms were observed at an organic farm in Chiayi, central Taiwan. The virome in the farm was analyzed by RNA-seq. Rose genomic sequences were filtered from the obtained reads. The remaining reads were de novo assembled to generate 294 contigs, 50 of which were annotated as viral sequences corresponding to 10 viruses. Through reverse transcription-polymerase chain reaction validation, a total of seven viruses were detected, including six known rose viruses, namely apple mosaic virus, prunus necrotic ringspot virus, rose partitivirus, apple stem grooving virus, rose spring dwarf-associated virus and rose cryptic virus 1, and a novel ilarvirus. After completing the whole genome sequencing and sequence analysis, the unknown ilarvirus was demonstrated as a new species, tentatively named rose ilarvirus 2. This is the first report of the rose viruses in Taiwan.

The objective of this study was to identify key transcription factors involved in lipid metabolism and immune response related to the differentially expressed genes (DEG) from the liver samples of 35 pig model for metabolic diseases fed diets containing either 1.5 or 3.0% soybean oil (SOY1.5 or SOY3.0). A total of 281 DEG between SOY1.5 and SOY3.0 diets (log2fold-change ≥ 1 or ≤ −1; FDR-corrected p-value < 0.1) were identified, in which 129 were down-regulated and 152 were up-regulated in SOY1.5 group. The functional annotation analysis detected transcription factors linked to lipid homeostasis and immune response, such as RXRA, EGFR, and SREBP2 precursor. These findings demonstrated that key transcription factors related to lipid metabolism could be modulated by dietary inclusion of soybean oil. It could contribute to nutrigenomics research field that aims to elucidate dietary interventions in animal and human health, as well as to drive the food technology and science.

Background: Jerusalem artichoke (Helianthus tuberosus L.) is tolerant to salinity stress and has high economic value. The salt tolerance mechanisms of Jerusalem artichoke are still unclear. Especially in the early stage of Jerusalem artichoke exposure to salt stress, the plant physiology, biochemistry and gene transcription are likely to undergo large changes. Elucidating these changes may be of great significance to understanding the salt tolerance mechanisms of it. Results: We obtained high-quality transcriptome from leaves and roots of Jerusalem artichoke exposed to salinity (300 mM NaCl) for 0 h, 6 h, 12 h, 24 h and 48 h, with 150,129 unigenes and 9023 DEGs (Differentially Expressed Genes). The RNA-seq data were clustered into time-dependent groups (nine clusters each in leaves and roots); gene functions were distributed evenly among the groups convergence. KEGG enrichment analysis showed the genes related to plant hormone signal transduction were enriched in almost all treatment comparisons. Under salt stress, genes belongs to PYL (abscisic acid receptor PYR / PYL family), PP2C (Type 2C protein phosphatases), GH3 (Gretchen Hagen3), ETR (ethylene receptor), EIN2/3 (ethylene-insensitive protein 2/3), JAZ (Genes such as jasmonate ZIM-domain gene) and MYC2 (Transcription factor MYC2) had extremely similar expression patterns. The results of qPCR of 12 randomly selected genes confirmed the accuracy of RNA-seq. Conclusions: Under the impact of high salinity (300mM) environment, Jerusalem artichoke in the seedling stage was difficult to survive for a long time, and the phenotype was severe in the short term. Based on the expression of genes on the time scale, we found that the distribution of gene functions in time is relatively even. Upregulation of the phytohormone signal transduction had a crucial role in the response of Jerusalem artichoke seedlings to salt stress, the genes of abscisic acid, auxin, ethylene, and jasmonic acid had the most obvious change pattern.

The rise of data science in biology stimulates interdisciplinary collaborations to address fundamental questions. Here, we report the outcome of the first SINFONIA symposium focused on revealing the mechanisms governing plant reproductive development across biological scales. The intricate and dynamic target networks of known regulators of flower development remain poorly understood. To analyze development from the genome to the final floral organ morphology, high-resolution data that capture spatiotemporal regulatory activities are necessary and require advanced computational methods for analysis and modeling. Moreover, frameworks to share data, practices and approaches that facilitate the combination of varied expertise to advance the field are called for. Training young researchers in interdisciplinary approaches and science communication offers the opportunity to establish a collaborative mindset to shape future research.

Single cell RNA-seq (scRNA-seq) profiles conceal temporal and spatial tissue developmental information. De novo reconstruction of single cell temporal trajectory has been fairly addressed, but reverse engineering single cell 3D spatial tissue localization is hitherto landmark based, and de novo spatial reconstruction is a compelling computational open problem. Here we show that a new algorithm - named D-CE - for coalescent embedding of single cell transcriptomic networks can address this open problem. We rely merely on the spatial information encoded in the expression patterns of developmental signal transcription factor (DST) genes, and we find that D-CE of cell-cell association DST-transcriptomic networks reliably reconstructs the Geo-seq or single cell samples’ 3D spatial tissue distribution. Comparison to the novoSpaRC and CSOmap (recent and only available de novo 3D spatial reconstruction methods) on 16 datasets and 681 reconstructions, reveals a significantly distinctive superior performance of D-CE.

Although rRT-PCR is the gold standard method for SARS-CoV-2 detection, some factors, such as amplification inhibitors presence, lead to false-negative results. Here we describe differences between rRT-PCR results for SARS-CoV-2 infection in normal and diluted samples, simulating the need for dilution due to amplification inhibitors presence. Viral RNA extraction of nasopharyngeal swabs samples from 20 patients previously detected as 'Negative' and 21 patients detected as 'Positive' for SARS-CoV-2 was realized with the EasyExtract DNA-RNA (Interprise®). rRT-PCR was realized with OneStep/COVID-19 (IBMP) kit with normal and diluted (80µl of H₂O RNAse free) samples, totaling 82 tests. The results indicate that there is an average variation (ɑ < 0.05) delaying Cq between the amplification results of internal control (IC), N Gene (NG), and ORF-1ab (OF) of 1.811 Cq, 3.840 Cq, and 3.842 Cq, respectively. The extraction kit does not completely purify the inhibitor compounds, therefore non-amplification by inhibitors may occur. In this study, we obtained a 19.04% false-negative diagnosis after sample dilution, and this process reduces the efficiency of rRT-PCR to 29.80% for detecting SARS-CoV-2. Knowing the rRT-PCR standards of diluted samples can help in the identification of false-negative cases, and consequently avoid a wrong diagnosis.

Background: DSCAM-AS1 is a cancer-related long noncoding RNA with higher expression levels in Luminal A, B and HER2-positive Breast Cancer (BC), where its expression is strongly dependent on Estrogen Receptor Alpha (ERα). Methods: To decipher its function, DSCAM-AS1 expression was measured by qRT-PCR in tissue samples from 93 BC patients in addition to a meta-analysis of 30 gene expression datasets, together with the evaluation of its association with clinical data. By computational analyses of our RNA-Seq in MCF-7 cells, we investigated the DSCAM-AS1 knock-down effects at both gene and isoform levels. Results: We confirmed DSCAM-AS1 overexpression in high grade Luminal A, B and HER2+ BCs and found a significant correlation with disease relapse. 908 genes were regulated by DSCAM-AS1-silencing, primarily involved in cell cycle and inflammatory response. Noteworthy, the analysis of alternative splicing and isoform regulation revealed 2,085 splicing events regulated by DSCAM-AS1, enriched in differential polyadenylation sites and 3’UTR shortening events. Finally, the DSCAM-AS1-interacting splicing factor hnRNPL was predicted as the most enriched RBP for exon skipping and 3’UTR events. Conclusion: The relevance of DSCAM-AS1 overexpression in BC is confirmed by clinical data and further enhanced by its possible involvement in the regulation of RNA processing, which is emerging as one of the most important dysfunctions in cancer.

Cervical cancer is known as one of the most important cancers in women worldwide. Chemotherapy is a standard treatment for advanced/recurrent cervical cancer in which the prognosis of the disease is really poor and the 1-year survival chance in these patients is maximally 20%. However, resistance to anticancer drugs is a major problem in treating cancer. Cervical cancer stem cells are considered as a fundamental cause of chemo and radio-resistance and also relapse after primary successful treatment. Signaling pathways include a wide range of molecular mechanisms contribute to drug resistance. Recently, microRNAs (miRNAs) are announced as a group of molecular biomarkers involving in response to chemotherapy in cancer patients. As the miRNAs, there are some long non-coding RNAs (LncRNAs) which their aberrant expression is considered as a biomarker for monitoring chemoresistance. In this review, we summarized current reports about the involvement of signaling pathways during chemoresistance in cervical cancer. Then, genes that have been demonstrated their involvement during drug resistance in cervical cancer were tabulated. Further, miRNAs that have been reported as biomarkers during treatment are listed. By bioinformatic analysis, we predictedmiR-335-5p and miR-16-5p as the most potential biomarkers for monitoring resistance to chemotherapy. Finally, long non-coding RNAs that have been introduced in recent studies as novel biomarkers during the response to chemotherapy were mentioned.

Emergence of zoonotic-human pathogens is proven to be a lethal threat to public health, and RNA virus including influenza viruses, severe acute respiratory syndrome coronavirus, middle east respiratory syndrome coronavirus, Wuhan coronavirus (COVID-19), plays a pivotal role. As those viruses as airborne microorganisms spread mainly by tiny airborne particles, it is important to de-active those airborne particles before their entry into human bodies. In this study, we investigated the effect of far infrared (FIR) radiation on inhibition of airborne microorganisms. The result confirmed that double stand DNA from airborne microorganisms were stable under mild FIR radiation. However, single strand RNA from them was found to be sensitive to FIR radiation, indicating that RNA virus in airborne particles is instable under FIR radiation. Based on this observation, two models on usage of FIR radiation to prevent RNA virus transmission and cure RNA virus infection were proposed, implying that FIR radiation might be a cheap, convenient, and efficient method in clinic to treat RNA virus.

Powdery mildew caused by Blumeria graminis f. sp. tritici (Bgt) is one of many severe diseases that threaten bread wheat (Triticum aestivum L.) yield and quality worldwide. The discovery and deployment of powdery mildew resistance genes (Pm) can prevent this disease epidemic in wheat. In a previous study, we transferred the powdery mildew resistance gene Pm57 from Aegilops searsii into common wheat and cytogenetically mapped the gene in a chromosome region with the fraction length (FL) 0.75-0.87, which represents 12% of 2Ss#1 segment on the long arm of chromosome 2Ss#1. In this study, we performed RNA-Seq on three infected and mock-infected wheat-Ae. searsii 2Ss#1 introgression lines with Bgt-isolates inoculation at 0, 12, 24, and 48 hours after inoculation. Then we designed 79 molecular markers based on transcriptome sequences and physically mapped them to Ae. searsii chromosome 2Ss#1- in seven intervals. We used these markers to identify 46 wheat-Ae. searsii 2Ss#1 recombinants induced by ph1b, a deletion mutant of pairing homoelogous (Ph) genes. Analysis of the 46 ph1b-induced 2Ss#1L recombinants with different Bgt-responses using 28 2Ss#1L-specific molecular markers in the interval FL0.72-0.87 where Pm57 is located, and the flanking intervals, we physically mapped Pm57 gene on the long arm of 2Ss#1 in a 5.13 Mb genomic region, which was flanked by markers X67593 (773.72 Mb) and X62492 (778.85 Mb). By comparative synteny analysis of the corresponding region on chromosome 2B in Chinese spring (T. aestivum L.) with other model species we identified ten genes that are putative plant defense-related (R) genes which includes six coiled-coil nucleotide-binding site-leucine-rich repeat (CNL), three nucleotide-binding site-leucine-rich repeat (NL) and a leucine-rich receptor-like repeat (RLP) encoding proteins. This study will lay a foundation for further cloning of Pm57, and benefit the understanding of interactions between resistance genes of wheat and powdery mildew pathogens.

Although there is a several array of diagnostic and therapeutic choices for pancreatic cancer in recent years, a crucial medical approach for the refractory disease is still needed. Oligonucleotide therapeutics, such as those based on antisense RNAs, RNA interference, aptamers and decoys, are promising agents against pancreatic cancer because they identify a specific nucleotide sequence or protein and interfere with gene expression as molecular-targeted agents. Within just the past quarter-century, the diversity and feasibility of these drugs as diagnostic or therapeutic tools have dramatically increased. Actually, there have been several clinical and preclinical studies of oligonucleotides for patients with pancreatic cancer so far. To support the discovery of effective diagnostic or therapeutic options by using oligonucleotide-based strategies in the absence of satisfactory therapies for long-term survival and the rising trend of diseases, we summarize the current clinical trials of oligonucleotide therapeutics for pancreatic cancer patients with underlying preclinical or scientific data and focus on the possibility of oligonucleotides to target pancreatic cancer in clinical implications.

A dogma is normally considered as a principle or a belief accepted as an indisputable truth by some individuals and/or groups. Theoretically there can be no dogmas in science, but it has been demonstrated that scientific thought operates by conceptual changes. A dogma therefore can be understood as a concept present at the heart of some contemporary research programmes that need to be altered to overcome paradigms. Here we argue that two ideas relating to emergence of the biological system research need to be re-evaluated. First, is the idea that research programmes about the emergence of the biological system are the same as those of the origin of cells. Cells are strikingly important biological entities, hard core concepts for the entire field of biology. The emergence of the biological system happened much earlier than the origin of cells and thus the First Universal Common Ancestor (FUCA) should be viewed as a great-grandfather to the Last Universal Cellular Ancestor (LUCA); i.e. the latter is the first cellular life form. Second, RNA-world theories are the focus of mainstream research programmes for the origin of life stricto sensu. In the RNA-world view, self-replication of nucleic acids is seen as one of the most relevant events in the pre-biotic world. Without denying the relevance of self-replication, we argue here that the most germane event which occurred in the pre-biotic world was the crosstalk between nucleic acids and peptides. When these two macromolecules started to interact, the singularity that aggregated the complexity required to produce life emerged. Thus, comprehension of the early origins of the translation machinery and the assembly of the genetic code is key. Therefore, the relevance of cell theory and self-replication should be re-evaluated as well as the concept of life itself.

Seed longevity is a crucial trait for the seed industry and genetic resource preservation. To develop excellent cultivars with extended seed lifespans, it is important to understand the mechanism of keeping seed germinability long-term and to find useful genetic resources as prospective breeding materials. This study was conducted to identify the best cultivars with a high and stable seed longevity trait in the germplasm of rice (Oryza sativa L.) and to analyse the correlation between seed longevity and embryonic RNA integrity. Seeds from 69 cultivars of the world rice core collection selected by the NIAS in Japan were harvested in different years and subjected to long-term storage or controlled deterioration treatment (CDT). The long-term storage (4 °C, RH under 35%, 10 years) was performed on seeds harvested in 2010 and 2013. The seeds harvested in 2016 and 2019 were used for CDT (36 °C, RH of 80%, 40 days). Seed longevity and embryonic RNA integrity were estimated by a decrease in germination rate and RNA integrity number (RIN) after long-term storage, or CDT. The RIN value was obtained by electrophoresis of total RNA extracted from seed embryos. Seeds of ‘Vandaran (Indica)’, ‘Tupa 729 (Japonica)’, and ‘Badari Dhan (Indica)’ consistently showed higher seed longevity and embryonic RNA integrity both under long-term storage and CDT conditions, regardless of the harvest year. A strong correlation (R2 = 0.93) was observed between germination rates and RIN values of the seeds after long-term storage or CDT among nine cultivars selected based on differences in their seed longevity. The study findings revealed the relationship between rice seed longevity and embryo RNA stability and suggested potential breeding materials, including both Japonica and Indica cultivars, for improving rice seed longevity.

Cancer-specific monoclonal antibodies (CasMabs) that recognize cancer-specific antigens with in vivo antitumor efficacy are innovative therapeutic strategies for minimizing the adverse effects. We previously established a cancer-specific anti-human epidermal growth factor receptor 2 (HER2)monoclonal antibody (mAb), H₂Mab-250/H₂CasMab-2. In flow cytometry and immunohistochemistry, H₂Mab-250 reacted with HER2-positive breast cancer cells but did not show the reactivity to normal epithelial cells. In contrast, a clinically approved anti-HER2 mAb, trastuzumab, strongly recognizes both breast cancer and normal epithelial cells in flow cytometry. The human IgG₁ version of H₂Mab-250 (H₂Mab-250-hG₁) possesses compatible in vivo antitumor effects against breast cancer xenografts with trastuzumab despite the lower affinity and effector activation than trastuzumab in vitro. This study compared the antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cellular cytotoxicity (CDC) between H₂Mab-250-hG₁ and trastuzumab. Both H₂Mab-250-hG₁ and trastuzumab showed ADCC activity against CHO/HER2 and breast cancer cell lines (BT-474 and SK-BR-3) in the presence of human natural killer cells. Some tendency was observed that trastuzumab showed a more significant ADCC effect compared to H₂Mab-250-hG₁. Importantly, H₂Mab-250-hG₁ exhibited superior CDC activity in these cells compared to trastuzumab. Similar results were obtained in mouse IgG_2a types of both H₂Mab-250 and trastuzumab. These results suggest the different contributions of ADCC and CDC activities to the antitumor effects of H₂Mab-250-hG₁ and trastuzumab and indicate the future direction for the clinical development of H₂Mab-250-hG₁ against HER2-positive tumors.

Present experimental study assesses the mechanical properties of glass/carbon/glass hybrid composite laminates after exposure to moisture and elevated temperatures for extended periods. The top and bottom layers of the hybrid laminates are glass fiber reinforced and the middle layer is carbon fiber reinforced with the matrix specified as a polymer material. The hybrid laminates were manufactured using the resin transfer molding method and their compressive and tensile properties were determined using a tensile testing machine. The material parameters such as the storage modulus, the loss modulus, and the damping factors of the laminates were identified using dynamic mechanical analysis as a function of the temperature and the vibration frequency. The experimental results on compressive and tensile properties revealed slight variations when the hybrid laminates were kept at low temperatures for extended periods. This might occur due to the increasing molecular cross-linking of the polymer network. As the temperature increased, compressive, tensile, storage modules, loss modulus, and damping factors decreased. This might occur due to the increasing mobility of the binder material. Particularly, the highest stiffness parameters were obtained on -80°C/GCG (Glass/Carbon/Glass) laminates due to the presence of beta transition on the glassy region. The relationships between the glass transitions and the targeted frequencies were characterized. The values of the glass transition shift towards higher temperatures as the frequency increases. This might occur due to a reduction in the gaps between the crosslinking of the epoxy network when the frequency increases. The accuracy of the storage modulus results was compared with the empirical models. The model based on the Arrhenius law provided the closest correlation. Meanwhile, another model was observed that was not accurate enough to predict when gamma and beta relaxations occur under a glassy state.

We previously developed a highly sensitive and specific anti-PDPN mAb, LpMab-23 (mouse IgG1, kappa). In this study, we produced a humanized IgG1 version (humLpMab-23) and its defucosylated form (humLpMab-23-f) of an anti‑PDPN mAb to potentiate the ADCC activity. The humLpMab-23 could recognize PDPN‑overexpressed Chinese hamster ovary (CHO)-K1 (CHO/PDPN) and PDPN-positive PC-10 and LN319 cells by flow cytometry. Furthermore, we found that humLpMab-23-f exerted ADCC and complement-dependent cytotoxicity against CHO/PDPN, PC-10 and LN319 cells in vitro and exhibited potent antitumor activities in the xenograft models. These results indicated that humLpMab-23-f could be useful for an antibody treatment regimen for PDPN-positive human cancers.

The focus of the current research indicates a new Bianchi type-V anisotropic, homogeneous astrophysical model with modified theory of f(R, T) gravity and Λ(t), time-dependent cosmological constant. The significant effect of the model is that the field equations solutions find using a time-dependent quadratic deceleration parameter. We observed anisotropy parameter remains constant both in the belated universe and early universe. The deportment of the equation of state (EOS) parameter, pressure, and energy density, cosmological constant and other parameters are also discussed. This cosmological model indicated the possibility of an accelerating universe with negative pressure, such as a universe dominated by dark energy. Om(z) diagnostic test suggested that the universe starts with quintessence nature and ends as a phantom model. Also, energy conditions of this model are represented here to ensure the model is physically reasonable and based on observations.

Metallo-β-lactamases (MBLs) are a group of Zn(II)-dependent enzymes that pose a major threat to global health. They are linked to an increasing number of multi-drug resistant bacterial pathogens, but no clinically useful inhibitor is yet available. Since β-lactam antibiotics, which are inactivated by MBLs, constitute ~65% of all antibiotics used to treat infections, the search for clinically relevant MBL inhibitors is urgent. Here, derivatives of a 2-amino-1-benzyl-4,5-diphenyl-1H-pyrrole-3-carbonitrile (1a) were synthesised and their inhibitory effects assessed against representatives of each of the three subgroups of MBLs (B1, B2, B3). Several compounds are potent inhibitors of each MBL tested, making them excellent candidates for the development of broad-spectrum drug leads. In particular, compound 5f is highly potent across the MBL subfamilies, with Ki values in the low µM range. Furthermore, this compound also dis-plays synergy in combination with antibiotics such as penicillin G, cefuroxime or meropenem. This molecule thus represents one of the most promising compounds developed yet to combat MBLs.

Converting natural language into machine language that can be recognized by distributed systems is the core challenge of intelligent interactive interfaces and human-machine dialogue systems. The human-machine interface interaction of large distributed SCADA measurement and control system is tedious and the operation and maintenance cost is high, so it is significant to design an intelligent natural language interaction interface for distributed measurement and control system. In this paper, we design the intermediate language format of SCADA system, i.e., Key-value logic form, and then formulate the Text2SCADA framework and propose the TICS algorithm and SDPA algorithm, the former adopts the keyword extraction and cosine similarity optimization algorithm to complete the structured extraction of natural language for basic natural language instructions, and the latter adopts the keyword extraction and cosine similarity optimization algorithm to complete the structured extraction of natural language for relatively The latter one adopts the algorithm of dependent syntactic analysis for the structured representation of natural language instructions with relatively complex natural language instructions. Based on the above algorithms, a lightweight information extraction model based on DGCNN and probabilistic graph ideas is constructed, aiming to enhance the scientific generalization ability of the framework on unknown instruction sets. The experimental results show that the proposed intelligent natural language interface can better solve the human-machine interface interaction problem of distributed SCADA measurement and control system. The average accuracy, recall and F-value of instruction parsing reach 89.27\%, 89.28\% and 89.27\%, respectively. The average response time is 1.593 s. Especially, it provides a more convenient means of interaction for industrial and agricultural information control.

Exercise affects various organs. However, its effects on nutrient digestion and absorption in the intestinal tract are not well understood. A few studies have reported that exercise training in-creases the expression of carbohydrate digestion and absorption molecules. Exercise was also shown to increase the concentration of blood glucagon like peptide-2(GLP-2), which regulates carbohydrate digestion and absorption in small intestinal epithelium. Therefore, we investigated the effects of exercise on intestinal digestion and absorption molecules and the levels of GLP-2. 6-wk-old of male mice were divided into 2 groups; sedentary (SED) and low-intensity exercise (LEx). LEx mice were required to run on a treadmill (12.5 m/min, 60 min), whereas SED mice rested. All mice were euthanized 1 h after exercise or rest and plasma, jejunum, ileum, and colon were sampled. Samples were analyzed using EIA and immunoblotting. The levels of plasma GLP-2 and the expression of the GLP-2 receptor, sucrase-isomaltase (SI), and glucose transporter (GLUT2) in the jejunum were increased in LEx group. We showed that acute low-intensity exer-cise affects the intestinal carbohydrate digestion and absorption molecules via GLP-2. Our results suggest that exercise might provide new benefits to the small intestine for people with intestinal frailty.

Cotton seeds as the main by-product of cotton are not only an important raw material for edible oil and feed but also a source of biofuel. The quality of cotton seeds directly affects cotton planting and is closely related to the yield and fiber quality. However, the molecular mechanism governing cotton seed size remains largely unexplored. This study investigates the regulatory mechanisms of cotton seed size by focusing on two cotton genotypes, N10 and N12, which exhibit notable phenotypic variations across multiple environments. Developing seeds were sampled at various stages (5, 20, 30, and 35 DAP) and subjected to RNA-seq. The temporal pattern clustering and WGCNA on differentially expressed genes identified 413 candidate genes, including these related to sugar metabolism that were significantly enriched in transcriptional regulation. A genetic transformation experiment indicated that the overexpression of the GhUXS5 gene encoding UDP-glucuronate decarboxylase 5 significantly increased seed size, suggesting an important role of GhUXS5 in regulating cotton seed size. This discovery provides crucial insights into the molecular mechanisms controlling cotton seed size, helping to unravel the complex regulatory network and offering new strategies and targets for cotton breeding to enhance the economic value of cotton seeds and overall cotton yield.

Streptococcus agalactiae is a highly contagious Gram- positive bacterium that causes mastitis, has a high infectivity for mammary epithelial cells, and is challenging to treat. However, the molecular interactions between it and mammary epithelial cells remains poorly understood. This study analyzed differential gene expression in mammary epithelial cells with varying levels of S. agalactiae infection using UID- Dual Seq and bioinformatics tools. This study identified 211 differentially expressed mRNAs (DEmRNAs) and 452 differentially expressed lncRNAs (DElncRNAs) in host cells, primarily enriched in anti-inflammatory responses, immune responses, and cancer-related processes. Additionally, 854 pathogen differentially expressed mRNAs (pDEmRNAs) were identified, mainly enriched in protein metabolism, gene expression, and biosynthesis processes. Mammary epithelial cells activate pathways, such as the ERK1/2 pathway to produce, to produce reactive oxygen species (ROS) to eliminate bacteria. However, the bacteria disrupt the host's innate immune mechanisms by interfering with the alternative splicing processes of mammary epithelial cells. Specifically, the bacterial genes of tsf, prfB, and infC can interfere with lncRNAs targeting RUNX1 and BCL2L11 in mammary epithelial cells, affecting the alternative splicing of target genes and altering normal molecular regulation.

Cytochrome P450 monooxygenases (P450s) and UDP-glycosyltransferases (UGTs) are involved in the evolution of insecticide resistance. Leptinotarsa decemlineata (Say), Colorado potato beetle (CPB), is the notorious insect that has developed resistance to various of insecticides including neonicotinoids. This study investigated whether the differentially expressed P450 genes CYP9Z140 and CYP9AY1 and UGT gene UGT321AP1, found from our transcriptome results conferred resistance to thiamethoxam in L. decemlineata. Resistance monitoring showed that sampled field populations of L. decemlineata adults collected from Urumqi City, Qapqal, Jimsar and Mulei County of Xinjiang in 2021-2023 developed low levels to thiamethoxam with resistance ratios ranging from 6.66- to 9.52-fold. Expression analyses indicated that CYP9Z140, CYP9AY1, and UGT321AP1 were significantly upregulated in thiamethoxam-resistant populations compared with susceptible population. The expression of all three genes also increased significantly after thiamethoxam treatment compared with control. Spatiotemporal expression patterns showed that the highest expression of CYP9Z140 and CYP9AY1 occurred in pupae and midgut, whereas UGT321AP1 was highly expressed in adults and Malpighian tubules. Knocking down all three genes individually or simultaneously using RNA interference increased the sensitivity of adult L. decemlineata to thiamethoxam. These results suggest that overexpression of CYP9Z140, CYP9AY1, and UGT321AP1 contribute to the development of thiamethoxam resistance in L. decemlineata and provide scientific basis for improving new resistance management of CPB.

With the rapid development of gene therapy technology in recent years, its abuse as a method of sports doping in athletic has become a concern. However, there is still room for improvement in gene doping testing methods, and a robust animal model needs to be developed. Therefore, the purposes of this study were to establish a model of gene doping using recombinant adeno-associated virus vector-9 including the human erythropoietin gene (rAAV9-hEPO), and to establish a relevant testing method. First, it was attempted to establish the model using rAAV9-hEPO on mice. The results showed a significant increase in erythrocyte volume accompanied by an increase in spleen weight, confirming the validity of the model. Next, we attempted to detect proof of gene doping by targeting DNA and RNA. Direct proof of gene doping was detected using a TaqMan-qPCR assay with certain primers/probes. In addition, some indirect proof was identified in RNAs through the combination of a TB Green qPCR assay with RNA sequencing. Taken together, these results could provide the foundation for an effective test for gene doping in human athletes in the future.

MicroRNAs are small non-coding RNAs, which contribute to the regulation of many physiolog-ical and pathological processes. Conventionally, miRNAs perform their activity in the cyto-plasm, where they regulate gene expression by interacting in a sequence-specific manner with mature messenger RNAs. Recent studies point to the presence of mature miRNAs in the nucleus. This review summarizes current findings regarding the molecular activities of nuclear miRNAs. These molecules can regulate gene expression at the transcriptional level by directly binding DNA on the promoter or the enhancer of regulated genes. MiRNAs recruit to these regions dif-ferent protein complexes, resulting both in activation or repression of transcription, through a number of molecular mechanisms. Haematopoiesis is presented as a paradigmatic biological process whereby nuclear miRNAs possess a relevant regulatory role. Nuclear miRNAs may af-fect gene expression also acting on nuclear mRNA processing and on the biogenesis of miRNA themselves by regulating pri-miRNA maturation. Overall, nuclear miRNAs are biologically ac-tive molecules that can be critical for the fine tuning of gene expression and deserve further studies in a number of physiological and pathological conditions

The addition of 50% vitreous humor to the media bathing lens explants results in the induction of both fiber cell differentiation and a significant immune/inflammatory response. Although Fgfr loss blocks differentiation in lens epithelial explants, this loss is partially rescued by deleting Pten. To investigate the functions of the Fgfrs and Pten during lens fiber cell differentiation, we utilized a lens epithelial explant system and conducted RNA sequencing on vitreous humor-exposed explants lacking Fgfrs, or Pten or both Fgfrs and Pten. We found that Fgfr loss impairs both vitreous-induced differentiation and inflammation while the additional loss of Pten restores these responses. Furthermore, transcriptomic analysis suggested that PDGFR-signaling in FGFR-deficient explants is required to mediate the rescue of vitreous-induced fiber differentiation in explants lacking both Fgfrs and Pten. The blockage of β-crystallin induction in explants lacking both Fgfrs and Pten in the presence of a PDGFR-inhibitor supports this hypothesis. Our findings demonstrate that a wide array of genes associated with fiber cell differentiation are downstream of FGFR-signaling and that the vitreous-induced immune responses also depend on FGFR-signaling. Our data also demonstrates that many of the vitreous-induced gene expression changes Fgfr-deficient explants are rescued in explants lacking both Fgfrs and Pten.

Glioblastoma multiforme (GBM), the most prevalent primary malignant brain tumor in adults, exhibits a dismal 6.9% five-year survival rate post-diagnosis. Thymoquinone (TQ), the most abundant bioactive compound in Nigella Sativa, has been extensively researched for its anti-cancer properties across various human cancers. Yet, its specific anticancer mechanisms and pathways in glioblastoma remain to be elucidated. In this study, we assessed the impact of different TQ concentrations on the viability of A172 cells using WST-8 and Toluidine blue assays, followed by RNA sequencing (RNA-seq) to identify differentially expressed genes (DEGs). We confirmed their expression levels through quantitative RT-PCR and performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses for these DEGs. RNA-seq revealed no significant gene expression changes at 2.5 µM and 5 µM TQ concentrations. However, at 25 µM and 50 µM, TQ significantly reduced cell viability in a dose-dependent manner. We identified 1548 DEGs at 25 µM TQ (684 upregulated, 864 downregulated) and 2797 DEGs at 50 µM TQ (1528 upregulated, 1269 downregulated), with 1202 DEGs common to both concentrations. TQ inhibited key pathways such as PI3K-Akt signaling, calcium signaling, focal adhesion, and ECM-receptor interaction in A172 cells. It downregulated several potential oncogenes (e.g., AEBP1, MIAT) and genes linked to GBM proliferation and migration (e.g., SOCS2, HCP5), while modulating Wnt signaling and upregulating tumor suppressor genes (e.g., SPRY4, BEX2). TQ also affected p53 downstream targets, maintaining p53 levels. This study elucidates the anticancer mechanisms of TQ in A172 GBM cells, underscoring its effects on multiple signaling pathways and positioning TQ as a promising candidate for innovative glioblastoma treatment strategies.

Background: RNA helicase DHX15 plays a significant role in vasculature development and lung metastasis in vertebrates. In addition, several studies have demonstrated the overexpression of DHX15 in the context of hepatocellular carcinoma. Therefore, we hypothesized that this helicase may play a significant role in liver regeneration, physiology and pathology. Methods: Dhx15 gene deficiency was generated by CRISPR/Cas9 in zebrafish and by TALEN-RNA in mice. FANA Antisense-Oligonucleotides were used to silence Dhx15 in wild-type mice. The hepatocellular carcinoma tumor induction model was generated by subcutaneous injection of Hepa 1-6 cells. Results: Homozygous Dhx15 gene deficiency was lethal in zebrafish and mouse embryos. Dhx15 gene deficiency impaired liver organogenesis in zebrafish embryos and liver regeneration after partial hepatectomy in mice. Also, heterozygous mice presented decreased number and size of liver metastasis after Hepa 1-6 cells injection compared to wild-type mice. Dhx15 gene silencing with FANA Antisense-Oligonucleotides in wild-type mice resulted in 80% reduced expression in the liver and a significant reduction in other major organs. In addition, Dhx15 gene silencing significantly hindered primary tumor growth in the hepatocellular carcinoma experimental model. Regarding the potential use of DHX15 as a diagnostic marker for liver disease, patients with hepatocellular carcinoma showed increased levels of DHX15 in blood samples compared with subjects without hepatic affectation. Conclusion: Dhx15 is a key regulator of liver physiology and organogenesis, is increased in the blood of cirrhotic and hepatocellular carcinoma patients and has a key role in controlling hepatocellular carcinoma tumor growth and expansion in experimental models.

Sugarcane mosaic virus (SCMV) is a (genus, Potyvirus; family, Potyviridae) is a widespread, deleterious, and the most damaging pathogen of sugarcane ((Saccharum officinarum L. and Saccharum spp.) which causes a substantial barrier to producing high sugarcane earning. Sugarcane mosaic disease (SCMD) is caused by, single or compound infection of SCMV, disseminated by the several aphid vectors in a non-persistent manner. SCMV has flexuous filamentous particle of 700-750 nm long, which encapsidated a positive-sense, single-stranded RNA molecule of 9575 nucleotides. RNA interference (RNAi)-mediated antiviral innate immunity is an evolutionary conserved, key biological process in eukaryotes and has evolved as an antiviral defence system to interfere with viral genomes for controlling infections in plants. The current study aims to analyze sugarcane (Saccharum officinarum L. and Saccharum spp.) locus-derived microRNAs (sof-miRNAs/ssp-miRNAs) with predicted potential for targeting the SCMV +ssRNA-encoded mRNAs, using a predictive approach that involves five algorithms. The ultimate goal of this research is to mobilize the in silico- predicted endogenous sof-miRNAs/ssp-miRNAs to experimentally trigger the catalytic RNAi pathway and generate sugarcane cultivars to evaluate the potential antiviral resistance surveillance ability and capacity for SCMV. Experimentally validated mature sugarcane (S. officinarum, 2n = 8X = 80) and (S. spp., 2n = 100-120) sof-miRNA/ssp-miRNA sequences (n = 28) were downloaded from the miRBase database and aligned with the SCMV genome (KY548506). Among the 28 targeting mature locus-derived sof-miRNAs/ssp-miRNAs evaluated, one sugarcane miRNA homolog, sof-miR159c, was identified to have a predicted miRNA binding site, at nucleotide position 3847 of the SCMV genome targeting CI ORF. To verify the accuracy of the target prediction accuracy and to determine, whether the sugarcane sof-miRNA/ssp-miRNA could bind the predicted SCMV mRNA target(s), we constructed an integrated Circos plot. A genome-wide in-silico-predicted miRNA-mediated target gene regulatory network has implicated to validate interactions necessary to warrant in vivo analysis. The current work provides valuable computational evidence for the generation of SCMV-resistant sugarcane cultivars.

Trichothecene mycotoxin T-2 toxin is an important environmental pollutant and poses a global threat to human and animal health. T-2 toxin could induce nephrotoxicity, however, the precise molecular mechanism remains unclear. In this study, the mice were intraperitoneally administrated with a single dose of 2 mg/kg T-2 toxin. The kidney function and ultrastructural observation were also assessed and found T-2 toxin exposure could cause kidney damage. Transmission electron microscopy showed a significant swelling and vacuolization of the mitochondria of renal cell. A total of 1122, 58, and 391 differential expression genes (DEGs) that were predominantly expressed in kidney tissues at 1 d, 3 d, and 7 d after T-2 toxin exposure, respectively. Early transcriptomic changes at 1 d after exposure were down-regulation of DEGs involved in the cell cycle, p53 signaling pathway, and cellular senescence, while up-regulation of DEGs referred to the ribosome pathway. The temporal variations in gene expression pattern in T-2 toxin exposure in mice kidney were presented and cellular metabolism was disturbed at the exposure recovery period with 7 d. In conclusion, this study, for the first time, provided a comprehensive comparative transcriptomic analysis of gene regulation in T-2 toxin exposure-induced nephrotoxicity at different temporal periods and explored the nephrotoxicity mechanism of T-2 toxin at the mRNA level.

The shoot apical meristem (SAM) gives rise to the aerial structure of plants by producing lateral organs and secondary meristems. The SAM is responsible for plant developmental patterns, thus determining plant morphology and, consequently, many agronomic traits such as the number and size of fruits and flowers and kernel yield. Our current understanding of SAM morphology and regulation is based on studies conducted mainly on some angiosperms, including economically important crops such as maize (Zea mays) and rice (Oryza sativa), and the model species Arabidopsis (Arabidopsis thaliana). However, studies in other plant species from the gymnosperm class are scant, making difficult comparative analyses that help us understand SAM regulation in diverse plant species. This limitation prevents deciphering the mechanisms by which evolution gave rise to the multiple plant structures within the plant kingdom, and determined the conserved mechanisms involved in SAM maintenance and operation. This review aims to integrate and analyze the current knowledge of SAM evolution by combining the morphological and molecular information recently reported from the plant kingdom.

Mycoviruses are widespread across the major taxa of fungi including yeasts. Mycoviruses in the yeast fungus Geotrichum candidum are not well studied with three G. candidum-associated viral species characterized to date, all of which belong to the Totiviridae genus Totivirus. In this study, we report the molecular characteristics of another two totiviruses co-infecting isolate Gc6 of G. candidum. The two totiviruses were tentatively named Geotrichum candidum totivirus 2 (GcTV2-Gc6) and GcTV4-Gc6). Both viruses have typical genome organization of totiviruses comprising two ORFs encoding capsid protein (CP) and RNA-dependent RNA polymerase (RdRp) at the N and C termini, respectively. Genomes of GcTV2-Gc6 and GcTV4-Gc6 are 4592 and 4530 bp long, respectively. Both viruses contain the -1 frameshifting elements and their proteins could be expressed as a single fusion protein. GcTV2-Gc6 is closely related to a totivirus isolated from the same host whereas GcTV4-Gc6 is related to insect-associated totiviruses. The phylogenetic analysis indicated that GcTV2-Gc6 and GcTV4-Gc6 belong to two different sister clades, I-A and I-B, respectively. It is interesting that all viruses identified from G. candidum belong to the genus Totivirus. It is possible that the RNA interference (RNAi) mechanism is not active to suppress totivirus accumulation in isolate Gc6.

The development of biosensors for target detection plays a crucial role in advancing various fields of bioscience. This work presents the development of a genosensor that exploits the colorimetric phenol-sulfuric acid sugar reaction for the detection of DNA, and RNA as specific targets, and DNA intercalator molecules. The biosensor combines simplicity and reliability to create a novel bio-assay for accurate and rapid analysis. A 96-well microplate based on polystyrene polymer was used as the platform for an unmodified capture DNA immobilization via a silanization process and with (3-Aminopropyl) triethoxysilane (APTES). After that, a hybridization step was carried out to catch the target molecule, followed by adding phenol and sulfuric acid to quantify the amount of DNA or RNA sugar backbone. This reaction generates a yellow-orange color on the wells measured at 490 nm that was proportional to the target concentration. Under the optimum conditions, a calibration curve was obtained for each target. The developed biosensor demonstrated high sensitivity, good selectivity, and linear response over a wide concentration range for DNA and RNA targets. Additionally, the biosensor was successfully employed for the detection of DNA intercalator agents that inhibit the hybridization of DNA complementary to the immobilized capture DNA. The developed biosensor offers a potential tool for sensitive and selective detection in various applications, including virus diagnosis, genetic analysis, pathogenic bacteria monitoring, and drug discovery.

Sugarcane mosaic virus (SCMV) is a deleterious pathogen which causes widespread Sugarcane mosaic disease (SCMD) and is classified in the genus Potyvirus (Potyviridae), disseminated by the aphid vector. RNA interference (RNAi)-mediated antiviral innate immunity is a key biological process and antiviral defence system to interfere with viral genomes for controlling plant pathogens. The current study aims to analyze sugarcane (Saccharum officinarum L. and Saccharum spp.) locus-derived microRNAs (sof-miRNAs/ssp-miRNAs) with predicted potential for targeting the SCMV +ssRNA-encoded mRNAs, using ‘five algorithms’ approach. The ultimate goal in this research is to mobilize the in silico endogenous predicted sof-miRNAs/ssp-miRNAs to trigger RNAi catalytic pathway experimentally and generate sugarcane cultivars for evaluating potential antiviral resistance monitoring capability and capacity for SCMV. Experimentally validated mature sugarcane (S. officinarum, 2n = 8X = 80) and (S. spp., 2n = 100-120) sof-miRNAs/ssp-miRNAs (n = 28) were acquired for alignment with the SCMV genome. Of the 28 targeting mature locus-derived sof-miRNAs/ssp-miRNAs investigated, one sugarcane miRNA homolog, sof-miR159c, was concluded to localize potential binding site at genomic nucleotide site 3847 targeting CI ORF of SCMV. In order to validate target prediction accuracy, whether the sugarcane sof-miRNA/ssp-miRNA might bind predicted SCMV mRNA target(s), we created an integrated Circos plot. Genome-wide in-silico-predicted miRNA-mediated target gene regulatory network validated interactions that warrant in vivo analysis. The current work provides valuable evidence and biological material for generating SCMV-resistant sugarcane varieties.

Because rice is native to tropical and subtropical regions, it is generally more sensitive to cold stress compared to other cereals. Low temperature stress has become one of the most important conditions that affects the growth, development, and yield of rice. Plant NAC (NAM, ATAF1/2, and CUC) transcription factors are known to play significant regulatory roles in the stress response. In our research, we found that OsNAC050 (LOC_Os03g60080） is mainly expressed in leaves, and low temperature can further up-regulate its expression. OsNAC050 mutants created using CRISPR-Cas9 gene editing technology showed significantly enhanced tolerance to low temperature treatment. Detection of enzyme activities related to the redox pathway also showed that the mutants had stronger viability under low temperature stress. Comparative transcriptome analysis showed that photosynthesis and soluble sugar metabolism were significantly affected in the osnac050 mutant lines, suggesting that OsNAC050 may participate in the above molecular pathways in the response to low temperature stress. The results will enhance our understanding of molecular mechanisms underlying the responses to cold stress in rice and can provide new strategies for engineering cold-tolerance in high-yielding rice varieties.

Olfaction plays a crucial role in many important behavioral activities of insects, such as finding sexual partners, locating hosts, and selecting oviposition sites. Ionotropic receptors (IRs) play a central role in detecting chemosensory information from the environment and guiding insect behaviors and are potential target genes for pest control. Empoasca onukii Matsuda is a major pest of the tea plant Camellia sinensis (L.) O. Ktze, and seriously influences tea yields and quality. In this study, the ionotropic receptor gene EnouIR25a in E. onukii was cloned, and the expression pattern of EnouIR25a was detected in various tissues. Behavioral responses of E. onukii to volatile compounds emitted by tea plants were determined by the olfactometer bioassay and field trials. To further explore the function of EnouIR25a in olfactory recognition of compounds, RNAi (RNA interference) of EnouIR25a was carried out by ingestion of in vitro synthesized dsRNAs. The CDS length of EnouIR25a was 1266 bp and it encoded a 48.87 kD protein. EnouIR25a was enriched in the antennae of E. onukii. E. onukii were more significantly attracted by 1-phenylethanol at concentration of 100 µl/ml. Feeding with dsRNA-IR25a significantly downregulated the expression level of EonuIR25a, after 3 h of treatment, which disturbed the behavioral responses of E. onukii to 1-phenylethanol at concentration of 100µl/ml. The response rate of E. onukii to 1-phenylethanol was significantly decreased after dsRNA-IR25a treatment for 12 h. In summary, the ionotropic receptor gene EnouIR25a was highly expressed in the antennae of E. onukii and was involved in olfactory recognition of the tea plant volatile 1-phenylethanol. The present study may help us to use the ionotropic receptor gene as a target for the behavioral manipulation of E. onukii in the future.

The emergence of drug resistant pathogenic bacteria is increasingly challenging conventional antibiotics. Plant derived flavonoids are considered as potential alternatives to antibiotics due to their antimicrobial properties. However, the mechanisms by which flavonoids modulate pathogenic microorganisms’ growth are not fully understood. In our previous studies we found that Rutin, a kind of flavonoids showed inhibition against Klebsiella pneumoniae strains. In order to better understand its inhibitory mechanism on strain growth, we used both Rutin and Luteolin as treatments to incubate K. pneumoniae ATCC700603 strain. After incubation for 4 hours, the homogenous and differential effects of two different flavonoids on the growth of K. pneumoniae were evaluated. The integrated metabolomic and transcriptomic analysis was performed. The expression levels of 5,483 genes and the contents of 882 metabolites were measured. The differentially expressed genes (DEGs) and metabolites (DEMs) were screened and analyzed. The correlation between DEGs and DEMs were also studied. Our results showed that Rutin could inhibit the strain growth by changing metabolic pathways and ABC transporters pathways. Our study also revealed FU841_RS17580 and FU841_RS19145 as functional genes that played vital roles in the strain growth.

The innate immune system is the first line of host defense sensing viral infection. Manganese (Mn) has recently been found to be involved in the activation of innate immune DNA sensing cGAS-STING pathway and subsequent anti-DNA virus function. However, whether Mn2+ mediates host defense against RNA viruses is still unclear. In the current study, we demonstrated that Mn2+ exhibited antiviral effects against various animal and human viruses including RNA viruses such as PRRSVs and the VSV as well as a DNA virus such as the HSV1 in a dose-dependent manner. Moreover, cGAS and STING were both investigated in the Mn2+ mediated antiviral roles using the knockout cells made by CRISPR-Cas9 approach. Unexpectedly, the results revealed that neither cGAS knockout nor STING knockout had any effect on Mn2+ mediated antiviral functions. Nevertheless, we verified that Mn2+ promoted the activation of cGAS-STING signaling pathway. These findings suggest that Mn2+ has broad spectrum antiviral activities in a cGAS-STING pathway independent manner. This study also provides significant insights into redundant mechanisms participating in the Mn2+ antiviral functions and also indicates new target for Mn2+ antiviral therapeutics.

The central dogma of molecular biology dictates that, with only a few exceptions, information proceeds from DNA to protein through an RNA intermediate. Examining the enigmatic steps from prebiotic to biological chemistry, we take another road suggesting that primordial peptides acted as template for the self-assembly of the first nucleic acids polymers. Arguing in favour of a sort of archaic “reverse translation” from proteins to RNA, our basic premise is a Hadean Hearth where key biomolecules such as amino acids, polypeptides, purines, pyrimidines, nucleosides and nucleotides were available under different prebiotically plausible conditions, including meteorites delivery, shallow ponds and hydrothermal vents scenarios. Supporting a protein-first scenario alternative to the RNA world hypothesis, we propose the primeval occurrence of short peptides termed “selective amino acid- and nucleotide-matching oligopeptides” (henceforward SANMAOs) that noncovalently bind at the same time the polymerized amino acids and the single nucleotides dispersed in the prebiotic milieu. We describe the chemical features of this hypothetical oligopeptide, its biological plausibility and its virtues from an evolutionary perspective. We provide a theoretical example of SANMAO’s selective pairing between amino acids and nucleosides, simulating a poly-Glycine peptide that acts as a template to build a purinic chain corresponding to the glycine’s extant triplet codon GGG. Further, we discuss how SANMAO might have endorsed the formation of low-fidelity RNA’s polymerized strains, well before the appearance of the accurate genetic material’s transmission ensured by the current translation apparatus.

The pandemic of COVID-19 ravaged most countries and made the healthcare system go for a toss. The impact of the disease is different in each patient and it progresses differently. Based on the severity, the COVID-19 infection is stratified into three main categories- mild, moderate, and severe. In this study, we performed a transcriptomic study of different stages and studied the progression of the disease. The study was based on an Indian population of 28 COVID-19 patients, which were classified into different groups. Our analysis has shown that as the disease progresses, the genes involved in the degranulation of the neutrophils and galactose metabolism increase. Furthermore, we identified the hub proteins in each stage. TB is one of the comorbidities of COVID-19 and a comparative study was done to identify the preserved module of genes in both. Enrichment analysis showed that the members of this module are significantly involved in translation and ribosome synthesis.

Systems genetics is key for integrating a large number of variants associated with diseases. Vitamin K (VK) is one of the scarcely studied conditions in lieu of ascertaining either the differentially expressed genes (DEGs) or variants in an individual subpopulation of diseased phenotypes associated with VK, viz. myocardial infarction, renal failure, prostate cancer, thrombosis, thrombocytopenia, coagulation related diseases to name a few. In this work, we have screened characteristic DEGs common to three VK-related diseases, viz. myocardial infarction, renal failure and prostate cancer and asked whether or not any DEGs in addition to pathogenic variants are common to these conditions. We attempt to bridge the gap in finding characteristic biomarkers and discuss the role of long noncoding RNAs (lncRNAs) in the biogenesis of VK deficiencies.

Single-cell RNA sequencing data facilitates investigation of cell heterogeneity and subpopulations as well as differentially abundant states however modern single-cell RNA sequencing datasets are growing in size and complexity requiring advances in the bioinformatic methods that analyze them. Many methods exist for each step of analysis including read alignment, normalization, quality control, batch effect correction, imputation and dimensionality reduction. With so many options to choose from at each step of the analysis, benchmarking and a synthesis of the literature on the methods available is necessary to inform biological researchers on the most optimal workflow for their data. Here, recent key methods of analysis are highlighted with a focus on methods that facilitate identification of cell subpopulations and differentially abundant cell states. With a constantly expanding toolset for each step in single-cell RNA sequencing dataset analysis, biological researchers should stay informed to utilize the most applicable methods for their own analyses.

Mosquitoes are widespread arthropods that serve as vectors for a broad spectrum of viruses, many of which pose a substantial threat to humans. Conversely, some viruses may seemingly present with beneficial implications for the health of man whilst impinging on other domains of life, such as the fungi-infecting mycoviruses. This study is only the second one so far to describe the exceptionally scarcely identified Xanthi chryso-like virus (XCLV), member of the mycopathogenic Chrysoviridae family, in a new geographical area and a novel potential arthropod vector, the Culex pipiens mosquito. Interestingly, the XCLV was initially fortuitously detected by West Nile virus-specific primers directed at a conserved part of the NS5 gene, possibly indicative of a genetic resemblance and shared ancestry reflected in the NS5 evolutionary heritage. Detection and characterization of the virus and insect alike was done via PCR and Sanger sequencing. This investigation draws attention to our knowledge of viral pervasiveness – be it topographical or vectorial – and how humble it truly is. Additionally, we would propose that more attention be given to arthropod-borne viral pathogens that might prove advantageous to human health.

Microglia activation causes neuroinflammation, which is a hallmark of neurodegenerative disorders, brain injury, and aging. Ladostigil, a bifunctional reagent with antioxidant and anti-inflammatory properties, reduced microglial activation and enhanced brain functioning in elderly rats. In this study, we studied SH-SY5Y, a human neuroblastoma cell line, and tested viability in the presence of hydrogen peroxide and Sin1 (3-morpholinosydnonimine), which generates reactive oxygen and nitrogen species (ROS/RNS). Both stressors caused significant apoptosis and necrotic cell death that was attenuated by ladostigil. Our results from RNA-seq experiments show that long non-coding RNAs (lncRNAs) account for 30% of all transcripts in SH-SY5Y cells treated with Sin1 for 24 hours. Altogether, we identify 94 differently expressed lncRNAs in the presence of Sin1, including MALAT1, a highly expressed lncRNA with anti-inflammatory and anti-apoptotic functions. Additional activities of Sin-1 upregulated lncRNAs include redox homeostasis (e.g., MIAT, GABPB1-AS1), energy metabolism (HAND2-AS1), and neurodegeneration (e.g., MIAT, GABPB1-AS1, NEAT1). Four lncRNAs implicated as enhancers were significantly upregulated in cells exposed to Sin1 and ladostigil. Finally, we show that H2O2 and Sin1 increased the expression of DJ-1, a redox sensor and modulator of Nrf2 (nuclear factor erythroid 2–related factor 2). Nrf2 (NFE2L2 gene) is a major transcription factor regulating antioxidant genes. In the presence of ladostigil, DJ-1 expression is restored to its baseline. The mechanisms governing SH-SY5Y cell survival and homeostasis are highlighted by the beneficial role of ladostigil in the crosstalk involving Nrf2, antioxidant transcription factor DJ-1, and lncRNAs. Stress-dependent induction of lncRNAs represents an underappreciated regulatory level that contributes to cellular homeostasis and the capacity of SH-SY5Y to cope with oxidative stress.

Intratumoral heterogeneity associates with more aggressive disease progression and worse patient outcomes. Understanding the reasons enabling the emergence of such heterogeneity remains incomplete, which restricts our ability to manage it from a therapeutic perspective. Technological advancements such as high-throughput molecular imaging, single-cell omics and spatial transcriptomics now allow recording the patterns of spatiotemporal heterogeneity in a longitudinal manner, thus offering insights into the multi-scale dynamics of its evolution. Here, we review latest technological trends and biological insights from molecular diagnostics as well as spatial transcriptomics, both of which have witnessed a burgeoning growth in recent past in terms of mapping heterogeneity within tumor cell types as well as stromal constitution. We also discuss ongoing challenges, indicating possible ways to integrate insights across these methods to have a systems-level spatiotemporal map of heterogeneity in each tumor, and a more systematic investigation of implications of heterogeneity for the patient outcomes.

Tilapia lake virus (TiLV) is the main tilapia-infecting virus worldwide, causing serious economic losses. However, there is no vaccine for this viral disease. Here, TiLV ORF10 (TiLV-ORF10) encoding a protein with abundant epitopes was constructed into the eukaryotic expression vector pcDNA3.1, and used to evaluate the immune protective effects in Nile tilapia (Oreochromis niloticus). RT-PCR and western blot analyses confirmed vaccine plasmid expression in tilapia muscle tissues. Moreover, the transcription levels of immunoglobulin M, toll-like receptor 2, myeloid differentiation factor 88, interleukin 8, tumor necrosis factor alpha, gamma-IFN, and nuclear factor κB immune-related genes were statistically significantly upregulated in the spleen, liver, and kidney of vaccinated tilapias (P < 0.05). TiLV challenge experiments showed that relative percent survival (RPS) was significantly enhanced in fish by this DNA vaccine. Moreover, RPS was enhanced further when using a higher amount of the DNA vaccine (85.72% RPS at a DNA dose of 45 μg pcDNA3.1–ORF10). Vaccination with pcDNA3.1–ORF10 significantly reduced virus replication, as evidenced by the low amount of virus in the spleen, liver, and kidney of vaccinated tilapias after TiLV challenge. Thus, pcDNA3.1–ORF10 could induce protective immunity in tilapia and may be a potential vaccine candidate for controlling diseases caused by TiLV.

Pratylenchus loosi is an important root-lesion nematode that cause damage to tea plantations in Iran and all over the world. The present study reports on the characterization and evolution of three ß-1,4-engoglucanase genes Pl-eng-2, Pl-eng-3 and Pl-eng-4. The gene structure of Pl-eng-2 was fully determined with the predicted signal peptide and devoid of the linker domain and carbohydrate-binding domain, while Pl-eng-3 and Pl-eng-4 were only partially sequenced. The transcription of Pl-eng-2 was localized in the secretory esophageal glands of all life stages, but it was upregulated in male and females stages. Exon/intron structures of Pl-eng-2, Pl-eng-3 and Pl-eng-4 confirmed that they resulted from gene duplication followed by sequence and gene structure diversification with loss of linker domain and carbohydrate-binding domain during evolution. Phylogenetic analysis further confirmed that nematode endoglucanases resulted from horizontal gene transfer of a bacterial gene as Pl-eng-3 showed sister relationships with CelB cellulase of Bacillus subtilis. Silencing Pl-eng-2 by in vitro RNA interference, produced a 60% decrease of the transcript level. The reproductive ability of silenced P. loosi showed a 35% reduction of eggs and larval stages compared to untreated nematodes suggesting that this gene is involved in the early steps of invasion.

Thyroid cancer is the most prevalent malignancy of the endocrine system and the ninth most common cancer globally. Despite the advances in the management of thyroid cancer, there are critical issues with the diagnosis and treatment of thyroid cancer that result in the poor overall survival of undifferentiated and metastatic thyroid cancer patients. Recent studies have revealed the role of different non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) that are dysregulated during thyroid cancer development or the acquisition of resistance to therapeutics, and may play key roles in treatment failure and poor prognosis of the thyroid cancer patients. Here, we systematically review the emerging roles and molecular mechanisms of ncRNAs that regulate thyroid tumorigenesis and drug response. We then propose the potential clinical implications of ncRNAs as novel diagnostic and prognostic biomarkers for thyroid cancer.

As a major infectious disease in chickens, Newcastle disease causes considerable economic losses in the poultry industry, especially in developing countries where there is limited access to effective vaccination. Therefore, enhancing resistance to the virus in commercial chickens through breeding is a promising way to promote poultry production. In this study, we investigated gene expression changes at 2 and 6 dpi after infection at day21 with a lentogenic Newcastle disease virus in a commercial egg-laying chicken hybrid using RNA sequencing analysis. By comparing NDV challenged and nonchallenged groups, 526 differentially expressed genes (DEGs) (FDR &lt; 0.05) were identified at 2 dpi, and only 36 at 6 dpi. For the DEGs at 2 dpi, IPA analysis predicted inhibition of multiple signaling pathways in response to NDV that regulate immune cell development and activity, neurogenesis and angiogenesis. Upregulation of Interferon Induced Protein with Tetratricopeptide Repeats 5 (IFIT5) in response to NDV was consistent between the current and most previous studies. Sprouty RTK Signaling Antagonist 1 (SPRY1), a DEG in the current study is located in a significant QTL associated with virus load at 6 dpi in the same population. These identified pathways and DEGs provide potential targets to further study breeding strategy to enhance NDV resistance in chickens.

The outbreak of SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) has caused severe damage to the world. With the support of classic evolutionary theories and population genetics principles, many studies on the origin of SARS-CoV-2 have revealed encouraging results but meanwhile are still under debate. We are concerned with the validity of applying classic evolutionary theories and formula to the evolution of RNA viruses. We have raised several factors like the RNA replication feature and the RNA modification systems of the hosts, which might jeopardize the validity of the application of classic methods to analyze the SARS-CoV-2 data.

An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurred in China towards the end of 2019, and has spread rapidly ever since. Previous studies showed that some virus could affect the reproductive system and cause long-term complications. Recent studies exploring the source of SARS-CoV-2 using genomic sequencing have revealed that SARS-CoV-2 enters the host cells via the angiotensin-converting enzyme II (ACE2), the receptor that recognizes SARS-CoV. To investigate the expression of ACE2 and to explore the potential risk of infection in the reproductive system, we performed a thorough bioinformatic analysis on data from public databases involving RNA expression, protein expression, and single-cell RNA expression studies. The analyzed data showed high levels of ACE2 mRNA and protein expression in the testis and spermatids and equal levels of ACE2 expression in the uterus and lung. Comprehensive single-cell analysis identified ACE2 expression in the lung, testis, spermatids, and uterus. In conclusion, this study revealed the potential risk associated with the SARS-CoV-2 infection in the reproductive system and predicted that long-term complications might have a significant impact on the prevention and management of COVID-19, the disease caused upon infection with SARS-CoV-2.

Autophagy is an evolutionarily conserved central process in host metabolism. Among its major functions are conservation of energy during starvation, recycling organelles, and turnover of long-lived proteins. Besides, autophagy plays a critical role in removing intracellular pathogens and very likely represents a primordial intrinsic cellular defence mechanism. More recent findings indicate that it has not only retained its ability to degrade intracellular pathogens, but also functions to augment and fine tune antiviral immune responses. Interestingly, viruses have also co-evolved strategies to manipulate this pathway and use it to their advantage. Particularly intriguing is infection-dependent activation of autophagy with positive stranded (+)RNA virus infections, which benefit from the pathway without succumbing to lysosomal degradation. In this review we summarise recent data on viral manipulation of autophagy, with a particular emphasis on +RNA viruses and highlight key unanswered questions in the field that we believe merit further attention.

The circulating transcriptome is a valuable source of cancer biomarkers, which with the exception of miRNAs, remains relatively unexplored. To elucidate which RNAs are present in plasma from melanoma patients and which could be used to distinguish cancer patients of healthy individuals, we used next generation sequencing (NGS) and validation was carried out by qPCR and/or ddPCR. We identified 442 different microRNAs in samples, eleven of which were differentially expressed (P < 0.05). Levels of miR-134-5p and miR-320a-3p were significantly down-regulated (P<0.001) in melanoma samples (n = 96) compared to healthy controls (n = 28). Differentially expressed protein-encoding mRNA, 5´-fragments, were enriched for the angiopoietin, PAK and EIF2 pathways. Levels of ATM1, AMFR, SOS1 and CD109 gene fragments were up-regulated (P < 0.001) in melanoma samples (n=144) compared to healthy controls (n = 41) (AUC = 0.825). Over 40% of mapped reads were YRNAs, a class of non-coding RNAs that to date has been little explored. Expression levels of RNY3P1, RNY4P1 and RNY4P25 were significantly higher in patients with stage 0 disease, than either healthy controls or more advanced stage disease (P < 0.001). In conclusion, we have identified a number of novel RNA biomarkers, which most importantly we validated in multi-centre retrospective and prospective cohorts suggesting potential diagnostic use of these RNA species.

Endo-reticular stress induces the unfolded protein response including a highly conserved set of genes crucial for cell survival against a variety of onslaughts. Among the activated stress response genes is Ire1, which undergoes auto-phosphorylation and acquires a regulated Ire1-dependent mRNA decay activity. Ire1P non-canonically splices the mRNA for Xbp1 in the cytoplasm. This spliced Xbp1 serves as mRNA encoding a transcription factor for unfolded protein response genes. Meanwhile the mRNA decay function of Ire1P degrades other cellular mRNAs and can cause changes to the translation machinery by altering regulators in a cell specific manner. Naïve splenic B cells differentiate into Antibody Secreting Cells and activate Ire1 phosphorylation early on after LPS stimulation, within 18 hrs. When Ire1 is activated in B cells, in addition to Xbp1 splicing, there are large-scale changes in mRNA; inhibition of the mRNA degradation function of Ire1 both reduces the number and changes the type of genes involved in altered splicing patterns, including factors for snRNA transcription. Some of the splicing changes seen at 18 hrs after LPS persist into the late stages of antibody secretion, up to 72 hrs, while others are supplanted by new splicing changes introduced by the induction of ELL2, a transcription elongation factor. ELL2 changes mRNA processing patterns and is necessary for Immunoglobulin secretion. RNA splicing patterns in antibody secreting cells are thus shaped by endo-reticular stress, ELL2 induction, and are associated with changes in the levels of snRNAs.

Retinoic acid (RA) is the biologically active metabolite of vitamin A and has become a well-established factor that induces neurite outgrowth and regeneration in both vertebrates and invertebrates. However, the underlying regulatory mechanisms that may mediate RA-induced neurite sprouting remain unclear. In the past decade, microRNAs have emerged as important regulators of nervous system development and regeneration, and have been shown to contribute to processes such as neurite sprouting. However, few studies have demonstrated the role of miRNAs in RA-induced neurite sprouting. By miRNA-Sequencing analysis, we identify 482 miRNAs in the regenerating CNS of the mollusc Lymnaea stagnalis, 219 of which represent potentially novel miRNAs. Of the remaining conserved miRNAs, 38 show a statistically significant up or downregulation in regenerating CNS as a result of RA treatment. We further characterized the expression of one neuronally-enriched miRNA upregulated by RA, miR-124. We demonstrate for the first time that miR-124 is expressed within the cell bodies and neurites of regenerating motorneurons. Moreover, we identify miR-124 expression within the growth cones of cultured ciliary motorneurons (Pedal A), whereas expression in the growth cones of another class of respiratory motorneurons (RPA) was absent in vitro. These findings support our hypothesis that miRNAs are important regulators of retinoic acid-induced neuronal outgrowth and regeneration in regeneration-competent species.

Retinoic acid (RA) is the biologically active metabolite of vitamin A,and has become a well-established factor that induces neurite outgrowth and regeneration in both vertebrates and invertebrates. However, the underlying regulatory mechanisms that may mediate RA-induced neurite sprouting remain unclear. In the past decade, microRNAs have emerged as important regulators of nervous system development and regeneration, and have been shown to contribute to processes such as neurite sprouting. However, few studies have demonstrated the role of miRNAs in RA-induced neurite sprouting. By R-Seq analysis, we identify 482 miRNAs in the regenerating CNS of the mollusc Lymnaea stagnalis, 219 of which represent potentially novel miRNAs. Of the remaining conserved miRNAs, 38 show a statistically significant up or downregulation in regenerating CNS as a result of RA treatment. We further characterized the expression of one neuronally-enriched miRNA upregulated by RA, miR-124. We demonstrate for the first time that miR-124 is expressed within the cell bodies and neurites of regenerating motorneurons. Moreover, we identify miR-124 expression within the growth cones of cultured ciliary motorneurons (Pedal A), whereas expression from the growth cones of another class of respiratory motorneurons (RPA) was absent in vitro. These findings support our hypothesis miRNAs are important regulators of retinoic acid induced neuronal outgrowth and regeneration in regeneration-competent species.

Currently there is little doubt left on the symbiogenetic nature of eukaryotes - genomes of archaeon and bacterium participated in shaping a genome of last eukaryotic common ancestor in equal albeit asymmetric manner, while a merger event itself indicated the advent of a new domain of life. The “symbiogenetic” framework of interaction of two partners is proposed, outlining similar steps essential for three major advents: the origin of life, the origin of complex life and the origin of humans. Given the immense importance of proper energy source for the evolution of life it seems plausible that for any principal increase in complexity, a partnership with a novel energy donor is required. Moreover, a “language” elaborated in the course of communication of partners might have been a prerequisite for a subsequent increase in complexity. Transitions, which led to RNA-protein world, eukaryotes and human brain, resulted in advent of complex languages via communication onsets between two entities in close partnership. Accordingly this further facilitated formation of first cells, multicellular organisms and human society.

Oxygen extraction fraction (OEF), the fraction of oxygen that tissue extracts from blood, is an es-sential biomarker for directly assessing tissue viability and function in neurologic disorders. For quantitative mapping of OEF, an integrative model of quantitative susceptibility mapping and quantitative blood oxygen level-dependent magnitude (QSM+qBOLD or QQ) was recently pro-posed. However, QQ assumes Gaussian noise in both susceptibility and multi-echo gradient echo (mGRE) magnitude signals for OEF estimation. This assumption is unreliable in low sig-nal-to-noise ratio (SNR) regions like disease-related lesions, risking inaccurate OEF estimation and potentially impacting clinical decisions. Addressing this, our study presents a novel multi-echo complex QQ (mcQQ) that models realistic noise in mGRE complex signals. The proposed mcQQ was implemented using a deep learning framework (mcQQ-NET) and compared with the existing deep learning-based QQ (QQ-NET) in simulations, ischemic stroke patients, and healthy subjects. Both mcQQ-NET and QQ-NET used identical training and testing datasets and schemes for a fair comparison. In simulations, mcQQ-NET provided more accurate OEF than QQ-NET. In the sub-acute stroke patients, mcQQ-NET showed a lower average OEF ratio in lesions relative to unaf-fected contralateral normal tissue than QQ-NET. In the healthy subjects, mcQQ-NET provided uniform OEF maps, similar to QQ-NET, but without unrealistically high OEF outliers in areas of low SNR. Therefore, mcQQ-NET improves OEF accuracy by better reflecting realistic data noise characteristics.

The study’s objective is to analyse the mechanical properties of steel pipe piles as a part of a trestle bridge subjected to five years of natural marine corrosion degradation. Sixteen tensile specimens were extracted from the steel pipe piles in the splash, tidal, and immersion zones. The experimental tensile test results are used to establish regression equations defining elastic modulus, yield strength, strain hardening index, and strength coefficient for the true stress-strain curves of the three regions. A non-linear time-dependent mathematical model is exploited to identify the corrosion degradation using the data from one single corrosion degradation measurement campaign. The analysis indicated that the splash zone experiences the most severe corrosion degradation, and there are progressive losses in the mechanical properties of each zone as the corrosion degradation progresses. The established relationships of the mechanical properties, as a function of the ratio of corroded plate thickness to the as-built one, can be used as a fast-engineering approach to identify the mechanical properties of severely corroded piles. The corrosion degradation allowance is also defined using the First Order Reliability Method, accounting for existing uncertainties covered by the partial safety factors. By examining the impact of marine corrosion on the mechanical properties of marine structures and developing predictive models to assess the corrosion’s effect on material strength and corrosion allowance, the study aims to improve offshore structures’ safety, design, and maintenance.

Durability of concrete requires a dense microstructure which can be achieved by using self-compacting concrete (SCC). Both calcined clay (CC) and rice husk ash (RHA) are promising supplementary cementitious materials (SCMs) that can partially replace cement, but their use in SCC is critical due to their higher water demand and specific surface area (SSA) compared to cement. Empirical method of SCC design was adopted considering the physical properties of both CC and RHA. The influence of partially substituting cement at 20 vol-% with binary and ternary blends of CC and RHA were investigated. The fresh properties of SCC were investigated using a variety of tests. The time dependent workability was monitored by plunger method and flow resistance determined based on the rheological measurements of SCC. The evolution of the hydrate phases of the binder in SCC was determined by thermogravimetric analysis, while the durability was evaluated by rapid chloride migration test. Cement partial replacement with 20 vol-% CC has no significant effect on SCC fresh, time dependent, compressive strength and durability properties. 20 vol-% RHA on the other hand requires higher dosage of SP to achieve self-compactability and increased the viscosity of SCC. Its workability retention is only up to 30 min after mixing and exhibited higher flow resistance. It consumes more CH and improves compressive strength and chloride resistance of SCC. The ternary blending with CC and RHA yielded better fresh SCC properties compared to the binary blend with RHA, while an improved chloride penetration resistance could be achieved compared to binary CC blend.

The mathematical modelling of reverse logistics inventory systems ignores that returned items may arrive out of sequence, i.e. with different number of remanufacturing times. Moreover, such modelling assumes that the retuned items may retain the same quality upon recovery regardless of how many times they have been previously remanufactured. This paper develops a new mathematical expression of the percentage of retuned items that can be remanufactured a finite number of times. The proposed expression is modelled as a function of the expected number of times an item can be remanufactured on its life cycle and the number of times an item can be technologically (or optimally) remanufactured based on its quality upon recovery. The model developed in this paper considers joint production and remanufacturing options. The return rate is a varying demand dependent rate, which is a decision variable with demand, product deterioration, manufacturing and remanufacturing rates being arbitrary functions of time. The model considers the initial inventory of returned items in the mathematical formulation, which enables decision makers to adjust all functions and input parameters for subsequent cycles. Illustrative examples indicate that dependent purchasing price of recovery items and the incorporation of remanufacturing investment cost significantly impact on the optimal remanufacturing policy.

This paper presents sufficient conditions for almost global stability of nonlinear switched systems consisting of both stable and unstable subsystems. Techniques from the stability analysis of switched systems have been combined with the multiple Lyapunov density approach - recently proposed by the authors for the almost global stability of nonlinear switched systems composed of stable subsystems. By using slow switching for stable subsystems and fast switching for unstable subsystems lower and upper bounds for mode-dependent average dwell times are obtained. In addition to that, by allowing each subsystem to perform slow switching and using some restrictions on total operation time of unstable subsystems and stable subsystems, we have obtained a lower bound for an average dwell time.

Here, I introduce a concept called autonomous selection to refer to a source of selection that is part of the individuals upon which it acts. The concept is motivated by a set of phenomena with the following characteristics: Natural selection shaped a variant (e.g., gene, epigenetic mark, or combination thereof) to act in a manner that reduces the frequency of one or more heritable traits of the individual in which it is located if those traits are detrimental to individual or group fitness. Phenomena with these characteristics are peculiar to traditional evolutionary theory but have been identified rather frequently in recent decades. They are also relevant to adaptive evolution: By reducing the frequency of a trait detrimental to fitness, the variant accelerates the evolution of adaptations, which allows its holders to adapt better to constantly changing environments. The variant is shaped by (natural) selection, but also does (autonomous) selection. Several phenomena with these characteristics have been invoked by proponents of the extended evolutionary synthesis (EES). The concept of autonomous selection helps resolve some of the controversy surrounding the EES: EES proponents call attention to the incompleteness of contemporary theory, emphasizing individuals’ processes that influence which adaptations those individuals evolve. I argue for the special importance of individuals’ processes that do not just influence those individuals’ adaptations, but also accelerate the adaptive evolution of those individuals. All known phenomena that fit this description are examples of autonomous selection. Other phenomena raised by EES proponents do not meet this threshold.

Based on the Expected Utility Theory and Regret Theory, the Extended Regret Theory (ERT) is proposed in this paper to study the optimal pricing strategy of retailers in e-commerce environment. Taking the diversity of sales channels and the uncertainty of consumers in e-commerce environment into consideration, author of the paper designs an extended regret utility function which comprehensively considers both pessimistic and optimistic attitudes of decision makers in retailing industry to describe their regret-avoidance behavior. According to the sensitivity analysis, it is found that the optimal retail price decreases as the consumer price sensitivity coefficient increases, yet does not show variation with changes of the consumers pessimism degree. Moreover, the optimal retail price(s) obtained under EUT, ERT and combination of EUT and ERT represent the same.

Akt1 is a proto-oncogene that is over active in most cancers. Akt1 activation requires phosphorylation at Thr308; phosphorylation at Ser473 further enhances catalytic activity. Akt1 activity is also regulated via interactions between the kinase domain and the N-terminal auto-inhibitory pleckstrin homology (PH) domain. As it was previously difficult to produce Akt1 in site-specifically phosphorylated forms, the contribution of each activating phosphorylation site to auto-inhibition was unknown. Using a combination of genetic code expansion and in vivo enzymatic phosphorylation, we produced Akt1 variants containing programmed phosphorylation to probe the interplay between Akt1 phosphorylation status and the auto-inhibitory function of the PH domain. Deletion of the PH domain increased the enzyme activity for all three phosphorylated Akt1 variants. For the doubly phosphorylated enzyme, deletion of the PH domain relieved auto-inhibition by 295-fold. We next found that phosphorylation at Ser473 provided resistance to chemical inhibition by Akti-1/2 inhibitor VIII. The Akti-1/2 inhibitor was most effective against pAkt1T308 and showed 4-fold decreased potency with Akt1 variants phosphorylated at Ser473. The data highlight the need to design more potent Akt1 inhibitors that are effective against the doubly phosphorylated and most pathogenic form of Akt1.

Acute myeloid leukemias are characterized by genetic alterations that lead to a complete or partial block at various stages of myeloid differentiation, leading to continual proliferation of myeloid progenitor cells. These alterations can include a well-documented chromosomal translocation that leads to the synthesis of the PML-retinoic acid receptor fusion protein that leads to a block in differentiation and the ability to induce differentiation with all-trans retinoic acid and other small molecules. In essence, in large part, the disease is due to stem cell-like cells that are blocked in their ability to undergo terminal differentiation to more mature, non-proliferative cell types. We discovered a long non-coding RNA (lncRNA), lncRNAp53int1, encoded from the first intron of the p53 tumor suppressor gene. Interestingly, lncRNAp53int1 appears to play an important regulatory role in maintaining the undifferentiated and proliferative state in a manner independent from p53 gene expression. lncRNAp53int1 is expressed at high levels in proliferating, undifferentiated promyelocytes and its levels fall significantly during their terminal differentiation to non-proliferating granulocytes or macrophages. Furthermore, forced overexpression of lncRNAp53int1 blocks terminal differentiation. The observation that the expression of this lncRNA is repressed during terminal differentiation of human leukemic cells and its expression blocks differentiation of leukemic myeloid progenitor cells, is likely to have clinical implications with regards to differentiation therapy for myeloid leukemia. Ongoing research aims to identify the molecular partners that it associates with and the signaling pathways that this lncRNA participates in with the long-term goal of identifying molecules that inhibit lncRNAp53int1 activity and serve as potential therapeutic drugs. The goal of this mini-review is to disseminate these novel and interesting findings to readers and to describe where we think this research is headed and the impact it can have on myeloid leukemias.