Spermatogenesis is critical for insect reproduction and is regulated by many different genes. In this study, we found that Forkhead transcription factor Fd59a functions as a key factor in spermatogenesis of Drosophila melanogaster. Fd59a contains a conversed Forkhead domain, and it is clustered to the FoxD subfamily with other FoxD members from some insect and vertebrate species. Mutation in Fd59a caused swelling in the apical region of the testis. More importantly, only a few mature sperm were present in the seminal vesicle of Fd59a mutant flies compared to the control flies, and the fertility of Fd59a2/2 mutant males was significantly lower than that of the control flies. Immunofluorescence staining showed that the homeostasis of testis stem cell niche in Fd59a2/2 mutant and Fd59a RNAi flies was disrupted, and apoptosis of sperm bundles was increased. Furthermore, results from RNA-sequencing and qRT-PCR suggest that Fd59a can regulate expression of genes related to reproductive process and cell death. Taken together, our results indicated that Fd59a plays a key role in the spermatogenesis of Drosophila.

Carotid intima-media thickness (CIMT) is a surrogate indicator for atherosclerosis and has been shown to predict cardiovascular risk in multiple large studies. Identifying and characterizing molecular markers for carotid atheroma plaque formation can be critical for early intervention and prevention of atherosclerosis. This study performed transcription factor (TF) network analysis of transcriptomic data focusing on two TF genes, ZNF385D, HAND2, whose polymorphisms reportedly associate with carotid atherosclerosis. Gene expression data were measured from pieces of carotid endarterectomy of hypertensive patients each paired with one sample of distant macroscopically intact tissue. TF networks were reconstructed for ZNF385D and HAND2 and their association with carotid atheroma progression examined using gene-set enrichment analysis with high statistical significance (p<6.95e-7) suggesting involvement of expression quantitative loci (eQTL). Examination of the regulation and correlation patterns suggests high clinical and interventional impacts of the two TF genes on impairing carotid atheroma plaque formation and preventing carotid atherosclerosis.

The TGACG motif-binding factor1 (TGA1) transcription factor, a significant protein in the bZIP transcription factor family, exhibits a myriad of functions, contributes to numerous biological events, and holds substantial application potential. In this study, our analysis revealed a diverse range of photoregulatory and hormone regulatory elements within the MtTGA1 promoter region. The expression profile of MtTGA1 indicated its highest expression in the root, with its regulation influenced by SA, ABA, BR, and GA. Under salt stress conditions, transgenic plants demonstrated significantly longer root lengths and heightened activities of antioxidant enzymes such as ascorbic acid catalase (APX), peroxidase (POD), catalase (CAT), and superoxide dismutase (SOD) in their roots and leaves compared to control plants. Simultaneously, the levels of endogenous hormones ABA and BR escalated in transgenic plants, with a marked change in the morphology of their leaf cells. Transcriptome analysis identified a total of 193 differentially expressed genes, implicating a wide array of biological processes. Furthermore, we found that MtTGA1 is able to interact with Medicago truncatula SPX domain containing protein 1 (SPX1). In conclusion, the MtTGA1 transcription factor plays a crucial role in enhancing salt tolerance, which provides new insights for improving plant survival under salt stress conditions.

: Tunnel instability and lining integrity are intimately tied to the creep properties of the surrounding rock. The acquisition of rock mass creep parameters is critical in ascertaining the appropriate timing for lining construction. Nevertheless, creep tests on rock specimens conducted in a controlled setting cannot be straightforwardly extrapolated to rock mass creep analysis. This study performs laboratory-based creep tests on mudstone samples and establishes the corresponding creep constitutive model. Integration of a Mohr-Coulomb element with the Burgers model in series serves to characterise the yield creep behaviour of the rock mass. Additionally, the research outlines a series of 100 orthogonal experiments utilising randomised creep parameters, and formulates a GA-BP neural network inversion model. Employing long-term deformation measurements from the crown and sidewalls of the project site, this study deduces the creep parameters of the mudstone in the investigated tunnel section and examines the prolonged deformation traits of the surrounding rock. Drawing on the deformation traits of the surrounding rock and the forces impacting the primary support and lining structures, this paper evaluates the earliest and latest viable lining casting periods and pinpoints an optimal timing interval for lining implementation. The methodologies employed herein can serve as a benchmark for analogous endeavors internationally.

Transcription factors (TFs) and microRNAs (miRNAs) are co-actors in genome-scale decoding and regulatory networks, often targeting common genes. In this paper, we describe the algebraic geometry of both TFs and miRNAs thanks to group theory. In TFs, the generator of the group is a DNA-binding domain while, in miRNAs, the generator is the seed of the sequence. For such a generated (infinite) group $\pi$, we compute the $SL(2,\mathbb{C})$ character variety, where $SL(2,\mathbb{C})$ is simultaneously a \lq space-time' (a Lorentz group) and a \lq quantum' (a spin) group. A noteworthy result of our approach is to recognize that optimal regulation occurs when $\pi$ looks like a free group $F_r$ ($r =1$ to $3$) in the cardinality sequence of its subgroups, a result obtained in our previous papers. A non free group structure features a potential disease. A second noteworthy result is about the structure of the Groebner basis $\mathcal{G}$ of the variety. A surface with simple singularities (like the well known Cayley cubic) within $\mathcal{G}$ is a signature of a potential disease even when $G$ looks like a free group $F_r$ in its structure of subgroups. Our methods apply to groups with a generating sequence made of two to four distinct DNA/RNA bases in $\{A,T/U,G,C\}$. Several human TFs and miRNAs are investigated in detail thanks to our approach.

Promoting green development has become an important way to optimize the ecological and economic structure and promote sustainable development. The Yangtze River Economic Belt is an important economic corridor in China, and it remains to be examined whether the implementation of environmental regulations has enhanced the green total factor productivity (GTFP) of cities. This paper calculates the green total factor productivity of 107 cities within the Yangtze River Economic Belt by using the super-efficient SBM model and the GML index with Chinese city panel data from 2007-2019 and measures the intensity of environmental regulations through textual analysis. The bidirectional fixed-effects model constructed in this paper suggests an inverted U-shaped relationship between environmental regulation and GTFP, which is confirmed by a series of robustness tests. Green technology innovation and advanced industrial structure play a mechanism role in this. In regions with lower levels of green technology and industrial structure, the inverted U-shaped relationship between environmental regulation and green total factor productivity is more significant. In addition, the phenomenon of GTFP rising and then falling because of environmental regulation is more obvious in cities in the middle and upper reaches of the Yangtze River and outside the urban agglomerations. Therefore, when formulating environmental regulation policies, it is necessary to balance the relationship between economic development and environmental protection and harmonize the environment and economic development of the entire Yangtze River Basin.

Neuronal PAS domain protein 2 (NPAS2) is a hemeprotein comprising a basic helix-loop-helix domain (bHLH) and two heme-binding sites, the PAS-A and PAS-B domains. This protein acts as a pyridine nucleotide-dependent and gas-responsive CO-dependent transcription factor and is encoded by a gene whose expression fluctuates with circadian rhythmicity. NPAS2 can heterodimerize with ARNTL in the activating limb of the transcriptional/translational feedback loop operating the circadian clock circuitry. NPAS2 can functionally substitute for the core transcription factor and histone/protein acetylase CLOCK in the molecular clockwork endowing central oscillators in the suprachiasmatic nuclei of hypothalamus as well as in peripheral oscillators in the cell of other body tissues, such as the liver and kidney.

Plants are subjected to abiotic stresses throughout their developmental period. Abiotic stresses include drought, salt, heat, cold, heavy metals, nutritional element and oxidative stresses. Improving plant response to various environmental stresses is critical for plant survival and perpetuation. The WRKY transcription factors have special structure (WRKY structural domains), which enable WRKY transcription factors to have different transcriptional regulatory functions. The WRKY transcription factors can not only regulate abiotic stresses response and plant growth and development by regulating phytohormone signalling pathways, but also promote or suppress the expression of downstream genes by binding to the W-box [TGACCA/TGACCT] in the promoters of their target genes. In addition, WRKY transcription factors not only interact with other families of transcription factors to regulate plant defence responses in abiotic stresses, but also self-regulate by recognizing and binding to W-boxes in their own target genes to regulate their defence responses to abiotic stresses. However, in recent years, research reviews on the regulatory roles of WRKY transcription factors in higher plants are scarce and shallow. In this review, we focus on the structure and classification of WRKY transcription factors, as well as the identification of their downstream target genes and molecular mechanisms involved in the response to abiotic stresses, which can improve the tolerance ability of plants in abiotic stress and we also look forward to their future research directions, with a view to providing theoretical support for the genetic improvement of crop abiotic stresses tolerance.

Abiotic stress is an adverse environmental factor that severely affects plant growth and development, and plants have developed complex regulatory mechanisms to adapt to these unfavourable conditions through long-term evolution. In recent years, many transcription factor families of genes have been identified to regulate the ability of plants to respond to abiotic stresses. Among them, AP2/ERF (APETALA2/ethylene responsive factor) family is a large class of plant-specific that regulate plant response to abiotic stresses and can also play a role in regulating plant growth and development. This paper reviews the structural features and classification of AP2/ERF transcription factors, that transcriptional regulation, reciprocal proteins, downstream genes and hormone-dependent signalling and hormone-independent signalling pathways are involved in the response to abiotic stress. The study of AP2/ERF transcription factors and interacting proteins, as well as the identification of their downstream target genes, can provide us with a more comprehensive understanding of the mechanism of plant action in response to abiotic stress, which can improve the tolerance ability of plants in abiotic stress, and provide more theoretical basis for rice to obtain more yields under abiotic stress.

Large-scale hydrological modeling in China is challenging given the sparse meteorological stations and large uncertainties associated with atmospheric forcing data.Here we introduce the development and use of the China Meteorological Assimilation Driving Datasets for the SWAT model (CMADS) in the Heihe River Basin(HRB) for improving hydrologic modeling, by leveraging the datasets from the China Meteorological Administration Land Data Assimilation System (CLDAS)(including climate data from nearly 40000 area encryption stations, 2700 national automatic weather stations, FengYun (FY) 2 satellite and radar stations). CMADS uses the Space Time Multiscale Analysis System (STMAS) to fuse data based on ECWMF ambient field and ensure data accuracy. In addition, compared with CLDAS, CMADS includes relative humidity and climate data of varied resolutions to drive hydrological models such as the Soil and Water Assessment Tool (SWAT) model. Here, we compared climate data from CMADS, Climate Forecast System Reanalysis (CFSR) and traditional weather station (TWS) climate forcing data and evaluatedtheir applicability for driving large scale hydrologic modeling with SWAT. In general, CMADS has higher accuracy than CFRS when evaluated against observations at TWS; CMADS also provides spatially continuous climate field to drive distributed hydrologic models, which is an important advantage over TWS climate data, particular in regions with sparse weather stations. Therefore, SWAT model simulations driven with CMADS and TWS achieved similar performances in terms of monthly and daily stream flow simulations, and both of them outperformed CFRS. For example, for the three hydrological stations (Ying Luoxia, Qilian Mountain, and ZhaMasheke) in the HRB at the monthly and daily Nash-Sutcliffe efficiency ranges of 0.75-0.95 and 0.58-0.78, respectively, which are much higher than corresponding efficiency statistics achieved with CFSR (monthly: 0.32-0.49 and daily: 0.26 – 0.45). The CMADS dataset is available free of charge and is expected to a valuable addition to the existing climate reanalysis datasets for deriving distributed hydrologic modeling in China and other countries in East Asia.

Akebia trifoliata is an economically important self-incompatible fruit tree in the family Lardiza-balaceae. Asexual propagation is the main strategy used to maintain excellent agronomic traits. However, the generation of adventitious roots during asexual propagation is very difficult. To study the important role of the WUSCHEL-related homeobox (WOX) transcription factor in fruit and adventitious root growth and development, we characterized this transcription factor family in the whole genome of A. trifoliata. A total of 10 AktWOXs were identified, with the fol-lowing characteristics: length (657~11328 bp), exon number (2~5), isoelectric point (5.65~9.03), amino acid number (176~361 AA), and molecular weight (20.500~40.173 kDa). 10 AktWOXs were classified into modern (6), intermediate (2), and ancient clades (2) and that all AktWOXs had undergone strong purifying selection during evolution. The expression profile of AktWOXs dur-ing A. trifoliata fruit development and adventitious root formation indicated that AktWOXs are widely involved in the development of the three fruit tissues, flesh, seeds and rind, and play an important role in the regulation of adventitious root development. Overall, this is the first study to identify and characterize the WOX family in A. trifoliata and will be helpful for further re-search on A. trifoliata fruit development and adventitious root formation.

Cyclic STAT3 decoy (CS3D) is a second-generation, double-stranded oligodeoxynucleotide (ODN) that mimics a genomic response element for signal transducer and activator of transcription 3 (STAT3), an oncogenic transcription factor. CS3D competitively inhibits STAT3 binding to target gene promoters, resulting in decreased expression of proteins that promote cellular proliferation and survival. Previous studies have demonstrated antitumor activity of CS3D in preclinical models of solid tumors. However, prior to entering human clinical trials, the efficiency of generating the CS3D molecule and its stability in biological fluids should be determined. CS3D is synthesized as a single-stranded ODN and must have its free ends ligated to generate the final cyclic form. In this study, we report a ligation efficiency of nearly 95 percent. The ligated CS3D demonstrated a half-life of 7.9 hours in human serum, indicating adequate stability for intravenous delivery. These results provide requisite biochemical characterization of CS3D that will inform upcoming clinical trials.

Iris laevigata Fisch. is a perennial aquatic plant with strong cold resistance and showy flowers. However, the flowering period of a single flower is only two days, greatly limiting its potential use in landscaping and the cutting-flower industry. In addition, I. laevigata is often challenged with various abiotic stresses including high salinity and drought in its native habitat. Thus, breeding novel cultivars with prolonged flowering time and higher resistance to abiotic stress is of high importance. In this study, we first performed genome-wide identification of WRKYs, key transcription factors in modulating flowering time and abiotic stress responses. We overexpressed IlWRKY22 in Arabidopsis thaliana and found the flowering time was delayed in the transgenic plants. Molecular characterization further revealed that IlWRKY22 promotes the expression of CO and GA20OX genes in the photoperiod and gibberellin pathways, respectively, and inhibits the expression of SPL3 in the aging pathway. We also created transgenic Nicotiana tabacum overexpressing IlWRKY22, which showed significantly improved resistance to both salt and drought compared to control plants. Specifically, the photosynthetic rate, maximum potential quantum efficiency of Photosystem II (Fv/Fm), and chlorophyll content were higher in the transgenic plants, which was accompanied with higher antioxidant enzyme activity and lower levels of reactive oxygen species. Thus, our study revealed a unique dual function of IlWRKY22, an excellent candidate gene for breeding novel I. laevigata cultivars of desirable traits.

The FTF (Fusarium Transcription Factor) gene family is composed of two members (FTF1 and FTF2) with high sequence homology. Both genes encode Zn(II)2Cys6 binuclear zinc finger transcription factors involved in the modulation of virulence in the F. oxysporum species complex (FOSC). While FTF1 is a multicopy gene exclusive of highly virulent strains of FOSC and is located in the accessory genome, FTF2 is a single copy gene, located in the core genome, and well conserved in all filamentous ascomycete fungi, except yeast. The involvement of FTF1 in the colonization of the vascular system and regulation of the expression of SIX effectors has been stablished. To address the role of FTF2 we generated and characterized null FTF2 mutants in a F. oxysporum f. sp. phaseoli weakly virulent strain and analyzed them together with the equivalent mutants formerly obtained in a highly virulent strain. The results obtained highlight a role for FTF2 as a negative regulator of the production of macroconidia and demonstrate that it is required for full virulence and positive regulation of SIX effectors. In addition, gene expression analyses provide compelling evidence that FTF2 is involved in the regulation of hydrophobins likely required for plant colonization.

Understanding the biology underlying the mechanisms and pathways regulating pancreatic β-cell development is necessary to understand the pathology of diabetes mellitus (DM), which is characterized by the progressive reduction in insulin producing β-cell mass. Pluripotent stem cells (PSCs) can potentially offer an unlimited supply of functional β-cells for cellular therapy and disease modeling of DM. Homeobox protein NKX6.1 is a transcription factor (TF) that plays a critical role in pancreatic β-cell function and proliferation. In human pancreatic islet, NKX6.1 expression is exclusive toβ-cells and is undetectable in other islet cells. Several reports showed that activation of NKX6.1 in PSC-derived pancreatic progenitors (MPCs), expressing PDX1 (PDX1⁺/NKX6.1⁺), warrants their future commitment to monohormonal β-cells. However, further differentiation of MPCs lacking NKX6.1 expression (PDX1⁺/NKX6.1^-) results in an undesirable generation of non-functional polyhormonal β-cells. The importance of NKX6.1 as a crucial regulator in MPC specification into functional β-cells directs attentions to further investigating its mechanism and enhancing NKX6.1 expression as a mean to increase β-cell function and mass. Here, we shed light on the role of NKX6.1 during pancreatic β-cell development and in directing the MPCs to functional monohormonal lineage. Furthermore, we address the transcriptional mechanisms and targets of NKX6.1 as well as its association with diabetes.

Cell autonomous circadian oscillation is present in central and various peripheral tissues. The intrinsic tissue clock and various extrinsic cues drive gene expression rhythms. Transcription regulation is thought to be the main driving force for gene rhythms. However, how transcription rhythms arise remains to be fully characterized, due to the fact that transcription is regulated at multiple steps. In particular, Pol II recruitment and pause release are two critical regulatory steps that determine the status of Pol II pausing. Recently, we showed that Pol II pausing exhibits genomewide changes during daily transcription in mouse liver. In this article, we review historical as well as recent findings on the regulation of transcription rhythms. We also discuss the possible mechanisms for daily changes in Pol II pausing and the critical involvement of Pol II pausing regulation in generating rhythmic transcription output.

Members of the SOX (SRY-related HMG-box) family of transcription factors are crucial for embryonic development and cell fate determination. This review investigates the role of SOX3 in cancer, as aberrations in SOX3 expression have been implicated in several cancers, including osteosarcoma, breast, esophageal, endometrial, ovarian, gastric, hepatocellular carcinomas, glioblastoma, and leukemia. These dysregulations modulate key cancer outcomes such as apoptosis, epithelial-mesenchymal transition (EMT), invasion, migration, cell cycle, and proliferation, contributing to cancer development. SOX3 exhibits varied expression patterns correlated with clinicopathological parameters in diverse tumor types. This review aims to elucidate the nuanced role of SOX3 in tumorigenesis, correlating its expression with clinical and pathological characteristics in cancer patients and cellular models. By providing a comprehensive exploration of SOX3 involvement in cancer, this review underscores the multifaceted role of SOX3 across distinct tumor types. The complexity uncovered in SOX3 function emphasizes the need for further research to unravel its full potential in cancer therapeutics.

Cellular Integrated Stress Response (ISR), the mitochondrial Unfolded Protein Response (UP-Rmt) and the IFN signaling are associated with viral infections. The Activating transcription fac-tor 4 (ATF4) plays a pivotal role in these pathways and controls the expression of many genes involved in redox processes, amino acid metabolism, protein misfolding, autophagy and apop-tosis. The precise role of ATF4 during viral infection is unclear and depends on cell hosts, viral agents and models. Furthermore, ATF4 signaling can be hijacked by pathogens to favor viral in-fection and replication. In this review, we summarize the ATF4-mediated signaling pathways in response to viral infections, focusing on human immunodeficiency virus (HIV). We examine the consequences of ATF4 activation for HIV replication and reactivation. The role of ATF4 in au-tophagy and apoptosis is explored as in the context of HIV infection programmed cell deaths contribute to the depletion of CD4 T cells. Furthermore, ATF4 can also participate in the estab-lishment of innate and adaptive immunity that are essential for the host to control viral infec-tions. We finally discuss the putative role of the ATF4 paralogue, named ATF5, in HIV infection. This review underlines the role of ATF4 at the crossroads of multiple processes reflecting host-pathogen interactions.

The Apetala2/ethylene response factor superfamily refers to a group of transcription factors that share a conserved AP2 DNA binding domain. These factors have been found to have different roles in plant responses to both biotic and abiotic stresses. Samples of hexaploid wheat, tetraploid pasta (or durum wheat), and diploid wheat progenitors were selected. The 29 dehydration-responsive element binding transcription factors in these samples were downloaded from NCBI GenBank for six different countries: Iran, China, Italy, France, Afghanistan, and Azerbaijan. The AP2 domain sequences were identified from the dehydration-responsive element binding transcription factors using PROSITE, ProDom, and SMART software. Next, all sequences were aligned using Multalin and Jalview software. The aligned sequences were then analyzed to identify amino acid locations, types, and frequencies. The multiple alignments showed that approximately 76% of the amino acid residues in the AP2 domains are conserved. According to the amino acid analysis, alanine, serine, and glutamic acid are the most abundant amino acids found in three motifs. The performed phylogenetic analysis illustrates the role of geographical effects on the transcription factor sequences of bread wheat in the Middle East. Significant differences were found between Iranian and Chinese transcription factor sequences. Moreover, genetic variation was observed in the transcription factors of Italian sequences found in pasta and wheat progenitors. Motif structures play a critical role in the domain organization of wheat proteins to enhance the characteristics of assorted metabolic pathways. The structure of the AP2 domain was analyzed by several programs, I-TASSER for instance, to identify the α-helix, β-sheets, and the regions of some significant amino acids in the 3-D model.

The early 2-factor (E2F) family of transcription factors, including E2F1-8, plays a critical role in apoptosis, metabolism, proliferation, and angiogenesis within glioblastoma (GBM). However, the specific functions of E2F transcription factors (E2Fs) and their impact on the malignancy of Bevacizumab (BVZ)-responsive GBM subtypes remain unclear. This study used data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to explore the impact of eight E2F family members on the clinical characteristics of BVZ-responsive GBM subtypes and possible mechanisms of recurrence after BVZ treatment.To predict the possibility of GBM patient survival and progression, we classified and comparedthe expression of E2Fs according to BVZ-responsive subtypes and employed a machine learning method-TreeBagger, one random forest algorithm. Multiple bioinformatics analyses have shown that the significant increased E2F8 post BVZ treatment may enhance the function of angiogenesis and stem cell proliferation, indicating one of the mechanisms of GBM recurrence after treatment. In addition, BVZ treatment in unresponsive GBM patients may potentially worsen disease progression. Our findings suggest that E2F family members play important roles in GBM malignancy and BVZ treatment response, highlighting their potential as prognostic biomarkers and therapeutic targets and recommending precise BVZ treatment for GBM patients.

The limited information available on the structure of complexes involving transcription factors and cognate DNA response elements represents a major obstacle in the quest to understand their mechanism of action at the molecular level. We implemented a concerted structural proteomics approach, which combined hydrogen-deuterium exchange (HDX), quantitative protein-protein and protein-nucleic acid cross-linking (XL), and homology analysis, to model the structure of the complex between the full-length DNA binding domain (DBD) of FOXO4 and its DNA binding element (DBE). The results confirmed that FOXO4-DBD assumes the characteristic forkhead topology shared by these types of transcription factors, but its binding mode differs significantly from those of other members of the family. The results showed that the binding interaction stabilized regions that were rather flexible and disordered in the unbound form. Surprisingly, the conformational effects were not limited only to the interface between bound components but extended also to distal regions that may be essential to recruiting additional factors to the transcription machinery. In addition to providing valuable new insights into the binding mechanism, this project provided an excellent evaluation of the merits of structural proteomics approaches in the investigation of systems that arematerial not directly amenable to traditional high-resolution techniques.

Type-2 diabetes mellitus (T2DM) have been strongly associated with single nucleotide polymorphisms (SNPs) in the TCF7L2 gene. This study investigated the association between rs12255372, rs7903146 and T2DM in a Ghanaian population. A case-control study design was used for this study. A total of 106 T2DM patients and 110 control participants were selected. Basic data collected included body mass index, blood pressure and socio-demographics. Fasting blood samples were collected and used for serum lipid analysis, HbA1c, plasma glucose estimation and DNA extraction. Common and allele-specific primers were designed for genotyping using the Modified Tetra-Primer Amplification assay. Associations were evaluated using logistic regression models. The rs7903146 risk variant was significantly associated with 2.16 vs 4.06 increased odds for T2DM in patients <60 years vs ≥60 years. Both rs7903146 and rs12255372 are significantly associated with increased odds of T2DM in women, overweight/obese; T2DM negative family history (T2DM-NFH) and low-HDL-C. In a multivariate model, rs7903146 but not rs12255372 was significantly associated with 2.18, 5.01 and 2.25 increased odds of T2DM, under the codominant, recessive and additive model, respectively (p<0.05). The association between rs7903146 and rs12255372 with T2DM is more highly associated in a subgroup- women and those with T2DM-NFH, yet have cardiometabolic risk.

Trophoblasts are the first cell-type to be specified during embryogenesis, and they are essential for placental morphogenesis and function. Trophoblast stem (TS) cells are the progenitor cells for all trophoblast lineages; control of TS cell differentiation into distinct trophoblast subtypes is not well understood. Mice lacking the transcription factor OVO-like 2 (OVOL2) fail to produce a functioning placenta, and die around embryonic day 10.5, suggesting that OVOL2 may be critical for trophoblast development. Therefore, our objective was to determine the role of OVOL2 in mouse TS cell fate. We found that OVOL2 was highly expressed in mouse placenta and differentiating TS cells. Placentas and TS cells lacking OVOL2 showed poor trophoblast differentiation potential, including increased expression of stem-state associated genes (Eomes, Esrrb, Id2) and decreased levels of differentiation-associated transcripts (Gcm1, Tpbpa, Prl3b1, Syna). Ectopic OVOL2 expression in TS cells elicited precocious differentiation. OVOL2 bound proximate to the gene encoding inhibitor of differentiation 2 (ID2), a dominant negative helix-loop-helix protein, and directly repressed its activity. Overexpression of ID2 was sufficient to reinforce the TS cell stem state. Our findings reveal a critical role of OVOL2 as a regulator of TS cell differentiation and placental development, in-part by coordinating repression of ID2.

Discovery of inhibitors for endothelial-related transcription factors can contribute to the development of angiogenic therapies that treat diseases ranging from cardiovascular to cancer. The role of transcription factor Vezf1 in vascular development and regulation of angiogenesis has been defined by several earlier studies. Through construction of a computational model for Vezf1, work here has identified a novel small molecule drug capable of inhibiting Vezf1 from binding to its cognate DNA binding site. Using structure-based design and virtual screening of the NCI Diversity Compound Library, 12 shortlisted compounds were tested for their ability to interfere with the binding of Vezf1 to DNA using electrophoretic gel mobility shift assays. We identified one compound, T4, which has an IC50 of 20uM. Using murine endothelial cells, MSS31, we tested the effect of T4 on endothelial cell viability and angiogenesis by using tube formation assay. Our data show that addition of T4 in cell culture medium does not affect cell viability at concentrations lower or equal to its IC 50 but strongly inhibits the network formation by MSS31 in the tube formation assays. Given its potential efficacy, this inhibitor has significant therapeutic potential in several human diseases raging from wound healing to cancer.

The 2-Acetyl-1-pyrroline (2-AP) is the most important volatile in determining the aroma of fragrant rice, however, the transcriptional regulation mechanism of 2-AP biosynthesis in fragrant rice is still unclear. In this study, the Osp5cs1 knockout mutant lines and OsP5CS1 over-expression lines were constructed by genetic transformation of indica rice cultivar i.e., ‘Zhonghua11’, which was knocked out OsBADH2 to produce fragrance in aromatic rice. The OsP5CS1 gene was also identified as a key gene in the 2-AP biosynthesis pathway of aromatic rice. The OsP5CS1 promoter was used as bait, and the transcription factor OsbZIP60-like was screened by yeast one-hybrid assays. The transcription factor OsbZIP60-like specifically bound to the OsP5CS1 gene. The dual luciferase reporting system found that OsbZIP60-like transcription factor promoted the transcriptional activation of OsP5CS1. Compared with the wild type, the OsP5CS1 gene expression was significantly down-regulated in Osbzip60-like mutant, and resulted in substantial reduction in 2-AP biosynthesis. Moreover, the OsP5CS1 gene expression was significantly up-regulated in OsbZIP60-like over-expressed plants, and the 2-AP concentrations were also increased whereas the Osbzip60-like mutants were found to be sensitive to Zn deficiency. Overall, the OsbZIP60-like transcription factor promoted the 2-AP accumulation. This study provides a theoretical basis for the transcriptional regulation mechanism of 2-AP biosynthesis and explores the function of OsbZIP transcription factor in fragrant rice.

The Myb family of transcription factors (TFs) is a large and functionally diverse group found in all eukaryotes, but its role in fungi remains poorly understood. Here, we characterized a Myb family TF called MoMyb13 in the rice blast fungus, Magnaporthe oryzae. MoMyb13 has two Myb domains and has orthologues only in ascomycete fungi. Localization experiments confirmed that MoMyb13 is located in the nuclei, as expected for a TF. Phenotypic analysis showed that MoMyb13 mutants exhibited reduced growth, whitened colony appearance and no conidia formation. Importantly, these mutants completely lost pathogenicity, despite being able to form appressoria at their hyphae ends, suggesting that these appressoria were non-functional for causing infection. Furthermore, the mutant colonies lost hydrophobicity and had significantly reduced expression of the hydrophobin MPG1. However, overexpression of MPG1 in the mutants restored their hydrophobicity, but not pathogenicity. Stress assay showed that the mutants were more sensitive to SDS, CR and H2O2, but more tolerant to NaCl and SOR. In summary, our study revealed the essential role of the MoMyb13 in the growth, conidiation, hydrophobicity, stress response and pathogenicity of M. oryzae, and provides valuable insights into the working mechanism of Myb TFs in fungi.

Transcription factors (TFs) are crucial in modulating gene expression and sculpting cellular and organismal phenotypes. The identification of TF-target gene interactions is pivotal for comprehending molecular pathways and disease etiologies but has been hindered by the demanding nature of traditional experimental approaches. This paper introduces a novel web application, utilizing the R programming language, which predicts TF-target gene relationships and vice versa. Our application integrates the predictive power of various bioinformatic tools, leveraging their combined strengths to provide robust predictions. It merges databases for enhanced precision, incorporates gene expression correlation for accuracy, and employs pan-tissue correlation analysis for context-specific insights. The application also enables the integration of user data with established resources to analyze TF-target gene networks. Despite its current limitation to human data, it provides a platform for exploring gene regulatory mechanisms comprehensively. This integrated, systematic approach offers researchers an invaluable tool for dissecting the complexities of gene regulation, with the potential for future expansions to include a broader range of species.

Aspalathin, a C-glucosyl dihydrochalcone, has previously been shown to protect cardiomyocytes against hyperglycemia-induced shifts in substrate preference and subsequent apoptosis. However, the precise gene regulatory network remains to be elucidated. To unravel the mechanism and provide insight into this supposition, the direct effect of aspalathin in an isolated cell-based system, without the influence of any variables, was tested using an H9c2 cardiomyocytes model. Cardiomyocytes were exposed to high glucose (33 mM) for 48 hours before post-treatment with or without aspalathin. Thereafter, RNA was extracted and RT2 PCR Profiler Arrays were used to profile the expression of 336 genes. Results showed that, 57 genes were differentially regulated in the high glucose or high glucose and aspalathin treated groups. STRING analysis revealed lipid metabolism and molecular transport as the biological processes altered after high glucose treatment, followed by inflammation and apoptosis. Aspalathin was able to modulate key regulators associated with lipid metabolism (Adipoq, Apob, Cd36, Cpt1, Pparγ, Srebf1/2, Scd1 and Vldlr), insulin resistance (Igf1, Akt1, Pde3 and Map2k1), inflammation (Il3, Il6, Jak2, Lepr, Socs3, and Tnf13) and apoptosis (Bcl2 and Chuk). Collectively, our results propose that aspalathin could reverse metabolic abnormalities by activating Adipoq while modulating the expression of Pparγ and Srebf1/2, decreasing inflammation via Il6/Jak2 pathway, which together with an observed increased expression of Bcl2 prevents myocardium apoptosis.

Transcription factors (TFs) are the regulatory proteins that act as molecular switches in controlling stress responsive gene expression. Among them MYB transcription factor family is one of the largest TF family in plants, playing a significant role in plant growth, development, phytohormone signaling and stress-responsive processes. Pearl millet (Pennisetum glaucum L.) is one of the most important C4 crop plant of the arid and semi-arid regions of Africa and South-east Asia for sustaining food and fodder productions. To explore the evolutionary mechanism and functional diversity of the MYB family in pearl millet, we conducted a comprehensive genome-wide survey and identified 279 MYB TFs (PgMYB) in pearl millet and distributed unevenly across seven chromosomes of pearl millet. Phylogenetic analysis of identified PgMYBs classified them into 18 subgroups and members of the same group showed a similar gene structure and conserved motif/s pattern. Further, duplication events were identified in pearl millet that indicated towards evolutionary progression and expansion of the MYB family. Transcriptome data and relative expression analysis by qRT-PCR identified differentially expressed candidate PgMYBs (PgMYB2, PgMYB9, PgMYB88 and PgMYB151) under dehydration, salinity, heat and phytohormones (ABA, SA and MeJA) treatment. Taken together, this study provides valuable information for a prospective functional characterization of MYB family members of pearl millet and genetic improvement of crop plants.

The sexual reproduction of ascomycetes is controlled by the mating-type(MAT) locus. (Pseudo)homothallic reproduction has been hypothesized based on genetic data from Hirsutella sinensis (Genotype #1 of Ophiocordyceps sinensis). In this study, the differential occurrence of the mating-type genes in the MAT1-1 and MAT1-2 idiomorphs, which constitute the genetic control of O. sinensis reproduction, was analyzed in 237 strains and 5 genomes of H. sinensis. The mating-type genes were differentially transcribed in H. sinensis Strain L0106, and the MAT1-2-1 transcript in H. sinensis Strain 1229 was alternatively spliced, with an unspliced intron I containing stop codons; these findings constitute O. sinensis reproduction controls at the transcriptional and coupled transcriptional-translational levels. The occurrence of the mating-type genes and a-/α-pheromone receptor genes differed among the 5 H. sinensis genomes. The differential occurrence and transcription of these genes are inconsistent with self-fertilization under (pseudo)homothallism but suggest self-sterility of H. sinensis, which therefore needs a mating partner to achieve sexual outcrossing under heterothallism or hybridization. Consistent occurrence and transcription of the mating-type genes of both the MAT1-1 and MAT1-2 idiomorphs have been reported in natural and cultivated Cordyceps sinensis, but these findings are insufficient to determine the reproduction mode(s) because of the co-occurrence of >90 fungal species and multiple genomically independent genotypes of O. sinensis. The mutant MAT1-1-1 and α-pheromone receptor transcripts in natural C. sinensis result in the N-terminus or middle-truncated proteins, with changes in hydrophobicity and secondary structures of the proteins, suggesting heterogeneous fungal source(s) of the proteins and hybridization reproduction.

Nowadays the relationship between planning land use and actual land use is not so clear in general. A lot of efforts have been put in the failures of regulation for the expansion of construction land. However, it still lacks an integrated approach to study the effectiveness of land use regulation in terms of different land use types. Furthermore, the existing evaluation of land use plan mainly focuses on a general level, a detailed research on the regulation effectiveness of each construction land use type is absent. Therefore, this research tries to evaluate regulation effectiveness of land use plan, which takes Cangwu country, Guangxi Province as an example. The finding by analysis is that the total area of construction land expansion was about 3494.73 ha, nearly 1.1 times of the plan quota. Moreover, the effectiveness differs greatly in various construction land use types. Town, industrial/mining sites can be well regulated through the quota of land use plan. While, the quota regulation system is not as effective for other type of construction land. Thus, we suggest to improve the regulation effectiveness of construction land through different plan instruments.

Background: Transcription factors (TFs) are main regulators of eukaryotic gene expression. The cooperative binding to genomic DNA of at least two TFs is the widespread mechanism of transcription regulation. Cooperating TFs can be revealed through the analysis of co-occurrence of their motifs. Methods: We applied Motifs Co-Occurrence Tool (MCOT) that predicted pairs of spaced or overlapped motifs (composite elements, CEs) for a single ChIP-seq dataset. We improved MCOT capability for prediction of asymmetric CEs with one of participating motifs possessing higher conservation than another does. Results: Analysis of 119 ChIP-seq datasets for 45 human TFs revealed that almost for all families of TFs the co-occurrence with an overlap between motifs of target TFs and more conserved partner motifs was significantly higher than that for less conserved partner motifs. The asymmetry toward partner TFs was the most clear for partner motifs of TFs from ETS family. Conclusion: Co-occurrence with an overlap of less conserved motif of a target TF and more conserved motifs of partner TFs explained a substantial portion of ChIP-seq data lacking conserved motifs of target TFs. Among other TF families, conservative motifs of TFs from ETS family were the most prone to mediate interaction of target TFs with its weak motifs in ChIP-seq.

Endothelial cell (EC) injury is a crucial contributor to progression of diabetic kidney disease (DKD), but the specific EC populations and mechanisms involved remain elusive. Kidney ECs (n=5,464) were collected at 3 timepoints from diabetic BTBRob/ob mice and non-diabetic littermates. Their heterogeneity, transcriptional changes, and alternative splicing during DKD progression were mapped using SmartSeq2 single-cell RNA sequencing (scRNAseq) and elucidated by pathway, network, and gene ontology enrichment analyses. We identified 13 distinct transcriptional EC phenotypes corresponding to different kidney vessel subtypes, confirmed by in-situ hybridization and immunofluorescence. EC subtypes along nephrons displayed extensive zonation related to their functions. Differential gene expression analyses in peritubular and glomerular EC in DKD underlined regulation of DKD-relevant pathways including EIF2 signaling, oxidative phosphorylation, and IGF1 signaling. Importantly, it revealed differential alteration of these pathways between the two EC subtypes and changes during disease progression. Furthermore, glomerular and peritubular EC also displayed aberrant and dynamic alteration of al-ternative splicing (AS), strongly associated with DNA repair. Strikingly, genes displaying differential transcription or alternative splicing participate in divergent biological processes. Our study reveals spatiotemporal regulation of gene transcription and AS linked to DKD progression, providing insight into pathomechanisms and clues to novel therapeutic targets for DKD treatment.

The calmodulin-binding transcription activators (CAMTAs) mediate transcriptional regulation of development, growth, and responses to various environmental stresses in plants. To characterize the biological processes of soybean CAMTA (GmCAMTA) family members in response to abiotic stress, we identified 15 GmCAMTA genes from soybean (Glycine max L.) and investigated their roles in the abiotic stress response. The transcriptions of GmCAMTAs exhibited distinct circadian regulation patterns and were expressed differently in response to salt, drought, and cold stresses, except ABA. Interestingly, the expression levels of GmCAMTA2, GmCAMTA8, and GmCAMTA12 were higher in stem tissue than in other soybean tissues. To determine the roles of GmCAMTAs in the regulation of developmental processes and stress responses, we isolated GmCAMTA2 and GmCAMTA8 cDNAs from soybean and generated Arabidopsis overexpressing transgenic plants. The GmCAMTA2-OX and GmCAMTA8-OX plants showed hypersensitivity to drought stress. The water in the leaves of GmCAMTA2-OX and GmCAMTA8-OX plants was lost faster than that in WT plants under drought stress conditions. In addition, stress-responsive genes in the GmCAMTA2-OX and GmCAMTA8-OX plants were down-regulated under drought stress conditions. Our results suggest that GmCAMTA2 and GmCAMTA8 genes are regulated by circadian rhythms and function as negative regulators in development and drought stress responses.

Background: Epithelial-mesenchymal transition (EMT) is a biological process where epithelial cells lose their adhesive properties and gain invasive, metastatic, and mesenchymal properties. Maintaining the balance between epithelial and mesenchymal stage is essential for tissue homeo-stasis. Many of the genes promoting mesenchymal transformation has been identified; however, our understanding of the genes responsible for maintaining the epithelial phenotype is limited. Our objective was to identify genes responsible for maintaining the epithelial phenotype and in-hibiting EMT. Methods: RNA seq was performed using an vitro model of EMT. CTGF expres-sion was determined by qPCR and Western blot analysis. Knockout of CTGF was done using the CTGF sgRNA CRISPR/CAS9. Tumorigenic potential was determined using NCG mice. Results: Knocked-out of CTGF in epithelial ovarian cancer cells leads to the acquisition of functional characteristics associated with the mesenchymal phenotype such as Anoikis resistance, cytoskel-eton remodeling, increased cell stiffness, and acquisition of invasion and tumorigenic capacity. Conclusions: We identified CTGF is an important regulator of the epithelial phenotype, and its loss is associated with early cellular modifications required for EMT. We describe a novel role for CTGF, regulating cytoskeleton and the extracellular matrix interactions necessary for conserva-tion of epithelial structure and function. These findings provide a new window to understand the early stages on mesenchymal transformation

Sesame seeds are abundant in sesamin, which exerts health-promoting effects such as extending the lifespan of adult Drosophila and suppression of oxidative stress accumulation by activating the Nrf2 transcription factor. Here, we investigated whether sesamin activated Nrf2 in larval tissues and induced the expression of Nrf2 target genes. In sesamin-fed larvae, Nrf2 was activated in the central nervous system (CNS), gut, and salivary glands. However, ectopic expression of Keap1 (Nrf2 inhibitor) in glial cells inhibited sesamin-induced Nrf2 activation in all tissues except in the neurons, indicating that sesamin activates Nrf2 in glia. We labeled the astrocytes as well as cortex and surface glia with red fluorescence to identify these glial cell types in which Nrf2 was activated; we observed their activation in both cell types. These data suggest that sesamin may stimulate the expression of antioxidative genes in glial cells. Among the 17 candidate Nrf2 targets, the mRNA levels of Cyp6a2 and Cyp6g1 in cytochrome P450 were elevated in the CNS, gut, and salivary glands of sesamin-fed larvae. However, this did not lead to resistance against imidacloprid, which is detoxified by these enzymes. Our results suggest that sesamin may exert similar health-promoting effects on the human CNS and digestive tissues.

Corynebacterium glutamicum is a Gram-positive bacterium found in soil where the condition changes demand plasticity of the regulatory interactions, which study at the global scale has been challenged by the lack of data integration. Here, we update the manually-curated C. glutamicum transcriptional regulatory network, now including protein-protein interactions having a direct effect on gene transcription. The network model with regulations supported by any experimental evidence increased by 557 interactions regarding the previous (2018) version. 73 interactions supported by directed experiments were also included in a second model. We included 545 sRNA-mediated regulations in a third model with a total of 5164 interactions. We deposited the three network models in Abasy Atlas v2.4. We study the C. glutamicum regulatory structure by comparing it against the networks for more than 40 species, finding it to contrast in several global structural properties. We analyze the system-level components of the networks, finding that the inclusion of the sRNAs regulations changes their proportions, transferring part of the basal machinery to the modular class and increasing the number of modules while decreasing their size. Finally, we use strong networks of three model organisms to provide insights in future directions of the C. glutamicum network characterization.

The p53 tumor suppressor protein shows antiviral activity. The replication of viruses is also antagonized by interferons (IFNs) – cytokines, which control immunity genes by the STAT transcription factors. The best studied interferons belong to type I (e.g. IFNα) and type II (IFNγ) groups. IFNα and IFNγ both induce activating phosphorylation of STAT1 on Tyr701. Previously, we noticed that p53 activates SOCS1, which is a negative regulator of STAT1 phosphorylation. Thus, we hypothesized that p53 by activating SOCS1 expression reduces phosphorylation of STAT1 and attenuates activation of genes stimulated either by IFNα or IFNγ. To test this hypothesis, we exposed p53-proficient and p53-deficient cells to strong p53 activators, and either to IFNα or IFNγ. Subsequently, we estimated the phosphorylation status of STAT1 and the expression of genes regulated by either of these cytokines. Strong activation of p53 reduced the phosphorylation of STAT1 on Tyr701, however surprisingly it did not lead to reduced expression of most tested interferon-stimulated genes. On contrary, p53 and IFNγ synergized in the activation of CASP1, IFIT1 and IFIT3 genes. We conclude that the interactions between p53 and interferon-activated pathways are more complicated than initially expected, but the apparent cooperation between p53 and IFNγ deserves further studies.

The p53 tumor suppressor protein is an activator of transcription. Diverse stress factors lead to various sets of posttranslational modifications of p53 what results in different sets of upregulat-ed genes. We noticed that actinomycin D and nutlin-3a (A+N) synergize in inducing activating phosphorylations of p53 and upregulation of selected p53-target genes. Here we found that one of these genes is DUSP13, which codes for poorly-studied, dual-specificity phosphatase having at least two isoforms, one expressed in testis and the other in skeletal muscles. In cancer cells ex-posed to A+N, DUSP13 is expressed from an alternative promoter in intron, what results in ex-pression of isoform named TMDP-L1. The luciferase reporter tests demonstrated that this pro-moter is activated by both endogenous and ectopically expressed p53. We showed for the first time that mRNA expressed from this promoter actually produces the protein, which can be de-tected by Western blotting in all examined cancer cell lines with wild-type p53 exposed to A+N. In some cell lines it is also induced by clinically relevant camptothecin or by nutlin-3a acting alone. This isoform, fused with green fluorescent protein localizes in perinuclear region of cells. Thus, TMDP-L1 isoform may be an important element of p53-regulated stress response system.

Chronic inflammatory diseases are considered the most significant cause of death worldwide. Current treatments for inflammatory diseases are limited due to the lack of understanding of the biological factors involved in early-stage disease progression. Nerve growth factor (NGF) is a neurotrophic factor directly associated with inflammatory and autoimmune diseases like osteoarthritis, multiple sclerosis, and rheumatoid arthritis. It has been shown that NGF levels are significantly upregulated at the site of inflammation and play a crucial role in developing a robust inflammatory response. However, little is known about NGF's temporal expression profile during the initial progressive phase of inflammation. This study aimed to determine the temporal expression pattern of NGF in rat skin during Adjuvant-Induced Arthritis (AIA). Sprague Dawley rats were randomly divided into control and Complete Freund's Adjuvant (CFA) treated groups. Levels of NGF were evaluated following unilateral AIA at different time points and it was found that peripheral inflammation due to AIA significantly upregulated the expression of NGF mRNA and Protein in a biphasic pattern. These results suggest that NGF signaling is crucial for initiating and maintaining peripheral neurogenic inflammation in rats during AIA.

The positional cloning of single nucleotide polymorphisms (SNPs) of the neutrophil cytosolic factor 1 (Ncf1) gene, advocating that a low oxidative burst drives autoimmune disease, demands an understanding of the underlying molecular causes. A cellular target could be T cells, which have been shown to be regulated by reactive oxygen species (ROS). However, the pathways by which ROS mediate T cell signaling remain unclear. The adaptor molecule linker for activation of T cells (LAT) is essential for coupling T cell receptor-mediated antigen recognition to downstream responses, and it contains several cysteine residues that have previously been suggested to be involved in redox regulation. To address the possibility that ROS regulate T cell-dependent inflammation through LAT, we established a mouse strain with cysteine-to-serine mutations at positions 120 and 172 (LATSS). We found that redox regulation of LAT through C120 and C172 mediate its localization and phosphorylation. LATSS mice had reduced numbers of double-positive thymocytes and naïve peripheral T cells. Importantly, redox insensitivity of LAT enhanced T cell-dependent autoimmune inflammation in collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis (RA). This effect was reversed on an NCF1-mutated (NCF1m1j), ROS-deficient, background. Overall, our data shows that LAT is redox-regulated, acts to repress T cell activation, and is targeted by ROS induced by NCF1 in antigen-presenting cells (APCs).

FoxP3 is a transcription factor essential for the differentiation and function of T regulatory cells (Tregs). There are two major subsets of Tregs: natural Tregs (nTregs) generated in thymus and inducible Tregs (iTregs) produced in peripheral immune system. It has been documented that iTreg development is dependent on soluble mediators including interleukin 2 (IL2), transforming growth factor β (TGFβ) and all-trans-retinoic acid (ATRA). In our experiments we performed a gene expression array, followed by Real-time PCR experiments, to study the expression of genes regulated by 1,25-dihydroxyvitamin D (1,25D) or ATRA in cells of myeloid origin. Our experiments revealed that ATRA alone, but also a cocktail of mediators consisting of IL2, TGFβ and ATRA, upregulate the expression of FOXP3 gene in lymphoid cells, but also in normal and leukemic myeloid cells. The FoxP3 expression is followed by a phenotypic changes in cells of myeloid origin. Our results indicate that signaling pathways which are used in the late stages of T cell differentiation, are also active in the cells of myeloid lineage

Heat shock transcription factors (HSFs) participate in regulating many environmental stress responses and biological processes in plants. Maize (Zea mays L.) is a major cash crop that is grown worldwide. However, the growth and yield of maize are affected by several adverse environmental inputs. Therefore, investigating the factors that regulate maize growth and development and resistance to abiotic stress is an essential task for developing stress-resilient maize varieties. Thus, a comprehensive genome-wide identification analysis was performed to identify HSFs in the maize genome. The current study identified 25 ZmHSFs, randomly distributed throughout the maize genome. Phylogenetic analysis revealed that ZmHSFs are divided into three classes and 13 sub-classes. Gene structure and protein motif analysis supported the results obtained through the phylogenetic analysis. Domain analysis showed the DNA-binding domain to be the most conserved region of ZmHSFs. Segmental duplication is shown to be responsible for the expansion of ZmHSFs. Most of the ZmHSFs are localized inside the nucleus, and the ZmHSFs which belong to the same group show similar physio-chemical properties. The 3D structures revealed comparable conserved ZmHSFs protein structures. RNA-seq analysis revealed a major role of class A HSFs including, ZmHSFA-1a and ZmHSFA-2a in all the maize growth stages, i.e., seed, vegetative, and reproductive development. Furthermore, ZmHSFs displayed an obvious spatiotemporal expression. Under abiotic stress conditions (heat, drought, cold, UV, and salinity), members of class A and B ZmHSFs are induced. Gene ontology (GO) annotation analysis indicated a major role of ZmHSFs in resistance to environmental stress and regulation of primary metabolism. Further, the protein-protein interaction analysis showed that ZmHSFs interact with several molecular chaperons and major stress-responsive proteins. To summarize, this study provides novel insights for functional studies on the ZmHSFs in maize breeding programs.

The Ramazzottius varieornatus tardigrade is an extremotolerant terrestrial invertebrate belonging to the phylum of Tardigrada. At a length of 0.1-1.0 mm, tardigrades are small animals with an exceptional tolerance to extreme conditions such as high pressure, chemicals and irradia-tion. These properties have been attributed to the recently-discovered Dsup protein. Dsup is a nucleosome-binding protein that prevents DNA damage against X-ray and oxidative stress without impairing cell life, also in Dsup-transfected animal and plant cells. However, the precise “protective” role of this protein is still under study. We performed experiments on human cells and shows that, as compared to control cells, Dsup+ cells are more resistant to UV-C exposure and H2O2. Real-time PCR identified different expression patterns of endogenous genes involved in apoptosis, cell survival and DNA damage repair in Dsup+ cells in response to H2O2 and UV-C. While H2O2 treatment in Dsup+ cells only marginally involved the activation of pathways responsible for DNA repair reinforcing the idea of a direct protective effect of the protein on DNA, in UV-C exposed cells, Dsup efficiently upregulates DNA damage repair genes. In conclusion, our data may help to delineate the different mechanisms by which the Dsup protein operates in response to different insults.

Abstract: The pathobiology of ascending aorta aneurysms (AAA) onset and progression is not well understood and only partially characterized. AAA are also complicated in case of bicuspid aorta valve (BAV) anatomy. There is emerging evidence about the crucial role of endothelium-related pathways, which show in AAA an altered expression and function. Here, we examined the involvement of ERG-related pathways in the differential progression of disease in aortic tissues from patients having a BAV or tricuspid aorta valve (TAV) with or without AAA. Our findings identified ERG as a novel endothelial-specific regulator of TGF-β-SMAD, Notch, and NO pathways, by modulating a differential fibrotic or calcified AAA progression in BAV and TAV aortas. We provided evidence that calcification is correlated to different ERG expression (as gene and protein), which appears to be under control of Notch signaling. The latter, when increased, associated with an early calcification in aortas with BAV valve and aneurysmatic, was demonstrated to favor the progression versus severe complications, i.e., dissection or rupture. In TAV aneurysmatic aortas, ERG appeared to modulate fibrosis. Therefore, we proposed that ERG may represent a sensitive tissue biomarker to monitor AAA progression and a target to develop therapeutic strategies and influence surgical procedures.

In silico analysis is a promising approach for understanding biological events in complex diseases. Herein, we report an in silico analysis of the entire genome of virus ZikaSPH2015 strain, which was performed in order to identify the occurrence of specific motifs on genomic sequence of Zika Virus that is able to bind and therefore, sequester host’s Transcription Factors (TFs) as well as subsequently predict a possible interactions within host genome. Accordingly to obtained results of this original computational work-flow it is possible to hypothesize that these TFs Binding Motifs might be able to explain the complex and heterogeneous phenotype presentation in Zika Virus affected fe-tus/newborns, as well as the less severe condition in adults. Moreover, the proposed in silico protocol identified thirty three different TFs same as the distribution of TFBSs (Transcription Factor Binding Sites) on ZikaSPH2015 strain, potentially able to influence genes and pathways with biological functions confirming that this approach could find potential answers on disease pathogenesis.

The stromal vascular cell fraction (SVF) of visceral and subcutaneous adipose tissue (VAT and SAT) has increasingly come into focus in stem cell research, since these compartments represent a rich source of multipotent adipose-derived stem cells (ASCs). ASCs exhibit a self- renewal potential and differentiation capacity. Our aim was to study the different expression of embryonic stem cell markers NANOG, SOX2 and OCT3/4 and to evaluate if there exists a hierarchal role in this network in ASCs derived from both SAT and VAT. ASCs were isolated from SAT and VAT biopsies of 72 consenting patients (23 men, 47 women; age 45 ± 10; BMI between 25 and 30 range) undergoing elective open-abdominal surgery. Sphere-forming capability was evaluated by plating cells in low adhesion plastic. Stem cell markers CD90 and CD105 were analyzed by flow cytometry and stem cell transcription factors NANOG, SOX2 and OCT3/4 were detected by immunoblotting and Real-Time PCR. NANOG, SOX2 and OCT3/4 interplay was explored by gene silencing. ASCs from VAT and SAT confirmed their mesenchymal stem cell (MSC) phenotype expressing the specific MSC markers CD90, CD105, NANOG, SOX2 and OCT3/4. NANOG silencing induced a significant OCT 3/4 (70% ± 0.05) and SOX2 (75% ± 0.03) down-regulation whereas SOX2 silencing did not affect NANOG gene expression. Adipose tissue is an important source of MSC, and siRNA experiments endorse a hierarchical role of NANOG in the complex transcription network that regulates pluripotency and plasticity.

Expression of Krüppel–like factor 15 (KLF15), a stress induced transcription factor, is induced during bovine herpesvirus 1 (BoHV-1) reactivation from latency, and KLF15 stimulates BoHV-1 replication. Transient transfection studies revealed KLF15 and glucocorticoid receptor (GR) cooperatively transactivate the BoHV-1 immediate early transcription unit 1 (IEtu1), herpes sim-plex virus type 1 (HSV-1) infected cell protein 0 (ICP0), and ICP4 promoter. The IEtu1 promoter drives expression of bICP0 and bICP4, two key BoHV-1 transcriptional regulatory proteins. Based on these studies, we hypothesized infection is a stressful stimulus that increases KLF15 ex-pression and enhances productive infection. New studies demonstrated that silencing KLF15 impaired HSV-1 productive infection and KLF15 steady state protein levels were increased at late stages of productive infection. KLF15 was primarily localized to the nucleus following in-fection of cultured cells with HSV-1, but not BoHV-1. When cells were transfected with a KLF15 promoter construct and then infected with HSV-1, promoter activity was significantly increased. The ICP0 gene and to a lesser extent bICP0 transactivated the KLF15 promoter in the absence of other viral proteins. In contrast, BoHV-1 or HSV-1 encoded VP16 had no effect on KLF15 pro-moter activity. Collectively, these studies revealed HSV-1 and BoHV-1 productive infection in-creased KLF15 steady state protein levels, which correlated with increased virus production.

The aim of this work is to compare two softwares (MAUD and TOPAS) based on the Rietveld algorithm and to test the concept of tolerance factor using the dissolution at high temperature of yttrium into BaTiO₃. In general, both softwares give up different values of the crystalline parameters however the trends are similar in most cases but the analysis of the strain and crystallite size in the BaTiO₃ crystals suggests that, in this particular case, MAUD offered results more consistent with the expected behavior. Using the crystalline parameters calculated by Rietveld, the tolerance factor values were obtained and these data suggest even better stability in the crystalline structure than that expected using theoretical parameters. Tolerance factor concept also indicates that Ti⁴⁺ should be preferred.

The retinoblastoma (RB) transcriptional corepressor 1 (RB1) is a critical tumor suppressor gene, governing diverse cellular processes implicated in cancer biology. Dysregulation or deletion in RB1 contributes to the development and progression of various cancers, making it a prime target for therapeutic intervention. RB1's canonical function in cell cycle control and DNA repair mechanisms underscores its significance in restraining aberrant cell growth and maintaining genomic stability. Understanding the complex interplay between RB1 and cellular pathways is beneficial to fully elucidate its tumor-suppressive role across different cancer types and for therapeutic development. As a result, investigating vulnerabilities arising from RB1 deletion-associated mechanisms offers promising avenues for targeted therapy. Recently, several findings highlighted multiple methods as a promising strategy for combating tumor growth driven by RB1 loss, offering potential clinical benefits in various cancer types. This review summarizes the multifaceted role of RB1 in cancer biology and its implications for targeted therapy.

Gene regulation is vital for cellular function and homeostasis, involving diverse mechanisms controlling specific gene products and contributing to tissue-specific gene expression. Dysregulation leads to diseases, emphasizing the need for understanding these mechanisms. Non-coding regions, notably enhancers and super-enhancers (SEs), act as crucial gene regulators, orchestrating transcriptional activity via transcription factors (TFs). SEs, with high activity, are pivotal in cell identity and disease progression. Current computational approaches focus on individual regulators like TFs and miRNAs, neglecting SE interactions. We emphasize incorporating SEs into models to enhance understanding. Experimental studies have recently linked miRNAs and TFs to SEs. Chromatin immunoprecipitation followed by sequencing (ChIP-Seq) provides valuable SE information. In this review, we categorize computational methods leveraging TF and miRNA data into three areas and explore challenges integrating enhancers/SEs. These include unraveling indirect regulatory networks, identifying network motifs, and enriching pathway identification by dissecting gene regulators, including SEs. We hypothesize that addressing these challenges will enhance our understanding of gene regulation, aiding in identifying therapeutic targets and disease biomarkers. We believe that understanding the role of ChIP-Seq data in predicting the effect of miRNA on gene regulation is crucial to construct statistical/computational model that would tackle these challenges.

Cysteine and its derivatives, including H2S, can influence bacterial virulence and sensitivity to antibiotics. In minimal sulfate media, H2S is generated under stress to prevent excess cysteine and, together with incorporation into glutathione and export into the medium, is a mechanism of cysteine homeostasis. Here, we studied the features of cysteine homeostasis in LB medium, where the main source of sulfur is cystine, whose import can create excess cysteine inside cells. We used mutants in the mechanisms of cysteine homeostasis and a set of microbiological and biochemical methods, including real-time monitoring of sulfide and oxygen, determination of cysteine and glutathione, and expression of the Fur, OxyR, and SOS regulons genes. During normal growth, the parental strain generated H2S when switching respiration to another substrate. The mutations affected the onset time, intensity and duration of H2S production, cysteine and glutathione levels, bacterial growth and respiration rates, and induction of defense systems. Exposure to chloramphenicol and high doses of ciprofloxacin increased cysteine content and GSH synthesis. A high inverse relationship between log CFU/ml and bacterial growth rate before ciprofloxacin addition was revealed. The study points to the important role of maintaining cysteine homeostasis during normal growth and antibiotic exposure in LB medium.

The paper examines the various uncertainties encountered in high-frequency trading (HFT) environments and delves into the multiple challenges faced by HFT firms in navigating the Dodd-Frank Wall Street Reform and Consumer Protection Act (referred to as the "Dodd-Frank Act"), particularly during the initial stages of its enactment. These challenges include the ambiguity surrounding the definition of HFT, the lack of clarity regarding regulatory requirements and boundaries, inconsistencies in enforcement resulting from deviations in understanding the content, and the absence of detailed descriptions of the Act’s provisions. These hurdles significantly impact not only the daily operations of HFT firms but also pose higher demands on their long-term strategic planning and risk management. Drawing upon the Data, Information, Knowledge, Wisdom, and Purpose (DIKWP) model, this study employs an innovative analytical framework. Through the comprehensive application of conceptual space, cognitive space, and semantic space, it provides a systematic methodology for identifying and analyzing the aforementioned issues. This approach not only aids firms in better comprehending and adhering to complex regulatory requirements but also enables them to explore new business opportunities and competitive advantages while ensuring compliance.

In this unprecedented era of computer-supported and distance learning, it is critical to rethink the way students are supported through vital skills like self-regulation and peer collaboration. A variety of digital media has emerged, allowing learners autonomy while requiring the ability to effectively regulate different components of the educational process for long-term academic success. We reviewed collaboration, communication, and self-regulation in digital learning environments as part of online learning. We discussed how these abilities are reflected in highly cited content. High-impact factor studies were identified using advanced software Herzing Publish or Perish to retrieve highly cited research publications metrics. The search resulted in 272 records from 2010 to 2022, 192 duplicates were identified to remove and 48 JCR articles were shortlisted for review. We examined and reflected on sufficient connections to make firm judgments about correlations of concepts. The review identified prominent themes surfaced in the high impact factor academic publication e.g., digital learning environment, interaction, engagement, feedback, self-efficacy, motivation, meta-cognition, achievement, technology, blended learning, and orientation of ICT. Many studies support different features of SRL &amp; PCL through different tools, access to educators or feedback, encouragement, and through peers. However, all of them discuss the processes that students use to self-regulate learning in these situations. It is suggested to examine whether the effectiveness of certain SRL processes varies by online learning mode.

Arboviruses are infections caused by arboviruses that may be either symptomatic or asymptomatic, according to individuals' resistance and immune response, which dietary patterns can influence. Thus, this study aimed to investigate the possible association between the occurrence of clinical manifestations of arboviruses and the dietary pattern of the population studied. The study was conducted in a rural population in the metropolitan area of Belém, Pará State, Brazil. The sampling consisted of 95 individuals during a febrile outbreak. Two investigations were conducted: clinical-epidemiological-dietary and laboratory investigation based on blood samples taken for arbovirus analysis. Out of the 95 individuals studied, more than half (57.89%) showed clinical manifestations. Following the laboratory serology (HI and IgM ELISA) analyses, viral isolation in C6/36 cells, and viral genome detection (RT-qPCR), the final diagnosis of the cases was 47.37% Oropouche Fever, 2.11% Oropouche Fever and Chikungunya Fever, and 1.05% Mayaro Fever. Regarding dietary pattern, as for the comparison analyses, statistical significance was observed between dietary pattern and classification regarding the presence of symptoms (p<0.05); after the correspondence analysis, symptomatic cases were more associated with a bad dietary pattern, while asymptomatic cases were more associated with a good dietary pattern.

PURPOSE: Breast cancer tumors frequently have intratumor heterogeneity. Tumors with high intratumor heterogeneity have caused therapeutic resistance and have human epidermal growth factor receptor 2 (HER2) heterogeneity in response to HER2-targeted therapies. This study aimed to investigate whether high HER2 heterogeneity levels were clinically related to poor prognosis for HER2-targeted adjuvant therapies resistance in primary breast cancers. METHODS: This study included patients with primary breast cancer (n = 251) treated with adjuvant HER2-targeted therapies. HER2 heterogeneity was manifested by the shape of HER2 fluorescence in situ hybridization amplification (FISH) distributed histograms with HER2 gene copy number within a tumor sample. Those heterogeneity classified each tumor into the biphasic grade graph (high heterogeneity [HH]) group and the monophasic grade graph (low heterogeneity [LH]) group. Both groups were evaluated for disease-free survival (DFS) and overall survival (OS) for a median of ten years of annual follow-up. RESULTS: Of 251 patients with HER2-positive breast cancer, 46 (18.3%) and 205 (81.7%) were classified into the HH and LH groups, respectively. The HH group had more distant metastases and a poorer prognosis than the LH group (DFS: P < 0.001 (HH:63% vs LH:91% at 10 years), and OS: P = 0.012 (HH:78% vs LH:95% at 10 years). CONCLUSION: High HER2 heterogeneity is a poor prognostic factor in patients with HER2-positive breast cancer. A novel approach of heterogeneity, which is manifested by the shape of HER2 FISH distributions, might be clinically useful in the prognosis prediction of patients after HER2 adjuvant therapy.

We have previously shown that the transmembrane protein ODZ1 promotes cytoskeletal remodelling of glioblastoma (GBM) cells and invasion of the surrounding parenchyma through activation of a RhoA-ROCK pathway. We also described that GBM cells can control the expression of ODZ1 through transcriptional mechanisms triggered by binding of IL-6 to its receptor and a hypoxic environment. Epidermal growth factor (EGF) plays a key role in the invasive capacity of GBM. However, the molecular mechanisms that enable tumor cells to acquire the morphological changes to migrate out from the tumor core have not been fully characterized. Here we show that EGF is able to induce the expression of ODZ1 in primary GBM cells. We analysed the levels of EGF receptor (EGFR) in 20 GBM primary cell lines and found expression in 19 of them by flow cytometry. We selected two cell lines that do or do not express EGFR and found that EGFR-expressing cells responded to EGF ligand by increasing ODZ1 at the mRNA and protein level. Moreover, blockade of EGF-EGFR binding by Cetuximab, inhibition of the p38 MAPK pathway or siRNA-mediated knockdown of MAPK11 (p38 MAPK) reduced the induction of ODZ1 in response to EGF. Overall, we show that EGF may activate an EGFR-mediated signalling pathway through p38 MAPK, to upregulate the invasion factor ODZ1, which may initiate morphological changes for tumor cells to invade the surrounding parenchyma. These data identify a new candidate of the EGF-EGFR pathway for novel therapeutic approaches.

Suicide is a public health problem influenced by a variety of biological, psychological, social, and environmental factors. Recognizing the warning signs at each stage is crucial for prevention and helping those at risk. In this context, body awareness, especially interoceptive body awareness, emerges as a potentially relevant and underexplored factor. In this study, binary logistic regression and linear regression analyses were used to examine the relationship between interoceptive body awareness and suicidal orientation in Colombian university students. In addition, the bootstrap technique was used to resample and estimate the distribution of the data. The results support the idea that greater interoceptive awareness may protect against suicidal orientation by improving emotional regulation. An inverse relationship was found between interoceptive awareness and suicidal ideation. These findings are consistent with previous literature on the importance of body awareness for emotional well-being. Further longitudinal research is needed to explore this relationship in depth.

The purpose of this review is to elucidate the actual threat of the most prevalent mycotoxins in agricultural commodities and human/animal food/feed for appearance of foodborne ailments and diseases. The underestimated hazard of joint mycotoxin uptake of animals or humans is critically discussed with regards to synergistic or additive interaction between some target mycotoxins. The real toxicity of target mycotoxin combinations as it happens in practice is evaluated and possible lower limit values or control measures are suggested in such cases. Some critical points in adequate risk assessment, hygiene control and regulation of mycotoxns are discussed. The efficiency of current mycotoxin regulations and control measures is evaluated in regards to human/animal health hazard. The risk assessment in the case of multiple mycotoxin exposure of humans/animals via the food/feed or agricultural commodities is evaluated and some suggestions are proposed in such cases. Appropriate control measures and food safety issues throughout the food supply chain are proposed in order to prevent target foodborne diseases. Some preventive measures and possible veterinary hygiene control or risk assessment are proposed in some practical cases of foodborne diseases for preventing mycotoxin contamination of animal products designed for human consumption and to avoid possible public health issues.

Mitochondria are semiautonomous organelles, which are pivotal for the energy metabolism of eukaryotic cells. These organelles contain their own genetic system (mtDNA, mitogenome) that encodes to some structural RNAs and organellar proteins. The biogenesis and function of mitochondria is tightly regulated by nuclear-encoded protein cofactors. The mtDNAs of land plants are characteristically large, with a complex mode of gene organization and expression, in particularly at the post-transcriptional level. To become functional, the primary organellar transcripts undergo extensive maturation steps, which include endo- and exo-nucleolytic cleavage, RNA-base editing, and both ‘cis’- and ‘trans’-splicing events. These essential processing steps rely on the activities of a large set of nuclear-encoded factors. Among these, the RNA helicases serve as key players in organellar (mt-)RNA metabolism. This review summarizes the important roles played by these factors in regulating the highly dynamic processes of transcription, RNA processing, and translation within the mitochondria of land plants. We further discuss recent advancements in understanding how dysregulation of mitochondrial RNA helicases affects the organellar gene expression, respiratory functions, and hence the growth, development and physiology of land plants.

Aim: To analysis the relationship between healthy adults right ventricular diameter (RVD) and geographical factors. Location: China’s 22 provinces, municipalities and autonomous regions. Methods: Using correlation analysis the relationship between RVD and nine geographic factors, build predictive models by factor analysis. Results: There is significant correlation between RVD and geographical factors, and the annual average temperature is most relevant geographical factors, a predictive model was built by factor analysis: Ŷ = 19.46 + 0.0007072X1 + 0.001034X2 -0.05412X3 -0.001405X4 -0.0006351X5 + 0.02903X6 + 0.01243X7 -0.01033X8 + 0.03816X9 ± 0.63. Then using Kriging interpolation interpolate the geographical distribution of Chinese healthy adult right ventricular diameter reference value in ArcGIS software. Main Conclusion: If geographic factors can be derived in anywhere of China, RVD can be calculated by the model, you can also get RVD from geographical distribution.

Dysregulation of cartilage homeostasis and the changes in the density and the architecture of the subchondral bone were postulated as a potent mechanically pathological activity contributing to osteoarthritis (OA) pathogenesis. Extracorporeal shockwave therapy (ESWT) is a new, none invasive and effective method in the treatment of animal OA model. In the current study, we demonstrated that shockwave induced the expression of protein-disulfide isomerase-associated 3 (Pdia-3) which is a multifunctional protein hypothesized to be a significant mediator for 1α,25-Dihydroxyvitamin D3 (1α,25(OH)₂D₃) signaling pathway using two-dimensional electrophoresis. Histological analysis and quantitative polymerase chain reaction (qPCR) were verified and observed that the expression of Pdia-3 at 2 weeks was significantly higher than that of any other group at 4 weeks, 8 weeks, and 12 weeks post-shockwave treatment in early OA knee of rat. The other factors of the 1α,25(OH)₂D₃ rapid membrane signaling pathway including extracellular signal-regulated protein kinases 1 (ERK1), osteopontin (OPG), alkaline phosphatase (ALP), and matrix metallopeptidase 13 (MMP13) were measured and significantly increased by qPCR at 2 weeks post-shockwave treatment in early OA knee. Our proteomic data revealed significant Pdia-3 expression in microenvironments of joint tissue that could be actively responded to ESWT, which may potentially regulate biological function of chondrocytes and osteoblasts in the treatment of OA knee.

Although there are a large number of databases available for regulatory elements, bottleneck has been created by the lack of bioinformatics tools for predicting types of mechanisms underlying actions of regulatory elements. To reduce the gap, we developed ARabidopsis Transcription regulatory Factor Domain-domain interaction Analysis Tool- Liquid-liquid phase separation (LLPS), Oligomerization, GO analysis (ART FounDATion-LOG), a useful toolkit for protein-nucleic acid interactions (PNI) and protein-protein interactions (PPI) analysis based on domain-domain interaction (DDI). LLPS, protein oligomerization, structural properties of protein domains, and protein modifications are major components in orchestrating spatio-temporal dynamics of PPI and PNI. Our goal is to integrate PPI/PNI information into development of prediction model for identifying important genetic variants in peach. The program unified inter-database relational keys by protein domains for facilitating inference from the model species. Key advantage of the program lies in the integrated information of related features: LOG, structural characterization of domain (e.g. domain linker, intrinsically disordered regions, DDI, domain-motif (peptide) interaction, beta-sheet and transmembrane helices), and post-translational modification. We provided simple tests to demonstrate how to use the program. The program may be applied to other eukaryotic organisms. The program codes and data are freely available for download at and https://sourceforge.net/projects/artfoundation-log/.

Neuronal cells are believed to rely on autophagy to maintain cellular homeostasis. Nevertheless, autophagy may be a therapeutic target for neurodegenerative diseases because of the role it plays in neuronal cell death. Despite Beclin 1 association with autophagy and apoptosis, the molecular mechanisms that underlie Tau-induced vesicular pathology and Tau protein aggregates in humans remain poorly understood. Here, we set out to examine the role of three genes-ATG14L, Beclin 1 and VPS34- in autophagy nucleation failure-associated Tau disorders in fruit fly models. We found that either reduced ATG14L levels improve neuronal outcomes, or transgenic expression of ATG6/Beclin 1 greatly reduced age-dependent neurodegeneration and Tau pathology; whereas, the loss of Beclin 1 exacerbated these effects. Prior to p-Tau accumulation, the neuronal Beclin 1 network is critical for reducing p-Tau accumulation, indicating that the loss of Beclin 1 causes Tau pathology and neurodegeneration. As neurodegeneration progressed, glial cells showed an upregulation of vesicular Beclin 1 immunoreactivities. The reduced VPS34 also resulted in p-Tau accumulation, suggesting that neurons require both Beclin 1 and VPS34 to reduce p-Tau accumulation. Our results provide mechanistic insight into the molecular pathways that cause age-dependent Tau pathology and neurodegeneration due to an excess of autophagy nucleation processes and autophagy activity, and we derive novel inferences on the therapeutic possibilities of rebalanced Beclin 1 network by reducing autophagic specific nucleation component of ATG14L.

Background: Despite a range of available treatments, there is a remaining unmet need for patients with severe post-partum hemorrhage (sPPH). Objective: This manuscript evaluated efficacy and safety of recombinant activated factor VIIa (rFVIIa) in sPPH management. Methods: An open-label, multi-center, randomized controlled trial (RCT; NCT00370877) and four observational studies (OS; OS-1 [NCT04723979], OS-2, OS-3 and OS-4) were analyzed regarding efficacy (need for subsequent invasive procedures, including uterine compression sutures, uterine or iliac artery ligation, arterial embolization or hysterectomy) and safety (incidence of thromboembolic events [TE] and maternal mortality) of rFVIIa for sPPH. The RCT, and OS-1 and OS-2, included a control group of women who did not receive rFVIIa (with propensity score-matching used in OS-1 and OS-2), whereas OS-3 and OS-4 provided descriptive data for rFVIIa exposed women only. Results: A total of 446 women exposed to rFVIIa and 1,717 non-exposed controls were included. In the RCT, fewer rFVIIa exposed women (50% [21/42]) had an invasive procedure versus non-exposed women (91% [38/42]; odds ratio 0.11, 95% confidence interval 0.03–0.35). In OS-1, more rFVIIa exposed women (58% [22/38]) had an invasive procedure versus non-exposed women (35% [13.3/38]; odds ratio 2.46, 95% confidence interval 1.06–5.99). In OS-2, 17% (3/18) of rFVIIa exposed women and 32% (5.6/17.8) of non-exposed women had an invasive procedure (odds ratio 0.33, 95% confidence interval 0.03–1.75). Across all included women, TEs occurred in 1.5% (0.2% arterial and 1.2% venous) of rFVIIa exposed women and 1.6% (0.2% arterial and 1.4% venous) of non-exposed women with available data. Conclusions: The positive treatment effect of rFVIIa in the RCT was not confirmed in the OS. However, the safety analysis did not show any increased incidence of TEs with rFVIIa treatment.

The DOF (DNA binding with one finger) family of plant-specific transcription factors (TF) was first identified in maize in 1995. Since then, DOF proteins have been shown to be present in the whole plant kingdom including the unicellular alga Chlamydomonas reinhardtii. The DOF TF family is characterised by a highly conserved DNA binding domain (DOF domain), consisting of a CX2C-X21-CX2C motif which is able to form a zinc finger structure. Early in the study of DOF proteins it became clear their relevance for seed biology. Indeed, the Prolamine Binding Factor (PBF), one of the first DOF proteins characterised, controls the endosperm-specific expression of the zein genes in maize. Subsequently, several DOF proteins from both monocots and dicots have been shown to be primarily involved in seed development, dormancy and germination, as well as in seedling development and other light-mediated processes. In the last two decades the molecular network underlying these processes have been outlined, and the main molecular players and their interactions have been identified. In this review, we will focus on the DOF TFs involved in these molecular networs, and on their interaction with other proteins.

The recent developments in the delivery and design of transcription factors put their therapeutic applications within reach, exemplified by cell replacement, cancer differentiation and T-cell based cancer therapies. The success of such applications depends on the efficacy and precision in the action of transcription factors. The biophysical and genetic characterization of the paradigmatic prokaryotic repressors, LacI and TetR and the designer transcription factors, TALE and CRISPR-Cas9 revealed common rules, which can help the optimization of activators and repressors. Further studies will be required to analyze the linkage between dissociation constants and enzymatic activity, the role of phase separation and squelching in activation and repression, and the long-range interaction of transcription factors with epigenetic regulators in the context of the chromosomes. Understanding these mechanisms will help to tailor systematically optimized designer transcription factors to the needs of specific applications.

This study aimed to investigate the relationship between sleep duration, dementia severity, age, and ANS regulation. This cross-sectional pilot study included 27 older patients with probable Alzheimer’s disease, hospitalized at a psychiatric center. We measured heart rate variability to assess ANS regulation at night, evaluated dementia severity using the Clinical Dementia Rating scale, and obtained sleep duration data from sleep diaries maintained by psychiatric nurses. The data were analyzed using repeated-measures generalized linear models with age, sex, dementia severity, and medication (antipsychotics) as covariates. A sleep duration of 7–8 h per night was associated with better ANS regulation than other sleep durations, as indicated by sympathovagal balance (p = 0.005). ANS dysregulation was characterized by a 20.7% increase in sympathetic nervous system activity and a 14.8% decrease in parasympathetic nervous system (PSNS) activity. We found a significant correlation between dementia severity and PSNS activity (p = 0.04) and observed an inverted U-shaped association between sleep duration and ANS regulation. This pilot study demonstrated that a sleep duration of 7–8 h per night may be critical in maintaining optimal ANS regulation. Bidirectional associations between sleep duration, inadequate sleep duration, aging, and ANS regulation warrant further investigation.

This review deals with the developmental origins of extraocular, jaw and laryngeal muscles, the expression, regulation and functional significance of myosin heavy chains (MyHCs) they express and changes in MyHC expression during phylogeny. Myogenic progenitors from mesoderm in the prechordal plate and branchial arches specify craniofacial muscle allotypes with different repertoires for MyHC expression. To cope with very complex eye movements, extraocular muscles express 11 MyHCs, ranging from the superfast extraocular MyHC to the slowest, non-muscle MyHC IIB. They have distinct global and orbital layers, singly- and multiply-innervated fibres, longitudinal MyHC variations, and palisade endings that mediate axon reflexes. Jaw-closing muscles express the high-force masticatory MyHC, cardiac or limb MyHCs depending on the appropriateness for the acquisition and mastication of their food. Laryngeal muscles express extraocular and limb muscle MyHCs but shift towards slower MyHCs in large animals. During postnatal development, MyHC expression of craniofacial muscles is subject to neural and hormonal modulation. The primary and secondary myotubes of developing EOMs are postulated to induce, via different retrogradely transported neurotrophins, the rich diversity of neural impulse patterns that regulate the specific MyHCs they express. Thyroid hormone shifts 2A MyHC towards 2B in jaw, laryngeal muscles and possibly extraocular muscles.

Hepatitis B virus (HBV) is the dominant risk factor for hepatocellular carcinoma (HCC). HBV X protein (HBx) plays crucial roles in HCC carcinogenesis. HBx interferes with several signaling pathways including Notch1 pathway in HCC. In our study, we found that Notch1 was highly expressed in HCC especially in large HCC. Notch1 and HBx co-localized in HCC and their levels were positively correlated with each other. Notch1 expression was more elevated in HepG2.2.15 than that in HepG2. HBx activated Notch1 pathway in HepG2.2.15. Repression of HBx and Notch1 pathway attenuated the growth of HepG2.2.15. Notch1, ERK and AKT pathways were inhibited after a γ-secretase inhibitor treatment. Dual-specificity phosphatase 1 (DUSP1) and phosphatase and tensin homolog (PTEN) were up-regulated after the γ-secretase inhibitor treatment and Hes1 inhibition. Luciferase reporter assays showed that Hes1 repressed the promoters of DUSP1 and PTEN and this was reverted by γ-secretase inhibitor treatment. Western blotting demonstrated that DUSP1 dephosphorylated pERK and PTEN dephosphorylated pAKT. Collectively, we reported a link among HBx, Notch1 pathway, DUSP1/PTEN, and ERK/AKT pathways, which influenced HCC cell survival and could be a therapeutic target for HCC.

This paper argues that popular misrepresentation of the nature of AI has important consequences concerning how it should be regulated. Viewing AI as something that exists in itself, rather than as a set of cognitive technologies whose characteristics – physical, cognitive, and systemic – are quite different from ours (and at times from each other) leads to inefficient approaches to regulation. It limits our ability to anticipate the consequences of its foreseeable developments and social diffusion. It undermines attempts to protect ourselves from the social and political dangers it presents. After a short introduction, section 2 retraces rapidly the history of the idea that intelligence is essentially a quality, one that AI shares with human intelligence and that this resemblance trumps the differences that exist between artificial and natural cognitive systems. Section 3 reviews two approaches to the dangers of AI that reflect the illusion that AI exists in itself. Section 4 turns to the proper understanding of regulations and what is their main goal and purpose. Section 5 analyses three central characteristics of artificial cognitive systems which section six compares with corresponding characteristics of natural cognitive systems. Finally, section 7 draws some conclusions regarding how we should regulate artificial intelligence.

Several recent studies have indicated that miR-30a plays critical roles in various biological processes and diseases. However, the mechanism of miR-30a participation in the regulation of idiopathic pulmonary fibrosis (IPF) is ambiguous. Our previous study demonstrated that miR-30a may function as a novel therapeutic target for lung fibrosis by blocking mitochondrial fission, which is dependent on dynamin-related protein-1 (Drp-1). However, the regulatory mechanism between miR-30a and Drp-1 has yet to be investigated. In addition, whether miR-30a can act as a potential therapeutic has not been verified in vivo. In this study, the miR-30a expression in IPF patients was evaluated. Computational analysis and a dual luciferase reporter system assay were used to identify the target gene of miR-30a, and cell transfection was used to confirm this relationship. Ten-eleven translocation 1 (TET1) was validated as a direct target of miR-30a, and the transfection of miR-30a mimic/inhibitor significantly reduced/increased the expression of TET1 protein. Further experiment verified that the interference on TET1(siRNA) could inhibit the hydroxymethlation of the Drp-1 promoter. Finally, miR-30a agomir was designed and applied to identify and validate the therapeutic effect of miR-30a in vivo. Our study demonstrated that miR-30a could inhibit the TET1 expression by base pairing with complementary sites in the 3′ untranslated region to regulate the hydroxymethlation of the Drp-1 promoter. Furthermore, miR-30a could act as a potential therapeutic target for IPF.

Several studies suggests that ghrelin (GHRL) has neurobiological effects that extend beyond control of food intake. Our previous results confirmed that GHRL modulates the secretory activity of the pineal gland (PG) through nocturnal melatonin (MEL) secretion in sheep, the seasonally reproductive animals. Here we investigated the effects of GHRL (10 ng/ml) on the expression of enzymes limiting synthesis of MEL, including tryptophan 5-hydroxylase 1 (TPH1), serotonin N-acetyltransferase (AA-NAT) and its phosphorylated form p31T-AA-NAT in sheep PG explants (n = 72) during the 4-hour incubation in a gas-liquid interface, at a short (SD) and long (LD) photoperiods. After each hour of incubation selected explants were frozen in liquid nitrogen and stored at -80°C for subsequent analysis (real-time PCR, western-blotting, ELISA). Results show that GHRL regulates nightly MEL secretion in a TPH1-independent manner. The factor modulating GHRL activity was photoperiod. During SD photoperiod GHRL significantly reduced the expression of p31T-AA-NAT, AA-NAT and inhibited MEL secretion from PG explants. Whereas, during LD photoperiod no effect of GHRL on MEL secretion and expression of examined enzymes was noted. Studies indicate that GHRL directly affects PG under in vitro conditions and causes MEL secretion in animals which exhibit seasonality in reproductive and metabolic processes.

Tumor to stroma ratio is a highly debated prognostic factor in the management of several solid tumors and there is no universal agreement on its practicality. In our study we proposed to confirm or dismiss the hypothesis that a simple measurement of stroma quantity is an easy-to-use and strong prognostic tool. We have included 74 consecutive patients with colorectal cancer who underwent primary curative abdominal surgery. The tumors have been grouped into stroma-poor (stroma &lt;10%), medium-stroma (between 10 and 50%) and stroma-rich (over 50%). The proportion of tumor stroma ranged from 5% to 70% with a median of 25%. Very few, only 6.8% of patients had stroma-rich tumors, 4% stroma-poor tumors and 89.2%tumors with a medium quantity of stroma. The proportion of stroma, at any cut-off, had no statistically significant influence on the disease specific survival. This can be explained by the low proportion of stroma-rich tumors in our patient group and the inverse correlation of stroma proportion with tumor grade. The real-life proportion of stroma-rich tumors and the complex nature of the stroma-tumor interaction has to be further elucidated.

This study aimed to investigate the appearance and frequencies of the booroola polymorphism of the bone morphogenetic protein receptor 1b (BMPR1B) gene (FecB) and the embrapa polymorphism of the growth differentiation factor 9 (GDF9) gene (FecGE) in sheep in Thailand. A total of 454 cross-bred sheep blood samples were collected from four provinces in Thailand during August 2022 to July 2023. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to identify the FecB and FecGE genotype. The history of ewe birth types was collected from the owners to analyze the association between Fecundity (Fec) genotypes and the history of birth types. The genotypic frequencies of FecB for homozygous genotype (B/B), heterozygous genotype (+/B) and wild-type (+/+) were 0.22%, 1.54%, and 98.24%, respectively. Meanwhile, the genotypic frequencies of FecGE for homozygous genotype (E/E), heterozygous genotype (+/E), and wildtype (+/+) were 0.00%, 2.42%, and 97.58%, respectively. Furthermore, three ewes exhibited both FecB and FecGE genotypes. Fisher’s exact test revealed that the possessor of FecB genotype was associated with multiple births (p&lt;0.01). Both FecB and FecGE mutations were identified in crossbred sheep in Thailand. Sheep containing FecB allele is a better candidate to be selected to improve the prolificacy of crossbred sheep in Thailand.

Placental growth factor (PlGF or PGF) is a member of the VEGF family, which is known to play a critical role in pathological angiogenesis, inflammation, and endothelial cell barrier function. However, the molecular mechanisms by which PlGF mediates its effects in non-proliferative diabetic retinopathy (DR) remain elusive. In this study, we performed transcriptome-wide profiling of differential gene expression for human retinal endothelial cells (HRECs) treated with PlGF antibody. The effect of antibody treatment on the samples was validated using trans-endothelial electric resistance (TEER), and western blot. A total of 3760 genes (1750 upregulated and 2010 downregulated) were found to be differentially expressed between the control and PlGF antibody treatment group. These differentially expressed genes (DEGs) were used for gene ontology and enrichment analysis to identify gene function, signal pathway, and interaction networks. The gene ontology results revealed that catalytic activity (GO:0003824) of molecular function, cell (GO:0005623) of the cellular component, and cellular process (GO:0009987) were among the most enriched biological processes. Pathways such as TGF-β, VEGF-VEGFR2, p53, apoptosis, pentose phosphate pathway, and ubiquitin-proteasome pathway, were among the most enriched, and TGF-β1 was identified as a primary upstream regulator. These data provide new insights into the underlying molecular mechanisms of PlGF in mediating biological functions, in relation to DR.

The draconian regulation required by the inherent instability of cognitive phenomena -- gene expression, immune function, cancer suppression, wound healing, animal consciousness, machine intelligence, network stabilization, institutional cognition, and their many and varied composites -- can be viewed through the lens of the asymptotic limit theorems of both information and control theories. Here, we explore the dynamics and sometimes highly punctuated failures of the regulation of cognition under increasing `noise'. The approach parallels, and indeed generalizes, the Data Rate Theorem of control theory, extending the theorem's requirement of a minimum channel capacity necessary for stabilization of an inherently unstable system. Various models are explored across different basic underlying probability distributions characteristic of the system under study, and across different hierarchical scales, finding the addition of adaptive -- learned -- regulation greatly extends the reach of innate -- e.g., AI-driven or otherwise pre-programmed -- regulation. This work points toward the construction of new statistical tools for the analysis of observational and empirical data across a wide spectrum of inherent pathologies and adversarial challenges afflicting a wide variety of cognitive processes.

Transcription factors (TFs) are proteins that recognize specific DNA fragments in order to decode the genome and ensure its optimal functioning. TFs work at the local and global scales by specifying cell type, cell growth and death, cell migration, organization and timely tasks. We investigate the structure of DNA-binding motifs with the theory of finitely generated groups. The DNA ‘word’ in the binding domain -the motif- may be seen as the generator of a finitely generated group Fdna on four letters, the bases A, T, G and C. It is shown that, most of the time, the DNA-binding motifs have subgroup structure close to free groups of rank three or less, a property that we call ‘syntactical freedom’. Such a property is associated to the aperiodicity of the motif when it is seen as a substitution sequence. Examples are provided for the major families of TFs such as leucine zipper factors, zinc finger factors, homeo-domain factors, etc. We also discuss the exceptions to the existence of such a DNA syntactical rule and their functional role. This includes the TATA box in the promoter region of some genes, the single nucleotide markers (SNP) and the motifs of some genes of ubiquitous role in transcription and regulation.

During cartilage development, the lineage commitment and condensation of stem cells into chondrocytes and their differentiation involves a ubiquitous signaling cascades and huge numbers of transcriptional factors. The kinetic requirements and the stoichiometry for the expression of key transcriptional factors are relevant and must be met to form proper and functionally competent cartilage tissue. More interestingly also, an exact and precise spatio-temporal distribution of these molecules are as necessary in the proper tissue morphogenesis and patterning as the relevant physical conditions and micro environmental forces playing at the background during embryogenesis. A milestone of experimental achievements has been obtained over the years on several signaling pathways involved in cartilage development. Several fate determining transcriptional factors has also been investigated and determined with regards to the transition of stem cells (pluripotent, embryonic, etc.) into chondrocytes. These transcriptional factors serve as master controllers in chondrocytes proliferation and hypertrophy. Concerns that variability in signaling and transcriptional factors have detrimental effect on cartilage formation and could potentiate most cartilage related diseases have led most scientists to investigate the role of signaling molecules and transcriptional factors implicated in osteoarthritis, rheumatoid arthritis, and other cartilage degenerative diseases. On bases of spatio-temporal distribution of transcriptional factors, there exist functional overlaps, hence, it is difficult to draw a hard line of demarcation of roles at each point of the cell’s life, nonetheless, it is also markedly established that some factors are skewed to the chondrocyte’ survival and proliferation, and others known for their master’s role in the cell’s apoptotic, necrotic and senescence. Here we review some published works on selected signaling pathways and transcriptional factors that are preferentially expressed in chondrogenic cells and their role as major players in cartilage formation, cartilage diseases, along with some highlights of unique signaling molecules that are indispensable in cartilage tissue regeneration and management.

In South Sudan, three case-control studies found a positive association between Nodding Syn-drome (NS) and a Mansonella perstans infection. To investigate whether M. perstans could play the primary and sole causal role in the development of NS, we examined blood films of persons with and without epilepsy in rural villages affected by NS in Mahenge, Tanzania, to identify M. perstans infections. Study participants were also examined for onchocercal nodules and skin lesions and tested for the presence of anti-O. volvulus antibodies (Ov16 ELISA). One hundred and thirteen epilepsy cases and 132 controls were enrolled, with a mean age of 28.3 years (interquartile range 22 – 34 years); 125 (51%) were females. Of the persons with epilepsy, 43 (38.1%) met the probable NS criteria. M. perstans infection was absent in all participants, but Ov16 prevalence and oncho-cerciasis-associated skin manifestations were positively associated with epilepsy, including probable NS. Onchocercal nodules in the mothers of cases were also positively associated with epilepsy. In conclusion, in contrast with O. volvulus, M. perstans is likely not endemic in Mahenge and therefore cannot be a co-factor for NS in the area. Hence, this filaria cannot be the primary and sole causal factor in the development of NS.

Approximately 240 million people are chronically infected with hepatitis B virus (HBV), despite four decades of an effective HBV vaccine. During chronic infection, HBV forms two distinct templates responsible for viral gene transcription: (1) episomal covalently closed circular (ccc)DNA and (2) host-genome integrated viral templates. Multiple ubiquitous and liver-specific transcription factors are recruited onto these templates and modulate viral gene transcription. This review details the latest developments in antivirals that inhibit HBV gene transcription, and their impact on the stability of viral transcripts. Notably, nuclear receptor agonists exhibit potent inhibition of viral gene transcription from cccDNA, small molecule inhibitors repress HBV X protein-mediated transcription from cccDNA and small interfering RNAs and single-stranded oligonucleotides result in transcript degradation from both cccDNA and integrant templates. These antivirals mediate their effects by reducing viral transcripts abundance, eventually leading to loss of surface antigen expression, and can potentially be added to the arsenal of drugs with demonstrable anti-HBV activity. Thus, these candidates deserve special attention for future repurposing or further development as anti-HBV therapeutics.

The GAI‐RGA ‐ and ‐SCR (GRAS) proteins belong to the plant-specific transcription factor gene family and involved in several developmental processes, phytohormone and phytochrome signaling, symbiosis, stress responses etc. GRAS proteins have a conserved GRAS domain at C-terminal and hypervariable N-terminal. The C-terminal conserved domain directly affects the function of the GRAS proteins. For instance, in Arabidopsis, mutations in this domain in Slender rice 1 (SLR1) and Repressor of GA (RGA) proteins cause significant phenotypic changes. GRAS proteins have been reported in more than 30 plant species and till now it has been divided into 17 subfamilies. This review highlighted GRAS protein's importance during several biological processes in plants, structural features of GRAS proteins, their expansion and diversification in the plants, GRAS-interacting proteins complexes and their role in biological processes. We also summarized available recent research that utilized CRISPR-Cas9 technology to manipulate GRAS genes in a plant for different traits. Further, the exploitation of GRAS genes in crop improvement programs has also been discussed

Cell division control 37 (CDC37) increases the stability of HSP90 client proteins and is thus essential for numerous intracellular oncogenic signaling pathways, playing a key role in prostate oncogenesis. Notably, elevated expression of CDC37 was found in prostate cancer cells, although the regulatory mechanisms through which CDC37 expression becomes increased are unknown. Here we show both positive and negative regulation of CDC37 gene transcription by two members of the SCAN transcription factor family- MZF1 and SCAND1, respectively. Consensus DNA-binding motifs for myeloid zinc finger 1 (MZF1 / ZSCAN6) were abundant in the CDC37 promoter region. MZF1 became bound to these regulatory sites and trans-activated the CDC37 gene whereas MZF1 depletion decreased CDC37 transcription and reduced tumorigenesis of prostate cancer cells. On the other hand, SCAND1, a zinc-fingerless SCAN box protein that potentially inhibits MZF1, accumulated at MZF1-binding sites in CDC37 gene, negatively regulated CDC37 gene and inhibited tumorigenesis. SCAND1 was abundantly expressed in normal prostate cells but was reduced in prostate cancer cells, suggesting a potential tumor suppressor role of SCAND1 in prostate cancer. These findings indicate that CDC37, a crucial protein in prostate cancer progression, is regulated reciprocally by MZF1 and SCAND1.

The features of a class of cubic curves with a shape factor are analyzed by means of the theory of envelope and topological mapping. The effects of the shape factor on the cubic curves are made clear. Necessary and sufficient conditions are derived for the curve to have one or two inflection points, a loop or a cusp, or to be locally or globally convex. Those conditions are completely characterized by the relative position of the edge vectors of the control polygon and the shape factor. The results are summarized in a shape diagram, which is useful when the cubic parametric curves are used for geometric modeling. Furthermore we discussed the influences of the shape factor on the shape diagram and the ability for adjusting the shape of the curve.

Osteoarthritis and rheumatoid arthritis are common cartilage and joint diseases that globally affect more than 200 and 20 million people, respectively. Several transcription factors have been implicated in the onset and progression of osteoarthritis, including Runx2, C/EBPβ, HIF2α, Sox4, and Sox11. IL-1β also leads to osteoarthritis through NF-ĸB, IκBζ, and Zn²⁺-ZIP8-MTF1 axis. IL-1, IL-6, and TNFα play a major pathological role in rheumatoid arthritis through NF-ĸB and JAK/STAT pathways. Indeed, inhibitory reagents for IL-1, IL-6, and TNFα provide clinical benefits for rheumatoid arthritis patients. Several growth factors, such as BMP, FGF, PTHrP, and Indian hedgehog, play roles regulating chondrocyte proliferation and differentiation. Disruption and excess of these signaling cause genetic disorders in cartilage and skeletal tissues. FOP, an autosomal genetic disorder characterized by ectopic ossification, is induced by mutant ACVR1. mTOR inhibitors were found to prevent ectopic ossification by ACVR1 mutations. ACH and related diseases are autosomal genetic diseases, which manifest severe dwarfism. CNP is currently the most promising therapy for ACH. In these ways, investigation of cartilage and chondrocyte diseases at molecular and cellular levels sheds light on the development of effective therapies. Thus, identification of signaling pathways and transcription factors implicated in these diseases is important.

Transcriptional regulations have been widely studied as one of the main bridges between biology and other basic sciences as well as medicine. The traffic across it has been mostly unidirectional: chemistry and physics provided a lot of tools for biology, although the supply is now saturating. The traffic in opposite direction, the supply of subjects to develop chemistry and physics, has been only a little. However, if there are any, the supply will be at least from transcription, because the notion of chemical reaction is the strongest. This topic is aimed to increase the opposite traffic by introducing the forefront of physicochemical studies of transcription.

Currently, obesity is a critical global public health burden. Numerous studies have demonstrated the regulation of the pathogenesis of obesity and metabolic abnormalities by the gut microbiota and microbial factors; however, their involvement in the various degrees of obesity is not yet understood well. Previously, obesity has been shown to be associated with decreased levels of vitamin B12. Considering exclusive microbial production of vitamin B12, we hypothesised that a decrease in cobalamin levels in obese individuals may be at least partially caused by its depleted production in the intestinal tract by the commensal microbiota. In the present study, our aim was to estimate the abundance of enzymes and metabolic pathways for vitamin B12 synthesis in the gut microbiota of mouse models of alimentary and genetically determined obesity, to evaluate the contribution of the obesogenic microbiome to vitamin B12 synthesis in the gut. We have defined a significantly lower representation of enzymes and metabolic pathways for vitamin B12 biosynthesis in obese mice compared to non-obese mice, wherein enzyme depletion was more pronounced in lepr(-/-) (db/db) mice, which developed severe obesity. The representation of enzymes involved in cobalamin synthesis is strongly correlated with representation of several microbes in high-fat diet fed mice, whereas there were almost no correlations in db/db mice. Therefore, the degree of obesity and the composition of the correspondent microbiota are the main contributors to the representation of genes and pathways for cobalamin biosynthesis in the mouse gut.

RNA transcripts play a crucial role as witnesses of gene expression health. Identifying disruptive short sequences in RNA transcription and regulation is essential for potentially treating diseases. Let’s delve into the mathematical intricacies of these sequences. We’ve previously devised a mathematical approach for defining a “healthy” sequence (10.14218/GE.2023.00079). This sequence is characterized by having at most four distinct nucleotides (denoted as nt≤4). It serves as the generator of a group denoted as fp. The desired properties of this sequence are as follows: fp should be close to a free group of rank nt−1, it must be aperiodic, fp should not have isolated singularities within its SL2(C) character variety (specifically within the corresponding Groebner basis). Now, let’s explore the concept of singularities. There are cubic surfaces associated with the character variety of a four-punctured sphere denoted as S24. When we encounter these singularities, we find ourselves dealing with some algebraic solutions of a dynamical second-order differential (and transcendental) equation known as the Painlevé VI equation (10.3390/dynamics4010001). In certain cases, S24 degenerates, in the sense that two punctures collapse, resulting in a “wild” dynamics governed by the Painlevé equations of an index lower than VI. In our paper, we provide examples of these fascinating mathematical structures within the context of miRNAs. Specifically, we find a clear relationship between decorated character varieties of Painlevé equations and the character variety calculated from the seed of oncomirs. These findings should find applications in cancer research.

Reactive oxygen species (ROS), which were originally classified as exclusively deleterious compounds, have gained increasing interest in the recent years given their action as bona fide signalling molecules. The main target of ROS action is the reversible oxidation of cysteines, leading to the formation of disulfide bonds, which modulate protein conformation and activity. ROS endowed with signalling properties are mainly produced by NADPH oxidases at the plasma membrane, but their action also involves a complex machinery of multiple redox-sensitive protein families that differs in their subcellular localization and their activity. Given that the levels and distribution of ROS are highly dynamic in part due to their limited stability, the development of various fluorescent ROS sensors, some of which are quantitative (ratiometric), represents a clear breakthrough in the field and have been adapted to both ex vivo and in vivo applications. The physiological implication of ROS signalling will be presented mainly in the frame of morphogenetics processes, embryogenesis, regeneration, and stem cell differentiation. Gain and loss of function as well as pharmacological strategies have demonstrated the wide but specific requirement of ROS signalling at multiple stages of these processes and its intricate relationship with other well-known signalling pathways.

This review article discusses the involvement of the Brain-Derived Neurotrophic Factor (BDNF) in the control of pain. BDNF, a neurotrophin known for its essential role in neuronal survival and plasticity, has garnered significant attention for its potential implications as a modulator of nociception and pain. This comprehensive review aims to provide insights into the multifaceted interactions between BDNF and pain pathways, encompassing both physiological and pathological pain conditions. I delve into the molecular mechanisms underlying BDNF's involvement in pain processing and discuss potential therapeutic applications of BDNF and its mimetics in managing pain. Furthermore, I highlight recent advancements and challenges in translating BDNF-related research into clinical practice.

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.

Inflammasomes are multimolecular complexes with potent inflammatory activity. As such, their activity is tightly regulated at the transcriptional and post-transcriptional levels. In this review, we present the transcriptional regulation of inflammasome genes from sensors (e.g NLRP3) to substrates (e.g. IL-1β). Lineage-determining transcription factors shape inflammasome responses in different cell types with profound consequences on the responsiveness to inflammasome-activating stimuli. Pro-inflammatory signals (sterile or microbial) have a key transcriptional impact on inflammasome genes, which is largely mediated by NF-κB and, that translates into higher antimicrobial immune responses. Furthermore, diverse intrinsic (e.g. circadian clock, metabolites) or extrinsic (e.g. xenobiotics) signals are integrated by signal-dependent transcription factors and chromatin structure changes to modulate transcriptionally inflammasome responses. Finally, anti-inflammatory signals (e.g. IL-10) counterbalance inflammasome genes induction to limit deleterious inflammation. Transcriptional regulations thus appear as the first line of inflammasome regulation to raise the defense level in front of stress and infections but also to limit excessive or chronic inflammation.

The genetic causes of the differentiated, highly treatable and mostly non-fatal papillary thyroid cancer (PTC) are not yet fully known. The widely accepted PTC etiology blames altered sequence or/and expression level of certain biomarker genes. However, our previous studies found that the PTC biomarkers played significantly lower roles than the personalized PTC Gene Master Regulators. Our publicly accessible gene expression data from the cancer nodule and the surrounding normal tissue of surgically removed PTC tumor were re-analyzed to determine the transcriptomic effects on the genomic fabrics responsible for the DNA replication, repair and transcription. Tumor results were compared to the gene expression profiles of the papillary (BCPAP) and the anaplastic (8505C) human thyroid cancer cell lines. The analyses were carried out from the Genomic Fabric Paradigm (GFP) perspective that provides the most theoretically possible comprehensive characterization of the transcriptome and its alterations in disease. The study indicated that, in addition to regulating numerous genes, changes in the homeostatic control of transcript abundances and remodeling of the gene networks had major contributions to the PTC occurrence, resilience and proliferation. Therefore, the molecular mechanisms responsible for gene expression control and inter-coordination should also be considered when designing personalized anti-cancer gene therapies.

Plant reproduction is a very important process on Earth from the perspective of biodiversity, biomass gain and crop productivity. It is therefore important to understand sex determination process and many researchers are investigating the molecular basis of this phenomenon. However, information on the influence of transcription factors (TFs) on this process is limited, although cucumber is a model plant in this regard. In the present study, based on RNA-seq data for differential gene expression (DEG) analyses, we aimed to investigate the regulatory TFs that may influence the metabolomic processes in the shoot apex containing the forming flower buds. Therefore, a robust TF database was established for the B10v3 cucumber genome. Sex-specific interactome network maps were generated, indicating the regulatory TFs by their effects on DEGs and further on processes leading to the formation of different sex flowers. The network analysis identified major families of regulatory TFs. The most abundant families were: MYB, AP2/ERF, NAC and bZIP, and those with the greatest impact on developmental processes were identified, namely the AP/ERF family, followed by DOF, MYB, MADS and others. Thus, the central nodes and key regulators in the networks were identified with respect to male, female and hermaphrodite. Here, we proposed the first model of the regulatory network of TFs that influences the metabolism of sex development in cucumber. These findings may help to understand the molecular genetics and functional mechanisms underlying sex determination processes.

Sepsis is an inflammatory disorder caused by the host’s dysfunctional response to infection. Septic patients present diverse clinical characteristics, and in the recent years it has been the main cause of death in intensive care units (ICU). Aquaporins, membrane proteins with role in water transportation, have been reported to participate in numerous biological processes. Their role in sepsis progression has been studied extensively. This review aims to examine recent literature on aquaporin expression and regulation in clinical sepsis, as well as established experimental models of sepsis. We will present how sepsis affects aquaporin expression at the molecular and protein level. Moreover, we will delve into the importance of aquaporin regulation at the transcriptional, post-transcriptional, translational, and post-translational level in sepsis, by presenting data on aquaporin regulation by non-coding RNAs and selected chemical molecules. Finally, we will focus on the importance of aquaporin single nucleotide polymorphisms in the setting of sepsis.

Artificial intelligence (AI) systems are poised to become deeply integrated into society. If developed responsibly, AI has potential to benefit humanity immensely. However, it also poses a range of risks, including risks of catastrophic accidents. It is crucial that we develop oversight mechanisms that prevent harm. This article outlines a framework for evaluating and auditing AI to provide assurance of responsible development and deployment, focusing on catastrophic risks. We argue that responsible AI development requires comprehensive auditing that is proportional to AI systems’ capabilities and available affordances. This framework offers recommendations toward that goal and may be useful in the design of AI auditing and governance regimes.

Pancreatic neuroendocrine tumors (PNETs) are characterized by dysregulated signaling pathways that are crucial for tumor formation and progression. The efficacy of traditional therapies is limited, particularly in treatment of PNETs at advanced stage. Epigenetic alterations profoundly impact the activity of signaling pathways in cancer development, offering potential opportunities for drug development. There is currently a lack of extensive research on epigenetic regulation in PNETs. To fill this gap, we first summarize major signaling events which are involved in PNET development. Then, we discuss the epigenetic regulation of these signaling pathways in the context of both PNET and commonly occurring, and therefore more extensively studied, malignancies. Finally, we will offer perspective on the future research direction of PNET epigenome and its potential applications in patient care.

The nervous system is composed of neurons, which conduct the signals, and glial cells that provide metabolic and functional support and protection to neurons. An important component of the nervous system is the myelin sheath, an insulating layer around the nerves of the brain and spinal cord, which allows a fast and efficient nerve conduction and therefore the proper transmission of signal to all tissues and organs. Myelin is made of protein and fatty substances and gives protection for the propagation of the electrical impulse. Myelin alterations determine the onset of several neuropathies as the electrical signal can be slowed or stopped. Myelin is formed by oligodendrocytes in the central nervous system (CNS) and by Schwann cells in the peripheral nervous system (PNS). Differences in myelination in the CNS and PNS have been found and molecules involved in membrane trafficking such as SNAREs and rabs have been proved to contribute to several aspects regarding the formation of myelin or dysmyelination. Here, I will describe the role of these proteins in regulating membrane trafficking and nerve conduction, myelin biogenesis and maintenance.

Past public health crises (e.g. tobacco, alcohol, opioids, cholera, HIV, lead, pollution, venereal disease, even COVID-19) have been met with interventions targeted both at the individual and all of society. While the healthcare community is very aware that the global pandemic of non-communicable diseases (NCD’s) has its origins in our Western ultraprocessed food diet, society has been slow to initiate any interventions other than public education, which has been ineffective, in part due to food industry interference. This article provides the rationale for such public health interventions, by compiling the evidence that added sugar, and by proxy the ultraprocessed food category, meets the four criteria set by the public health community as necessary and sufficient for regulation — addiction, toxicity, ubiquity, and externalities (how does your consumption affect me?). To its credit, some countries have recently heeded this science and have instituted sugar taxation policies to help ameliorate NCD’s within their borders. This article also supplies scientific counters to food industry talking points, in order to guide both scientists and policy makers in instituting further appropriate public health measures to quell this pandemic.

RNA epigenetics is perhaps the most recent aspect of interest for translational epigeneticists. RNA modifications create such an extensive network of epigenetically driven combination whose role in physiology and pathophysiology is still far from being elucidated. Not surprisingly, some of the players determining changes into RNA structure are in common with those involved in DNA and chromatin structure regulation, while other molecules seem very specific to RNA. It is envisaged, then, that new small molecules, acting selectively on RNA epigenetic changes, will be reported soon, opening new therapeutic interventions based on the correction of the RNA epigenetic landscape. In this review, we shall summarize some aspects of RNA epigenetics limited to those in which the potential clinical translatability to cardiovascular disease is emerging.