Targeting STAT3 in Cancer with Nucleotide Therapeutics.

Signal transducer and activator of transcription 3 (STAT3) plays a critical role in promoting the proliferation and survival of tumor cells. As a ubiquitously-expressed transcription factor, STAT3 has commonly been considered an "undruggable" target for therapy; thus, much research has focused on targeting upstream pathways to reduce the expression or phosphorylation/activation of STAT3 in tumor cells. Recently, however, novel approaches have been developed to directly inhibit STAT3 in human cancers, in the hope of reducing the survival and proliferation of tumor cells. Several of these agents are nucleic acid-based, including the antisense molecule AZD9150, CpG-coupled STAT3 siRNA, G-quartet oligodeoxynucleotides (GQ-ODNs), and STAT3 decoys. While the AZD9150 and CpG-STAT3 siRNA interfere with STAT3 expression, STAT3 decoys and GQ-ODNs target constitutively activated STAT3 and modulate its ability to bind to target genes. Both STAT3 decoy and AZD9150 have advanced to clinical testing in humans. Here we will review the current understanding of the structures, mechanisms, and potential clinical utilities of the nucleic acid-based STAT3 inhibitors

RNase HI Is Essential for Survival of Mycobacterium smegmatis

RNases H are involved in the removal of RNA from RNA/DNA hybrids. Type I RNases H are thought to recognize and cleave the RNA/DNA duplex when at least four ribonucleotides are present. Here we investigated the importance of RNase H type I encoding genes for model organism Mycobacterium smegmatis. By performing gene replacement through homologous recombination, we demonstrate that each of the two presumable RNase H type I encoding genes, rnhA and MSMEG4305, can be removed from M. smegmatis genome without affecting the growth rate of the mutant. Further, we demonstrate that deletion of both RNases H type I encoding genes in M. smegmatis leads to synthetic lethality. Finally, we question the possibility of existence of RNase HI related alternative mode of initiation of DNA replication in M. smegmatis, the process initially discovered in Escherichia coli. We suspect that synthetic lethality of double mutant lacking RNases H type I is caused by formation of R-loops leading to collapse of replication forks. We report Mycobacterium smegmatis as the first bacterial species, where function of RNase H type I has been found essential.The study was supported by POIG.01.01.02-10-107/09 project implemented under Innovative Economy Operational Programme, years 2007–2013 "Studies of the molecular mechanisms at the interface the human organism - the pathogen - environmental factors" and by grant of Polish National Center of Science 2011/01/N/NZ6/04186 “Identification of a novel mechanism of initiation of DNA replication in Mycobacterium smegmatis”

Faktor-Faktor Mempengaruhi Penurunan Pendapatan Petani Padi Tadah Hujan Akibat Pandemi Covid-19 di Desa Sungai Dua Kabupaten Banyuasin

Niasarah, K., Aryani, D., Lifianthi, L., Rosana, E., & Malini, H. (2023). Factors affecting the decreased income of rain-fed rice farmers due to the Covid-19 Pandemic in Sungai Dua Village, Banyuasin Regency. In: Herlinda S et al. (Eds.), Prosiding Seminar Nasional Lahan Suboptimal ke-11 Tahun 2023, Palembang  21 Oktober 2023. (pp. 683-695).  Palembang: Penerbit & Percetakan Universitas Sriwijaya (UNSRI).The existence of Covid-19 pandemic affected many sectors, one of which was the agricultural sector, namely rice farming in Sungai Dua Village. The government's policy of implementing Large-Scale Social Restrictions causes farmers difficulty obtaining subsidized fertilizers, so farmers are forced to reduce the use of fertilizers. During the Covid-19 Pandemic, farmers were forced to buy non-subsidized fertilizers at higher prices, this resulted in increased production costs, thereby reducing farmers' income. The objectives of this study are to: 1) analyze the difference in income of rice farmers before and during the Covid-19 Pandemic; and 2) Analyze the factors that affected the decline in rice farmers' income during the Covid-19 Pandemic. This research was conducted in May until June 2023 in Sungai Dua Village, Rambutan District, Banyuasin Regency. The data collection method used the survey method and sample selection was carried out by simple random sampling method. Analysis was carried out by t test and multiple linear regression. The results showed that there was a significant difference between farmers' income before and during the Covid-19 Pandemic. During the Covid-19 Pandemic, farmers' income fell by around 29.95 percent. Before the Covid-19 Pandemic, rice farmers' income was IDR 16,332,667/la/yr, whereas during the Covid-19 Pandemic, rice farmers' income fell to IDR 11,440,267/la/yr. Factors that had a significant effect on rice farmers' income, namely land area, level of education, fertilizer costs, and labor costs, while the time period dummy has no significant effect on the income of rice farmers

A Novel in vitro Human Macrophage Model to Study the Persistence of Mycobacterium tuberculosis Using Vitamin D3 and Retinoic Acid Activated THP-1 Macrophages

Mycobacterium tuberculosis (Mtb) replicates within the human macrophages and we investigated the activating effects of retinoic acid (RA) and vitamin D3 (VD) on macrophages in relation to the viability of intracellular Mtb. A combination of these vitamins (RAVD) enhanced the levels of DC-SIGN and mannose receptors on THP-1 macrophages that increased mycobacterial uptake but inhibited the subsequent intracellular growth of Mtb by inducing reactive oxygen species and autophagy. RAVD also enhanced antigen presenting and chemotactic receptors on THPs suggesting an activated phenotype for RAVD activated THPs. RAVD mediated activation was also associated with a marked phenotypic change in Mtb infected THPs that fused with adjacent THPs to form multinucleated giant cells (MNGCs). Typically, MNGCs occurred over 30 days of in vitro culture and contained non-replicating persisting Mtb for more than 60 days in culture. Latent tuberculosis occurs in over a third of mankind and we propose that RAVD mediated induction of persistent Mtb within human macrophages provides a novel model to develop therapeutic approaches and investigate pathogenesis of latency

Challenges of Early Years leadership preparation: a comparison between early and experienced Early Years practitioners in England

Leadership has been under-researched in the Early Years (EY) sector of primary schools in England, especially in leading change for professional development. The aim of this paper is to theorise what the leadership culture for EY practitioners looks like, and how Initial Teacher Training providers and schools are preparing practitioners for leadership. Using case studies of EY practitioners in different stages of their career in primary schools, we offer an insight into their preparedness for leadership in EY, the implication being that leadership training requires an understanding and embedding of the EY culture and context. Interviews with both sample groups allowed for deeper insight into the lived world. Interviews were also conducted with the head teachers to gain an overview of the leadership preparation they provided. The main findings suggest that newer EY practitioners are better prepared for leadership from their university training in comparison to more experienced EY practitioners

Template-Assisted Synthesis and Characterization of Passivated Nickel Nanoparticles

Potential applications of nickel nanoparticles demand the synthesis of self-protected nickel nanoparticles by different synthesis techniques. A novel and simple technique for the synthesis of self-protected nickel nanoparticles is realized by the inter-matrix synthesis of nickel nanoparticles by cation exchange reduction in two types of resins. Two different polymer templates namely strongly acidic cation exchange resins and weakly acidic cation exchange resins provided with cation exchange sites which can anchor metal cations by the ion exchange process are used. The nickel ions which are held at the cation exchange sites by ion fixation can be subsequently reduced to metal nanoparticles by using sodium borohydride as the reducing agent. The composites are cycled repeating the loading reduction cycle involved in the synthesis procedure. X-Ray Diffraction, Scanning Electron Microscopy, Transmission Electron microscopy, Energy Dispersive Spectrum, and Inductively Coupled Plasma Analysis are effectively utilized to investigate the different structural characteristics of the nanocomposites. The hysteresis loop parameters namely saturation magnetization and coercivity are measured using Vibrating Sample Magnetometer. The thermomagnetization study is also conducted to evaluate the Curie temperature values of the composites. The effect of cycling on the structural and magnetic characteristics of the two composites are dealt in detail. A comparison between the different characteristics of the two nanocomposites is also provided

Compromising the 19S proteasome complex protects cells from reduced flux through the proteasome

Proteasomes are central regulators of protein homeostasis in eukaryotes. Proteasome function is vulnerable to environmental insults, cellular protein imbalance and targeted pharmaceuticals. Yet, mechanisms that cells deploy to counteract inhibition of this central regulator are little understood. To find such mechanisms, we reduced flux through the proteasome to the point of toxicity with specific inhibitors and performed genome-wide screens for mutations that allowed cells to survive. Counter to expectation, reducing expression of individual subunits of the proteasome's 19S regulatory complex increased survival. Strong 19S reduction was cytotoxic but modest reduction protected cells from inhibitors. Protection was accompanied by an increased ratio of 20S to 26S proteasomes, preservation of protein degradation capacity and reduced proteotoxic stress. While compromise of 19S function can have a fitness cost under basal conditions, it provided a powerful survival advantage when proteasome function was impaired. This means of rebalancing proteostasis is conserved from yeast to humans

The Spectrum of Scarring in Craniofacial Wound Repair

Fibrosis is intimately linked to wound healing and is one of the largest causes of wound-related morbidity. While scar formation is the normal and inevitable outcome of adult mammalian cutaneous wound healing, scarring varies widely between different anatomical sites. The spectrum of craniofacial wound healing spans a particularly diverse range of outcomes. While most craniofacial wounds heal by scarring, which can be functionally and aesthetically devastating, healing of the oral mucosa represents a rare example of nearly scarless postnatal healing in humans. In this review, we describe the typical wound healing process in both skin and the oral cavity. We present clinical correlates and current therapies and discuss the current state of research into mechanisms of scarless healing, toward the ultimate goal of achieving scarless adult skin healing

Multimedia e-learning on technologies for efficient water use

One of the Millennium Development Goals is “To ensure environmental sustainability”, with a special task dedicated to halve by 2015 the proportion of people without sustainable access to safe drinking water. This task collides with alarming studies that, for instance, foresee an acute water shortage in India and other Asian countries by 2050. In this conflicting context we present ED-WAVE, a developing project funded by the Asia-Link Programme, participating six countries (India, Sri Lanka, Thailand, Greece, Spain and Finland). Its goal is to create a sustainable international cooperation framework and to develop a multimedia tool for e-Learning on technologies for conservation, reclamation and reuse of natural resources. We therefore use IT tools aimed at improving people’s education, including analysis of current water use status in Asia and Europe, review of potential technological interventions, simulation of impacts of specific technology interventions and translation of knowledge into electronic teaching material

Magnetic and processability studies on rubber ferrite composites based on natural rubber and mixed ferrite

Polycrystalline single phasic mixed ferrites belonging to the series Ni 1−x Zn x Fe 2 O 4 for various values of x have been prepared by conventional ceramic techniques. Pre-characterized nickel zinc ferrites were then incorporated into a natural rubber matrix according to a specific recipe for various loadings. The processability and cure parameters were then determined. The magnetic properties of the ceramic filler as well as the ferrite loaded rubber ferrite composites (RFC) were evaluated and compared. A general equation for predicting the magnetic properties was also formulated. The validity of these equations were then checked and correlated with the experimental data. The coercivity of the RFCs almost resemble that of the ceramic component in the RFC. Percolation threshold is not reached for a maximum loading of 120 phr (parts per hundred rubber by weight) of the filler. These studies indicate that flexible magnets can be made with appropriate magnetic properties namely saturation magnetisation (M s ) and magnetic field strength (H c ) by a judicious choice of x and a corresponding loading. These studies also suggest that there is no possible interaction between the filler and the matrix at least at the macroscopic level. The formulated equation will aid in synthesizing RFCs with predetermined magnetic properties. C 2001 Kluwer Academic Publisher