CK2 (an acronym derived from the misnomer "casein kinase 2") denotes a ubiquitous, highly pleiotropic protein kinase which has been implicated in global human pathologies, with special reference to cancer. A large spectrum of fairly selective, cell permeable CK2 inhibitors are available, one of which, CX4945 is already in clinical trials for the treatment of neoplasia. Another recently developed CK2 inhibitor, GO289, displays in vitro potency and selectivity comparable to CX4945. Here the cellular efficiency of these two inhibitors has been evaluated by treating C2C12 myoblasts for 5 h with each of them at 4 μM concentration and running a quantitative phosphoproteomics analysis of phosphosites affected by the two compounds. A small but significant proportion of the quantified phosphosites is decreased by treatment with CX4945 and, even more with GO289. This figure substantially increases if a subset of quantified phosphosites conforming to the CK2 consensus (pS/pT-x-x-D/E/pS/pT) is considered. Also in this case GO289 is more effective than CX4945. By adopting stringent criteria two shortlists of 70 and 35 sites whose phosphorylation is decreased >50% by GO289 and CX4945, respectively, have been generated. All these phosphosites conform to the consensus of CK2 with just sporadic exceptions. Their WebLogos are indistinguishable from that of bona fide CK2 phosphosites and their Two-Sample Logos rule out any significant contribution of Pro-directed and basophilic protein kinases to their generation. To sum up, we can conclude that by treating C2C12 cells for 5 h with either CX4945 or GO289 off-target effects are negligible since almost all the phosphosites undergoing a substantial reduction are attributable to CK2, with a higher inhibitory efficacy displayed by GO289. CX4945 and GO289 provide highly selective tools to control the CK2-dependent phosphoproteome compared with previously developed CK2 inhibitors.

The discovery of natural specialized pro-resolving mediators and their corresponding receptors, such as formyl peptide receptor 2 (FPR2), indicated that resolution of inflammation (RoI) is an active process which could be harnessed for innovative approaches to tame pathologies with underlying chronic inflammation. In this work, homology modelling, molecular docking and pharmacophore studies were deployed to assist the rationalization of the structure-activity relationships of known FPR2 agonists. The developed pharmacophore hypothesis was then used in parallel with the homology model for the design of novel ligand structures and in virtual screening. In the first round of optimization compound 8, with a cyclopentane core, was chosen as the most promising agonist (β-arrestin recruitment EC50 = 20 nM and calcium mobilization EC50 = 740 nM). In a human neutrophil static adhesion assay, compound 8 decreased the number of adherent neutrophils in a concentration dependent manner. Further investigation led to the more rigid cycloleucines (compound 22 and 24) with improved ADME profiles and maintaining FPR2 activity. Overall, we identified novel cyclopentane urea FPR2 agonists with promising ADMET profiles and the ability to suppress the inflammatory process by inhibiting the neutrophil adhesion cascade, which indicates their anti-inflammatory and pro-resolving properties.

Even today, the role of the histamine H2 receptor (H2R) in the central nervous system (CNS) is widely unknown. In previous research, many dimeric, high-affinity and subtype-selective carbamoylguanidine-type ligands such as UR-NK22 (5, pKi = 8.07) were reported as H2R agonists. However, their applicability to the study of the H2R in the CNS is compromised by their molecular and pharmacokinetic properties, such as high molecular weight and, consequently, a limited bioavailability. To address the need for more drug-like H2R agonists with high affinity, we synthesized a series of monomeric (thio)carbamoylguanidine-type ligands containing various spacers and side-chain moieties. This structural simplification resulted in potent (partial) agonists (guinea pig right atrium, [35S]GTPγS and β-arrestin2 recruitment assays) with human (h) H2R affinities in the one-digit nanomolar range (pKi (139, UR-KAT523): 8.35; pKi (157, UR-MB-69): 8.69). Most of the compounds presented here exhibited an excellent selectivity profile towards the hH2R, e.g. 157 being at least 3800-fold selective within the histamine receptor family. The structural similarities of our monomeric ligands to pramipexole (6), a dopamine receptor agonist, suggested an investigation of the binding behavior at those receptors. The target compounds were (partial) agonists with moderate affinity at the hD2longR and agonists with high affinity at the hD3R (e.g. pKi (139, UR-KAT523): 7.80; pKi (157, UR-MB-69): 8.06). In summary, we developed a series of novel, more drug-like H2R and D3R agonists for the application in recombinant systems in which either the H2R or the D3R is solely expressed. Furthermore, our ligands are promising lead compounds in the development of selective H2R agonists for future in vivo studies or experiments utilizing primary tissue to unravel the role and function of the H2R in the CNS.

The outbreak of COVID-19 may differentially exacerbate anxiety and stress in people subjected to the real or perceived threat of the virus.

Six human induced pluripotent stem cell sublines (hiPSCs) were generated from human dermal fibroblasts (HDFs) derived from skin biopsies donated from monozygotic twin women wherein one woman had proven fertility and her sister was infertile due to ovarian failure. Three hiPSC sublines were created from each twin's HDFs. hiPSCs were reprogrammed using Sendai virus vectors and were subsequently positive for markers of self-renewal including OCT4, NANOG, TRA-1-81 and SSEA-4. Pluripotency was further verified using PluriTest. We show here that the hiPSC lines created from the twins are equivalent in measures of pluripotency and self-renewal, despite their differential diagnosis.

Previous studies have reported poor survival rates in inflammatory breast cancer (IBC) patients than non-inflammatory local advanced breast cancer (non-IBC) patients. However, until now, the survival rate of IBC and other T4 non-IBC (T4-non-IBC) patients remains unexplored.

Calf mortality generally occurs in calves prior to weaning, which is a serious problem in cattle breeding. Several causative variants of monogenic Mendelian disorders in calf mortality have been identified, whereas genetic factors affecting the susceptibility of calves to death are not well known. To identify variants associated with calf mortality in Japanese Black cattle, we evaluated calf mortality as a categorical trait with a threshold model and performed a genome-wide copy number variation (CNV) association study on calf mortality.

Dissolved oxygen (DO) in the water is a vital abiotic factor in aquatic animal farming. A hypoxic environment affects the growth, metabolism, and immune system of fish. Glycolipid metabolism is a vital energy pathway under acute hypoxic stress, and it plays a significant role in the adaptation of fish to stressful environments. In this study, we used multi-omics integrative analyses to explore the mechanisms of hypoxia adaptation in Genetically Improved Farmed Tilapia (GIFT, Oreochromis niloticus).

The treatment strategies for Myelodysplastic Syndromes (MDS) are usually based on the risk stratification system. However, few risk signatures which integrate the revised international prognostic scoring system (IPSS-R) with gene mutations can be easily applied in the real world.

The introduction of generics after the loss of patent exclusivity plays a major role in budget savings by significantly decreasing drug prices. The aims of this study were to estimate the budget savings from off-patent cancer drugs in 2020-2024 and to inform decision makers on how these savings could be used to improve the affordability of innovative cancer treatments in South Korea.

A limitation of current anticancer nanocarriers is the contradiction between multiple functions and favorable biocompatibility. Thus, we aimed to develop a compatible drug delivery system loaded with paclitaxel (PTX) for hepatocellular carcinoma (HCC) therapy. A basic backbone, PTX-loaded poly (3-hydroxybutyrate-co-3-hydroxyvalerate) PHBV nanoparticle (PHBV-PTX-NPs), was prepared by emulsion solvent evaporation. As a gatekeeper, the pH-sensitive coating was formed by self-polymerization of dopamine (PDA). The HCC-targeted arginine-glycine-aspartic acid (RGD)-peptide and PDA-coated nanoparticles (NPs) were combined through the Michael addition. Subsequently, the physicochemical properties of RGD-PDA-PHBV-PTX-NPs were characterized by dynamic light scattering-autosizer, transmission electron microscope, fourier transform infrared spectroscopy, differential scanning calorimetry, thermogravimetry and X-ray spectroscopy. As expected, the RGD-PDA-PHBV-PTX-NPs showed robust anticancer efficacy in a xenograft mouse model. More importantly, they exhibited lower toxicity than PTX to normal hepatocytes and mouse in vitro and in vivo, respectively. Taken together, these results indicate that the RGD-PDA-PHBV-PTX-NPs are potentially beneficial for easing conflict between multifunction and biocompatible characters of nanocarriers.

Alveolar epithelial cells play an essential role in the initiation and progression of pulmonary fibrosis, and the occurrence of epithelial-mesenchymal transition (EMT) may be the early events of pulmonary fibrosis. Recent studies have shown chemokines are involved in the complex process of EMT, and CXC chemokine ligand 16 (CXCL16) is also associated with many fibrosis-related diseases. However, whether CXCL16 is dysregulated in alveolar epithelial cells and the role of CXCL16 in modulating EMT in pulmonary fibrosis has not been reported. In this study, we found that CXCL16 and its receptor C-X-C motif chemokine receptor 6 (CXCR6) were upregulated in bleomycin induced EMT in human alveolar type II-like epithelial A549 cells. Synergistic effect of CXCL16 and bleomycin in promoting EMT occurrence, extracellular matrix (ECM) excretion, as well as the pro-inflammatory and pro-fibrotic cytokines productions in A549 cells were observed, and those biological functions were impaired by CXCL16 siRNA. We further confirmed that CXCL16 regulated EMT in A549 cells via the TGF-β1/Smad3 pathways. These results indicated that CXCL16 could promote pulmonary fibrosis by promoting the process of EMT via the TGF-β1/Smad3 signaling pathway.

Melanoma is the deadliest of skin cancers and has an increasing annual incidence worldwide. It is a multi-factorial disease most likely arising from both genetic predisposition and environmental exposure to ultraviolet light. Genetic variability of the components of the biological circadian clock is recognized to be a risk factor for different type of cancers. Moreover, two variants of a clock gene, RORA, have been associated with melanoma patient's prognosis. Our aim is to test the hypothesis that specific single nucleotide polymorphisms (SNPs) of the circadian clock genes may significantly influence the predisposition to develop cutaneous melanoma or the outcome of melanoma patients.

Casbene synthase (CS) is responsible for the first committed step in the biosynthesis of phorbol esters (PE) in the Euphorbiaceae. PE are abundant in the seeds of the biofuel crop Jatropha curcas and its toxicity precludes the use of the protein-rich cake obtained after oil extraction as an animal feed and the toxicity of the fumes derived from burning PE containing biofuel is also a matter of concern. This toxicity is a major hindrance to exploit the potential of this crop as a source of raw material to produce biodiesel. For this reason, the current research on J. curcas is mainly focused on the understanding of the biosynthesis and site of synthesis of PE, as an avenue for the development of genotypes unable to synthesize PE in its seeds.

Woody plants with high glucose content are alternative bioresources for the production of biofuels and biochemicals. Various pretreatment methods may be used to reduce the effects of retardation factors such as lignin interference and cellulose structural recalcitrance on the degradation of the lignocellulose material of woody plants.

The gut microbiota plays a central role in host physiology and in several pathological mechanisms in humans. Antibiotics compromise the composition and functions of the gut microbiota inducing long-lasting detrimental effects on the host. Recent studies suggest that the efficacy of different clinical therapies depends on the action of the gut microbiota. Here, we investigated how different antibiotic treatments affect the ability of the gut microbiota to control intestinal inflammation upon fecal microbiota transplantation in an experimental colitis model and in ex vivo experiments with human intestinal biopsies.

To mitigate the COVID-19 pandemic, countries worldwide have enacted unprecedented movement restrictions, physical distancing measures, and face mask requirements. Until safe and efficacious vaccines or antiviral drugs become widely available, viral testing remains the primary mitigation measure for rapid identification and isolation of infected individuals. We aimed to assess the economic trade-offs of expanding and accelerating testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) across the USA in different transmission scenarios.

Does an association exist between ovarian reserve, ovarian response and embryonic euploidy in female patients under age 35 years?

Migraine is associated with the activation and sensitisation of the trigeminovascular system and is often accompanied by mechanical hyperalgesia and allodynia. The mechanisms of mechanotransduction during a migraine attack are yet unknown. We have proposed that the ion channel Piezo1 may be involved, since it is expressed in endothelial cells as well as in trigeminal ganglion neurons, and thus, may contribute to the activation of both the vascular and neuronal component of the trigeminovascular system. We took advantage of extracellular recordings from the trigeminocervical complex - a key relay centre in the migraine pain pathway, to directly assess the impact of the differently applied Piezo1 agonist Yoda1 on the sensory processing at the spinal level. At a low dose, Yoda1 slightly facilitated the ongoing firing of central trigeminovascular neurons, however, at a high dose, this substance contributed to the suppression of their activity. Using intravital microscopy, we have revealed that Yoda1 at high dose can also induce the dilation of meningeal arteries innervated by trigeminal afferents. Collectively, here we have identified both neuronal and vascular modulation via selective activation of mechanosensitive Piezo1 channels, which provide new evidence in favour of the Piezo1 role in migraine pathogenesis. We propose several mechanisms that may underlie the revealed effects of Yoda1.

Chromosome ends are protected by guanosine-rich telomere DNA that forms stable G-quadruplex (G4) structures. The heterodimeric POT1-TPP1 complex interacts specifically with telomere DNA to shield it from illicit DNA damage repair and to resolve secondary structure that impedes telomere extension. The mechanism by which POT1-TPP1 accomplishes these tasks is poorly understood. Here, we establish the kinetic framework for POT1-TPP1 binding and unfolding of telomere G4 DNA. Our data identify two modes of POT1-TPP1 destabilization of G4 DNA that are governed by protein concentration. At low concentrations, POT1-TPP1 passively captures transiently unfolded G4s. At higher concentrations, POT1-TPP1 proteins bind to G4s to actively destabilize the DNA structures. Cancer-associated POT1-TPP1 mutations impair multiple reaction steps in this process, resulting in less efficient destabilization of G4 structures. The mechanistic insight highlights the importance of cell cycle dependent expression and localization of the POT1-TPP1 complex and distinguishes diverse functions of this complex in telomere maintenance.