Establishment of safe and efficient infertile goat model using cyclophosphamide and its implications at the cellular and molecular level

At present, research progress of anthracene's toxicity lags far behind the pollution caused on its application fields such as petroleum and minerals. In this paper, anthracene-induced oxidative stress effects and genetic toxicity were investigated at both the molecular and cellular levels. The intracellular oxidative stress effect of anthracene on earthworm primary coelomocyte was confirmed by the detection of reactive oxygen species, antioxidant enzymes activity, and malondialdehyde content. Moreover, after anthracene exposure, the decrease in the mitochondrial membrane potential and cell viability also indicated the adverse effects of anthracene on earthworm coelomocyte. The comet assay proved the break in DNA strand, revealing the anthracene-induced DNA damage. On the molecular level, we revealed that anthracene caused the shrinkage of the catalase skeleton and altered the microenvironment of chromophores of catalase by multi-spectral methods. Molecular simulation results indicated that anthracene interacted with His74 by "arene-arene" force and the dominant binding site between anthracene and catalase was close to the active site of catalase. In addition, anthracene was shown to bind to the DNA molecule by groove binding mode. This study proposed a new combined analysis method for the toxicity evaluation of anthracene at the cellular and molecular levels. Graphical abstract This study creatively proposed a new combined analysis for the toxicity evaluation of ANT at the cellular and molecular levels.

Raw bioelectrical impedance parameters as informative markers of body composition in youth.

Personalized medicine: from disease-centered to human-centered medicine Personalized medicine deals with individual diversities and the complexity of the human body. Current healthcare models are diseaseoriented and focus on pathogens and environmental or external factors [4]. Personalized medicine would enable the change from such disease-centered medicine to human-centered medicine. Pharmacogenomics arose in response to such recognition. Pharmacogenomics studies genetic variations among individuals to predict disease susceptibility and responses to therapeutic agents [5,6]. The investigation of genetic diversity may enable the identification of optimal drug targets for certain patient populations, and empower physicians to make the right decisions. By focusing on patients’ genetic or biomarker profiles, pharmacogenomics represents the evolution from treating the disease itself to treating the malfunction of an individual person, the ‘root’ of the disease [7]. With such practices, patients can be regrouped and drugs can be recategorized. For instance, similar diseases may require different treatments, while different diseases may be treated with the same or similar approaches. Because of the diversity of patients’ biological backgrounds, the same disease may be caused by genetic variation in different people, who will respond differently to the same drug. For example, polymorphisms in the ABCB1 gene contribute to cancer risk and different therapeutic responses [8]. Patients with certain genotypes, such as 1236C/C, showed poorer survival than patients with other genotypes. Such situations require individualized treatments for the same disease (cancer) to ensure the best possible results. On the other hand, Challenges & new concepts in biomedicine In this era of change, biomedicine is heading toward a revolutionary new path. This path is a transformation from reductionism toward a holistic paradigm, from ‘one-size-fits-all’ therapeutics towards personalized medicine. Such changes are necessary to meet the challenges in healthcare and the pharmaceutical industry, for example, the high costs in healthcare, low efficacy of drugs and increased incidents of adverse drug reactions (ADRs). ADRs are one of the leading causes of death and illness in the USA [1]. Although the research and development costs in the pharmaceutical industry are soaring, high-profile drug withdrawals are elevating, while the US FDA’s approval for new drugs is decreasing [2]. At the same time, the gap between biomedical science and clinical practice has made it hard to translate scientific advancements into improved healthcare. These challenges and difficulties are calling for the development of new strategies, new concepts, or even a new kind of medicine to meet these goals:

Special Issue on Lipidomics.

Molecular and cellular mechanisms for zoledronic acid-loaded magnesium-strontium alloys to inhibit giant cell tumors of bone

The extensive product and application of cadmium-quantum dots (Cd-QDs), one kind of semiconductor nanomaterials, lead to prolonged exposure to the environment. Cd-QDs have shown good properties in biomedical and imaging-related fields; the safety of Cd-QDs limits the application of these materials and technologies, however. The systematic distribution of CdTe QDs in organisms has been ascertained in previous studies. Nevertheless, it is relatively less reported about the toxicity of CdTe QDs to immune macromolecules and organs. Based on this, immunocytes (including lymphocyte subsets-CD4+ T and CD8+ T cells, splenocytes) and selenoprotein P (SelP) were chosen as targets for CdTe QDs immunotoxicity studies. Results indicate that CdTe QDs induced cytotoxicity to CD4+ T cells, CD8+ T cells and splenocytes by reducing cell viability and causing apoptosis as CdTe QDs and Cd2+ enter cells. At the molecular level, the direct interaction between CdTe QDs and SelP is proved by multispectral measurements, which demonstrated the alteration of protein structure. The combined results show that CdTe QDs induced adverse effects on the immune system at the cellular and molecular levels. This research contributes to a better understanding of CdTe QDs cause harmful damage to the immune system and provides new strategies for the inhibition and treatment of health damages caused by CdTe QDs.

The oral DPP8/9 inhibitor BXCL701 in combination with an anti-PD-1 antibody (aPD-1) [AACR 2017] or in triple combination with aPD-1 and pegylated IL-2 (NKTR-214) [ASCO 2018] has demonstrated inhibition of tumor growth or complete regression respectively in animal models of pancreatic cancer. In the present study, the mechanism of action of BXCL701 has been elucidated in a sub-chronic pharmacokinetic / pharmacodynamic study at molecular and cellular level, by administering BXCL701 as a single agent. BXCL701 (20 μg) was administered orally every day for 14 days in tumor (Pan02) bearing mice. Tumor and serum samples were harvested after 0, 1, 8 and 16 hrs after BXCL701 administration on day 1, 7 and 14. Serum samples were analysed for cytokines and tumor tissues were analysed for infiltrating immune cells and gene expression. BXCL701 is known to inhibit regulatory proteases DPP8/9, consequently activating Nlrp1b inflammasome, which in turn activates pro-caspase-1 to mediate pyroptosis in mouse macrophages [Okondo et al, 2018]. Caspase-1 is involved in cleavage of pro-IL-1β and pro-IL-18 to their active forms, IL-1β and IL-18 respectively [Walle et al, 2016,]. IL-18 was observed to be significantly (p<0.05) upregulated (>50 fold) at 8 hrs on day 1 and achieved steady state levels by day 7 in BXCL701-treated animals. Other cytokines like IL-1β, IFN-γ, G-CSF, IL-5, IL-6, CXCL9, MCP-1, KC and Eotaxin were also observed to be upregulated in BXCL701-treated animals at the 8 hr timepoint on day 1, 7 and 14 in comparison to day 1, 0 hr. BXCL701 significantly upregulates T cells (total T cells, CD4+ T helper cells and CD8+ T cells) infiltration along with NK cells within the tumor microenvironment. It also appears to enhance antigen presentation by upregulating MHC class I genes and MHC class I expressing cells within the tumor. The mechanism of action of BXCL701 was evaluated at the molecular level as well. The comparison of genes in tumor tissues from BXCL701-treated animals vs respective vehicle-treated animals on Day 7 and 14 demonstrated that the upregulated gene clusters were innate and adaptive immune response genes, T-cell receptor genes and MHC genes. Also, genes associated with T cell and NK cell mediated apoptosis and cytolysis e.g. FasL, GzmA, were upregulated and indicates enhanced cell death (e.g. upregulation of pdcd1) within tumor. On the other hand, downregulated gene clusters belonged to functional categories like cell cycle, DNA repair, several genes associated with cancer progression (GPCRs and Olfactory receptors) and extra cellular matrix (ECM) modification (collagen and metalloproteases). In conclusion, BXCL701-treatment induces innate and adaptive immune responses that leads to tumor growth inhibition probably via inducing cell death and reducing ECM modification. Citation Format: Veena Agarwal, John MacDougall, shubhendu Trivedi, Dimple Bhatia, Zeenia Jagga, Hemant Banga, Diane Healy, Sreenivas Adurthi, Vince O'Neill. The dipeptidyl peptidase inhibitor BXCL701 activates innate immunity followed by adaptive immunity on a molecular and cellular level in a mouse model of pancreatic cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 962.

Chicken ovarian follicular atresia: interaction network at organic, cellular, and molecular levels

Many cellular processes are carried out by large macromolecular assemblies. We systematically analyzed large macromolecular assemblies in the cytoplasm of mouse macrophages (RAW264.7 cell line), cells with crucial roles in immunity and inflammation. Fractionation of the cytoplasmic fraction was performed using sucrose density gradient centrifugation, and individual fractions were subjected in parallel to (i) identification of constituent proteins by mass spectrometry and (ii) structural visualization by electron microscopy. Macromolecular assemblies present in the fractions were analyzed by integrating available data using bioinformatic approaches. We identified 368 unique proteins in our sample. Among these are components of some well-characterized assemblies involved in diverse cellular processes and structures including translation, proteolysis, protein folding, metabolism, and the cytoskeleton, as well as less characterized proteins that may correspond to additional components of known assemblies or other homo- or hetero-oligomeric structures. Single-particle analysis of electron micrographs of negatively stained samples allowed the identification of clearly distinguishable two-dimensional projections of discrete protein assemblies. Among these, we can identify small ribosomal subunits and preribosomal particles, the 26S proteasome complex and small ringlike structures resembling the molecular chaperone complexes. In addition, a broad range of discrete and different complexes were seen at size ranges between 11 to 38 nm in diameter. Our procedure selects the assemblies on the basis of abundance and ease of isolation, and therefore provides an immediately useful starting point for further study of structure and function of large assemblies. Our results will also contribute toward building a molecular cell atlas.

Trace elements are intimately involved in biological function and dysfunction at all levels of biological organization. At the molecular level, trace elements perform innumerable catalytic and structural roles in macromolecules and other cell constituents. At the cellular level, trace elements are necessary for maintenance and regulation of compartmentation of cell function, stimulus-response coupling, gene regulation, etc. Perturbations in trace element homeostasis and utilization at the molecular and cellular level is manifested in many disease states. Biological systems have evolved elaborate and diverse control mechanisms to provide for trace element homeostasis at the sub-cellular, cellular, and organismal levels. These critical functions of trace elements have profound influence on human health and disease states. Trace elements are well recognized as contribution factors in modifying development, aging, oncogenesis, and many chronic diseases including cardiovascular disorders.KeywordsLiver ParenchymaTrace Element ContentTrace Element AnalysisPerivenous RegionBile Acid SecretionThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Mechanical circulatory support is a life-saving therapy that will become either a bridge-to-transplantation or definitive therapy if heart transplantation is not possible. Failing hearts supported by a ventricular assist device were often found to recover at molecular and cellular level but translation of these changes into functionally-stable cardiac recovery allowing long-term heart transplantation/ventricular assist device-free outcomes after weaning from ventricular assist device is relatively rare and related to the etiology, severity and duration of myocardial damage. The reason for the discrepancy between high recovery rates on the cellular and molecular levels and the low rate of cardiac recovery allowing ventricular assist device explantation is unknown.

The biological effects of Piezocision™ on bone for accelerated tooth movement: A systematic review of animal studies

Perfluorodecanoic acid-induced oxidative stress and DNA damage investigated at the cellular and molecular levels

Sleep, Plasticity and Memory from Molecules to Whole-Brain Networks

Optical spectroscopic techniques such as CD, Raman scattering, and fluorescence imaging allowed us to analyze the complex formation and vectorization of a single-stranded 20-mer phosphorothioate oligodeoxynucleotide with a 15-mer amphipathic peptide at molecular and cellular levels. Different solvent mixtures (methanol and water) and molecular ratios of peptide/oligodeoxynucleotide complexes were tested in order to overcome the problems related to solubility. Optimal conditions for both spectroscopic and cellular experiments were obtained with the molecular ratio peptide/oligodeoxynucleotide equal to 21:4, corresponding to a 7:5 ratio for their respective +/- charge ratio. At the molecular level, CD and Raman spectra were consistent with a alpha-helix conformation of the peptide in water or in a methanol-water mixture. The presence of methanol increased considerably the solubility of the peptide without altering its alpha-helix conformation, as evidenced by CD and Raman spectroscopies. UV absorption melting profile of the oligodeoxynucleotide gave rise to a flat melting profile, corresponding to its random structure in solution. Raman spectra of oligodeoxynucleotide/peptide complexes could only be studied in methanol/water mixture solutions. Drastic changes observed in Raman spectra have undoubtedly shown: (a) the perturbation occurred in the peptide secondary structure, and (b) possible interaction between the lysine residues of the peptide and the oligodeoxynucleotide. At the cellular level, the complex was prepared in a mixture of 10% methanol and 90% cell medium. Cellular uptake in optimal conditions for the oligodeoxynucleotide delivery with low cytotoxicity was controlled by fluorescence imaging allowing to specifically locate the compacted oligonucleotide labeled with fluorescein at its 5'-terminus with the peptide into human glioma cells after 1 h of incubation at 37 degrees C.