Docking and Molecular Dynamic of Microalgae Compounds as Potential Inhibitors of Beta-Lactamase

Bacterial resistance is responsible for a wide variety of health problems, both in children and adults. The persistence of symptoms and infections are mainly treated with beta-lactam antibiotics. The increasing resistance to those antibiotics by bacterial pathogens generated the emergence of extended-spectrum beta-lactamases (ESBLs), an actual public health problem. This is due to rapid mutations of bacteria when exposed to antibiotics. In this case, beta-lactamases are enzymes used by bacteria to hydrolyze the beta-lactam rings present in the antibiotics. Therefore, it was necessary to explore novel molecules as potential beta-lactamases inhibitors to find antibacterial compounds against infection caused by ESBLs. A computational methodology based on molecular docking and molecular dynamic simulations was used to find new microalgae metabolites inhibitors of beta-lactamase. Six 3D beta-lactamase proteins were selected, and the molecular docking revealed that the metabolites belonging to the same structural families, such as phenylacridine (4-Ph), quercetin (Qn), and cryptophycin (Cryp), exhibit a better binding score and binding energy than commercial clinical medicine beta-lactamase inhibitors, such as clavulanic acid, sulbactam, and tazobactam. These results indicate that 4-Ph, Qn, and Cryp molecules, homologous from microalgae metabolites, could be used, likely as novel beta-lactamase inhibitors or as structural templates for new in-silico pharmaceutical designs, with the possibility of combatting beta-lactam resistanc

Indentation of the Pamirs with respect to the northern margin of Tibet: constraints from the Tarim basin sedimentary record

The Pamirs represent the indented westward continuation of the northern margin of the Tibetan Plateau, dividing the Tarim and Tajik basins. Their evolution may be a key factor influencing aridification of the Asian interior, yet the tectonics of the Pamir Salient are poorly understood. We present a provenance study of the Aertashi section, a Paleogene to late Neogene clastic succession deposited in the Tarim basin to the north of the NW margin of Tibet (the West Kunlun) and to the east of the Pamirs. Our detrital zircon U-Pb ages coupled with zircon fission track, bulk rock Sm-Nd, and petrography data document changes in contributing source terranes during the Oligocene to Miocene, which can be correlated to regional tectonics. We propose a model for the evolution of the Pamir and West Kunlun (WKL), in which the WKL formed topography since at least ~200 Ma. By ~25 Ma, movement along the Pamir-bounding faults such as the Kashgar-Yecheng Transfer System had commenced, marking the onset of Pamir indentation into the Tarim-Tajik basin. This is coincident with basinward expansion of the northern WKL margin, which changed the palaeodrainage pattern within the Kunlun, progressively cutting off the more southerly WKL sources from the Tarim basin. An abrupt change in the provenance and facies of sediments at Aertashi has a maximum age of 14 Ma; this change records when the Pamir indenter had propagated sufficiently far north that the North Pamir was now located proximal to the Aertashi region

IRE1/bZIP60-Mediated Unfolded Protein Response Plays Distinct Roles in Plant Immunity and Abiotic Stress Responses

Endoplasmic reticulum (ER)-mediated protein secretion and quality control have been shown to play an important role in immune responses in both animals and plants. In mammals, the ER membrane-located IRE1 kinase/endoribonuclease, a key regulator of unfolded protein response (UPR), is required for plasma cell development to accommodate massive secretion of immunoglobulins. Plant cells can secrete the so-called pathogenesis-related (PR) proteins with antimicrobial activities upon pathogen challenge. However, whether IRE1 plays any role in plant immunity is not known. Arabidopsis thaliana has two copies of IRE1, IRE1a and IRE1b. Here, we show that both IRE1a and IRE1b are transcriptionally induced during chemically-induced ER stress, bacterial pathogen infection and treatment with the immune signal salicylic acid (SA). However, we found that IRE1a plays a predominant role in the secretion of PR proteins upon SA treatment. Consequently, the ire1a mutant plants show enhanced susceptibility to a bacterial pathogen and are deficient in establishing systemic acquired resistance (SAR), whereas ire1b is unaffected in these responses. We further demonstrate that the immune deficiency in ire1a is due to a defect in SA- and pathogen-triggered, IRE1-mediated cytoplasmic splicing of the bZIP60 mRNA, which encodes a transcription factor involved in the expression of UPR-responsive genes. Consistently, IRE1a is preferentially required for bZIP60 splicing upon pathogen infection, while IRE1b plays a major role in bZIP60 processing upon Tunicamycin (Tm)-induced stress. We also show that SA-dependent induction of UPR-responsive genes is altered in the bzip60 mutant resulting in a moderate susceptibility to a bacterial pathogen. These results indicate that the IRE1/bZIP60 branch of UPR is a part of the plant response to pathogens for which the two Arabidopsis IRE1 isoforms play only partially overlapping roles and that IRE1 has both bZIP60-dependent and bZIP60-independent functions in plant immunity

Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk

Climate, people and faunal succession on Java, Indonesia: evidence from Song Gupuh

Song Gupuh, a partially collapsed cave in the Gunung Sewu Limestones of East Java, Indonesia, contains over 16 m of deposits with a faunal sequence spanning some 70 ka. Major changes in the range of animals represented show the impact of climate change and humans. The Terminal Pleistocene and Early Holocene was a period of maximum biodiversity. Human use of Song Gupuh and other cave sites in the region also intensified significantly from ca. 12 ka, together with a new focus on exploitation of small-bodied species (macaque monkeys and molluscs), the first evidence for import of resources from the coast, and use of bone and shell tools. Human activity, especially after the onset of the Neolithic around 2.6 ka, subsequently contributed to a progressive loss of many species from the area, including tapir, elephant, Malayan bear, rhino and tiger, and this extinction process is continuing. We conclude by discussing the biogeographical significance of Song Gupuh in the context of other sites in Java (e.g. Punung, Wajak) and further afield (e.g. Liang Bua)

Pyrolysis of Spent Biomass from Mallee Leaf Steam Distillation: Biochar Properties and Recycling of Inherent Inorganic Nutrients

A set of 24 biochars were produced from the slow and fast pyrolysis (at 400-700 °C) of a mallee leaf and two spent leaves collected after distilling the leaf in steam for 30 and 60 min. Under the same experimental conditions, the pyrolysis of the raw and spent leaves produced biochars of similar proximate and elemental analyses at similar char yields. However, the biochars from the raw leaf generally have higher contents of Na, K, Mg, Ca, and Cl than those from the spent leaves. The biochars were then leached via water to evaluate the recycling of inherent inorganic nutrients (i.e., Na, K, Mg, Ca, and Cl) and the leaching of organic carbon (C) in these biochars. On the basis of those in the mallee leaf, the quantities of Na, K, and Cl leached out by water from the biochars of the mallee leaf are considerably higher than those from the biochars of the spent leaves.However, the leaching of Mg in the slow-pyrolysis biochars follows an opposite trend. At pyrolysis temperatures higher than 400 °C, there are considerable decreases in the quantities of Na and Mg leached out from all of the biochars as well as in those of K and C from the fast-pyrolysis biochars. The results suggest that fast pyrolysis (at 500 °C) of the spent leaf collected after 60 min of steam distillation appears to produce favorable biochar for recycling inherent inorganic nutrients to soil