In silico investigation of Alsin RLD conformational dynamics and phosphoinositides binding mechanism

Alsin is a protein known for its major role in neuronal homeostasis and whose mutation is associated with early-onset neurodegenerative diseases. It has been shown that its relocalization from the cytoplasm to the cell membrane is crucial to induce early endosomes maturation. In particular, evidences suggest that the N-terminal regulator of chromosome condensation 1 like domain (RLD) is necessary for membrane association thanks to its affinity to phosphoinositides, membrane lipids involved in the regulation of several signaling processes. Interestingly, this domain showed affinity towards phosphatidylinositol 3-phosphate [PI(3)P], which is highly expressed in endosomes membrane. However, Alsin structure has not been experimentally resolved yet and molecular mechanisms associated with its biological functions are mostly unknown. In this work, Alsin RLD has been investigated through computational molecular modeling techniques to analyze its conformational dynamics and obtain a representative 3D model of this domain. Moreover, a putative phosphoinositide binding site has been proposed and PI(3)P interaction mechanism studied. Results highlight the substantial conformational stability of Alsin RLD secondary structure and suggest the role of one highly flexible region in the phosphoinositides selectivity of this domain

Prediction of Protein–Protein Interactions Between Alsin DH/PH and Rac1 and Resulting Protein Dynamics

Alsin is a protein of 1,657 amino acids known for its crucial role in vesicular trafficking in neurons thanks to its ability to interact with two guanosine triphosphatases, Rac1 and Rab5. Evidence suggests that Rac1 can bind Alsin central region, composed by a Dbl Homology (DH) domain followed by a Pleckstrin Homology (PH) domain, leading to Alsin relocalization. However, Alsin three-dimensional structure and its relationship with known biological functions of this protein are still unknown. In this work, a homology model of the Alsin DH/PH domain was developed and studied through molecular dynamics both in the presence and in the absence of its binding partner, Rac1. Due to different conformations of DH domain, the presence of Rac1 seems to stabilize an open state of the protein, while the absence of its binding partner results in closed conformations. Furthermore, Rac1 interaction was able to reduce the fluctuations in the second conserved region of DH motif, which may be involved in the formation of a homodimer. Moreover, the dynamics of DH/PH was described through a Markov State Model to study the pathways linking the open and closed states. In conclusion, this work provided an all-atom model for the DH/PH domain of Alsin protein; moreover, molecular dynamics investigations suggested underlying molecular mechanisms in the signal transduction between Rac1 and Alsin, providing the basis for a deeper understanding of the whole structure–function relationship for Alsin protein

Machine Learning Aided Molecular Modelling of Taste to Identify Food Fingerprints

Nature has developed fascinating mechanisms for selecting and monitoring nutrients through refined systems for food intake and uptake. One of the most important is the sense of taste. Taste is an emergent property involving a complex network of multilevel biological interactions beginning with the activation of specific protein receptors as a consequence of interaction with food molecules. In this context, crucial information about the mechanisms underlying the functioning of taste can be obtained by using molecular mechanistic modelling and machine learning tools borrowed from the field of drug design and the study of structural biology and protein biophysics. The ultimate goal is to develop predictive models capable of studying the intricate connection of molecular, sub-cellular and cellular phenomena underlying the complex biological mechanisms that regulate the relationships between food constituents and perceived taste. Artificial intelligence-driven digital tools for taste prediction and the study of molecular features of the interaction between food molecules and taste receptors have been recently developed by our group. Such tools are the operating engines of the decision support tool developed during the VIRTUOUS project (https://virtuoush2020.com). In this work, these tools were used to generate molecular fingerprints of coffee starting from its chemical composition. Through methods that integrate molecular modelling techniques and machine learning, molecules extracted from coffee were characterized in terms of binding affinity, specificity, and selectivity toward bitter receptors. The targeting ability of coffee-extracted molecules for human TAS2Rs was studied with an atomistic resolution to obtain a virtual fingerprint that links the molecular structure of food ingredients with their bitter profile. The study fits within the digital transition vision that leverages modelling and computational approaches to develop decision-supporting tools for developing solutions in the areas of nutrition, health and the modern food industry

Intermittent existence of a southern Californian upwelling cell during submillennial climate change of the last 60 kyr

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95021/1/palo1108.pd

In Silico Analysis of the Multi-Targeted Mode of Action of Ivermectin and Related Compounds

Some clinical studies have indicated activity of ivermectin, a macrocyclic lactone, against COVID-19, but a biological mechanism initially proposed for this anti-viral effect is not applicable at physiological concentrations. This in silico investigation explores potential modes of action of ivermectin and 14 related compounds, by which the infectivity and morbidity of the SARS-CoV-2 virus may be limited. Binding affinity computations were performed for these agents on several docking sites each for models of (1) the spike glycoprotein of the virus, (2) the CD147 receptor, which has been identified as a secondary attachment point for the virus, and (3) the alpha-7 nicotinic acetylcholine receptor (α7nAChr), an indicated point of viral penetration of neuronal tissue as well as an activation site for the cholinergic anti-inflammatory pathway controlled by the vagus nerve. Binding affinities were calculated for these multiple docking sites and binding modes of each compound. Our results indicate the high affinity of ivermectin, and even higher affinities for some of the other compounds evaluated, for all three of these molecular targets. These results suggest biological mechanisms by which ivermectin may limit the infectivity and morbidity of the SARS-CoV-2 virus and stimulate an α7nAChr-mediated anti-inflammatory pathway that could limit cytokine production by immune cells

Diagenetic behavior of barite in a coastal upwelling setting

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95374/1/palo1635.pd

Is pore water oxygen content decoupled from productivity on the California Margin? Trace element results from Ocean Drilling Program Hole 1017E, San Lucia slope, California

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95250/1/palo1223.pd

South China Sea surface water evolution over the last 12 Myr: A south-north comparison from Ocean Drilling Program Sites 1143 and 1146

Planktonic foraminifera (PF) from Ocean Drilling Program (ODP) Sites 1143 and 1146 in the southern and northern South China Sea (SCS), respectively, were quantitatively analyzed in order to reconstruct the sea-surface environment over the last 12 Myr. The observed decrease in deep-dwelling PF species after ∼10 Ma at both sites is interpreted to reflect a depression of the upper water thermocline, corresponding to the closure of the Indonesian Seaway around 11-9 Ma. This upper water column structure implies the intensification of equatorial Pacific warm currents and the initial formation of the western Pacific "warm pool" (WPWP) during the early Late Miocene. The consistent pattern of south-north thermocline evolution and the synchronous disappearance of Globoquadrina dehiscens (9.8 Ma) at both Sites 1143 and 1146 together imply that the entire SCS was likely under the influence of the newly developed WPWP at ∼10 Ma. After ∼8 Ma, sea-surface temperatures and thermocline variations evolved differently between the southern and northern SCS. The total deep-dwelling PF fauna at Site 1143 decreased gradually in abundance from 6.6 to 2 Ma, indicating a deepening of the thermocline in the southern SCS. In contrast, deep-dwelling PF species increased in abundance from 3.1 to 2 Ma at Site 1146, reflecting a shoaling of the thermocline in the northern SCS. This south-north contrast reflects two major environmental regimes: (1) the southern SCS, which has mainly been under the influence of the WPWP since the late Late Miocene, and (2) the northern SCS, where effects of the east Asian winter monsoon have prevailed, especially since the Late Pliocene. Estimate of past sea-surface temperatures (SSTs) at Site 1143 suggests a relatively stable and warm environment in the southern SCS since about 2.5 Ma, with an increased influence of warm subsurface waters after the mid-Pleistocene transition (1.2-0.9 Ma). In the northern SCS, however, a gradual decrease in winter SST recorded at Site 1146 over the last 4 Myr records east Asian monsoon evolution, especially the enhancement of the east Asian winter monsoon between 3.1 and 2 Ma. Copyright 2004 by the American Geophysical Union.Baohua Li, Jiliang Wang, Baoqi Huang, Qianyu Li, Zhimin Jian, Quanhong Zhao, Xin Su and Pinxian Wan

Formation and preservation of greigite (Fe₃S₄) in sediments from the Santa Barbara Basin: implications for paleoenvironmental changes during the past 35 ka

Diagenetic processes are known to modify sedimentary records, but they can also reveal important paleoenvironmental changes. Here we investigate variations in sedimentary iron diagenesis and depositional environments for the last 35 ka by analyzing the rock magnetic and geochemical properties of two sediment cores collected in the Santa Barbara Basin (California). In organic-rich sediments, early diagenesis often leads to partial dissolution of detrital iron oxides and stepwise formation of authigenic pyrite (FeS2). The pyritization process takes place following several geochemical pathways, sometimes involving intermediate iron sulfide species such as greigite (Fe3S4). Sedimentary conditions in the basin appear to have recurrently favored preservation of greigite (identified by its magnetic properties) and inhibited its complete transformation into pyrite. The Holocene interval contains a series of centimeter-thick greigite-bearing layers that are associated with large flood deposits, which are known in the basin as ‘‘gray layers.’’ We propose that greigite preservation was enabled in these sediments by their relative enrichment in reactive iron over organic matter and/or hydrogen sulfide (because of their high ratio of terrigenous over organic material), which limited pyritization reactions. Within the glacial deposits, formation and preservation of meter-thick greigite layers occurred in terrigenous-rich and organic-poor sedimentary layers and is proposed to result from a similar diagenetic process to that in the Holocene greigite-bearing layers (dominance of reactive iron over organic matter and/or HS�). The terrigenous enrichments in the glacial greigite-bearing layers are probably related to climatic or sea level changes because they occur at times of massive iceberg releases in the North Atlantic, the so-called Heinrich events

Sub-Milankovitch cycles in periplatform carbonates from the early Pliocene Great Bahama Bank

High-resolution bulk sediment (magnetic susceptibility and aragonite content) and δ18O records from two different planktonic foraminifera species were analyzed in an early Pliocene core interval from the Straits of Florida (Ocean Drilling Program site 1006). The δ18O record of the shallow-dwelling foraminifera G. sacculifer and the aragonite content are dominated by sub-Milankovitch variability. In contrast, magnetic susceptibility and the δ18O record of the deeper-dwelling foraminifera G. menardii show precession cycles. The relationship between the aragonite and the paleoproxy data suggests that the export of sediment from the adjacent Great Bahama Bank was triggered directly by atmospheric processes rather than by sea level change. We propose a climate mechanism that bears similarities with the semiannual cycle component of eastern equatorial Pacific sea surface temperatures under present-day conditions