Price of disorder in the lac repressor hinge helix

The Lac system of genes has been pivotal in understanding gene regulation. When the lac repressor protein binds to the correct DNA sequence, the hinge region of the protein goes through a disorder to order transition. The structure of this region of the protein is well understood when it is in this bound conformation, but less so when it is not. Structural studies show that this region is flexible. Our simulations show this region is extremely flexible in solution; however, a high concentration of salt can help kinetically trap the hinge helix. Thermodynamically, disorder is more favorable without the DNA present.     

People’s desire to be in nature and how they experience it are partially heritable

Nature experiences have been linked to mental and physical health. Despite the importance of understanding what determines individual variation in nature experience, the role of genes has been overlooked. Here, using a twin design (TwinsUK, number of individuals = 2,306), we investigate the genetic and environmental contributions to a person’s nature orientation, opportunity (living in less urbanized areas), and different dimensions of nature experience (frequency and duration of public nature space visits and frequency and duration of garden visits). We estimate moderate heritability of nature orientation (46%) and nature experiences (48% for frequency of public nature space visits, 34% for frequency of garden visits, and 38% for duration of garden visits) and show their genetic components partially overlap. We also find that the environmental influences on nature experiences are moderated by the level of urbanization of the home district. Our study demonstrates genetic contributions to individuals’ nature experiences, opening a new dimension for the study of human–nature interactions.

Nature experiences have been linked to mental and physical health. This twin study reveals genetic influences on an individual’s orientation towards nature and nature experiences, opening a new dimension to understanding human-nature interactions.     

On the Vertical Distribution of the Metazoan Meiofauna in Shelf Break and Upper Slope Habitats of the NE Atlantic

The metazoan meiofauna of nine stations in shelf break and upper slope areas (70 to 1500 m water depth) of the N.E. Atlantic were investigated in order to assess which environmental factors are important in the control of densities and sediment profiles. Total meiofaunal densities (ranging between 368 and 1523 ind/10 cm²) were correlated with bacterial densities, an important food source for meiofauna. However, considering sediment vertical distribution profiles, the relative importance of both food and oxygen on the meiofauna became obvious. A combination of both bacterial densities and oxygen supply could explain about 95% of the variability in the vertical profiles of the meiofauna densities. Meiofauna numbers increase in proportion to food availability in the surface sediment layers, but this relationship breaks down in deeper sediment layers where the oxygen supply is often limiting, particularly in fine sediments.     

Efficient incorporation and template-dependent polymerase inhibition are major determinants for the broad-spectrum antiviral activity of remdesivir

Remdesivir (RDV) is a direct-acting antiviral agent that is approved in several countries for the treatment of coronavirus disease 2019 caused by the severe acute respiratory syndrome coronavirus 2. RDV exhibits broad-spectrum antiviral activity against positive-sense RNA viruses, for example, severe acute respiratory syndrome coronavirus and hepatitis C virus, and nonsegmented negative-sense RNA viruses, for example, Nipah virus, whereas segmented negative-sense RNA viruses such as influenza virus or Crimean-Congo hemorrhagic fever virus are not sensitive to the drug. The reasons for this apparent efficacy pattern are unknown. Here, we expressed and purified representative RNA-dependent RNA polymerases and studied three biochemical parameters that have been associated with the inhibitory effects of RDV-triphosphate (TP): (i) selective incorporation of the nucleotide substrate RDV-TP, (ii) the effect of the incorporated RDV-monophosphate (MP) on primer extension, and (iii) the effect of RDV-MP in the template during incorporation of the complementary UTP. We found a strong correlation between antiviral effects and efficient incorporation of RDV-TP. Inhibition in primer extension reactions was heterogeneous and usually inefficient at higher NTP concentrations. In contrast, template-dependent inhibition of UTP incorporation opposite the embedded RDV-MP was seen with all polymerases. Molecular modeling suggests a steric conflict between the 1′-cyano group of the inhibitor and residues of the structurally conserved RNA-dependent RNA polymerase motif F. We conclude that future efforts in the development of nucleotide analogs with a broader spectrum of antiviral activities should focus on improving rates of incorporation while capitalizing on the inhibitory effects of a bulky 1′-modification.     

Biogeographic consequences of shifting climate for the western massasauga (Sistrurus tergeminus)

The western massasauga (Sistrurus tergeminus) is a small pit viper with an extensive geographic range, yet observations of this species are relatively rare. They persist in patchy and isolated populations, threatened by habitat destruction and fragmentation, mortality from vehicle collisions, and deliberate extermination. Changing climates may pose an additional stressor on the survival of isolated populations. Here, we evaluate historic, modern, and future geographic projections of suitable climate for S. tergeminus to outline shifts in their potential geographic distribution and inform current and future management. We used maximum entropy modeling to build multiple models of the potential geographic distribution of S. tergeminus. We evaluated the influence of five key decisions made during the modeling process on the resulting geographic projections of the potential distribution, allowing us to identify areas of model robustness and uncertainty. We evaluated models with the area under the receiver operating curve and true skill statistic. We retained 16 models to project both in the past and future multiple general circulation models. At the last glacial maximum, the potential geographic distribution associated with S. tergeminus occurrences had a stronghold in the southern part of its current range and extended further south into Mexico, but by the mid‐Holocene, its modeled potential distribution was similar to its present‐day potential distribution. Under future model projections, the potential distribution of S. tergeminus moves north, with the strongest northward trends predicted under a climate scenario increase of 8.5 W/m². Some southern populations of S. tergeminus have likely already been extirpated and will continue to be threatened by shifting availability of suitable climate, as they are already under threat from desertification of grasslands. Land use and habitat loss at the northern edge of the species range are likely to make it challenging for this species to track suitable climates northward over time.     

Perforin-dependent brain-infiltrating cytotoxic CD8+ T lymphocytes mediate experimental cerebral malaria pathogenesis

Experimental cerebral malaria (ECM) resulting from Plasmodium berghei ANKA infection involves T lymphocytes. However, the mechanisms of T cell-mediated pathogenesis remain unknown. We found that, in contrast to ECM-susceptible C57BL6 mice, perforin-deficient (PFP-KO) mice were resistant to ECM in the absence of brain lesions, whereas cytoadherence of parasitized erythrocytes and massive accumulation of activated/effector CD8 lymphocytes were observed in both groups of mice. ECM is induced in PFP-KO mice after adoptive transfer of cytotoxic CD8+ cells from infected C57BL6 mice, which were directed to the brain of PFP-KO mice. This specific recruitment might involve chemokine/chemokine receptors, since their expression was up-regulated on activated CD8 cells, and susceptibility to ECM was delayed in CCR5-KO mice. Thus, lymphocyte cytotoxicity and cell trafficking are key players in ECM pathogenesis.     

Angiotensin II and its receptors in human endocardial endothelial cells: role in modulating intracellular calcium

The aims of the present study are to investigate the presence and distribution of angiotensin II (Ang II), as well as AT1 and AT2 receptors, in endocardial endothelial cells (EECs) and to determine if the effect of Ang II on intracellular calcium in these cells is mediated via the AT1 or the AT2 receptor. Immunofluorescence and 3D confocal microscopy techniques were used on 20-week-old fetal human EECs. Our results showed that Ang II and its receptors, the AT1 and the AT2 types, are present and exhibit a different distribution in human EECs. Ang II labelling is found throughout the cell with a fluorescence signal higher in the cytosol when compared with the nucleus. Like Ang II, the AT1 receptor fluorescence signal is also homogeneously distributed in human EECs but with a preferential labelling at the level of the nucleus, while the AT2 receptor labelling is solely present in the nucleus. Using fluo-3 and 3D confocal microscopy technique, superfusion of human EECs with increasing concentration of Ang II induced a dose-dependent sustained increase in free cytosolic and nuclear Ca2+ levels. This effect of Ang II on human EEC's intracellular Ca2+ ([Ca2+]) was completely prevented by losartan, an AT1 receptor antagonist. Our results suggest that Ang II, as well as AT1 and AT2 receptors, is present but differentially distributed in EECs of 20-week-old fetal human hearts, and that the AT1 receptor mediates the effects of Ang II on [Ca2+]i in these cells.