Predicting the duration of reach-to-grasp movements to objects with asymmetric contact surfaces.

The duration of reach-to-grasp movements is influenced by the size of the contact surfaces, such that grasping objects with smaller contact surface areas takes longer. But what is the influence of asymmetric contact surfaces? In Experiment 1a, participants reached-to-lift wooden blocks off a table top, with the contact locations for the thumb and index finger varying in surface size. The time taken to lift the block was driven primarily by the thumb contact surface, which showed a larger effect size for the dependent variable of movement duration than the index finger's contact surface. In Experiment 1b participants reached-to-grasp (but not lift) the blocks. The same effect was found with duration being largely driven by contact surface size for the thumb. Experiment 2 tested whether this finding generalised to movements towards conical frusta grasped in a different plane mounted off the table top. Experiment 2 showed that movement duration again was dictated primarily by the size of the thumb's contact surface. The thumb contact surface was the visible surface in experiments 1 and 2 so Experiment 3 explored grasping when the index finger's contact surface was visible (participants grasped the frusta with the index finger at the top). An interaction between thumb and finger surface size was now found to determine movement duration. These findings provide the first empirical report of the impact of asymmetric contact surfaces on prehension, and may have implications for scientists who wish to model reach-to-grasp behaviours

Comparing antiviral strategies against COVID-19 via multiscale within-host modelling

Within-host models of COVID-19 infection dynamics enable the merits of different forms of antiviral therapy to be assessed in individual patients. A stochastic agent-based model of COVID-19 intracellular dynamics is introduced here, that incorporates essential steps of the viral life cycle targeted by treatment options. Integration of model predictions with an intercellular ODE model of within-host infection dynamics, fitted to patient data, generates a generic profile of disease progression in patients that have recovered in the absence of treatment. This is contrasted with the profiles obtained after variation of model parameters pertinent to the immune response, such as effector cell and antibody proliferation rates, mimicking disease progression in immunocompromised patients. These profiles are then compared with disease progression in the presence of antiviral and convalescent plasma therapy against COVID-19 infections. The model reveals that using both therapies in combination can be very effective in reducing the length of infection, but these synergistic effects decline with a delayed treatment start. Conversely, early treatment with either therapy alone can actually increase the duration of infection, with infectious virions still present after the decline of other markers of infection. This suggests that usage of these treatments should remain carefully controlled in a clinical environment

Simulations of a Line W-based observing system for the Atlantic meridional overturning circulation

In a series of observing system simulations, we test whether the Atlantic meridional overturning circulation (AMOC) can be observed based on the existing Line W deep western boundary array. We simulate a Line W array, which is extended to the surface and to the east to cover the basin to the Bermuda Rise. In the analyzed ocean circulation model ORCA025, such an extended Line W array captures the main characteristics of the western boundary current. Potential trans-basin observing systems for the AMOC are tested by combining the extended Line W array with a mid-ocean transport estimate obtained from thermal wind "measurements" and Ekman transport to the total AMOC (similarly to Hirschi et al., Geophys Res Lett 30(7):1413, 2003). First, we close Line W zonally supplementing the western boundary array with several "moorings" in the basin (Line W-32A degrees N). Second, we supplement the western boundary array with a combination of observations at Bermuda and the eastern part of the RAPID array at 26A degrees N (Line W-B-RAPID). Both, a small number of density profiles across the basin and also only sampling the eastern and western boundary, capture the variability of the AMOC at Line W-32A degrees N and Line W-B-RAPID. In the analyzed model, the AMOC variability at both Line W-32A degrees N and Line W-B-RAPID is dominated by the western boundary current variability. Away from the western boundary, the mid-ocean transport (east of Bermuda) shows no significant relation between the two Line W-based sections and 26A degrees N. Hence, a Line W-based AMOC estimate could yield an estimate of the meridional transport that is independent of the 26A degrees N RAPID estimate. The model-based observing system simulations presented here provide support for the use of Line W as a cornerstone for a trans-basin AMOC observing system

Plausible self-reported dietary intakes in a residential facility are not necessarily reliable

Background/Objectives: Comparing reported energy intakes with estimated energy requirements as multiples of basal metabolic rate (Ein:BMR) is an established method of identifying implausible food intake records. The present study aimed to examine the validity of self-reported food intakes believed to be plausible. Subjects/Methods: One hundred and eighty men and women were provided with all food and beverages for two consecutive days in a residential laboratory setting. Subjects self-reported their food and beverage intakes using the weighed food diary method (WDR). Investigators covertly measured subjects’ actual consumption over the same period. Subjects also reported intakes over four consecutive days at home. BMR was measured by indirect calorimetry. Results: Average reported energy intakes were significantly lower than actual intakes (11.2 and 11.8 MJ/d, respectively, P<0.001). Two-thirds (121) of the WDR were under-reported to varying degrees. Only five of these were considered as implausible using an Ein:BMR cut-off value of 1.03*BMR. Under-reporting of food and beverage intakes, as measured by the difference between reported and actual intake, was evident at all levels of Ein;BMR. Reported energy intakes were lower still (10.2 MJ/d) while subjects were at home. Conclusions: Under-recording of self-reported food intake records was extensive but very few under-reported food intake records were identified as implausible using energy intake to BMR ratios. Under-recording was evident at all levels of energy intake

Evolution of a virus-like architecture and packaging mechanism in a repurposed bacterial protein

Viruses are ubiquitous pathogens of global impact. Prompted by the hypothesis that their earliest progenitors recruited host proteins for virion formation, we have used stringent laboratory evolution to convert a bacterial enzyme that lacks affinity for nucleic acids into an artificial nucleocapsid that efficiently packages and protects multiple copies of its own encoding messenger RNA. Revealing remarkable convergence on the molecular hallmarks of natural viruses, the accompanying changes reorganized the protein building blocks into an interlaced 240-subunit icosahedral capsid that is impermeable to nucleases, and emergence of a robust RNA stem-loop packaging cassette ensured high encapsidation yields and specificity. In addition to evincing a plausible evolutionary pathway for primordial viruses, these findings highlight practical strategies for developing nonviral carriers for diverse vaccine and delivery applications

Genome-regulated Assembly of a ssRNA Virus May Also Prepare It for Infection.

Many single-stranded, positive-sense RNA viruses regulate assembly of their infectious virions by forming multiple, cognate coat protein (CP)-genome contacts at sites termed Packaging Signals (PSs). We have determined the secondary structures of the bacteriophage MS2 ssRNA genome (gRNA) frozen in defined states using constraints from X-ray synchrotron footprinting (XRF). Comparison of the footprints from phage and transcript confirms the presence of multiple PSs in contact with CP dimers in the former. This is also true for a virus-like particle (VLP) assembled around the gRNA in vitro in the absence of the single-copy Maturation Protein (MP) found in phage. Since PS folds are present at many sites across gRNA transcripts, it appears that this genome has evolved to facilitate this mechanism of assembly regulation. There are striking differences between the gRNA-CP contacts seen in phage and the VLP, suggesting that the latter are inappropriate surrogates for aspects of phage structure/function. Roughly 50% of potential PS sites in the gRNA are not in contact with the protein shell of phage. However, many of these sit adjacent to, albeit not in contact with, PS-binding sites on CP dimers. We hypothesize that these act as PSs transiently during assembly but subsequently dissociate. Combining the XRF data with PS locations from an asymmetric cryo-EM reconstruction suggests that the genome positions of such dissociations are non-random and may facilitate infection. The loss of many PS-CP interactions towards the 3′ end of the gRNA would allow this part of the genome to transit more easily through the narrow basal body of the pilus extruding machinery. This is the known first step in phage infection. In addition, each PS-CP dissociation event leaves the protein partner trapped in a non-lowest free-energy conformation. This destabilizes the protein shell which must disassemble during infection, further facilitating this stage of the life-cycle

DNA topoisomerase I inhibition by camptothecin induces escape of RNA polymerase II from promoter-proximal pause site, antisense transcription and histone acetylation at the human HIF-1α gene locus

Top1 inhibition by camptothecin (CPT) perturbs RNA polymerase II (Pol II) density at promoters and along transcribed genes suggesting an involvement of Top1 in Pol II pausing. Here, we demonstrate that Top1 inhibition favors Pol II escape from a promoter-proximal pausing site of the human HIF-1α gene in living cells. Interestingly, alternative splicing at exon 11 was markedly altered in nascent HIF-1α mRNAs, and chromatin structure was also affected with enhanced histone acetylation and reduced nucleosome density in a manner dependent on cdk activity. Moreover, CPT increases transcription of a novel long RNA (5′aHIF1α), antisense to human HIF-1α mRNA, and a known antisense RNA at the 3′-end of the gene, while decreasing mRNA levels under normoxic and hypoxic conditions. The effects require Top1, but are independent from Top1-induced replicative DNA damage. Chromatin RNA immunoprecipitation results showed that CPT can activate antisense transcription mediated by cyclin-dependent kinase (cdk) activity. Thus, Top1 inhibition can trigger a transcriptional stress, involving antisense transcription and increased chromatin accessibility, which is dependent on cdk activity and deregulated Pol II pausing. A changed balance of antisense transcripts and mRNAs may then lead to altered regulation of HIF-1α activity in human cancer cells

Ocean impact on decadal Atlantic climate variability revealed by sea-level observations

Decadal variability is a notable feature of the Atlantic Ocean and the climate of the regions it influences. Prominently, this is manifested in the Atlantic Multidecadal Oscillation (AMO) in sea surface temperatures. Positive (negative) phases of the AMO coincide with warmer (colder) North Atlantic sea surface temperatures. The AMO is linked with decadal climate fluctuations, such as Indian and Sahel rainfall1, European summer precipitation2, Atlantic hurricanes3 and variations in global temperatures4. It is widely believed that ocean circulation drives the phase changes of the AMO by controlling ocean heat content5. However, there are no direct observations of ocean circulation of sufficient length to support this, leading to questions about whether the AMO is controlled from another source6. Here we provide observational evidence of the widely hypothesized link between ocean circulation and the AMO. We take a new approach, using sea level along the east coast of the United States to estimate ocean circulation on decadal timescales. We show that ocean circulation responds to the first mode of Atlantic atmospheric forcing, the North Atlantic Oscillation, through circulation changes between the subtropical and subpolar gyres—the intergyre region7. These circulation changes affect the decadal evolution of North Atlantic heat content and, consequently, the phases of the AMO. The Atlantic overturning circulation is declining8 and the AMO is moving to a negative phase. This may offer a brief respite from the persistent rise of global temperatures4, but in the coupled system we describe, there are compensating effects. In this case, the negative AMO is associated with a continued acceleration of sea-level rise along the northeast coast of the United States9, 10