Harbofischer0364

This allows us to reconcile the seemingly contradictory experimental observations. Furthermore, we predict that incremental changes of the homotypic and heterotypic interactions among the molecules that undergo LLPS, such as those that are caused by mutations in the genes encoding the proteins, may increase the efficiency of concentration buffering of a given system. Thus, we hypothesize that evolution may optimize concentration buffering as an efficient mechanism to maintain LLPS homeostasis and suggest experimental approaches to test this in different systems.Proteome-wide profiling of protein phosphorylation has been widely used to reveal the underlying mechanism of diverse cellular signaling events. Yet, characterizing subcellular phosphoproteome with high spatial-temporal resolution has remained challenging. selleckchem Herein, we developed a subcellular-specific uncaging-assisted biotinylation and mapping of phosphoproteome (SubMAPP) strategy to monitor the phosphorylation dynamics of subcellular proteome in living cells and animals. Our method capitalizes on the genetically encoded bioorthogonal decaging strategy, which enables the rapid activation of subcellular localized proximity labeling biotin ligase through either light illumination or small-molecule triggers. By further adopting an integrated orthogonal pull-down strategy with quantitative mass spectrometry, SubMAPP allowed for the investigation of subcellular phosphoproteome dynamics, revealing the altered phosphorylation patterns of endoplasmic reticulum (ER) luminal proteins under ER stress. Finally, we further expanded the scope of the SubMAPP strategy to primary neuron culture and living mice.Ultrathin foam films containing supramolecular structures like micelles in bulk and adsorbed surfactant at the liquid-air interface undergo drainage via stratification. At a fixed surfactant concentration, the stepwise decrease in the average film thickness of a stratifying micellar film yields a characteristic step size that also describes the quantized thickness difference between coexisting thick-thin flat regions. Even though many published studies claim that step size equals intermicellar distance obtained using scattering from bulk solutions, we found no reports of a direct comparison between the two length scales. It is well established that step size is inversely proportional to the cubic root of surfactant concentration but cannot be estimated by adding micelle size to Debye length, as the latter is inversely proportional to the square root of surfactant concentration. In this contribution, we contrast the step size obtained from analysis of nanoscopic thickness variations and transitions in stratifying foam films using Interferometry Digital Imaging Optical Microscopy (IDIOM) protocols, that we developed, with the intermicellar distance obtained using small-angle X-ray scattering. We find that stratification driven by the confinement-induced layering of micelles within the liquid-air interfaces of a foam film provides a sensitive probe of non-DLVO (Derjaguin-Landau-Verwey-Overbeek) supramolecular oscillatory structural forces and micellar interactions.Tracking deep ocean animals over their daily cycles will revolutionize our understanding of the largest biome on Earth.A bioinspired soft robot burrows through shallow dry sand with remarkable speed and maneuverability.Robotic navigation on land, through air, and in water is well researched; numerous robots have successfully demonstrated motion in these environments. However, one frontier for robotic locomotion remains largely unexplored-below ground. Subterranean navigation is simply hard to do, in part because the interaction forces of underground motion are higher than in air or water by orders of magnitude and because we lack for these interactions a robust fundamental physics understanding. We present and test three hypotheses, derived from biological observation and the physics of granular intrusion, and use the results to inform the design of our burrowing robot. These results reveal that (i) tip extension reduces total drag by an amount equal to the skin drag of the body, (ii) granular aeration via tip-based airflow reduces drag with a nonlinear dependence on depth and flow angle, and (iii) variation of the angle of the tip-based flow has a nonmonotonic effect on lift in granular media. Informed by these results, we realize a steerable, root-like soft robot that controls subterranean lift and drag forces to burrow faster than previous approaches by over an order of magnitude and does so through real sand. We also demonstrate that the robot can modulate its pullout force by an order of magnitude and control its direction of motion in both the horizontal and vertical planes to navigate around subterranean obstacles. Our results advance the understanding and capabilities of robotic subterranean locomotion.Mesobot, an autonomous underwater vehicle, addresses specific unmet needs for observing and sampling a variety of phenomena in the ocean's midwaters. The midwater hosts a vast biomass, has a role in regulating climate, and may soon be exploited commercially, yet our scientific understanding of it is incomplete. Mesobot has the ability to survey and track slow-moving animals and to correlate the animals' movements with critical environmental measurements. Mesobot will complement existing oceanographic assets such as towed, remotely operated, and autonomous vehicles; shipboard acoustic sensors; and net tows. Its potential to perform behavioral studies unobtrusively over long periods with substantial autonomy provides a capability that is not presently available to midwater researchers. The 250-kilogram marine robot can be teleoperated through a lightweight fiber optic tether and can also operate untethered with full autonomy while minimizing environmental disturbance. We present recent results illustrating the vehicle's ability to automatically track free-swimming hydromedusae (Solmissus sp.) and larvaceans (Bathochordaeus stygius) at depths of 200 meters in Monterey Bay, USA. In addition to these tracking missions, the vehicle can execute preprogrammed missions collecting image and sensor data while also carrying substantial auxiliary payloads such as cameras, sonars, and samplers.

About half of the rheumatology trainees do not use a portfolio. This project was established to reach consensus about the content of a EULAR portfolio for Rheumatology training and subsequently develop portfolio assessment forms.

After establishing a portfolio working group (WG), including nine rheumatologists and one educationalist, a systematic literature review (SLR) on the content and structure of portfolios for postgraduate learning was conducted (November 2018). This was followed by a survey among WG members and members of the EMerging EUlar NETwork, inquiring about the content and structure of existing national portfolios. The portfolio WG selected the key components of the portfolio, taking previous experience and feasibility into account. Assessment forms (eg, case-based discussion) were developed and pilot-tested.

13/2034 articles were included in the SLR (12 high/1 moderate risk of bias). Information on procedural skills, personal reflections, learning goals and multisource feedback was most Europe.

Fatigue in rheumatoid arthritis (RA) is hypothesised to be caused by inflammation. Still ~50% of the variance of fatigue in RA cannot be explained by the Disease Activity Score (DAS), nor by background or psychological factors. Since MRI can detect joint inflammation more sensitively than the clinical joint counts as incorporated in the DAS, we hypothesised that inflammation detected by MRI could aid in explaining fatigue in RA at diagnosis and during the follow-up.

526 consecutive patients with RA were followed longitudinally. Fatigue was assessed yearly on a Numerical Rating Scale. Hand and foot MRIs were performed at inclusion, after 12 and 24 months in 199 patients and were scored for inflammation (synovitis, tenosynovitis and osteitis combined). We studied whether patients with RA with more MRI-inflammation were more fatigued at diagnosis (linear regression), whether the 2-year course of MRI-inflammation associated with the course of fatigue (linear mixed models) and whether decrease in MRI-inflammation in year 1 associated with subsequent improvement in fatigue in year 2 (cross-lagged models). Similar analyses were done with DAS as inflammation measure.

At diagnosis, higher DAS scores were associated with more severe fatigue (p<0.001). However, patients with more MRI-inflammation were not more fatigued (p=0.94). During 2-year follow-up, DAS decrease associated with improvement in fatigue (p<0.001), but MRI-inflammation decrease did not (p=0.96). DAS decrease in year 1 associated with fatigue improvement in year 2 (p=0.012), as did MRI-inflammation decrease (p=0.039), with similar effect strength.

Sensitive measurements of joint inflammation did not explain fatigue in RA at diagnosis and follow-up. This supports the concept that fatigue in RA is partly uncoupled from inflammation.

Sensitive measurements of joint inflammation did not explain fatigue in RA at diagnosis and follow-up. This supports the concept that fatigue in RA is partly uncoupled from inflammation.More than 50% of the world population is chronically infected with herpesviruses. Herpes simplex virus (HSV) infections are the cause of herpes labialis (cold sores), genital herpes, and sight-impairing keratitis. Less frequently, life-threatening disseminated disease (encephalitis and generalized viremia) can also occur, mainly in immunocompromised patients and newborns. After primary infection, HSV persists for life in a latent state in trigeminal or sacral ganglia and, triggered by diverse stimuli, disease recurs in more than 30% of patients up to several times a year. Current therapy with nucleoside analogs targeting the viral polymerase is somewhat effective but limited by poor exposure in the nervous system, and latent infections are not affected by therapy. Here, we report on an inhibitor of HSV helicase-primase with potent in vitro anti-herpes activity, a different mechanism of action, a low frequency of HSV resistance, and a favorable pharmacokinetic and safety profile. Improved target tissue exposure results in superior efficacy in preventing and treating HSV infection and disease in animal models as compared to standard of care. Therapy of primary HSV infections with drug candidate IM-250 (S)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-methyl-5-(S-methylsulfon-imidoyl)thiazol-2-yl)acetamide not only reduces the duration of disease symptoms or time to healing but also prevents recurrent disease in guinea pigs. Treatment of recurrent infections reduces the frequency of recurrences and viral shedding, and, unlike nucleosidic drugs, IM-250 remains effective for a time after cessation of treatment. Hence, IM-250 has advantages over standard-of-care therapies and represents a promising therapeutic for chronic HSV infection, including nucleoside-resistant HSV.Intermittent fasting may impart metabolic benefits independent of energy balance by initiating fasting-mediated mechanisms. This randomized controlled trial examined 24-hour fasting with 150% energy intake on alternate days for 3 weeks in lean, healthy individuals (0150; n = 12). Control groups involved a matched degree of energy restriction applied continuously without fasting (75% energy intake daily; 7575; n = 12) or a matched pattern of fasting without net energy restriction (200% energy intake on alternate days; 0200; n = 12). Primary outcomes were body composition, components of energy balance, and postprandial metabolism. Daily energy restriction (7575) reduced body mass (-1.91 ± 0.99 kilograms) almost entirely due to fat loss (-1.75 ± 0.79 kilograms). Restricting energy intake via fasting (0150) also decreased body mass (-1.60 ± 1.06 kilograms; P = 0.46 versus 7575) but with attenuated reductions in body fat (-0.74 ± 1.32 kilograms; P = 0.01 versus 7575), whereas fasting without energy restriction (0200) did not significantly reduce either body mass (-0.