A blinded trial involving patients with resected stage III melanoma showed that adjuvant pembrolizumab every 3 weeks for a year was associated with a 1-year recurrence-free survival rate of 75%, as ...compared with 61% for placebo.
New biological models are incorporating the realistic processes underlying biological responses to climate change and other human-caused disturbances. However, these more realistic models require ...detailed information, which is lacking for most species on Earth. Current monitoring efforts mainly document changes in biodiversity, rather than collecting the mechanistic data needed to predict future changes. We describe and prioritize the biological information needed to inform more realistic projections of species' responses to climate change. We also highlight how trait-based approaches and adaptive modeling can leverage sparse data to make broader predictions. We outline a global effort to collect the data necessary to better understand, anticipate, and reduce the damaging effects of climate change on biodiversity.
Dysphagia is reported in advanced stages of Duchenne muscular dystrophy (DMD). The population of DMD is changing due to an increasing survival. We aimed to describe the dysphagia in consecutive ...stages and to assess the underlying mechanisms of dysphagia in DMD, in order to develop mechanism based recommendations for safe swallowing. In this cross-sectional study, participants were divided into: early and late ambulatory stage (AS,
n
= 6), early non-ambulatory stage (ENAS,
n
= 7), and late non-ambulatory stage (LNAS,
n
= 11). Quantitative oral muscle ultrasound was performed to quantify echo intensity. Swallowing was assessed with a video fluoroscopic swallow study, surface electromyography (sEMG) of the submental muscle group and tongue pressure. Differences in outcome parameters among the three DMD stages were tested with analysis of variance. Oral muscles related to swallowing were progressively affected, starting in the AS with the geniohyoid muscle. Tongue (pseudo) hypertrophy was found in 70 % of patients in the ENAS and LNAS. Oral phase problems and post-swallow residue were observed, mostly in the LNAS with solid food. sEMG and tongue pressure data of swallowing solid food revealed the lowest sEMG amplitude, the longest duration and lowest tongue pressure in the LNAS. In case of swallowing problems in DMD, based on the disturbed mechanisms of swallowing, it is suggested to (1) adjust meals in terms of less solid food, and (2) drink water after meals to clear the oropharyngeal area.
Transition metal hydrides play a critical role in stoichiometric and catalytic transformations. Knowledge of free energies for cleaving metal hydride bonds enables the prediction of chemical ...reactivity, such as for the bond-forming and bond-breaking events that occur in a catalytic reaction. Thermodynamic hydricity is the free energy required to cleave an M–H bond to generate a hydride ion (H–). Three primary methods have been developed for hydricity determination: the hydride transfer method establishes hydride transfer equilibrium with a hydride donor/acceptor pair of known hydricity, the H2 heterolysis method involves measuring the equilibrium of heterolytic cleavage of H2 in the presence of a base, and the potential–pK a method considers stepwise transfer of a proton and two electrons to give a net hydride transfer. Using these methods, over 100 thermodynamic hydricity values for transition metal hydrides have been determined in acetonitrile or water. In acetonitrile, the hydricity of metal hydrides spans a range of more than 50 kcal/mol. Methods for using hydricity values to predict chemical reactivity are also discussed, including organic transformations, the reduction of CO2, and the production and oxidation of hydrogen.
Anthropogenic increases in atmospheric greenhouse gas
concentrations are the main driver of current and future climate change. The
integrated assessment community has quantified anthropogenic ...emissions for
the shared socio-economic pathway (SSP) scenarios, each of which represents
a different future socio-economic projection and political environment.
Here, we provide the greenhouse gas concentrations for these SSP scenarios
– using the reduced-complexity climate–carbon-cycle model MAGICC7.0. We
extend historical, observationally based concentration data with SSP
concentration projections from 2015 to 2500 for 43 greenhouse gases with monthly and latitudinal resolution. CO2 concentrations by 2100 range
from 393 to 1135 ppm for the lowest (SSP1-1.9) and highest (SSP5-8.5)
emission scenarios, respectively. We also provide the concentration
extensions beyond 2100 based on assumptions regarding the trajectories of fossil
fuels and land use change emissions, net negative emissions, and the
fraction of non-CO2 emissions. By 2150, CO2 concentrations in the
lowest emission scenario are approximately 350 ppm and approximately plateau
at that level until 2500, whereas the highest fossil-fuel-driven scenario
projects CO2 concentrations of 1737 ppm and reaches concentrations
beyond 2000 ppm by 2250. We estimate that the share of CO2 in the total
radiative forcing contribution of all considered 43 long-lived greenhouse
gases increases from 66 % for the present day to roughly 68 % to 85 % by
the time of maximum forcing in the 21st century. For this estimation,
we updated simple radiative forcing parameterizations that reflect the Oslo
Line-By-Line model results. In comparison to the representative concentration pathways (RCPs), the five main SSPs
(SSP1-1.9, SSP1-2.6, SSP2-4.5, SSP3-7.0, and SSP5-8.5) are more evenly spaced
and extend to lower 2100 radiative forcing and temperatures. Performing two
pairs of six-member historical ensembles with CESM1.2.2, we estimate the
effect on surface air temperatures of applying latitudinally and seasonally
resolved GHG concentrations. We find that the ensemble differences in the
March–April–May (MAM) season provide a regional warming in higher northern
latitudes of up to 0.4 K over the historical period, latitudinally averaged
of about 0.1 K, which we estimate to be comparable to the upper bound
(∼5 % level) of natural variability. In comparison to the
comparatively straight line of the last 2000 years, the greenhouse gas
concentrations since the onset of the industrial period and this studies'
projections over the next 100 to 500 years unequivocally depict a
“hockey-stick” upwards shape. The SSP concentration time series derived in
this study provide a harmonized set of input assumptions for long-term
climate science analysis; they also provide an indication of the wide set of
futures that societal developments and policy implementations can lead to –
ranging from multiple degrees of future warming on the one side to
approximately 1.5 ∘C warming on the other.
The formation of condensed (compacted) protein phases is associated with a wide range of human disorders, such as eye cataracts, amyotrophic lateral sclerosis, sickle cell anaemia and Alzheimer's ...disease. However, condensed protein phases have their uses: as crystals, they are harnessed by structural biologists to elucidate protein structures, or are used as delivery vehicles for pharmaceutical applications. The physiochemical properties of crystals can vary substantially between different forms or structures ('polymorphs') of the same macromolecule, and dictate their usability in a scientific or industrial context. To gain control over an emerging polymorph, one needs a molecular-level understanding of the pathways that lead to the various macroscopic states and of the mechanisms that govern pathway selection. However, it is still not clear how the embryonic seeds of a macromolecular phase are formed, or how these nuclei affect polymorph selection. Here we use time-resolved cryo-transmission electron microscopy to image the nucleation of crystals of the protein glucose isomerase, and to uncover at molecular resolution the nucleation pathways that lead to two crystalline states and one gelled state. We show that polymorph selection takes place at the earliest stages of structure formation and is based on specific building blocks for each space group. Moreover, we demonstrate control over the system by selectively forming desired polymorphs through site-directed mutagenesis, specifically tuning intermolecular bonding or gel seeding. Our results differ from the present picture of protein nucleation, in that we do not identify a metastable dense liquid as the precursor to the crystalline state. Rather, we observe nucleation events that are driven by oriented attachments between subcritical clusters that already exhibit a degree of crystallinity. These insights suggest ways of controlling macromolecular phase transitions, aiding the development of protein-based drug-delivery systems and macromolecular crystallography.
The physics of star formation and the deposition of mass, momentum and energy into the interstellar medium by massive stars ('feedback') are the main uncertainties in modern cosmological simulations ...of galaxy formation and evolution
. These processes determine the properties of galaxies
but are poorly understood on the scale of individual giant molecular clouds (less than 100 parsecs)
, which are resolved in modern galaxy formation simulations
. The key question is why the timescale for depleting molecular gas through star formation in galaxies (about 2 billion years)
exceeds the cloud dynamical timescale by two orders of magnitude
. Either most of a cloud's mass is converted into stars over many dynamical times
or only a small fraction turns into stars before the cloud is dispersed on a dynamical timescale
. Here we report high-angular-resolution observations of the nearby flocculent spiral galaxy NGC 300. We find that the molecular gas and high-mass star formation on the scale of giant molecular clouds are spatially decorrelated, in contrast to their tight correlation on galactic scales
. We demonstrate that this decorrelation implies rapid evolutionary cycling between clouds, star formation and feedback. We apply a statistical method
to quantify the evolutionary timeline and find that star formation is regulated by efficient stellar feedback, which drives cloud dispersal on short timescales (around 1.5 million years). The rapid feedback arises from radiation and stellar winds, before supernova explosions can occur. This feedback limits cloud lifetimes to about one dynamical timescale (about 10 million years), with integrated star formation efficiencies of only 2 to 3 per cent. Our findings reveal that galaxies consist of building blocks undergoing vigorous, feedback-driven life cycles that vary with the galactic environment and collectively define how galaxies form stars.
The effective design of an artificial photosynthetic system entails the optimization of several important interactions. Herein we report stopped-flow UV-visible (UV-vis) spectroscopy, X-ray ...crystallographic, density functional theory (DFT), and electrochemical kinetic studies of the Re(bipy- t Bu)(CO) ₃(L) catalyst for the reduction of CO ₂ to CO. A remarkable selectivity for CO ₂ over H ⁺ was observed by stopped-flow UV-vis spectroscopy of Re(bipy- t Bu)(CO) ₃ ⁻¹. The reaction with CO ₂ is about 25 times faster than the reaction with water or methanol at the same concentrations. X-ray crystallography and DFT studies of the doubly reduced anionic species suggest that the highest occupied molecular orbital (HOMO) has mixed metal-ligand character rather than being purely doubly occupied Formula, which is believed to determine selectivity by favoring CO ₂ (σ + π) over H ⁺ (σ only) binding. Electrocatalytic studies performed with the addition of Brönsted acids reveal a primary H/D kinetic isotope effect, indicating that transfer of protons to Re -CO ₂ is involved in the rate limiting step. Lastly, the effects of electrode surface modification on interfacial electron transfer between a semiconductor and catalyst were investigated and found to affect the observed current densities for catalysis more than threefold, indicating that the properties of the electrode surface need to be addressed when developing a homogeneous artificial photosynthetic system.
Summary Background Infectious complications and associated mortality are a major concern in acute pancreatitis. Enteral administration of probiotics could prevent infectious complications, but ...convincing evidence is scarce. Our aim was to assess the effects of probiotic prophylaxis in patients with predicted severe acute pancreatitis. Methods In this multicentre randomised, double-blind, placebo-controlled trial, 298 patients with predicted severe acute pancreatitis (Acute Physiology and Chronic Health Evaluation APACHE II score ≥8, Imrie score ≥3, or C-reactive protein >150 mg/L) were randomly assigned within 72 h of onset of symptoms to receive a multispecies probiotic preparation (n=153) or placebo (n=145), administered enterally twice daily for 28 days. The primary endpoint was the composite of infectious complications—ie, infected pancreatic necrosis, bacteraemia, pneumonia, urosepsis, or infected ascites—during admission and 90-day follow-up. Analyses were by intention to treat. This study is registered, number ISRCTN38327949. Findings One person in each group was excluded from analyses because of incorrect diagnoses of pancreatitis; thus, 152 individuals in the probiotics group and 144 in the placebo group were analysed. Groups were much the same at baseline in terms of patients' characteristics and disease severity. Infectious complications occurred in 46 (30%) patients in the probiotics group and 41 (28%) of those in the placebo group (relative risk 1·06, 95% CI 0·75–1·51). 24 (16%) patients in the probiotics group died, compared with nine (6%) in the placebo group (relative risk 2·53, 95% CI 1·22–5·25). Nine patients in the probiotics group developed bowel ischaemia (eight with fatal outcome), compared with none in the placebo group (p=0·004). Interpretation In patients with predicted severe acute pancreatitis, probiotic prophylaxis with this combination of probiotic strains did not reduce the risk of infectious complications and was associated with an increased risk of mortality. Probiotic prophylaxis should therefore not be administered in this category of patients.
The prevalence of transition metal-mediated hydride transfer reactions in chemical synthesis, catalysis, and biology has inspired the development of methods for characterizing the reactivity of ...transition metal hydride complexes. Thermodynamic hydricity represents the free energy required for heterolytic cleavage of the metal-hydride bond to release a free hydride ion, H
−
, as determined through equilibrium measurements and thermochemical cycles. Kinetic hydricity represents the rate of hydride transfer from one species to another, as measured through kinetic analysis. This tutorial review describes the common methods for experimental and computational determination of thermodynamic and kinetic hydricity, including advice on best practices and precautions to help avoid pitfalls. The influence of solvation on hydricity is emphasized, including opportunities and challenges arising from comparisons across several different solvents. Connections between thermodynamic and kinetic hydricity are discussed, and opportunities for utilizing these connections to rationally improve catalytic processes involving hydride transfer are highlighted.
This review of thermodynamic and kinetic hydricity provides conceptual overviews, tutorials on how to determine hydricity both experimentally and computationally, and salient case studies.
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