Target identification (determining the correct drug targets for a disease) and target validation (demonstrating an effect of target perturbation on disease biomarkers and disease end points) are ...important steps in drug development. Clinically relevant associations of variants in genes encoding drug targets model the effect of modifying the same targets pharmacologically. To delineate drug development (including repurposing) opportunities arising from this paradigm, we connected complex disease- and biomarker-associated loci from genome-wide association studies to an updated set of genes encoding druggable human proteins, to agents with bioactivity against these targets, and, where there were licensed drugs, to clinical indications. We used this set of genes to inform the design of a new genotyping array, which will enable association studies of druggable genes for drug target selection and validation in human disease.
Before Rosetta, the space missions Giotto and Stardust shaped our view on cometary dust, supported by plentiful data from Earth based observations and interplanetary dust particles collected in the ...Earth’s atmosphere. The Rosetta mission at comet 67P/Churyumov-Gerasimenko was equipped with a multitude of instruments designed to study cometary dust. While an abundant amount of data was presented in several individual papers, many focused on a dedicated measurement or topic. Different instruments, methods, and data sources provide different measurement parameters and potentially introduce different biases. This can be an advantage if the complementary aspect of such a complex data set can be exploited. However, it also poses a challenge in the comparison of results in the first place. The aim of this work therefore is to summarize dust results from Rosetta and before. We establish a simple classification as a common framework for intercomparison. This classification is based on the dust particle structure, porosity, and strength and also on its size. Depending on the instrumentation, these are not direct measurement parameters, but we chose them because they were the most reliable for deriving our model. The proposed classification has proved helpful in the Rosetta dust community, and we offer it here also for a broader context. In this manner, we hope to better identify synergies between different instruments and methods in the future.
The performance of the missing transverse momentum (
E
T
miss
) reconstruction with the ATLAS detector is evaluated using data collected in proton–proton collisions at the LHC at a centre-of-mass ...energy of 13 TeV in 2015. To reconstruct
E
T
miss
, fully calibrated electrons, muons, photons, hadronically decaying
τ
-leptons
, and jets reconstructed from calorimeter energy deposits and charged-particle tracks are used. These are combined with the soft hadronic activity measured by reconstructed charged-particle tracks not associated with the hard objects. Possible double counting of contributions from reconstructed charged-particle tracks from the inner detector, energy deposits in the calorimeter, and reconstructed muons from the muon spectrometer is avoided by applying a signal ambiguity resolution procedure which rejects already used signals when combining the various
E
T
miss
contributions. The individual terms as well as the overall reconstructed
E
T
miss
are evaluated with various performance metrics for scale (linearity), resolution, and sensitivity to the data-taking conditions. The method developed to determine the systematic uncertainties of the
E
T
miss
scale and resolution is discussed. Results are shown based on the full 2015 data sample corresponding to an integrated luminosity of
3.2
fb
-
1
.
A measurement of the mass of the
W
boson is presented based on proton–proton collision data recorded in 2011 at a centre-of-mass energy of 7 TeV with the ATLAS detector at the LHC, and corresponding ...to
4.6
fb
-
1
of integrated luminosity. The selected data sample consists of
7.8
×
10
6
candidates in the
W
→
μ
ν
channel and
5.9
×
10
6
candidates in the
W
→
e
ν
channel. The
W
-boson mass is obtained from template fits to the reconstructed distributions of the charged lepton transverse momentum and of the
W
boson transverse mass in the electron and muon decay channels, yielding
m
W
=
80370
±
7
(
stat.
)
±
11
(
exp. syst.
)
±
14
(
mod. syst.
)
MeV
=
80370
±
19
MeV
,
where the first uncertainty is statistical, the second corresponds to the experimental systematic uncertainty, and the third to the physics-modelling systematic uncertainty. A measurement of the mass difference between the
W
+
and
W
-
bosons yields
m
W
+
-
m
W
-
=
-
29
±
28
MeV.
Strong excitonic interactions are a key design strategy in photosynthetic light harvesting, expanding the spectral cross-section for light absorption and creating considerably faster and more robust ...excitation energy transfer. These molecular excitons are a direct result of exceptionally densely packed pigments in photosynthetic proteins. The main light-harvesting complexes of diatoms, known as fucoxanthin–chlorophyll proteins (FCPs), are an exception, displaying surprisingly weak excitonic coupling between their chlorophyll (Chl) a’s, despite a high pigment density. Here,we show, using single-molecule spectroscopy, that the FCP complexes of Cyclotella meneghiniana switch frequently into stable, strongly emissive states shifted 4–10 nm toward the red. A few percent of isolated FCPa complexes and ∼20% of isolated FCPb complexes, on average, were observed to populate these previously unobserved states, percentages that agree with the steady-state fluorescence spectra of FCP ensembles. Thus, the complexes use their enhanced sensitivity to static disorder to increase their light-harvesting capability in a number of ways. A disordered exciton model based on the structure of the main plant light-harvesting complex explains the red-shifted emission by strong localization of the excitation energy on a single Chl a pigment in the terminal emitter domain due to very specific pigment orientations. We suggest that the specific construction of FCP gives the complex a unique strategy to ensure that its light-harvesting function remains robust in the fluctuating protein environment despite limited excitonic interactions.
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•9 novel PE-degrading bacteria were isolated from Cerrado soil.•PE-degrading bacteria are from Comamonas, Delftia and Stenotrophomonas genera.•Strains are capable of degrading PE of ...191.000 without additives or pre-treatments.•Nitrogen metabolism is involved in the chemical modification of PE.
Discarded PE-based products pose a social and environmental threat because of their recalcitrance to degradation, a consequence of the unique set of PE’s physicochemical properties. In this study we isolated nine novel PE-degrading bacteria from plastic debris found in soil of the savanna-like Brazilian Cerrado. These bacterial strains from the genera Comamonas, Delftia, and Stenotrophomonas showed metabolic activity and cellular viability after a 90-day incubation with PE as the sole carbon source. ATR/FTIR indicated that biodegraded PE undergone oxidation, vinylene formation, chain scission, among other chemical changes. Considerable nanoroughness shifts and vast damages to the micrometric surface were confirmed by AFM and SEM. Further, phase imaging revealed a 46.7% decrease in the viscous area of biodegraded PE whereas Raman spectroscopy confirmed a loss in its crystalline content, suggesting the assimilation of smaller fragments. Intriguingly, biodegraded PE chemical fingerprint suggests that these strains use novel biochemical strategies in the biodegradation process. Our results indicate that these microbes are capable of degrading unpretreated PE of very high molecular weight (191,000gmol−1) and survive for long periods under this condition, suggesting not only practical applications in waste management and environmental decontamination, but also future directions to understand the unraveled metabolism of synthetic polymers.
In the past decade, anisometric rod‐shaped microgels have attracted growing interest in the materials‐design and tissue‐engineering communities. Rod‐shaped microgels exhibit outstanding potential as ...versatile building blocks for 3D hydrogels, where they introduce macroscopic anisometry, porosity, or functionality for structural guidance in biomaterials. Various fabrication methods have been established to produce such shape‐controlled elements. However, continuous high‐throughput production of rod‐shaped microgels with simultaneous control over stiffness, size, and aspect ratio still presents a major challenge. A novel microfluidic setup is presented for the continuous production of rod‐shaped microgels from microfluidic plug flow and jets. This system overcomes the current limitations of established production methods for rod‐shaped microgels. Here, an on‐chip gelation setup enables fabrication of soft microgel rods with high aspect ratios, tunable stiffness, and diameters significantly smaller than the channel diameter. This is realized by exposing jets of a microgel precursor to a high intensity light source, operated at specific pulse sequences and frequencies to induce ultra‐fast photopolymerization, while a change in flow rates or pulse duration enables variation of the aspect ratio. The microgels can assemble into 3D structures and function as support for cell culture and tissue engineering.
Compartmentalized microfluidic jet gelation allows for the continuous high‐throughput fabrication of anisometric microgel rods with adjustable aspect ratio and stiffness. High‐frequency laser pulses initiate local ultrafast photopolymerization in the jet leading to microgels with rod diameter significantly smaller than the channel diameter to overcome the size limits of established microfluidic plug flow gelation.
Light-harvesting pigment-protein complexes of photosystem II of plants have a dual function: they efficiently use absorbed energy for photosynthesis at limiting sunlight intensity and dissipate the ...excess energy at saturating intensity for photoprotection. Recent single-molecule spectroscopy studies on the trimeric LHCII complex showed that environmental control of the intrinsic protein disorder could in principle explain the switch between their light-harvesting and photoprotective conformations in vivo. However, the validity of this proposal depends strongly on the specificity of the protein dynamics. Here, a similar study has been performed on the minor monomeric antenna complexes of photosystem II (CP29, CP26, and CP24). Despite their high structural homology, similar pigment content and organization compared to LHCII trimers, the environmental response of these proteins was found to be rather distinct. A much larger proportion of the minor antenna complexes were present in permanently weakly fluorescent states under most conditions used; however, unlike LHCII trimers the distribution of the single-molecule population between the strongly and weakly fluorescent states showed no significant sensitivity to low pH, zeaxanthin, or low detergent conditions. The results support a unique role for LHCII trimers in the regulation of light harvesting by controlled fluorescence blinking and suggest that any contribution of the minor antenna complexes to photoprotection would probably involve a distinct mechanism.
A combined experimental and theoretical study is reported on the vibrational properties of tenorite CuO and paramelaconite Cu4O3. The optically active modes have been measured by Raman scattering and ...infrared absorption spectroscopy. First-principles calculations have been carried out with the LDA+U approach to account for strong electron correlation in the copper oxides. The vibrational properties have been computed ab initio using the so-called direct method. Excellent agreement is found between the measured Raman and infrared peak positions and the calculated phonon frequencies at the Brillouin zone center, which allows the assignment of all prominent peaks of the Cu4O3 spectra. Through a detailed analysis of the displacement eigenvectors, it is shown that a close relationship exists between the Raman modes of CuO and Cu4O3.
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