A systematic analysis of experimental immunotherapies on tumors differing in size and duration of growth

We conducted a systematic analysis to determine the reason for the apparent disparity of success of immunotherapy between clinical and experimental cancers. To do this, we performed a search of PubMed using the keywords “immunotherapy” AND “cancer” for the years of 1980 and 2010. The midspread of experimental tumors used in all the relevant literature published in 2010 were between 0.5–121 mm3 in volume or had grown for four to eight days. Few studies reported large tumors that could be considered representative of clinical tumors, in terms of size and duration of growth. The predominant effect of cancer immunotherapies was slowed or delayed outgrowth. Regression of tumors larger than 200 mm3 was observed only after passive antibody or adoptive T cell therapy. The effectiveness of other types of immunotherapy was generally scattered. By comparison, very few publications retrieved by the 1980 search could meet our selection criteria; all of these used tumors smaller than 100 mm3, and none reported regression. In the entire year of 2010, only 13 used tumors larger than 400 mm3, and nine of these reported tumor regression. Together, these results indicate that most recent studies, using many diverse approaches, still treat small tumors only to report slowed or delayed growth. Nevertheless, a few recent studies indicate effective therapy against large tumors when using passive antibody or adoptive T cell therapy. For the future, we aspire to witness the increased use of experimental studies treating tumors that model clinical cancers in terms of size and duration of growth

Transit Photometry as an Exoplanet Discovery Method

Photometry with the transit method has arguably been the most successful exoplanet discovery method to date. A short overview about the rise of that method to its present status is given. The method's strength is the rich set of parameters that can be obtained from transiting planets, in particular in combination with radial velocity observations; the basic principles of these parameters are given. The method has however also drawbacks, which are the low probability that transits appear in randomly oriented planet systems, and the presence of astrophysical phenomena that may mimic transits and give rise to false detection positives. In the second part we outline the main factors that determine the design of transit surveys, such as the size of the survey sample, the temporal coverage, the detection precision, the sample brightness and the methods to extract transit events from observed light curves. Lastly, an overview over past, current and future transit surveys is given. For these surveys we indicate their basic instrument configuration and their planet catch, including the ranges of planet sizes and stellar magnitudes that were encountered. Current and future transit detection experiments concentrate primarily on bright or special targets, and we expect that the transit method remains a principal driver of exoplanet science, through new discoveries to be made and through the development of new generations of instruments.Comment: Review chapte

Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation.

The normally soluble TAR DNA-binding protein 43 (TDP-43) is found aggregated both in reversible stress granules and in irreversible pathogenic amyloid. In TDP-43, the low-complexity domain (LCD) is believed to be involved in both types of aggregation. To uncover the structural origins of these two modes of β-sheet-rich aggregation, we have determined ten structures of segments of the LCD of human TDP-43. Six of these segments form steric zippers characteristic of the spines of pathogenic amyloid fibrils; four others form LARKS, the labile amyloid-like interactions characteristic of protein hydrogels and proteins found in membraneless organelles, including stress granules. Supporting a hypothetical pathway from reversible to irreversible amyloid aggregation, we found that familial ALS variants of TDP-43 convert LARKS to irreversible aggregates. Our structures suggest how TDP-43 adopts both reversible and irreversible β-sheet aggregates and the role of mutation in the possible transition of reversible to irreversible pathogenic aggregation

A four-helix bundle stores copper for methane oxidation

Methane-oxidising bacteria (methanotrophs) require large quantities of copper for the membrane-bound (particulate) methane monooxygenase (pMMO). Certain methanotrophs are also able to switch to using the iron-containing soluble MMO (sMMO) to catalyse methane oxidation, with this switchover regulated by copper. MMOs are Nature’s primary biological mechanism for suppressing atmospheric levels of methane, a potent greenhouse gas. Furthermore, methanotrophs and MMOs have enormous potential in bioremediation and for biotransformations producing bulk and fine chemicals, and in bioenergy, particularly considering increased methane availability from renewable sources and hydraulic fracturing of shale rock. We have discovered and characterised a novel copper storage protein (Csp1) from the methanotroph Methylosinus trichosporium OB3b that is exported from the cytosol, and stores copper for pMMO. Csp1 is a tetramer of 4-helix bundles with each monomer binding up to 13 Cu(I) ions in a previously unseen manner via mainly Cys residues that point into the core of the bundle. Csp1 is the first example of a protein that stores a metal within an established protein-folding motif. This work provides a detailed insight into how methanotrophs accumulate copper for the oxidation of methane. Understanding this process is essential if the wide-ranging biotechnological applications of methanotrophs are to be realised. Cytosolic homologues of Csp1 are present in diverse bacteria thus challenging the dogma that such organisms do not use copper in this location

Discovery and characterization of a new family of lytic polysaccharide monooxygenases

Lytic polysaccharide monooxygenases (LPMOs) are a recently discovered class of enzymes capable of oxidizing recalcitrant polysaccharides. They are attracting considerable attention owing to their potential use in biomass conversion, notably in the production of biofuels. Previous studies have identified two discrete sequence-based families of these enzymes termed AA9 (formerly GH61) and AA10 (formerly CBM33). Here, we report the discovery of a third family of LPMOs. Using a chitin-degrading exemplar from Aspergillus oryzae, we show that the three-dimensional structure of the enzyme shares some features of the previous two classes of LPMOs, including a copper active center featuring the 'histidine brace' active site, but is distinct in terms of its active site details and its EPR spectroscopy. The newly characterized AA11 family expands the LPMO clan, potentially broadening both the range of potential substrates and the types of reactive copper-oxygen species formed at the active site of LPMOs

Search for Gluinos and Scalar Quarks in ppˉp\bar{p} Collisions at s=1.8\sqrt{s}=1.8 TeV using the Missing Energy plus Multijets Signature

We have performed a search for gluinos (\gls) and squarks (\sq) in a data sample of 84 pb$^{-1}$ of \ppb collisions at $\sqrt{s}$ = 1.8 TeV, recorded by the Collider Detector at Fermilab, by investigating the final state of large missing transverse energy and 3 or more jets, a characteristic signature in R-parity-conserving supersymmetric models. The analysis has been performed `blind', in that the inspection of the signal region is made only after the predictions from Standard Model backgrounds have been calculated. Comparing the data with predictions of constrained supersymmetric models, we exclude gluino masses below 195 \gev (95% C.L.), independent of the squark mass. For the case \msq \approx \mgls, gluino masses below 300 \gev are excluded.Comment: 7 pages, 3 figure

Company for the Ultra-high Density, Ultra-short Period Sub-Earth GJ 367 b: Discovery of Two Additional Low-mass Planets at 11.5 and 34 Days

GJ 367 is a bright (V ≈ 10.2) M1 V star that has been recently found to host a transiting ultra-short period sub-Earth on a 7.7 hr orbit. With the aim of improving the planetary mass and radius and unveiling the inner architecture of the system, we performed an intensive radial velocity follow-up campaign with the HARPS spectrograph—collecting 371 high-precision measurements over a baseline of nearly 3 yr—and combined our Doppler measurements with new TESS observations from sectors 35 and 36. We found that GJ 367 b has a mass of M b = 0.633 ± 0.050 M ⊕ and a radius of R b = 0.699 ± 0.024 R ⊕, corresponding to precisions of 8% and 3.4%, respectively. This implies a planetary bulk density of ρ b = 10.2 ± 1.3 g cm−3, i.e., 85% higher than Earth’s density. We revealed the presence of two additional non-transiting low-mass companions with orbital periods of ∼11.5 and 34 days and minimum masses of M c sin i c = 4.13 ± 0.36 M ⊕ and M d sin i d = 6.03 ± 0.49 M ⊕, respectively, which lie close to the 3:1 mean motion commensurability. GJ 367 b joins the small class of high-density planets, namely the class of super-Mercuries, being the densest ultra-short period small planet known to date. Thanks to our precise mass and radius estimates, we explored the potential internal composition and structure of GJ 367 b, and found that it is expected to have an iron core with a mass fraction of 0.91 − 0.23 + 0.07 . How this iron core is formed and how such a high density is reached is still not clear, and we discuss the possible pathways of formation of such a small ultra-dense planet

TOI-733 b: A planet in the small-planet radius valley orbiting a Sun-like star

We report the discovery of a hot (Teq ≈ 1055 K) planet in the small-planet radius valley that transits the Sun-like star TOI-733. It was discovered as part of the KESPRINT follow-up program of TESS planets carried out with the HARPS spectrograph. TESS photometry from sectors 9 and 36 yields an orbital period of {equation presented} days and a radius of {equation presented}. Multi-dimensional Gaussian process modelling of the radial velocity measurements from HARPS and activity indicators gives a semi-amplitude of K = 2.23 ± 0.26 m s-1, translating into a planet mass of {equation presented}. These parameters imply that the planet is of moderate density ({equation presented}) and place it in the transition region between rocky and volatile-rich planets with H/He-dominated envelopes on the mass-radius diagram. Combining these with stellar parameters and abundances, we calculated planet interior and atmosphere models, which in turn suggest that TOI-733 b has a volatile-enriched, most likely secondary outer envelope, and may represent a highly irradiated ocean world. This is one of only a few such planets around G-type stars that are well characterised

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO