•It provides recommendations for risk reduction and screening in hereditary breast and ovarian cancer syndrome.•It focuses on risk reduction and screening mainly in unaffected carriers and ...high-resource settings.•The panel encompasses an international multidisciplinary group of experts.•Recommendations are based on available scientific data and the authors’ collective expert opinion.
Thalidomide and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as ...the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, lenalidomide and another immunomodulatory drug, pomalidomide, bound endogenous CRBN and recombinant CRBN-DNA damage binding protein-1 (DDB1) complexes. CRBN mediated antiproliferative activities of lenalidomide and pomalidomide in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. Lenalidomide and pomalidomide inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN(YW/AA). Overexpression of CRBN wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21(WAF-1) expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both pomalidomide and lenalidomide, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide.
Elements that can occur in more than one valence state, such as Fe, C and S, play an important role in Earth's systems at all levels, and can drive planetary evolution as they cycle through the ...various geochemical reservoirs. Subduction introduces oxidised Fe, C and S in sediments, altered ocean crust, and partially serpentinised lithospheric mantle to the relatively reduced mantle, with short- and long-term consequences for the redox state of the mantle. The distribution of redox-sensitive elements in the mantle controls the redox state of mantle-derived material added to the lithosphere and atmosphere, such as arc volcanic gases and the magmas that form arc-related ore deposits.
The extent of mantle oxidation induced by subduction zone cycling can be assessed, albeit with large uncertainties, with redox budget calculations that quantify the inputs and outputs to subduction zones. Literature data are augmented by new measurements of the chemical composition of partially serpentinised lithospheric mantle from New Caledonia and ODP 209. Results indicate that there is a net addition of Fe (55±13×1012molyear−1), C (4.6±4.0×1012molyear−1), S (2.4±0.9×1012molyear−1), and redox budget (5–89×1012molyear−1) at subduction zones. Monte Carlo calculations of redox budget fluxes indicate that fluxes are 46±12×1012molyear−1 entering subduction zones, if input and output parameters are assumed to be normally distributed, and 46–58×1012molyear−1 if input and output parameters are assumed to be log-normally distributed.
Thus, inputs into subduction zones for Fe, C, S and redox budget are in excess of subduction zone outputs. If MORB and plume-related fluxes are taken into account then Fe, C and S fluxes balance, within error. However, the redox budget does not balance, unless the very lowest estimates for the extent of slab oxidation are taken. Thus it is likely that subduction continuously increases the redox budget of the mantle, that is, there is addition of Fe, C and S that are oxidised relative to the Fe, C and S in the mantle.
The fate of this redox budget can be constrained by consideration of element mobility under mantle conditions. If slab fluids are assumed to be dominantly aqueous and relatively low salinity then fluxes of Fe3+, C4+, and S6+ are limited to less than 109, 2.3×1012molyear−1 and 2×1012molyear−1 respectively by the low solubility of these elements in slab-derived fluids. Nevertheless, such fluxes can produce the increased fO2 inferred for sub-arc mantle from arc lavas after around 10Ma subduction.
The rest of the redox budget added by the subduction process is likely to be carried to the deep mantle by the slab, and mix slowly with the whole mantle reservoir, depending on the timescale of reincorporation of subducted lithosphere into the mantle. Simple mixing calculations indicate that these fluxes will only cause a measurable difference to mantle redox on a 1Ga timescale, which is longer than the 550Ma during which redox budget fluxes are likely to have been at present day levels. However, measurable effects, with potential consequences for the Earth's evolution may be expected in the future.
A number of lines of evidence point to a causal link between oxidised slab-derived fluids, oxidised sub-arc mantle, and the formation of economic concentrations of metals such as Cu and Au that ...require oxidised magmas. However, trace element evidence from some trace element and isotope data suggests that sub-arc mantle is no more oxidised than mantle elsewhere.
A simple analytical model is applied to constrain the evolution of sub-arc mantle oxidation state as a function of redox-budget fluxes from the subducting slab. Influential variables include the solubility of Fe
3+ and SO
4
2
−
in slab-derived fluids, the geometry of the infiltration of slab-derived fluids in sub-arc mantle, the coupling between slab-derived and arc-output redox budgets, and the concentration of redox-buffering elements such as Fe and S in the sub-arc mantle.
Plausible Archean and Proterozoic redox budget fluxes would not have created oxidised sub-arc mantle without input from ferric iron or sulphate dissolved in non-aqueous fluids such as silicate melts. Aqueous-borne Phanerozoic redox budget fluxes, on the other hand, which are dominated by the sulphate component, could have increased sub-arc
f
O
2
by up to three log
10 units. The results are generally consistent with the proposed elevated
f
O
2
for sub-arc mantle, but no resolution was found for the apparent contradiction between high proposed
f
O
2
values derived from iron-based oxybarometry and the lower values inferred from trace element and isotope evidence.
Increases in sub-arc mantle
f
O
2
are favoured by focussed fluid infiltration and magma generation, weak coupling between slab and arc-output redox budgets, and restricted redox-buffering in the sub-arc mantle. Fertile arc segments for ore deposits associated with oxidised magmas require fluid chemistry and pressure–temperature gradients that enhance Fe
3+ and SO
4
2
−
solubility in aqueous and silica-rich fluids, tectonic stress regimes that favour focussed transfer of components into the sub-arc mantle, and a relatively weak redox buffer for the sub-arc mantle. The paucity of Cu and Au deposits associated with oxidised magmas in Precambrian rocks may be explained as a consequence of a lack of subducted oxidised material, rather than simply as a consequence of preservation potential. Additionally, the reduced nature of subducted material in the Precambrian may have caused S and metal enrichment in the sub-arc mantle.
► Slab-derived fluids are unlikely to have oxidised sub-arc mantle prior to 550
Ma. ► Oxidised slab-derived fluids may have oxidised sub-arc mantle after 550
Ma. ► The lack of >
550
Ma Cu–Au deposits is linked to a lack of oxidised slab-derived fluids. ► Subduction processes >
550
Ma increased metal and sulphur contents of sub-arc mantle.
Aims
Use of the CamAPS FX hybrid closed loop (CL) system is associated with improved time in range and glycated haemoglobin A1c across the age span, but little is known about its effects on ...patient‐reported outcomes (PROs).
Methods
This open‐label, randomized, multi‐site study compared CamAPS FX to sensor‐augmented pump (SAP) in a sample of older adults (≥60 years) with type 1 diabetes (T1D). Thirty‐five older adults completed PROs surveys at the start of the study and after each period of 16 weeks using either CL or SAP. At the end of the study, 19 participated in interviews about their experiences with CL.
Results
Results examining the 16 weeks of CL use showed that the overall Diabetes Distress Scale score and two subscales (powerlessness and physician distress) improved significantly along with trust on the Glucose Monitoring Satisfaction Survey. User experience interview responses were consistent in noting benefits of ‘improved glycaemic control’ and ‘worrying less about diabetes’.
Conclusion
In this sample of older adults with T1D who have previously shown glycaemic benefit, there are indicators of improved PROs and subjective user experience benefits.
We discuss the parameter spaces of supersymmetry (SUSY) scenarios taking into account the improved Higgs-mass prediction provided by FeynHiggs 2.14.1. Among other improvements, this prediction ...incorporates three-loop renormalization-group effects and two-loop threshold corrections, and can accommodate three separate mass scales:
m
q
~
(for squarks),
m
g
~
(for gluinos) and
m
χ
~
(for electroweakinos). Furthermore, it contains an improved treatment of the
DR
¯
scalar top parameters avoiding problems with the conversion to on-shell parameters, that yields more accurate results for large SUSY-breaking scales. We first consider the CMSSM, in which the soft SUSY-breaking parameters
m
0
and
m
1
/
2
are universal at the GUT scale, and then sub-GUT models in which universality is imposed at some lower scale. In both cases, we consider the constraints from the Higgs-boson mass
M
h
in the bulk of the
(
m
0
,
m
1
/
2
)
plane and also along stop coannihilation strips where sparticle masses may extend into the multi-TeV range. We then consider the minimal anomaly-mediated SUSY-breaking scenario, in which large sparticle masses are generic. In all these scenarios the substantial improvements between the calculations of
M
h
in FeynHiggs 2.14.1 and FeynHiggs 2.10.0, which was used in an earlier study, change significantly the preferred portions of the models’ parameter spaces. Finally, we consider the pMSSM11, in which sparticle masses may be significantly smaller and we find only small changes in the preferred regions of parameter space.
Airway diseases, including cigarette smoke-induced chronic bronchitis, cystic fibrosis, and primary ciliary dyskinesia are associated with decreased mucociliary clearance (MCC). However, it is not ...known whether a simple reduction in MCC or concentration-dependent mucus adhesion to airway surfaces dominates disease pathogenesis or whether decreasing the concentration of secreted mucins may be therapeutic. To address these questions, Scnn1b-Tg mice, which exhibit airway mucus dehydration/adhesion, were compared and crossed with Muc5b- and Muc5ac-deficient mice. Absence of Muc5b caused a 90% reduction in MCC, whereas Scnn1b-Tg mice exhibited an ∼50% reduction. However, the degree of MCC reduction did not correlate with bronchitic airway pathology, which was observed only in Scnn1b-Tg mice. Ablation of Muc5b significantly reduced the extent of mucus plugging in Scnn1b-Tg mice. However, complete absence of Muc5b in Scnn1b-Tg mice was associated with increased airway inflammation, suggesting that Muc5b is required to maintain immune homeostasis. Loss of Muc5ac had few phenotypic consequences in Scnn1b-Tg mice. These data suggest that: (i) mucus hyperconcentration dominates over MCC reduction alone to produce bronchitic airway pathology; (ii) Muc5b is the dominant contributor to the Scnn1b-Tg phenotype; and (iii) therapies that limit mucin secretion may reduce plugging, but complete Muc5b removal from airway surfaces may be detrimental.
Modern high-power lasers can generate extreme states of matter that are relevant to astrophysics, equation-of-state studies and fusion energy research. Laser-driven implosions of spherical polymer ...shells have, for example, achieved an increase in density of 1,000 times relative to the solid state. These densities are large enough to enable controlled fusion, but to achieve energy gain a small volume of compressed fuel (known as the 'spark') must be heated to temperatures of about 108 K (corresponding to thermal energies in excess of 10 keV). In the conventional approach to controlled fusion, the spark is both produced and heated by accurately timed shock waves, but this process requires both precise implosion symmetry and a very large drive energy. In principle, these requirements can be significantly relaxed by performing the compression and fast heating separately; however, this 'fast ignitor' approach also suffers drawbacks, such as propagation losses and deflection of the ultra-intense laser pulse by the plasma surrounding the compressed fuel. Here we employ a new compression geometry that eliminates these problems; we combine production of compressed matter in a laser-driven implosion with picosecond-fast heating by a laser pulse timed to coincide with the peak compression. Our approach therefore permits efficient compression and heating to be carried out simultaneously, providing a route to efficient fusion energy production.
Much of global gold production has come from deposits with uneconomic concentrations of base metals, such as copper, lead and zinc. These 'gold-only' deposits are thought to have formed from hot, ...aqueous fluids rich in carbon dioxide, but only minor significance has been attached to the role of the CO2 in the process of gold transport. This is because chemical bonding between gold ions and CO2 species is not strong, and so it is unlikely that CO2 has a direct role in gold transport. An alternative indirect role for CO2 as a weak acid that buffers pH has also appeared unlikely, because previously inferred pH values for such gold-bearing fluids are variable. Here we show that such calculated pH values are unlikely to record conditions of gold transport, and propose that CO2 may play a critical role during gold transport by buffering the fluid in a pH range where elevated gold concentration can be maintained by complexation with reduced sulphur. Our conclusions, which are supported by geochemical modelling, may provide a platform for new gold exploration methods.
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