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Purpose Athletes are trained to choose the pace which is perceived to be correct during a specific effort, such as the 1500-m speed skating competition. The purpose of the present study was to “override” self-paced (SP) performance by instructing athletes to execute a theoretically optimal pacing profile. Methods Seven national-level speed-skaters performed a SP 1500-m which was analysed by obtaining velocity (every 100 m) and body position (every 200 m) with video to calculate total mechanical power output. Together with gross efficiency and aerobic kinetics, obtained in separate trials, data were used to calculate aerobic and anaerobic power output profiles. An energy flow model was applied to SP, simulating a range of pacing strategies, and a theoretically optimal pacing profile was imposed in a second race (IM). Results Final time for IM was ∼2 s slower than SP. Total power distribution per lap differed, with a higher power over the first 300 m for IM (637.0 (49.4) vs 612.5 (50.0) W). Anaerobic parameters did not differ. The faster first lap resulted in a higher aerodynamic drag coefficient and perhaps a less effective push-off. Conclusion Experienced athletes have a well-developed performance template, and changing pacing strategy towards a theoretically optimal fast start protocol had negative consequences on speed-skating technique and did not result in better performance.

Background Low-normal thyroid function within the euthyroid range may contribute to increased atherosclerosis susceptibility. The leptin/adiponectin (L/A) ratio is associated with cardiovascular disease and reflects adipose tissue dysfunction. Relationships of the L/A ratio with low-normal thyroid function are unknown. Methods Relationships of thyroid stimulating hormone (TSH) and free thyroxine (free T 4 ) with leptin, adiponectin and the L/A ratio in euthyroid subjects were documented in 67 fasting subjects with metabolic syndrome (Mets) and 86 euthyroid subjects without MetS (TSH and free T 4 levels within the institutional reference range). Results Neither plasma leptin nor adiponectin was significantly correlated with TSH or free T 4 in subjects with and without MetS. In the whole group, high sensitivity C-reactive protein (hs-CRP) was positively correlated with the L/A ratio ( r  = 0.485, P  < 0.001). Notably, the L/A ratio was positively correlated with TSH in subjects with MetS ( r  = 0.252, P  = 0.040) but not in subjects without MetS ( r  = −0.068, P  = 0.54; interaction term, P  = 0.027). In MetS subjects, the L/A ratio remained positively related with TSH after adjustment for age, sex, diabetes status, hs-CRP and the use of antihypertensive and glucose lowering medication (β = 0.283, P  = 0.018), as well as after adjustment for individual MetS components (β = 0.294, P  = 0.020). Conclusions In the context of MetS, a higher TSH within the euthyroid range confers an increased L/A ratio, a proposed marker of atherosclerosis susceptibility and adipocyte dysfunction.

The concept is emerging that low-normal thyroid function, i.e., either higher thyroid-stimulating hormone or lower free thyroxine levels within the euthyroid reference range, could contribute to the development of atherosclerotic cardiovascular disease. It is possible that adverse effects of low-normal thyroid function on cardiovascular outcome may be particularly relevant for specific populations, such as younger people and subjects with high cardiovascular risk. Low-normal thyroid function probably relates to modest increases in plasma total cholesterol, low density lipoprotein cholesterol, triglycerides and insulin resistance, but effects on high density lipoprotein (HDL) cholesterol and non-alcoholic fatty liver disease are inconsistent. Low-normal thyroid function may enhance plasma cholesteryl ester transfer, and contribute to an impaired ability of HDL to inhibit oxidative modification of LDL, reflecting pro-atherogenic alterations in lipoprotein metabolism and HDL function, respectively. Low-normal thyroid function also confers lower levels of bilirubin, a strong natural anti-oxidant. Remarkably, all these effects of low-normal thyroid functional status appear to be more outspoken in the context of chronic hyperglycemia and/or insulin resistance. Collectively, these data support the concept that low-normal thyroid function may adversely affect several processes which conceivably contribute to the pathogenesis of atherosclerotic cardiovascular disease, beyond effects on conventional lipoprotein measures.

Genetic testing of an Irish kindred identified an exonic nucleotide substitution c.1664T>C (p.Leu555Pro) in the MLH1 mismatch repair (MMR) gene. This previously unreported variant is classified as a “variant of uncertain significance” (VUS). Immunohistochemical (IHC) analysis and microsatellite instability (MSI) studies, genetic testing, a literature and online MMR mutation database review, in silico phenotype prediction tools, and an in vitro MMR activity assay were used to study the clinical significance of this variant. The MLH1 c.1664T>C (p.Leu555Pro) VUS co-segregated with three cases of classic Lynch syndrome-associated malignancies over two generations, with consistent loss of MLH1 and PMS2 protein expression on IHC, and evidence of the MSI-High mutator phenotype. The leucine at position 555 is well conserved across a number of species, and this novel variant has not been reported as a normal polymorphism in the general population. In silico and in vitro analyses suggest that this variant may have a deleterious effect on the MLH1 protein and abrogate MMR activity. Evidence from clinical, histological, immunohistochemical, and molecular genetic data suggests that MLH1 c.1664T>C (p.Leu555Pro) is likely to be the pathogenic cause of Lynch syndrome in this family.

DNA mismatch repair ensures genomic integrity on DNA replication. Recognition of a DNA mismatch by a dimeric MutS protein initiates a cascade of reactions and results in repair of the newly synthesized strand; however, details of the molecular mechanism remain controversial. Here we present the crystal structure at 2.2 Å of MutS from Escherichia coli bound to a G·T mismatch. The two MutS monomers have different conformations and form a heterodimer at the structural level. Only one monomer recognizes the mismatch specifically and has ADP bound. Mismatch recognition occurs by extensive minor groove interactions causing unusual base pairing and kinking of the DNA. Nonspecific major groove DNA-binding domains from both monomers embrace the DNA in a clamp-like structure. The interleaved nucleotide-binding sites are located far from the DNA. Mutations in human MutSα (MSH2/MSH6) that lead to hereditary predisposition for cancer, such as hereditary non-polyposis colorectal cancer, can be mapped to this crystal structure.

MutS plays a critical role in DNA mismatch repair in Escherichia coli by binding to mismatches and initiating repair in an ATP‐dependent manner. Mutational analysis of a highly conserved glutamate, Glu38, has revealed its role in mismatch recognition by enabling MutS to discriminate between homoduplex and mismatched DNA. Crystal structures of MutS have shown that Glu38 forms a hydrogen bond to one of the mismatched bases. In this study, we have analyzed the crystal structures, DNA binding and the response to ATP binding of three Glu38 mutants. While confirming the role of the negative charge in initial discrimination, we show that in vivo mismatch repair can proceed even when discrimination is low. We demonstrate that the formation of a hydrogen bond by residue 38 to the mismatched base authorizes repair by inducing intramolecular signaling, which results in the inhibition of rapid hydrolysis of distally bound ATP. This allows formation of the stable MutS–ATP–DNA clamp, a key intermediate in triggering downstream repair events.

The transition metal dichalcogenide IrTe2 displays a remarkable series of first-order phase transitions below room temperature, involving lattice displacements as large as 20 percents of the initial bond length. This is nowadays understood as the result of strong electron-phonon coupling leading to the formation of local multicentre dimers that arrange themselves into one-dimensional stripes. In this work, we study the out-of-equilibrium dynamics of these dimers and track the time evolution of their population following an infrared photoexcitation using free-electron lased-based time-resolved X-ray photoemission spectroscopy. First, we observe that the dissolution of dimers is driven by the transfer of energy from the electronic subsystem to the lattice subsystem, in agreement with previous studies. Second, we observe a surprisingly fast relaxation of the dimer population on the timescale of a few picoseconds. By comparing our results to published ultrafast electron diffraction and angle-resolved photoemission spectroscopy data, we reveal that the long-range order needs tens of picoseconds to recover, while the local dimer distortion recovers on a short timescale of a few picoseconds.

A new type of objective lens has recently been proposed for use in X-ray photoemission electron microscopes (XPEEMs) and momentum microscopes. Adding a ring electrode concentric with the extractor allows the field in the gap between the sample and the extractor to be shaped. Forming a lens field in this gap reduces the field strength at the sample by up to an order of magnitude. This mitigates the risk of field emission, particularly for cleaved samples with sharp edges. A retarding field can redirect all slow electrons, thus eliminating the primary contribution to the space-charge interaction. Here we present the first experimental investigation of the new lens, examining its performance at photon energies ranging from the extreme ultraviolet produced by a high-harmonic generation (HHG)-based source to soft and hard X-rays at two synchrotron facilities. The gap lens in a region without electrodes enables large working distances up to 23 mm. Reduced aberrations allow for larger fields of view in both k-space and real-space imaging, with resolutions comparable to those of conventional cathode lenses. However, field strengths are an order of magnitude smaller. The zero-field mode enables the study of 3D structured objects and is therefore beneficial for small cleaved samples as well as for operando devices involving top electrodes. The repeller mode reduces space-charge effects, but results in a smaller k-field diameter. This reduction ranges from 10% at hard X-ray energies to 50% in the XUV range. The usable energy interval is also reduced by a factor of two. In time-of-flight XPEEM mode the raw data show a resolution of 250 nm, which can be improved to better than 100 nm through data processing.

DNA mismatch repair ensures genomic integrity on DNA replication. Recognition of a DNA mismatch by a dimeric MutS protein initiates a cascade of reactions and results in repair of the newly synthesized strand; however, details of the molecular mechanism remain controversial. Here we present the crystal structure of 2.2 angstrom resolution of MutS from Escherichia coli bound to a G times T mismatch. The two MutS monomers have different conformations and form a heterodimer at the structural level. Only one monomer recognizes the mismatch specifically and has ADP bound. Mismatch recognition occurs by extensive minor groove interactions causing unusual base pairing and kinking of the DNA. Nonspecific major groove DNA-binding domains from both monomers embrace the DNA in a clamp-like structure. The interleaved nucleotide-binding sites are located far from the DNA. Mutations in human MutS alpha (MSH2/MSH6) that lead to hereditary predisposition for cancer, such as hereditary non-polyposis colorectal cancer, can be mapped to this crystal structure.

We have experimentally demonstrated different operating modes for the front lenses of the momentum microscopes described in Part I. Measurements at energies from vacuum UV at a high-harmonic generation (HHG)-based source to the soft and hard X-ray range at a synchrotron facility validated the results of theoretical ray-tracing calculations. The key element is a ring electrode concentric with the extractor electrode, which can tailor the field in the gap. First, the gap-lens-assisted extractor mode reduces the field strength at the sample while mitigating image aberrations. This mode gave good results in all spectral ranges. Secondly, by compensating the field at the sample surface with a negative voltage at the ring electrode we can operate in zero-field mode, which is beneficial for operando experiments. Finally, higher negative voltages establish the repeller mode, which removes all slow electrons below a certain kinetic energy to eliminate the primary contribution to the space-charge interaction in pump-probe experiments. The switch from extractor to repeller mode is associated with a reduction in the k-field-of-view (10-20 % at hard-X-ray energies, increasing to ~50% at low energies). Real-space imaging also benefits from the new lens modes as confirmed by ToF-XPEEM imaging with 650 nm resolution.