Mild Cardiotoxicity and Continued Trastuzumab Treatment in the Context of HER2-Positive Breast Cancer.

Breast cancer is the leading cause of cancer death in women worldwide. Trastuzumab, the main HER2-targeted treatment, faces limitations due to potential cardiotoxicity. The management of patients with mild cardiotoxicity on trastuzumab remains uncertain, resulting in treatment discontinuation and negative oncological outcomes.

The lockdown effect: A counterfactual for Sweden.

While most countries imposed a lockdown in response to the first wave of COVID-19 infections, Sweden did not. To quantify the lockdown effect, we approximate a counterfactual lockdown scenario for Sweden through the outcome in a synthetic control unit. We find, first, that a 9-week lockdown in the first half of 2020 would have reduced infections and deaths by about 75% and 38%, respectively.

Hyaluronan Nanoparticles Selectively Target Plaque-Associated Macrophages and Improve Plaque Stability in Atherosclerosis.

Hyaluronan is a biologically active polymer, which can be formulated into nanoparticles. In our study, we aimed to probe atherosclerosis-associated inflammation by using hyaluronan nanoparticles and to determine whether they can ameliorate atherosclerosis. Hyaluronan nanoparticles (HA-NPs) were prepared by reacting amine-functionalized oligomeric hyaluronan (HA) with cholanic ester and labeled with a fluorescent or radioactive label.

Water Dynamics from THz Spectroscopy Reveal the Locus of a Liquid-Liquid Binodal Limit in Aqueous CaCO Solutions.

Many phenomena depend on CaCO nucleation where the role of water remains enigmatic. Changes in THz absorption during the early stages of CaCO nucleation evidence altered coupled motions of hydrated calcium and carbonate ions. The direct link between these changes and the continuous development of the ion activity product reveals the locus of a liquid-liquid binodal limit.

Enzymatic turnover of macromolecules generates long-lasting protein-water-coupled motions beyond reaction steady state.

The main focus of enzymology is on the enzyme rates, substrate structures, and reactivity, whereas the role of solvent dynamics in mediating the biological reaction is often left aside owing to its complex molecular behavior. We used integrated X-ray- and terahertz- based time-resolved spectroscopic tools to study protein-water dynamics during proteolysis of collagen-like substrates by a matrix metalloproteinase. We show equilibration of structural kinetic transitions in the millisecond timescale during degradation of the two model substrates collagen and gelatin, which have different supersecondary structure and flexibility.

Circular trimers of gelatinase B/matrix metalloproteinase-9 constitute a distinct population of functional enzyme molecules differentially regulated by tissue inhibitor of metalloproteinases-1.

Gelatinase B/matrix metalloproteinase-9 (MMP-9) (EC 3.4.24.

Protein stabilization by macromolecular crowding through enthalpy rather than entropy.

The interior of the cell is a densely crowded environment in which protein stability is affected differently than in dilute solution. Macromolecular crowding is commonly understood in terms of an entropic volume exclusion effect based on hardcore repulsions among the macromolecules. We studied the thermal unfolding of ubiquitin in the presence of different cosolutes (glucose, dextran, poly(ethylene glycol), KCl, urea).

Zn2+-Aβ40 complexes form metastable quasi-spherical oligomers that are cytotoxic to cultured hippocampal neurons.

The roles of metal ions in promoting amyloid β-protein (Aβ) oligomerization associated with Alzheimer disease are increasingly recognized. However, the detailed structures dictating toxicity remain elusive for Aβ oligomers stabilized by metal ions. Here, we show that small Zn(2+)-bound Aβ1-40 (Zn(2+)-Aβ40) oligomers formed in cell culture medium exhibit quasi-spherical structures similar to native amylospheroids isolated recently from Alzheimer disease patients.

Correlated structural kinetics and retarded solvent dynamics at the metalloprotease active site.

Solvent dynamics can play a major role in enzyme activity, but obtaining an accurate, quantitative picture of solvent activity during catalysis is quite challenging. Here, we combine terahertz spectroscopy and X-ray absorption analyses to measure changes in the coupled water-protein motions during peptide hydrolysis by a zinc-dependent human metalloprotease. These changes were tightly correlated with rearrangements at the active site during the formation of productive enzyme-substrate intermediates and were different from those in an enzyme-inhibitor complex.

Antifreeze glycoprotein activity correlates with long-range protein-water dynamics.

Antifreeze proteins (AFPs) and antifreeze glycoproteins (AFGPs) enable the survival of organisms living in subfreezing habitats and serve as preservatives. Although their function is known, the underlying molecular mechanism was not understood. Mutagenesis experiments questioned the previous assumption of hydrogen bonding as the dominant mechanism.

Rattling in the cage: ions as probes of sub-picosecond water network dynamics.

We present terahertz (THz) measurements of salt solutions that shed new light on the controversy over whether salts act as kosmotropes (structure makers) or chaotropes (structure breakers), which enhance or reduce the solvent order, respectively. We have carried out precise measurements of the concentration-dependent THz absorption coefficient of 15 solvated alkali halide salts around 85 cm(-1) (2.5 THz).

Solvation dynamics of model peptides probed by terahertz spectroscopy. Observation of the onset of collective network motions.

We have studied the solvation of model peptides at low hydration levels by terahertz absorption spectroscopy. We have recorded the concentration-dependent terahertz absorption coefficients of N-acetyl-glycine-amide (NAGA), N-acetyl-glycine-methylamide (NAGMA), N-acetyl-leucine-amide (NALA), N-acetyl-leucine-methylamide (NALMA), and N-acetyl-tryptophan-amide (NATA) in aqueous solution. We find a dramatic decrease in the THz absorption, if the number of water molecules per solute is less than 18-20.

The terahertz dance of water with the proteins: the effect of protein flexibility on the dynamical hydration shell of ubiquitin.

The role of water in the functioning of proteins has been a hot topic over the years. We use terahertz (THz) spectroscopy as an experimental tool to probe the protein-induced fast solvation dynamics of ubiquitin. In order to investigate the effect of protein flexibility on the changes in the solvation dynamics, we have measured the concentration-dependent THz absorption of several site-specific ubiquitin mutants.