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Roaming mechanisms, involving the brief generation of a neutral atom or molecule that stays in the vicinity before reacting with the remaining atoms of the precursor, are providing valuable insights into previously unexplained chemical reactions. Here, the mechanistic details and femtosecond time-resolved dynamics of H 3 + formation from a series of alcohols with varying primary carbon chain lengths are obtained through a combination of strong-field laser excitation studies and ab initio molecular dynamics calculations. For small alcohols, four distinct pathways involving hydrogen migration and H 2 roaming prior to H 3 + formation are uncovered. Despite the increased number of hydrogens and possible combinations leading to H 3 + formation, the yield decreases as the carbon chain length increases. The fundamental mechanistic findings presented here explore the formation of H 3 + , the most important ion in interstellar chemistry, through H 2 roaming occurring in ionic species. H 2 roaming is associated with H 3 + formation when certain organic molecules are exposed to strong laser fields. Here, the mechanistic details and time-resolved dynamics of H 3 + formation from a series of alcohols were obtained and found that the product yield decreases as the carbon chain length increases.

In contrast to Andean natives, high-altitude Tibetans present with a lower hemoglobin concentration that correlates with reproductive success and exercise capacity. Decades of physiological and genomic research have assumed that the lower hemoglobin concentration in Himalayan natives results from a blunted erythropoietic response to hypoxia (i.e., no increase in total hemoglobin mass). In contrast, herein we test the hypothesis that the lower hemoglobin concentration is the result of greater plasma volume, rather than an absence of increased hemoglobin production. We assessed hemoglobin mass, plasma volume and blood volume in lowlanders at sea level, lowlanders acclimatized to high altitude, Himalayan Sherpa, and Andean Quechua, and explored the functional relevance of volumetric hematological measures to exercise capacity. Hemoglobin mass was highest in Andeans, but also was elevated in Sherpa compared with lowlanders. Sherpa demonstrated a larger plasma volume than Andeans, resulting in a comparable total blood volume at a lower hemoglobin concentration. Hemoglobin mass was positively related to exercise capacity in lowlanders at sea level and in Sherpa at high altitude, but not in Andean natives. Collectively, our findings demonstrate a unique adaptation in Sherpa that reorientates attention away from hemoglobin concentration and toward a paradigm where hemoglobin mass and plasma volume may represent phenotypes with adaptive significance at high altitude.

Roaming mechanisms, involving the brief generation of a neutral atom or molecule that stays in the vicinity before reacting with the remaining atoms of the precursor, are providing valuable insights into previously unexplained chemical reactions. Here, the mechanistic details and femtosecond time-resolved dynamics of H formation from a series of alcohols with varying primary carbon chain lengths are obtained through a combination of strong-field laser excitation studies and ab initio molecular dynamics calculations. For small alcohols, four distinct pathways involving hydrogen migration and H roaming prior to H formation are uncovered. Despite the increased number of hydrogens and possible combinations leading to H formation, the yield decreases as the carbon chain length increases. The fundamental mechanistic findings presented here explore the formation of H , the most important ion in interstellar chemistry, through H roaming occurring in ionic species.

The M2 proton channel from influenza A virus is an essential protein that mediates transport of protons across the viral envelope. This protein has a single transmembrane helix, which tetramerizes into the active channel. At the heart of the conduction mechanism is the exchange of protons between the His37 imidazole moieties of M2 and waters confined to the M2 bundle interior. Protons are conducted as the total charge of the four His37 side chains passes through 2 + and 3 + with a pK a near 6. A 1.65 Å resolution X-ray structure of the transmembrane protein (residues 25–46), crystallized at pH 6.5, reveals a pore that is lined by alternating layers of sidechains and well-ordered water clusters, which offer a pathway for proton conduction. The His37 residues form a box-like structure, bounded on either side by water clusters with well-ordered oxygen atoms at close distance. The conformation of the protein, which is intermediate between structures previously solved at higher and lower pH, suggests a mechanism by which conformational changes might facilitate asymmetric diffusion through the channel in the presence of a proton gradient. Moreover, protons diffusing through the channel need not be localized to a single His37 imidazole, but instead may be delocalized over the entire His-box and associated water clusters. Thus, the new crystal structure provides a possible unification of the discrete site versus continuum conduction models.

Strong-field laser-matter interactions often lead to exotic chemical reactions. Trihydrogen cation formation from organic molecules is one such case that requires multiple bonds to break and form. We present evidence for the existence of two different reaction pathways for H 3 + formation from organic molecules irradiated by a strong-field laser. Assignment of the two pathways was accomplished through analysis of femtosecond time-resolved strong-field ionization and photoion-photoion coincidence measurements carried out on methanol isotopomers, ethylene glycol, and acetone. Ab initio molecular dynamics simulations suggest the formation occurs via two steps: the initial formation of a neutral hydrogen molecule, followed by the abstraction of a proton from the remaining CHOH 2+ fragment by the roaming H 2 molecule. This reaction has similarities to the H 2  + H 2 + mechanism leading to formation of H 3 + in the universe. These exotic chemical reaction mechanisms, involving roaming H 2 molecules, are found to occur in the ~100 fs timescale. Roaming molecule reactions may help to explain unlikely chemical processes, involving dissociation and formation of multiple chemical bonds, occurring under strong laser fields.

Left atrial (LA) enlargement is common in obesity. We sought to determine the influence of ventricular (LV) remodeling on LA size in obesity. We studied 50 otherwise healthy obese subjects (body mass index 37.2 ± 4.6 kg/m2, 50 ± 6 years) and 58 age and gender-matched nonobese controls (body mass index 26.2 ± 2.9 kg/m2, 52 ± 5 years). Diastolic function, relative wall thickness (RWT), and LV mass were assessed using echocardiography. LA and LV volume was measured by 3D-echocardiography. Primary outcome was the ratio of LA volume indexed to LV volume in obese and control subjects. Obese subjects had substantially larger LA volumes compared with control subjects (61.0 ± 16.9 vs 38.9 ± 9.2 ml, p < 0.0001). When scaled to body size or lean mass, differences in LA size persisted. However, when indexed to LV end-diastolic volume, LA volumes between control and obese subjects were comparable (obese vs controls: 0.44 ± 0.15 vs 0.42 ± 0.10, p = 0.46). A small subset of obese subjects (26%) had LA volume markedly out of proportion to LV volume (LA/LV volume ratio ≥0.5) and displayed concentric LV remodeling with larger RWT and LV mass compared with obese subjects with LA/LV <0.5 (RWT: 0.46 ± 0.09 vs 0.36 ± 0.06, p < 0.0001; LV mass: 79 ± 18 vs 62 ± 13 g/m2 p < 0.01). In conclusion, LA enlargement in patients with obesity generally occurs commensurate with LV enlargement and parallels eccentric LV remodeling. LA enlargement out of proportion to LV size is associated with increased RWT and mass. This unique signature may identify obese subjects with pathologic LA remodeling.

Sudden cardiac arrest and death occur among competitive and recreational athletes across the entire spectrum of age, sex, and level of competition. These events are tragic, potentially preventable, and represent a global public health concern. Currently, the precise incidence of sudden cardiac arrest and death among all athletes is uncertain due to the lack of both mandatory case reporting and the infrastructure to process all cases that occur within the general population. Disparities in outcomes between Black and White athletes also exist without explanation. Causes of sudden cardiac arrest and death are age-dependent, with genetic heart conditions and unexplained cases (ie, normal autopsy) predominant among younger athletes, and coronary artery disease accounting for most cases among veteran Masters athletes. Determining best practices for prevention of primary sudden cardiac arrest and death, including preparticipation screening, remains controversial. However, secondary prevention grounded in an emergency action plan incontrovertibly represents a fundamental aspect of comprehensive cardiac care for all athletes.

Land managers, researchers, and regulators increasingly utilize environmental DNA (eDNA) techniques to monitor species richness, presence, and absence. In order to properly develop a biological assay for eDNA metabarcoding or quantitative PCR, scientists must be able to find not only reference sequences (previously identified sequences in a genomics database) that match their target taxa but also reference sequences that match non-target taxa. Determining which taxa have publicly available sequences in a time-efficient and accurate manner currently requires computational skills to search, manipulate, and parse multiple unconnected DNA sequence databases. Our team iteratively designed a Graphic User Interface (GUI) Shiny application called the Reference Sequence Browser (RSB) that provides users efficient and intuitive access to multiple genetic databases regardless of computer programming expertise. The application returns the number of publicly accessible barcode markers per organism in the NCBI Nucleotide, BOLD, or CALeDNA CRUX Metabarcoding Reference Databases. Depending on the database, we offer various search filters such as min and max sequence length or country of origin. Users can then download the FASTA/GenBank files from the RSB web tool, view statistics about the data, and explore results to determine details about the availability or absence of reference sequences.

Heart failure with preserved ejection fraction (HFpEF) is a disease of the elderly with cardiovascular stiffening and reduced exercise capacity. Exercise training appears to improve exercise capacity and cardiovascular function in heart failure with reduced ejection fraction. However, it is unclear whether exercise training could improve cardiovascular stiffness, exercise capacity, and ventricular-arterial coupling in HFpEF. Eleven HFpEF patients and 13 healthy controls underwent invasive measurements with right heart catheterization to define Starling and left ventricular (LV) pressure-volume curves; secondary functional outcomes included Doppler echocardiography, arterial stiffness, cardiopulmonary exercise testing with cardiac output measurement, and ventricular-arterial coupling assessed by the dynamic Starling mechanism. Seven of 11 HFpEF patients (74.9 ± 6 years; 3 men/4 women) completed 1 year of endurance training followed by repeat measurements. Pulmonary capillary wedge pressures and LV end-diastolic volumes were measured at baseline during decreased and increased cardiac filling. LV compliance was assessed by the slope of the pressure-volume curve. Beat-to-beat LV end-diastolic pressure (estimated from pulmonary arterial diastolic pressure) and stroke volume index were obtained, and spectral transfer function analysis was used to assess the dynamic Starling mechanism. Before training, HFpEF patients had reduced exercise capacity, distensibility and dynamic Starling mechanism but similar LV compliance and end-diastolic volumes compared to controls albeit with elevated filling pressure and increased wall stress. One year of training had little effect on LV compliance and volumes, arterial stiffness, exercise capacity or ventricular-arterial coupling. Contrary to our hypothesis, 1 year of endurance training failed to impart favorable effects on cardiovascular stiffness or function in HFpEF.

ObjectiveThe time needed to increase oxygen utilisation to meet metabolic demand (V̇O2 kinetics) is impaired in heart failure (HF) with reduced ejection fraction and is an independent risk factor for HF mortality. It is not known if V̇O2 kinetics are slowed in HF with preserved ejection fraction (HFpEF). We tested the hypothesis that V̇O2 kinetics are slowed during submaximal exercise in HFpEF and that slower V̇O2 kinetics are related to impaired peripheral oxygen extraction.MethodsEighteen HFpEF patients (68±7 years, 10 women) and 18 healthy controls (69±6 years, 10 women) completed submaximal and peak exercise testing. Cardiac output (acetylene rebreathing, Q̇c), ventilatory oxygen uptake (V̇O2, Douglas bags) and arterial-venous O2 difference (a-vO2 difference) derived from Q̇c and V̇O2 were assessed during exercise. Breath-by-breath O2 uptake was measured continuously throughout submaximal exercise, and V̇O2 kinetics was quantified as mean response time (MRT).ResultsHFpEF patients had markedly slowed V̇O2 kinetics during submaximal exercise (MRT: control: 40.1±14.2, HFpEF: 65.4±27.7 s; p<0.002), despite no relative impairment in submaximal cardiac output (Q̇c: control: 8.6±1.7, HFpEF: 9.7±2.2 L/min; p=0.79). When stratified by MRT, HFpEF with an MRT ≥60 s demonstrated elevated Q̇c, and impaired peripheral oxygen extraction that was apparent during submaximal exercise compared with HFpEF with a MRT <60 s (submaximal a-vO2 difference: MRT <60 s: 9.7±2.1, MRT ≥60 s: 7.9±1.1 mL/100 mL; p=0.03).ConclusionHFpEF patients have slowed V̇O2 kinetics that are related to impaired peripheral oxygen utilisation. MRT can identify HFpEF patients with peripheral limitations to submaximal exercise capacity and may be a target for therapeutic intervention.