The Continuous Inhalation of Oxygen Gas in Pneumonia and in Other Diseases

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MULTI-FACETED SPECTROSCOPIC STUDY OF THE STRUCTURAL CHANGES ASSOCIATED WITH ELECTRONIC EXCITATION OF METHYL ANTHRANILATE

Methyl anthranilate (MA) is the methyl ester of anthranilic acid. We present the jet-cooled Laser Induced Fluorescence (LIF) UV excitation spectrum, ground (S$_{0}$) and excited state (S$_{1}$) Fluorescence Dip Infrared (FDIR) spectra, IR-UV Holeburning (IR-UV HB) spectra, and Dispersed Fluorescence (DFL) spectra of the MA monomer and MA-H$_{2}$O complex. MA is a close analog of salicylic acid, a well-studied molecule thought to undergo keto-enol tautomerism involving excited state H-atom transfer. In the MA monomer, the C6 ring formed by the H$_{a}$NH$_{b}$ $^{...}$ O=C hydrogen bond in the ground state undergoes an unusual increase in hydrogen bond strength following electronic excitation to the S$_{1}$ state. This is evident in the spectroscopy in several ways. The LIF excitation and DFL spectra both show long progressions in several modes involving motion of the NH$_{2}$ and COOMe groups relative to one another. Furthermore, the coupled NH$_{2}$ symmetric and asymmetric stretch fundamentals appear to uncouple upon UV excitation, giving rise to a broadened (8 cm$^{-1}$ FWHM), nominally “free” N-H$_{a}$ stretch at 3458 cm$^{-1}$ and an N-H$_{b}$ stretch shifted all the way down to \~{}2900 cm$^{-1}$. FDIR spectra collected in the mid-IR frequency range show the change in hydrogen bond strength from the perspective of the C=O acceptor group, where the stretch fundamental is shifted down from its S$_{0}$ position at 1721 cm$^{-1}$ to 1637 cm$^{-1}$ in S$_{1}$. Calculations at the B3LYP-D3/def2TZVP level of theory in large measure capture these frequency shifts and give insight into likely explanations for such drastic changes. Similar behavior is observed in the MA-H$_{2}$O complex, although the extent of the hydrogen bond strengthening in the S$_{1}$ state is modulated by the HOH interactions with both the NH$_{2}$ and C=O groups

JET-COOLED, CONFORMER-SPECIFIC IR SPECTRA OF CYCLICALLY-CONSTRAINED β-PEPTIDES. DOES CONDENSED PHASE STRUCTURE SURVIVE THE VACUUM?

We present laser-desorbed, jet-cooled, conformation-specific UV and IR data on a series of increasingly complex $\beta$-peptide oligomers: Ac-(ACHC)$_{2}$-NHBn, Ac-ACHC-m$_{4}$ACHC-NHBn, Ac-m$_{5}$ACHC-m$_{4}$ACHC-NHBn, Ac-m$_{4}$ACHC-ACHC-NHBn, Ac-m$_{4}$ACHC-m$_{5}$ACHC-NHBn, Ac-(ACHC)$_{3}$-NHBn, and Ac-(ACHC)$_{4}$-NHBn. Synthetic foldamers are polymers composed of non-natural building blocks which either mimic, or expand upon, nature’s preferred secondary structures which are accessible to pure $\alpha$-amino acid sequences. The ring-constrained $\beta$-amino acid, \textit{cis}-2-aminocyclohexanecarboxylic acid (ACHC), is one such non-natural building block which when polymerized with alternating chirality has been shown to adopt both right- and left-handed 12/10 mixed helices in solution and crystalline form. ACHC may adopt two local minima conformations: one in which the NH is axial (ax) with respect to the cyclohexane chair and the C=O is equatorial (eq), and vice versa. In poly-ACHC sequences, the cooperative conformational isomerization between these two minima switches the screw-sense of the 12/10 helix. The use of the more rigid $\beta$-amino acids, \textit{cis}-2-amino-\textit{cis}-4-methylcyclohexanecarboxylic acid (m$_{4}$ACHC) and \textit{cis}-2-amino-\textit{cis}-5-methylcyclohexanecarboxylic acid (m$_{5}$ACHC) sterically lock the ACHC residue into one of its two minima, depending on the stereochemical patterning at the ring’s three stereocenters. The isolated, solvent-free conformational preferences will be compared with condensed phase data, and the energetic impact of the benzyl chromophore on preferred structure will be discussed

Single-conformation IR and UV spectroscopy of a prototypical heterogeneous α/β-peptide: is it a mixed-helix former?

Synthetic foldamers are non-natural polymers designed to fold into unique secondary structures that either mimic nature’s preferred secondary structures, or expand their possibilities. Among the most studied synthetic foldamers are $\beta$-peptides, which lengthen the distance between amide groups from the single substituted carbon spacer in $\alpha$-peptides by one additional carbon. We present data on a mixed $\alpha$/$\beta$ tri-peptide in which a single $\beta$-residue with a conformationally constrained cis-2-aminocyclohexanecarboxylic acid (cis-ACHC) substitution is inserted in an $\alpha$-peptide backbone to form Ac-Ala-$\beta$-ACHC-Ala-NHBn. This $\alpha$$\beta$$\alpha$ structure is known in longer sequences to prefer formation of a 9/11 mixed helix. Under isolated, jet cooled conditions, four unique conformers were observed in the expansion. The dominant conformer is configured in a tetramer cycle with every amide carbonyl and amine group involved in hydrogen bonding, giving rise to a tightly folded C12/C7/C8/C7 structure reminiscent of a $\beta$-turn. This talk will describe the conformation specific IR and UV spectroscopy methods used to study this mixed peptide, as well as its experimentally observed conformational preferences

STUDYING THE FOLDING PROPENSITY OF ASPARAGINE-CONTAINING PEPTIDES IN A MOLECULAR BEAM

Asparagine (Asn) and Glutamine (Gln) are the only two naturally-occuring amino acids that incorporate an amide group in the side chain, differing only by a single methylene group that lengthens the chain in Gln relative to Asn. These two amino acids appear with unusual abundance in the prion forming domain of proteins that are implicated in neurodegenerative disease pathogenesis. In a bottom-up approach towards understanding nature's preference for Asn and Gln in prion domains, we build off of our previous study of Gln-containing peptides by elucidating the inherent folding propensities of three Asn-containing peptides: Ac-Asn-NHBn, Ac-Ala-Asn-NHBn, and Ac-Asn-Asn-NHBn. These molecules are brought into the gas phase by laser desorption and cooled in a supersonic expansion before interrogation via resonant two-photon ionization (R2PI), IR-UV holeburning, and resonant ion-dip infrared (RIDIR) spectroscopies. This talk will describe the conformation-specific IR and UV spectroscopy of these three peptides, concentrating on the fundamental question of whether side-chain/side-chain, backbone/backbone, or side-chain/backbone interactions are preferred in each case. Assignment of the observed conformations are deduced from a comparison of the experimental IR spectra with the predictions of calculations. Two unique conformational isomers are assigned to the capped Asn amino acid while only one conformational isomer is present in both dipeptides. These structures will be compared with those found in the analogous glutamine-containing peptides. Best fit calculated structures reveal intriguing incipient secondary structure formation at the first possible instance

THE ROLE OF THE LOCAL CONFORMATION OF A CYCLICALLY CONSTRAINED β-AMINO ACID IN THE SECONDARY STRUCTURES OF A MIXED α/β DIASTEREOMER PAIR

Synthetic foldamers are non-natural polymers designed to fold into unique secondary structures that either mimic nature’s preferred secondary structures, or expand their possibilities. Among the most studied synthetic foldamers are $beta$-peptides, which lengthen the distance between amide groups from the single substituted carbon spacer in $alpha$-peptides by one ($beta$) additional carbon. Cyclically constrained $beta$-amino acids can impart rigidity to the secondary structure of oligomers by locking in a particular conformation. The $beta$-residue emph{cis}-2-aminocyclohexanecarboxylic acid (emph{cis}-ACHC) is one such amino acid which has been shown to drive vastly different secondary structures as a function of the local conformation of the cyclohexane ring. We present data on two diastereomers of the mixed $alpha$/$beta$ tri-peptide Ac-Ala-$beta$$_{ACHC}$-Ala-NHBn which differ from one another by the chirality along the ACHC residue (SRSS vs. SSRS). The first oligomer is known to crystallize to a 9/11 mixed helix while the second forms no intramolecular hydrogen bonds in the crystal state. This talk will describe the conformation-specific IR and UV spectroscopy of the above two diastereomers under jet cooled conditions in the gas phase. Assignments based on comparison with calculations show the presence of incipient 9/11 mixed helices and competing structures containing more tightly folded hydrogen-bonded networks. The calculated global minimum structures are observed in each case, and in each case these folded structures are reminiscent of a $beta$-turn

Blood glucose variance measured by continuous glucose monitors across the menstrual cycle

Past studies on how blood glucose levels vary across the menstrual cycle have largely shown inconsistent results based on limited blood draws. In this study, 49 individuals wore a Dexcom G6 continuous glucose monitor and a Fitbit Sense smartwatch while measuring their menstrual hormones and self-reporting characteristics of their menstrual cycles daily. The average duration of participation was 79.3 ± 21.2 days, leading to a total of 149 cycles and 554 phases in our dataset. We use periodic restricted cubic splines to evaluate the relationship between blood glucose and the menstrual cycle, after which we assess phase-based changes in daily median glucose level and associated physiological parameters using mixed-effects models. Results indicate that daily median glucose levels increase and decrease in a biphasic pattern, with maximum levels occurring during the luteal phase and minimum levels occurring during the late-follicular phase. These trends are robust to adjustments for participant characteristics (e.g., age, BMI, weight) and self-reported menstrual experiences (e.g., food cravings, bloating, fatigue). We identify negative associations between each of daily estrogen level, step count, and low degrees of fatigue with higher median glucose levels. Conversely, we find positive associations between higher food cravings and higher median glucose levels. This study suggests that blood glucose could be an important parameter for understanding menstrual health, prompting further investigation into how the menstrual cycle influences glucose fluctuation

Wavepacket insights into the photoprotection mechanism of the UV filter methyl anthranilate

Meradimate is a broad-spectrum ultraviolet absorber used as a chemical filter in commercial sunscreens. Herein, we explore the ultrafast photodynamics occurring in methyl anthranilate (precursor to Meradimate) immediately after photoexcitation with ultraviolet radiation to understand the mechanisms underpinning Meradimate photoprotection. Using time-resolved photoelectron spectroscopy, signal from the first singlet excited state of methyl anthranilate shows an oscillatory behavior, i.e. quantum beats. Our studies reveal a dependence of the observed beating frequencies on photoexcitation wavelength and photoelectron kinetic energy, unveiling the different Franck-Condon overlaps between the vibrational levels of the ground electronic, first electronic excited, and ground cationic states of methyl anthranilate. By evaluating the behavior of these beats with increasing photon energy, we find evidence for intramolecular vibrational energy redistribution on the first electronic excited state. Such energy redistribution hinders efficient relaxation of the electronic excited state, making methyl anthranilate a poor choice for an efficient, efficacious sunscreen chemical filter

Vigorous Intermittent Lifestyle Physical Activity and Cancer Incidence Among Nonexercising Adults: The UK Biobank Accelerometry Study

IMPORTANCE: Vigorous physical activity (VPA) is a time-efficient way to achieve recommended physical activity (PA) for cancer prevention, although structured longer bouts of VPA (via traditional exercise) are unappealing or inaccessible to many individuals. OBJECTIVES: To evaluate the dose-response association of device-measured daily vigorous intermittent lifestyle physical activity (VILPA) with incident cancer, and to estimate the minimal dose required for a risk reduction of 50% of the maximum reduction. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective cohort analysis of 22 398 self-reported nonexercising adults from the UK Biobank accelerometry subsample. Participants were followed up through October 30, 2021 (mortality and hospitalizations), or June 30, 2021 (cancer registrations). EXPOSURES: Daily VILPA of up to 1 and up to 2 minutes, assessed by accelerometers worn on participants' dominant wrist. MAIN OUTCOMES AND MEASURES: Incidence of total cancer and PA-related cancer (a composite outcome of 13 cancer sites associated with low PA levels). Hazard ratios and 95% CIs were estimated using cubic splines adjusted for age, sex, education level, smoking status, alcohol consumption, sleep duration, fruit and vegetable consumption, parental cancer history, light- and moderate-intensity PA, and VPA from bouts of more than 1 or 2 minute(s), as appropriate. RESULTS: The study sample comprised 22 398 participants (mean [SD] age, 62.0 [7.6] years; 10 122 [45.2%] men and 12 276 [54.8%] women; 21 509 [96.0%] White individuals). During a mean (SD) follow-up of 6.7 (1.2) years (149 650 person-years), 2356 total incident cancer events occurred, 1084 owing to PA-related cancer. Almost all (92.3%) of VILPA was accrued in bouts of up to 1 minute. Daily VILPA duration was associated with outcomes in a near-linear manner, with steeper dose-response curves for PA-related cancer than total cancer incidence. Compared with no VILPA, the median daily VILPA duration of bouts up to 1 minute (4.5 minutes per day) was associated with an HR of 0.80 (95% CI, 0.69-0.92) for total cancer and 0.69 (95% CI, 0.55-0.86) for PA-related cancer. The minimal dose was 3.4 minutes per day for total (HR, 0.83; 95% CI, 0.73-0.93) and 3.7 minutes for PA-related (HR, 0.72; 95% CI, 0.59-0.88) cancer incidence. Findings were similar for VILPA bout of up to 2 minutes. CONCLUSIONS AND RELEVANCE: The findings of this prospective cohort study indicate that small amounts of VILPA were associated with lower incident cancer risk. Daily VILPA may be a promising intervention for cancer prevention in populations not able or motivated to exercise in leisure time

End Sequence Analysis Toolkit (ESAT) expands the extractable information from single-cell RNA-seq data

RNA-seq protocols that focus on transcript termini are well suited for applications in which template quantity is limiting. Here we show that, when applied to end-sequencing data, analytical methods designed for global RNA-seq produce computational artifacts. To remedy this, we created the End Sequence Analysis Toolkit (ESAT). As a test, we first compared end-sequencing and bulk RNA-seq using RNA from dendritic cells stimulated with lipopolysaccharide (LPS). As predicted by the telescripting model for transcriptional bursts, ESAT detected an LPS-stimulated shift to shorter 3\u27-isoforms that was not evident by conventional computational methods. Then, droplet-based microfluidics was used to generate 1000 cDNA libraries, each from an individual pancreatic islet cell. ESAT identified nine distinct cell types, three distinct beta-cell types, and a complex interplay between hormone secretion and vascularization. ESAT, then, offers a much-needed and generally applicable computational pipeline for either bulk or single-cell RNA end-sequencing