Induced Circular Dichroism of Jet-Cooled Phenol Complexes with (R)-(-)-2-Butanol.

The induced circular dichroism (ICD) of phenol complexed with (R)-(-)-2-butanol [PhOH-(-)BOH] in a supersonic jet is investigated using resonant two-photon ionization circular dichroism (R2PICD) spectroscopy. The R2PICD spectrum of PhOH-(-)BOH exhibits nonzero ICD bands near the absorption region of bare PhOH, where (-)BOH is transparent. Two different conformers containing a single hydrogen bond between PhOH and (-)BOH are identified using ultraviolet-ultraviolet hole-burning and infrared ion-dip spectroscopy combined with quantum theoretical calculations. The ICD values of the two conformers are similar to each other. To understand these similar ICD effects of the conformers, the geometrical asymmetry of the PhOH moiety bound to (-)BOH and the coupling strength of the electric transition dipole moments between PhOH and (-)BOH are estimated. Comparing the ICD values of PhOH-(-)BOH with those of PhOH-(-)-l-methyl lactate in the previous report [ Hong , A. ; J. Phys. Chem. Lett. 2018 , 9 , 476 -480 ], we investigate the physical properties that may govern the differences of the ICD values between the two complexes.

Fluorescence-detected circular dichroism spectroscopy of jet-cooled ephedrine.

The resonant two-photon ionization circular dichroism (R2PICD) spectrum represents the cumulative circular dichroism (CD) of one-photon excitation and the subsequent one-photon ionization, whereas the fluorescence-detected circular dichroism (FDCD) spectra exhibit only the CD of one-photon excitation, similar to conventional CD spectra. We obtained the FDCD spectra of jet-cooled ephedrine (EPD) near the origin band of the S0-S1 transition to measure the CD of one-photon absorption and thus the CD of the ionization process in R2PI in comparison with the R2PICD spectra. The CD effects of the ionization following excitation of the A (0-0) and C (930 cm(-1)) bands in the spectrum are small, whereas those of the B band (530 cm(-1)) are anomalously large, leading to opposite CD signs for the FDCD and R2PICD spectra. Based on the intermediate state-selective fragmentation patterns in the R2PI spectra, this large CD effect is attributed to the state-selective isomerization that occurs after excitation of the B band. By comparing the experimental and theoretical spectra, we determined that the B band corresponds to an asymmetric ring distortion mode that involves torsional motions of the side chain, which may facilitate the isomerization process. This study demonstrates that FDCD spectroscopy combined with R2PICD spectroscopy provides a powerful tool to measure the CD effects of the excitation and ionization processes separately in R2PI and thus probe the structural changes that occur during the ionization process following excitation to an intermediate state.

Conformation-specific circular dichroism spectroscopy of cold, isolated chiral molecules.

The CD spectroscopy of a chiral compound in solution yields an average CD value derived from all of the conformations of a chiral molecule. By contrast, CD spectroscopy of cold chiral molecules in the gas phase distinguishes specific conformers of a chiral molecule, but the weak CD effect has limited the practical application of this technique. Reported herein is the first resonant two-photon ionization CD spectra of ephedrines in a supersonic jet using circularly polarized laser pulses, which were generated by synchronizing the oscillation of the photoelastic modulator with the laser firing. The spectra exhibited well-resolved CD bands which were specific for the conformations and vibrational modes of each enantiomer. The CD signs and magnitudes of the jet-cooled chiral molecules were very sensitive to their conformations and thus offered crucial information for determining the three-dimensional structures of chiral species, as conducted in combination with quantum chemical calculations.

Efficient differential expression analysis of large-scale single cell transcriptomics data using dreamlet.

Advances in single-cell and -nucleus transcriptomics have enabled generation of increasingly large-scale datasets from hundreds of subjects and millions of cells. These studies promise to give unprecedented insight into the cell type specific biology of human disease. Yet performing differential expression analyses across subjects remains difficult due to challenges in statistical modeling of these complex studies and scaling analyses to large datasets. Our open-source R package dreamlet (DiseaseNeurogenomics.github.io/dreamlet) uses a pseudobulk approach based on precision-weighted linear mixed models to identify genes differentially expressed with traits across subjects for each cell cluster. Designed for data from large cohorts, dreamlet is substantially faster and uses less memory than existing workflows, while supporting complex statistical models and controlling the false positive rate. We demonstrate computational and statistical performance on published datasets, and a novel dataset of 1.4M single nuclei from postmortem brains of 150 Alzheimer's disease cases and 149 controls.

Efficient differential expression analysis of large-scale single cell transcriptomics data using dreamlet.

Advances in single-cell and -nucleus transcriptomics have enabled generation of increasingly large-scale datasets from hundreds of subjects and millions of cells. These studies promise to give unprecedented insight into the cell type specific biology of human disease. Yet performing differential expression analyses across subjects remains difficult due to challenges in statistical modeling of these complex studies and scaling analyses to large datasets. Our open-source R package dreamlet (DiseaseNeurogenomics.github.io/dreamlet) uses a pseudobulk approach based on precision-weighted linear mixed models to identify genes differentially expressed with traits across subjects for each cell cluster. Designed for data from large cohorts, dreamlet is substantially faster and uses less memory than existing workflows, while supporting complex statistical models and controlling the false positive rate. We demonstrate computational and statistical performance on published datasets, and a novel dataset of 1.4M single nuclei from postmortem brains of 150 Alzheimer's disease cases and 149 controls.

Discoidin Domain Receptor 1 (DDR1) tyrosine kinase is upregulated in PKD kidneys but does not play a role in the pathogenesis of polycystic kidney disease.

Tolvaptan is the only drug approved to slow cyst growth and preserve kidney function in patients with autosomal dominant polycystic kidney disease (ADPKD). However, its limited efficacy combined with significant side effects underscores the need to identify new and safe therapeutic drug targets to slow progression to end stage kidney disease. We identified Discoidin Domain Receptor 1 (DDR1) as receptor tyrosine kinase upregulated in vivo in 3 mouse models of ADPKD using a novel mass spectrometry approach to identify kinases upregulated in ADPKD. Previous studies demonstrating critical roles for DDR1 to cancer progression, its potential role in the pathogenesis of a variety of other kidney disease, along with the possibility that DDR1 could provide new insight into how extracellular matrix impacts cyst growth led us to study the role of DDR1 in ADPKD pathogenesis. However, genetic deletion of DDR1 using CRISPR/Cas9 failed to slow cyst growth or preserve kidney function in both a rapid and slow mouse model of ADPKD demonstrating that DDR1 does not play a role in PKD pathogenesis and is thus a not viable drug target. In spite of the negative results, our studies will be of interest to the nephrology community as it will prevent others from potentially conducting similar experiments on DDR1 and reinforces the potential of performing unbiased screens coupled with in vivo gene editing using CRISPR/Cas9 to rapidly identify and confirm new potential drug targets for ADPKD.

Isomer-Specific Induced Circular Dichroism Spectroscopy of Jet-Cooled Phenol Complexes with (-)-Methyl l-Lactate.

Induced circular dichroism (ICD) is the CD observed in the absorption of an achiral molecule bound to a transparent chiral molecule through noncovalent interactions. ICD spectroscopy has been used to probe the binding between molecules, such as protein-ligand interactions. However, most ICD spectra have been measured in solution, which only exhibit the averaged CD values of all conformational isomers in solution. Here, we obtained the first isomer-selective ICD spectra by applying resonant two-photon ionization CD spectroscopy to jet-cooled phenol complexes with (-)-methyl l-lactate (PhOH-(-)ML). The well-resolved CD bands in the spectra were assigned to two conformers, which contained different types of hydrogen-bonding interactions between PhOH and (-)ML. The ICD values of the two conformers have different signs and magnitudes, which were explained by differences both in the geometrical asymmetries of PhOH bound to (-)ML and in the electronic coupling strengths between PhOH and (-)ML.

Electronic Circular Dichroism Spectroscopy of Jet-Cooled Phenylalanine and Its Hydrated Clusters.

We obtained resonant two-photon ionization circular dichroism (R2PICD) spectra of jet-cooled phenylalanine (Phe) and its hydrated clusters (Phe(H2O)n, n = 1-2) near the origin band of the S0-S1 transition. The R2PICD spectra of Phe exhibit well-resolved CD bands of six different conformers present in the jet, which vary in sign and magnitude depending on their conformations. We revised the previous structural assignments of the Phe conformers based on the comparison between the experimental and theoretical CD signs, infrared spectra, and rotational band contours. The R2PICD spectra of Phe(H2O)n reveal that hydration with one or two water molecule(s) does not affect the CD signs of Phe conformers but significantly increases their CD magnitudes. Furthermore, conformational selection by solvation alters relative populations of Phe conformers, leading to a sign inversion in the CD spectra of Phe(H2O)n compared with that of Phe monomer.

Effectiveness of Intraluminal Air Decompression on Postcolonoscopic Pain According to Reinsertion Site.

BACKGROUND: Colonoscopy is a very effective and essential examination to diagnose colorectal cancer; however, many patients experience discomfort due to post-examination abdominal pain, which reduces colonoscopy compliance. This study was conducted to determine methods for reducing post-colonoscopic abdominal pain. METHODS: We conducted a randomized controlled study of 405 male and female adults who visited Hana General Hospital in Cheongju. We surveyed general characteristics, history of colonoscopy, and other related factors, then categorized examinees into 5 groups (0-5) according to the site of scope reinsertion. Pain was measured using a numeric rating scale (NRS). RESULTS: The mean age of examinees in this study was 47.8 years, and 210 participants had prior experience of colonoscopy. No significant difference was observed between variables, with the exception of reinsertion duration (P=0.005). Pain scores were different between performing physicians (P=0.006), and were higher when the subjective level of procedure difficulty was low (P=0.026) in univariate analysis. Pain scores decreased as the reinsertion site became closer to the proximal colon (P<0.001), but there was no significant difference between groups 3 and 4. The results of multiple logistic regression analysis, including univariate analysis, showed that group 1 had 0.48 times, group 2 had 0.38 times, group 3 had 0.09 times, and group 4 had 0.03 times odds ratio (moderate-to-severe pain, NRS ≥4) than control group 0. CONCLUSION: Air decompression by scope reinsertion is an effective way to reduce abdominal pain after colonoscopy. Removing air when the reinserted scope approaches the hepatic flexure seems to be the most effective method to reduce post-colonoscopic pain.

The effect of burn rehabilitation massage therapy on hypertrophic scar after burn: a randomized controlled trial.

OBJECTIVE: To evaluate the effect of burn rehabilitation massage therapy on hypertrophic scar after burn. METHOD: One hundred and forty-six burn patients with hypertrophic scar(s) were randomly divided into an experimental group and a control group. All patients received standard rehabilitation therapy for hypertrophic scars and 76 patients (massage group) additionally received burn scar rehabilitation massage therapy. Both before and after the treatment, we determined the scores of visual analog scale (VAS) and itching scale and assessed the scar characteristics of thickness, melanin, erythema, transepidermal water loss (TEWL), sebum, and elasticity by using ultrasonography, Mexameter(®), Tewameter(®), Sebumeter(®), and Cutometer(®), respectively. RESULTS: The scores of both VAS and itching scale decreased significantly in both groups, indicating a significant intragroup difference. With regard to the scar characteristics, the massage group showed a significant decrease after treatment in scar thickness, melanin, erythema, TEWL and a significant intergroup difference. In terms of scar elasticity, a significant intergroup difference was noted in immediate distension and gross skin elasticity, while the massage group significant improvement in skin distensibility, immediate distension, immediate retraction, and delayed distension. CONCLUSION: Our results suggest that burn rehabilitation massage therapy is effective in improving pain, pruritus, and scar characteristics in hypertrophic scars after burn.