Examined here are the structures of complexes of benzophenone microsolvated with up to three water molecules by using broadband rotational spectroscopy and the cold conditions of a molecular jet. The ...analysis shows that the water molecules dock sideways on benzophenone for the water monomer and dimer moieties, and they move above one of the aromatic rings when the water cluster grows to the trimer. The rotational spectra shows that the water trimer moiety in the complex adopts an open‐loop arrangement. Ab initio calculations face a dilemma of identifying the global minimum between the open loop and the closed loop, which is only solved when zero‐point vibrational energy correction is applied. An OH⋅⋅⋅π bond and a Bürgi‐Dunitz interaction between benzophenone and the water trimer are present in the cluster. This work shows the subtle balance between water–water and water–solute interactions when the solute molecule offers several different anchor sites for water molecules.
The subtle discrepancy between the experimental and theoretical structures of the Ph2CO‐(H2O)3 complex has been unveiled. An open‐looped structure, instead of the cyclic structure, of the water trimer moiety above one of the π clouds was determined by rotational spectroscopy.
Amyloid precursor protein (APP) is a member of the APP family of proteins, and different enzymatic processing leads to the production of several derivatives that are shown to have distinct biological ...functions. APP is involved in the pathology of Alzheimer’s disease (AD), the most common neurodegenerative disorder causing dementia. Furthermore, it is believed that individuals with Down syndrome (DS) have increased APP expression, due to an extra copy of chromosome 21 (Hsa21), that contains the gene for APP. Nevertheless, the physiological function of APP remains unclear. It is known that APP plays an important role in neural growth and maturation during brain development, possibly by influencing proliferation, cell fate specification and neurogenesis of neural stem cells (NSCs). Proteolytic cleavage of APP occurs mainly via two mutually exclusive pathways, the non-amyloidogenic pathway or the amyloidogenic pathway. Other alternative pathways (η-secretase, δ-secretase and meprin pathways) have also been described for the physiological processing of APP. The different metabolites generated from these pathways, including soluble APPα (sAPPα), soluble APPβ (sAPPβ), β-amyloid (Aβ) peptides and the APP intracellular domain (AICD), have different functions determined by their structural differences, equilibrium and concentration with respect to other fragments derived from APP. This review discusses recent observations regarding possible functions of APP and its proteolytic derivatives in the biology and phenotypic specification of NSCs. This can be important for a better understanding of the pathogenesis and the development of future therapeutic applications for AD and/or DS, diseases in which alterations in neurogenesis have been described.
A semi-quantitative analysis of the components of two natural essential oils has been carried out using broadband rotational spectroscopy, which is inherently molecule specific. The samples under ...study were two thyme essential oils from Spain with different compositions: (a) with thymol as the most abundant species (
thyme I
) and (b) with linalool and 4-carvomenthenol being the most abundant ones (
thyme II
). Relative intensity measurements of selected rotational transitions were carried out to estimate the abundances of the different species present in these complex mixtures, taking into account the square of the respective dipole moment components. One strength of rotational spectroscopy is its structure sensitivity. Here, we also re-investigated the microwave spectrum of linalool and determined the accurate experimental gas-phase structures of thymol and linalool through the assignment of all
13
C isotopologues of their lowest energy conformers. A characteristic splitting pattern of the rotational transitions due to internal rotation of two non-equivalent methyl groups of linalool was observed in the
thyme II
spectrum. Their internal rotation barriers were experimentally determined to 4.7703(96) kJ mol
−1
and 9.2581(74) kJ mol
−1
, respectively.
A semi-quantitative analysis as well as determination of the structures and internal dynamics of components of two natural essential oils have been carried out using rotational spectroscopy.
For complexes involving aromatic species, substitution effects can influence the preferred geometry. Using broadband rotational spectroscopy, we report the structures of three naphthol-aromatic ring ...complexes with different heteroatoms (furan and thiophene) and alkyl groups (2,5-dimethylfuran). The aim was to analyze the influence of the presence of heteroatoms or alkyl groups on the structure of the complex and the kind of intermolecular forces that control it. Face or edge arrangements can take place in these complexes
via
π-π or O-H O/O-H π interactions, respectively. All the experimentally observed complexes present O-H O/O-H π interactions with the hydroxyl group, with different structures and intermolecular interactions depending on the heteroatom present in the five-membered aromatic rings, yielding different symmetries in the experimental structure. Structures are experimentally identified through the use of planar moments of inertia. Further results from SAPT calculations show that dispersion and electrostatic interactions contribute similarly to the stabilization of all the studied complexes. These new spectroscopic results shed light on the influence of dispersion and hydrogen bonding in molecular aggregation of systems with substituted aromatic residues.
For complexes involving aromatic species, substitution effects can influence the preferred geometry.
Background and Aims
Mounting evidence supports an association between cholestatic liver disease and changes in the composition of the microbiome. Still, the role of the microbiome in the pathogenesis ...of this condition remains largely undefined.
Approach and Results
To address this, we have used two experimental models, administering alpha‐naphtylisocyanate or feeding a 0.1% 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine diet, to induce cholestatic liver disease in germ‐free mice and germ‐free mice conventionalized with the microbiome from wild‐type, specific pathogen‐free animals. Next, we have inhibited macrophage activation by depleting these cells using clodronate liposomes and inhibiting the inflammasome with a specific inhibitor of NOD‐, LRR‐, and pyrin domain‐containing protein 3. Our results demonstrate that cholestasis, the accumulation of bile acids in the liver, fails to promote liver injury in the absence of the microbiome in vivo. Additional in vitro studies supported that endotoxin sensitizes hepatocytes to bile‐acid–induced cell death. We also demonstrate that during cholestasis, macrophages contribute to promoting intestinal permeability and to altered microbiome composition through activation of the inflammasome, overall leading to increased endotoxin flux into the cholestatic liver.
Conclusions
We demonstrate that the intestinal microbiome contributes to cholestasis‐mediated cell death and inflammation through mechanisms involving activation of the inflammasome in macrophages.
Fluorinated derivatives of biological molecules have proven to be highly efficient at modifying the biological activity of a given protein through changes in the stability and the kind of docking ...interactions. These interactions can be hindered or facilitated based on the hydrophilic/hydrophobic character of a particular protein region. Diadamantyl ether (C20H30O) possesses both kinds of docking sites, serving as a good template to model these important contacts with aromatic fluorinated counterparts. In this work, an experimental study on the structures of several complexes between diadamantyl ether and benzene as well as a series of fluorinated benzenes is reported to analyze the effect of H→F substitution on the interaction and structure of the resulting molecular clusters using rotational spectroscopy. All experimentally observed complexes are largely dominated by London dispersion interactions with the hydrogen‐terminated surface areas of diadamantyl ether. Already single substitution of one hydrogen atom with fluorine changes the preferred docking site of the complexes. However, the overall contributions of the different intermolecular interactions are similar for the different complexes, contrary to previous studies focusing on the difference in interactions using fluorinated and non‐fluorinated molecules.
The effect of H→F substitution on the interactions and structure of complexes between diadamantyl ether and benzene and a series of fluorinated benzenes have been studied using rotational spectroscopy. London dispersion is the governing factor in directing spatial arrangement. The preferred binding position changes upon partial or full substitution, whereas the overall contributions of the intermolecular interactions involved are similar.
In individuals or animals suffering from genetic or acquired diseases, it is important to identify which clinical or phenotypic variables can be used to discriminate between disease and non-disease ...states, the response to treatments or sexual dimorphism. However, the data often suffers from low number of samples, high number of variables or unbalanced experimental designs. Moreover, several parameters can be recorded in the same test. Thus, correlations should be assessed, and a more complex statistical framework is necessary for the analysis. Packages already exist that provide analysis tools, but they are not found together, rendering the decision method and implementation difficult for non-statisticians.
We present Gdaphen, a fast joint-pipeline allowing the identification of most important qualitative and quantitative predictor variables to discriminate between genotypes, treatments, or sex. Gdaphen takes as input behavioral/clinical data and uses a Multiple Factor Analysis (MFA) to deal with groups of variables recorded from the same individuals or anonymize genotype-based recordings. Gdaphen uses as optimized input the non-correlated variables with 30% correlation or higher on the MFA-Principal Component Analysis (PCA), increasing the discriminative power and the classifier's predictive model efficiency. Gdaphen can determine the strongest variables that predict gene dosage effects thanks to the General Linear Model (GLM)-based classifiers or determine the most discriminative not linear distributed variables thanks to Random Forest (RF) implementation. Moreover, Gdaphen provides the efficacy of each classifier and several visualization options to fully understand and support the results as easily readable plots ready to be included in publications. We demonstrate Gdaphen capabilities on several datasets and provide easily followable vignettes.
Gdaphen makes the analysis of phenotypic data much easier for medical or preclinical behavioral researchers, providing an integrated framework to perform: (1) pre-processing steps as data imputation or anonymization; (2) a full statistical assessment to identify which variables are the most important discriminators; and (3) state of the art visualizations ready for publication to support the conclusions of the analyses. Gdaphen is open-source and freely available at https://github.com/munizmom/gdaphen , together with vignettes, documentation for the functions and examples to guide you in each own implementation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We present a rotational spectroscopy study of alpha-methoxy phenylacetic acid in the gas phase. This acid is a derivative of mandelic acid and is used in various organic reactions. The conformational ...landscape of alpha-methoxy phenylacetic acid was explored to gain insight into its intramolecular dynamics. A rich rotational spectrum was obtained using chirped-pulse Fourier transform microwave spectroscopy in the 2-8 GHz range. Five conformers out of six calculated low-energy forms were identified in the spectrum, and the assignment of the
13
C singly substituted isotopologues for the lowest-energy conformer led to its accurate structure determination. Splitting patterns were analyzed and attributed to the internal rotation of a methyl top. The analysis of the non-covalent interactions within the molecule highlights the subtle balance in the stabilization of the different conformers. We thus provide high-level structural and intramolecular dynamics information that is also used to benchmark the performance of quantum-chemical calculations.
Five conformers of the flexible molecule alpha-methoxy phenylacetic acid were identified using rotational spectroscopy. The conformational landscape, internal dynamics, and intramolecular interactions were investigated.
Background
Pelvic floor dysfunction and urinary incontinence are two of the most frequent gynecological problems, and pelvic floor muscle training is recommended as a first‐line treatment, with new ...approaches such as hypopressive exercises. This study aimed to analyze the efficacy of an 8‐week supervised training program of hypopressive exercises on pelvic floor muscle strength and urinary incontinence symptomatology.
Design
Blinded randomized controlled trial.
Settings
Women with pelvic floor dysfunction and urinary incontinence symptoms, aged 18–60 years.
Participants
A total of 117 participants were randomly allocated to the hypopressive exercises group (n = 62) or a control group that received no intervention (n = 55) and completed the study.
Main Outcome Measures
Clinical and sociodemographic data were collected, as well as pelvic floor muscle strength (using the Modified Oxford Scale); the genital prolapse symptoms, colorectal symptoms, and urinary symptoms (with the Pelvic Floor Distress Inventory PFDI‐20); the impact of pelvic floor disorders (PFD) on women's lives (with the Pelvic Floor Impact Questionnaire PFIQ‐7); and the severity of urinary incontinence symptoms (using the International Consultation on Incontinence Questionnaire ICIQ).
Results
The results showed an improvement in the hypopressive group in the pelvic floor muscle strength F (1117) = 89.514, p < 0.001, a significantly lower score for the PFIQ7 total score, t (112) = 28.895, p < 0.001 and FPDI20 t (112) = 7.037, p < 0.001 as well as an improvement in ICIQ‐SF values after 8 weeks of intervention in comparison with the control group.
Conclusions
After performing an 8‐week of hipopressive exercises intervention, a decrease in pelvic floor disorders associated symptoms can be observed. In addition, pelvic floor muscle contractility is improved and a decrease in severity and symptoms associated with urinary incontinence has been reported.
Four mononuclear CoII complexes of formula Co(L)(SCN)2(CH3OH)0.5(H2O)0.5·1.5H2O·0.75CH3OH (1), Co(L1)Cl2·H2O·2CH3CN (2), Co(L1)(SCN)2·1.5H2O·CH3OH (3) and Co(L1)ClO4·2CH3OH (4) were prepared from the ...N6-tripodal Schiff base ligands (S)PN(Me)N=C(H)2-Q3 (L) and (S)PN(Me)N=C(H)1-ISOQ3 (L1), where Q and ISOQ represent quinolyl and isoquinolyl moieties, respectively. In 1, the L ligand does not coordinate to the CoII ion in a tripodal manner but using a new N,N,S tridentate mode, which is due to the fact that the N6-tripodal coordination promotes a strong steric hindrance between the quinolyl moieties. However, L1 can coordinate to the CoII ions either in a tripodal manner using CoII salts with poorly coordinating anions to give 4 or in a bisbidentate fashion using CoII salt-containing medium to strongly coordinating anions to afford 2 and 3. In the case of L1, there is no steric hindrance between ISOQ moieties after coordination to the CoII ion. The CoII ion exhibits a distorted octahedral geometry for compounds 1–3, with the anions in cis positions for the former and in trans positions for the two latter compounds. Compound 4 shows an intermediate geometry between an octahedral and trigonal prism but closer to the latter one. DC magnetic properties, HFEPR and FIRMS measurements and ab initio calculations demonstrate that distorted octahedral complexes 1–3 exhibit easy-plane magnetic anisotropy (D > 0), whereas compound 4 shows large easy-axis magnetic anisotropy (D < 0). Comparative analysis of the magneto-structural data underlines the important role that is played not only by the coordination geometry but also the electronic effects in determining the anisotropy of the CoII ions. Compounds 2–3 show a field-induced slow relaxation of magnetization. Despite its large easy-axis magnetic anisotropy, compound 4 does not show significant slow relaxation (SMR) above 2 K under zero applied magnetic fields, but its magnetic dilution with ZnII triggers SMR at zero field. Finally, it is worth remarking that compounds 2–4 show smaller relaxation times than the analogous complexes with the tripodal ligand bearing in its arms pyridine instead of isoquinoline moieties, which is most likely due to the increase of the molecular size in the former one.
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