Infrared spectra of SinH4n-1+ ions (n = 2-8): inorganic H-(Si-H)n-1 hydride wires of penta-coordinated Si in 3c-2e and charge-inverted hydrogen bonds.

SinHm+ cations are important constituents in silane plasmas and astrochemical environments. Protonated disilane (Si2H7+) was shown to have a symmetric three-centre two-electron (3c-2e) Si-H-Si bond that can also be considered as a strong ionic charge-inverted hydrogen bond with polarity Siδ+-Hδ--Siδ+. Herein, we extend our previous work to larger SinH4n-1+ cations, formally resulting from adding SiH4 molecules to a SiH3+ core. Infrared spectra of size-selected SinH4n-1+ ions (n = 2-8) produced in a cold SiH4/H2/He plasma expansion are analysed in the SiH stretch range by complementary dispersion-corrected density functional theory calculations (B3LYP-D3/aug-cc-pVTZ) to reveal their bonding characteristics and cluster growth. The ions with n = 2-4 form a linear inorganic H-(Si-H)n hydride wire with adjacent Si-H-Si 3c-2e bridges, whose strength decreases with n, as evident from their characteristic and strongly IR active SiH stretch fundamentals in the range 1850-2100 cm-1. These 3c-2e bonds result from the lowest-energy valence orbitals, and their high stability arises from their delocalization along the whole hydride wire. For SinH4n-1+ with n ≥ 5, the added SiH4 ligands form weak van der Waals bonds to the Si4H19+ chain. Significantly, because the SinH4n-1+ hydride wires are based on penta-coordinated Si atoms leading to supersaturated hydrosilane ions, analogous wires cannot be formed by isovalent carbon.

Microhydration of the adamantane cation: intracluster proton transfer to solvent in [Ad(H2O)n=1-5]+ for n ≥ 3.

Radical cations of diamondoids are important intermediates in their functionalization reactions in polar solvents. To explore the role of the solvent at the molecular level, we characterize herein microhydrated radical cation clusters of the parent molecule of the diamondoid family, adamantane (C10H16, Ad), by infrared photodissociation (IRPD) spectroscopy of mass-selected [Ad(H2O)n=1-5]+ clusters. IRPD spectra of the cation ground electronic state recorded in the CH/OH stretch and fingerprint ranges reveal the first steps of this fundamental H-substitution reaction at the molecular level. Analysis of size-dependent frequency shifts with dispersion-corrected density functional theory calculations (B3LYP-D3/cc-pVTZ) provides detailed information about the acidity of the proton of Ad+ as a function of the degree of hydration, the structure of the hydration shell, and the strengths of the CH⋯O and OH⋯O hydrogen bonds (H-bonds) of the hydration network. For n = 1, H2O strongly activates the acidic C-H bond of Ad+ by acting as a proton acceptor in a strong CH⋯O ionic H-bond with cation-dipole configuration. For n = 2, the proton is almost equally shared between the adamantyl radical (C10H15, Ady) and the (H2O)2 dimer in a strong C⋯H⋯O ionic H-bond. For n ≥ 3, the proton is completely transferred to the H-bonded hydration network. The threshold for this size-dependent intracluster proton transfer to solvent is consistent with the proton affinities of Ady and (H2O)n and confirmed by collision-induced dissociation experiments. Comparison with other related microhydrated cations reveals that the acidity of the CH proton of Ad+ is in the range of strongly acidic phenol+ but lower than for cationic linear alkanes such as pentane+. Significantly, the presented IRPD spectra of microhydrated Ad+ provide the first spectroscopic molecular-level insight of the chemical reactivity and reaction mechanism of the important class of transient diamondoid radical cations in aqueous solution.

Microhydrated clusters of a pharmaceutical drug: infrared spectra and structures of amantadineH+(H2O)n.

Solvation of pharmaceutical drugs has an important effect on their structure and function. Analysis of infrared photodissociation spectra of amantadineH+(H2O)n=1-4 clusters in the sensitive OH, NH, and CH stretch range by quantum chemical calculations (B3LYP-D3/cc-pVTZ) provides a first impression of the interaction of this pharmaceutically active cation with water at the molecular level. The size-dependent frequency shifts reveal detailed information about the acidity of the protons of the NH3+ group of N-protonated amantadineH+ (AmaH+) and the strength of the NH⋯O and OH⋯O hydrogen bonds (H-bonds) of the hydration network. The preferred cluster growth begins with sequential hydration of the NH3+ group by NH⋯O ionic H-bonds (n = 1-3), followed by the extension of the solvent network through OH⋯O H-bonds. However, smaller populations of cluster isomers with an H-bonded solvent network and free N-H bonds are already observed for n ≥ 2, indicating the subtle competition between noncooperative ion hydration and cooperative H-bonding. Interestingly, cyclic water ring structures are identified for n ≥ 3, each with two NH⋯O and two OH⋯O H-bonds. Despite the increasing destabilization of the N-H proton donor bonds upon gradual hydration, no proton transfer to the (H2O)n solvent cluster is observed up to n = 4. In addition to ammonium cluster ions, a small population of microhydrated iminium isomers is also detected, which is substantially lower for the hydrophilic H2O than for the hydrophobic Ar environment.

Impaired fasting glucose levels among perinatally HIV-infected adolescents and youths in Dar es Salaam, Tanzania.

Objective: This study assessed impaired fasting glucose and associated factors among perinatally HIV-infected adolescents and youths in Dar es salaam Tanzania. Background: Impaired fasting glucose is a marker of heightened risk for developing type 2 diabetes among perinatally HIV-infected individuals. Therefore, identifying individuals at this stage is crucial to enable early intervention. Therefore, we assessed impaired fasting glucose (IFG) and associated factors among perinatally HIV-infected population in Dar es salaam Tanzania. Methods: A cross-sectional study was conducted among 152 adolescents and youth attending HIV clinic at Muhimbili National Hospital and Infectious Disease Centre from July to August 2020. Fasting blood glucose (>8 hours) was measured using one-touch selects LifeScan, CA, USA. We also examined C-Reactive Protein and interleukin-6 inflammatory biomarkers in relation to impaired fasting glucose (IFG). Associations between categorical variables were explored using Chi-square, and poison regression with robust variance was used to calculate the prevalence ratios. Results: Of the 152 participants, the majority were male (n=83[54.6%]), and the median age was 15(14-18) years. Overweight or obesity was prevalent in 16.4%, while more than one in ten (13.2%) had high blood pressure (≥149/90mmHg). All participants were on antiretroviral therapy (ART); 46% had used medication for over ten years, and about one in three had poor medication adherence. Among the recruited participants, 29% had impaired fasting glucose. The odds of IFG were two times higher in males compared to females (PR, 2.07, 95% CI 1.19 -3.59 p=0.001). Moreover, we found with every increase of Interleukin 6 biomarker there was a 1.01 probability increase of impaired fasting glucose (PR, 1.01, 95% CI 1.00 - 1.02 p=0.003). Conclusion: About one in three perinatally HIV-infected youths had impaired fasting glucose in Dar es Salaam, Tanzania, with males bearing the biggest brunt. Moreover, with every increase of 1.101 of the probability of having IFG increased. This calls for urgent measures to interrupt the progression to diabetes disease and prevent the dual burden of disease for this uniquely challenged population.

Infrared spectra and structures of protonated amantadine isomers: detection of ammonium and open-cage iminium ions.

The protonated form of amantadine (1-C10H15NH2, Ama), the amino derivative of adamantane (C10H16, Ada), is a wide-spread antiviral and anti-Parkinsonian drug and plays a key role in many pharmaceutical processes. Recent studies reveal that the adamantyl cage (C10H15) of Ama can open upon ionization leading to distonic bicyclic iminium isomers, in addition to the canonical nascent Ama+ isomer. Herein, we study protonation of Ama using infrared photodissociation spectroscopy (IRPD) of Ar-tagged ions and density functional theory calculations to characterize cage and open-cage isomers of AmaH+ and the influence of the electron-donating NH2 group on the cage-opening reaction potential. In addition to the canonical ammonium isomer (AmaH+(I)) with an intact adamantyl cage, we identify at least one slightly less stable protonated bicyclic iminium ion (AmaH+(II)). While the ammonium ion is generated by protonation of the basic NH2 group, AmaH+(II) is formally formed by H addition to a distonic bicyclic iminium ion produced upon ionization of Ama and subsequent cage opening.

Opening of the Diamondoid Cage upon Ionization Probed by Infrared Spectra of the Amantadine Cation Solvated by Ar, N2 , and H2 O.

Radical cations of diamondoids, a fundamental class of very stable cyclic hydrocarbon molecules, play an important role in their functionalization reactions and the chemistry of the interstellar medium. Herein, we characterize the structure, energy, and intermolecular interaction of clusters of the amantadine radical cation (Ama+ , 1-aminoadamantane) with solvent molecules of different interaction strength by infrared photodissociation (IRPD) spectroscopy of mass-selected Ama+ Ln clusters, with L=Ar (n≤3) and L=N2 and H2 O (n=1), and dispersion-corrected density functional theory calculations (B3LYP-D3/cc-pVTZ). Three isomers of Ama+ generated by electron ionization are identified by the vibrational properties of their rather different NH2 groups. The ligands bind preferentially to the acidic NH2 protons, and the strength of the NH…L ionic H-bonds are probed by the solvation-induced red-shifts in the NH stretch modes. The three Ama+ isomers include the most abundant canonical cage isomer (I) produced by vertical ionization, which is separated by appreciable barriers from two bicyclic distonic iminium ions obtained from cage-opening (primary radical II) and subsequent 1,2 H-shift (tertiary radical III), the latter of which is the global minimum on the Ama+ potential energy surface. The effect of solvation on the energetics of the potential energy profile revealed by the calculations is consistent with the observed relative abundance of the three isomers. Comparison to the adamantane cation indicates that substitution of H by the electron-donating NH2 group substantially lowers the barriers for the isomerization reaction.

Infrared Spectrum of the Amantadine Cation: Opening of the Diamondoid Cage upon Ionization.

Radical cations of diamondoids, a fundamental class of highly stable cycloalkanes, are intermediates in functionalization reactions and possibly present in the interstellar medium. Herein, we characterize the structure of the radical cation of 1-amantadine (1-C10H15NH2+, Ama+), the amino derivative of the parent adamantane (C10H16+, Ada+), by infrared spectroscopy and density functional theory calculations. The structural isomers of Ama+ produced by electron ionization are probed by infrared photodissociation of cold Ar-tagged ions. In addition to the canonical nascent Ama+ isomer with an intact C10H15 cage, we identify two distonic bicyclic iminium isomers in which the adamantyl cage opens upon ionization, one of which is lower in energy than the cage isomer. The reaction profile with barriers and intermediates for this cage-opening reaction are determined. Comparison with Ada+ suggests that this type of ionization-induced cage-opening may be a common feature for diamondoids and important for their reactivity.

Microhydration of substituted diamondoid radical cations of biological relevance: infrared spectra of amantadine+-(H2O)n = 1-3 clusters.

Hydration of biomolecules and pharmaceutical compounds has a strong impact on their structure, reactivity, and function. Herein, we explore the microhydration structure around the radical cation of the widespread pharmaceutical drug amantadine (C16H15NH2, Ama) by infrared photodissociation (IRPD) spectroscopy of mass-selected Ama+Wn = 1-3 clusters (W = H2O) recorded in the NH, CH, and OH stretch range of the cation ground electronic state. Analysis of the size-dependent frequency shifts by dispersion-corrected density functional theory calculations (B3LYP-D3/cc-pVTZ) provides detailed information about the acidity of the protons of the NH2 group of Ama+ and the structure and strength of the NHO and OHO hydrogen bonds (H-bonds) of the hydration network. The preferred sequential cluster growth begins with hydration of the two acidic NH protons of the NH2 group (n = 1-2) and continues with an extension of the H-bonded hydration network by forming an OHO H-bond of the third W to one ligand in the first hydration subshell (n = 3), like in the W2 dimer. For n = 2, a minor population corresponds to Ama+W2 structures with a W2 unit attached to Ama+via a NHW2 H-bond. Although the N-H proton donor bonds are progressively destabilized by gradual microhydration, no proton transfer to the Wn solvent cluster is observed in the investigated size range (n ≤ 3). Besides the microhydration structure, we also obtain a first impression of the structure and IR spectrum of bare Ama+, as well as the effects of both ionization and hydration on the structure of the adamantyl cage. Comparison of Ama+ with aliphatic and aromatic primary amine radical cations reveals differences in the acidity of the NH2 group and the resulting interaction with W caused by substitution of the cycloalkyl cage.

Infrared Spectrum of the Adamantane+ -Water Cation: Hydration-Induced C-H Bond Activation and Free Internal Water Rotation.

Diamondoid cations are reactive intermediates in their functionalization reactions in polar solution. Hydration is predicted to strongly activate their C-H bonds in initial proton abstraction reactions. To study the effects of microhydration on the properties of diamondoid cations, we characterize herein the prototypical monohydrated adamantane cation (C10 H16 + -H2 O, Ad+ -W) in its ground electronic state by infrared photodissociation spectroscopy in the CH and OH stretch ranges and dispersion-corrected density functional theory (DFT) calculations. The water (W) ligand binds to the acidic CH group of Jahn-Teller distorted Ad+ via a strong CH⋅⋅⋅O ionic H-bond supported by charge-dipole forces. Although W further enhances the acidity of this CH group along with a proton shift toward the solvent, the proton remains with Ad+ in the monohydrate. We infer essentially free internal W rotation from rotational fine structure of the ν3 band of W, resulting from weak angular anisotropy of the Ad+ -W potential.

IR Spectrum and Structure of Protonated Monosilanol: Dative Bonding between Water and the Silylium Ion.

We report the spectroscopic characterization of protonated monosilanol (SiH3 OH2+ ) isolated in the gas phase, thus providing the first experimental determination of the structure and bonding of a member of the elusive silanol family. The SiH3 OH2+ ion is generated in a silane/water plasma expansion, and its structure is derived from the IR photodissociation (IRPD) spectrum of its Ar cluster measured in a tandem mass spectrometer. The chemical bonding in SiH3 OH2+ is analyzed by density functional theory (DFT) calculations, providing detailed insight into the nature of the dative H3 Si+ -OH2 bond. Comparison with protonated methanol illustrates the differences in bonding between carbon and silicon, which are mainly related to their different electronegativity and the different energy of the vacant valence pz orbital of SiH3+ and CH3+ .

Infrared spectrum of the Si3H8+ cation: evidence for a bridged isomer with an asymmetric three-center two-electron Si-H-Si bond.

The IR spectrum of Si3H8(+) ions produced in a supersonic plasma molecular beam expansion of SiH4, He, and Ar is inferred from photodissociation of cold Si3H8(+)-Ar complexes. Vibrational analysis of the spectrum is consistent with a Si3H8(+) structure (2(+)) obtained by a barrierless addition reaction of SiH4 to the disilene ion (H2Si=SiH2(+)) in the silane plasma. In this structure, one of the electronegative H atoms of SiH4 donates electron density into the partially filled electrophilic π orbital of the disilene cation. The resulting asymmetric Si-H-Si bridge of the 2(+) isomer with a bond energy of approximately 60 kJ mol(-1) is characteristic for a weak three-center two-electron bond, which is identified by its strongly IR active asymmetric Si-H-Si stretching fundamental at about 1765 cm(-1). The observed 2(+) isomer is calculated to be only a few kJ mol(-1) less stable than the global minimum structure of Si3H8(+) (1(+)), which is derived from vertical ionization of trisilane. Although more stable, 1(+) is not detected in the measured IR spectrum of Si3H8(+)-Ar, and its lower abundance in the supersonic plasma is rationalized by the production mechanism of Si3H8(+) in the silane plasma, in which a high barrier between 2(+) and 1(+) prevents the efficient formation of 1(+). The potential energy surface of Si3H8(+) is characterized in some detail by quantum chemical calculations. The structural, vibrational, electronic and energetic properties as well as the chemical bonding mechanism are investigated for a variety of low-energy Si3H8(+) isomers and their fragments. The weak intermolecular bonds of the Ar ligands in the Si3H8(+)-Ar isomers arise from dispersion and induction forces and induce only a minor perturbation of the bare Si3H8(+) ions. Comparison with the potential energy surface of C3H8(+) reveals the differences between the silicon and carbon species.

Direct activation of a mouse Hoxd11 axial expression enhancer by Gdf11/Smad signalling.

A Hoxd11/lacZ reporter, expressed with a Hoxd11-like axial expression pattern in transgenic mouse embryos, is stimulated in tailbud fragments when cultured in presence of Gdf11, a TGF-ß growth/differentiation factor. The same construct is also stimulated by Gdf11 when transiently transfected into cultures of HepG2 cells. Stimulation of the reporter in HepG2 cells is enhanced where it contains only the 332 bp Hoxd11 enhancer region VIII upstream or downstream of a luciferase or lacZ reporter. This enhancer contains three elements conserved from fish to mice, one of which has the sequence of a Smad3/4 binding element. Mutation of this motif inhibits the ability of Gdf11 to enhance reporter activity in the HepG2 cell assay. Chromatin immunoprecipitation experiments show direct evidence of Smad2/3 protein binding to the Hoxd11 region VIII enhancer. The action of Gdf11 upon Hoxd11 in HepG2 cells is inhibited, at least in part, by SIS3, a specific inhibitor of Smad3. SIS3 also produces partial inhibition of Hoxd11/lacZ expression in cultured transgenic tailbuds, indicating that Smad3 may play a similar role in the embryonic expression of Hoxd11. Transgenic mouse experiments show that the Smad binding motif is essential for the axial expression of Hoxd11/lacZ reporter in the embryo tailbud, posterior mesoderm and neurectoderm.

Infrared spectrum of the disilane cation (Si2H6+) from Ar-tagging spectroscopy.

The infrared spectrum of the disilane cation, Si(2)H(6)(+), in its (2)A(1g) ground state is inferred from photodissociation of cold Si(2)H(6)(+)-Ar(n) complexes (n = 1, 2). Vibrational analysis is consistent with a D(3d) symmetric structure of H(3)SiSiH(3)(+) generated by ionization from the bonding σ(SiSi) orbital. Structural, vibrational, and electronic properties of Si(2)H(6)((+)) and Si(2)H(6)(+)-Ar(1,2) are determined at the MP2/aug-cc-pVTZ and B3LYP/aug-cc-pVTZ levels. Ar ligands bind weakly at the C(3) axis on opposite sides to Si(2)H(6)(+) with only a minor impact on the Si(2)H(6)(+) properties. The calculations reveal a low-energy H(2)SiHSiH(3)(+) isomer with C(s) symmetry and a Si-H-Si bridge, which is only ~15 kJ mol(-1) above the D(3d) structure.

Mapping metals in Parkinson's and normal brain using rapid-scanning x-ray fluorescence.

Rapid-scanning x-ray fluorescence (RS-XRF) is a synchrotron technology that maps multiple metals in tissues by employing unique hardware and software to increase scanning speed. RS-XRF was validated by mapping and quantifying iron, zinc and copper in brain slices from Parkinson's disease (PD) and unaffected subjects. Regions and structures in the brain were readily identified by their metal complement and each metal had a unique distribution. Many zinc-rich brain regions were low in iron and vice versa. The location and amount of iron in brain regions known to be affected in PD agreed with analyses using other methods. Sample preparation is simple and standard formalin-fixed autopsy slices are suitable. RS-XRF can simultaneously and non-destructively map and quantify multiple metals and holds great promise to reveal metal pathologies associated with PD and other neurodegenerative diseases as well as diseases of metal metabolism.

Cephalosporin-derived inhibitors of beta-lactamase. Part 4: The C3 substituent.

New C3-substituted beta-lactamase inhibitors were prepared and evaluated against representative class A and class C enzymes. It was possible to improve simultaneous inhibitory activity of both classes of serine hydrolase. Other inhibitors showed high selectivity for either the class C cephalosporinases or the class A penicillinases. This represents the first time that cephalosporin-derived inhibitors have demonstrated selectivity for the class A beta-lactamases.

Organisation and assembly of the surface membrane during early cleavage of the mouse embryo.

An attempt was made to understand the ways in which 'newly inserted' membrane was organised in relation to existing membrane during early cleavage of the mouse embryo by (i) monitoring the redistribution of a variety of surface-binding ligands (applied to the embryo during the previous cell cycle) and (ii) analysing the localisation of newly synthesised lipid at defined stages during the second cell cycle. The membrane dynamics of the embryo appear similar to those of somatic cells during cytokinesis and/or motility, and are consistent with previous suggestions (Pratt 1985) that the main cytocortical domains of the polarised 8-cell blastomere may start to diverge during early cleavage as a result of localised assembly and reorganisation of the embryo cytocortex.

Fluorescent latex microparticles: A non-invasive short-term cell lineage marker suitable for use in the mouse early embryo.

We have examined the potential of fluorescent latex microparticles for use as a short term cell lineage marker in the mouse preimplantation embryo. Isolated blastomeres and intact embryos rapidly adsorb and subsequently endocytose the particles (0.2 µm diameter) from a monodisperse suspension in normal medium, so that cytoplasmic endocytic organelles, but not the cytosol itself, becomes labelled. Latex fluorescence, either within intact embryos, disaggregated cells or thick resin sections, is stable during UV irradiation. The development of labelled embryos, both in terms of sequential morphological changes and their time of expression, was comparable to controls and resulted in blastocysts with normal cell numbers and capacity for tissue differentiation. Latex fluorescence is preserved within all the progeny of labelled blastomeres over several cell cycles (e.g. from 8-cell stage to 64-cell stage) and is not transmitted to unlabelled cells either by exocytosis or via midbodies. The particles are particularly suitable for labelling exclusively the entire population of outside cells in the intact embryo from the 16-cell stage onwards.