Conformational Tuning of Magnetic Interactions in Coupled Nanographenes.

Phenalenyl (C13H9) is an open-shell spin-1/2 nanographene. Using scanning tunneling microscopy (STM) inelastic electron tunneling spectroscopy (IETS), covalently bonded phenalenyl dimers have been shown to feature conductance steps associated with singlet-triplet excitations of a spin-1/2 dimer with antiferromagnetic exchange. Here, we address the possibility of tuning the magnitude of the exchange interactions by varying the dihedral angle between the two molecules within a dimer. Theoretical methods ranging from density functional theory calculations to many-body model Hamiltonians solved within different levels of approximation are used to explain STM-IETS measurements of phenalenyl dimers on a hexagonal boron nitride (h-BN)/Rh(111) surface, which exhibit signatures of twisting. By means of first-principles calculations, we also propose strategies to induce sizable twist angles in surface-adsorbed phenalenyl dimers via functional groups, including a photoswitchable scheme. This work paves the way toward tuning magnetic couplings in carbon-based spin chains and two-dimensional lattices.

Stability Assessment in Aqueous and Organic Solvents of Metal-Organic Framework PCN 333 Nanoparticles through a Combination of Physicochemical Characterization and Computational Simulations.

Mesoporous metal-organic frameworks (MOFs) have been recognized as powerful platforms for drug delivery, especially for biomolecules. Unfortunately, the application of MOFs is restricted due to their relatively poor stability in aqueous media, which is crucial for drug delivery applications. An exception is the porous coordination network (PCN)-series (e.g., PCN-333 and PCN-332), a series of MOFs with outstanding stability in aqueous media at the pH range from 3 to 9. In this study, we fabricate PCN-333 nanoparticles (nPCN) and investigate their stability in different solvents, including water, ethanol, and methanol. Surprisingly, the experimental characterizations in terms of X-ray diffraction, Brunauer-Emmett-Teller (BET), and scanning electron microscopy demonstrated that nPCN is not as stable in water as previously reported. Specifically, the crystalline structure of nPCN lost its typical octahedral shape and even decomposed into an irregular amorphous form when exposed to water for only 2 h, but not when ethanol and methanol were used. Meanwhile, the porosity of nPCN substantially diminished while being exposed to water, as demonstrated by the BET measurement. With the assistance of computational simulations, the mechanism behind the collapse of PCN-333 is illuminated. By molecular dynamics simulation and umbrella sampling, we elucidate that the degradation of PCN-333 occurs by hydrolysis, wherein polar solvent molecules initiate the attack and subsequent breakage of the metal-ligand reversible coordination bonds.

GlycoNote with Iterative Decoy Searching and Open-Search Component Analysis for High-Throughput and Reliable Glycan Spectral Interpretation.

Mass spectrometry-based glycome analysis is a viable strategy for the compositional and functional exploration of glycosylation. However, the lack of generic tools for high-throughput and reliable glycan spectral interpretation largely hampers the broad usability of glycomic research. Here, we developed a generic and reliable glycomic tool, GlycoNote, for comprehensive and precise glycome analysis. GlycoNote supports interpretation of tandem-mass spectrometry glycomic data from any sample source, uses a novel target-decoy method with iterative decoy searching for highly reliable result output, and embeds an open-search component analysis mode for heterogeneity analysis of monosaccharides and modifications. We tested GlycoNote on several different large-scale glycomic datasets, including human milk oligosaccharides, N- and O-glycome from human cell lines, plant polysaccharides, and atypical glycans from Caenorhabditis elegans, demonstrating its high capacity for glycome analysis. An application of GlycoNote to the analysis of labeled and derived glycans further demonstrates its broad usability in glycomic studies. By enabling generic characterization of various glycan types and elucidation of component heterogeneity in glycomic samples, the freely available GlycoNote is a promising tool for facilitating glycomics in glycobiology research.

A data-science approach to predict the heat capacity of nanoporous materials.

The heat capacity of a material is a fundamental property of great practical importance. For example, in a carbon capture process, the heat required to regenerate a solid sorbent is directly related to the heat capacity of the material. However, for most materials suitable for carbon capture applications, the heat capacity is not known, and thus the standard procedure is to assume the same value for all materials. In this work, we developed a machine learning approach, trained on density functional theory simulations, to accurately predict the heat capacity of these materials, that is, zeolites, metal-organic frameworks and covalent-organic frameworks. The accuracy of our prediction is confirmed with experimental data. Finally, for a temperature swing adsorption process that captures carbon from the flue gas of a coal-fired power plant, we show that for some materials, the heat requirement is reduced by as much as a factor of two using the correct heat capacity.

Influence of Ring Modifications on Nucleolar Stress Caused by Oxaliplatin-Like Compounds.

Oxaliplatin, a platinum compound in broad clinical use, can induce cell death through a nucleolar stress pathway rather than the canonical DNA damage response studied for other Pt(II) compounds. Previous work has found that the oxaliplatin 1,2-diaminocyclohexane (DACH) ring but not the oxalate leaving group is important to the ability to induce nucleolar stress. Here we study the influence of DACH ring substituents at the 4-position on the ability of DACH-Pt(II) compounds to cause nucleolar stress. We determine that DACH-Pt(II) compounds with 4-position methyl, ethyl, or propyl substituents induce nucleolar stress, but DACH-Pt(II) compounds with 4-isopropyl substituents do not induce nucleolar stress. This effect is independent of whether the substituent is in the axial or equatorial position relative to the trans diamines of the ligand. These results suggest that spatially sensitive interactions could be involved in the ability of platinum compounds to cause nucleolar stress.

Pyrene-based metal organic frameworks: from synthesis to applications.

Pyrene is one of the most widely investigated aromatic hydrocarbons given to its unique optical and electronic properties. Hence, pyrene-based ligands have been attractive for the synthesis of metal-organic frameworks (MOFs) in the last few years. In this review, we will focus on the most important characteristics of pyrene, in addition to the development and synthesis of pyrene-based molecules as bridging ligands to be used in MOF structures. We will summarize the synthesis attempts, as well as the post-synthetic modifications of pyrene-based MOFs by the incorporation of metals or ligands in the structure. The discussion of promising results of such MOFs in several applications; including luminescence, photocatalysis, adsorption and separation, heterogeneous catalysis, electrochemical applications and bio-medical applications will be highlighted. Finally, some insights and future prospects will be given based on the studies discussed in the review. This review will pave the way for the researchers in the field for the design and development of novel pyrene-based structures and their utilization for different applications.

Surveying the POSNA Landscape: What Can We Learn From Society Survey Studies?

BACKGROUND: A growing trend of survey-based research has been seen in the field of pediatric orthopaedics. The purpose of this study was to describe patterns of surveys of Pediatric Orthopaedic Society of North America (POSNA) membership and evaluate for associations between study characteristics and response rates in order to inform future research efforts. We hypothesized that studies with fewer survey questions and study group or committee involvement would demonstrate higher response rates. METHODS: A systematic review of the literature was performed to identify all peer-reviewed survey publications targeting POSNA members published up to December 2017. Included studies were reviewed to identify author and publication characteristics, survey development and methodology, survey distribution procedures, and response rates. Statistical analyses were performed to describe publication patterns and evaluate for associations between study characteristics and response rates. RESULTS: Thirty-four studies published from 1991 to 2017 were identified as meeting inclusion criteria, with a substantial increase noted over the last 3 years. Studies included 4.6 (SD 1.9) authors and 14.7% had affiliations with study groups or committees. Survey development methodology was detailed in only 1 study. Surveys included a median of 19.5 questions (3 to 108) and were primarily electronically distributed. The mean survey response rate was 42% with a downward trend noted over the studied time period. None of the studied author, publication, and design characteristics were associated with increased response rates. CONCLUSIONS: Survey-based studies of the POSNA membership have become increasingly popular study designs in recent years. Response rates are lower than reports in other physician cohorts, and appear to be declining, possibly representative of respondent fatigue. No associations were identified between response rates and the modifiable study characteristics evaluated (number of authors, committee or subgroup affiliation, number of questions, and mode of distribution). Efforts should be made to identify tactics to sustain participation as these studies become more widely utilized within our field. Optimizing study design and implementation features while valuing physician time and effort spent on survey completion is important to avoid member survey fatigue. LEVEL OF EVIDENCE: Level V-systematic review of Level V research.

Strategy for Structural Elucidation of Polysaccharides: Elucidation of a Maize Mucilage that Harbors Diazotrophic Bacteria.

The recruitment of a bacterial consortium by the host is a strategy not limited to animals but is also used in plants. A maize aerial root mucilage has been found that harbors nitrogen fixing bacteria that are attracted to the carbohydrate rich environment. This synbiotic relationship is facilitated by a polysaccharide, whose complicated structure has been previously unknown. In this report, we present the characterization of the maize polysaccharide by employing new analytical strategies combining chemical depolymerization, oligosaccharide sequencing, and monosaccharide and glycosidic linkage quantitation. The mucilage contains a single heterogeneous polysaccharide composed of a highly fucosylated and xylosylated galactose backbone with arabinan and mannoglucuronan branches. This unique polysaccharide structure may select for the diazotrophic community by containing monosaccharides and linkages that correspond to the glycosyl hydrolases associated with the microbial community. The elucidation of this complicated structure illustrates the power of the analytical methods, which may serve as a general platform for polysaccharide analysis in the future.

TRPV1 channel as a target for cancer therapy using CNT-based drug delivery systems.

Carbon nanotubes are being considered for the design of drug delivery systems (DDSs) due to their capacity to internalize molecules and control their release. However, for cellular uptake of drugs, this approach requires an active translocation pathway or a channel to transport the drug into the cell. To address this issue, it is suggested to use TRPV1 ion channels as a potential target for drug release by nano-DDSs since these channels are overexpressed in cancer cells and allow the permeation of large cationic molecules. Considering these facts, this work presents three studies using molecular dynamics simulations of a human TRPV1 (hTRPV1) channel built here. The purpose of these simulations is to study the interaction between a single-wall carbon nanotube (SWCNT) and hTRPV1, and the diffusion of doxorubicin (DOX) across hTRPV1 and across a POPC lipid membrane. The first study shows an attractive potential between the SWCNT surface and hTRPV1, tilting the adsorbed SWCNT. The second study shows low diffusion probability of DOX across the open hTRPV1 due to a high free energy barrier. Although, the potential energy between DOX and hTRPV1 reveals an attractive interaction while DOX is inside hTRPV1. These results suggest that if the channel is dilated, then DOX diffusion could occur. The third study shows a lower free energy barrier for DOX across the lipid membrane than for DOX across hTRPV1. Taking into account the results obtained, it is feasible to design novel nano-DDSs based on SWCNTs to accomplish controlled drug release into cells using as translocation pathway, the hTRPV1 ion channel.

Mechanistic peptidomics: factors that dictate specificity in the formation of endogenous peptides in human milk.

An extensive mass spectrometry analysis of the human milk peptidome has revealed almost 700 endogenous peptides from 30 different proteins. Two in-house computational tools were created and used to visualize and interpret the data through both alignment of the peptide quasi-molecular ion intensities and estimation of the differential enzyme participation. These results reveal that the endogenous proteolytic activity in the mammary gland is remarkably specific and well conserved. Certain proteins-not necessarily the most abundant ones-are digested by the proteases present in milk, yielding endogenous peptides from selected regions. Our results strongly suggest that factors such as the presence of specific proteases, the position and concentration of cleavage sites, and, more important, the intrinsic disorder of segments of the protein drive this proteolytic specificity in the mammary gland. As a consequence of this selective hydrolysis, proteins that typically need to be cleaved at specific positions in order to exert their activity are properly digested, and bioactive peptides encoded in certain protein sequences are released. Proteins that must remain intact in order to maintain their activity in the mammary gland or in the neonatal gastrointestinal tract are unaffected by the hydrolytic environment present in milk. These results provide insight into the intrinsic structural mechanisms that facilitate the selectivity of the endogenous milk protease activity and might be useful to those studying the peptidomes of other biofluids.

Current peptidomics: applications, purification, identification, quantification, and functional analysis.

Peptidomics is an emerging field branching from proteomics that targets endogenously produced protein fragments. Endogenous peptides are often functional within the body-and can be both beneficial and detrimental. This review covers the use of peptidomics in understanding digestion, and identifying functional peptides and biomarkers. Various techniques for peptide and glycopeptide extraction, both at analytical and preparative scales, and available options for peptide detection with MS are discussed. Current algorithms for peptide sequence determination, and both analytical and computational techniques for quantification are compared. Techniques for statistical analysis, sequence mapping, enzyme prediction, and peptide function, and structure prediction are explored.

Combined High-Density Lipoprotein Proteomic and Glycomic Profiles in Patients at Risk for Coronary Artery Disease.

OBJECTIVES: To test whether recently developed methods for comprehensive profiling of the high-density lipoprotein (HDL) glycome combined with the HDL proteome can distinguish individuals with coronary artery disease (CAD) from those without. METHODS: Twenty subjects at risk for CAD, who underwent diagnostic coronary arteriography, were analyzed. Ten subjects had CAD, and ten did not. HDL was extracted from fasting plasma samples by ultracentrifugation, followed by shotgun proteomic, glycomic, and ganglioside analyses using LC-MS. CAD vs non-CAD subjects' data were compared using univariate and multivariate statistics. RESULTS: Principal components analysis showed a clear separation of CAD and non-CAD subjects, confirming that combined HDL proteomic and glycomic profiles distinguished at-risk subjects with atherosclerosis from those without. CAD patients had lower HDL apolipoprotein content (specifically ApoA-I, A-II, and E, p < 0.05), and lower serum amyloid A2 (SAA2, p = 0.020) and SAA4 (p = 0.007) but higher sialylated glycans (p < 0.05). CONCLUSION: Combined proteomic and glycomic profiling of isolated HDL was tested as a novel analytical approach for developing biomarkers of disease. In this pilot study we found that HDL proteome and glycome distinguished between individuals who had CAD from those who did not within a group of individuals equally at risk for heart disease.

Site-specific glycosylation of secretory immunoglobulin A from human colostrum.

Secretory immunoglobulin A (sIgA) is a major glycoprotein in milk and plays a key role in mediating immune protection of the gut mucosa. Although it is a highly glycosylated protein, its site-specific glycosylation and associated glycan micro-heterogeneity have still not been fully elucidated. In this study, the site-specific glycosylation of sIgA isolated from human colostrum (n = 3) was analyzed using a combination of LC-MS and LC-MS/MS and in-house software (Glycopeptide Finder). The majority of the glycans found are biantennary structures with one or more acidic Neu5Ac residues; however, a large fraction belonged to truncated complex structures with terminal GlcNAc. Multiple glycosites were identified with nearly 30 glycan compositions located at seven sites on the secretory component, six compositions at a single site on the J chain, and 16 compositions at five sites on the IgA heavy (H) chain. Site-specific heterogeneity and relative quantitation of each composition and the extent of occupation at each site were determined using nonspecific proteases. Additionally, 54 O-linked glycan compositions located at the IgA1 hinge region (HR) were identified by comparison against a theoretical O-glycopeptide library. This represents the most comprehensive report to date detailing the complexity of glycan micro-heterogeneity with relative quantitation of glycoforms for each glycosylation site on milk sIgA. This strategy further provides a general method for determining site-specific glycosylation in large protein complexes.

Endogenous human milk peptide release is greater after preterm birth than term birth.

BACKGROUND: Hundreds of naturally occurring milk peptides are present in term human milk. Preterm milk is produced before complete maturation of the mammary gland, which could change milk synthesis and secretion processes within the mammary gland, leading to differences in protein expression and enzymatic activity, thereby resulting in an altered peptide profile. OBJECTIVE: This study examined differences in peptides present between milk from women delivering at term and women delivering prematurely. METHODS: Nano-LC tandem mass spectrometry was employed to identify naturally occurring peptides and compare their abundances between term and preterm human milk samples at multiple time points over lactation. Term milk samples were collected from 8 mothers and preterm milk was collected from 14 mothers. The 28 preterm and 32 term human milk samples were divided into 4 groups based on day of collection (<14, 14-28, 29-41, and 42-58 d). RESULTS: Preterm milk peptide counts, ion abundance, and concentration were significantly higher in preterm milk than term milk. Bioinformatic analysis of the cleavage sites for peptides identified suggested that plasmin was more active in preterm milk than term milk and that cytosol aminopeptidase and carboxypeptidase B2 likely contribute to extensive milk protein breakdown. Many identified milk peptides in both term and preterm milk overlapped with known functional peptides, including antihypertensive, antimicrobial, and immunomodulatory peptides. CONCLUSION: The high protein degradation by endogenous proteases in preterm milk might attenuate problems because of the preterm infant's immature digestive system. This trial was registered at clinicaltrials.gov as NCT01817127.

σ-Hole···π and lone pair···π interactions in benzylic halides.

Intermolecular and intramolecular halogen···π interactions in benzylic halides (Ph-CR2-X; X = F, Cl, Br and I) derived from 7-phenylnorbornane were investigated. The imposed geometry of the 7-arylnorbornane moiety prevents the participation of intramolecular attractive interactions between the σ-hole region of the halogen atom and the π electrons of the aromatic ring. Crystallographic data show intermolecular halogen bonds in iodide 1 and bromide 2 in the solid state. On the other hand, both UV-Vis and D-NMR data suggest the occurrence of intramolecular interactions between the halogen atoms and the phenyl rings in these compounds in solution. To provide more insight into the nature of the observed stabilizing interactions, density functional calculations were also carried out. These computations confirm the presence of genuine lone pairπ intramolecular interactions which strongly affect the stability and the electronic structure of these species.

Peptidomic analysis of healthy and subclinically mastitic bovine milk.

A variety of proteases release hundreds of endogenous peptide fragments from intact bovine milk proteins. Mass spectrometry-based peptidomics allows for high throughput sequence assignment of a large number of these peptides. Mastitis is known to result in increased protease activity in the mammary gland. Therefore, we hypothesized that subclinically mastitic milks would contain higher concentrations of released peptides. In this work, milks were sampled from three cows and, for each, one healthy and one subclinically mastitic teat were sampled for milk. Peptides were analyzed by nano-liquid chromatography quadrupole time of flight tandem mass spectrometry and identified with database searching. In total, 682 peptides were identified. The total number of released peptides increased 146% from healthy to subclinically mastitic milks (p < 0.05), and the total abundance of released peptides also increased significantly (p < 0.05). Bioinformatic analysis of enzyme cleavage revealed increases in activity of cathepsin D and elastase (p < 0.05) with subclinical mastitis.

Following the digestion of milk proteins from mother to baby.

Little is known about the digestive process in infants. In particular, the chronological activity of enzymes across the course of digestion in the infant remains largely unknown. To create a temporal picture of how milk proteins are digested, enzyme activity was compared between intact human milk samples from three mothers and the gastric samples from each of their 4-12 day postpartum infants, 2 h after breast milk ingestion. The activities of 7 distinct enzymes are predicted in the infant stomach based on their observed cleavage pattern in peptidomics data. We found that the same patterns of cleavage were evident in both intact human milk and gastric milk samples, demonstrating that the enzyme activities that begin in milk persist in the infant stomach. However, the extent of enzyme activity is found to vary greatly between the intact milk and gastric samples. Overall, we observe that milk-specific proteins are cleaved at higher levels in the stomach compared to human milk. Notably, the enzymes we predict here only explain 78% of the cleavages uniquely observed in the gastric samples, highlighting that further investigation of the specific enzyme activities associated with digestion in infants is warranted.

A peptidomic analysis of human milk digestion in the infant stomach reveals protein-specific degradation patterns.

In vitro digestion of isolated milk proteins results in milk peptides with a variety of actions. However, it remains unclear to what degree protein degradation occurs in vivo in the infant stomach and whether peptides previously annotated for bioactivity are released. This study combined nanospray LC separation with time-of-flight mass spectrometry, comprehensive structural libraries, and informatics to analyze milk from 3 human mothers and the gastric aspirates from their 4- to 12-d-old postpartum infants. Milk from the mothers contained almost 200 distinct peptides, demonstrating enzymatic degradation of milk proteins beginning either during lactation or between milk collection and feeding. In the gastric samples, 649 milk peptides were identified, demonstrating that digestion continues in the infant stomach. Most peptides in both the intact milk and gastric samples were derived from ß-casein. The numbers of peptides from ß-casein, lactoferrin, α-lactalbumin, lactadherin, κ-casein, serum albumin, bile salt-associated lipase, and xanthine dehydrogenase/oxidase were significantly higher in the gastric samples than in the milk samples (P < 0.05). A total of 603 peptides differed significantly in abundance between milk and gastric samples (P < 0.05). Most of the identified peptides have previously identified biologic activity. Gastric proteolysis occurs in the term infant in the first 2 wk of life, releasing biologically active milk peptides with immunomodulatory and antibacterial properties of clinical relevance to the proximal intestinal tract. Data are available via ProteomeXchange (identifier PXD000688).

Comprehensive peptidomic and glycomic evaluation reveals that sweet whey permeate from colostrum is a source of milk protein-derived peptides and oligosaccharides.

Whey permeate is a co-product obtained when cheese whey is passed through an ultrafiltration membrane to concentrate whey proteins. Whey proteins are retained by the membrane, whereas the low-molecular weight compounds such as lactose, salts, oligosaccharides and peptides pass through the membrane yielding whey permeate. Research shows that bovine milk from healthy cows contains hundreds of naturally occurring peptides - many of which are homologous with known antimicrobial and immunomodulatory peptides - and nearly 50 oligosaccharide compositions (not including structural isomers). As these endogenous peptides and oligosaccharides have low-molecular weight and whey permeate is currently an under-utilized product stream of the dairy industry, we hypothesized that whey permeate may serve as an inexpensive source of naturally occurring functional peptides and oligosaccharides. Laboratory fractionation of endogenous peptides and oligosaccharides from bovine colostrum sweet whey was expanded to pilot-scale. The membrane fractionation methodology used was similar to the methods commonly used industrially to produce whey protein concentrate and whey permeate. Pilot-scale fractionation was compared to laboratory-scale fractionation with regard to the identified peptides and oligosaccharide compositions. Results were interpreted on the basis of whether industrial whey permeate could eventually serve as a source of functional peptides and oligosaccharides. The majority (96%) of peptide sequences and the majority (96%) of oligosaccharide compositions found in the laboratory-scale process were mirrored in the pilot-scale process. Moreover, the pilot-scale process recovered an additional 33 peptides and 1 oligosaccharide not identified from the laboratory-scale extraction. Both laboratory- and pilot-scale processes yielded peptides deriving primarily from the protein ß-casein. The similarity of the laboratory-and pilot-scale's resulting peptide and oligosaccharide profiles demonstrates that whey permeate can serve as an industrial-scale source of bovine milk peptides and oligosaccharides.

Synthesis, characterization and supra-molecular analysis for (E)-3-(pyridin-4-yl)acrylic acid.

The title compound, C8H7NO2, crystallizes as prismatic colourless crystals in space group P , with one mol-ecule in the asymmetric unit. The pyridine ring is fused to acrylic acid, forming an almost planar structure with an E-configuration about the double bond with a torsion angle of -6.1 (2)°. In the crystal, strong O-H⋯N inter-actions link the mol-ecules, forming chains along the [101] direction. Weak C-H⋯O inter-actions link adjacent chains along the [100] direction, generating an R 2 2(14) homosynthon. Finally, π-π stacking inter-actions lead to the formation of the three-dimensional structure. The supra-molecular analysis was supported by Hirshfeld surface and two-dimensional fingerprint plot analysis, indicating that the most abundant contacts are associated with H⋯H, O⋯H/H⋯O, N⋯H/H⋯N and C⋯H/H⋯C inter-actions.