The constant evolution of the illicit drug market makes the identification of unknown compounds problematic. Obtaining certified reference materials for a broad array of new analogues can be ...difficult and cost prohibitive. Machine learning provides a promising avenue to putatively identify a compound before confirmation against a standard. In this study, machine learning approaches were used to develop class prediction and retention time prediction models. The developed class prediction model used a naïve Bayes architecture to classify opioids as belonging to either the fentanyl analogues, AH series or U series, with an accuracy of 89.5%. The model was most accurate for the fentanyl analogues, most likely due to their greater number in the training data. This classification model can provide guidance to an analyst when determining a suspected structure. A retention time prediction model was also trained for a wide array of synthetic opioids. This model utilised Gaussian process regression to predict the retention time of analytes based on multiple generated molecular features with 79.7% of the samples predicted within ±0.1 min of their experimental retention time. Once the suspected structure of an unknown compound is determined, molecular features can be generated and input for the prediction model to compare with experimental retention time. The incorporation of machine learning prediction models into a compound identification workflow can assist putative identifications with greater confidence and ultimately save time and money in the purchase and/or production of superfluous certified reference materials.
Machine learning approaches for the identification of unknown compounds in equine plasma are presented. The optimisation of a classification model to predict opioid subclasses and a regression model to predict experimental retention times is presented.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The inositol hexakisphosphate kinases (IP6Ks) are the principal enzymes that generate inositol pyrophosphates. There are three IP6Ks (IP6K1, 2, and 3). Functions of IP6K1 and IP6K2 have been ...substantially delineated, but little is known of IP6K3's role in normal physiology, especially in the brain. To elucidate functions of IP6K3, we generated mice with targeted deletion of IP6K3. We demonstrate that IP6K3 is highly concentrated in the brain in cerebellar Purkinje cells. IP6K3 physiologically binds to the cytoskeletal proteins adducin and spectrin, whose mutual interactions are perturbed in IP6K3-null mutants. Consequently, IP6K3 knock-out cerebella manifest abnormalities in Purkinje cell structure and synapse number, and the mutant mice display deficits in motor learning and coordination. Thus, IP6K3 is a major determinant of cytoskeletal disposition and function of cerebellar Purkinje cells.
We identified and cloned a family of three inositol hexakisphosphate kinases (IP6Ks) that generate the inositol pyrophosphates, most notably 5-diphosphoinositol pentakisphosphate (IP7). Of these, IP6K3 has been least characterized. In the present study we generated IP6K3 knock-out mice and show that IP6K3 is highly expressed in cerebellar Purkinje cells. IP6K3-deleted mice display defects of motor learning and coordination. IP6K3-null mice manifest aberrations of Purkinje cells with a diminished number of synapses. IP6K3 interacts with the cytoskeletal proteins spectrin and adducin whose altered disposition in IP6K3 knock-out mice may mediate phenotypic features of the mutant mice. These findings afford molecular/cytoskeletal mechanisms by which the inositol polyphosphate system impacts brain function.
Topic sentiment joint model aims to deal with the problem about the mixture of topics and sentiment simultaneously from online reviews. Most of existing topic sentiment modeling algorithms are mainly ...based on the state-of-art latent Dirichlet allocation (LDA) and probabilistic latent semantic analysis (PLSA), which infer sentiment and topic distributions from the co-occurrence of words. These methods have been proposed and successfully used for topic and sentiment analysis. However, when the training corpus is small or when the documents are short, the textual features become sparse, so that the results of the sentiment and topic distributions might be not very satisfied. In this paper, we propose a novel topic sentiment joint model called weakly supervised topic sentiment joint model with word embeddings (WS-TSWE), which incorporates word embeddings and HowNet lexicon simultaneously to improve the topic identification and sentiment recognition. The main contributions of WS-TSWE include the following two aspects. (1) Existing models generate the words only from the sentiment-topic-to-word Dirichlet multinomial component, but the WS-TSWE model replaces it with a mixture of two components, a Dirichlet multinomial component and a word embeddings component. Since the word embeddings are trained on a very large corpora and can be used to extend the semantic information of the words, they can provide a certain solution for the problem of the textual sparse. (2) Most of previous models incorporate sentiment knowledge in the β priors. And the priors are usually set from a dictionary and completely rely on previous domain knowledge to identify positive and negative words. In contrast, the WS-TSWE model calculates the sentiment orientation of each word with the HowNet lexicon and automatically infers sentiment-based β priors for sentiment analysis and opinion mining. Furthermore, we implement WS-TSWE with Gibbs sampling algorithms. The experimental results on Chinese and English data sets show that WS-TSWE achieved significant performance in the task of detecting sentiment and topics simultaneously.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Femtosecond carrier recombination in PbI2 is measured using tabletop high-harmonic extreme ultraviolet (XUV) transient absorption spectroscopy and ultrafast electron diffraction. XUV absorption from ...45 to 62 eV measures transitions from the iodine 4d core level to the conduction-band density of states. Photoexcitation at 400 nm creates separate and distinct transient absorption signals for holes and electrons, separated in energy by the 2.4 eV band gap of the semiconductor. The shape of the conduction band, and therefore the XUV absorption spectrum, is temperature-dependent, and nonradiative recombination converts the initial electronic excitation into thermal excitation within picoseconds. Ultrafast electron diffraction (UED) is used to measure the lattice temperature and confirm the recombination mechanism. The XUV and UED results support a second-order recombination model with a rate constant of 2.5 × 10–9 cm3/s.
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IJS, KILJ, NUK, PNG, UL, UM
Photoresponsive polymers capable of luminescence switching are attracting significant interest due to their potential application in fluorescence patterning, bioimaging, optical data storage, and ...anti-counterfeiting. In this work, we have developed aqueous-soluble copolymers of 1-naphthyl methacrylate and oligo(ethylene glycol) methyl ether methacrylate P(1-NMA-co-OEGMA) that undergo a significant shift in fluorescence emission wavelength after UV irradiation. Irradiation of the 1-naphthyl methacrylate moieties results in the photo-Fries rearrangement to form hydroxy aryl ketones, which exhibit strong emission at 475 nm through excited-state intramolecular proton transfer (ESIPT) and excited-state proton transfer (ESPT). The resultant shift in fluorescence emission maximum from 338 to 475 nm after rearrangement can potentially be exploited for fluorescence patterning. Furthermore, the copolymers are thermally sensitive in aqueous solutions. The lower critical solution temperature (LCST) of the copolymers depends on the content of hydrophobic 1-naphthyl methacrylate units; the photo-Fries rearrangement results in a more polar structure, shifting the LCST to a higher temperature. Of note, the temperature-triggered volume phase transition of copolymer hydrogels selectively ″switches off″ fluorescence arising from the ESPT mechanism, while the ESIPT emission is unaffected. We also demonstrate that films formed by coating the copolymers onto various substrates can be selectively patterned to form gradients in fluorescence intensity. These versatile P(1-NMA-co-OEGMA) copolymers are simple to prepare at low cost, demonstrate effective photoswitching, and have excellent water solubility, thus ensuring potential applications in a number of important areas.
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IJS, KILJ, NUK, PNG, UL, UM
Successful treatment of solid cancers relies on complete surgical excision of the tumor either for definitive treatment or before adjuvant therapy. Intraoperative and postoperative radial sectioning, ...the most common form of margin assessment, can lead to incomplete excision and increase the risk of recurrence and repeat procedures. Mohs Micrographic Surgery is associated with complete removal of basal cell and squamous cell carcinoma through real-time margin assessment of 100% of the peripheral and deep margins. Real-time assessment in many tumor types is constrained by tissue size, complexity, and specimen processing / assessment time during general anesthesia. We developed an artificial intelligence platform to reduce the tissue preprocessing and histological assessment time through automated grossing recommendations, mapping and orientation of tumor to the surgical specimen. Using basal cell carcinoma as a model system, results demonstrate that this approach can address surgical laboratory efficiency bottlenecks for rapid and complete intraoperative margin assessment.
Pain-related adverse events (AEs) to ultrasound enhancing agents (UEAs) have been reported in patients with sickle cell disease (SCD). The aims of this study were to characterize the scope of these ...AEs in the SCD population and to investigate potential mechanisms on the basis of pathways involved in SCD vaso-occlusive crisis (VOC) and pain.
The prevalence and classification of AEs were analyzed from two clinical trials in which high-dose Definity infusions were used in patients with SCD (n = 55) or matched control subjects (n = 43) to study muscle or myocardial microvascular perfusion. Because complement (C') activation can trigger VOC in SCD, C' activation and surface adhesion of C' proteins on lipid UEAs were studied in vitro. C'-mediated UEA attachment to bone marrow immune cells was assessed using flow cytometry in a murine SCD model (Townes mice). Blood from patients receiving Definity was obtained to measure specific lysophospholipid metabolites of lipids in Definity thought to mediate SCD pain.
Moderate or greater AEs, all of which were nociceptive (back or bone pain), occurred in one control subject and nine SCD subjects (2% vs 16%, P = .02). Patients with SCD who had AEs tended to have more severe manifestations of SCD. Three of the subjects with SCD had previously received Definity without complications. In patients with SCD, four AEs were classified as severe in intensity and as serious AEs on the basis of need for medical intervention. AEs were described to be similar to SCD-related pain, but there was no evidence for VOC, hemolysis, hypotension, or hypoxemia. At baseline, markers of C' activation were greater in patients with SCD than control subjects. However, after administration of lipid UEAs, SCD and control subjects were similar with regard to C' activation response, anaphylatoxin production, bone marrow microbubble retention, and production of lysophospholipids. There was a trend toward increased deposition of C3b and C3bi on lipid UEAs exposed to serum from patients with SCD.
Patients with SCD are particularly susceptible to nociceptive AEs when given Definity at high doses. The mechanism for these AEs remains unclear but most are not related to the triggering of classic VOC.
Background
Perihematomal edema (PHE) expansion rate may predict functional outcome following spontaneous intracerebral hemorrhage (ICH). We hypothesized that the effect of PHE expansion rate on ...outcome is greater for deep versus lobar ICH.
Methods
Subjects (
n
= 115) were retrospectively identified from a prospective ICH cohort enrolled from 2000 to 2013. Inclusion criteria were age ≥ 18 years, spontaneous supratentorial ICH, and known onset time. Exclusion criteria were primary intraventricular hemorrhage (IVH), trauma, subsequent surgery, or warfarin-related ICH. ICH and PHE volumes were measured from CT scans and used to calculate expansion rates. Logistic regression assessed the association between PHE expansion rates and 90-day mortality or poor functional outcome (modified Rankin Scale > 2). Odds ratios are per 0.04 mL/h.
Results
PHE expansion rate from baseline to 24 h (PHE24) was associated with mortality for deep (
p
= 0.03, OR 1.131.02–1.26) and lobar ICH (
p
= 0.02, OR 1.031.00–1.06) in unadjusted regression and in models adjusted for age (deep
p
= 0.02, OR 1.151.02–1.28; lobar
p
= 0.03, OR 1.031.00–1.06), Glasgow Coma Scale (deep
p
= 0.03, OR 1.131.01–1.27; lobar
p
= 0.02, OR 1.031.01–1.06), or time to baseline CT (deep
p
= 0.046, OR 1.121.00–1.25; lobar
p
= 0.047, OR 1.031.00–1.06). PHE expansion rate from baseline to 72 h (PHE72) was associated with mRS > 2 for deep ICH in models that were unadjusted (
p
= 0.02, OR 4.041.25–13.04) or adjusted for ICH volume (
p
= 0.02, OR 4.31.25–14.98), age (
p
= 0.03, OR 5.41.21–24.11), GCS (
p
= 0.02, OR 4.191.2–14.55), or time to first CT (
p
= 0.03, OR 4.021.19–13.56).
Conclusions
PHE72 was associated with poor functional outcomes after deep ICH, whereas PHE24 was associated with mortality for deep and lobar ICH.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Tandem mass spectrometry based on diagnostic gas-phase ion–molecule reactions represents a robust method for functional group identification in unknown compounds. To date, most of these reactions ...have been studied using unit-resolution instruments, such as linear quadrupole ion traps and triple quadrupoles, which cannot be used to obtain elemental composition information for the species of interest. In this study, a high-resolution mass spectrometer, a quadrupole/orbitrap/linear quadrupole ion trap tribrid, was modified by installing a portable reagent inlet system to obtain high-resolution data for ion–molecule reactions. Examination of a previously published test system, the reaction between protonated 1,1′-sulfonyldiimizadole with 2-methoxypropene, demonstrated the ability to perform ion–molecule reactions on the modified tribrid mass spectrometer. High-resolution data were obtained for ion–molecule reactions of three isobaric ions (protonated glycylalanine, protonated glutamine, and protonated lysine) with diethylmethoxyborane. On the basis of these data, the isobaric ions can be differentiated based on both their measured accurate mass as well as the different product ions they generated upon the ion–molecule reactions. In a different experiment, analyte ions were subjected to collision-induced dissociation (CID), and the structures of the resulting fragment ions were examined via diagnostic ion–molecule reactions. This experiment allows for the functional group interrogation of fragment ions and can be used to improve the understanding of the structures of fragment ions generated in the gas phase.
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IJS, KILJ, NUK, PNG, UL, UM, UPUK
The effects of the SARS-CoV-2 virus on the body, and why the effects are more severe in certain patients, remain incompletely understood. One population of special interest is transplant recipients ...because of their immunosuppressed state. Understanding the pathophysiology of graft dysfunction in transplant patients with the COVID-19 viral syndrome is important for prognosticating the risk to the graft as well as understanding how best to prevent and, if necessary, treat graft injury in these patients.
We analyzed multiple types of solid organ transplant recipients (liver, kidney, heart or lung) at our institution who died from SARS-CoV-2 and underwent autopsy (n = 6) or whose grafts were biopsied during active SARS-CoV-2 infection (n = 8). Their serum inflammatory markers were examined together with the histological appearance, viral load, and TCR repertoire of their graft tissue and, for autopsy patients, several native tissues.
Histology and clinical lab results revealed a systemic inflammatory pattern that included elevated inflammatory markers and diffuse tissue damage regardless of graft rejection. Virus was detected throughout all tissues, although most abundant in lungs. The TCR repertoire was broadly similar throughout the tissues of each individual, with greater sharing of dominant clones associated with more rapid disease course. There was no difference in viral load or clonal distribution of overall, COVID-associated, or putative SARS-CoV-2-specific TCRs between allograft and native tissue. We further demonstrated that SARSCoV-2-specific TCR sequences in transplant patients lack a donor HLArestricted pattern, regardless of distribution in allograft or native tissues,suggesting that recognition of viral antigens on infiltrating recipient cells can effectively trigger host T cell anti-viral responses in both the host and graft.
Our findings suggest a systemic immune response to the SARS-CoV-2 virus in solid organ transplant patients that is not associated with rejection and consistent with a largely destructive effect of recipient HLA-restricted T cell clones that affects donor and native organs similarly.
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