Detection and Exclusion of False-Positive Molecular Formula Assignments via Mass Error Distributions in UHR Mass Spectra of Natural Organic Matter.

Ultrahigh resolution mass spectrometry (UHRMS) routinely detects and identifies thousands of mass peaks in complex mixtures, such as natural organic matter (NOM) and petroleum. The assignment of several chemically plausible molecular formulas (MFs) for a single accurate mass still poses a major problem for the reliable interpretation of NOM composition in a biogeochemical context. Applying sensible chemical rules for MF validation is often insufficient to eliminate multiple assignments (MultiAs)─especially for mass peaks with low abundance or if ample heteroatoms or isotopes are included - and requires manual inspection or expert judgment. Here, we present a new approach based on mass error distributions for the identification of true and false assignments among MultiAs. To this end, we used the mass error in millidalton (mDa), which was superior to the commonly used relative mass error in ppm. We developed an automatic workflow to group MultiAs based on their shared formula units and Kendrick mass defect values and to evaluate the mass error distribution. In this way, the number of valid assignments of chlorinated disinfection byproducts was increased by 8-fold as compared to only applying 37Cl/35Cl isotope ratio filters. Likewise, phosphorus-containing MFs can be differentiated against chlorine-containing MFs with high confidence. Further, false assignments of highly aromatic sulfur-containing MFs ("black sulfur") to sodium adducts in negative ionization mode can be excluded by applying our approach. Overall, MFs for mass peaks that are close to the detection limit or where naturally occurring isotopes are rare (e.g., 15N) or absent (e.g., P and F) can now be validated, substantially increasing the reliability of MF assignments and broadening the applicability of UHRMS analysis to even more complex samples and processes.

Tunable sub-terahertz resonance absorption in high-coercivity magnetodielectric ceramics.

Recently, giant coercivities (20-42 kOe) and sub-terahertz natural ferromagnetic resonance (NFMR) at 100-300 GHz were observed for single-domain M-type hexaferrite particles with high aluminum substitution. Herein, we fabricated dense ceramics of Sr0.67Ca0.33Fe8Al4O19 and, for the first time, investigated their magnetostatic and magnetodynamic properties in the temperature range of 5-300 K. It was shown that dense ceramics maintain their high magnetic hardness (a coercivity of 10-20 kOe) and NFMR frequencies of 140-200 GHz durably in the entire temperature range. Magnetizing the initially non-magnetized ceramics leads to a considerable decrease in the resonance absorption and to almost complete vanishing of the resonance line at 5 kOe. At the same time, an efficient linear frequency tuning by the external magnetic field was observed for the remanent sample. These findings open new horizons for developing industrial terahertz electronics based on dielectric ferrimagnets.

The dorsal part of the anterior tuberal nucleus responds to auditory stimulation in zebrafish (Danio rerio).

The zebrafish, a widely used model in neurobiology, relies on hearing in aquatic environments. Unfortunately, its auditory pathways have mainly been studied in larvae. In this study, we examined the involvement of the anterior tuberal nucleus (AT) in auditory processing in adult zebrafish. Our tract-tracing experiments revealed that the dorsal subdivision of AT is strongly bidirectionally connected to the central nucleus of the torus semicircularis (TSc), a major auditory nucleus in fishes. Immunohistochemical visualisation of the ribosomal protein S6 (pS6) phosphorylation to map neural activity in response to auditory stimulation substantiated this finding: the dorsal but not the ventral part of AT responded strongly to auditory stimulation. A similar response to auditory stimulation was present in the TSc but not in the nucleus isthmi (NI), a visual region, which we used as a control for testing if the pS6 activation was specific to the auditory stimulation. We also measured the time course of pS6 phosphorylation, which was previously unreported in teleost fish. After auditory stimulation, we found that pS6 phosphorylation peaked between 100-130 minutes and returned to baseline levels after 190 minutes. This information will be valuable for the design of future pS6 experiments. Our results suggest an anatomical and functional subdivision of AT, where only the dorsal part connects to the auditory network and processes auditory information.Significant statement We investigated the involvement of the anterior tuberal nucleus in zebrafish in auditory processing. Our study revealed a functional and anatomical subdivision of this region. We show that its dorsal subdivision is strongly connected to the central nucleus of the torus semicircularis, a major auditory nucleus in fishes. pS6 phosphorylation, as an indirect marker of neuronal activity after auditory stimulation, substantiated that only the dorsal anterior tuberal nucleus, processes auditory information. We also show that after auditory stimulation, pS6 phosphorylation peaked between 100-130 minutes and returned to baseline levels after 190 minutes, providing valuable information for future studies.

Post column infusion of an internal standard into LC-FT-ICR MS enables semi-quantitative comparison of dissolved organic matter in original samples.

Ultrahigh resolution mass spectrometry hyphenated with liquid chromatography (LC) is an emerging tool to explore the isomeric composition of dissolved organic matter (DOM). However, matrix effects limit the potential for semi-quantitative comparison of DOM molecule abundances across samples. We introduce a post-column infused internal standard (PCI-IS) for reversed-phase LC-FT-ICR MS measurements of DOM and systematically evaluate matrix effects, detector linearity and the precision of mass peak intensities. Matrix effects for model compounds spiked into freshwater DOM samples ranging from a headwater stream to a major river were reduced by 5-10% for PCI-IS corrected mass peak intensities as compared to raw (i.e., untransformed) intensities. A linear regression of PCI-IS corrected DOM mass peak intensities across a typical DOM concentration range (2-15 mg dissolved organic carbon L-1) in original, non-extracted freshwater samples demonstrates excellent linearity of the detector response (r2 > 0.9 for 98% of detected molecular formulas across retention times). Importantly, PCI-IS could compensate for 80% of matrix effects across an environmental gradient of DOM composition from groundwater to surface water. This enabled studying the ionization efficiency of DOM isomers and linking the observed differences to the biogeochemical sources. With PCI-IS original, non-extracted DOM samples can be analysed by LC-FT-ICR MS without carbon load adjustment, and mass peak intensities can be reliably used to semi-quantitatively compare isomer abundances between compositionally similar DOM samples.

Novel Detection and Progression Markers for Diabetes Based on Continuous Glucose Monitoring Data Dynamics.

PURPOSE: Develop a diabetes diagnostic tool based on two markers of continuous glucose monitoring (CGM) dynamics: CGM entropy rate (ER) and Poincaré plot (PP) ellipse area (S). METHODS: 5,754 daily CGM profiles from 843 individuals with type 1, type 2 diabetes, or healthy individuals with or without islet autoantibody status were used to compute two individual dynamic markers: ER (in bits per transition; BPT) of daily probability matrices describing CGM transitions between eight glycemic states, and the area S (mg2/dL2) of individual CGM PP ellipses using standard PP descriptors. The Youden's index was used to determine "optimal" cut-points for ER and S for health vs. diabetes (case 1); type 1 vs. type 2 (case 2); and low vs. high type 1 immunological risk (case 3). The markers' discriminative power was assessed through the area under the receiver operating characteristics curves (AUC). RESULTS: Optimal cut-off points were determined for ER and S for each of the three cases. ER and S discriminated case 1 with AUC = 0.98 (95% CI: 0.97-0.99) and AUC = 0.99 (95% CI: 0.99-1.00), respectively, (cut-offs ERcase1 = 0.76 BPT, Scase1 = 1993.91 mg2/dL2), case 2 with AUC = 0.81 (95% CI, 0.77-0.84) and AUC = 0.76 (95% CI, 0.72-0.81), respectively (ERcase2 = 1.00 BPT, Scase2 = 5112.98 mg2/dL2), and case 3 with AUC = 0.81 (95% CI, 0.77-0.84) and AUC = 0.76 (95% CI, 0.72-0.81), respectively (ERcase3 = 0.52 BPT, Scase3 = 923.65 mg2/dL2). CONCLUSIONS: CGM dynamics markers can be an alternative to fasting plasma glucose or glucose tolerance testing and identifying individuals at higher immunological risk of progressing to type 1 diabetes.

The great tit HapMap project: A continental-scale analysis of genomic variation in a songbird.

A major aim of evolutionary biology is to understand why patterns of genomic diversity vary within taxa and space. Large-scale genomic studies of widespread species are useful for studying how environment and demography shape patterns of genomic divergence. Here, we describe one of the most geographically comprehensive surveys of genomic variation in a wild vertebrate to date; the great tit (Parus major) HapMap project. We screened ca 500,000 SNP markers across 647 individuals from 29 populations, spanning ~30 degrees of latitude and 40 degrees of longitude - almost the entire geographical range of the European subspecies. Genome-wide variation was consistent with a recent colonisation across Europe from a South-East European refugium, with bottlenecks and reduced genetic diversity in island populations. Differentiation across the genome was highly heterogeneous, with clear 'islands of differentiation', even among populations with very low levels of genome-wide differentiation. Low local recombination rates were a strong predictor of high local genomic differentiation (FST), especially in island and peripheral mainland populations, suggesting that the interplay between genetic drift and recombination causes highly heterogeneous differentiation landscapes. We also detected genomic outlier regions that were confined to one or more peripheral great tit populations, probably as a result of recent directional selection at the species' range edges. Haplotype-based measures of selection were related to recombination rate, albeit less strongly, and highlighted population-specific sweeps that likely resulted from positive selection. Our study highlights how comprehensive screens of genomic variation in wild organisms can provide unique insights into spatio-temporal evolutionary dynamics.

Direct Analysis of Marine Dissolved Organic Matter Using LC-FT-ICR MS.

Marine dissolved organic matter (DOM) is an important component of the global carbon cycle, yet its intricate composition and the sea salt matrix pose major challenges for chemical analysis. We introduce a direct injection, reversed-phase liquid chromatography ultrahigh resolution mass spectrometry approach to analyze marine DOM without the need for solid-phase extraction. Effective separation of salt and DOM is achieved with a large chromatographic column and an extended isocratic aqueous step. Postcolumn dilution of the sample flow with buffer-free solvents and implementing a counter gradient reduced salt buildup in the ion source and resulted in excellent repeatability. With this method, over 5,500 unique molecular formulas were detected from just 5.5 nmol carbon in 100 µL of filtered Arctic Ocean seawater. We observed a highly linear detector response for variable sample carbon concentrations and a high robustness against the salt matrix. Compared to solid-phase extracted DOM, our direct injection method demonstrated superior sensitivity for heteroatom-containing DOM. The direct analysis of seawater offers fast and simple sample preparation and avoids fractionation introduced by extraction. The method facilitates studies in environments, where only minimal sample volume is available e.g. in marine sediment pore water, ice cores, or permafrost soil solution. The small volume requirement also supports higher spatial (e.g., in soils) or temporal sample resolution (e.g., in culture experiments). Chromatographic separation adds further chemical information to molecular formulas, enhancing our understanding of marine biogeochemistry, chemodiversity, and ecological processes.

The spiral wave frequency effect in atrial fibrillation.

A spiral wavefront (WF), generated by a cardiac rotor that drifts between surface electrodes during atrial fibrillation, exhibits frequency changes inconsistent with classical Doppler effect (CDE) phenomena. Recent clinical studies reveal three repeatedly observed events--1) side-dependent frequency changes across the path of the rotor, 2) one additional WF strike on the higher frequency side, and 3) a reversal of WF strike sequence--which constitute a diametrical property of spinning WF sources. A linear ray model is first used to reveal and develop the diametrical phenomena. Mathematical models of an Archimedean spiral and a spiral generated by the diffusion equation are developed and compared. Each formulation predicts the diametrical property that CDE does not capture and illuminates the occurrence of a strong side and weak side with respect to the rotor path. Whereas CDE exhibits higher and lower frequencies from approaching and receding sources of WFs, respectively, spiral rotors generate higher and lower frequencies on opposite sides of the migration path. This motivates the reconsideration of mapping and ablation strategies that have traditionally been based on identifying sites of the dominant frequency. While this research aims to characterize the path of a spiral rotor during atrial fibrillation accurately, the results are applicable in other fields of science and engineering in which rotating spiral waves occur.

Report of the First ONTOX Stakeholder Network Meeting: Digging Under the Surface of ONTOX Together With the Stakeholders.

The first Stakeholder Network Meeting of the EU Horizon 2020-funded ONTOX project was held on 13-14 March 2023, in Brussels, Belgium. The discussion centred around identifying specific challenges, barriers and drivers in relation to the implementation of non-animal new approach methodologies (NAMs) and probabilistic risk assessment (PRA), in order to help address the issues and rank them according to their associated level of difficulty. ONTOX aims to advance the assessment of chemical risk to humans, without the use of animal testing, by developing non-animal NAMs and PRA in line with 21st century toxicity testing principles. Stakeholder groups (regulatory authorities, companies, academia, non-governmental organisations) were identified and invited to participate in a meeting and a survey, by which their current position in relation to the implementation of NAMs and PRA was ascertained, as well as specific challenges and drivers highlighted. The survey analysis revealed areas of agreement and disagreement among stakeholders on topics such as capacity building, sustainability, regulatory acceptance, validation of adverse outcome pathways, acceptance of artificial intelligence (AI) in risk assessment, and guaranteeing consumer safety. The stakeholder network meeting resulted in the identification of barriers, drivers and specific challenges that need to be addressed. Breakout groups discussed topics such as hazard versus risk assessment, future reliance on AI and machine learning, regulatory requirements for industry and sustainability of the ONTOX Hub platform. The outputs from these discussions provided insights for overcoming barriers and leveraging drivers for implementing NAMs and PRA. It was concluded that there is a continued need for stakeholder engagement, including the organisation of a 'hackathon' to tackle challenges, to ensure the successful implementation of NAMs and PRA in chemical risk assessment.

New supporting data to guide the use of evident toxicity in acute oral toxicity studies (OECD TG 420).

Currently there are three test guidelines (TG) for acute oral toxicity studies of substances or mixtures from the Organisation for Economic Co-operation and Development (OECD). TG 423 and TG 425 use lethality as an endpoint, while TG 420 replaces death with 'evident toxicity', defined as clear signs that exposure to a higher dose would result in death. However, the perceived subjectivity of 'evident toxicity' may be preventing wider use of TG 420. To address this, the UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) and the European Partnership for Alternative Approaches to Animal Testing (EPAA) collaborated to provide recommendations on the recognition of 'evident toxicity'. Historical data from acute oral toxicity studies were analysed for clinical signs at the lower dose that could have predicted death at the higher dose. Several signs including ataxia, laboured respiration, and eyes partially closed, alone or in combination, are highly predictive. Others such as lethargy, decreased respiration, and loose faeces have lower but still appreciable positive predictive value (PPV). The data has been used to develop recommendations to promote use of TG 420 and thus reduce the suffering and numbers of animals used in acute oral toxicity studies.

Timing and precision of rattlesnake spinal motoneurons are determined by the KV72/3 potassium channel.

The evolution of novel motor behaviors requires modifications in the central pattern generators (CPGs) controlling muscle activity. How such changes gradually lead to novel behaviors remains enigmatic due to the long time course of evolution. Rattlesnakes provide a unique opportunity to investigate how a locomotor CPG was evolutionarily modified to generate a novel behavior-in this case, acoustic signaling. We show that motoneurons (MNs) in the body and tail spinal cord of rattlesnakes possess fundamentally different physiological characteristics, which allow MNs in the tail to integrate and transmit CPG output for controlling superfast muscles with high temporal precision. Using patch-clamp electrophysiology, we demonstrate that these differences in locomotor and rattle MNs are mainly determined by KV72/3 potassium channels. However, although KV72/3 exerted a significantly different influence on locomotor and rattle MN physiology, single-cell RNA-seq unexpectedly did not reveal any differences in KV72/3 channels' expression. VIDEO ABSTRACT.

Lanthanide Contraction in LnF3 (Ln = Ce-Lu) and Its Chemical and Structural Consequences: Part 1: Location of YF3 in the LnF3 Series According to Its Chemical and Structural Characteristics.

A lanthanide contraction(LC) of 14 lanthanides (Ln) from 58Ce to 71Lu consists of the interaction of Ln nucleus with 4f-electrons. Rare earth elements (REEs-R) include Sc, Y, La, and 14 Ln. They are located in 4-6th periods of the subgroup of group III. The electronic structure divides R into short (d- Sc, Y, La) and long (14 f-elements Ce-Lu) homologous series. The most important chemical consequence of LC is the creation of a new conglomerate of 16 RF3 by mixing fluorides of d- (Y, La) and f-elements. This determines the location of YF3 among LnF3. The location of YF3 depends on the structural (formula volumes-Vform) and thermochemical (temperatures and heats of phase transformations, phase diagrams) properties. The location of YF3 between HoF3 and ErF3 was determined by Vform at a standard pressure (Pst) and temperature (Tst). The location of YF3 according to heats of phase transformations ΔHfus and ΔHtrans is in a dimorphic structural subgroup (SSGr) D (Ln = Er-Lu), but without the exact "pseudo ZY". According to the temperatures of phase transformations (Ttrans) in LnF3 (Ln = Dy-Lu), YF3 is located in the SSGr D between ErF3 and TmF3. The ErF3-YF3 and YF3-TmF3 phase diagrams show it to be between ErF3 and TmF3. The crystals of five ß-LnF3 (Ln = Ho-Lu) and ß-YF3 were obtained in identical conditions and their crystal structures were studied. Vform (at Pst and Tst) with "pseudo" atomic numberZY = 67.42 was calculated from the unit cell parameters, which were defined with ±5 × 10-4 Å accuracy. It determines the location of YF3 between HoF3 and ErF3.

Lanthanide Contraction in LnF3 (Ln = Ce-Lu) and Its Chemical and Structural Consequences: Part 2: Specialized Empirical System of R3+ (R = Y, La, and 14 Ln) and F1- Ionic Radii for RF3 Series.

A specialized empirical (Spec-zd Emp) system of ionic radii (SIR) for R = Y3+, La3+, Ln3+, and F1- (R rare earth elements (REE)) was derived from the dependence of lanthanide contraction (LC) on the atomic number (Z) of lanthanides (Ln). LC decreased the radius of the cation with increasing Z. The structures of t-RF3 (LaF3-NdF3, "pseudot-SmF3") of the LaF3 type, 11 ß-LnF3 (Ln = Sm-Lu), and ß-YF3 of the ß-YF3 type were studied. The empirical basis of the shortest (F-F)min and (R-F)min distances was calculated from the structural data for the RF3 complete series. The dependence of (F-F)min on Z reached saturation at Z = 67 (Ho). The base F1- radius r- = 1.2539(16) Å was calculated as the arithmetic mean of five (F-F)min in LnF3 with Ln = Ho-Lu. For the LnF3 series with Ln contributions up to 75 % wt., the dependence of (Ln-F)min on Z reflected the non-uniformity of the 4f orbital filling. SIR was calculated as the difference in the empirical constants of RF3 (ionic radii of (R,Ln)3+ (r+) and F1- (r-)), the change in which was continuous over the series and did not depend on the type of structure: r+ = (ZR-F)min - ½(F-F)min (Z = 57-71). The changes in LC in the LnF3 series were described by a third-degree polynomial. LC reduced r+ by 24% (percentage relative to less) from 1.1671(16) Å (La3+) to 0.9439(17) Å (Lu3+). In the Spec-zd Emp SIR, r+ were constants that did not require corrections for a coordination number (CN). A comparison of r+ in the Spec-zd Emp SIR with other SIRs was performed.

Fluorine and chlorine substituted adamantyl-urea as molecular tools for inhibition of human soluble epoxide hydrolase with picomolar efficacy.

Series of 1,3-disubstituted ureas and diadamantyl disubstituted diureas with fluorinated and chlorinated adamantane residues were shown to inhibit human soluble epoxide hydrolase (sEH) with inhibition potency ranging from 40 pM to 9.2 nM. The measured IC50 values for some molecules were below the accuracy limit of the existing in vitro assays. Such an increase in activity was achieved by minimal structural modifications to the molecules of known inhibitors, including 4-[trans-4-(1-adamantylcarbamoylamino)cyclohexyl]oxybenzoic acid. For the chlorinated homologue of the latter the sharp jump in inhibitory activity can be (according to molecular dynamics data) the result of interactions - Cl-π interaction. Considering the extremely high inhibitory activity, acceptable solubility and partial blockage of metabolically sensitive centres in their structures, some compounds are of interest for further in vivo biotesting.

Unusual Oligomeric Laccase-like Oxidases from Ascomycete Curvularia geniculata VKM F-3561 Polymerizing Phenylpropanoids and Phenolic Compounds under Neutral Environmental Conditions.

The unique oligomeric alkaliphilic laccase-like oxidases of the ascomycete C. geniculata VKM F-3561 (with molecular masses about 1035 and 870 kDa) were purified and characterized for the first time. The ability of the enzymes to oxidize phenylpropanoids and phenolic compounds under neutral environmental conditions with the formation of previously unknown di-, tri-, and tetrameric products of transformation was shown. The possibility to obtain industrially valuable compounds (dihydroxybenzyl alcohol and hydroxytyrosol) from caffeic acid using laccase-like oxidases of C. geniculata VKM F-3561 has been shown. Complete nucleotide sequence of the laccase gene, which is expressed at the peak of alkaliphilic laccase activity of the fungus, and its promoter region were determined. Based on the phylogenetic analysis of the nucleotide sequence, the nearest relationship of the isolated laccase gene with similar genes of fungi of the genera Alternaria, Bipolaris, and Cochliobolus was shown. Homologous model of the laccase structure was predicted and a proton channel was found, which was presumably responsible for the accumulation and transport of protons to T2/T3-copper center in the alkaliphilic laccase molecule and providing the functional activity of the enzyme in the neutral alkaline environment conditions.

Thermodynamic Origin of Negative Thermal Expansion Based on a Phase Transition-Type Mechanism in the GdF3-TbF3 System.

Multicomponent fluorides of rare earth elements (REEs-R) are phase transition-type negative thermal expansion (NTE-II) materials. NTE-II occurs in RF3-R'F3 systems formed by "mother" single-component dimorphic RF3 (R = Pm, Sm, Eu, and Gd) with a giant NTE-II. There are two structural types of RF3 polymorphic modifications: low-temperature ß-YF3 (ß-) and high-temperature LaF3 (t-). The change in a structural type is accompanied by a density anomaly: a volume of one formula unit (Vform) Vß- >Vt-. The empirical signs of volumetric changes ΔV/V of NTE-II materials were considered. For the GdF3-TbF3 model system, an "operating-temperature window ΔT" and a two-phase composition of NTE-II materials follows from the thermodynamics of chemical systems: the phase rule and the principle of continuity. A necessary and sufficient sign of NTE-II is a combination of polymorphism and the density anomaly. Isomorphism in RF3-R'F3 systems modifies RF3 chemically by forming two-component t- and ß- type R1-xR'xF3solid solutions (ss). Between the two monovariant curves of ss decay, a two-phase area with ΔTtrans > 0 (the "window ΔT") forms. A two-phase composite (t-ss + ß-ss) is an NTE-II material. Its constituent t-ss and ß-ss phases have different Vform corresponding to the selected T. According to the lever rule on a conode, Vform is calculated from the t-ss and ß-ss compositions, which vary with T along two monovariant curves of ss decay. For the GdF3-TbF3 system, ΔV/V = f(T), ΔV/V = f(ΔT) and the "window ΔT" = f(x) dependencies were calculated.

Safety and Efficacy of Sustained Automated Insulin Delivery Compared With Sensor and Pump Therapy in Adults With Type 1 Diabetes at High Risk for Hypoglycemia: A Randomized Controlled Trial.

OBJECTIVE: Assess the safety and efficacy of automated insulin delivery (AID) in adults with type 1 diabetes (T1D) at high risk for hypoglycemia. RESEARCH DESIGN AND METHODS: Participants were 72 adults with T1D who used an insulin pump with Clarke Hypoglycemia Perception Awareness scale score >3 and/or had severe hypoglycemia during the previous 6 months confirmed by time below range (TBR; defined as sensor glucose [SG] reading <70 mg/dL) of at least 5% during 2 weeks of blinded continuous glucose monitoring (CGM). Parallel-arm, randomized trial (2:1) of AID (Tandem t:slim ×2 with Control-IQ technology) versus CGM and pump therapy for 12 weeks. The primary outcome was TBR change from baseline. Secondary outcomes included time in target range (TIR; 70-180 mg/dL), time above range (TAR), mean SG reading, and time with glucose level <54 mg/dL. An optional 12-week extension with AID was offered to all participants. RESULTS: Compared with the sensor and pump (S&P), AID resulted in significant reduction of TBR by -3.7% (95% CI -4.8, -2.6), P < 0.001; an 8.6% increase in TIR (95% CI 5.2, 12.1), P < 0.001; and a -5.3% decrease in TAR (95% CI -87.7, -1.8), P = 0.004. Mean SG reading remained similar in the AID and S&P groups. During the 12-week extension, the effects of AID were sustained in the AID group and reproduced in the S&P group. Two severe hypoglycemic episodes occurred using AID. CONCLUSIONS: In adults with T1D at high risk for hypoglycemia, AID reduced the risk for hypoglycemia more than twofold, as quantified by TBR, while improving TIR and reducing hyperglycemia. Hence, AID is strongly recommended for this specific population.

Two-Component Rare-Earth Fluoride Materials with Negative Thermal Expansion Based on a Phase Transition-Type Mechanism in 50 RF3-R'F3 (R = La-Lu) Systems.

The formation of materials with negative thermal expansion (NTE) based on a phase transition-type mechanism (NTE-II) in 50 T-x (temperature-composition) RF3-R'F3 (R = La-Lu) systems out of 105 possible is predicted. The components of these systems are "mother" RF3 compounds (R = Pm, Sm, Eu, and Gd) with polymorphic transformations (PolTrs), which occur during heating between the main structural types of RF3: ß-(ß-YF3) → t-(mineral tysonite LaF3). The PolTr is characterized by a density anomaly: the formula volume (Vform) of the low-temperature modification (Vß-) is higher than that of the high-temperature modification (Vt-) by a giant value (up to 4.7%). In RF3-R'F3 systems, isomorphic substitutions chemically modify RF3 by forming R1-xR'xF3solid solutions (ss) based on both modifications. A two-phase composite (ß-ss + t-ss) is a two-component NTE-II material with adjustable parameters. The prospects of using the material are estimated using the parameter of the average volume change (ΔV/Vav). The Vav at a fixed gross composition of a system is determined by the ß-ss and t-ss decay (synthesis) curves and the temperature T. The regulation of ΔV/Vav is achieved by changing T within a "window ΔT". The available ΔT values are determined using phase diagrams. A chemical classification (ChCl) translates the search for NTE-II materials from 15 RF3 into an array of 105 RF3-R'F3 systems. Phase diagrams are divided into 10 types of systems (TypeSs), in four of which NTE-II materials are formed. The tables of the systems that comprise these TypeSs are presented. The position of Ttrans of the PolTr on the T scale for a short quasi-system (QS) "from PmF3 to TbF3" determines the interval of the ΔTtrans offset achievable in the RF3-R'F3 systems: from -148 to 1186 ± 10 °C. NTE-II fluoride materials exceed known NTE-II materials by almost three times in this parameter. Equilibrium in RF3-R'F3 systems is established quickly. The number of qualitatively different two-component fluoride materials with the giant NTE-II can be increased by more than ten times compared to RF3 with NTE-II.

Activated Carbon-Enriched Electrospun-Produced Scaffolds for Drug Delivery/Release in Biological Systems.

To vectorize drug delivery from electrospun-produced scaffolds, we introduce a thin outer drug retention layer produced by electrospinning from activated carbon nanoparticles (ACNs)-enriched polycaprolacton (PCL) suspension. Homogeneous or coaxial fibers filled with ACNs were produced by electrospinning from different PCL-based suspensions. Stable ACN suspensions were selected by sorting through solvents, stabilizers and auxiliary components. The ACN-enriched scaffolds produced were characterized for fiber diameter, porosity, pore size and mechanical properties. The scaffold structure was analyzed by scanning electron microscopy and X-ray photoelectron spectroscopy. It was found that ACNs were mainly coated with a polymer layer for both homogeneous and coaxial fibers. Drug binding and release from the scaffolds were tested using tritium-labeled sirolimus. We showed that the kinetics of sirolimus binding/release by ACN-enriched scaffolds was determined by the fiber composition and differed from that obtained with a free ACN. ACN-enriched scaffolds with coaxial and homogeneous fibers had a biocompatibility close to scaffold-free AC, as was shown by the cultivation of human gingival fibroblasts and umbilical vein cells on scaffolds. The data obtained demonstrated that ACN-enriched scaffolds had good physico-chemical properties and biocompatibility and, thus, could be used as a retaining layer for vectored drug delivery.

Effect of Sterilization Methods on Electrospun Scaffolds Produced from Blend of Polyurethane with Gelatin.

Fibrous polyurethane-based scaffolds have proven to be promising materials for the tissue engineering of implanted medical devices. Sterilization of such materials and medical devices is an absolutely essential step toward their medical application. In the presented work, we studied the effects of two sterilization methods (ethylene oxide treatment and electron beam irradiation) on the fibrous scaffolds produced from a polyurethane-gelatin blend. Scaffold structure and properties were studied by scanning electron microscopy (SEM), atomic force microscopy (AFM), infrared spectroscopy (FTIR), a stress-loading test, and a cell viability test with human fibroblasts. Treatment of fibrous polyurethane-based materials with ethylene oxide caused significant changes in their structure (formation of glued-like structures, increase in fiber diameter, and decrease in pore size) and mechanical properties (20% growth of the tensile strength, 30% decline of the maximal elongation). All sterilization procedures did not induce any cytotoxic effects or impede the biocompatibility of scaffolds. The obtained data determined electron beam irradiation to be a recommended sterilization method for electrospun medical devices made from polyurethane-gelatin blends.