Search

Supercompensated brain glycogen levels may contribute to the development of hypoglycemia-associated autonomic failure (HAAF) following recurrent hypoglycemia (RH) by providing energy for the brain during subsequent periods of hypoglycemia. To assess the role of glycogen supercompensation in the generation of HAAF, we estimated the level of brain glycogen following RH and acute hypoglycemia (AH). After undergoing 3 hyperinsulinemic, euglycemic and 3 hyperinsulinemic, hypoglycemic clamps (RH) on separate occasions at least 1 month apart, five healthy volunteers received [1-13C]glucose intravenously over 80+ h while maintaining euglycemia. 13C-glycogen levels in the occipital lobe were measured by 13C magnetic resonance spectroscopy at ∼8, 20, 32, 44, 56, 68 and 80 h at 4 T and glycogen levels estimated by fitting the data with a biophysical model that takes into account the tiered glycogen structure. Similarly, prior 13C-glycogen data obtained following a single hypoglycemic episode (AH) were fitted with the same model. Glycogen levels did not significantly increase after RH relative to after euglycemia, while they increased by ∼16% after AH relative to after euglycemia. These data suggest that glycogen supercompensation may be blunted with repeated hypoglycemic episodes. A causal relationship between glycogen supercompensation and generation of HAAF remains to be established. [ABSTRACT FROM AUTHOR]

Reaction of the nitrogen-rich triazole–tetrazole hybrid ligand 5-(4H-1,2,4-triazol-yl)-2H-tetrazole (trz–tetH) with Li+, Na+, K+ and Ba2+ in water leads to the coordination polymers [Li(trz–tet)H2O]n, [Na(trz–tet)(H2O)2]n, [K(trz–tetH)(trz–tet)(H2O)2]n and [Ba2(trz–tet)4(H2O)9]n, exhibiting different topologies and coordination modes. Salt-like structures with anionic triazole–tetrazole building blocks [Mg(H2O)6](trz–tet)2 and [Ca(H2O)8](trz–tet)2 were also obtained. All structures were simplified by topological analysis, which showed that the structures of [Mg(H2O)6](trz–tet)2 and [Ca(H2O)8](trz–tet)2 can be considered as underlying networks, constructed from the hydrogen bonded [Mg(H2O)6]2+ or [Ca(H2O)8]2+ cations and trz–tet ligands, with the rare binodal 5,10-connected topology alb-5,10,P21/c-1 and a unique binodal 5,12-connected topology, respectively. According to TGA/DTA analysis, all compounds show endothermic mass losses below 200 °C due to dehydration processes. The dehydrated residues are stable up to 300 °C. It was also established that the anionic form of the coordinated ligand trz–tet decomposes with an abrupt mass loss accompanied by a sharp and intense exothermic effect, while the non-coordinated trz–tet, as in the structures of the Mg- and Ca-based compounds, decomposes with a more gradual mass loss and significantly broad exothermic effect. Static DFT, ab initio molecular dynamics simulations as well as charge and energy decomposition (ETS-NOCV) based studies are performed in order to shed light on the stability of the newly obtained crystals. [ABSTRACT FROM AUTHOR]

In the present research, we developed and conducted a field test of the computerized adaptive rating scale (CARS) for assessing military officer performance. Participants completed the CARS and a behaviorally anchored rating scale (BARS) which were both designed to assess five leadership competencies (action orientation/initiative, communication, developing self and others, behavioral flexibility, and teamwork). We obtained data from 116 supervisors and 207 peers who provided ratings on 126 officer ratees. Although interrater reliability estimates were lower for CARS ratings on some competencies, there was a 20-25% improvement in standard error of measurement, the measurement precision in CARS ratings compared to the BARS. Results support findings from a previous lab study. [ABSTRACT FROM AUTHOR]

Nitrones are important building blocks for natural and biologically active compounds, used as spin-trap reagents and therapeutic agents. All this makes nitrones intriguing and valuable compounds for fundamental studies and as useful chemicals in various synthetic strategies. Therefore, nitrones are still of great interest and in the limelight of researches. With our initial goal to solve synthetic problems toward 5-phenyl-2,2′-bipyridine (Phbpy), we found that this reaction can proceed through the formation of 6-phenyl-3-(pyridin-2-yl)-1,2,4-triazin-4(3H)-ol (4-OH), which rapidly isomerizes to a 3,4-dihydro-1,2,4-triazine-based nitrone, namely 6-phenyl-3-pyridin-2-yl-2,3-dihydro-1,2,4-triazin-4-oxide (4′), This encouraged us to study condensation of hydrazonophenylacetaldehyde oxime (2), obtained from 2-isonitrosoacetophenone (1), with other aldehydes. The reaction with both salicylaldehyde and p-tolualdehyde leads to the open-chain isomers, namely (2-hydroxybenzylidene)hydrazono-2-phenylacetaldehyde oxime (5) and (4-methylbenzylidene)hydrazono-2-phenylacetaldehyde oxime (6), respectively. The latter product exists in solution in equilibrium with its cyclic isomer 6-phenyl-3-(4-methylphenyl)-2,3-dihydro-1,2,4-triazin-4-oxide (6′), while the former one exists in solution exclusively in the open-chain form. It was also found that 2 reacts with acetone with the formation of 3,3-dimethyl-6-phenyl-2,3-dihydro-1,2,4-triazin-4-oxide (7′), which also exists in solution in equilibrium with its open-chain isomer 2-phenyl-2-(propan-2-ylidenehydrazono)acetaldehyde oxime (7). The static DFT as well as ab initio molecular dynamics simulations have corroborated the experimental findings. [ABSTRACT FROM AUTHOR]

The reaction of the N-thiophosphorylated thiourea (HOCH2)(Me)2CNHC(S)NHP(S)(O iPr)2 (HL), deprotonated by the thiophosphorylamide group, with NiCl2 leads to green needles of the pseudotetrahedral complex [Ni(L-1,5- S, S′)2] ⋅0.5 ( n-C6H14) or pale green blocks of the trans square-planar complex trans-[Ni(L-1,5- S, S′)2]. The former complex is stabilized by homopolar dihydrogen CH⋅⋅⋅HC interactions formed by n-hexane solvent molecules with the [Ni(L-1,5- S, S′)2] unit. Furthermore, the dispersion-dominated CH⋅⋅⋅ HC interactions are, together with other noncovalent interactions (CH⋅⋅⋅N, CH⋅⋅⋅Ni, CH⋅⋅⋅S), responsible for pseudotetrahedral coordination around the NiII center in [Ni( L-1,5- S, S′)2] ⋅0.5 ( n-C6H14). [ABSTRACT FROM AUTHOR]

Aims Impaired awareness of hypoglycemia (IAH) is a limiting factor in the treatment of type 1 diabetes (T1D) and is a challenging condition to reverse. The objective of this study was to test the hypothesis that naltrexone therapy in subjects with T1D and IAH will improve counterregulatory hormone response and recognition of hypoglycemia symptoms during hypoglycemia. Methods We performed a pilot randomized double blind trial of 4 weeks of naltrexone therapy (n = 10) or placebo (n = 12) given orally in subjects with T1D and IAH. Outcome measures included hypoglycemia symptom scores, counterregulatory hormone levels and thalamic activation as measured by cerebral blood flow using MRI during experimental hypoglycemia in all subjects before and after 4 weeks of intervention. Results After 4 weeks of therapy with naltrexone or placebo, no significant differences in response to hypoglycemia were seen in any outcomes of interest within each group. Conclusions In this small study, short-term treatment with naltrexone did not improve recognition of hypoglycemia symptoms or counterregulatory hormone response during experimental hypoglycemia in subjects with T1D and IAH. Whether this lack of effect is related to the small sample size or due to the dose, the advanced stage of study population or the drug itself should be the subject of future investigation. [ABSTRACT FROM AUTHOR]

Several pyrene based fluorescent probes undergo lysine assisted monomer to excimer conversion in a ratiometric manner. Intracellular lysine is detected using fluorescence microscopy. [ABSTRACT FROM AUTHOR]

Objectives To determine the effect of home-based primary care ( HBPC) on Medicare costs and mortality in frail elders. Design Case-control concurrent study using Medicare administrative data. Setting HBPC practice in Washington, District of Columbia. Participants HBPC cases (n = 722) and controls (n = 2,161) matched for sex, age bands, race, Medicare buy-in status (whether Medicaid covers Part B premiums), long-term nursing home status, cognitive impairment, and frailty. Cases were eligible if enrolled in MedStar Washington Hospital Center's HBPC program during 2004 to 2008. Controls were selected from Washington, District of Columbia, and urban counties in Virginia, Maryland, and Pennsylvania. Intervention HBPC clinical service. Measurements Medicare costs, utilization events, mortality. Results Mean age was 83.7 for cases and 82.0 for controls ( P < .001). A majority of both groups was female (77%) and African American (90%). During a mean 2-year follow-up, in univariate analysis, cases had lower Medicare ($44,455 vs $50,977, P = .01), hospital ($17,805 vs $22,096, P = .003), and skilled nursing facility care ($4,821 vs $6,098, P = .001) costs, and higher home health ($6,579 vs $4,169; P < .001) and hospice ($3,144 vs. $1,505; P = .005) costs. Cases had 23% fewer subspecialist visits ( P = .001) and 105% more generalist visits ( P < .001). In a multivariate model, cases had 17% lower Medicare costs, averaging $8,477 less per beneficiary ( P = .003) over 2 years of follow-up. There was no difference between cases and controls in mortality (40% vs 36%, hazard ratio = 1.06, P = .44) or in average time to death (16.2 vs 16.8 months, P = .30). Conclusion HBPC reduces Medicare costs for ill elders, with similar survival outcomes in cases and controls. [ABSTRACT FROM AUTHOR]

Zinc is required for the folding and function of many proteins. In Saccharomyces cerevisiae, homeostatic and adaptive responses to zinc deficiency are regulated by the Zap1 transcription factor. One Zap1 target gene encodes the Tsa1 peroxiredoxin, a protein with both peroxidase and protein chaperone activities. Consistent with its regulation, Tsa1 is critical for growth under low zinc conditions. We previously showed that Tsa1's peroxidase function decreases the oxidative stress that occurs in zinc deficiency. In this report, we show that Tsa1 chaperone, and not peroxidase, activity is the more critical function in zinc-deficient cells. Mutations restoring growth to zinc-deficient tsa1 cells inactivated TRR1, encoding thioredoxin reductase. Because Trr1 is required for oxidative stress tolerance, this result implicated the Tsa1 chaperone function in tolerance to zinc deficiency. Consistent with this hypothesis, the tsa1Δ zinc requirement was complemented by a Tsa1 mutant allele that retained only chaperone function. Additionally, growth of tsa1Δ was also restored by overexpression of holdase chaperones Hsp26 and Hsp42, which lack peroxidase activity, and the Tsa1 paralog Tsa2 contributed to suppression by trr1Δ, even though trr1Δ inactivates Tsa2 peroxidase activity. The essentiality of the Tsa1 chaperone suggested that zinc-deficient cells experience a crisis of disrupted protein folding. Consistent with this model, assays of protein homeostasis suggested that zinc-limited tsa1Δ mutants accumulated unfolded proteins and induced a corresponding stress response. These observations demonstrate a clear physiological role for a peroxiredoxin chaperone and reveal a novel and unexpected role for protein homeostasis in tolerating metal deficiency. [ABSTRACT FROM AUTHOR]

The N-phosphorylated thiourea iPrNHC(S)NHP(O)(OPh)2 (HL) has been synthesized by the reaction of iPrNH2 and (PhO)2P(O)NCS. Recrystallization of HL from aqueous acetone leads to [iPrNH3]+[P(O)2(OPh)2]− in a quantitative yield. Reaction of the deprotonated HL with NiCl2 leads to violet [NiL2] crystals with a 1,3-N,S-coordination mode of the ligands. Static DFT and ab initio molecular dynamics studies indicated that [NiL2] is stabilized predominantly by intramolecular N–H…O=P hydrogen bonding and dynamically by secondary CPh–H…S interactions. All compounds have been characterized by IR, diffuse reflectance, UV-vis and NMR spectroscopy, single crystal X-ray diffraction analysis and elemental analysis. Thermal properties investigated in an air atmosphere by means of TGA revealed a residue corresponding to NiPS3. [ABSTRACT FROM AUTHOR]

Reaction of the deprotonated N-thiophosphorylated thioureas RC(S)NHP(S)(O iPr)2 [R = EtNH ( HLI), iPrNH ( HLII), Et2N ( HLIII), 2,5-Me2C6H3NH ( HLIV), 4-Me2NC6H4NH ( HLV)] with NiII leads to complexes of the formula [NiLI-V2]. The molecular structures of the complexes in the solid were elucidated by single-crystal X-ray diffraction analysis. In the complexes, the metal atom is found to be in a square-planar trans- N2 S2 ( [NiLII,IV2]) environment formed by the C=S sulfur atoms and the P-N nitrogen atoms, or in a square-planar trans- S2 S′2 ( [NiLI,III2]) environment formed by the C=S and P=S sulfur atoms of two deprotonated ligands. Reaction of deprotonated N-thiophosphorylated thiourea HLV with NiCl2 leads to violet [Ni(L-1,3- N, S)2] or dark violet [Ni(L-1,5- S, S′)2]·(CH3)2C=O crystals that were isolated by recrystallization from a mixture of CH2Cl2 or acetone, respectively, and n-hexane. DFT calculations confirmed that the [Ni(LI,II,IV,V- N, S)2] conformers are more stable (by 5-7 kcal/mol) than [Ni(LI,II,IV,V- S, S′)2], whereas [Ni(LIII- N, S)2] is less stable (by 7-9 kcal/mol) than [Ni(LIII- S, S′)2]. The main reason for higher stability of the 1,3- N, S versus 1,5- S, S′ isomers is the formation of intramolecular N-H ···S=P hydrogen bonds. The same hydrogen bonds are impossible in complex [NiLIII2]. In solution, complex [NiLIII2] has revealed an exclusively 1,5- S, S′ coordination, whereas compounds [NiLI,II,IV,V2] reveal at least two isomers in the 1H and 31P{1H} NMR spectra. The major species is assigned to the 1,3- N, S-coordinated isomer, and the minor signals are assigned to the 1,5- S, S′ isomer, which was confirmed by UV/Vis spectroscopic results. The electrochemical measurements reveal reversible one-electron reduction and irreversible oxidations both assigned to ligand-centred processes. Ligand-based oxidation processes agree well with TD-DFT results. [ABSTRACT FROM AUTHOR]

Reaction of the deprotonated N-thiophosphorylated thiourea p-Me2NC6H4NHC(S)NHP(S)(OiPr)2(HL) with NiCl2leads to violet [Ni(L-1,3-N,S)2] or dark violet [Ni(L-1,5-S,S′)2]·(CH3)2CO crystals that were isolated by recrystallization from a mixture of CH2Cl2or acetone, respectively, and n-hexane. [ABSTRACT FROM AUTHOR]

Introduction: The increase of fungal infections is widely observed all over the world. Neonates, particularly those with immature immunity and multiple medications, parenteral nutrition and invasive diagnostic procedures are very prone to fungal infection. Aim: Assesment of risk of fungal infections in neonates requiring intensive care. Material and methods: 3544 blood samples and other samples like urine, skin swabs and mucous membrane swabs obtained from neonates were analysed. All neonates were hospitalised in Department of Neonatology at Poznan University of Medical Sciences. Samples were obtained in the second week of life and underwent a standard, mycological diagnostic procedure. Results: Yeast like fungi were grown in 194 cultures. The dominant was Candida albicans - present in 74.1%. Other isolated species were: C. glabrata, C. parapsilosis, C. sake, C. tropicalis and C. lusitaniae. There was no statistically important correlations between sites of isolations of yeast were found. Medium weight of neonates diagnosed with fungal infections was lower than the one of neonates with no infection, but it was not statistically significant. No lipophylic yeast were cultured. Conclusions: Candida-yeast are a real danger in neonatal intensive care units. [ABSTRACT FROM AUTHOR]

In this paper, systematic studies concerning the influence of selected oxysterols on the structure and fluidity of human erythrocyte membrane modeled as Langmuir monolayers have been performed. Three oxidized cholesterol derivatives, namely 7α-hydroxycholesterol (7α-OH) 7β-hydroxycholesterol (7β-OH) and 7-ketocholesterol (7-K) have been incorporated in two different proportions (10 and 50%) into artificial erythrocyte membrane, modeled as two-component (cholesterol:POPC) Langmuir monolayer. All the studied oxysterols were found to alter membrane fluidity and the effect was more pronounced for higher oxysterol content. 7α-OH increased membrane fluidity while opposite effect was observed for 7β-OH and 7-K. Experiments performed on model systems have been verified in biological studies on red blood cells (RBC). Consistent results have been found, i.e. under the influence of 7α-OH, the elasticity of erythrocytes increased, and in the presence of other investigated oxysterols - decreased. The strongest effect was noticed for 7-K. Change of membrane elasticity was associated with the change of erythrocytes shape, being most noticeable under the influence of 7-K. Unlabelled Image • Influence of B-ring-substituted oxysterols on RBC was determined. • Results from Langmuir monolayers are consistent with biological experiments on RBCs. • The investigated oxysterols (7-K, 7α-OH and 7β-OH) alter RBC elasticity. • The strongest influence on RBC has been observed for 7-K. [ABSTRACT FROM AUTHOR]

The battle against emerging viral infections has been uneven, as there is currently no broad-spectrum drug available to contain the spread of novel pathogens throughout the population. Consequently, the pandemic outbreak that occurred in early 2020 laid bare the almost empty state of the pandemic box. Therefore, the development of novel treatments with broad specificity has become a paramount concern in this post-pandemic era. Here, we propose copolymers of poly (sodium 2-(acrylamido)-2-methyl-1-propanesulfonate) (PAMPS) and poly (sodium 11-(acrylamido)undecanoate (AaU), both block (PAMPS 75 -b-PAaU n ) and random (P(AMPS m -co-AaU n )) that show efficacy against a broad range of alpha and betacoronaviruses. Owing to their intricate architecture, these polymers exhibit a highly distinctive mode of action, modulating nano-mechanical properties of cells and thereby influencing viral replication. Through the employment of confocal and atomic force microscopy techniques, we discerned perturbations in actin and vimentin filaments, which correlated with modification of cellular elasticity and reduction of glycocalyx layer. Intriguingly, this process was reversible upon polymer removal from the cells. To ascertain the applicability of our findings, we assessed the efficacy and underlying mechanism of the inhibitors using fully differentiated human airway epithelial cultures, wherein near-complete abrogation of viral replication was documented. Given their mode of action, these polymers can be classified as biologically active nanomaterials that exploit a highly conserved molecular target-cellular plasticity-proffering the potential for truly broad-spectrum activity while concurrently for drug resistance development is minimal., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests Krzysztof Pyrc reports financial support was provided by 10.13039/501100004281National Science Centre Poland. Maria Nowakowska reports financial support was provided by 10.13039/501100004281National Science Centre Poland., (© 2023 The Authors.)

Endothelial cells (ECs) play a crucial role in the development and propagation of the severe COVID-19 stage as well as multiorgan dysfunction. It remains, however, controversial whether COVID-19-induced endothelial injury is caused directly by the infection of ECs with SARS-CoV-2 or via indirect mechanisms. One of the major concerns is raised by the contradictory data supporting or denying the presence of ACE2, the SARS-CoV-2 binding receptor, on the EC surface. Here, we show that primary human pulmonary artery ECs possess ACE2 capable of interaction with the viral Spike protein (S-protein) and demonstrate the crucial role of the endothelial glycocalyx in the regulation of the S-protein binding to ACE2 on ECs. Using force spectroscopy method, we directly measured ACE2- and glycocalyx-dependent adhesive forces between S-protein and ECs and characterized the nanomechanical parameters of the cells exposed to S-protein. We revealed that the intact glycocalyx strongly binds S-protein but screens its interaction with ACE2. Reduction of glycocalyx layer exposes ACE2 receptors and promotes their interaction with S-protein. These results indicate that the susceptibility of ECs to COVID-19 infection may depend on the glycocalyx condition.