Unimolecular isomerizations of C6H6•+ radical cations: a computational study.

CONCEPT: Eighteen concerted isomerization reactions of various C6H6•+ radical cation (RC) species are studied and found to proceed via well-defined transition states, whose relative positions along the reaction pathway generally agree with Hammond's postulate. From the barrier heights, the rate coefficients of these reactions are estimated by using transition state theory, and the activation energies are computed. Through combination among themselves, these 18 isomerizations yielded 15 multi-step conversion routes of various C6H6•+ species to the lowest energy benzene radical cation isomer 1, which routes are compared. METHODS: Use is made of DFT with the B3LYP and M06-2X functionals, along with the CBS-QB3 approach to arrive at better energies. From the barrier heights for each of the concerted reactions, canonical transition state theory was applied to evaluate rate coefficients k over the temperature range 200-500 K. The Arrhenius activation energies were computed using the plot of ln k vs. 1/T.

Safety and efficacy of a feed additive consisting of endo-1,4-ß-xylanase produced with Trichoderma reesei CBS 114044 (ECONASE® XT) for pigs for fattening, laying hens and minor poultry species (AB Enzymes Finland Oy).

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety and efficacy of a product containing endo-1,4-ß-xylanase (ECONASE® XT) as a zootechnical feed additive (digestibility enhancer) for pigs for fattening, laying hens and minor poultry species. ECONASE® XT is available in two liquid and three solid forms and is produced with a genetically modified strain of Trichoderma reesei (CBS 114044). The FEEDAP Panel concluded that the genetic modification of the production strain does not raise any safety concerns, and viable cells of the production strain and its DNA were not detected in the final products. The Panel also concluded that ECONASE® XT is safe for pigs for fattening, laying hens and minor poultry species at the proposed conditions of use. The use of the additive raises no safety concerns for the consumers of products derived from animals fed with the additive or for the environment. The liquid and solid forms of ECONASE® XT are non-irritant to the skin, but only the liquid forms were confirmed as non-irritant to the eyes and not dermal sensitisers. The Panel could not conclude on the irritation potential to the eyes and the dermal sensitisation potential for the solid forms. Due to the proteinaceous nature of the active substance, the additive is considered to be a respiratory sensitiser. The additive has the potential to be efficacious in pigs for fattening at 20,000 BXU/kg complete feed, in all laying poultry species at 12,000 BXU/kg complete feed and in minor poultry species other than laying birds at 8000 BXU/kg complete feed.

CBS/CSE mediated H2S production induced AMPs expression through Toll pathway in crabs with black gill syndrome.

The occurrence of black gill syndrome (BGS) is a serious threat to the healthy culture of Eriocheir sinensis. Studying the innate immune ability of E. sinensis with BGS can help develop new strategies for disease prevention and treatment. Antimicrobial peptides (AMPs) have crucial roles in crustacean humoral immunity. In this study, we found that the expression levels of two antilipopolysaccharide factor (EsALF7 and EsALF-L), one Toll receptor 3 (EsToll3), and one Pelle kinase (EsPelle) were upregulated in E. sinensis with BGS. Moreover, ALFs expressions in E. sinensis with BGS were positively regulated by EsToll3 and EsPelle. The content of hydrogen sulfide (H2S) in the gills of E. sinensis with BGS was increased. Further studies showed that the expressions of cystathionine ß-synthase (EsCBS) and cystathionine γ-lyase (EsCSE) in the gills of E. sinensis with BGS were upregulated, which positively regulate the production of H2S. Whether there was a correlation between the upregulation of ALFs expression and changes in H2S content? Further studies showed that 1) the expressions of EsToll3, EsPelle, EsALF7, and EsALF-L in the gills of E. sinensis were upregulated under H2S exposure and 2) the knockdown of EsCBS and EsCSE in E. sinensis reduced the transcriptions of EsToll3, EsPelle, EsALF7, and EsALF-L. To sum up, these findings suggest that upregulation of H2S content induced by CBS/CSE promotes the expression of ALFs through the Toll pathway in E. sinensis suffering from BGS.

Flammability and Mechanical Testing of Sandwich Composite for Rolling Stock Structural Applications.

Components made of composite materials are being increasingly used in the construction of rolling stock. Currently, the use of components made of composite materials as train structural elements is increasingly being considered. Non-structural components made of composites are most often found inside rail vehicles (e.g., the interior lining), while structural components made of sandwich composite materials can be used for the roof, sidewalls, and underframe constructions. This article provides a description of an innovative sandwich composite developed for a metro's underframe, as well as the production process and preparation of the composite specimens. The main parts of the work are flammability and mechanical (static and fatigue) tests of the innovative sandwich composite. The scope of the flammability tests included the testing of the fire properties using the radial plate method, the optical density of smoke, and the content of toxic gases. The mechanical strength of the sandwich composite was examined during a flexural (three-point bending) test and a fatigue strength under a given dynamic load. The results presented in the article are very significant, both in terms of flammability and the mechanical strength tests. In order to produce large-size train components, appropriately large patches of component layers of the composite are required; this may pose production problems.

Reactions with Criegee intermediates are the dominant gas-phase sink for formyl fluoride in the atmosphere.

Atmospheric oxidation processes are of central importance in atmospheric climate models. It is often considered that volatile organic molecules are mainly removed by hydroxyl radical; however, the kinetics of some reactions of hydroxyl radical with volatile organic molecules are slow. Here we report rate constants for rapid reactions of formyl fluoride with Criegee intermediates. These rate constants are calculated by dual-level multistructural canonical variational transition state theory with small-curvature tunneling (DL-MS-CVT/SCT). The treatment contains beyond-CCSD(T) electronic structure calculations for transition state theory, and it employs validated density functional input for multistructural canonical variational transition state theory with small-curvature tunneling and for variable-reaction-coordinate variational transition state theory. We find that the M11-L density functional has higher accuracy than CCSD(T)/CBS for the HC(O)F + CH2OO and HC(O)F + anti-CH3CHOO reactions. We find significant negative temperature dependence in the ratios of the rate constants for HC(O)F + CH2OO/anti-CH3CHOO to the rate constant for HC(O)F + OH. We also find that different Criegee intermediates have different rate-determining-steps in their reactions with formyl fluoride, and we find that the dominant gas-phase removal mechanism for HC(O)F in the atmosphere is the reaction with CH2OO and/or anti-CH3CHOO Criegee intermediates.

A systematic review of the quantitative markers of speech and language of the frontotemporal degeneration spectrum and their potential for cross-linguistic implementation.

Frontotemporal dementia (FTD) is a neurodegenerative disease spectrum with an urgent need for reliable biomarkers for early diagnosis and monitoring. Speech and language changes occur in the early stages of FTD and offer a potential non-invasive, early, and accessible diagnostic tool. The use of speech and language markers in this disease spectrum is limited by the fact that most studies investigate English-speaking patients. This systematic review examines the literature on psychoacoustic and linguistic features of speech that occur across the FTD spectrum across as many different languages as possible. 76 papers were identified that investigate psychoacoustic and linguistic markers in discursive speech. 75 % of these papers studied English-speaking patients. The most generalizable features found across different languages, are speech rate, articulation rate, pause frequency, total pause duration, noun-verb ratio, and total number of nouns. While there are clear interlinguistic differences across patient groups, the results show promise for implementation of cross-linguistic markers of speech and language across the FTD spectrum particularly for psychoacoustic features.

The single-phase CTA Clot Burden Score is independently associated with DSA ASITN collateral score.

OBJECTIVES: The variation in quality and quantity of collateral status (CS) is in part responsible for a wide variability in extent of neural damage following acute ischemic stroke from large vessel occlusion (AIS-LVO). Single-phase CTA based Clot Burden Score (CBS) is a promising marker in estimating CS. The aim of this study is to assess the relationship of pretreatment CTA based CBS with the reference standard DSA based American Society of Interventional and Therapeutic Neuroradiology (ASITN) CS. METHODS: In this retrospective study, inclusion criteria were as follows: a) Anterior circulation LVO confirmed on CTA from 9/1/2017 to 10/01/2023; b) diagnostic CTA; and c) underwent MT with documented DSA CS. Spearman's rank correlation analysis, multivariate logistic regression and ROC analysis was performed to assess the correlation of CTA CBS with DSA CS. p ≤ 0.05 was considered significant. RESULTS: 292 consecutive patients (median age = 68 years; 56.2% female) met our inclusion criteria. CTA CBS and DSA CS showed significant positive correlation (ρ = 0.51, p < 0.001). On multivariate logistic regression analysis CBS was found to be independently associated with DSA CS (adjusted OR = 1.83, p < 0.001, 95% CI: 1.54-2.19), after adjusting for age, sex, race, hyperlipidemia, hypertension, diabetes, prior stroke or TIA, atrial fibrillation, premorbid mRS, admission NIH stroke scale, and ASPECTS. ROC analysis of CBS in predicting good DSA CS showed AUC of 0.76 (p < 0.001; 95%CI: 0.68-0.82). CBS threshold of > 6 has 84.6% sensitivity and 42.3% specificity in predicting good DSA CS. CONCLUSION: CTA CBS is independently associated with DSA CS and serves as a valuable supplementary tool for collateral status estimation. Further research is necessary to enhance our understanding of the role of CTA CBS in clinical decision-making for patients with AIS-LVO. ADVANCES IN KNOWLEDGE: CBS by indirectly estimating CS has shown to predict outcomes in AIS-LVO patients. No studies report association of CBS with reference standard DSA. In this study we further establish CBS as an independent marker of CS.

The role of cystathionine ß-synthase in cancer.

Cystathionine ß-synthase (CBS) occupies a key position as the initiating and rate-limiting enzyme in the sulfur transfer pathway and plays a vital role in health and disease. CBS is responsible for regulating the metabolism of cysteine, the precursor of glutathione (GSH), an important antioxidant in the body. Additionally, CBS is one of the three enzymes that produce hydrogen sulfide (H2S) in mammals through a variety of mechanisms. The dysregulation of CBS expression in cancer cells affects H2S production through direct or indirect pathways, thereby influencing cancer growth and metastasis by inducing angiogenesis, facilitating proliferation, migration, and invasion, modulating cellular energy metabolism, promoting cell cycle progression, and inhibiting apoptosis. It is noteworthy that CBS expression exhibits complex changes in different cancer models. In this paper, we focus on the CBS synthesis and metabolism, tissue distribution, potential mechanisms influencing tumor growth, and relevant signaling pathways. We also discuss the impact of pharmacological CBS inhibitors and silencing CBS in preclinical cancer models, supporting their potential as targeted cancer therapies.

Asynchronous changes of hydrogen sulfide and its generating enzymes in most tissues with the aging process.

Aging is an inevitable and irreversible biological process that gradually heightens the risks of various diseases and death. As a newly discovered endogenous gasotransmitter, hydrogen sulfide (H2S) has been identified to exert multiple beneficial impacts on the regulation of aging and age-related pathologies. This study was aimed at systematically exploring the relationship between asynchronous aging processes and H2S concentrations in various tissues of aging mice. Samples of plasma and 13 tissues were collected from four cross-sectional age groups (3, 6, 12 and 18 months of age) covering the lifespan of male C57BL/6J mice. The H2S concentration was quantified by a reported liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with monobromobimane derivatization. Additionally, the expressions of cystathionine γ-lyase (CSE), cystathionine ß-synthase and 3-mercaptopyruvate sulfurtransferase, in those tissues were analyzed by Western blotting. We discovered that the H2S concentrations decreased asynchronously with the aging process in plasma, heart, liver, kidney, spleen, subcutaneous fat and brown fat and increased in brain and lung. At least one of the three H2S-generating enzymes expressions was compensatorily up-regulated with the aging process in most tissues, among which the up-regulation of CSE was the most prominent.

Clinical and molecular predictors of survival among atypical parkinsonian syndromes in a North African tertiary referral center.

INTRODUCTION: Atypical Parkinsonian Syndromes(APS) are challenging neurodegenerative disorders due to their heterogeneous phenotypic overlaps.So far,there are no validated biomarkers that can accurately predict disease progression,and survival studies were highly different and contradictory. AIM: To investigate clinical and molecular survival factors among Tunisian APS patients. METHODS: A retrospective study included Tunisian APS-patients.Using clinical and molecular parameters,survival was explored by Kaplan-Meier analysis. RESULTS: We included 409-APS patients divided into 166-DLB,112-PSP,81-MSA and 50-CBS.Survival rate was similar in synucleinopathies, while it differed in tauopathies,being shorter in PSP compared to CBS.Median survival in DLB was different according to gender(p = 0.0048),early parkinsonism and cognitive disorders. Among MSA, prognosis was worse in MSA-C-patients(p = 0.012) and those with stridor(p = 0.0049),oculomotor and neuropsychiatric disorders. For tauopathies, survival was shorter in PSP-RS(p = 0.027),cerebellar phenotype, those with tremor and swallowing problems at onset, early parkinsonism and memory impairment. For CBS,prognosis was worse in patients with tremor,swallowing and cognitive problems.Significant differences were noted in terms of survival across APS non-carriers of APOE-ε4(p < 0.001) as well APS patients carriers of MAPT-H1.PSP patients had lower survival rate according to MAPT haplotype carriage. Moreover, the number of copies had an influence as patients with H1/H2-MAPT profile had better prognosis than those with H1/H1. CONCLUSION: This study determined survival rates in APS subgroups,which were comparable across synucleinopathies but shorter in PSP and longer in CBS.It also characterized demographic,phenotypic,and genetic profiles identifying more aggressive forms within APS subgroups.These findings address clinical gaps,aiding counseling for patients and families and guiding clinical management.Furthermore,they could facilitate patient stratification in clinical trials where mortality is an outcome measure.

Quantitative diagnosis of carotid blowout syndrome with CT perfusion: Carotid blowout syndrome CTP quantitative diagnosis.

BACKGROUND AND PURPOSE: Carotid blowout syndrome (CBS) is a potentially fatal disease. The CBS diagnosis mainly relies on subjective observations and the quantitative diagnotic method was not well established. This study aimed to diagnose CBS severity by computed tomography perfusion (CTP) parameters with different region-of-interest (ROI) models. MATERIALS AND METHOD: We prospectively recruited CBS patients between February 1, 2018 and July 31, 2023 in a tertiary medical center, and CTP was performed using the same 128-detector CT machine. Digital subtraction angiography (DSA) and elective endovascular intervention were performed within 3 days post-CTP for diagnosis confirmation and treatments. CBS severity was classified into ongoing (threatened + impending) or acute CBS based on DSA findings and clinical features. Pericarotid soft-tissue (PCST) CTP parameters, including blood flow (BF), blood volume (BV), mean transit time (MTT) and flow extraction product (FEP), were evaluated and correlated on DSA. We depicted models A, B and C for the small focal lesion in 1 cm of PCST, 1 cm around PCST and the whole PCST respectively. RESULTS: CTP images of 110 patients (77 ongoing (45 threatened + 32 impending); 33 acute) were analyzed. Pericarotid BV (1.8 ± 1.2vs.3.5 ± 2.0; p < 0.001) in Model A and BF in Model B (42.6 ± 11.0vs.50.9 ± 20.4; p = 0.031) were lower in acute-CBS than in ongoing-CBS patients. Subgroup analysis demonstrated lower BV in acute (1.8 ± 1.2) compared with threatened (3.7 ± 2.3; p < 0.001; p < 0.001) and impending (3.2 ± 1.6; p = 0.009) CBS patients in Model A. CONCLUSION: CBS severity can be quantitatively diagnosed by pericarotid soft-tissue CTP parameters. In Model A (small focus), BV was capable of differentiating acute CBS from other subtypes, demonstrating its potential role as a CBS imaging biomarker.

A cystathionine beta-synthase domain containing protein, OsCBSCBS4, interacts with OsSnRK1A and OsPKG and functions in abiotic stress tolerance in rice.

The Cystathionine-ß-Synthase (CBS) domain-containing proteins (CDCPs) constitute a functionally diverse protein superfamily, sharing an evolutionary conserved CBS domain either in pair or quad. Rice genome (Oryza sativa subsp. indica) encodes 42 CDCPs; their functions remain largely unexplored. This study examines OsCBSCBS4, a quadruple CBS domain containing protein towards its role in regulating the abiotic stress tolerance in rice. Gene expression analyses revealed upregulation of OsCBSCBS4 in response to diverse abiotic stresses. Further, the cytoplasm-localised OsCBSCBS4 showed interaction with two different kinases, a cytoplasmic localised cGMP-dependant protein kinase (OsPKG) and the nucleo-cytoplasmic catalytic subunit of sucrose-nonfermentation 1-related protein kinase 1 (OsSnRK1A). The interaction with the latter assisted in trafficking of OsCBSCBS4 to the nucleus as well. Overexpression of OsCBSCBS4 in rice resulted in enhanced tolerance to drought and salinity stress, via maintaining better physiological parameters and antioxidant activity. Additionally, OsCBSCBS4-overexpressing rice plants exhibited reduced yield penalty under stress conditions. The in silico docking and in vitro binding analyses of OsCBSCBS4 with ATP suggest its involvement in cellular energy balance. Overall, this study provides novel insight into the unexplored functions of OsCBSCBS4 and demonstrates it as a new promising target for augmenting crop resilience.

Elevated homocysteine is negatively correlated with plasma cystathionine ß-synthase activity in givosiran-treated patients.

Givosiran is a subcutaneously administered, liver-targeted RNA interference (RNAi) therapeutic that has been approved for treating acute hepatic porphyria (AHP). Elevation in plasma homocysteine (hyperhomocysteinemia) has been reported in AHP patients, and treatment with givosiran has been reported to further increase homocysteine levels in some patients. The mechanism of homocysteine elevation during givosiran treatment is unknown, but has been hypothesized to be mediated by a reduction in activity of cystathionine ß-synthase (CBS), which uses homocysteine as a substrate. A liquid chromatography-tandem mass spectrometry-based assay was adapted to measure circulating CBS activity. Using plasma collected from the Phase III ENVISION study, CBS activity was measured to directly evaluate whether it is associated with elevated homocysteine levels in givosiran-treated patients. CBS activity was reduced following givosiran treatment and both homocysteine and methionine levels were inversely correlated with CBS activity. Following administration of a supplement containing vitamin B6, a cofactor for CBS, in four patients during the trial, plasma CBS activity was found to increase, mirroring a corresponding decrease in homocysteine levels. These results support the hypothesis that elevated homocysteine levels following givosiran treatment result from a reduction of CBS activity and that vitamin B6 supplementation lowers homocysteine levels by increasing CBS activity.

Radiation Maculopathy in Patients with Malignant Melanoma of the Corpus Ciliare and Choroidea Following One-Day Session of Stereotactic Radiosurgery.

The aim of the thesis is to present the case of a patient in whom bilateral calcification of the hydrophilic intraocular lens (IOL) Lentis M+ LS-313 MF30 (Oculentis) has developed. Due to the negative effect on visual functions, explantation and replacement of the artificial lens was necessary in both eyes. Case Report: An overview of the available literature summarized the diagnostics, current examination methods and possibilities of the surgical solution of calcification of the bifocal hydrophilic lens Lentis M+ LS-313 MF30 (Oculentis). The specific solution is described in a case report of a patient in whom calcification of both lenses developed 6 years after implantation of the IOL. In 2015, the patient underwent uncomplicated cataract surgery of both eyes with the implantation of an artificial intraocular lens into the capsule. In September 2021, an 82-year-old man was examined at our outpatient clinic for deterioration of visual acuity and changes in the material of the artificial IOL which were perceptible during a clinical examination, on the recommendation of a local ophthalmologist. Blurred vision predominated. A diagnosis of intraocular lens opacification was confirmed and documented using a Scheimpflug camera (OCULUS Pentacam HR) and anterior OCT (Avanti RTVue XR Optovue,). The patient was indicated for explantation and replacement of the opacified intraocular lens in the left and subsequently in the right eye- The same type of IOL was used for reimplantation with good functional results. Conclusion: Since 2010, multifocal lens implantation has been on an upward trend worldwide. This type of MF IOL has also been used in thousands of implantations. A number of other explantations can be expected in the coming years. The optimal solution is the correct replacement of the calcified IOL with the same construction made of safer hydrophobic material.

Identification of Hydrocarbon Sulfonates as Previously Overlooked Transthyretin Ligands in the Environment.

Incidences of thyroid disease, which has long been hypothesized to be partially caused by exposure to thyroid hormone disrupting chemicals (TDCs), have rapidly increased in recent years. However, known TDCs can only explain a small portion (∼1%) of in vitro human transthyretin (hTTR) binding activities in environmental samples, indicating the existence of unknown hTTR ligands. In this study, we aimed to identify the major environmental hTTR ligands by employing protein Affinity Purification with Nontargeted Analysis (APNA). hTTR binding activities were detected in all 11 indoor dust and 9 out of 10 sewage sludge samples by the FITC-T4 displacement assay. By using APNA, 31 putative hTTR ligands were detected including perfluorooctanesulfonate (PFOS). Two of the most abundant ligands were identified as hydrocarbon surfactants (e.g., dodecyl benzenesulfonate). Moreover, another abundant ligand was surprisingly identified as a disulfonate fluorescent brightener, 4,4'-bis(2-sulfostyryl)biphenyl sodium (CBS). CBS was validated as a nM-affinity hTTR ligand with an IC50 of 345 nM. In total, hydrocarbon surfactants and fluorescent brighteners explain 1.92-17.0 and 5.74-54.3% of hTTR binding activities in dust and sludge samples, respectively, whereas PFOS only contributed <0.0001%. Our study revealed for the first time that hydrocarbon sulfonates are previously overlooked hTTR ligands in the environment.

Radiolytic degradation of 1,2,4-trichlorobenzene (TCB) in some organic solvents by gamma rays: The kinetic properties of complete dechlorination of TCB and its pathway.

This study investigates the degradation of TCB in methanol, ethanol, hexane, and benzene solutions using gamma radiolysis. Kinetic properties of TCB dechlorination and its pathway are examined, with TCB selected as a representative chlorinated organic compound. Chromatograms of irradiated samples and mass spectra of liquid-phase products are presented. The change in concentration of TCB, dichlorobenzenes (DCB), chlorobenzene (MCB), and benzene with absorbed doses are observed. The radiation-chemical yield (G values) of TCB in the solvents are calculated as 1.83, 2.56, 1.93, and 1.84 100eV-1 in methanol, ethanol, hexane, and benzene solutions, respectively. 100 % degradation of TCB by gamma irradiation is found to be efficient in polar solvents but leads to a wide variety of byproducts in low polar solvents, particularly the formation of polychlorinated biphenyls in TCB + benzene solutions, making benzene an incompatible medium. The main dechlorination pathway of TCB involves the formation of 1,4-DCB, MCB, and benzene. Environmental Implication. The gamma irradiation of chlorinated organic compounds, focusing on TCB as a model compound, was investigated due to its status as a hazardous material for the environment and living organisms. TCB is a byproduct of the dechlorination of certain chlorinated pesticides listed under the Stockholm Convention's Persistent Organic Pollutants (POPs) list, which prohibits their production and use. Gamma irradiation was found to be an effective method for the degradation of chlorinated compounds, achieving 100 % degradation during irradiation. The study underscores the potential of gamma irradiation as a viable approach for the treatment of chlorinated compounds, particularly in addressing environmental and health concerns associated with TCB and related compounds.

On the fate of protonated chloroformates in the gas phase: a competition between forming HCl and chloroformic acid.

Chloroformates are prevalent in the atmosphere due to their utilization as fuel additives and industrial solvents. These species may undergo interactions with atmospheric water resulting in protonated chloroformates. This study delves into the gas-phase dissociation of these protonated species. Tandem mass spectrometry was employed to scrutinize the unimolecular dissociation of protonated methyl (1), ethyl (2), neopentyl (3), and phenyl chloroformate (4). Notably, 1 and 4 exhibited HCl loss, yielding CH3OCO+ and C6H5OCO+, respectively, with 1 additionally generating neutral methanol and ClCO+. 4 additionally loses CO and CO2. In contrast, 2 and 3 each only exhibit a single fragmentation channel, with 2 losing C2H4 to generate protonated chloroformic acid and 3 generating protonated 2-methylbutene by losing neutral chloroformic acid. Density functional theory at the B3LYP/6-311+G(d,p) level of theory was employed to explore minimum energy reaction pathways for each ion, and CBS-QB3 single-point energy calculations were added to provide reliable energetics. The Rice-Ramsperger-Kassel-Marcus (RRKM) calculations of the rate constants for selected competing processes were carried out to link theory and experiment. One common unimolecular process observed was the 1,3-H shift of the proton from the carbonyl oxygen to the ester oxygen before dissociation.

The Use of Ground Coal Bottom Ash/Slag as a Cement Replacement for Sustainable Concrete Infrastructure.

Cement production requires considerable energy and natural resources, severely impacting the environment due to harmful gas emissions. Coal bottom ash (CBA) and coal boiler slag (CBS), byproducts of coal-fired powerplants having pozzolanic properties, can be mechanically ground and replace cement in concrete, which reduces waste in landfills, preserves natural resources, and reduces health hazards. This study was performed to determine the optimum cement replacement amount of ground CBA (GCBA) and ground CBS (GCBS) in concrete, which was 10% for GCBA and 5% for GCBS. GCBA-based concrete exhibited superior tensile strength, modulus of elasticity, and durability compared to the control. In the Rapid Chloride Penetration Test, 10% GCBA concrete resulted in 2026 coulombs at 56 days, compared to 3405 coulombs for the control, indicating more resistance to chloride penetration. Incorporating 2.5% nanoclay in GCBA-based concrete increased the optimum GCBA content by 5%, and the compressive strength of 15% GCBA concrete increased by 4 MPa. The mortar consisting of the finest GCBA(L1) having Blaine fineness of 3072 g/cm2 yielded the highest compressive strength (32.7 MPa). The study discovered that the compressive strength of GCBA and GCBS-based mortars increases with fineness, and meeting the recommended fineness limit in ASTM C618 enhances concrete or mortar properties.

AMP-activated protein kinase can be allosterically activated by ADP but AMP remains the key activating ligand.

The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status. When activated by increases in ADP:ATP and/or AMP:ATP ratios (signalling energy deficit), AMPK acts to restore energy balance. Binding of AMP to one or more of three CBS repeats (CBS1, CBS3, CBS4) on the AMPK-γ subunit activates the kinase complex by three complementary mechanisms: (i) promoting α-subunit Thr172 phosphorylation by the upstream kinase LKB1; (ii) protecting against Thr172 dephosphorylation; (iii) allosteric activation. Surprisingly, binding of ADP has been reported to mimic the first two effects, but not the third. We now show that at physiologically relevant concentrations of Mg.ATP2- (above those used in the standard assay) ADP binding does cause allosteric activation. However, ADP causes only a modest activation because (unlike AMP), at concentrations just above those where activation becomes evident, ADP starts to cause competitive inhibition at the catalytic site. Our results cast doubt on the physiological relevance of the effects of ADP and suggest that AMP is the primary activator in vivo. We have also made mutations to hydrophobic residues involved in binding adenine nucleotides at each of the three γ subunit CBS repeats of the human α2ß2γ1 complex and examined their effects on regulation by AMP and ADP. Mutation of the CBS3 site has the largest effects on all three mechanisms of AMP activation, especially at lower ATP concentrations, while mutation of CBS4 reduces the sensitivity to AMP. All three sites appear to be required for allosteric activation by ADP.

Preventing hyperhomocysteinemia using vitamin B6 supplementation in Givosiran-treated acute intermittent porphyria: Highlights from a case report and brief literature review.

Acute hepatic porphyrias are inherited metabolic disorders of heme biosynthesis characterized by the accumulation of toxic intermediate metabolites responsible for disabling acute neurovisceral attacks. Givosiran is a newly approved siRNA-based treatment of acute hepatic porphyria targeting the first and rate-limiting δ-aminolevulinic acid synthase 1 (ALAS1) enzyme of heme biosynthetic pathway. We described a 72-year old patient who presented with severe inaugural neurological form of acute intermittent porphyria evolving for several years which made her eligible for givosiran administration. On initiation of treatment, the patient developed a major hyperhomocysteinemia (>400 µmol/L) which necessitated to discontinue the siRNA-based therapy. A thorough metabolic analysis in the patient suggests that hyperhomocysteinemia could be attributed to a functional deficiency of cystathionine ß-synthase (CBS) enzyme induced by givosiran. Long-term treatment with vitamin B6, a cofactor of CBS, allowed to normalize homocysteinemia while givosiran treatment was maintained. We review the recently published cases of hyperhomocysteinemia in acute hepatic porphyria and its exacerbation under givosiran therapy. We also discuss the benefits of vitamin B6 supplementation in the light of hypothetic pathophysiological mechanisms responsible for hyperhomocysteinemia in these patients. Our results confirmed the importance of monitoring homocysteine metabolism and vitamin status in patients with acute intermittent porphyria in order to improve management by appropriate vitamin supplementation during givosiran treatment.