Mitochondrial ATP generation is more proteome efficient than glycolysis.

Metabolic efficiency profoundly influences organismal fitness. Nonphotosynthetic organisms, from yeast to mammals, derive usable energy primarily through glycolysis and respiration. Although respiration is more energy efficient, some cells favor glycolysis even when oxygen is available (aerobic glycolysis, Warburg effect). A leading explanation is that glycolysis is more efficient in terms of ATP production per unit mass of protein (that is, faster). Through quantitative flux analysis and proteomics, we find, however, that mitochondrial respiration is actually more proteome efficient than aerobic glycolysis. This is shown across yeast strains, T cells, cancer cells, and tissues and tumors in vivo. Instead of aerobic glycolysis being valuable for fast ATP production, it correlates with high glycolytic protein expression, which promotes hypoxic growth. Aerobic glycolytic yeasts do not excel at aerobic growth but outgrow respiratory cells during oxygen limitation. We accordingly propose that aerobic glycolysis emerges from cells maintaining a proteome conducive to both aerobic and hypoxic growth.

Synergetic Dual-Additive Electrolyte Enables Highly Stable Performance in Sodium Metal Batteries.

Sodium (Na)-metal batteries (SMBs) are considered one of the most promising candidates for the large-scale energy storage market owing to their high theoretical capacity (1,166 mAh g-1) and the abundance of Na raw material. However, the limited stability of electrolytes still hindered the application of SMBs. Herein, sulfolane (Sul) and vinylene carbonate (VC) are identified as effective dual additives that can largely stabilize propylene carbonate (PC)-based electrolytes, prevent dendrite growth, and extend the cycle life of SMBs. The cycling stability of the Na/NaNi0.68Mn0.22Co0.1O2 (NaNMC) cell with this dual-additive electrolyte is remarkably enhanced, with a capacity retention of 94% and a Coulombic efficiency (CE) of 99.9% over 600 cycles at a 5 C (750 mA g-1) rate. The superior cycling performance of the cells can be attributed to the homogenous, dense, and thin hybrid solid electrolyte interphase consisting of F- and S-containing species on the surface of both the Na metal anode and the NaNMC cathode by adding dual additives. Such unique interphases can effectively facilitate Na-ion transport kinetics and avoid electrolyte depletion during repeated cycling at a very high rate of 5 C. This electrolyte design is believed to result in further improvements in the performance of SMBs.

Modifications of surgical techniques in laparoscopic percutaneous extraperitoneal closure of inguinal ring for childhood inguinal hernia to achieve zero recurrence and zero subcutaneous stitch granuloma.

PURPOSE: To present our technical modifications of single incision laparoscopic percutaneous extraperitoneal closure (SILPEC) of the internal inguinal ring (IIR) for pediatric inguinal hernia (PIH). METHODS: The prospectively collected data of all children diagnosed with PIH undergoing SILPEC at our center from 2016 to 2023 were reviewed and divided into two groups for result comparison: Group A: before and Group B: after the implementation of full modifications. Our modifications included using a nonabsorbable monofilament suture, creating a peritoneal thermal injury at the internal inguinal ring (IIR), employing a cannula to ensure the suture at the IIR ligates only the peritoneum, and double ligation of the IIR in selected cases. RESULTS: 1755 patients in group A and in group B (1 month to 14 years old) were enrolled. There were no significant differences regarding baseline patient characteristics between the two groups. At a median follow-up of 40 months, the rate of recurrent CIH and subcutaneous stitch granuloma (SSG) was 2.3% and 1.5% in group A vs. 0% and 0% in group B (p < 0.001). There were no hydroceles, no ascended or atrophic testis. CONCLUSIONS: Our SILPEC technical modifications can achieve zero recurrence and zero SSG for PIH.

Dedicated farnesyl diphosphate synthases circumvent isoprenoid-derived growth-defense tradeoffs in Zea mays.

Zea mays (maize) makes phytoalexins such as sesquiterpenoid zealexins, to combat invading pathogens. Zealexins are produced from farnesyl diphosphate in microgram per gram fresh weight quantities. As farnesyl diphosphate is also a precursor for many compounds essential for plant growth, the question arises as to how Z. mays produces high levels of zealexins without negatively affecting vital plant systems. To examine if specific pools of farnesyl diphosphate are made for zealexin synthesis we made CRISPR/Cas9 knockouts of each of the three farnesyl diphosphate synthases (FPS) in Z. mays and examined the resultant impacts on different farnesyl diphosphate-derived metabolites. We found that FPS3 (GRMZM2G098569) produced most of the farnesyl diphosphate for zealexins, while FPS1 (GRMZM2G168681) made most of the farnesyl diphosphate for the vital respiratory co-factor ubiquinone. Indeed, fps1 mutants had strong developmental phenotypes such as reduced stature and development of chlorosis. The replication and evolution of the fps gene family in Z. mays enabled it to produce dedicated FPSs for developmentally related ubiquinone production (FPS1) or defense-related zealexin production (FPS3). This partitioning of farnesyl diphosphate production between growth and defense could contribute to the ability of Z. mays to produce high levels of phytoalexins without negatively impacting its growth.

Evaluating proteome allocation of Saccharomyces cerevisiae phenotypes with resource balance analysis.

Saccharomyces cerevisiae is an important model organism and a workhorse in bioproduction. Here, we reconstructed a compact and tractable genome-scale resource balance analysis (RBA) model (i.e., named scRBA) to analyze metabolic fluxes and proteome allocation in a computationally efficient manner. Resource capacity models such as scRBA provide the quantitative means to identify bottlenecks in biosynthetic pathways due to enzyme, compartment size, and/or ribosome availability limitations. ATP maintenance rate and in vivo apparent turnover numbers (kapp) were regressed from metabolic flux and protein concentration data to capture observed physiological growth yield and proteome efficiency and allocation, respectively. Estimated parameter values were found to vary with oxygen and nutrient availability. Overall, this work (i) provides condition-specific model parameters to recapitulate phenotypes corresponding to different extracellular environments, (ii) alludes to the enhancing effect of substrate channeling and post-translational activation on in vivo enzyme efficiency in glycolysis and electron transport chain, and (iii) reveals that the Crabtree effect is underpinned by specific limitations in mitochondrial proteome capacity and secondarily ribosome availability rather than overall proteome capacity.

Comparative study of two Saccharomyces cerevisiae strains with kinetic models at genome-scale.

The parameterization of kinetic models requires measurement of fluxes and/or metabolite levels for a base strain and a few genetic perturbations thereof. Unlike stoichiometric models that are mostly invariant to the specific strain, it remains unclear whether kinetic models constructed for different strains of the same species have similar or significantly different kinetic parameters. This important question underpins the applicability range and prediction limits of kinetic reconstructions. To this end, herein we parameterize two separate large-scale kinetic models using K-FIT with genome-wide coverage corresponding to two distinct strains of Saccharomyces cerevisiae: CEN.PK 113-7D strain (model k-sacce306-CENPK), and growth-deficient BY4741 (isogenic to S288c; model k-sacce306-BY4741). The metabolic network for each model contains 306 reactions, 230 metabolites, and 119 substrate-level regulatory interactions. The two models (for CEN.PK and BY4741) recapitulate, within one standard deviation, 77% and 75% of the fitted dataset fluxes, respectively, determined by 13C metabolic flux analysis for wild-type and eight single-gene knockout mutants of each strain. Strain-specific kinetic parameterization results indicate that key enzymes in the TCA cycle, glycolysis, and arginine and proline metabolism drive the metabolic differences between these two strains of S. cerevisiae. Our results suggest that although kinetic models cannot be readily used across strains as stoichiometric models, they can capture species-specific information through the kinetic parameterization process.

Synthesis and biological evaluation of tert-butyl ester and ethyl ester prodrugs of L-γ-methyleneglutamic acid amides for cancer.

In cancer cells, glutaminolysis is the primary source of biosynthetic precursors. Recent efforts to develop amino acid analogues to inhibit glutamine metabolism in cancer have been extensive. Our lab recently discovered many L-γ-methyleneglutamic acid amides that were shown to be as efficacious as tamoxifen or olaparib in inhibiting the cell growth of MCF-7, SK-BR-3, and MDA-MB-231 breast cancer cells after 24 or 72 h of treatment. None of these compounds inhibited the cell growth of nonmalignant MCF-10A breast cells. These L-γ-methyleneglutamic acid amides hold promise as novel therapeutics for the treatment of multiple subtypes of breast cancer. Herein, we report our synthesis and evaluation of two series of tert-butyl ester and ethyl ester prodrugs of these L-γ-methyleneglutamic acid amides and the cyclic metabolite and its tert-butyl esters and ethyl esters on the three breast cancer cell lines MCF-7, SK-BR-3, and MDA-MB-231 and the nonmalignant MCF-10A breast cell line. These esters were found to suppress the growth of the breast cancer cells, but they were less potent compared to the L-γ-methyleneglutamic acid amides. Pharmacokinetic (PK) studies were carried out on the lead L-γ-methyleneglutamic acid amide to establish tissue-specific distribution and other PK parameters. Notably, this lead compound showed moderate exposure to the brain with a half-life of 0.74 h and good tissue distribution, such as in the kidney and liver. Therefore, the L-γ-methyleneglutamic acid amides were then tested on glioblastoma cell lines BNC3 and BNC6 and head and neck cancer cell lines HN30 and HN31. They were found to effectively suppress the growth of these cancer cell lines after 24 or 72 h of treatment in a concentration-dependent manner. These results suggest broad applications of the L-γ-methyleneglutamic acid amides in anticancer therapy.

Isolation of Two Plasticizers, Bis(2-ethylhexyl) Terephthalate and Bis(2-ethylhexyl) Phthalate, from Capparis spinosa L. Leaves.

Many plants have been known to be contaminated and accumulate plasticizers from the environment, including water sources, soil, and atmosphere. Plasticizers are used to confer elasticity and flexibility to various fiber and plastic products. Consumption of plasticizers can lead to many adverse effects on human health, including reproductive and developmental toxicity, endocrine disruption, and cancer. Herein, we report for the first time that two plasticizers, bis(2-ethylhexyl) terephthalate (DEHT) and bis(2-ethylhexyl) phthalate (DEHP), have been isolated from the leaves of Capparis spinosa L. (the caper bush), a plant that is widely used in food seasonings and traditional medicine. 297 mg/kg of DEHT and 48 mg/kg of DEHP were isolated from dried and grounded C. spinosa L. leaves using column chromatography and semi-preparative high-performance liquid chromatography. Our study adds to the increase in the detection of plasticizers in our food and medicinal plants and to the alarming concern about their potential adverse effects on human health.

Laparoscopic percutaneous closure of patent processus vaginalis without hydrocelectomy for childhood primary hydrocele.

PURPOSE: To present our surgical technique and the outcome of single-incision laparoscopic percutaneous extraperitoneal closure (SILPEC) of patent processus vaginalis (PPV) without hydrocelectomy for childhood primary hydrocele (CPH). METHODS: A prospective study was conducted on all cases of CPH treated with SILPEC at our center between June 2016 and December 2021. In our SILPEC procedure, PPV was closed extraperitoneally using a percutaneous needle with a wire lasso. No hydrocelectomy or fenestration of the hydrocele was performed. Percutaneous aspiration was performed when the hydrocele fluid could not be pushed back to the peritoneal cavity. RESULTS: 553 patients were enrolled, with a median age of 34 months (range from 22 months to 13 years). Ipsilateral PPV was present in all cases. There were no intraoperative complications and no conversion. At follow-up 6-72 months, recurrent hydrocele occurred in 0.36%, and subcutaneous stitch inflammatory reaction was noted in 0.7%. There was no case of testicular atrophy or iatrogenic cryptorchidism. Postoperative cosmesis was excellent as all patients were virtually scarless. CONCLUSIONS: Ipsilateral PPV was present in all cases of CPH in our series. Our technique of SILPEC of PPV without hydrocelectomy is feasible and safe, with excellent postoperative cosmesis in the management of CPH.

Reduction of recurrence by peritoneal thermal injury in laparoscopic percutaneous extraperitoneal closure of internal ring for inguinal hernia in children.

PURPOSE: To evaluate the impact of peritoneal thermal injury (PTI) in the reduction of recurrence incidence in laparoscopic percutaneous extra-peritoneal closure of internal ring (LPEC) for pediatric inguinal hernia (PIH) in children. METHODS: Medical records of patients undergoing LPEC for PIH at our center were reviewed and divided into 2 groups: Group A (period from June 2017 to December 2017)-without PTI and Group B (period from January 2018 to December 2018) with PTI. The surgical technique and the type of suture used for LPEC were the same for both groups. The outcomes of the two groups were analyzed and compared. RESULTS: 277 patients with 283 IHs in group A were compared to 376 patients with 389 IHs in group B. There were no significant differences between the two groups in terms of age, gender, uni- or bilateral hernia. At a median follow-up period of 48 months, there was no hydrocele, suture granuloma, testicular atrophy, or iatrogenic cryptorchidism in both groups. The recurrence rate in group A was 6.4%, significantly higher than 1.8% in group B (p = 0.002). CONCLUSIONS: Our study showed that PTI in LPEC for PIH is safe and associated with a significant reduction of recurrence incidence.

Quantifying the propagation of parametric uncertainty on flux balance analysis.

Flux balance analysis (FBA) and associated techniques operating on stoichiometric genome-scale metabolic models play a central role in quantifying metabolic flows and constraining feasible phenotypes. At the heart of these methods lie two important assumptions: (i) the biomass precursors and energy requirements neither change in response to growth conditions nor environmental/genetic perturbations, and (ii) metabolite production and consumption rates are equal at all times (i.e., steady-state). Despite the stringency of these two assumptions, FBA has been shown to be surprisingly robust at predicting cellular phenotypes. In this paper, we formally assess the impact of these two assumptions on FBA results by quantifying how uncertainty in biomass reaction coefficients, and departures from steady-state due to temporal fluctuations could propagate to FBA results. In the first case, conditional sampling of parameter space is required to re-weigh the biomass reaction so as the molecular weight remains equal to 1 g mmol-1, and in the second case, metabolite (and elemental) pool conservation must be imposed under temporally varying conditions. Results confirm the importance of enforcing the aforementioned constraints and explain the robustness of FBA biomass yield predictions.

Phytochemistry, Biological Activities, Therapeutic Potential, and Socio-Economic Value of the Caper Bush (Capparis Spinosa L.).

Capparis spinosa L., commonly known as the caper bush, is an aromatic plant growing in most of the Mediterranean basin and some parts of Western Asia. C. spinosa L. has been utilized as a medicinal plant for quite a long time in conventional phytomedicine. Polyphenols and numerous bioactive chemicals extracted from C. spinosa L. display various therapeutic properties that have made this plant a target for further research as a health promoter. This review is meant to systematically summarize the traditional uses, the phytochemical composition of C. spinosa L., and the diverse pharmacological activities, as well as the synthetic routes to derivatives of some identified chemical components for the improvement of biological activities and enhancement of pharmacokinetic profiles. This review also addresses the benefits of C. spinosa L. in adapting to climate change and the socio-economic value that C. spinosa L. brings to the rural economies of many countries.

Synthesis of 3,4,5-trisubstituted isoxazoles in water via a [3 + 2]-cycloaddition of nitrile oxides and 1,3-diketones, ß-ketoesters, or ß-ketoamides.

Herein we report a method for the synthesis of 3,4,5-trisubstituted isoxazoles in water under mild basic conditions at room temperature via a [3 + 2]-cycloaddition of nitrile oxides and 1,3-diketones, ß-ketoesters, or ß-ketoamides. We optimized the reaction conditions to control the selectivity of the production of isoxazoles and circumvent other competing reactions, such as O-imidoylation or hetero [3 + 2]-cycloaddition. The reaction happens fast in water and completes within 1-2 hours, which provides an environmentally friendly access to 3,4,5-trisubstituted isoxazoles, an important class of structures found in numerous bioactive natural products and pharmaceuticals. Additionally, we optimized the reaction conditions to produce trifluoromethyl-substituted isoxazoles, a prevalent scaffold in biomedical research and drug discovery programs. We also proposed a plausible mechanism for the selectivity of the [3 + 2]-cycloaddition reaction to produce 3,4,5-trisubstituted isoxazoles. Not to be overlooked are our optimized reaction conditions for the dimerization of hydroximoyl chlorides to form furoxans also known as 1,2,5-oxadiazole 2-oxides, a class of structures with important biological activities due to their unique electronic nature and coordination ability.

The Pup-Proteasome System Protects Mycobacteria from Antimicrobial Antifolates.

Protein turnover via the Pup-proteasome system (PPS) is essential for nitric oxide resistance and virulence of Mycobacterium tuberculosis, the causative agent of tuberculosis. Our study revealed components of PPS as novel determinants of intrinsic antifolate resistance in both M. tuberculosis and nonpathogenic M. smegmatis The lack of expression of the prokaryotic ubiquitin-like protein (Pup) or the ligase, PafA, responsible for ligating Pup to its protein targets, enhanced antifolate susceptibility in M. smegmatis Cross-species expression of M. tuberculosis homologs restored wild-type resistance to M. smegmatis proteasomal mutants. Targeted deletion of prcA and prcB, encoding the structural components of the PPS proteolytic core, similarly resulted in reduced antifolate resistance. Furthermore, sulfonamides were synergistic with acidified nitrite, and the synergy against mycobacteria was enhanced in the absence of proteasomal activity. In M. tuberculosis, targeted mutagenesis followed by genetic complementation of mpa, encoding the regulatory subunit responsible for translocating pupylated proteins to the proteolytic core, demonstrated a similar function of PPS in antifolate resistance. The overexpression of dihydrofolate reductase, responsible for the reduction of dihydrofolate to tetrahydrofolate, or disruption of the Lonely Guy gene, responsible for PPS-controlled production of cytokinins, abolished PPS-mediated antifolate sensitivity. Together, our results show that PPS protects mycobacteria from antimicrobial antifolates via regulating both folate reduction and cytokinin production.

A maize leucine-rich repeat receptor-like protein kinase mediates responses to fungal attack.

MAIN CONCLUSION: A maize receptor kinase controls defense response to fungal pathogens by regulating jasmonic acid and antimicrobial phytoalexin production. Plants use a range of pattern recognition receptors to detect and respond to biotic threats. Some of these receptors contain leucine-rich repeat (LRR) domains that recognize microbial proteins or peptides. Maize (Zea mays) has 226 LRR-receptor like kinases, making it challenging to identify those important for pathogen recognition. In this study, co-expression analysis with genes for jasmonic acid and phytoalexin biosynthesis was used to identify a fungal induced-receptor like protein kinase (FI-RLPK) likely involved in the response to fungal pathogens. Loss-of-function mutants in fi-rlpk displayed enhanced susceptibility to the necrotrophic fungal pathogen Cochliobolus heterostrophus and reduced accumulation of jasmonic acid and the anti-microbial phytoalexins -kauralexins and zealexins- in infected tissues. In contrast, fi-rlpk mutants displayed increased resistance to stem inoculation with the hemibiotrophic fungal pathogen Fusarium graminearum. These data indicate that FI-RLPK is important for fungal recognition and activation of defenses, and that F. graminearum may be able to exploit FI-RLPK function to increase its virulence.

Prevalence and genotype distribution of JC polyomavirus in urine from patients with hematological malignancies in Vietnam.

JC virus (JCV) causes progressive multifocal leukoencephalopathy in immunocompromised patients. The prevalence and genotype patterns of JCV vary between different geographical regions. This study was done to investigate the prevalence and genotype distribution of JCV in patients with hematological malignancies in Vietnam. A total of 48 urine samples were collected from patients with hematological malignancies. DNA was extracted and detection of JCV was by nested-polymerase chain reaction. Sequence analysis was obtained and a phylogenetic tree was constructed for genotyping of JCV. Twenty-seven (56.25%) urine samples tested positive for JCV. JCV genotype 7 was only observed in this study. Subtype analysis showed that JCV subtype 7A was the most commonly prevalent, followed by 7B1 and 7C1. Other subtypes were not detected in this population. There were no significant differences associated with age, gender, and biochemical parameters between patients with JCV and without JCV excretion in urine. The present study showed a high prevalence of JCV in the urine of patients with hematologic malignancies. The most common genotype found in this population was JCV subtype 7A.

Identification of Human Kinin-Forming Enzyme Inhibitors from Medicinal Herbs.

The goal of this study was to assess the pharmacological effects of black tea (Camellia sinensis var. assamica) water extract on human kinin-forming enzymes in vitro. Tea is a highly consumed beverage in the world. Factor XII (FXII, Hageman factor)-independent- and -dependent activation of prekallikrein to kallikrein leads to the liberation of bradykinin (BK) from high-molecular-weight kininogen (HK). The excessive BK production causes vascular endothelial and nonvascular smooth muscle cell permeability, leading to angioedema. The prevalence of angiotensin-converting enzyme inhibitor (ACEI)-induced angioedema appears to be through BK. Both histamine and BK are potent inflammatory mediators. However, the treatments for histamine-mediated angioedema are unsuitable for BK-mediated angioedema. We hypothesized that long-term consumption of tea would reduce bradykinin-dependent processes within the systemic and pulmonary vasculature, independent of the anti-inflammatory actions of polyphenols. A purified fraction of the black tea water extract inhibited both kallikrein and activated FXII. The black tea water extracts inhibited factor XII-induced cell migration and inhibited the production of kallikrein on the endothelial cell line. We compared the inhibitory effects of the black tea water extract and twenty-three well-known anti-inflammatory medicinal herbs, in inhibiting both kallikrein and FXII. Surprisingly, arjunglucoside II specifically inhibited the activated factor XII (FXIIa), but not the kallikrein and the activated factor XI. Taken together, the black tea water extract exerts its anti-inflammatory effects, in part, by inhibiting kallikrein and activated FXII, which are part of the plasma kallikrein-kinin system (KKS), and by decreasing BK production. The inhibition of kallikrein and activated FXII represents a unique polyphenol-independent anti-inflammatory mechanism of action for the black tea.

Pectoralis muscle area is associated with bone mineral density and lung function in lung transplant candidates.

Loss of bone mineral density and skeletal muscle area are linked in lung transplant patients. This loss is greater in patients with restrictive compared with obstructive lung diseases. INTRODUCTION: Sarcopenia and osteoporosis are associated with aging and chronic illnesses and may be linked in patients with advanced lung disease. Pectoralis muscle index (PMI) quantitated on computed tomography (CT) of the chest can be used to measure skeletal muscle mass. This study aimed to determine the relationship of PMI to clinical parameters including bone mineral density (BMD) in candidates for lung transplantation. METHODS: A retrospective review of transplant candidates at a single center was performed. Demographic, anthropomorphic, and clinical data were recorded. Pectoralis muscle area (PMA) was determined on an axial slice from a chest CT. PMI was calculated as the PMA divided by height squared. BMD was obtained from routine dual-energy X-ray absorptiometry (DXA) scan. RESULTS: In 226 included patients, mean PMI was 8.2 ± 3.0 cm2/m2 in males and 6.1 ± 2.1 cm2/m2 in females. Osteopenia was present in 44.4%, and 23.2% of patients had osteoporosis. Patients with obstructive lung disease had lower body mass index (22.0 ± 4.9 versus 27.9 ± 4.9 kg/m2, p < 0.001), PMI (6.0 ± 2.3 versus 8.2 ± 2.8 cm2/m2, p < 0.001), and BMD (- 2.3 ± 1.1 versus - 1.3 ± 1.1, p < 0.001) compared with patients with restrictive lung disease. PMI was a significant predictor of BMD (ß = 0.16, p < 0.001). CONCLUSION: The association between muscle area and BMD in lung transplant candidates suggests that similar mechanisms may underlie the development of both. Differences in PMI and BMD in patients with obstructive versus restrictive lung disease may result from differences in respiratory physiology or disease processes.

PLP and GABA trigger GabR-mediated transcription regulation in Bacillus subtilis via external aldimine formation.

The Bacillus subtilis protein regulator of the gabTD operon and its own gene (GabR) is a transcriptional activator that regulates transcription of γ-aminobutyric acid aminotransferase (GABA-AT; GabT) upon interactions with pyridoxal-5'-phosphate (PLP) and GABA, and thereby promotes the biosynthesis of glutamate from GABA. We show here that the external aldimine formed between PLP and GABA is apparently responsible for triggering the GabR-mediated transcription activation. Details of the "active site" in the structure of the GabR effector-binding/oligomerization (Eb/O) domain suggest that binding a monocarboxylic γ-amino acid such as GABA should be preferred over dicarboxylic acid ligands. A reactive GABA analog, (S)-4-amino-5-fluoropentanoic acid (AFPA), was used as a molecular probe to examine the reactivity of PLP in both GabR and a homologous aspartate aminotransferase (Asp-AT) from Escherichia coli as a control. A comparison between the structures of the Eb/O-PLP-AFPA complex and Asp-AT-PLP-AFPA complex revealed that GabR is incapable of facilitating further steps of the transamination reaction after the formation of the external aldimine. Results of in vitro and in vivo assays using full-length GabR support the conclusion that AFPA is an agonistic ligand capable of triggering GabR-mediated transcription activation via formation of an external aldimine with PLP.

Twenty-five year trends (1986-2011) in hospital incidence and case-fatality rates of ventricular tachycardia and ventricular fibrillation complicating acute myocardial infarction.

BACKGROUND: Long-term trends in the incidence rates (IRs) and hospital case-fatality rates (CFRs) of ventricular tachycardia (VT) and ventricular fibrillation (VF) among patients hospitalized with acute myocardial infarction (AMI) have not been recently examined. METHODS: We used data from 11,825 patients hospitalized with AMI at all 11 medical centers in central Massachusetts on a biennial basis between 1986 and 2011. Multivariable adjusted logistic regression modeling was used to examine trends in hospital IRs and CFRs of VT and VF complicating AMI. RESULTS: The median age of the study population was 71 years, 57.9% were men, and 94.7% were white. The hospital IRs declined from 14.3% in 1986/1988 to 10.5% in 2009/2011 for VT and from 8.2% to 1.7% for VF. The in-hospital CFRs declined from 27.7% to 6.9% for VT and from 49.6% to 36.0% for VF between 1986/1988 and 2009/2011, respectively. The IRs of both early (<48 hours) and late VT and VF declined over time, with greater declines in those of late VT and VF. The incidence rates of VT declined similarly for patients with either an ST-segment elevation myocardial infarction (STEMI) or non-STEMI, whereas they only declined in those with VF and a STEMI. CONCLUSIONS: The hospital IRs and CHRs of VT and VF complicating AMI have declined over time, likely because of changes in acute monitoring and treatment practices. Despite these encouraging trends, efforts remain needed to identify patients at risk for these serious ventricular arrhythmias so that preventive and treatment strategies might be implemented as necessary.