The pleiotropic phenotype of FlbA of Aspergillus niger is explained in part by the activity of seven of its downstream-regulated transcription factors.

Inactivation of flbA in Aspergillus niger results in thinner cell walls, increased cell lysis, abolished sporulation, and an increased secretome complexity. A total of 36 transcription factor (TF) genes are differentially expressed in ΔflbA. Here, seven of these genes (abaA, aslA, aslB, azf1, htfA, nosA, and srbA) were inactivated. Inactivation of each of these genes affected sporulation and, with the exception of abaA, cell wall integrity and protein secretion. The impact on secretion was strongest in the case of ΔaslA and ΔaslB that showed increased pepsin, cellulase, and amylase activity. Biomass was reduced of agar cultures of ΔabaA, ΔaslA, ΔnosA, and ΔsrbA, while biomass was higher in liquid shaken cultures of ΔaslA and ΔaslB. The ΔaslA and ΔhtfA strains showed increased resistance to H2O2, while ΔaslB was more sensitive to this reactive oxygen species. Together, inactivation of the seven TF genes impacted biomass formation, sporulation, protein secretion, and stress resistance, and thereby these genes explain at least part of the pleiotropic phenotype of ΔflbA of A. niger.

Heart Failure and Echocardiography Derived Myocardial Wall Stress Link in Diabetic Cases with Acute Myocardial Infarction Managed by Revascularization.

Background: Diabetes is associated with left ventricular remodeling. Myocardial wall stress is a measurable factor connected to the ventricular breadth and force and is related to myocardial thickness; it can be measured by echocardiography. The present study aimed to assess the link between heart failure (HF) and echocardiography-derived myocardial wall stress in diabetic patients with ST elevation myocardial infarction (STEMI) who were managed with revascularization. Methods: This study was a comparative prospective study that took place between February 2022 and February 2023. It included 100 diabetic patients presented with STEMI and managed by percutaneous coronary intervention (PCI). Patients were selected from the cardiology departments at Al-Azhar University Hospital, Damietta, Egypt. During the hospital stay, patients were checked for HF symptoms and signs. They were also observed for 3 months after discharge for detection of HF. Those who did not develop HF were assigned to group I, and those with HF were assigned to group II. Results: The mean value of end-systolic wall stress (ESWS) was 77.09 ± 12.22 and 97 ± 13.44, and the mean value of end-diastolic wall stress (EDWS) was 12.61 ± 2.76 and 15.87 ± 2.86 in groups I and II respectively, with significant differences between the 2 groups. The cutoff point to detect HF was 88 KPa for ESWS and 13.5 KPa for EDWS, with a sensitivity of 70% and 79% and a specificity of 80% and 61% for ESWS and EDWS, respectively. Conclusion: Elevated left ventricle (LV) myocardial stress is related to increased HF in diabetic patients whose HF was managed by PCI after STEMI. LV wall stress is a potentially helpful risk stratification tool using routine echocardiography to determine the treatment plane according to the risk status.

Disrupting Central Carbon Metabolism Increases ß-Lactam Antibiotic Susceptibility in Vibrio cholerae.

Antibiotic tolerance, the ability of bacteria to sustain viability in the presence of typically bactericidal antibiotics for extended time periods, is an understudied contributor to treatment failure. The Gram-negative pathogen Vibrio cholerae, the causative agent of cholera, becomes highly tolerant to ß-lactam antibiotics (penicillin and related compounds) in a process requiring the two-component system VxrAB. VxrAB is induced by exposure to cell wall damaging conditions, which results in the differential regulation of >100 genes. While the effectors of VxrAB are relatively well known, VxrAB environment-sensing and activation mechanisms remain a mystery. Here, we used transposon mutagenesis to screen for mutants that spontaneously upregulate VxrAB signaling. This screen was answered by genes known to be required for proper cell envelope homeostasis, validating the approach. Unexpectedly, we also uncovered a new connection between central carbon metabolism and antibiotic tolerance in Vibrio cholerae. Inactivation of pgi (vc0374, coding for glucose-6-phosphate isomerase) resulted in an intracellular accumulation of glucose-6-phosphate and fructose-6-phosphate, concomitant with a marked cell envelope defect, resulting in VxrAB induction. Deletion of pgi also increased sensitivity to ß-lactams and conferred a growth defect on salt-free LB, phenotypes that could be suppressed by deleting sugar uptake systems and by supplementing cell wall precursors in the growth medium. Our data suggest an important connection between central metabolism and cell envelope integrity and highlight a potential new target for developing novel antimicrobial agents. IMPORTANCE Antibiotic tolerance (the ability to survive exposure to antibiotics) is a stepping stone toward antibiotic resistance (the ability to grow in the presence of antibiotics), an increasingly common cause of antibiotic treatment failure. The mechanisms promoting tolerance are poorly understood. Here, we identified central carbon metabolism as a key contributor to antibiotic tolerance and resistance. A strain with a mutation in a sugar utilization pathway accumulates metabolites that likely shut down the synthesis of cell wall precursors, which weakens the cell wall and thus increases susceptibility to cell wall-active drugs. Our results illuminate the connection between central carbon metabolism and cell wall homeostasis in V. cholerae and suggest that interfering with metabolism may be a fruitful future strategy for the development of antibiotic adjuvants.

Crosstalk between the calcineurin and cell wall integrity pathways prevents chitin overexpression in Candida albicans.

Echinocandins such as caspofungin are frontline antifungal drugs that compromise ß-1,3 glucan synthesis in the cell wall. Recent reports have shown that fungal cells can resist killing by caspofungin by upregulation of chitin synthesis, thereby sustaining cell wall integrity (CWI). When echinocandins are removed, the chitin content of cells quickly returns to basal levels, suggesting that there is a fitness cost associated with having elevated levels of chitin in the cell wall. We show here that simultaneous activation of the calcineurin and CWI pathways generates a subpopulation of Candida albicans yeast cells that have supra-normal chitin levels interspersed throughout the inner and outer cell wall, and that these cells are non-viable, perhaps due to loss of wall elasticity required for cell expansion and growth. Mutations in the Ca2+-calcineurin pathway prevented the formation of these non-viable supra-high chitin cells by negatively regulating chitin synthesis driven by the CWI pathway. The Ca2+-calcineurin pathway may therefore act as an attenuator that prevents the overproduction of chitin by coordinating both chitin upregulation and negative regulation of the CWI signaling pathway. This article has an associated First Person interview with the first author of the paper.

VdERG2 was involved in ergosterol biosynthesis, nutritional differentiation and virulence of Verticillium dahliae.

The ergosterol biosynthesis pathway plays an important role in model pathogenic bacteria Saccharomyces cerevisiae, but little is known about the biosynthesis of ergosterol in the pathogenic fungus Verticillium dahliae. In this study, we identified the VdERG2 gene encoding sterol C-8 isomerase from V. dahliae and investigated its function in virulence by generating gene deletion mutants (ΔVdERG2) and complemented mutants (C-ΔVdERG2). Knockout of VdERG2 reduced ergosterol content. The conidial germination rate and conidial yield of ΔVdERG2 significantly decreased and abnormal conidia were produced. In spite of VdERG2 did not affect the utilization of carbon sources by V. dahliae, but the melanin production of ΔVdERG2 was decreased in cellulose and pectin were used as the sole carbon sources. Furthermore, the ΔVdERG2 mutants produced less microsclerotia and melanin with a significant decrease in the expression of microsclerotia and melanin-related genes VaflM, Vayg1, VDH1, VdLAC, VdSCD and VT4HR. In addition, mutants ΔVdERG2 were very sensitive to congo red (CR), sodium dodecyl sulfate (SDS) and hydrogen peroxide (H2O2) stresses, indicating that VdERG2 was involved in the cell wall and oxidative stress response. The absence of VdERG2 weakened the penetration ability of mycelium on cellophane and affected the growth of mycelium. Although ΔVdERG2 could infect cotton, its pathogenicity was significantly impaired. These phenotypic defects in ΔVdERG2 could be complemented by the reintroduction of a full-length VdERG2 gene. In summary, as a single conservative secretory protein, VdERG2 played a crucial role in ergosterol biosynthesis, nutritional differentiation and virulence in V. dahliae.

Effects of switching from sacubitril/valsartan to valsartan alone on plasma levels of natriuretic peptides and myocardial remodeling in heart failure with reduced ejection fraction.

BACKGROUND: We examined the effect of switching from angiotensin receptor-neprilysin inhibitor (ARNI) to angiotensin-receptor blocker (ARB) on plasma levels of natriuretic peptides and myocardial remodeling. METHODS: This is a prospective study that included 11 patients with heart failure (HF) treated with ARNI. The patients were divided into two groups: 5 patients who continued treatment with sacubitril/valsartan 194/206 mg/day (ARNI-continue group) and 6 patients who were switched to valsartan 160 mg/day (ARB-switch group). The primary endpoint was percent change (%Change) in plasma A-, B-, and N-terminal pro-B-type natriuretic peptide (ANP, BNP, and NT-proBNP) levels from the baseline to week 24. The secondary endpoint was the change in echocardiographic parameters related to myocardial remodeling from the baseline to week 24. RESULTS: ANP levels in the ARB-switch group significantly decreased (from 1155.7 ± 592.6 pg/mL to 231.6 ± 233.8 pg/mL, p = 0.035), whereas those in the ARNI-continue group were not significant (p = 0.180). The %Change of decrease in ANP levels was significantly greater in the ARB-switch group than the ARNI-continue group (- 76.9% vs. -9.1%, p = 0.009). BNP levels were not significantly different between the baseline and week 24 in both groups. NT-proBNP levels in the ARB-switch group increased from 1185.3 ± 835.6 pg/mL to 1515.2 ± 1213.5 pg/mL, although the changes were not statistically significant (p = 0.345). The %Change of increase in NT-proBNP levels was significantly greater in the ARB-switch group than the ARNI-continue group (57.9% vs. 17.3%, p = 0.016). In the ARB-switch group, there was a significant increase in left ventricular (LV) end-systolic volume (from 41.3 ± 24.1 mL/m2 to 71.4 ± 8.8 mL/m2, p = 0.043) and LV peak-systolic wall stress (from 187.0 ± 42.7 × 103 dynes/cm2 to 279.7 ± 34.1 × 103 dynes/cm2, p = 0.012) from the baseline to week 24 and a trend toward a decrease in LV ejection fraction (p = 0.080). In the ARNI-continue group, no differences in echocardiographic parameters were observed from the baseline to week 24. CONCLUSION: Switching from ARNI to ARB may worsen HF due to returning to myocardial remodeling induced by a sustained decline in ANP levels.

Estimation of the segmental left ventricular physical and mechanical parameters using echocardiographic imaging for stent candidate patients.

PURPOSE: Left ventricular (LV) dysfunction can be assessed by quantifying LV structure. In this study, physical parameters were extracted, including the systolic strain, wall stress, and elastic modulus of LV to diagnose stent candidate patients from the control group. METHODS: Based on angiography results, 88 patients with coronary artery disease (CAD) were divided into 64 patients candidates for PCI (percutaneous coronary intervention) and 24 patients in the control group. With the thick-walled ellipsoidal model, the passive wall stresses at end-systole and end-diastole were estimated. Regional circumferential strain and regional longitudinal strain were obtained by speckle tracking technique. RESULTS: The inferoseptal circumferential wall stress in end-systole was statistically significant for the PCI group compared to the control group (p = .026). Anterior and inferoseptal circumferential strain for the PCI group (-17.25 ± 4.22 and -18.21 ± 4.04%) compared to the control group (-21.71 ± 4.74 and 20.58 ± 3.04%) were statistically significant, respectively (p = .000 and p = .011). Anterior and inferoseptal circumferential elastic modulus were statistically significant (p = .000 and p = .005). The receiver operator characteristic (ROC) curve analysis revealed that anterior and inferoseptal circumferential elastic modulus had the highest area under the curve with 76.6% sensitivity, 83.3% specificity for anterior circumferential, 68.8% sensitivity, and 70.8% specificity for inferoseptal circumferential, for the diagnosis of stent candidate patients. CONCLUSIONS: Regional elastic modulus parameter is suggested as a noninvasive and quantitative method for measuring LV function. Strain and stress parameters using the STE method and geometrical model can be helpful for diagnostic stent candidate patients.

Sex Differences in Left Ventricular Wall Stress in Apparently Healthy Adults with Similar Cuff-Measured Blood Pressure.

Outcome-based evidence shows that women have a higher risk of heart failure than men at a similar level of blood pressure. Left ventricular wall stress (Ó) or afterload is an important determinant of myocardial performance. Thus, it might play a key role in determining the sex differences in heart failure.The Ó at the beginning of aortic valve opening (Ó-AVO), the systolic peak value of the Ó (Ó-peak), and the Ó at the end systole (Ó-ES) were determined using transthoracic echocardiography combined with cuff-measured brachial blood pressure in 990 age- and heart rate- and cuff-measured blood pressure-matched apparently healthy adults (495 men). The sex differences in the aortic pressure, the ratio of left ventricular wall volume to cavity volume (VW/VC), and Ó were analyzed.Compared with men, women demonstrated higher aortic systolic blood pressure (106.7 versus 101.7 mmHg), smaller VW/VC (1.12 versus 1.25 for the end-diastole VW/VC, 3.49 versus 3.82 for the end-systole VW/VC), and greater Ó (340.0 versus 315.6 for Ó-AVO, 471.9 versus 412.5 for Ó-peak, and 256.2 versus 230.3 kdynes/cm2 for Ó-ES) (all P < 0.001).At the same level of cuff-measured blood pressure, women have a greater Ó or afterload than men in consequence of the sex differences in left ventricular geometry and pulse pressure amplification. The evidence indicates that non-sex-specific categories of blood pressure factitiously impose a relatively higher afterload on the left ventricle in women and may therefore increase potential risk of heart failure in women.

Comparison of two ellipsoidal models for the estimation of left ventricular end-systolic stress in patients with significant coronary artery disease.

Background: The shape of the left ventricle (LV) is an important index to explore cardiac pathophysiology. A comparison was provided to estimate circumferential, longitudinal, and radial wall stress in LV based on the thick-walled ellipsoidal models of Mirsky and Ghista-Sandler for discriminating significant coronary artery disease (CAD) patients from no CAD patients. Materials and Methods: According to the angiography findings, 82 patients with CAD were divided into two groups: 25 patients without significant CAD and 57 patients with significant CAD of single vessel and multivessel. An ellipsoidal LV geometry was used to calculate end-systolic passive stress as the mechanical behavior of LV. Echocardiographic views-based measurements of LV diameters used to estimate the end-systolic wall stress. Results: Circumferential wall stress between the control group and significant CAD groups was significantly elevated for the Ghista model (P = 0.008); also, radial and longitudinal stress of the multi-vessel CAD group was significantly higher than the control group (P = 0.01 and P = 0.005, respectively). All stress parameters of the multi-vessel CAD group were statistically significant compared to the control group for the Mirsky model. Receiver operating characteristics curve analysis was shown the circumferential stress of multi-vessel CAD with an area under the curve (AUC) of 0.736 for the Ghista model and an AUC of 0.742 for the Mirsky model. Conclusion: These results indicated that Ghista and Mirsky model estimates of circumferential passive stress were the potential biomechanical markers to predict patients with multi-vessel CAD. It could be a noninvasive and helpful tool to quantify the contractility of LV.

Structural characterization of the novel stress response facilitator (SrfA) from Pseudomonas aeruginosa.

Chronic pulmonary infections in those living with cystic fibrosis or chronic obstructive pulmonary disease are promoted by production of alginate by the opportunistic pathogen Pseudomonas aeruginosa. Alginate biosynthesis enzymes in P. aeruginosa are regulated by the extracytoplasmic function alternative sigma factor σ22 either by mutation in mucA or in response to envelope stress. An intergenic region between ORFs PA2559 and PA2560 in P. aeruginosa is σ22-dependent and its transcription is activated by cell wall stress. This stress-responsive transcript encodes a novel stress response facilitator, SrfA, that is exclusively conserved only in P. aeruginosa species. Here we report the first three-dimensional structure of SrfA determined by molecular replacement using fold prediction to generate a search model. The SrfA structure adopts a helix-loop-helix fold that shares some similarity with structures of anti-activator or effector proteins. A ΔsrfA mutant strain of P. aeruginosa PAO1 exhibited significantly reduced biofilm formation, which was restored to wild-type levels when ΔsrfA was complemented with srfA. The ΔsrfA strain also exhibited increased sensitivity to macrolide antibiotics. We further show using MicroScale Thermophoresis that SrfA interacts with both PA2559 and PA2560 with high affinity. This work provides a starting point for further investigation into the role of SrfA in response to cell wall stress.

Dysregulation of Cell Envelope Homeostasis in Staphylococcus aureus Exposed to Solvated Lignin.

Lignin is an aromatic plant cell wall polymer that facilitates water transport through the vasculature of plants and is generated in large quantities as an inexpensive by-product of pulp and paper manufacturing and biorefineries. Although lignin's ability to reduce bacterial growth has been reported previously, its hydrophobicity complicates the ability to examine its biological effects on living cells in aqueous growth media. We recently described the ability to solvate lignin in Good's buffers with neutral pH, a breakthrough that allowed examination of lignin's antimicrobial effects against the human pathogen Staphylococcus aureus. These analyses showed that lignin damages the S. aureus cell membrane, causes increased cell clustering, and inhibits growth synergistically with tunicamycin, a teichoic acid synthesis inhibitor. In the present study, we examined the physiological and transcriptomic responses of S. aureus to lignin. Intriguingly, lignin restored the susceptibility of genetically resistant S. aureus isolates to penicillin and oxacillin, decreased intracellular pH, impaired normal cell division, and rendered cells more resistant to detergent-induced lysis. Additionally, transcriptome sequencing (RNA-Seq) differential expression (DE) analysis of lignin-treated cultures revealed significant gene expression changes (P < 0.05 with 5% false discovery rate [FDR]) related to the cell envelope, cell wall physiology, fatty acid metabolism, and stress resistance. Moreover, a pattern of concurrent up- and downregulation of genes within biochemical pathways involved in transmembrane transport and cell wall physiology was observed, which likely reflects an attempt to tolerate or compensate for lignin-induced damage. Together, these results represent the first comprehensive analysis of lignin's antibacterial activity against S. aureus. IMPORTANCE S. aureus is a leading cause of skin and soft tissue infections. The ability of S. aureus to acquire genetic resistance to antibiotics further compounds its ability to cause life-threatening infections. While the historical response to antibiotic resistance has been to develop new antibiotics, bacterial pathogens are notorious for rapidly acquiring genetic resistance mechanisms. As such, the development of adjuvants represents a viable way of extending the life span of current antibiotics to which pathogens may already be resistant. Here, we describe the phenotypic and transcriptomic response of S. aureus to treatment with lignin. Our results demonstrate that lignin extracted from sugarcane and sorghum bagasse restores S. aureus susceptibility to ß-lactams, providing a premise for repurposing these antibiotics in treatment of resistant S. aureus strains, possibly in the form of topical lignin/ß-lactam formulations.

Effect of Telmisartan on the Peak Wall Stress and Peak Wall Rupture Index of Small Abdominal Aortic Aneurysms: An Exploratory Analysis of the TEDY Trial.

OBJECTIVE: This study was an unplanned exploratory analysis of a subset of participants from the Telmisartan in the Management of Abdominal Aortic Aneurysm (TEDY) trial. It aimed to assess the efficacy of the angiotensin 1 receptor blocker telmisartan in reducing abdominal aortic aneurysm (AAA) peak wall stress (PWS) and peak wall rupture index (PWRI) among individuals with small AAAs. METHODS: Participants with AAAs measuring 35 - 49 mm in maximum diameter were randomised to receive telmisartan 40 mg or identical placebo in the TEDY trial. Participants who had computed tomography angiography performed at entry and at least one other time point during the trial (12 or 24 months) were included in the current study. Orthogonal AAA diameter, PWS, and PWRI were measured using previously validated methods. The annual change in PWS and PWRI from baseline was compared between participants allocated telmisartan or placebo using linear mixed effects models. These models were either unadjusted or adjusted for risk factors that were different in the groups at entry (p < .100) or systolic blood pressure (SBP) at one year. RESULTS: Of the 207 participants recruited to TEDY, 124 were eligible for inclusion in this study. This study included 65 and 59 participants from the telmisartan and placebo groups, respectively. The PWS and PWRI were not significantly different in the two groups at baseline. Participants allocated telmisartan had a slower annual increase in PWS (-4.19; 95% CI -8.24, -0.14 kPa/year; p = .043) and PWRI (-0.014; 95% CI -0.026, -0.001; p = .032) compared with those allocated placebo after adjusting for risk factors. After adjustment for SBP at one year, telmisartan did not significantly reduce annual increases in PWS or PWRI. CONCLUSION: The findings of this study suggest that telmisartan limits the rate of increase in PWS and PWRI of small AAAs by reducing blood pressure.

Stress Analysis in AAA does not Predict Rupture Location Correctly in Patients with Intraluminal Thrombus.

BACKGROUND: A biomechanical approach to the rupture risk of an abdominal aortic aneurysm could be a solution to ensure a personalized estimate of this risk. It is still difficult to know in what conditions, the assumptions made by biomechanics, are valid. The objective of this work was to determine the individual biomechanical rupture threshold and to assess the correlation between their rupture sites and the locations of their maximum stress comparing two computed tomography scan (CT) before and at time of rupture. METHODS: We included 5 patients who had undergone two CT; one within the last 6 months period before rupture and a second CT scan just before the surgical procedure for the rupture. All DICOM data, both pre- and rupture, were processed following the same following steps: generation of a 3D geometry of the abdominal aortic aneurysm, meshing and computational stress analysis using the finite element method. We used two different modelling scenarios to study the distribution of the stresses, a "wall" model without intraluminal thrombus (ILT) and a "thrombus" model with ILT. RESULTS: The average time between the pre-rupture and rupture CT scans was 44 days (22-97). The median of the maximum stresses applied to the wall between the pre-rupture and rupture states were 0.817 MPa (0.555-1.295) and 1.160 MPa (0.633-1.625) for the "wall" model; and 0.365 MPa (0.291-0.753) and 0.390 MPa (0.343-0.819) for the "thrombus" model. There was an agreement between the site of rupture and the location of maximum stress for only 1 patient, who was the only patient without ILT. CONCLUSIONS: We observed a large variability of stress values at rupture sites between patients. The rupture threshold strongly varied between individuals depending on the intraluminal thrombus. The site of rupture did not correlate with the maximum stress except for 1 patient.

Effect of food intake on echocardiographic measurements in healthy elderly.

OBJECTIVE: This study evaluates whether food intake affects systolic and diastolic echocardiographic measurements in healthy seniors. METHODS: Thirty healthy subjects 65-70 years of age were investigated with echocardiography, at fasting and then 30, 90, and 180 min after a meal. RESULTS: After 30 min the biggest changes were seen in left ventricular wall stress and myocardial performance index with a decrease of 45% and 33%, respectively, compared to fasting values. Significant (p < .05) increases also were seen in left ventricular stroke volume, left ventricular cardiac output, left ventricular cardiac index, left ventricular outflow velocity-time integral, peak of early diastolic (E) and late diastolic (A) mitral flow velocities, the E/A ratio, pulsed tissue Doppler peak systolic (s') and early (e') and late (a') diastolic velocities, pulmonary vein peak velocities in systole (S) and diastole (D), mitral annular plane systolic excursion (MAPSE), tricuspid annular plane systolic excursion (TAPSE), and global longitudinal strain (GLS) (increases ranging 6%-19%). After 90 min there remained a decrease in wall stress and myocardial performance index of 31% and 17%, respectively, and smaller, but still significant, changes could be seen in left ventricular stroke volume, left ventricular outflow velocity-time integral, MAPSE (lateral), TAPSE, GLS, and a few pulsed tissue Doppler peak systolic velocities and late diastolic velocities. An increase also could be seen in deceleration time of E-wave (DT). After 180 min, all variables except DT were back at baseline or below. No significant changes were seen in S/D ratio, lateral early diastolic velocity (e' lateral) and E/e'ratio. CONCLUSIONS: This study shows that food intake affects commonly used echocardiographic parameters, both systolic and diastolic, in healthy seniors. With a few exceptions, the changes seen in the older population were less pronounced than previous studies in younger subjects.

Heterogeneous reduction in regional wall stress after aortic valve replacement for aortic regurgitation: a distinct feature from aortic stenosis.

Geometric changes caused by volume reduction early after aortic valve replacement (AVR) for aortic regurgitation (AR) may not be uniform, resulting in varying regional end-systolic wall stress (ESS). This study compared changes in regional ESS between AR and aortic stenosis (AS) patients in the early phase following AVR. Computer-tomographic left ventricular (LV) angiography was performed for 10 patients with AR and 13 with AS before and three months after AVR. Regional ESS at the base, middle, and apex levels, each subdivided into four segments, was calculated based on the Janz equation: ESS = end-systolic LV pressure × local cross-sectional area of LV cavity/that of LV wall. Following AVR, median LV end-diastolic volume index fell from 106 to 69 ml/m2 (P = 0.001) in AR and 60 to 46 ml/m2 (P = 0.01) in AS patients. Global ESS also declined in both (AR, 186 to 124 kdyne/cm2, P = 0.02; AS, 187 to 108 kdyne/cm2, P < 0.001, respectively). Regional ESS was reduced in all segments in AS patients, accompanied by left ventricular ejection fraction (LVEF) improvement (71-80%, P = 0.02). In contrast, regional ESS in AR patients was heterogeneously reduced, as regional ESS fell significantly in the antero-septal wall but was unchanged in the infero-lateral wall, and LVEF remained unchanged (65 to 62%, P = 0.42). In the early postoperative phase after AVR, the loading condition of the regional LV wall in AR patients was characterized by a heterogeneous reduction in regional ESS in contrast to a uniform decline in AS patients.

Comparative Proteomic Analysis of Transcriptional and Regulatory Proteins Abundances in S. lividans and S. coelicolor Suggests a Link between Various Stresses and Antibiotic Production.

Streptomyces coelicolor and Streptomyces lividans constitute model strains to study the regulation of antibiotics biosynthesis in Streptomyces species since these closely related strains possess the same pathways directing the biosynthesis of various antibiotics but only S. coelicolor produces them. To get a better understanding of the origin of the contrasted abilities of these strains to produce bioactive specialized metabolites, these strains were grown in conditions of phosphate limitation or proficiency and a comparative analysis of their transcriptional/regulatory proteins was carried out. The abundance of the vast majority of the 355 proteins detected greatly differed between these two strains and responded differently to phosphate availability. This study confirmed, consistently with previous studies, that S. coelicolor suffers from nitrogen stress. This stress likely triggers the degradation of the nitrogen-rich peptidoglycan cell wall in order to recycle nitrogen present in its constituents, resulting in cell wall stress. When an altered cell wall is unable to fulfill its osmo-protective function, the bacteria also suffer from osmotic stress. This study thus revealed that these three stresses are intimately linked in S. coelicolor. The aggravation of these stresses leading to an increase of antibiotic biosynthesis, the connection between these stresses, and antibiotic production are discussed.

Can We Better Differentiate Type A Dissections: Evaluating the Role of Aortic Ratios.

OBJECTIVES: Type A aortic dissection (ATAAD) is hypothesised as a progression of aneurysmal dilation, but 60% of patients in the International Registry of Acute Aortic Dissection (iRAD) registry had a maximum aortic diameter (MAD)<55 mm. We aim to demonstrate that size ratios and aortic wall stress, assessed using a simplified markers, are unique to aortic patients who have had adverse events (ATAAD) compared to those who have not (thoracic aortic aneurysm [TAA]). METHODS: A retrospective cohort analysis of patients who underwent aortic intervention at Waikato Hospital, New Zealand between 2015-2020, comparing dissection (ATAAD) to TAA patients. MAD; ratio of MAD to standardised-points within the aorta; and MAD-to-height collected from computed tomography (CT)-scans of all patients was undertaken. Receiver operating characteristic (ROC)-analysis to determine cut-off point for each marker was undertaken together with multivariable logistic regression comparing both cohorts, cross-validated by propensity-score matched analysis. RESULTS: Cohort of 215 patients, 78 (36.3%) ATAAD and 137 (63.7%) TAA; median age at intervention 63.3 years, 52 (24.2%) females, both cohorts matched for size. Using the entire cohort, the MAD: sinus of Valsalva (SoV) ratio>1.06 (cut-off value) had 4.5-times greater association with ATAAD (95%CI 1.46-13.8) and a 0.1-unit increased conferred 1.45-times greater association with ATAAD (95%CI 1.00-2.08). MAD>55 mm only seen in 33.3% of ATAAD (n=26/78), and not associated with ATAAD (OR 1.88, 95%CI 0.64-5.51). Compared to MAD, MAD:SoV ratio had greater sensitivity (33% vs 73%), lower number-needed-to-treat (17.9 vs 2.7) and superior discrimination (area under the curve [AUC] 0.54 vs 0.71). Findings were consistent with propensity score matched analysis. CONCLUSIONS: MAD:SoV ratio significantly correlates with ATAAD (4.5 times), with superior sensitivity, discrimination, and attributable-risk-percentage compared to MAD alone.

Modern diagnostic approach to patients with abdominal aortic aneurysm.

INTRODUCTION: Abdominal aortic aneurysm (AAA) is a relatively frequent and serious condition in vascular surgery. The diagnostic and indication process and its treatment are driven by the guidelines which dictate an intervention when the maximum AAA diameter is more than 55 mm. Nevertheless, this approach is not fully sufficient in all AAA cases and thus we have been seeking to develop a modern diagnostic tool using computer modeling and vascular wall stress analysis. METHODS: The project has been ongoing in cooperation with engineers from VUT Brno (Brno University of Technology) and VŠB Ostrava (Technical University of Ostrava) for ten years. The design of the analytical tool was created during the first, experimental period of the project; this tool is able to assess vascular wall stress from regular CT scans using the finite element method. This primary model was gradually altered and its precision was increased considerably in the course of the years using data from mechanical and histological tests of AAA wall specimens harvested during open repairs. Additionally, other patient specific data are included in the analysis such as blood pressure, gender and material characteristics. RESULTS: The effectiveness of the method was evaluated in a pseudo-prospective study, showing clear superiority of the vascular wall stress analysis over the maximum diameter approach. The method was used in clinical practice for the first time during restrictions due to the COVID-19 pandemic; based on the analysis we were able to assess which AAA cases can be postponed and which had a high risk of rupture and an intervention was required despite the restrictions. The method achieved 100% sensitivity, and its specificity was also much better compared to the maximum diameter approach. CONCLUSION: The vascular wall stress analysis of AAA seems to be much more precise than the classic indication approach based only on the maximum diameter, and it can be used to determine the therapy based on patient specific parameters.

IreK-Mediated, Cell Wall-Protective Phosphorylation in Enterococcus faecalis.

Enterococcus faecalis is a Gram-positive bacterium that is a major cause of hospital-acquired infections due, in part, to its intrinsic resistance to cell wall-active antimicrobials. One critical determinant of this resistance is the transmembrane kinase IreK, which belongs to the penicillin-binding protein and serine/threonine kinase-associated kinase family of bacterial signaling proteins involved with the regulation of cell wall homeostasis. The activity of IreK is enhanced in response to cell wall stress, but direct substrates of IreK phosphorylation, leading to antimicrobial resistance, are largely unknown. To better understand stress-modulated phosphorylation events contributing to antimicrobial resistance, wild type E. faecalis cells treated with cell wall-active antimicrobials, chlorhexidine or ceftriaxone, were examined via phosphoproteomics. Among the most prominent changes was increased phosphorylation of divisome components after both treatments, suggesting that E. faecalis modulates cell division in response to cell wall stress. Phosphorylation mediated by IreK was then determined via a similar analysis with a E. faecalis ΔireK mutant strain, revealing potential IreK substrates involved with the regulation of peptidoglycan biosynthesis and within the E. faecalis CroS/R two-component system, another signal transduction pathway that promotes antimicrobial resistance. These results reveal critical insights into the biological functions of IreK.

The role of mechanotransduction in heart failure pathobiology-a concise review.

This review evaluates the role of mechanotransduction (MT) in heart failure (HF) pathobiology. Cardiac functional and structural modifications are regulated by biomechanical forces. Exposing cardiomyocytes and the myocardial tissue to altered biomechanical stress precipitates changes in the end-diastolic wall stress (EDWS). Thereby various interconnected biomolecular pathways, essentially mediated and orchestrated by MT, are launched and jointly contribute to adapt and remodel the myocardium. This cardiac MT-mediated feedback decisively determines the primary cardiac cellular and tissue response, the sort (concentric or eccentric) of hypertrophy/remodeling, to mechanical and/or hemodynamic alterations. Moreover, the altered EDWS affects the diastolic myocardial properties independent of the systolic function, and elevated EDWS causes diastolic dysfunction. The close interconnection between MT pathways and the cell nucleus, the genetic endowment, principally allows for the wide variety of phenotypic appearances. However, demographic, environmental features, comorbidities, and also the genetic make-up may modulate the phenotypic result. Cardiac MT takes a fundamental and superordinate position in the myocardial adaptation and remodeling processes in all HF categories and phenotypes. Therefore, the effects of MT should be integrated in all our scientific, clinical, and therapeutic considerations.