Sugar shock: Probing Streptococcus pyogenes metabolism through bioluminescence imaging

Streptococcus pyogenes (S. pyogenes) can thrive in its host during an infection, and, as a result, it must be able to respond to external stimuli and available carbon sources. The pre-clinical use of engineered pathogens capable of constitutive light production may provide real-time information on microbial-specific metabolic processes. Here we mapped the central metabolism of a luxABCDE-modified S. pyogenes Xen20 (Strep. Xen20) to its de novo synthesis of luciferase substrates as assessed by the rate of light production in response to different environmental triggers. Previous characterization predicted that the lux operon was under the myo-inositol iolE promotor. Here we show that supplementation with myo-inositol generated increased Xen20 luminescence. Surprisingly, when supplemented with infection-relevant carbon sources, such as glucose or glycine, light production was diminished. This was presumably due to the scavenging of pyruvate by L-lactate dehydrogenase (LDH). Inhibition of LDH by its inhibitor, oxamate, partially restored luminescent signal in the presence of glucose, presumably by allowing the resulting pyruvate to proceed to acetyl-coenzyme A (CoA). This phenomenon appeared specific to the lactic acid bacterial metabolism as glucose or glycine did not reduce signal in an analogous luxABCDE-modified Gram-positive pathogen, Staph. Xen29. The Strep. Xen20 cells produced light in a concentration-dependent manner, inversely related to the amount of glucose present. Taken together, our measures of microbial response could provide new information regarding the responsiveness of S. pyogenes metabolism to acute changes in its local environments and cellular health.

To Study Acute Changes in Brain Oxygenation on MRI in Healthcare Workers Using N95 Mask and PPE Kits for Six Hours a Day

Background Due to long working hours wearing an N95 mask and PPE kit during the COVID-19 pandemic, the healthcare workers (HCWs) complained of headaches, confusion, and exhaustion. This study was therefore performed to study the changes in brain oxygenation. Aim To compare brain oxygenation in health care workers wearing an N95 mask with a PPE kit versus a three-ply mask during an intensive care setting for 6 hours. Materials and Methods Thirty clinicians and 30 paramedical staff participated in the study. The control (three-ply mask) and subject (N95 mask with PPE) groups included 15 clinicians and 15 paramedical staff. A comparative analysis of brain oxygenation using a 3T magnetic resonance imaging (MRI) machine was performed in these two groups at the beginning and the end of their work shift. Results The mean age of the individuals in the control and subject groups was 30.8 and 30.13 years, respectively. The median value of brain oxygenation in the control and subject groups in the pre-shift was between 33 and 31 and post-shift was 30 and 24. The drop in brain oxygenation in subjects was more than the controls (p = 0.004) in the post-shift assessments. The cerebral blood flow (CBF) in the bilateral middle cerebral artery (MCA) using arterial spin labeling (ASL) showed a rise in CBF in both groups post-shift as compared with the pre-shift values. The median values of the right and left MCA in the control and subject groups pre-shift were 82.75/83.45 and 89.75/106.65. The post-shift median values of both MCAs of the control and subject groups were 115.65/115.55 and 109.60/119.49. Conclusion MRI-BOLD imaging revealed a significant drop in brain oxygenation in the subject group as compared with the control group. Multiphasic-ASL showed a compensatory rise in CBF in both groups.

Leptin: Mechanisms Involved In Signaling and Resistance

Leptin is secreted mainly by white adipocyte tissue, and it circulates at levels positively correlated with fat mass, thus reflecting primarily the amount of energy stored in adipose tissue. Leptin levels also change with acute changes in energy intake and thus, secondarily reflect acute energy availability. Several potential mechanisms behind leptin resistance have been identified including: Inflammatory signaling, elevated free fatty acids, high leptin and genetic mutation in OB and DBU genes. This review summaries all the physiological, biological aspects of leptin hormone including increases energy expenditure, thermogenesis, heart rate, blood pressure but decreases glycaemia. This review summarizes the pharmacological and nonpharmacological treatment of leptin hormone imbalances.

Acute Treatment Effects on GFR in Randomized Clinical Trials of Kidney Disease Progression

Background Acute changes in glomerular filtration rate (GFR) can occur following initiation of interventions targeting progression of chronic kidney disease (CKD). These acute changes complicate the interpretation of long-term treatment effects. Methods To assess the magnitude and consistency of acute effects in randomized clinical trials and explore factors that might affect them, we performed a meta-analysis of 53 randomized clinical trials for CKD progression enrolling 56,413 participants with at least one estimated GFR measurement by 6 months following randomization. We defined acute treatment effects as the mean difference in GFR slope from baseline to 3 months between randomized groups. We performed univariable and multivariable meta-regression to assess the effect of intervention type, disease state, baseline GFR, and albuminuria on the magnitude of acute effects. Results The mean acute effect across all studies was -0.21 mL/min per 1.73m2 (95% confidence interval, -0.63 to 0.22) over 3 months, with substantial heterogeneity across interventions (95% coverage interval across studies, -2.50 to +2.08 mL/min per 1.73m2). We observed negative average acute effects in renin angiotensin system blockade, BP lowering, and sodium-glucose cotransporter 2 inhibitor trials, and positive acute effects in trials of immunosuppressive agents. Larger negative acute effects were observed in trials with a higher mean baseline GFR. Conclusion The magnitude and consistency of acute GFR effects vary across different interventions, and are larger at higher baseline GFR. Understanding the nature and magnitude of acute effects can help inform the optimal design of randomized clinical trials evaluating disease progression in CKD.

Effects of Exercise Training on Neurotrophic Factors and Subsequent Neuroprotection in Persons with Multiple Sclerosis—A Systematic Review and Meta-Analysis

Background: Evidence indicates that exercise holds the potential to counteract neurodegeneration experienced by persons with multiple sclerosis (pwMS), which is in part believed to be mediated through increases in neurotrophic factors. There is a need to summarize the existing evidence on exercise-induced effects on neurotrophic factors alongside neuroprotection in pwMS. Aim: To (1) systematically review the evidence on acute (one session) and/or chronic (several sessions) exercise-induced changes in neurotrophic factors in pwMS and (2) investigate the potential translational link between exercise-induced changes in neurotrophic factors and neuroprotection. Methods: Five databases (Medline, Scopus, Web of Science, Embase, Sport Discus) were searched for randomized controlled trials (RCT) examining the effects of exercise (all modalities included) on neurotrophic factors as well as measures of neuroprotection if reported. The quality of the study designs and the exercise interventions were assessed by use of the validated tool TESTEX. Results: From N = 337 identified studies, N = 14 RCTs were included. While only N = 2 of the identified studies reported on the acute changes in neurotrophic factors, all N = 14 RCTs reported on the chronic effects, with N = 9 studies revealing between-group differences in favor of exercise. This was most prominent for brain-derived neurotrophic factor (BDNF), with between-group differences in favor of exercise being observed in N = 6 out of N = 12 studies. Meta-analyses were applicable for three out of 10 different identified neurotrophic factors and revealed that exercise can improve the chronic levels of BDNF (delta changes; N = 9, ES = 0.78 (0.27; 1.28), p = 0.003, heterogeneity between studies) and potentially also ciliary neurotrophic factor (CNTF) (N = 3, ES = 0.24 (−0.07; 0.54), p = 0.13, no heterogeneity between studies) but not nerve growth factor (NGF) (N = 4, ES = 0.28 (−0.55; 1.11), p = 0.51, heterogeneity between studies). Indicators of neuroprotection (e.g., with direct measures of brain structure assessed by MRI) were assessed in N = 3 of the identified studies only, with N = 2 partly supporting and thus indicating a potential translational link between increases in neurotrophic factors and neuroprotection. Conclusion: The present study reveals that exercise can elicit improvements in chronic levels of BDNF in pwMS, whereas the effects of exercise on chronic levels of other neurotrophic factors and on acute levels of neurotrophic factors in general, along with a potential translational link (i.e., with exercise-induced improvements in neurotropic factors being associated with or even mediating neuroprotection), are sparse and inconclusive. There is a need for more high-quality studies that assess neurotrophic factors (applying comparable methods of blood handling and analysis) concomitantly with neuroprotective outcome measures. Review Registration: PROSPERO (ID: CRD42020177353).

Endolymphatic Hydrops is a Marker of Synaptopathy Following Traumatic Noise Exposure

After acoustic trauma, there can be loss of synaptic connections between inner hair cells and auditory neurons in the cochlea, which may lead to hearing abnormalities including speech-in-noise difficulties, tinnitus, and hyperacusis. We have previously studied mice with blast-induced cochlear synaptopathy and found that they also developed a build-up of endolymph, termed endolymphatic hydrops. In this study, we used optical coherence tomography to measure endolymph volume in live CBA/CaJ mice exposed to various noise intensities. We quantified the number of synaptic ribbons and postsynaptic densities under the inner hair cells 1 week after noise exposure to determine if they correlated with acute changes in endolymph volume measured in the hours after the noise exposure. After 2 h of noise at an intensity of 95 dB SPL or below, both endolymph volume and synaptic counts remained normal. After exposure to 2 h of 100 dB SPL noise, mice developed endolymphatic hydrops and had reduced synaptic counts in the basal and middle regions of the cochlea. Furthermore, round-window application of hypertonic saline reduced the degree of endolymphatic hydrops that developed after 100 dB SPL noise exposure and partially prevented the reduction in synaptic counts in the cochlear base. Taken together, these results indicate that endolymphatic hydrops correlates with noise-induced cochlear synaptopathy, suggesting that these two pathologic findings have a common mechanistic basis.

Acute hemodynamic changes during far infrared treatment of the arteriovenous fistula in hemodialysis patients

Background: The arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis (HD) treatment and preservation of a stable vascular access is crucial. Long term Far Infrared Radiation (FIR) has been found to increase access flow together with an enhanced maturation and patency of the AVF. The acute effects of FIR on access flow have been sparsely described and the results are contradictory, perhaps due to differences in measurement conditions and other factors of importance for access flow. Methods: Twenty patients in HD with an AVF were included. Each patient was randomized to receive either FIR (FIR group) or no FIR (control group). The acute changes in access flow were investigated in both groups on the second dialysis day of the week and during the first 1.5 h of the dialysis session. Concomitant changes in hemodynamic parameters of importance for access flow were also explored. Results: There was no significant change in access flow in the FIR group compared with the control group (median (Interquartile Range)) (−10 (−413.8; 21.3) ml/min vs −17.5 (−83.8; 76.3) ml/min, p = 0.58). There was no significant difference in any of the hemodynamic parameters between the FIR and the control group; cardiac output (−0.7 (−1.2; −0.2) l/min vs −0.4 (−0.9; 0.1) l/min, p = 0.58), cardiac index (−0.3 (−0.5; −0.1)) l/min/m2 vs −0.3 (−0.4; 0) l/min/m2, p = 0.68), mean arterial pressure (5.5 (−1.8; 8.4) mmHg vs 1.5 (−3; 6.3) mmHg, p = 0.35) and total peripheral resistance (2 (1.8; 3.4) mmHg × min/l vs 1 (−0.3; 3.1) mmHg × min/l, p = 0.12). Conclusion: In this trial, with a highly standardized set-up, one session of FIR did not result in any acute changes in access flow. This was not due to differences in the hemodynamic parameters between the groups.

Exercise Training and Circulating Small Extracellular Vesicles: Appraisal of Methodological Approaches and Current Knowledge

In response to acute exercise, an array of metabolites, nucleic acids, and proteins are enriched in circulation. Collectively termed “exercise factors,” these molecules represent a topical area of research given their speculated contribution to both acute exercise metabolism and adaptation to exercise training. In addition to acute changes induced by exercise, the resting profile of circulating exercise factors may be altered by exercise training. Many exercise factors are speculated to be transported in circulation as the cargo of extracellular vesicles (EVs), and in particular, a sub-category termed “small EVs.” This review describes an overview of exercise factors, small EVs and the effects of exercise, but is specifically focused on a critical appraisal of methodological approaches and current knowledge in the context of changes in the resting profile small EVs induced by exercise training, and the potential bioactivities of preparations of these “exercise-trained” small EVs. Research to date can only be considered preliminary, with interpretation of many studies hindered by limited evidence for the rigorous identification of small EVs, and the conflation of acute and chronic responses to exercise due to sample timing in proximity to exercise. Further research that places a greater emphasis on the rigorous identification of small EVs, and interrogation of potential bioactivity is required to establish more detailed descriptions of the response of small EVs to exercise training, and consequent effects on exercise adaptation.