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Antibiotic resistance threatens to put modern medicine into reverse. But we are not at the end of our options for currently available drugs. Baym et al. review what can be done by using combinations of antibiotics to circumvent bacteria's evolutionary strategies. For instance, resistance to one drug may cause sensitivity to another, the effectiveness of two drugs can be synergized by a resistance mutation, and some negative drug interactions may even be beneficial in selecting against resistance. Although not simple to assess, drug combinations still have something to offer for the development of sorely needed anti-infectives. Science , this issue p. 10.1126/science.aad3292 Antibiotic treatment has two conflicting effects: the desired, immediate effect of inhibiting bacterial growth and the undesired, long-term effect of promoting the evolution of resistance. Although these contrasting outcomes seem inextricably linked, recent work has revealed several ways by which antibiotics can be combined to inhibit bacterial growth while, counterintuitively, selecting against resistant mutants. Decoupling treatment efficacy from the risk of resistance can be achieved by exploiting specific interactions between drugs, and the ways in which resistance mutations to a given drug can modulate these interactions or increase the sensitivity of the bacteria to other compounds. Although their practical application requires much further development and validation, and relies on advances in genomic diagnostics, these discoveries suggest novel paradigms that may restrict or even reverse the evolution of resistance.

Changes in brain structure and cortical function are associated with many chronic pain conditions including low back pain and fibromyalgia. The magnitude of these changes correlates with the duration and/or the intensity of chronic pain. Most studies report changes in common areas involved in pain modulation, including the prefrontal cortex (PFC), and pain-related pathological changes in the PFC can be reversed with effective treatment. While the mechanisms underlying these changes are unknown, they must be dynamically regulated. Epigenetic modulation of gene expression in response to experience and environment is reversible and dynamic. Epigenetic modulation by DNA methylation is associated with abnormal behavior and pathological gene expression in the central nervous system. DNA methylation might also be involved in mediating the pathologies associated with chronic pain in the brain. We therefore tested a) whether alterations in DNA methylation are found in the brain long after chronic neuropathic pain is induced in the periphery using the spared nerve injury modal and b) whether these injury-associated changes are reversible by interventions that reverse the pathologies associated with chronic pain. Six months following peripheral nerve injury, abnormal sensory thresholds and increased anxiety were accompanied by decreased global methylation in the PFC and the amygdala but not in the visual cortex or the thalamus. Environmental enrichment attenuated nerve injury-induced hypersensitivity and reversed the changes in global PFC methylation. Furthermore, global PFC methylation correlated with mechanical and thermal sensitivity in neuropathic mice. In summary, induction of chronic pain by peripheral nerve injury is associated with epigenetic changes in the brain. These changes are detected long after the original injury, at a long distance from the site of injury and are reversible with environmental manipulation. Changes in brain structure and cortical function that are associated with chronic pain conditions may therefore be mediated by epigenetic mechanisms.

Chronic pain is at epidemic proportions in the United States, represents a significant burden on our public health system, and is coincident with a growing opioid crisis. While numerous genome-wide association studies have been reported for specific pain-related traits, many of these studies were underpowered, and the genetic relationship among these traits remains poorly understood. Here, we conducted a joint analysis of genome-wide association study summary statistics from seventeen pain susceptibility traits in the UK Biobank. This analysis revealed 99 genome-wide significant risk loci, 65 of which overlap loci identified in earlier studies. The remaining 34 loci are novel. We applied leave-one-trait-out meta-analyses to evaluate the influence of each trait on the joint analysis, which suggested that loci fall into four categories: loci associated with nearly all pain-related traits; loci primarily associated with a single trait; loci associated with multiple forms of skeletomuscular pain; and loci associated with headache-related pain. Overall, 664 genes were mapped to the 99 loci by genomic proximity, eQTLs, and chromatin interaction and ~15% of these genes showed differential expression in individuals with acute or chronic pain compared to healthy controls. Risk loci were enriched for genes involved in neurological and inflammatory pathways. Genetic correlation and two-sample Mendelian randomization indicated that psychiatric, metabolic, and immunological traits mediate some of these effects.

The intervertebral disc (IVD) aids in motion and acts to absorb energy transmitted to the spine. With little inherent regenerative capacity, degeneration of the intervertebral disc results in intervertebral disc disease, which contributes to low back pain and significant disability in many individuals. Increasing evidence suggests that IVD degeneration is a disease of the whole joint that is associated with significant inflammation. Moreover, studies show elevated macrophage accumulation within the IVD with increasing levels of disease severity; however, we still need to understand the roles, be they causative or consequential, of macrophages during the degenerative process. In this narrative review, we discuss hallmarks of IVD degeneration, showcase evidence of macrophage involvement during disc degeneration, and explore burgeoning research aimed at understanding the molecular pathways regulating macrophage functions during intervertebral disc degeneration.

BackgroundThe proximity of transverse sinus stenosis (TSS) to inner ear structures and the temporal bone makes it a substantial cause of pulsatile tinnitus (PT). Treatment typically involves venous sinus stenting. This study investigates the hemodynamic stressors in TSS patients with PT along the pulse-transmitting temporal bone area and evaluates its treatment effects.MethodsFour patients with idiopathic intracranial hypertension, PT, and TSS, and four control patients were imaged using MR venography (MRV) and flat panel CT (FP-CT). Patient-specific blood flow simulations were conducted using boundary conditions based on quantitative MR angiography before and after VSS. Catheter-based trans-stenotic pressure gradient measurements were used to validate the simulation results.ResultsThe prediction of pressure gradients was close to catheter-based measurements using FP-CT-based segmentations (absolute deviation of 0.35 mm Hg) and is superior to MRV-based reconstructions (absolute deviation of 6.9 mm Hg). In TSS patients, the sinus temporal bone contact areas revealed notably higher time-averaged wall shear stress by 47±22% and velocity values by 41±18% compared with the sinus brain side. The relative residence time decreased by 57±58%. After stenting, the hemodynamic parameters dropped at the temporal side and throughout the sigmoid sinus. Almost all control patient hemodynamics remained lower than post-interventional results.ConclusionOur simulations based on patient-specific flows highly predicts pressure gradients across the stenosis. Flow conditions in TSS reveal flow jet formation and high shear rates at the temporal bone, potentially causing sound transmission. The treatment reduces these stressors, demonstrating its targeted therapeutic effect.

The authors investigated improvisational theater and the possibilities that it presents for reconsidering reading pedagogy, with a focus on discussions of reading. The authors conducted empirical, qualitative studies of improvisational practice and instruction and analyzed improv through the construct of worlding. In this article, the authors explore different dimensions of worlding, a concept that generally describes how ensembles make present and create unique events in time. Next, the authors offer a vision of reading discussions that emerges from rethinking and refeeling such discussions through forms of worlding found in improvisation. The authors conclude by offering five improvinspired teaching practices for discussions of reading: (1) teaching as invoking the text, (2) teaching as exchanging offers, (3) teaching as attuning, (4) teaching as following lines of flight, and (5) teaching as activating embodied energy.

Our group previously demonstrated that administration of a CD34-negative fraction of human non- hematopoietic umbilical cord blood stem cells (UCBSC) 48 h after ischemic injury could reduce infarct volume by 50% as well as significantly ameliorate neurological deficits. In the present study, we explored possible mechanisms of action using next generation RNA sequencing to analyze the brain transcriptome profiles in rats with ischemic brain injury following UCBSC therapy. Two days after ischemic injury, rats were treated with UCBSC. Five days after administration, total brain mRNA was then extracted for RNAseq analysis using Illumina Hiseq 2000. We found 275 genes that were significantly differentially expressed after ischemic injury compared with control brains. Following UCBSC treatment, 220 of the 275 differentially expressed genes returned to normal levels. Detailed analysis of these altered transcripts revealed that the vast majority were associated with activation of the immune system following cerebral ischemia which were normalized following UCBSC therapy. Major alterations in gene expression profiles after ischemia include blood-brain-barrier breakdown, cytokine production, and immune cell infiltration. These results suggest that UCBSC protect the brain following ischemic injury by down regulating the aberrant activation of innate and adaptive immune responses.

BackgroundEmbolization of brain arteriovenous malformations (bAVMs) is often used as adjuvant therapy to microsurgical resection to reduce the high-risk features of bAVMs such as large size and high flow. However, the effect of preoperative embolization on surgical performance and patient outcome has shown mixed results. Heterogeneity in treatment goals, selection criteria, and unpredictable changes in bAVM hemodynamics after partial embolization may account for these uncertain findings. In this study we use an objective quantitative technique to assess the impact of preoperative embolization on intraoperative blood loss (IBL).MethodsPatients with bAVM treated with microsurgical resection only or in combination with preoperative embolization from 2012 to 2022 were retrospectively reviewed. Patients were included if quantitative magnetic resonance angiography was performed prior to any treatment. Correlation of baseline bAVM flow, volume, and IBL was evaluated between the two groups. Additionally, bAVM flow prior to and after embolization was compared.ResultsForty-three patients were included, 31 of whom required preoperative embolization (20 had more than one session). Mean bAVM initial flow (362.3 mL/min vs 89.6 mL/min, p=0.001) and volume (9.6 mL vs 2.8 mL, p=0.001) were significantly higher in the preoperative embolization group; flow decreased significantly after embolization (408.0 mL/min vs 139.5 mL/min, p<0.001). IBL was comparable between the two groups (258.6 mL vs 141.3 mL, p=0.17). Linear regression continued to show a significant difference in initial bAVM flow (p=0.03) but no significant difference in IBL (p=0.53).ConclusionPatients with larger bAVMs who underwent preoperative embolization had comparable IBL to those with smaller bAVMs undergoing only surgical treatment. Preoperative embolization of high-flow bAVMs facilitates surgical resection, reducing the risk of IBL.

Objective Gulf War Illness is a chronic multisymptom disorder severely impacting the health and well-being of many Veterans of the 1990–1991 Gulf War. Symptoms that define the disease include pain, fatigue, mood and memory impairments, gastrointestinal problems, lung disorders, and skin rashes. In our previous biomarker study, we discovered Gulf War Illness-associated proinflammatory blood biomarkers. Therefore, we hypothesized that chronic inflammation causes the symptoms that define this disorder. Testing the chronic inflammation hypothesis is the objective of this study. Results The biomarker fingerprint of Gulf War Illness is the end-product of a cascade of proinflammatory cytokine signals. In particular, the observed increase in C-reactive protein predicts a corresponding increase in interleukin 6, the cytokine that stimulates hepatocytes to produce C-reactive protein. Therefore, in this study we measured potential upstream cytokine signals in plasma samples from Gulf War Veterans. As predicted, a positive correlation between interleukin 6 and C-reactive protein was observed.

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is threatening public health as it spreads worldwide across diverse environments. Its genetic hallmark, the mecA gene, confers resistance to many β-lactam antibiotics. Here, we show that, in addition, mecA provides a broad selective advantage across diverse chemical environments. Competing fluorescently labelled wild-type and mecA -deleted CA-MRSA USA400 strains across ~57,000 compounds supplemented with subinhibitory levels of the β-lactam drug cefoxitin, we find that mecA provides a widespread advantage across β-lactam and non β-lactam antibiotics, non-antibiotic drugs and even diverse natural and synthetic compounds. This advantage depends on the presence of cefoxitin and is strongly associated with the compounds’ physicochemical properties, suggesting that it may be mediated by differential compounds permeability into the cell. Indeed, mecA protects the bacteria against increased cell-envelope permeability under subinhibitory cefoxitin treatment. Our findings suggest that CA-MRSA success might be driven by a cell-envelope mediated selective advantage across diverse chemical compounds. The mecA gene confers resistance to many β-lactam antibiotics in community-associated MRSA bacteria. Here, Snitser et al . show that mecA also provides broad selective advantage across diverse chemical environments in the presence of subinhibitory β-lactam concentrations, by protecting the bacteria against increased cell-envelope permeability.