Epigenetic Control of NRF2-Directed Cellular Antioxidant Status in Dictating Life-Death Decisions.

In this issue of Molecular Cell, Chen et al. (2017) demonstrate that the tumor suppressor protein ARF sensitizes cancer cells to programmed death through a surprising mechanism: ARF physically interacts with and antagonizes activation by acetylation of the master redox regulator NRF2, providing an unusual mode of posttranslational NRF2 regulation.

Dietary interventions improve diabetic kidney disease, but not peripheral neuropathy, in a db/db mouse model of type 2 diabetes.

Patients with type 2 diabetes often develop the microvascular complications of diabetic kidney disease (DKD) and diabetic peripheral neuropathy (DPN), which decrease quality of life and increase mortality. Unfortunately, treatment options for DKD and DPN are limited. Lifestyle interventions, such as changes to diet, have been proposed as non-pharmacological treatment options for preventing or improving DKD and DPN. However, there are no reported studies simultaneously evaluating the therapeutic efficacy of varying dietary interventions in a type 2 diabetes mouse model of both DKD and DPN. Therefore, we compared the efficacy of a 12-week regimen of three dietary interventions, low carbohydrate, caloric restriction, and alternate day fasting, for preventing complications in a db/db type 2 diabetes mouse model by performing metabolic, DKD, and DPN phenotyping. All three dietary interventions promoted weight loss, ameliorated glycemic status, and improved DKD, but did not impact percent fat mass and DPN. Multiple regression analysis identified a negative correlation between fat mass and motor nerve conduction velocity. Collectively, our data indicate that these three dietary interventions improved weight and glycemic status and alleviated DKD but not DPN. Moreover, diets that decrease fat mass may be a promising non-pharmacological approach to improve DPN in type 2 diabetes given the negative correlation between fat mass and motor nerve conduction velocity.

Unit size influences ad libitum intake in a snacking context via eating rate.

Geometric and textural properties of food, like unit size, have previously been shown to influence energy intake. While mechanism(s) driving this effect are unclear, unit size may relate to intake by affecting eating microstructure (e.g., eating rate, bite size). In a randomized crossover study, we investigated relationships between unit size, eating microstructure, and intake. Adults (n = 75, 75% women) consumed an ad libitum snack three times in our laboratory. This snack was a 70-g portion (∼2.5 servings) of one of three sizes of pretzel (small, medium, large). Intake was measured in grams by difference in weight before and after the snack. Each session was video recorded to measure eating microstructure; snack duration (min) and number of bites were annotated and used to calculate mean eating rate (g/min) and mean bite size (g/bite). Results revealed unit size influenced intake (grams and kcal; both p's ≤ 0.001), such that participants consumed 31% and 22% more of the large pretzels (16.9 ± 2.3 g) compared to the small (12.9 ± 2.3 g) and medium sizes (13.8 ± 2.3 g), respectively. Unit size also influenced eating rate and bite size (both p's < 0.001); the largest pretzel size yielded the fastest eating rate and largest mean bite size. Further analysis revealed that after accounting for eating microstructure, the effects of unit size on intake were no longer significant, suggesting eating microstructure was driving these effects. Together, these findings indicate that unit size influences intake by affecting eating microstructure and that food properties like unit size can be leveraged to moderate snack intake.

Reasons for meal termination, eating frequency, and typical meal context differ between persons with and without a spinal cord injury.

Overeating associated with neurogenic obesity after spinal cord injury (SCI) may be related to how persons with SCI experience satiation (processes leading to meal termination), their eating frequency, and the context in which they eat their meals. In an online, cross-sectional study, adults with (n = 688) and without (Controls; n = 420) SCI completed the Reasons Individuals Stop Eating Questionnaire-15 (RISE-Q-15), which measures individual differences in the experience of factors contributing to meal termination on five scales: Physical Satisfaction, Planned Amount, Decreased Food Appeal, Self-Consciousness, and Decreased Priority of Eating. Participants also reported weekly meal and snack frequency and who prepares, serves, and eats dinner with them at a typical dinner meal. Analysis revealed that while Physical Satisfaction, Planned Amount, and Decreased Food Appeal were reported as the most frequent drivers of meal termination in both groups, scores for the RISE-Q-15 scales differed across the groups. Compared to Controls, persons with SCI reported Physical Satisfaction and Planned Amount as drivers of meal termination less frequently, and Decreased Food Appeal and Decreased Priority of Eating more frequently (all p < 0.001). This suggests that persons with SCI rely less on physiological satiation cues for meal termination than Controls and instead rely more on hedonic cues. Compared to Controls, persons with SCI less frequently reported preparing and serving dinner meals and less frequently reported eating alone (all p < 0.001), indicating differences in meal contexts between groups. Individuals with SCI reported consuming fewer meals than Controls but reported a higher overall eating frequency due to increased snacking (p ≤ 0.015). A decrease in the experience of physical fullness, along with a dependence on a communal meal context and frequent snacking, likely contribute to overeating associated with neurogenic obesity after SCI.

Calculation method for novel upright CT scanner isodose curves.

PURPOSE: A computational method based on Monte-Carlo calculations is presented and used to calculate isodose curves for a new upright and tilting CT scanner useful for radiation protection purposes. METHODS: The TOPAS code platform with imported CAD files for key components was used to construct a calculation space for the scanner. A sphere of water acts as the patient would by creating scatter out of the bore. Maximum intensity dose maps are calculated for various possible tilt angles to make sure radiation protection for site planning uses the maximum possible dose everywhere. RESULTS: The resulting maximum intensity isodose lines are more rounded than ones for just a single tilt angle and so closer to isotropic. These maximum intensity curves are closer to the isotropic assumption used in CTDI or DLP based methods of site planning and radiation protection. The isodose lines are similar to those of a standard CT scanner, just tilted upwards. There is more metal above the beam that lessens the dose above versus below isocenter. CONCLUSION: Aside from the orientation, this upright scanner is very similar to a typical CT scanner, and nothing different for shielding needs to be done for this new upright tilting CT scanner, because an isotropic scatter source is often assumed for any CT scanner.

Distinct Sensory Hedonic Functions for Sourness in Adults.

Over the last half-century, variable responses to sweetness have repeatedly been shown to fall into a small number of hedonic responses, implying that looking only at group means may can obfuscate meaningfully different response patterns. Comparative data for sourness is quite sparse, especially in adults. While increased liking with higher acid concentration has been reported for some children, in adults, sourness is classically assumed to be aversive, with a monotonic drop in liking with increasing sourness. Here, we test this assumption using a simple model system or experimental beverage in convenience samples of adults from the United States (increasing citric acid in water) and Italy (increasing citric acid in pear juice). Participants rated intensity and liking of sampled stimuli. For both cohorts, we find clear evidence of three distinct patterns of responses: a strong negative group where liking dropped with increased sourness, an intermediate group who showed a more muted drop in liking with more sourness, and a strong positive group where liking increased with more sourness. Strikingly, both cohorts showed similar proportions of response patterns, with ~63-70% in the strong negative group, and 11-12% in the strong positive group, suggesting these proportions may be stable across cultures. Notably, the three groups did not differ by age or gender. These data support the existence of different hedonic response profiles to sour stimuli in adults, once again highlighting the importance of looking at individual differences and potential consumer segments, rather than merely averaging hedonic responses across all individuals within a group.

Single-cell RNA-seq uncovers novel metabolic functions of Schwann cells beyond myelination.

Schwann cells (SCs) support peripheral nerves under homeostatic conditions, independent of myelination, and contribute to damage in prediabetic peripheral neuropathy (PN). Here, we used single-cell RNA sequencing to characterize the transcriptional profiles and intercellular communication of SCs in the nerve microenvironment using the high-fat diet-fed mouse, which mimics human prediabetes and neuropathy. We identified four major SC clusters, myelinating, nonmyelinating, immature, and repair in healthy and neuropathic nerves, in addition to a distinct cluster of nerve macrophages. Myelinating SCs acquired a unique transcriptional profile, beyond myelination, in response to metabolic stress. Mapping SC intercellular communication identified a shift in communication, centered on immune response and trophic support pathways, which primarily impacted nonmyelinating SCs. Validation analyses revealed that neuropathic SCs become pro-inflammatory and insulin resistant under prediabetic conditions. Overall, our study offers a unique resource for interrogating SC function, communication, and signaling in nerve pathophysiology to help inform SC-specific therapies.

Hollow core fiber Fabry-Perot interferometers with reduced sensitivity to temperature: erratum.

In the original publication of our research article "Hollow core fiber Fabry-Perot interferometers with reduced sensitivity to temperature" [Opt. Lett.47, 2510 (2022)10.1364/OL.456589OPLEDP0146-9592], we identified an error that requires correction. The authors sincerely apologize for any confusion that may have arisen from this error. The correction does not affect the overall conclusions of the paper.

Hollow-core fiber with stable propagation delay between -150°C and +60°C.

Optical fibers with a low thermal coefficient of delay (TCD) have been developed for frequency and timing transmission/distribution. However, their temperature sensitivity changes as a function of temperature and, to date, no study of such fibers has demonstrated improved performance over extended temperature ranges, especially at sub-zero temperatures. Here, we show that a hollow core fiber (HCF) with a thin acrylate coating can have a TCD within ±2.0 ps/km/°C over a broad temperature range from -150°C to +60°C. In addition, this thinly coated HCF can be fully insensitive to temperature around -134°C, making it of interest, e.g., for laser stabilization close to cryogenic temperatures.

Covid-19 affects taste independent of taste-smell confusions: results from a combined chemosensory home test and online survey from a large global cohort.

People often confuse smell loss with taste loss, so it is unclear how much gustatory function is reduced in patients self-reporting taste loss. Our pre-registered cross-sectional study design included an online survey in 12 languages with instructions for self-administering chemosensory tests with 10 household items. Between June 2020 and March 2021, 10,953 individuals participated. Of these, 5,225 self-reported a respiratory illness and were grouped based on their reported COVID test results: COVID-positive (COVID+, N = 3,356), COVID-negative (COVID-, N = 602), and COVID unknown for those waiting for a test result (COVID?, N = 1,267). The participants who reported no respiratory illness were grouped by symptoms: sudden smell/taste changes (STC, N = 4,445), other symptoms excluding smell or taste changes (OthS, N = 832), and no symptoms (NoS, N = 416). Taste, smell, and oral irritation intensities and self-assessed abilities were rated on visual analog scales. Compared to the NoS group, COVID+ was associated with a 21% reduction in taste (95% confidence interval (CI): 15-28%), 47% in smell (95% CI: 37-56%), and 17% in oral irritation (95% CI: 10-25%) intensity. There were medium to strong correlations between perceived intensities and self-reported abilities (r = 0.84 for smell, r = 0.68 for taste, and r = 0.37 for oral irritation). Our study demonstrates that COVID-19-positive individuals report taste dysfunction when self-tested with stimuli that have little to none olfactory components. Assessing the smell and taste intensity of household items is a promising, cost-effective screening tool that complements self-reports and may help to disentangle taste loss from smell loss. However, it does not replace standardized validated psychophysical tests.

Peripheral nerve involvement in hereditary spastic paraplegia characterized by quantitative magnetic resonance neurography.

BACKGROUND AND OBJECTIVES: Hereditary spastic paraplegias (HSPs) are heterogenous genetic disorders. While peripheral nerve involvement is frequent in spastic paraplegia 7 (SPG7), the evidence of peripheral nerve involvement in SPG4 is more controversial. We aimed to characterize lower extremity peripheral nerve involvement in SPG4 and SPG7 by quantitative magnetic resonance neurography (MRN). METHODS: Twenty-six HSP patients carrying either the SPG4 or SPG7 mutation and 26 age-/sex-matched healthy controls prospectively underwent high-resolution MRN with large coverage of the sciatic and tibial nerve. Dual-echo turbo-spin-echo sequences with spectral fat-saturation were utilized for T2-relaxometry and morphometric quantification, while two gradient-echo sequences with and without an off-resonance saturation rapid frequency pulse were applied for magnetization transfer contrast (MTC) imaging. HSP patients additionally underwent detailed neurologic and electroneurographic assessments. RESULTS: All microstructural (proton spin density [ρ], T2-relaxation time, magnetization transfer ratio) and morphometric (cross-sectional area) quantitative MRN markers were decreased in SPG4 and SPG7 indicating chronic axonopathy. ρ was superior in differentiating subgroups and identifying subclinical nerve damage in SPG4 and SPG7 without neurophysiologic signs of polyneuropathy. MRN markers correlated well with clinical scores and electroneurographic results. CONCLUSIONS: MRN characterizes peripheral nerve involvement in SPG4 and SPG7 as a neuropathy with predominant axonal loss. Evidence of peripheral nerve involvement in SPG4 and SPG7, even without electroneurographically manifest polyneuropathy, and the good correlation of MRN markers with clinical measures of disease progression, challenge the traditional view of the existence of HSPs with isolated pyramidal signs and suggest MRN markers as potential progression biomarkers in HSP.

Hollow-core fiber Fabry-Perot interferometers with reduced sensitivity to temperature.

We demonstrate a 3× thermal phase sensitivity reduction for a hollow-core fiber (HCF) Fabry-Perot interferometer by winding the already low temperature sensitivity HCF on to a spool made from an ultralow thermal expansion material. A record low room temperature fiber coil phase thermal sensitivity of 0.13 ppm/K is demonstrated. The result is of particular interest in reducing the thermal sensitivity of HCF-based Fabry-Perot interferometers (for which existing thermal sensitivity reduction methods are not applicable). Our theoretical analysis predicts that significantly lower (or even zero) thermal sensitivity should be achievable when a spool with a slightly negative coefficient of thermal expansion is used. We also suggest a method to fine-tune the thermal sensitivity and analyze it with simulations.

The Adaptive Olfactory Measure of Threshold (ArOMa-T): a rapid test of olfactory function.

Many widely used psychophysical olfactory tests have limitations that can create barriers to adoption. For example, tests that measure the ability to identify odors may confound sensory performance with memory recall, verbal ability, and prior experience with the odor. Conversely, classic threshold-based tests avoid these issues, but are labor intensive. Additionally, many commercially available tests are slow and may require a trained administrator, making them impractical for use in situations where time is at a premium or self-administration is required. We tested the performance of the Adaptive Olfactory Measure of Threshold (ArOMa-T)-a novel odor detection threshold test that employs an adaptive Bayesian algorithm paired with a disposable odorant delivery card-in a non-clinical sample of individuals (n = 534) at the 2021 Twins Day Festival in Twinsburg, OH. Participants successfully completed the test in under 3 min with a false alarm rate of 7.5% and a test-retest reliability of 0.61. Odor detection thresholds differed by sex (~3.2-fold lower for females) and age (~8.7-fold lower for the youngest versus the oldest age group), consistent with prior studies. In an exploratory analysis, we failed to observe evidence of detection threshold differences between participants who reported a history of COVID-19 and matched controls who did not. We also found evidence for broad-sense heritability of odor detection thresholds. Together, this study suggests the ArOMa-T can determine odor detection thresholds. Additional validation studies are needed to confirm the value of ArOMa-T in clinical or field settings where rapid and portable assessment of olfactory function is needed.

Quantitative magnetic resonance neurographic characterization of peripheral nerve involvement in manifest and pre-ataxic spinocerebellar ataxia type 3.

BACKGROUND AND PURPOSE: Knowledge about the exact underlying pathophysiological changes involved in the genesis and progression of spinocerebellar ataxia type 3 (SCA3) is limited. Lower extremity peripheral nerve lesions in clinically, genetically and electrophysiologically classified ataxic and pre-ataxic SCA3 mutation carriers were characterized and quantified by magnetic resonance neurography (MRN). METHODS: Eighteen SCA3 mutation carriers and 20 age-/sex-matched healthy controls were prospectively enrolled. All SCA3 mutation carriers underwent detailed neurological and electrophysiological examinations. 3 T MRN covered the lumbosacral plexus and proximal thigh to the tibiotalar joint by using T2-weighted inversion recovery sequences, dual-echo relaxometry sequences with spectral fat saturation, and two gradient-echo sequences with and without an off-resonance saturation rapid frequency pulse. Detailed quantification of nerve lesions by morphometric and microstructural MRN markers, including T2 relaxometry and magnetization transfer contrast imaging, was conducted in all study participants. RESULTS: MRN detected peripheral nerve damage in ataxic and pre-ataxic SCA3. The quantitative markers proton spin density (ρ), T2 relaxation time, magnetization transfer ratio and cross-sectional area were decreased in SCA3, indicating chronic axonopathy. MTR and ρ identified early, subclinical nerve damage in pre-ataxic SCA3 and in SCA3 mutation carriers without polyneuropathy and were superior in differentiating between all subgroups. Additionally, microstructural markers correlated well with clinical symptom scores and electrophysiological results. CONCLUSIONS: Our data provide a comprehensive characterization of peripheral nerve damage in SCA3 and assist in understanding the mechanisms of the multisystemic disease evolution. Evidence of peripheral nerve involvement prior to the onset of clinically overt ataxia might have important implications for designing early intervention studies.

Characterization and quantification of alcohol-related polyneuropathy by magnetic resonance neurography.

BACKGROUND: We characterized and quantified peripheral nerve damage in alcohol-dependent patients (ADP) by magnetic resonance neurography (MRN) in correlation with clinical and electrophysiologic findings. METHODS: Thirty-one adult patients with a history of excessive alcohol consumption and age-/sex-matched healthy controls were prospectively examined. After detailed neurologic and electrophysiologic testing, the patient group was subdivided into ADP with alcohol-related polyneuropathy (ALN) and without ALN (Non-ALN). 3T MRN with anatomical coverage from the proximal thigh down to the tibiotalar joint was performed using dual-echo 2-dimensional relaxometry sequences with spectral fat saturation. Detailed quantification of nerve injury by morphometric (cross-sectional area [CSA]) and microstructural MRN markers (proton spin density [ρ], apparent T2-relaxation-time [T2app ]) was conducted in all study participants. RESULTS: MRN detected nerve damage in ADP with and without ALN. A proximal-to-distal gradient was identified for nerve T2-weighted (T2w)-signal and T2app in ADP, indicating a proximal predominance of nerve lesions. While all MRN markers differentiated significantly between ADP and controls, microstructural markers were able to additionally differentiate between subgroups: tibial nerve ρ at thigh level was increased in ALN (p < 0.0001) and in Non-ALN (p = 0.0052) versus controls, and T2app was higher in ALN versus controls (p < 0.0001) and also in ALN versus Non-ALN (p = 0.0214). T2w-signal and CSA were only higher in ALN versus controls. CONCLUSIONS: MRN detects and quantifies peripheral nerve damage in ADP in vivo even in the absence of clinically overt ALN. Microstructural markers (T2app , ρ) are most suitable for differentiating between ADP with and without manifest ALN, and may help to elucidate the underlying pathomechanism in ALN.

Obesity-induced neuroinflammation and cognitive impairment in young adult versus middle-aged mice.

BACKGROUND: Obesity rates are increasing worldwide. Obesity leads to many complications, including predisposing individuals to the development of cognitive impairment as they age. Immune dysregulation, including inflammaging (e.g., increased circulating cytokines) and immunosenescence (declining immune system function), commonly occur in obesity and aging and may impact cognitive impairment. As such, immune system changes across the lifespan may impact the effects of obesity on neuroinflammation and associated cognitive impairment. However, the role of age in obesity-induced neuroinflammation and cognitive impairment is unclear. To further define this putative relationship, the current study examined metabolic and inflammatory profiles, along with cognitive changes using a high-fat diet (HFD) mouse model of obesity. RESULTS: First, HFD promoted age-related changes in hippocampal gene expression. Given this early HFD-induced aging phenotype, we fed HFD to young adult and middle-aged mice to determine the effect of age on inflammatory responses, metabolic profile, and cognitive function. As anticipated, HFD caused a dysmetabolic phenotype in both age groups. However, older age exacerbated HFD cognitive and neuroinflammatory changes, with a bi-directional regulation of hippocampal inflammatory gene expression. CONCLUSIONS: Collectively, these data indicate that HFD promotes an early aging phenotype in the brain, which is suggestive of inflammaging and immunosenescence. Furthermore, age significantly compounded the impact of HFD on cognitive outcomes and on the regulation of neuroinflammatory programs in the brain.

Do children really eat what they like? Relationships between liking and intake across laboratory test-meals.

Liking plays a primary role in determining what and how much children eat. Despite this, the relationship between liking and intake of foods and beverages served as part of a meal is not often reported, even though pediatric feeding studies frequently collect such data. In addition, few studies have reported on the test-retest reliability of both hedonic ratings and laboratory intake among children. To address these gaps, this study was designed to assess the relationship between children's liking of items at a meal and subsequent intake. 61, 4-6 year-olds were recruited to participate in two identical laboratory sessions where liking of 7 foods (i.e., chicken nuggets, ketchup, potato chips, grapes, broccoli, cherry tomatoes, cookie) and 2 beverages (i.e., fruit punch, milk) was assessed (5-point hedonic scale) prior to ad libitum consumption of the same items at a meal. Spearman's correlations tested the relationship between liking and intake and intra-class correlations assessed inter-session reliability of both measures. Liking for potato chips (p < 0.01), grapes (p < 0.05), cherry tomatoes (p < 0.001), and fruit punch (p < 0.001) was positively associated with amount consumed, but no associations were found between liking and intake of other meal items. For the majority of meal items, test-retest reliability of liking and intake were significant (ranging from 0.34 for cookies to 0.93 for tomatoes). At a multi-component meal, children's hedonic ratings were both reliable and modestly predictive of subsequent intake, and the relationships were stronger for lower energy, less well-liked foods. Rather than eating what they like, these data are more consistent with the notion that children do not eat what they dislike.

Evidence based opioid weaning with behavioral support - Forum for Behavioral Science Edition.

Nationally published guidelines state that many patients prescribed chronic opioids would benefit from gradually reducing and/or eliminating their use of these medications. This is easier said than done. Patients are often resistant or fearful, physicians are often uncomfortable prescribing an opioid taper, and patients often do not get the needed behavioral health support in this process. It is critical to develop a comprehensive behavioral and medical plan, however the field lacks practical approaches to guide physicians (and patients) through this challenge. In this manuscript our team of primary care providers and behaviorists walk through a case involving complex opioid weaning in a Family Medicine residency clinic environment. Through the lens of our patient's case, we will discuss best practices for getting patient buy-in, opioid weaning strategies, behavioral support during the wean, identifying co-morbid opioid use disorders, and deciding on acceptable end points for the taper.

Massively collaborative crowdsourced research on COVID19 and the chemical senses: Insights and outcomes.

In March 2020, the Global Consortium of Chemosensory Research (GCCR) was founded by chemosensory researchers to address emerging reports of unusual smell and taste dysfunction arising from the SARS-CoV-2 pandemic. Over the next year, the GCCR used a highly collaborative model, along with contemporary Open Science practices, to produce multiple high impact publications on chemosensation and COVID19. This invited manuscript describes the founding of the GCCR, the tools and approaches it used, and a summary of findings to date. These findings are contextualized within a summary of some of the broader insights about chemosensation (smell, taste, and chemesthesis) and COVID19 gained over the last 18 months, including potential mechanisms of loss. Also, it includes a detailed discussion of some current Open Science approaches and practices used by the GCCR to increase transparency, rigor, and reproducibility.

Metastatic Myxofibrosarcoma with Durable Response to Temozolomide Followed by Atezolizumab: A Case Report.

Myxofibrosarcoma (MFS) is a well-recognized histotype of soft tissue sarcomas that generally presents with localized disease. Herein, we describe the case of a patient with metastatic MFS who experienced durable response to sixth-line therapy with temozolomide. Upon further progression, his tumor was notable for a high tumor mutational burden, and he was subsequently treated with seventh-line immunotherapy, atezolizumab, achieving a second durable response. This case highlights the role of immunotherapy after administration of alkylating agents. Review of the literature indicates that recurrent tumors treated with alkylating agents often experience hypermutation as a means of developing resistance and that checkpoint inhibitors are subsequently effective in these tumors. KEY POINTS: To the authors' knowledge, this is the first report of a patient with myxofibrosarcoma with high tumor mutational burden after administration of temozolomide monotherapy. Hypermutation may be a resistance mechanism for patients with soft tissue sarcoma who develop resistance to alkylating agents. Checkpoint inhibition may be effective therapy in patients with soft tissue sarcoma with high tumor mutational burden as a consequence of alternate systemic therapy resistance.