Small Heat Shock Protein 22 Improves Cognition and Learning in the Tauopathic Brain

The microtubule-associated protein tau pathologically accumulates and aggregates in Alzheimer’s disease (AD) and other tauopathies, leading to cognitive dysfunction and neuronal loss. Molecular chaperones, like small heat-shock proteins (sHsps), can help deter the accumulation of misfolded proteins, such as tau. Here, we tested the hypothesis that the overexpression of wild-type Hsp22 (wtHsp22) and its phosphomimetic (S24,57D) Hsp22 mutant (mtHsp22) could slow tau accumulation and preserve memory in a murine model of tauopathy, rTg4510. Our results show that Hsp22 protected against deficits in synaptic plasticity and cognition in the tauopathic brain. However, we did not detect a significant change in tau phosphorylation or levels in these mice. This led us to hypothesize that the functional benefit was realized through the restoration of dysfunctional pathways in hippocampi of tau transgenic mice since no significant benefit was measured in non-transgenic mice expressing wtHsp22 or mtHsp22. To identify these pathways, we performed mass spectrometry of tissue lysates from the injection site. Overall, our data reveal that Hsp22 overexpression in neurons promotes synaptic plasticity by regulating canonical pathways and upstream regulators that have been characterized as potential AD markers and synaptogenesis regulators, like EIF4E and NFKBIA.

Continuous dynamics in behavior reveal perceptual nonlinearities aid speech categorization in noise

Spoken language comprehension requires listeners map continuous features of the speech signal to discrete category labels. Categories are however malleable to surrounding context; listeners’ percept can dynamically shift depending on the sequencing of adjacent stimuli resulting in a warping of the heard phonetic category (i.e., hysteresis). Here, we investigated whether such perceptual nonlinearities—which amplify categorical hearing—might further aid speech processing in noise-degraded listening scenarios. We measured continuous dynamics in perception and category judgments of an acoustic-phonetic vowel gradient via mouse tracking. Tokens were presented in serial vs. random orders to induce more/less perceptual warping while listeners categorized continua in clean and noise conditions. Listeners’ responses were faster and their mouse trajectories closer to the ultimate behavioral selection (marked visually on the screen) in serial vs. random order, suggesting increased perceptual attraction to category exemplars. Interestingly, order effects emerged earlier and persisted later in the trial time course when categorizing speech in noise. These data describe a new functional benefit of perceptual nonlinearities to speech perception yet undocumented: warping strengthens the behavioral attraction to relevant speech categories while simultaneously assisting perception in degraded acoustic environments.

Assistive Devices: Technology Development for the Visually Impaired

Technology has been contributing significantly to the development of assistive devices for disabled persons (DPs). Many of these devices aim to assist people who are blind or visually impaired, providing them with friendlier ways to interact with their surroundings (obstacles, objects, and navigation). However, the high cost of these devices makes it difficult for DPs to purchase them. The development of an assistive device kit to be used by the visually impaired in controlled environments (indoor) or urban spaces (outdoor) is presented in this work with a didactic and detailed approach. This low-cost kit (USD 50 per device) consists of a Smart Cane, Smart Cap, and Smart Glove. The methodology addressed aims to support and encourage the reproduction, customization, and manufacture of new assistive devices with low cost and wide applicability. The devices are functional, benefit usability, and, due to the characteristics of the project and the materials used in their construction, do not impact the ergonomics of the visually impaired or disabled person who may use these devices. The devices that integrate the assistive kit can be used independently or combined. In addition to having detection, fall-control, navigation, and real-time tracking functions, they are independent of additional local infrastructure for their use.

Aging consumers and their brands: the customer journey perspective

PurposeWith the increasing numbers of the elderly people, the aging segment represents a potential huge market. While this trend is obvious, still little literature focuses on this group. The study thus fills up this gap. Furthermore, the study aims to examine the aging consumers' journeys from the lens of brand resonance pyramid and has its importance using context-specific theories to understand the elderly consumers.Design/methodology/approachCase study method is conducted using the in-depth interview to collect data and inductive method via MaxQda software to analyze. Two types of aging brand (i.e. age-denial and age-adaptive) are investigated (Moody and Sood, 2010). This study interviews 26 elderly consumers, among whom, 12 have experiences in sports gyms (i.e. age-denial) and 14 in hospital services (i.e. age-adaptive). The author also triangulates the results by interviewing two additional experts in these contexts.FindingsThe findings of the paper reveal that (1) brand functional benefit is important for both age-denial and age-adaptive brands while each has different dimensions. Brand experiential benefit (e.g. social, behavioral and intellectual experience) is important motivation for the age-denial brand and brand symbolic and brand psychological benefits are the emotional drivers for the age-adaptive brand. (2) Consequences of this journey include those, for example, brand satisfaction, brand loyalty, word-of-mouth and recommendation and (3) mediating mechanisms, e.g. brand sense of identification, brand psychological attachment and customization for both brand types, with exceptions of diversification and brand psychological attachment, and mutual interaction for the age-denial brand and doctor–patient relationship and consumer inertia for the age-adaptive brand. (4) The current study finds two new concepts for aging consumers, i.e. brand social experience in the age-denial brand and brand psychological benefit in the age-adaptive brand.Research limitations/implications(1) Results of the paper are context dependent and generalization issue might occur. (2) While it is analyzed using inductive method via MaxQda software, the interviewer's subjective bias might occur. (3) Interviewees are at their different life stages, i.e. early-old vs mid-old, and thus, these contextual factors might also influence the results.Originality/value(1) The current study explores the elderly consumers' experience journeys at three stages (i.e. pre-service, during-service and pro-service/loyalty loop) for age-denial and age-adaptive brands and deepen an understanding of this aging market; (2) offers practical implications to brands targeting at the elderly consumers, particularly the age-denial and age-adaptive brands; (3) uses customer journey theory and brand resonance pyramid as the lens to understand aging consumers, and results also partly echo with the theories and (4) explores two new concepts for aging consumers, i.e. brand social experience and brand psychological benefit, thus adding new dimensions to important constructs, i.e. brand experience and brand benefit.

P.059 Results From the Randomized and Open-Label Periods of the CENTAUR Trial of Sodium Phenylbutyrate and Ursodoxicoltaurine in Amyotrophic Lateral Sclerosis (ALS)

Background: An oral, fixed-dose sodium phenylbutyrate-ursodoxicoltaurine (PB-TURSO) coformulation was evaluated in a multicenter ALS trial (CENTAUR). Methods: Adults with definite ALS, ≤18 months from symptom onset, (N=137) were randomized 2:1 to PB-TURSO or placebo for 6 months. Completing participants were eligible to receive PB-TURSO in the open-label extension (OLE) (≤30 months). The primary efficacy endpoint in both periods was rate of ALS Functional Rating Scale–Revised (ALSFRS-R) total score decline. All-cause survival was analyzed July 2020 (longest follow-up, 35 months). Safety was assessed in both periods. Results: Over 6-month randomized treatment, mean ALSFRS-R total score decline was slower with PB-TURSO vs placebo (difference, 0.42 points/month; P=0.03). Participants receiving PB-TURSO in the OLE (continued or crossover from placebo) maintained or initiated functional benefit beyond 6 months of therapy. Mean hazard of death was 44% lower (P=0.02) in the original PB-TURSO group. Overall adverse event (AE) incidence was similar, though early (week ≤3) gastrointestinal AEs were more frequent during initial exposure to PB-TURSO (randomized period or OLE). Conclusions: PB-TURSO resulted in superior retention of function in the randomized period. Long-term OLE results support functional benefits of early vs delayed therapy and of sustained treatment. Survival was longer in the original PB-TURSO group after nearly 3 years.

Ribonuclease-1 treatment after traumatic brain injury preserve the integrity of the neurovascular unit, decreases inflammatory response and delays secondary brain damage in mice

Traumatic brain injury (TBI) involves primary mechanical damage and delayed secondary damage caused by vascular dysfunction and neuroinflammation. Intracellular components released into the parenchyma and systemic circulation, termed danger-associated molecular patterns (DAMPs), are major drivers of vascular dysfunction and neuroinflammation. These DAMPs include cell-free RNAs (cfRNAs), which damage the blood–brain barrier (BBB), thereby promoting edema, procoagulatory processes, and infiltration of inflammatory cells. We tested the hypothesis that intraperitoneal injection of Ribonuclease-1 (RNase1, two doses of 20, 60, or 180 µg/kg) at 30 min and 12h after controlled-cortical-impact (CCI) can reduce secondary lesion expansion compared to vehicle treatment 24h and 120h post-CCI. The lowest total dose (40 µg/kg) was most effective at reducing lesion volume (−31% RNase 40µg/kg vs. vehicle), brain water accumulation (−5.5%), and loss of BBB integrity (−21.6%) at 24h post-CCI. RNase1 also reduced perilesional leukocyte recruitment (−53.3%) and microglial activation (−18.3%) at 120h post-CCI, but there was no difference in lesion volume at this time and no functional benefit. Treatment with RNase1 in the early phase following TBI stabilizes the BBB and impedes leukocyte immigration, thereby suppressing neuroinflammation. RNase1-treatment may be a novel approach to delay brain injury to extend the window for treatment opportunities after TBI.

From Microns to Meters: Exploring Advances in Legume Microbiome Diversity for Agroecosystem Benefits

Legumes are of primary importance for agroecosystems because they provide protein-rich foods and enhance soil fertility through fixed atmospheric nitrogen. The legume-rhizobia symbiosis that makes this possible has been extensively studied, from basic research on biochemical signaling to practical applications in cropping systems. While rhizobia are the most-studied group of associated microorganisms, the functional benefit they confer to their legume hosts by fixing nitrogen is not performed in isolation. Indeed, non-rhizobia members of the rhizosphere and nodule microbiome are now understood to contribute in multiple ways to nodule formation, legume fitness, and other agroecosystem services. In this review, we summarize advances contributing to our understanding of the diversity and composition of bacterial members of the belowground legume microbiome. We also highlight applied work in legume food and forage crops that link microbial community composition with plant functional benefits. Ultimately, further research will assist in the development of multi-species microbial inoculants and cropping systems that maximize plant nutrient benefits, while reducing sources of agricultural pollution.

Hygienic Assessment of Disposable Baby Diapers Made with Innovative Materials

Background: It is of current importance to develop an algorithm for assessing chemical and physical safety of products for children and adolescents made with such innovative materials as organic cotton, bamboo, fibers and threads containing silver ions used for children’s underwear, materials impregnated with marigold extract for insoles of children’s footwear, and diapers from plant raw materials. The institute conducts testing and scientific substantiation of children’s goods made using innovative technologies. Objective: To assess safety of diapers made with innovative materials (ECO-diapers). Materials and methods: We conducted physicochemical, toxicological and organoleptic testing of 200 samples of medium size disposable baby ECO-diapers made with innovative materials. Results: The results of chemical and toxicological tests of ECO-diapers in a model aqueous environment showed that the formaldehyde concentration in aqueous extracts of the diaper samples ranged from 0.08 ± 0.020 to 0.1 mg/dm3; toxicity index values – from 74.1 to 89.1 %; pH – from 0.35 to 0.5 units, and the total phenolic content – from < 0.005 to 0.024 ± 0.002 mg/dm3, thus being within permissible limits. Measured concentrations of acetaldehyde, acrylonitrile, acetone, benzene, hexane, methyl and propyl alcohols, toluene, ethyl acetate, lead, arsenic, zinc, chromium were also below threshold values. Chemical testing of the samples of baby diapers in a model air environment with exposure duration of 4, 12, and 24 hours detected migration of chemicals already after four hours of exposure, which did not change following 12 and 24 hours. The value of water absorption capacity, which is one of the main indicators of functional benefit of diapers, ranged from 307.6 ± 30.8 g to 355.5 ± 35.5 g and significantly exceeded the established standard (not less than 240.0 g for medium size diapers) owing to the use of innovative materials in the production of ECO-diapers. Conclusions: Our findings demonstrate the necessity to develop special methodological approaches to measuring breathability of ECO- and traditional diapers, to regulate smell by including this organoleptic quality criterion in the list of safety requirements, and to limit exposure duration in a model air environment to four hours.

Mitochondrial augmentation of CD34+ cells from healthy donors and patients with mitochondrial DNA disorders confers functional benefit

Mitochondria are cellular organelles critical for numerous cellular processes and harboring their own circular mitochondrial DNA (mtDNA). Most mtDNA associated disorders (either deletions, mutations, or depletion) lead to multisystemic disease, often severe at a young age, with no disease-modifying therapies. Mitochondria have a capacity to enter eukaryotic cells and to be transported between cells. We describe a method of ex vivo augmentation of hematopoietic stem and progenitor cells (HSPCs) with normal exogenous mitochondria, termed mitochondrial augmentation therapy (MAT). Here, we show that MAT is feasible and dose dependent, and improves mitochondrial content and oxygen consumption of healthy and diseased HSPCs. Ex vivo mitochondrial augmentation of HSPCs from a patient with a mtDNA disorder leads to superior human engraftment in a non-conditioned NSGS mouse model. Using a syngeneic mouse model of accumulating mitochondrial dysfunction (Polg), we show durable engraftment in non-conditioned animals, with in vivo transfer of mitochondria to recipient hematopoietic cells. Taken together, this study supports MAT as a potential disease-modifying therapy for mtDNA disorders.