Enabling usable science takes a community: Using our roles as funders to catalyze change.

Calls to support co-designed and usable science to inform management of natural resources are growing. Making the shift will require diverse collaborations between those who hold, share, and use knowledge.

Severely Attenuated Visual Feedback Processing in Children on the Autism Spectrum.

Individuals on the autism spectrum often exhibit atypicality in their sensory perception, but the neural underpinnings of these perceptual differences remain incompletely understood. One proposed mechanism is an imbalance in higher-order feedback re-entrant inputs to early sensory cortices during sensory perception, leading to increased propensity to focus on local object features over global context. We explored this theory by measuring visual evoked potentials during contour integration as considerable work has revealed that these processes are largely driven by feedback inputs from higher-order ventral visual stream regions. We tested the hypothesis that autistic individuals would have attenuated evoked responses to illusory contours compared with neurotypical controls. Electrophysiology was acquired while 29 autistic and 31 neurotypical children (7-17 years old, inclusive of both males and females) passively viewed a random series of Kanizsa figure stimuli, each consisting of four inducers that were aligned either at random rotational angles or such that contour integration would form an illusory square. Autistic children demonstrated attenuated automatic contour integration over lateral occipital regions relative to neurotypical controls. The data are discussed in terms of the role of predictive feedback processes on perception of global stimulus features and the notion that weakened "priors" may play a role in the visual processing anomalies seen in autism.SIGNIFICANCE STATEMENT Children on the autism spectrum differ from typically developing children in many aspects of their processing of sensory stimuli. One proposed mechanism for these differences is an imbalance in higher-order feedback to primary sensory regions, leading to an increased focus on local object features rather than global context. However, systematic investigation of these feedback mechanisms remains limited. Using EEG and a visual illusion paradigm that is highly dependent on intact feedback processing, we demonstrated significant disruptions to visual feedback processing in children with autism. This provides much needed experimental evidence that advances our understanding of the contribution of feedback processing to visual perception in autism spectrum disorder.

It's all in the timing: delayed feedback in autism may weaken predictive mechanisms during contour integration.

Humans rely on predictive and integrative mechanisms during visual processing to efficiently resolve incomplete or ambiguous sensory signals. Although initial low-level sensory data are conveyed by feedforward connections, feedback connections are believed to shape sensory processing through automatic conveyance of statistical probabilities based on prior exposure to stimulus configurations. Individuals with autism spectrum disorder (ASD) show biases in stimulus processing toward parts rather than wholes, suggesting their sensory processing may be less shaped by statistical predictions acquired through prior exposure to global stimulus properties. Investigations of illusory contour (IC) processing in neurotypical (NT) adults have established a well-tested marker of contour integration characterized by a robust modulation of the visually evoked potential (VEP)-the IC-effect-that occurs over lateral occipital scalp during the timeframe of the visual N1 component. Converging evidence strongly supports the notion that this IC-effect indexes a signal with significant feedback contributions. Using high-density VEPs, we compared the IC-effect in 6- to 17-yr-old children with ASD (n = 32) or NT development (n = 53). Both groups of children generated an IC-effect that was equivalent in amplitude. However, the IC-effect notably onset 21 ms later in ASD, even though initial VEP afference was identical across groups. This suggests that feedforward information predominated during perceptual processing for 15% longer in ASD compared with NT children. This delay in the feedback-dependent IC-effect, in the context of known developmental differences between feedforward and feedback fibers, suggests a potential pathophysiological mechanism of visual processing in ASD, whereby ongoing stimulus processing is less shaped by visual feedback.NEW & NOTEWORTHY Children with autism often present with an atypical visual perceptual style that emphasizes parts or details over the whole. Using electroencephalography (EEG), this study identifies delays in the visual feedback from higher-order sensory brain areas to primary sensory regions. Because this type of visual feedback is thought to carry information about prior sensory experiences, individuals with autism may have difficulty efficiently using prior experience or putting together parts into a whole to help make sense of incoming new visual information. This provides empirical neural evidence to support theories of disrupted sensory perception mechanisms in autism.

Targeting Molecular Mechanisms of Obesity- and Type 2 Diabetes Mellitus-Induced Skeletal Muscle Atrophy with Nerve Growth Factor.

Skeletal muscle plays a critical role in metabolic diseases, such as obesity and type 2 diabetes mellitus (T2DM). Muscle atrophy, characterized by a decrease in muscle mass and function, occurs due to an imbalance between the rates of muscle protein synthesis and degradation. This study aimed to investigate the molecular mechanisms that lead to muscle atrophy in obese and T2DM mouse models. Additionally, the effect of nerve growth factor (NGF) on the protein synthesis and degradation pathways was examined. Male mice were divided into three groups: a control group that was fed a standard chow diet, and two experimental groups that were fed a Western diet. After 8 weeks, the diabetic group was injected with streptozotocin to induce T2DM. Each group was then further divided into NGF-treated or non-treated control group. In the gastrocnemius muscles of the Western diet group, increased expressions of myostatin, autophagy markers, and ubiquitin ligases were observed. Skeletal muscle tissue morphology indicated signs of muscle atrophy in both obese and diabetic mice. The NGF-treated group showed a prominent decrease in the protein levels of myostatin and autophagy markers. Furthermore, the NGF-treated group showed an increased Cyclin D1 level. Western diet-induced obesity and T2DM may be linked to muscle atrophy through upregulation of myostatin and subsequent increase in the ubiquitin and autophagy systems. Moreover, NGF treatment may improve muscle protein synthesis and cell cycling.

The strength of feedback processing is associated with resistance to visual backward masking during Illusory Contour processing in adult humans.

Re-entrant feedback processing is a key mechanism of visual object-recognition, especially under compromised viewing conditions where only sparse information is available and object features must be interpolated. Illusory Contour stimuli are commonly used in conjunction with Visual Evoked Potentials (VEP) to study these filling-in processes, with characteristic modulation of the VEP in the ∼100-150 ms timeframe associated with this re-entrant processing. Substantial inter-individual variability in timing and amplitude of feedback-related VEP modulation is observed, raising the question whether this variability might underlie inter-individual differences in the ability to form strong perceptual gestalts. Backward masking paradig ms have been used to study inter-individual variance in the ability to form robust object perceptions before processing of the mask interferes with object-recognition. Some individuals recognize objects when the time between target object and mask is extremely short, whereas others struggle to do so even at longer target-to-mask intervals. We asked whether timing and amplitude of feedback-related VEP modulations were associated with individual differences in resistance to backward masking. Participants (N=40) showed substantial performance variability in detecting Illusory Contours at intermediate target-to-mask intervals (67 ms and 117 ms), allowing us to use kmeans clustering to divide the population into four performance groups (poor, low-average, high-average, superior). There was a clear relationship between the amplitude (but not the timing) of feedback-related VEP modulation and Illusory Contour detection during backward masking. We conclude that individual differences in the strength of feedback processing in neurotypical humans lead to differences in the ability to quickly establish perceptual awareness of incomplete visual objects.

Hypothetical proteins play a role in stage conversion, virulence, and the stress response in the Entamoeba species.

Entamoeba histolytica is a protozoan parasite that causes amoebic dysentery and amoebic liver abscess in humans, affecting millions of people worldwide. This pathogen possesses a two-stage life cycle consisting of an environmentally stable cyst and a pathogenic amoeboid trophozoite. As cysts can be ingested from contaminated food and water, this parasite is prevalent in underdeveloped countries and poses a significant health burden. Until recently there was no reliable method for inducing stage conversion in E. histolytica in vitro. As such, the reptilian pathogen, Entamoeba invadens, has long-served as a surrogate. Much remains unclear about stage conversion in these parasites and current treatments for amoebiasis are lacking, as they cause severe side effects. Therefore, new therapeutic strategies are needed. The genomes of these parasites remain enigmatic as approximately 54% of E. histolytica genes and 66% of E. invadens genes are annotated as hypothetical proteins. In this study, we characterized two hypothetical proteins in the Entamoeba species, EIN_059080, in E. invadens, and its homolog, EHI_056700, in the human pathogen, E. histolytica. EHI_056700 has no homolog in the human host. We used an RNAi-based silencing system to reduce expression of these genes in E. invadens and E. histolytica trophozoites. Loss of EIN_059080 resulted in a decreased rate of encystation and an increased rate of erythrophagocytosis, an important virulence function. Additionally, mutant parasites were more susceptible to oxidative stress. Similarly, loss of EHI_056700 in E. histolytica trophozoites resulted in increased susceptibility to oxidative stress and glucose deprivation, but not to nitrosative stress. Unlike the E. invadens mutants, E. histolytica parasites with decreased reduced expression of EHI_056700 exhibited a decreased rate of erythrophagocytosis of and adhesion to host cells. Taken together, these data suggest that these hypothetical proteins play a role in stage conversion, virulence, and the response to stress in the Entamoebae. Since parasites with reduced expression of EHI_056700 show decreased virulence functions and increased susceptibility to physiologically relevant stressors, EHI_056700 may represent a possible therapeutic target for the treatment of amoebiasis.

pH: the silent variable significantly impacting meiotic spindle assembly in mouse oocytes.

RESEARCH QUESTION: Temperature fluctuation negatively impacts the assembly and function of the meiotic spindle, but does pH have a similar effect? DESIGN: Polarized light microscopy was used to study the spindle in living mouse oocytes under different pH conditions. Female mice (n = 53) were superovulated, and oocytes collected, denuded and allocated to treatment groups. All experiments were performed at 37°C, and standard bicarbonate-buffered medium was used either pre-equilibrated in 6% CO2 or unequilibrated (in ambient CO2). Mean oocyte spindle retardance was measured over time in response to changing pH. Spindles were also assessed to understand whether this effect was reversible, by using a fixed pH in a zwitterionic buffer. RESULTS: The data show the spindle is impacted by pH fluctuation, with mean retardance significantly higher at pH 7.4-7.5 than at the point of media equilibration (P < 0.001). This effect was found to be reversible; retardance significantly decreased after transition of the oocytes from pH 7.43 or pH 7.53 back to the original pre-equilibration pH of 7.32 (P < 0.05). CONCLUSIONS: This study has shown that the meiotic spindle in mouse oocytes is highly sensitive to changes in oocyte culture media pH. If comparable in humans, this has significance as to the pH level of culture media currently used in assisted reproductive technology clinics worldwide, and reinforces the requirement for stringent control over extrinsic variables in the IVF laboratory.

Identification of an active metabolite of PAR-1 antagonist RWJ-58259 and synthesis of analogues to enhance its metabolic stability.

The discontinuation of PAR-1 antagonist RWJ-58259 beyond use as a biological probe is most likely due to it's short half-life in vivo. However, retention of significant in vivo activity beyond the point where most of the RWJ-58259 had been consumed implies the generation of an active metabolite. Herein we describe the biological activity of a predicted metabolite of RWJ-58259 and the synthesis of analogues designed to enhance the metabolic stability of RWJ-58259.

Synthesis of novel and potent vorapaxar analogues.

Vorapaxar is a first-in-class PAR-1 antagonistic drug based on the ent-himbacine scaffold. Detailed in this article are enantioselective and racemic routes to various novel vorapaxar analogues. Biological testing revealed these compounds to have moderate to excellent potencies against PAR-1 with the most potent analogue demonstrating an IC50 of 27 nM.

Stimulation-Induced Transient Nonmotor Psychiatric Symptoms following Subthalamic Deep Brain Stimulation in Patients with Parkinson's Disease: Association with Clinical Outcomes and Neuroanatomical Correlates.

BACKGROUND: The clinical and neurobiological underpinnings of transient nonmotor (TNM) psychiatric symptoms during the optimization of stimulation parameters in the course of subthalamic nucleus deep brain stimulation (STN-DBS) remain under intense investigation. METHODS: Forty-nine patients with refractory Parkinson's disease underwent bilateral STN-DBS implants and were enrolled in a 24-week prospective, naturalistic follow-up study. Patients who exhibited TNM psychiatric manifestations during DBS parameter optimization were evaluated for potential associations with clinical outcome measures. RESULTS: Twenty-nine TNM+ episodes were reported by 15 patients. No differences between TNM+ and TNM- groups were found in motor outcome. However, unlike the TNM- group, TNM+ patients did not report improvement in subsyndromal depression or quality of life. TNM+ episodes were more likely to emerge during bilateral monopolar stimulation of the medial STN. CONCLUSIONS: The occurrence of TNM psychiatric symptoms during optimization of stimulation parameters was associated with the persistence of subsyndromal depression and with lower quality of life ratings at 6 months. The neurobiological underpinnings of TNM symptoms are investigated yet remain difficult to explain.

Frequency-dependent functional neuromodulatory effects on the motor network by ventral lateral thalamic deep brain stimulation in swine.

Thalamic deep brain stimulation (DBS) is an FDA-approved neurosurgical treatment for medication-refractory essential tremor. Its therapeutic benefit is highly dependent upon stimulation frequency and voltage parameters. We investigated these stimulation parameter-dependent effects on neural network activation by performing functional magnetic resonance imaging (fMRI) during DBS of the ventral lateral (VL) thalamus and comparing the blood oxygenation level-dependent (BOLD) signals induced by multiple stimulation parameter combinations in a within-subject study of swine. Low (10 Hz) and high (130 Hz) frequency stimulation was applied at 3, 5, and 7 V in the VL thalamus of normal swine (n = 5). We found that stimulation frequency and voltage combinations differentially modulated the brain network activity in the sensorimotor cortex, the basal ganglia, and the cerebellum in a parameter-dependent manner. Notably, in the motor cortex, high frequency stimulation generated a negative BOLD response, while low frequency stimulation increased the positive BOLD response. These frequency-dependent differential effects suggest that the VL thalamus is an exemplary target for investigating functional network connectivity associated with therapeutic DBS.

Phase 1 dose escalation trial of ilorasertib, a dual Aurora/VEGF receptor kinase inhibitor, in patients with hematologic malignancies.

BACKGROUND: Ilorasertib (ABT-348) is a novel inhibitor of Aurora kinase, vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptors, and the Src families of tyrosine kinases. Ilorasertib alone or in combination with azacitidine demonstrated activity in preclinical models in various hematological malignancies, indicating that pan-Aurora kinase and multiple kinase inhibition may have preferential antileukemic activity. This phase 1 trial determined the safety, pharmacokinetics, and preliminary antitumor activity of ilorasertib alone or combined with azacitidine in advanced hematologic malignancies. PATIENTS AND METHODS: Fifty-two patients (median age, 67 years; 35 % with >4 prior regimens) with acute myelogenous leukaemia (AML; n = 38), myelodysplastic syndrome (n = 12), or chronic myelomonocytic leukaemia (n = 2) received 3 or 6 doses of ilorasertib per 28-day cycle and were assigned to arm A (once-weekly oral), B (twice-weekly oral), C (once-weekly oral plus azacitidine), or D (once-weekly intravenous) treatment. RESULTS: Maximum tolerated doses were not determined; the recommended phase 2 oral monotherapy doses were 540 mg once weekly and 480 mg twice weekly. The most common grade 3/4 adverse events were hypertension (28.8 %), hypokalemia (15.4 %), anemia (13.5 %), and hypophosphatemia (11.5 %). Oral ilorasertib pharmacokinetics appeared dose proportional, with a 15-hour half-life and no interaction with azacitidine. Ilorasertib inhibited biomarkers for Aurora kinase and VEGF receptors, and demonstrated clinical responses in 3 AML patients. CONCLUSIONS: Ilorasertib exhibited acceptable safety and pharmacokinetics at or below the recommended phase 2 dose, displayed evidence of dual Aurora kinase and VEGF receptor kinase inhibition, and activity in AML.

Prescribing physical activity for healthy aging: longitudinal follow-up and mixed method analysis of a primary care intervention.

BACKGROUND: There is a shortage of literature describing the experience of individuals who have participated in a physical activity and mobile health (mHealth) intervention. Many physical activity interventions are of short duration and do not report long-term changes in clinical measures or adoption of prescribed health behaviors. Previously, we have reported the clinical and behavioral outcomes from the first phase of a physical activity prescription and mHealth intervention delivered through the primary care setting. The purpose of this next phase is to perform a longitudinal follow-up 6-months postintervention. METHODS: Mixed methods analysis including repeated measures ANOVA of functional aerobic capacity (VO2max) at preintervention, postintervention, and follow-up clinic visits, and whole text analysis of semistructured interviews discussing the participant experience in a health behavior intervention. RESULTS: Twenty participants, mean age 63 ± 5 years, participated. Gains made in VO2max were maintained at 6 months (P < 0.05). Participants reported engaging in sustained and routine physical activity, yet some identified a need for additional support to adopt the prescribed health behaviors. Emergent themes included the desire for short-term mHealth intervention to educate individuals about prescribed health behaviors without need for ongoing management by clinicians, leveraging mHealth to build social networks around prescribed health behaviors and to connect individuals to build a sense of community, and participant views of physical activity as medicine. CONCLUSIONS: The present study investigated both the long-term adoption of physical activity behaviors as well as the participant experience in a physical activity and mHealth intervention. Findings from the current study may be used to inform the development of user-centered lifestyle interventions.

Prescribing physical activity through primary care: does activity intensity matter?

BACKGROUND: Physical activity guidelines recommend engaging in moderate- and vigorous-intensity physical activity to elicit health benefits. Similarly, these higher intensity ranges for activity are typically targeted in healthy living interventions (ie, exercise prescription). Comparatively less attention has been focused on changing lower intensity physical activity (ie, sedentary activity) behaviors. The purpose of this study was to explore the effects of prescribing changes to physical activity of various intensities (ie, sedentary through exercise) through the primary care setting. METHODS: Sixty older adults (aged 55-75 years; mean age 63 = 5 years) volunteered to participate, and were randomly assigned to 4 groups: 3 receiving an activity prescription intervention targeting a specific intensity of physical activity (exercise, sedentary, or both), and 1 control group. During the 12-week intervention period participants followed personalized activity programs at home. Basic clinical measures (anthropometrics, blood pressure, aerobic fitness) and blood panel for assessing cardiometabolic risk (glucose, lipid profile) were conducted at baseline (week 0) and follow-up (week 12) in a primary care office. RESULTS: There were no differences between groups at baseline (P > 0.05). The intervention changed clinical (F5,50 = 20.458, P = 0.000, ηP² = 0.672) and blood panel measures (F5,50 = 4.576, P = 0.002, ηP² = 0.314) of cardiometabolic health. Post hoc analyses indicted no differences between groups (P > 0.05). CONCLUSION: Physical activity prescription of various intensities through the primary care setting improved cardiometabolic health status. To our knowledge, this is the first report of sedentary behavior prescription (alone, or combined with exercise) in primary care. The findings support the ongoing practice of fitness assessment and physical activity prescription for chronic disease management and prevention.

Health promotion through primary care: enhancing self-management with activity prescription and mHealth.

BACKGROUND: It is well established in the literature that regular participation in physical activity is effective for chronic disease management and prevention. Remote monitoring technologies (ie, mHealth) hold promise for engaging patients in self-management of many chronic diseases. The purpose of this study was to test the effectiveness of an mHealth study with tailored physical activity prescription targeting changes in various intensities of physical activity (eg, exercise, sedentary behavior, or both) for improving physiological and behavioral markers of lifestyle-related disease risk. METHODS: Forty-five older adults (aged 55-75 years; mean age 63 ± 5 years) were randomly assigned to receive a personal activity program targeting changes to either daily exercise, sedentary behavior, or both. All participants received an mHealth technology kit including smartphone, blood pressure monitor, glucometer, and pedometer. Participants engaged in physical activity programming at home during the 12-week intervention period and submitted physical activity (steps/day), blood pressure (mm Hg), body weight (kg), and blood glucose (mmol/L) measures remotely using study-provided devices. RESULTS: There were no differences between groups at baseline (P > 0.05). The intervention had a significant effect (F(10 488) = 2.947, P = 0.001, ηP² = 0.057), with similar changes across all groups for physical activity, body weight, and blood pressure (P > 0.05). Changes in blood glucose were significantly different between groups, with groups prescribed high-intensity activity (ie, exercise) demonstrating greater reductions in blood glucose than the group prescribed changes to sedentary behavior alone (P < 0.05). CONCLUSIONS: Findings demonstrate the utility of pairing mHealth technologies with activity prescription for prevention of lifestyle-related chronic diseases among an at-risk group of older men and women. RESULTS support the novel approach of prescribing changes to sedentary behaviors (alone, and in conjunction with exercise) to reduce risk of developing lifestyle-related chronic conditions.

It's all in the timing: Delayed feedback in autism may weaken predictive mechanisms during contour integration.

Humans rely on predictive mechanisms during visual processing to efficiently resolve incomplete or ambiguous sensory signals. While initial low-level sensory data are conveyed by feedforward connections, feedback connections are believed to shape sensory processing through conveyance of statistical predictions based on prior exposure to stimulus configurations. Individuals with autism spectrum disorder (ASD) show biases in stimulus processing toward parts rather than wholes, suggesting their sensory processing may be less shaped by statistical predictions acquired through prior exposure to global stimulus properties. Investigations of illusory contour (IC) processing in neurotypical (NT) adults have established a well-tested marker of contour integration characterized by a robust modulation of the visually evoked potential (VEP) - the IC-effect - that occurs over lateral occipital scalp during the timeframe of the N1 component. Converging evidence strongly supports the notion that this IC-effect indexes a signal with significant feedback contributions. Using high-density VEPs, we compared the IC-effect in 6-17-year-old children with ASD (n=32) or NT development (n=53). Both groups of children generated an IC-effect that was equivalent in amplitude. However, the IC-effect notably onset 21ms later in ASD, even though timing of initial VEP afference was identical across groups. This suggests that feedforward information predominated during perceptual processing for 15% longer in ASD compared to NT children. This delay in the feedback dependent IC-effect, in the context of known developmental differences between feedforward and feedback fibers, suggests a potential pathophysiological mechanism of visual processing in ASD, whereby ongoing stimulus processing is less shaped by statistical prediction mechanisms.

Moderate-Intensity Exercise Enhances Mitochondrial Biogenesis Markers in the Skeletal Muscle of a Mouse Model Affected by Diet-Induced Obesity.

Skeletal muscle is composed of bundles of muscle fibers with distinctive characteristics. Oxidative muscle fiber types contain higher mitochondrial content, relying primarily on oxidative phosphorylation for ATP generation. Notably, as a result of obesity, or following prolonged exposure to a high-fat diet, skeletal muscle undergoes a shift in fiber type toward a glycolytic type. Mitochondria are highly dynamic organelles, constantly undergoing mitochondrial biogenesis and dynamic processes. Our study aims to explore the impact of obesity on skeletal muscle mitochondrial biogenesis and dynamics and also ascertain whether the skeletal muscle fiber type shift occurs from the aberrant mitochondrial machinery. Furthermore, we investigated the impact of exercise in preserving the oxidative muscle fiber types despite obesity. Mice were subjected to a normal standard chow and water or high-fat diet with sugar water (HFS) with or without exercise training. After 12 weeks of treatment, the HFS diet resulted in a noteworthy reduction in the markers of mitochondrial content, which was recovered by exercise training. Furthermore, higher mitochondrial biogenesis markers were observed in the exercised group with a subsequent increase in the mitochondrial fission marker. In conclusion, these findings imply a beneficial impact of moderate-intensity exercise on the preservation of oxidative capacity in the muscle of obese mouse models.

Measuring Dynamic Glycosomal pH Changes in Living Trypanosoma brucei.

Glucose metabolism is critical for the African trypanosome, Trypanosoma brucei, as an essential metabolic process and regulator of parasite development. Little is known about the cellular responses generated when environmental glucose levels change. In both bloodstream and procyclic form (insect stage) parasites, glycosomes house most of glycolysis. These organelles are rapidly acidified in response to glucose deprivation, which likely results in the allosteric regulation of glycolytic enzymes such as hexokinase. In previous work, localizing the chemical probe used to make pH measurements was challenging, limiting its utility in other applications. This paper describes the development and use of parasites that express glycosomally localized pHluorin2, a heritable protein pH biosensor. pHluorin2 is a ratiometric pHluorin variant that displays a pH (acid)-dependent decrease in excitation at 395 nm while simultaneously yielding an increase in excitation at 475 nm. Transgenic parasites were generated by cloning the pHluorin2 open reading frame into the trypanosome expression vector pLEW100v5, enabling inducible protein expression in either lifecycle stage. Immunofluorescence was used to confirm the glycosomal localization of the pHluorin2 biosensor, comparing the localization of the biosensor to the glycosomal resident protein aldolase. The sensor responsiveness was calibrated at differing pH levels by incubating cells in a series of buffers that ranged in pH from 4 to 8, an approach we have previously used to calibrate a fluorescein-based pH sensor. We then measured pHluorin2 fluorescence at 405 nm and 488 nm using flow cytometry to determine glycosomal pH. We validated the performance of the live transgenic pHluorin2-expressing parasites, monitoring pH over time in response to glucose deprivation, a known trigger of glycosomal acidification in PF parasites. This tool has a range of potential applications, including potentially being used in high-throughput drug screening. Beyond glycosomal pH, the sensor could be adapted to other organelles or used in other trypanosomatids to understand pH dynamics in the live cell setting.

The Role of Dietary Antioxidants and Their Potential Mechanisms in Alzheimer's Disease Treatment.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with cognitive decline and characterized by amyloid-ß plaques and neurofibrillary tau tangles. Although AD's exact pathophysiology remains unclear, oxidative stress is known to play a role in the neurodegenerative process. Since no curative treatment exists, antioxidants represent a potential treatment for AD due to their ability to modulate oxidative stress. Therefore, this review aims to examine the impact of antioxidant supplementation and its potential mechanisms on cognitive function. The review primarily discusses research articles published between 2012 and 2022 reporting the results of clinical trials involving antioxidant supplementation on cognitive function in individuals with AD. Antioxidant supplementation included probiotics, selenium, melatonin, resveratrol, rosmarinic acid, carotenoids, curcumin, vitamin E, and coenzyme Q. While the studies included in this review did not provide much evidence for the beneficial role of antioxidant supplements on cognitive function in AD, the results varied from antioxidant to antioxidant and among trials examining the same antioxidant. Furthermore, many of the studies' findings face several limitations, including short trial durations, small sample sizes, and a lack of diversity among study participants. As a result, more research is required to examine the impact of antioxidant supplementation on cognitive function in AD.

Enolase Inhibitors as Early Lead Therapeutics against Trypanosoma brucei.

Glucose metabolism is critical for the African trypanosome, Trypanosoma brucei, serving as the lone source of ATP production for the bloodstream form (BSF) parasite in the glucose-rich environment of the host blood. Recently, phosphonate inhibitors of human enolase (ENO), the enzyme responsible for the interconversion of 2-phosphoglycerate (2-PG) to phosphoenolpyruvate (PEP) in glycolysis or PEP to 2-PG in gluconeogenesis, have been developed for the treatment of glioblastoma multiforme (GBM). Here, we have tested these agents against T. brucei ENO (TbENO) and found the compounds to be potent enzyme inhibitors and trypanocides. For example, (1-hydroxy-2-oxopyrrolidin-3-yl) phosphonic acid (deoxy-SF2312) was a potent enzyme inhibitor (IC50 value of 0.60 ± 0.23 µM), while a six-membered ring-bearing phosphonate, (1-hydroxy-2-oxopiperidin-3-yl) phosphonic acid (HEX), was less potent (IC50 value of 2.1 ± 1.1 µM). An analog with a larger seven-membered ring, (1-hydroxy-2-oxoazepan-3-yl) phosphonic acid (HEPTA), was not active. Molecular docking simulations revealed that deoxy-SF2312 and HEX had binding affinities of -6.8 and -7.5 kcal/mol, respectively, while the larger HEPTA did not bind as well, with a binding of affinity of -4.8 kcal/mol. None of these compounds were toxic to BSF parasites; however, modification of enzyme-active phosphonates through the addition of pivaloyloxymethyl (POM) groups improved activity against T. brucei, with POM-modified (1,5-dihydroxy-2-oxopyrrolidin-3-yl) phosphonic acid (POMSF) and POMHEX having EC50 values of 0.45 ± 0.10 and 0.61 ± 0.08 µM, respectively. These findings suggest that HEX is a promising lead against T. brucei and that further development of prodrug HEX analogs is warranted.