Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 50
Filter
1.
J Investig Med ; : 10815589241248073, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38594222

ABSTRACT

The aim of this study was to evaluate the clinical features, pathological characteristics, and prognosis in myeloperoxidase (MPO)-antineutrophil cytoplasmic antibodies (ANCA)-associated glomerulonephritis (AAGN) with renal arteritis. The study involved 97 children from five pediatric clinical centers with MPO-AAGN who exhibited distinct clinical features. The patients were divided into AAGN-A+ and AAGN-A-, based on the presence or absence of arteritis, and the disparities in clinical, histopathological characteristics, and prognosis between the two groups was evaluated. In contrast to the AAGN-A- group, the children in the AAGN-A+ group exhibited more pronounced clinical symptoms and renal pathological injury. Arteritis positively moderately correlated with the serum creatinine, interleukin-6, urinary neutrophil gelatinase-associated lipocalin, negatively moderately correlated with serum complement C3. The renal survival rate in the AAGN-A+ group was significantly poorer than AAGN-A- group (χ2 = 4.278, p = 0.039). Arteritis showed a good predictive value for end-stage kidney disease (ESKD), and C3 deposition, ANCA renal risk score and arteritis were independent risk factors for the development of ESKD in children with MPO-AAGN. Arteritis is a significant pathological change observed in children with MPO-AAGN, and the formation of arteritis may be related to the inflammatory response and activation of the complement system.

2.
JAMA Neurol ; 81(1): 59-68, 2024 Jan 01.
Article in English | MEDLINE | ID: mdl-38048087

ABSTRACT

IMPORTANCE: Nonmotor symptoms of Parkinson disease (PD) often predate the movement disorder by decades. Currently, there is no blood biomarker to define this prodromal phase. OBJECTIVE: To investigate whether α-synuclein in neuronally derived serum-extracellular vesicles identifies individuals at risk of developing PD and related dementia. DESIGN, SETTING, and PARTICIPANTS: This retrospective, cross-sectional multicenter study of serum samples included the Oxford Discovery, Marburg, Cologne, and Parkinson's Progression Markers Initiative cohorts. Participants were recruited from July 2013 through August 2023 and samples were analyzed from April 2022 through September 2023. The derivation group (n = 170) included participants with isolated rapid eye movement sleep behavior disorder (iRBD) and controls. Two validation groups were used: the first (n = 122) included participants with iRBD and controls and the second (n = 263) included nonmanifest GBA1N409S gene carriers, participants with iRBD or hyposmia, and available dopamine transporter single-photon emission computed tomography, healthy controls, and patients with sporadic PD. Overall the study included 199 participants with iRBD, 20 hyposmic participants with available dopamine transporter single-photon emission computed tomography, 146 nonmanifest GBA1N409S gene carriers, 21 GBA1N409S gene carrier patients with PD, 50 patients with sporadic PD, and 140 healthy controls. In the derivation group and validation group 1, participants with polysomnographically confirmed iRBD were included. In the validation group 2, at-risk participants with available Movement Disorder Society prodromal markers and serum samples were included. Among 580 potential participants, 4 were excluded due to alternative diagnoses. EXPOSURES: Clinical assessments, imaging, and serum collection. MAIN OUTCOME AND MEASURES: L1CAM-positive extracellular vesicles (L1EV) were immunocaptured from serum. α-Synuclein and syntenin-1 were measured by electrochemiluminescence. Area under the receiver operating characteristic (ROC) curve (AUC) with 95% CIs evaluated biomarker performance. Probable prodromal PD was determined using the updated Movement Disorder Society research criteria. Multiple linear regression models assessed the association between L1EV α-synuclein and prodromal markers. RESULTS: Among 576 participants included, the mean (SD) age was 64.30 (8.27) years, 394 were male (68.4%), and 182 were female (31.6%). A derived threshold of serum L1EV α-synuclein distinguished participants with iRBD from controls (AUC = 0.91; 95% CI, 0.86-0.96) and those with more than 80% probability of having prodromal PD from participants with less than 5% probability (AUC = 0.80; 95% CI, 0.71-0.89). Subgroup analyses revealed that specific combinations of prodromal markers were associated with increased L1EV α-synuclein levels. Across all cohorts, L1EV α-synuclein differentiated participants with more than 80% probability of having prodromal PD from current and historic healthy control populations (AUC = 0.90; 95% CI, 0.87-0.93), irrespective of initial diagnosis. L1EV α-synuclein was increased in at-risk participants with a positive cerebrospinal fluid seed amplification assay and was above the identified threshold in 80% of cases (n = 40) that phenoconverted to PD or related dementia. CONCLUSIONS AND RELEVANCE: L1EV α-synuclein in combination with prodromal markers should be considered in the stratification of those at high risk of developing PD and related Lewy body diseases.


Subject(s)
Extracellular Vesicles , Lewy Body Disease , Parkinson Disease , REM Sleep Behavior Disorder , Female , Humans , Male , Middle Aged , alpha-Synuclein/metabolism , Biomarkers/cerebrospinal fluid , Cross-Sectional Studies , Dopamine Plasma Membrane Transport Proteins , Extracellular Vesicles/metabolism , Lewy Body Disease/complications , Parkinson Disease/complications , REM Sleep Behavior Disorder/diagnosis , Retrospective Studies
3.
Exp Brain Res ; 242(1): 275-293, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38015245

ABSTRACT

The purpose of this study was to examine kinematic and neuromuscular responses of the head and body to pelvis perturbations with different intensities and frequencies during sitting astride in children with CP. Sixteen children with spastic CP (mean age 7.4 ± 2.4 years old) were recruited in this study. A custom designed cable-driven robotic horse was used to apply controlled force perturbations to the pelvis during sitting astride. Each participant was tested in four force intensity conditions (i.e., 10%, 15%, 20%, and 25% of body weight (BW), frequency = 1 Hz), and six force frequency conditions (i.e., 0.5 Hz, 1 Hz, 1.5 Hz, 2 Hz, 2.5 Hz, and 3 Hz, intensity = 20% of BW). Each testing session lasted for one minute with a one-minute rest break inserted between two sessions. Kinematic data of the head, trunk, and legs were recorded using wearable sensors, and EMG signals of neck, trunk, and leg muscles were recorded. Children with CP showed direction-specific trunk and neck muscle activity in response to the pelvis perturbations during sitting astride. Greater EMG activities of trunk and neck muscles were observed for the greater intensities of force perturbations (P < .05). Participants also showed enhanced activation of antagonistic muscles rather than direction-specific trunk and neck muscle activities for the conditions of higher frequency perturbations (P < .05). Children with CP may modulate trunk and neck muscle activities in response to greater changes in intensity of pelvis perturbation during sitting astride. Perturbations with too high frequency may be less effective in inducing direction-specific trunk and neck muscle activities.


Subject(s)
Cerebral Palsy , Posture , Sitting Position , Child , Child, Preschool , Humans , Electromyography , Muscle, Skeletal/physiology , Posture/physiology
4.
Article in English | MEDLINE | ID: mdl-38082689

ABSTRACT

Common manifestation of spastic Cerebral Palsy (CP) are abnormal gait pathologies. These conditions require greater energy expenditure to successfully ambulate and are linked with significant deterioration in joint health and childhood musculoskeletal development. Crouch gait presents with knee hyperflexion throughout stance due to extensor muscle weakness and spasticity in flexor muscles stemming from neurological damage. The goal of this study was to develop a wearable cable-driven robotic system that applies controlled perturbation to the knee joint during overground walking in children with CP. Two children with spastic CP were recruited in this pilot study. They were tested in two conditions, i.e., applying knee resistance vs. knee assistance during overground walking. Kinematic and EMG data were recorded during overground walking. Data indicated that it was feasible to apply controlled knee perturbation torque during overground walking in children with crouch and preliminary results showed an improvement in crouch gait pattern in children with CP after one session of walking with the robotic system.Clinical Relevance- This study might have a potential clinical significance modifying neuromuscular control of CP patients with Crouch Gait.


Subject(s)
Cerebral Palsy , Child , Humans , Cerebral Palsy/complications , Pilot Projects , Knee , Gait/physiology , Knee Joint
6.
Anal Chem ; 95(20): 7906-7913, 2023 05 23.
Article in English | MEDLINE | ID: mdl-37167073

ABSTRACT

The analysis of cargo proteins in exosome subpopulations has considerable value in diagnostics but a translatable impact has been limited by lengthy or complex exosome extraction protocols. We describe herein a scalable, fast, and low-cost exosome extraction using an alternating (AC) magnetic field to support the dynamic mixing of antibody-coated magnetic beads (MBs) with serum samples within 3D-printed microfluidic chips. Zwitterionic polymer-coated MBs are, specifically, magnetically agitated and support ultraclean exosome capture efficiencies >70% from <50 µL of neat serum in 30 min. Applied herein to the immunocapture of neuronal exosomes using anti-L1CAM antibodies, prior to the array-based assaying of α-synuclein (α-syn) content by a standard duplex electrochemical sandwich ELISA, sub pg/mL detection was possible with an excellent coefficient of variation and a sample-to-answer time of ∼75 min. The high performance and semiautomation of this approach hold promise in underpinning low-cost Parkinson's disease diagnostics and is of value in exosomal biomarker analyses more generally.


Subject(s)
Exosomes , Parkinson Disease , Humans , Parkinson Disease/diagnosis , Parkinson Disease/metabolism , Exosomes/chemistry , Magnetic Fields , Microfluidics
7.
J Neurophysiol ; 130(1): 43-55, 2023 07 01.
Article in English | MEDLINE | ID: mdl-37198133

ABSTRACT

Targeting enhancing the use of the paretic leg during locomotor practice might improve motor function of the paretic leg. The purpose of this study was to determine whether application of constraint force to the nonparetic leg in the posterior direction during overground walking would enhance the use of the paretic leg in people with chronic stroke. Fifteen individuals after stroke participated in two experimental conditions, i.e., overground walking with a constraint force applied to the nonparetic leg and overground walking only. Each participant was tested in the following procedures that consisted of overground walking with either constraint force or no constraint force, instrumented split-belt treadmill walking, and pressure-sensitive gait mat walking before and after the overground walking. Overground walking practice with constraint force resulted in greater enhancement in lateral weight shift toward the paretic side (P < 0.01), muscle activity of the paretic hip abductors (P = 0.04), and propulsion force of the paretic leg (P = 0.05) compared with the results of the no-constraint condition. Overground walking practice with constraint force tended to induce greater increase in self-selected overground walking speed (P = 0.06) compared with the effect of the no-constraint condition. The increase in propulsion force from the paretic leg was positively correlated with the increase in self-selected walking speed (r = 0.6, P = 0.03). Overground walking with constraint force applied to the nonparetic leg during swing phase of gait may enhance use of the paretic leg, improve weight shifting toward the paretic side and propulsion of the paretic leg, and consequently increase walking speed.NEW & NOTEWORTHY Application of constraint force to the nonparetic leg during overground walking induced improved lateral weight shifts toward the paretic leg and enhanced muscle activity of the paretic leg during walking. In addition, one session of overground walking with constraint force might induce an increase in propulsive force of the paretic leg and an increase in self-selected overground walking speed, which might be partially due to the improvement in motor control of the paretic leg.


Subject(s)
Stroke Rehabilitation , Stroke , Humans , Leg , Stroke Rehabilitation/methods , Walking/physiology , Stroke/complications , Gait/physiology , Biomechanical Phenomena , Paresis/etiology
8.
Am J Phys Med Rehabil ; 102(9): 795-802, 2023 09 01.
Article in English | MEDLINE | ID: mdl-36946368

ABSTRACT

OBJECTIVE: The aim of this study is to determine the effects of bilateral trunk support during walking on trunk and leg kinematics and neuromuscular responses in children with cerebral palsy. DESIGN: Fourteen children with spastic cerebral palsy (Gross Motor Function Classification System level I to III) participated in this study. Children walked on a treadmill under four different conditions, that is, without support (Baseline), with bilateral support applied to the upper trunk (upper trunk support), the lower trunk (lower trunk support), and combined upper and lower trunk (combined trunk support). The trunk and leg kinematics and muscle activity were recorded. RESULTS: Providing bilateral support to the trunk had a significant impact on the displacement of the pelvis and trunk ( P < 0.003) during walking. Children's weaker leg showed greater step length ( P = 0.032) and step height ( P = 0.012) in combined trunk support compared with baseline and greater step length in upper trunk support ( P = 0.02) and combined trunk support ( P = 0.022) compared with lower trunk support. Changes in soleus electromyographic activity during stance phase of gait mirrored the changes in step length across all conditions. CONCLUSIONS: Providing bilateral upper or combined upper and lower trunk support during walking may induce improvements in gait performance, which may be due to improved pelvis kinematics. Improving trunk postural control may facilitate walking in children with cerebral palsy.


Subject(s)
Cerebral Palsy , Humans , Child , Pilot Projects , Walking/physiology , Gait/physiology , Postural Balance/physiology , Biomechanical Phenomena
9.
Complement Med Res ; 30(3): 248-257, 2023.
Article in English | MEDLINE | ID: mdl-35358967

ABSTRACT

INTRODUCTION: Traditional Chinese medicine (TCM) is a type of alternative medicine that has been widely utilized in the prevention and treatment of neuropsychiatric diseases such as schizophrenia, ADHD, Alzheimer disease, and Tourette syndrome (TS) in many countries. However, the results regarding TCM's effectiveness and safety in treating TS are conflicting. Therefore, the goal of the present study is to analyze and summarize the available literature related to the efficacy of TCM in the treatment of tic disorders, especially TS. METHODS: Relevant articles for the meta-analysis were searched using appropriate keywords from PubMed, MEDLINE, and CENTRAL databases. Event data for TCM for the treatment of TS in the control and intervention arms were determined from the randomized controlled trials, and diagnostic odds ratio (DOR) and risk of bias analysis were performed. Meta-analysis was performed using MedCalc software, and suitable parameters to assess heterogeneity were computed. RESULTS: Twelve randomized clinical trials with a total of 1,681 TS patients were included as per the inclusion criteria. The patients' clinical symptoms were improved to a greater extent, and the pooled DOR of 1.311 with a 95% confidence interval (CI) value ranging from 0.804 to 2.139 and I2 value of 72.04% were obtained. The pooled relative risk was 1.09, with a 95% CI value ranging from 0.97 to 1.268. The data heterogeneity was assessed, and we achieved a Q value of 33.54, a p value of 0.0004, and I2 value of 67.21% with a 95% CI value of 32.91-82.10. All these values are statistically significant, with p < 0.005, and confirmed the effectiveness of TCM for TS patients. CONCLUSION: The present meta-analysis on account of these statistically significant results highly recommends using TCM to treat TS.


Subject(s)
Complementary Therapies , Tic Disorders , Tourette Syndrome , Humans , Tourette Syndrome/drug therapy , Medicine, Chinese Traditional , Randomized Controlled Trials as Topic , Tic Disorders/therapy
10.
Environ Res ; 218: 115034, 2023 02 01.
Article in English | MEDLINE | ID: mdl-36502900

ABSTRACT

Using an indoor air purifier is an important solution for improving indoor air quality and protecting people from the harmful effects of air pollution on their health. The filter air purifiers can remove particulate matter including bioaerosols, but their filter media can cause secondary pollution. To fulfill this need, a new filterless indoor air purifier, the Cloud-Air-Purifying (CAP) air purifier, is presented in this study. Using heterogeneous condensation and supergravity technology, the CAP air purifier grows and collects fine particles, while rapidly disinfecting bioaerosols with chemical disinfection and ultraviolet (UV) disinfection. Furthermore, the purifying performance of the CAP air purifier was tested in a simulated cabin. The results showed the clean air delivery rate (CADR) of the CAP air purifier was approximately 150 m3/h, and the effective coefficient was 0.93. The CAP air purifier was highly efficient in purifying fine particulate matter, 93% for PM10 and 91% for particle size of 0.5-1 µm in 60 min, which was 13-58 times more than natural decay. The reason for the efficient removal of fine particles is that they can condense and grow in water vapor supersaturated environment and be collected in a supergravity field. Moreover, the CAP air purifier has significant bactericidal effects on bioaerosols. It achieved a disinfection efficiency of 99.99997% by decreasing bioaerosols from 108 CFU/m3 to less than 30 CFU/m3 in only 20 min when particle purification in combination with UV disinfection and disinfectant (ClO2). Furthermore, ClO2 release concentrations, noise, and power consumption were investigated for application purposes, with results showing that they were within acceptable limits. The study presents an innovative idea and design for preventing airborne microorganisms and particulate matter through heterogeneous condensation technology.


Subject(s)
Air Filters , Air Pollutants , Air Pollution, Indoor , Air Pollution , Humans , Particulate Matter/analysis , Particle Size , Air Pollution, Indoor/prevention & control , Air Pollution, Indoor/analysis , Air Pollutants/analysis , Environmental Monitoring/methods
11.
Exp Brain Res ; 241(1): 67-80, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36355211

ABSTRACT

Gaze direction and use of visual feedback can affect illusory influences over perceptions and manual length size estimates of the vertical-horizontal (V-H) illusion, in which the vertical, bisecting segment of an inverted T (IT) appears longer than the horizontal, bisected segment. We questioned whether V-H illusory influences would also exist for the lower limb. Participants stepped forward in an attempt to make the toe-to-toe distance of their dominant foot equal to a short or long bisecting segment length of a vertically projected IT. Performances under three gaze conditions included: maintaining gaze on the IT intersection throughout a trial for target fixation (TF); viewing the intersection for 4 s then looking down and performing the step for movement fixation (MF); and viewing the intersection for 4 s then maintaining gaze on the remembered location of the intersection and performing the step for remembered target fixation (RTF). Variables included step displacement, peak velocity (PV), and normalized ground reaction force amplitude (GRFampN), as well as time to peak and peak amplitude of the center of pressure (COPtime and COPamp, respectively). Main effects of gaze on PV, GRFampN, COPtime, and COPamp revealed lower values for MF compared to TF and RTF, which did not exist for step displacement. No significant correlations existed between step displacement and other variables across participants. Together, we found evidence to suggest differences between movement planning and movement completion. Exploitation of deceptive visual cues can guide step planning and early step execution, but do not guide final step estimations.


Subject(s)
Illusions , Humans , Fixation, Ocular , Movement , Cues , Foot
12.
bioRxiv ; 2023 Dec 23.
Article in English | MEDLINE | ID: mdl-38187535

ABSTRACT

PIEZO1 channels play a critical role in numerous physiological processes by transducing diverse mechanical stimuli into electrical and chemical signals. Recent studies underscore the importance of endogenous PIEZO1 activity and localization in regulating mechanotransduction. To enable physiologically and clinically relevant human-based studies, we genetically engineered human induced pluripotent stem cells (hiPSCs) to express a HaloTag fused to endogenous PIEZO1. Combined with super-resolution imaging, our chemogenetic approach allows precise visualization of PIEZO1 in various cell types. Further, the PIEZO1-HaloTag hiPSC technology allows non-invasive monitoring of channel activity via Ca2+-sensitive HaloTag ligands, with temporal resolution approaching that of patch clamp electrophysiology. Using lightsheet imaging of hiPSC-derived neural organoids, we also achieve molecular scale PIEZO1 imaging in three-dimensional tissue samples. Our advances offer a novel platform for studying PIEZO1 mechanotransduction in human cells and tissues, with potential for elucidating disease mechanisms and development of targeted therapeutics.

13.
Micromachines (Basel) ; 13(10)2022 Sep 23.
Article in English | MEDLINE | ID: mdl-36295936

ABSTRACT

Dry film photoresists are widely employed to fabricate high-aspect-ratio microstructures, such as molds for microfluidic devices. Unlike liquid resists, such as SU-8, dry films do not require a cleanroom facility, and it is straightforward to prepare uniform and reproducible films as thick as 500 µm. Multilayer patterning, however, can be problematic with dry film resists even though it is critical for a number of microfluidic devices. Layer-to-layer mask alignment typically requires the first layer to be fully developed, making the pattern visible, before applying and patterning the second layer. While a liquid resist can flow over the topography of previous layers, this is not the case with dry film lamination. We found that post-exposure baking of dry film photoresists can preserve a flat topography while revealing an image of the patterned features that is suitable for alignment to the next layer. We demonstrate the use of this technique with two different types of dry film resist to fabricate master molds for a hydrophoresis size-sorting device and a cell chemotaxis device.

14.
J Neurophysiol ; 127(6): 1642-1654, 2022 06 01.
Article in English | MEDLINE | ID: mdl-35583975

ABSTRACT

Locomotor adaptation to novel walking patterns induced by external perturbation has been tested to enhance motor learning for improving gait parameters in individuals poststroke. However, little is known regarding whether repeated adaptation and de-adaptation to the externally perturbed walking pattern may facilitate or degrade the retention of locomotor learning. In this study, we examined whether the intermittent adaptation to novel walking patterns elicited by external perturbation induces greater retention of the adapted locomotion in stroke survivors, compared with effects of the continuous adaptation. Fifteen individuals poststroke participated in two experimental conditions consisting of 1) treadmill walking with intermittent (i.e., interspersed 2 intervals of no perturbation) or continuous (no interval) adaptation to externally perturbed walking patterns and 2) overground walking before, immediately, and 10 min after treadmill walking. During the treadmill walking, we applied a laterally pulling force to the pelvis toward the nonparetic side during the stance phase of the paretic leg to disturb weight shifts toward the paretic side. Participants showed improved weight shift toward the paretic side and enhanced muscle activation of hip abductor/adductors immediately after the removal of the pelvis perturbation for both intermittent and continuous conditions (P < 0.05) and showed longer retention of the improved weight shift and enhanced muscle activation for the intermittent condition, which transferred from treadmill to overground walking (P < 0.05). In conclusion, repeated motor adaptation and de-adaptation to the pelvis resistance force during walking may promote the retention of error-based motor learning for improving weight shift toward the paretic side in individuals poststroke.NEW & NOTEWORTHY We examined whether the intermittent versus the continuous adaptation to external perturbation induces greater retention of the adapted locomotion in stroke survivors. We found that participants showed longer retention of the improved weight shift and enhanced muscle activation for the intermittent versus the continuous conditions, suggesting that repeated motor adaptation and de-adaptation to the pelvis perturbation may promote the retention of error-based motor learning for improving weight shift toward the paretic side in individuals poststroke.


Subject(s)
Stroke Rehabilitation , Stroke , Adaptation, Physiological/physiology , Biomechanical Phenomena/physiology , Gait/physiology , Humans , Pelvis/physiology , Stroke/complications , Survivors , Walking/physiology
15.
Cell Rep ; 38(1): 110179, 2022 01 04.
Article in English | MEDLINE | ID: mdl-34986353

ABSTRACT

G protein-coupled receptors (GPCRs) in intestinal enteroendocrine cells (EECs) respond to nutritional, neural, and microbial cues and modulate the release of gut hormones. Here we show that Gpr17, an orphan GPCR, is co-expressed in glucagon-like peptide-1 (GLP-1)-expressing EECs in human and rodent intestinal epithelium. Acute genetic ablation of Gpr17 in intestinal epithelium improves glucose tolerance and glucose-stimulated insulin secretion (GSIS). Importantly, inducible knockout (iKO) mice and Gpr17 null intestinal organoids respond to glucose or lipid ingestion with increased secretion of GLP-1, but not the other incretin glucose-dependent insulinotropic polypeptide (GIP). In an in vitro EEC model, overexpression or agonism of Gpr17 reduces voltage-gated calcium currents and decreases cyclic AMP (cAMP) production, and these are two critical factors regulating GLP-1 secretion. Together, our work shows that intestinal Gpr17 signaling functions as an inhibitory pathway for GLP-1 secretion in EECs, suggesting intestinal GPR17 is a potential target for diabetes and obesity intervention.


Subject(s)
Enteroendocrine Cells/metabolism , Glucagon-Like Peptide 1/metabolism , Glucose/metabolism , Intestinal Mucosa/metabolism , Nerve Tissue Proteins/genetics , Receptors, G-Protein-Coupled/genetics , Animals , Blood Glucose/analysis , Calcium/metabolism , Cell Line , Cyclic AMP/metabolism , Diabetes Mellitus/pathology , Female , Gastric Inhibitory Polypeptide/metabolism , Glucose Tolerance Test , HEK293 Cells , HeLa Cells , Humans , Incretins/metabolism , Insulin/metabolism , Insulin Secretion/physiology , Intestinal Mucosa/cytology , Male , Mice , Mice, Knockout , Obesity/pathology , Receptors, Gastrointestinal Hormone/metabolism
16.
J Biol Chem ; 298(1): 101431, 2022 01.
Article in English | MEDLINE | ID: mdl-34801552

ABSTRACT

Insulin resistance impairs postprandial glucose uptake through glucose transporter type 4 (GLUT4) and is the primary defect preceding type 2 diabetes. We previously generated an insulin-resistant mouse model with human GLUT4 promoter-driven insulin receptor knockout (GIRKO) in the muscle, adipose, and neuronal subpopulations. However, the rate of diabetes in GIRKO mice remained low prior to 6 months of age on normal chow diet (NCD), suggesting that additional factors/mechanisms are responsible for adverse metabolic effects driving the ultimate progression of overt diabetes. In this study, we characterized the metabolic phenotypes of the adult GIRKO mice acutely switched to high-fat diet (HFD) feeding in order to identify additional metabolic challenges required for disease progression. Distinct from other diet-induced obesity (DIO) and genetic models (e.g., db/db mice), GIRKO mice remained leaner on HFD feeding, but developed other cardinal features of insulin resistance syndrome. GIRKO mice rapidly developed hyperglycemia despite compensatory increases in ß-cell mass and hyperinsulinemia. Furthermore, GIRKO mice also had impaired oral glucose tolerance and a limited glucose-lowering benefit from exendin-4, suggesting that the blunted incretin effect contributed to hyperglycemia. Secondly, GIRKO mice manifested severe dyslipidemia while on HFD due to elevated hepatic lipid secretion, serum triglyceride concentration, and lipid droplet accumulation in hepatocytes. Thirdly, GIRKO mice on HFD had increased inflammatory cues in the gut, which were associated with the HFD-induced microbiome alterations and increased serum lipopolysaccharide (LPS). In conclusion, our studies identified important gene/diet interactions contributing to diabetes progression, which might be leveraged to develop more efficacious therapies.


Subject(s)
Diabetes Mellitus, Type 2 , Diet, High-Fat , Glucose Intolerance , Glucose Transporter Type 4 , Hyperglycemia , Insulin Resistance , Animals , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/metabolism , Diet, High-Fat/adverse effects , Glucose Transporter Type 4/biosynthesis , Glucose Transporter Type 4/metabolism , Hyperglycemia/blood , Hyperglycemia/etiology , Hyperglycemia/metabolism , Insulin/metabolism , Insulin Resistance/physiology , Mice , Mice, Inbred C57BL , Mice, Knockout
17.
Aging Cell ; 20(5): e13368, 2021 05.
Article in English | MEDLINE | ID: mdl-33951271

ABSTRACT

Mitochondrial dysfunction is one of the early pathological features of Alzheimer's disease (AD). Accumulation of cerebral and mitochondrial Aß links to mitochondrial and synaptic toxicity. We have previously demonstrated the mechanism by which presequence peptidase (PITRM1)-mediated clearance of mitochondrial Aß contributes to mitochondrial and cerebral amyloid pathology and mitochondrial and synaptic stress in adult transgenic AD mice overexpressing Aß up to 12 months old. Here, we investigate the effect of PITRM1 in an advanced age AD mouse model (up to 19-24 months) to address the fundamental unexplored question of whether restoration/gain of PITRM1 function protects against mitochondrial and synaptic dysfunction associated with Aß accumulation and whether this protection is maintained even at later ages featuring profound amyloid pathology and synaptic failure. Using newly developed aged PITRM1/Aß-producing AD mice, we first uncovered reduction in PITRM1 expression in AD-affected cortex of AD mice at 19-24 months of age. Increasing neuronal PITRM1 activity/expression re-established mitochondrial respiration, suppressed reactive oxygen species, improved synaptic function, and reduced loss of synapses even at advanced ages (up to 19-24 months). Notably, loss of PITRM1 proteolytic activity resulted in Aß accumulation and failure to rescue mitochondrial and synaptic function, suggesting that PITRM1 activity is required for the degradation and clearance of mitochondrial Aß and Aß deposition. These data indicate that augmenting PITRM1 function results in persistent life-long protection against Aß toxicity in an AD mouse model. Therefore, augmenting PITRM1 function may enhance Aß clearance in mitochondria, thereby maintaining mitochondrial integrity and ultimately slowing the progression of AD.


Subject(s)
Alzheimer Disease/enzymology , Metalloendopeptidases/metabolism , Mitochondria/enzymology , Neurons/enzymology , Synapses/metabolism , Aging , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Animals , Brain/metabolism , Cognition , Disease Models, Animal , Female , Inflammation , Male , Metalloendopeptidases/genetics , Mice, Transgenic , Mitochondria/metabolism , Neurons/metabolism , Synapses/physiology
18.
Neurosci Lett ; 752: 135833, 2021 05 01.
Article in English | MEDLINE | ID: mdl-33746007

ABSTRACT

We investigated whether visually guided reaching differs for sitting and standing postures while the eyes and hand are coupled to move in the same direction or decoupled to move in opposite directions. We also investigated how coupled and decoupled reaching tasks influenced standing postural control. Eighteen healthy young adults (M = 21 years) moved a cursor using finger movements along a vertical touchscreen while sitting or standing. In an eye-hand coupling (EH) task, participants moved their finger/cursor from a central target to a peripheral target located either up, down, left, or right. In an eye-hand decoupling (EHD) task, participant's finger movement moved the cursor in the opposite direction. Sway measures during the standing condition and kinematic variables for the cursor offered insight into whole-body control. Performances in EH revealed smaller errors and faster movements than EHD regardless of postural condition. Similar hand movements existed between sitting and standing when accounting for task, while greater variability in absolute endpoint errors existed for standing than sitting when task was ignored. Less postural sway existed for EHD than EH when standing. These data provide evidence that when participants decoupled the eyes and hand movement direction while standing, they attenuated sway to support control of this complex, cognitively demanding, visuomotor task.


Subject(s)
Eye Movements/physiology , Hand/physiology , Postural Balance/physiology , Psychomotor Performance/physiology , Female , Healthy Volunteers , Humans , Male , Sitting Position , Standing Position , Young Adult
19.
J Med Virol ; 93(6): 3890-3898, 2021 06.
Article in English | MEDLINE | ID: mdl-32779745

ABSTRACT

Oncolytic virus therapy is perhaps the next major breakthrough in cancer treatment following the success in immunotherapy using immune checkpoint inhibitors. However, the potential oncolytic ability of the recombinant newcastle disease virus (NDV) Anhinga strain carried with tumor necrosis factor-related apoptosis inducing ligand (TRAIL) has not been fully explored at present. In the present study, the recombinant NDV/Anh-TRAIL that secretes soluble TRAIL was constructed and the experiment results suggested NDV/Anh-TRAIL as a promising candidate for glioma therapy. Growth kinetic and TRAIL secreted quantity of recombinant NDV/Anh-TRAIL virus were measured. Cytotoxic and cell apoptosis were analyzed for its anti-glioma therapy in vitro. Nude mice were used for the in vivo evaluation. Both tumor volume and mice behavior after injection were observed. The recombinant virus replicated with the same kinetics as the parental virus and the highest expression of TRAIL (77.8 ng/L) was found at 48 hours. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, a tetrazole and flow cytometry data revealed that the recombinant NDV/Anh-TRAIL (56.1 ± 8.2%) virus could induce a more severe apoptosis rate, when compared with the NDV wild type (37.2 ± 7.0%) and mock (7.0 ± 1.8%) groups (P < .01), in U251 cells. Furthermore, in the present animal study, the average tumor volume was smaller in the NDV/Anh-TRAIL group (97.21 mm3 ), when compared with the NDV wild type (205.03 mm3 , P < .05) and PBS (310.30 mm3 , P < .01) groups.


Subject(s)
Glioma/therapy , Newcastle disease virus/genetics , Newcastle disease virus/immunology , Oncolytic Virotherapy/methods , TNF-Related Apoptosis-Inducing Ligand/genetics , Animals , Apoptosis , Cell Line, Tumor , Disease Models, Animal , Female , Humans , Mice , Mice, Nude , Oncolytic Viruses , Virus Replication
20.
J Mot Behav ; 53(1): 92-104, 2021.
Article in English | MEDLINE | ID: mdl-32107981

ABSTRACT

We examined potentially deceptive influences of the vertical-horizontal (V-H) illusion on manual length estimations. When viewing V-H illusory configurations, people perceive that the bisecting segment length exceeds the bisected segment length when segments are actually equal. Participants used downward or rightward pointing movements to manually estimate the length of a short bisecting segment of the V-H illusion in upright or rotated configurations. Participants directed their gaze freely, on the configuration, or on the movement space. Manual length estimations for upright and rotated configurations depended on gaze direction, revealing bisection influences only for restricted viewing. People produced illusory influences on perceptuomotor control only when gaze was directed toward V-H configurations or their movement. Exploitation of deceptive visual cues can direct upper limb control for sensorimotor coordination.


Subject(s)
Eye Movements/physiology , Illusions/physiology , Judgment/physiology , Psychomotor Performance/physiology , Biomechanical Phenomena/physiology , Female , Humans , Male , Young Adult
SELECTION OF CITATIONS
SEARCH DETAIL
...