A DNA vaccine against GII.4 human norovirus VP1 induces blocking antibody production and T cell responses.

Human noroviruses (HuNoVs) are highly contagious and a leading cause of epidemics of acute gastroenteritis worldwide. Among the various HuNoV genotypes, GII.4 is the most prevalent cause of outbreaks. However, no vaccines have been approved for HuNoVs to date. DNA vaccines are proposed to serve as an ideal platform against HuNoV since they can be easily produced and customized to express target proteins. In this study, we constructed a CMV/R vector expressing a major structural protein, VP1, of GII.4 HuNoV (CMV/R-GII.4 HuNoV VP1). Transfection of CMV/R-GII.4 HuNoV VP1 into human embryonic kidney 293T (HEK293T) cells resulted in successful expression of VP1 proteins in vitro. Intramuscular or intradermal immunization of mice with the CMV/R-GII.4 HuNoV VP1 construct elicited the production of blocking antibodies and activation of T cell responses against GII.4 HuNoV VP1. Our collective data support the utility of CMV/R-GII.4 HuNoV VP1 as a promising DNA vaccine candidate against GII.4 HuNoV.

Cycloastragenol inhibits adipogenesis and fat accumulation in vitro and in vivo through activating Hedgehog signaling.

In this study, we investigated the effect of cycloastragenol (CAG), a triterpenoid isolated from Astragalus membranaceus roots, on regulating the adipogenesis and fat accumulation in vitro and in vivo. During the adipogenesis of 3T3-L1 cells, CAG inhibited lipid accumulation and the expression of key adipogenic factors, proliferator-activated receptor γ (PPARγ) and CCAAT enhancer binding protein α (C/EBPα) and increased the expression of Gli1, a key mediator in Hedgehog (Hh) signaling. In HFD-induced animal experiment, CAG significantly reduced body weight gain without affecting brown fat weight. In addition, CAG regulated the expression of PPARγ, C/EBPα, and Gli1 in visceral white adipose tissue (vWAT). We also confirmed the inhibitory effect of CAG on specifically targeting white adipose tissue (WAT) formation in stromal vascular fraction (SVF) cell differentiation. Taken together, these results suggest that CAG may be a potent phytochemical preventing adipogenesis and obesity via Hh signaling. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-023-01403-0.

Curcumol metabolized by rat liver S9 fraction and orally administered in mouse suppressed the proliferation of colon cancer in vitro and in vivo.

Following 3R (reduction, refinement, and replacement) principles, we employed the rat liver S9 fraction to mimic liver metabolism of curcumol having high in vitro IC50 on cancer cells. In HCT116 and HT29 colon cancer cells, the metabolites of curcumol by S9 fraction exerted more enhanced activity in inducing cell cycle arrest and apoptosis via regulating the expression of cyclin D1, CDK1, p21, PARP and Bcl-2 than curcumol. In addition, oral administration of curcumol at 4 mg/kg BW significantly suppressed the development of colon tumor induced by azoxymethane/dextran sulfate sodium, and induced cell cycle arrest and apoptosis in tumor tissues. In mass analysis, curcumenol and curzerene were identified as the metabolites of curcumol by S9 fraction metabolism. Taken together, curcumol metabolites showed the enhanced suppressive effect on colon cancer, suggesting that S9 fraction can be considered as simple, fast, and bio-mimicking platform for the screening of chemical libraries on different chronic diseases.

Efficacy of Wheelchair Skills Training Program in Enhancing Sitting Balance and Pulmonary Function in Chronic Tetraplegic Patients: A Randomized Controlled Study.

Background and Objectives: This study aimed to evaluate the effectiveness of a wheelchair skills training program (WSTP) in improving sitting balance and pulmonary function in patients with chronic tetraplegia resulting from cervical spinal cord injury (cSCI). Materials and Methods: Twenty-four patients were randomly divided into WSTP and control groups. The WSTP group participated in the WSTP for eight weeks, while the control group underwent conventional physical therapy for the same eight-week period. Sitting balance was evaluated using the activity-based balance level evaluation (ABLE) scale, and pulmonary function was evaluated using forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and peak expiratory flow (PEF). Results: The WSTP group showed significant improvements in both sitting balance and pulmonary function during the intervention period (p < 0.05), whereas the control group did not show any significant changes. A strong positive correlation was found between ABLE scores and all three pulmonary function parameters across all time points. Conclusions: Our results suggest that the WSTP significantly improves sitting balance and specific aspects of lung function in patients with tetraplegia.

The efficacy of sling exercise combined with extracorporeal shock wave on office workers with chronic neck pain.

This study aimed to investigate the effect of extracorporeal shockwave therapy on the anterior surface line of the fascia meridian, including the oblique muscle, combined with sling exercise, on the stability of the spine in the neck disability index (NDI), neck joint range of motion (ROM), craniovertebral angle, neck alignment, and posture control. A total of 20 office workers with chronic neck pain were randomly assigned to an experimental group that combined extracorporeal shock wave therapy and sling exercise (n = 10) and a control group (CG) consisting of sling exercise (n = 10) performed twice weekly for 4 weeks. All subjects were evaluated using the NDI, ROM, neck alignment, and spine stability tests. Following the intervention, there were significant differences in the For example, NDI, craniovertebral angle, Cobb's angle, Centaur data, and ROM. Except for Cobb's angle and Centaur data (-90 degrees), all variables showed significant differences in the CG. Comparing changes before and after the intervention, The For example, showed significantly more significant changes in all variables than the CG. The combination of extracorporeal shockwave therapy and sling exercises improved NDI, ROM, and neck and spine alignment in office workers with chronic neck pain more effectively than the sling exercise alone. This study could be recommended as a new approach to enable individuals with chronic neck pain to perform better.

Biomechanical Analysis of Unplanned Gait Termination According to a Stop-Signal Task Performance: A Preliminary Study.

There is a correlation between cognitive inhibition and compensatory balance response; however, the correlation between response inhibition and gait termination is not clear. OBJECTIVES: The purpose of this study was to investigate the gait parameters of the lower extremity that occurred during unplanned gait termination (UGT) in two groups classified by the stop-signal reaction time (SSRT). METHODS: Twenty young adults performed a stop-signal task and an unplanned gait termination separately. UGT required subjects to stop on hearing an auditory cue during randomly selected trials. The spatiotemporal and kinematic gait parameters were compared between the groups during UGT. RESULTS: In phase one, the fast group had a significantly greater angle and angular velocity of knee flexion and ankle plantar flexion than the slow group (p < 0.05). Phase two showed that the fast group had a significantly greater angle and angular velocity of knee extension than the slow group (p < 0.05). Concerning the correlation analysis, the angle and angular velocity of knee flexion and ankle plantar flexion showed a negative correlation with the SSRT during UGT in phase one (p < 0.05). Phase two showed that the angle and angular velocity of knee extension was negatively correlated with the SSRT during UGT (p < 0.05). CONCLUSION: The shorter the SSRT, the greater the angle and joint angular velocity of the ankle or knee joint that were prepared and adjusted for gait termination. The correlation between the SSRT and UGT suggests that a participant's capacity to inhibit an incipient finger response is associated with their ability to make a corrective gait pattern in a choice-demanding environment.

Immediate Effects of the Reverse Plank Exercise on Muscle Thickness and Postural Angle in Individuals with the Forward Shoulder Posture.

The forward shoulder posture (FSP) results from shoulders being pulled forward by shortened anterior shoulder girdle muscles. The objective of this study was to investigate the short-term effectiveness of the reverse plank exercise on parascapular muscle thickness and forward shoulder angle (FSA) in patients with FSP. Participants were divided into the FSP and non-FSP (NFSP) groups based on the observed angle between the horizontal line of the C7 spinous process and the acromion process. All participants performed a total of five sets of reverse plank exercises at 30 s per set. FSA and muscle thickness of the pectoralis major (PM), serratus anterior (SA), upper trapezius (UT), and lower trapezius (LT) were measured before and after the reverse plank exercise. The muscle thicknesses of the SA and LT, and the FSA, were significantly increased after exercise in the FSP group (p < 0.05). Muscle thickness of the PM and UT significantly decreased after the exercise. In the NFSP group, muscle thickness of the LT was significantly increased, and muscle thickness of the PM and UT were significantly reduced after exercise (p < 0.05). Upon using between-group analysis, there were significant differences between the FSA, SA, UT, and LT groups (p < 0.05). The reverse plank exercise has the short-term benefit of correcting and preventing FSP by increasing SA and LT thickness while decreasing PM and UT thickness. We believe that the reverse plank exercise significantly improved the ability to prevent FSP in FSP-related muscles and was beneficial in achieving optimal postural alignment.

EEG-based analysis of various sensory stimulation effects to reduce visually induced motion sickness in virtual reality.

The use of virtual reality (VR) is frequently accompanied by motion sickness, and approaches for preventing it are not yet well established. We explored the effects of synchronized presentations of sound and motion on visually induced motion sickness (VIMS) in order to reduce VIMS. A total of 25 participants bicycle riding for 5 min with or without sound and motion synchronization presented on a head-mounted display. As a result, the VIMS scores measured by the fast motion sickness scale and simulator sickness questionnaire were significantly lower in the participants who experienced the riding scene with sound and motion than those who experienced the riding scene with sound only, motion only, or neither. Furthermore, analysis of the EEG signal showed that the higher the VIMS, the significant increase in alpha and theta waves in the parietal and occipital lobes. Therefore, we demonstrate that the simultaneous presentation of sound and motion, closely associated with synchronous and visual flow speed, is effective in reducing VIMS while experiencing simulated bicycle riding in a VR environment.

Motor Imagery Combined With Physical Training Improves Response Inhibition in the Stop Signal Task.

Background: Motor imagery training has a similar effect to that of physical training on motor performance. The objective of this study was to investigate the short-term effectiveness of motor imagery training on response inhibition using the stop signal task (SST). Methods: Participants were divided into a physical training group (PT, n = 17), a motor imagery training group (MIT, n = 17), and a motor imagery combined with physical training group (MIPT, n = 17). All participants performed 10 SST training sessions over 5 days. Both stop signal reaction time (SSRT) and non-signal reaction time (NSRT) were measured before and after SST training. Results: There were significant interaction (time × group) and time effects, although the group effect was not statistically significant. Bonferroni post hoc analysis showed that MIPT group revealed a significantly greater change in SSRT than PT and MIT groups, while there was no significant difference between PT and MIT groups. SSRT significantly decreased after training in all groups. In NSRT, there was a significant effect of time, but there was no significant interaction effect (time × group) or group effect. Conclusion: Response inhibition could be enhanced via training, and it was most effective when motor imagery and physical training were combined. We demonstrate that motor imagery training significantly improves response inhibition and should be accompanied by physical training when performing SST.

Liposomal Dexamethasone Reduces A/H1N1 Influenza-Associated Morbidity in Mice.

Re-emerging viral threats have continued to challenge the medical and public health systems. It has become clear that a significant number of severe viral infection cases are due to an overreaction of the immune system, which leads to hyperinflammation. In this study, we aimed to demonstrate the therapeutic efficacy of the dexamethasone nanomedicine in controlling the symptoms of influenza virus infection. We found that the A/Wisconsin/WSLH34939/2009 (H1N1) infection induced severe pneumonia in mice with a death rate of 80%, accompanied by significant epithelial cell damage, infiltration of immune cells, and accumulation of pro-inflammatory cytokines in the airway space. Moreover, the intranasal delivery of liposomal dexamethasone during disease progression reduced the death rate by 20%. It also significantly reduced the protein level of tumor necrosis factor-alpha (TNFα), interleukin-1ß (IL-1ß), IL-6, and the C-X-C motif chemokine ligand 2 (CXCL2) as well as the number of infiltrated immune cells in the bronchoalveolar lavage fluids as compared to the control and free dexamethasone. The liposomal dexamethasone was mainly distributed into the monocyte/macrophages as a major cell population for inducing the cytokine storm in the lungs. Taken together, the intranasal delivery of liposomal dexamethasone may serve as a novel promising therapeutic strategy for the treatment of influenza A-induced pneumonia.

Comparative study of vestibular projection pathway connectivity in cerebellar injury patients and healthy adults.

OBJECTIVE: Cerebellar injury can not only cause gait and postural instability, nystagmus, and vertigo but also affect the vestibular system. However, changes in connectivity regarding the vestibular projection pathway after cerebellar injury have not yet been reported. Therefore, in the current study, we investigated differences in the connectivity of the vestibular projection pathway after cerebellar injury using diffusion tensor imaging (DTI) tractography. METHODS: We recruited four stroke patients with cerebellar injury. Neural connectivity in the vestibular nucleus (VN) of the pons and medulla oblongata in patients with cerebellar injury was measured using DTI. Connectivity was defined as the incidence of connection between the VN on the pons and medulla oblongata and target brain regions such as the cerebellum, thalamus, parieto-insular vestibular cortex (PIVC), and parietal lobe. RESULTS: At thresholds of 10 and 30, there was lower connectivity in the ipsilateral hemisphere between the VN at the medullar level and thalamus in the patients than in healthy adults. At a threshold of 1 and 10, the patient group showed lower VN connectivity with the PIVC than healthy adults. At a threshold of 1, VN connectivity with the parietal lobe in the contralateral hemisphere was lower in the patients than in healthy adults. Additionally, at a threshold of 30, VN connectivity at the pons level with the cerebellum was lower in healthy adults than in the patients. CONCLUSION: Cerebellar injury seems to be associated with decreased vestibular projection pathway connectivity, especially in the ipsilateral thalamus, PIVC, and contralateral parietal lobe.

Comparison of Abdominal Muscle Thickness between the Abdominal Draw-in Maneuver and Maximum Abdominal Contraction Maneuver.

All abdominal muscles, including the transverse abdominis (TrA), should be modulated to improve core stability. This study aimed to investigate easier and more effective core exercise methods by comparing thickness changes in the TrA, internal oblique (IO), external oblique (EO), and rectus abdominis (RA) muscles during the abdominal draw-in maneuver (ADIM) and maximum abdominal contraction maneuver (MACM). Thirty healthy subjects who participated in this study underwent ADIM and MACM three times in random order. We measured the abdominal muscle thickness during ADIM and MACM using ultrasonography and compared the changes in the thickness of TrA, IO, EO, and RA muscles using a paired t-test. Significant differences were observed in the thicknesses of all the abdominal muscles between the ADIM and MACM groups (p < 0.05). The MACM immediately increased the thickness of the TrA (p < 0.001, effect size (ES) = 0.931), IO (p = 0.001, ES = 0.761), EO (p = 0.008, ES = 0.415), and RA (p < 0.001, ES = 0.767) muscles. These results suggest that MACM is useful for immediately increasing the thickness of TrA, IO, EO, and RA muscles and may contribute to the clinical effect of simultaneous contractions on the changes in abdominal muscle thickness.

Comparison of forward versus backward walking on spatiotemporal and kinematic parameters on sand: A preliminary study.

The purpose of this study was to investigate the spatiotemporal and kinematic parameters of backward walking (BW) and forward walking (FW) on sand. Randomly selected subjects (n = 28) were categorized into a sand group (SG, n = 14) and an overground group (OG, n = 14). SG was directed to perform both FW and BW on sand, while OG performed the same on the overground. Spatiotemporal and kinematic parameters were measured using the LegSys + device. The comparative findings of both the groups showed that the spatiotemporal parameters of SG varied significantly from those of OG in both FW and BW conditions (p < 0.05). The kinematic parameters varied significantly between the two groups only in the FW condition (p < 0.05). When compared within each group, spatiotemporal and kinematic parameters in the BW condition were significantly different from those in the FW condition. However, the percentages of stance, swing, and double support were not significantly different between FW and BW conditions (p > 0.05). This study suggests that sand walking is associated with a different gait pattern than overground walking, as evident from the analysis of the results of spatiotemporal and kinematic parameters in both FW and BW conditions. Therefore, sand walking can be used as a new approach to gait and balance training in clinical practice.

Effects of Dual-Task Training on Gait Parameters in Elderly Patients with Mild Dementia.

This study aimed to investigate the effectiveness of dual-task training (DTT) compared to single-task training (STT), on gait parameters in elderly patients with mild dementia (MD). Twenty-four elderly patients with MD were randomly assigned to the DTT (n = 13) or the STT group (n = 11). The DTT group performed a specific cognitive-motor DTT, while the STT group received only motor task training. Both training sessions lasted 8 weeks, with a frequency of 3 days per week, and the cognitive functions and gait parameters were measured. A statistically significant interaction effect was found between the two groups in stride length, stride velocity, cadence, step length, swing phase, stance phase, and double support phase (p < 0.05). After 8 weeks, the DTT group showed significant improvement in spatiotemporal parameters, except for the kinematic parameters (p < 0.05). In the between-group analysis, the DTT group showed more improvement than the STT group in stride velocity, step length, swing phase, stance phase, and double support (p < 0.05). These findings suggest that improvements in spatiotemporal gait parameters after DTT are reported in patients with MD. Our results can guide therapists to include dual tasks in their gait rehabilitation programs for the treatment of mild dementia.

Breathing Exercise Called the Maximal Abdominal Contraction Maneuver.

Background and objectives: The maximal abdominal contraction maneuver (MACM) was designed as an effective and efficient breathing exercise to increase the stability of the spinal joint. However, it has not been determined whether MACM is more effective and efficient than the maximal expiration method. Thus, the present study was undertaken to investigate whole abdominal muscle thickness changes after MACM. Materials and Methods: Thirty healthy subjects (17 males and 13 females) participated in this study. An experimental comparison between MACM and the maximal expiration task was conducted by measuring the change of abdominal muscle thickness such as the transverse abdominis (TrA), internal oblique (IO), external oblique (EO) and rectus abdominis (RA) using ultrasound images. Results: The results indicated that MACM resulted in significantly greater muscle thickness increases of the TrA and RA than the maximal expiration exercise (p < 0.05). Conclusion: MACM provided better exercise than the maximal expiration exercise in terms of increasing spine stability, at least from a co-contraction perspective.

Patients carrying DPYD variant alleles have increased risk of severe toxicity and related treatment modifications during fluoropyrimidine chemotherapy.

Aim: To evaluate toxicity risk in carriers of four DPYD variants using an institutional genetic repository. Materials & methods: Of over 65,000 patients in the repository, 582 were evaluated for the primary composite end point of grade 3 or higher toxicity or treatment modification due to toxicity. Results: The primary end point was more common in DPYD variant carriers (36.5 vs 18.1%, adjusted odds ratio 2.42, 95% CI: 1.05-5.55, p = 0.04), and in patients with decreased DPD activity (≤1 vs 2) (75.6 vs 17.0%, adjusted odds ratio 16.31, 95% CI: 2.64-100.68, p = 0.003). Conclusion: Patients carrying any of the four DPYD variants are at increased risk of severe toxicity or subsequent treatment modifications, suggesting such patients may benefit from genotype-informed treatment.

Histamine causes an imbalance between pro-angiogenic and anti-angiogenic factors in the retinal pigment epithelium of diabetic retina via H4 receptor/p38 MAPK axis.

INTRODUCTION: Systemic histaminergic activity is elevated in patients with diabetes mellitus. There are a few studies suggesting that histamine is implicated in the pathogenesis of diabetes, but the exact role of histamine in the development of diabetic retinopathy is unclear. The aim of this study was to investigate the role of histamine receptor H4 (HRH4) in the regulation of retinal pigment epithelium (RPE)-derived pro-angiogenic and anti-angiogenic factors under diabetic conditions. RESEARCH DESIGN AND METHODS: The levels of vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), histamine and histidine decarboxylase (HDC) in the serum and vitreous samples of patients with diabetes were compared with those of patients without diabetes. The effect of hyperglycemia on expression levels of HRH4, VEGF, IL-6 and pigment epithelium-derived factor (PEDF) in the RPE was determined. The role of HRH4 in high glucose-induced regulation of VEGF, IL-6 and PEDF in ARPE-19 cells and the underlying regulatory mechanism were verified using an RNA interference-mediated knockdown study. RESULTS: The serum and vitreous levels of VEGF, IL-6, histamine and HDC were more increased in patients with diabetic retinopathy than in patients without diabetes. HRH4 was overexpressed in RPE both in vitro and in vivo. Histamine treatment upregulated VEGF and IL-6 and downregulated PEDF expression in ARPE-19 cells cultivated under hyperglycemic conditions. Hyperglycemia-induced phosphorylation of p38 and subsequent upregulation of VEGF and IL-6 and downregulation of PEDF were dampened by small interfering RNA-mediated knockdown of HRH4 in ARPE-19 cells. CONCLUSIONS: Taken together, HRH4 was a critical regulator of VEGF, IL-6 and PEDF in the RPE under hyperglycemic conditions and the p38 mitogen-activated protein kinase pathway mediated this regulatory mechanism.

Protein Kinase A Catalytic Subunit Is a Molecular Switch that Promotes the Pro-tumoral Function of Macrophages.

As current therapies benefit only a minority of cancer patients, additional therapeutic targets are needed. Tumor-associated macrophages (TAMs) have attracted attention for improving therapeutic responses, yet regulatory strategies remain elusive. Here, we show that the protein kinase A catalytic subunit (PKA-C) acts as a molecular switch, inducing a pro-tumoral immunosuppressive macrophage phenotype within tumors. In human and murine breast cancer, overactivated PKA in TAMs creates a detrimental microenvironment for cancer progression by inducing vascular endothelial growth factor A (VEGFA), interleukin-10 (IL-10), and macrophage-derived arginase 1 (ARG1) expression. Macrophages with genetic deletion of PKA-C are prone to be pro-inflammatory, suggesting a possible immunotherapeutic target. Delivery of liposomal PKA inhibitor facilitates tumor regression and abrogates pro-tumoral TAM functions in mice. The therapeutic effect of targeting PKA is pronounced when combined with αCTLA-4 antibody, increasing cluster of differentiation 8 (CD8)+GranzymeB+ T cells by about 60-fold. Our findings demonstrate critical roles of TAM PKA-C in tumor progression and suggest that targeting PKA-C efficiently augments cancer treatment responses.

Three-Dimensional Identification of the Medial Longitudinal Fasciculus in the Human Brain: A Diffusion Tensor Imaging Study.

BACKGROUND: The medial longitudinal fasciculus (MLF) interacts with eye movement control circuits involved in the adjustment of horizontal, vertical, and torsional eye movements. In this study, we attempted to identify and investigate the anatomical characteristics of the MLF in human brain, using probabilistic diffusion tensor imaging (DTI) tractography. METHODS: We recruited 31 normal healthy adults and used a 1.5-T scanner for DTI. To reconstruct MLFs, a seed region of interest (ROI) was placed on the interstitial nucleus of Cajal at the midbrain level. A target ROI was located on the MLF of the medulla in the reticular formation of the medulla. Mean values of fractional anisotropy, mean diffusivity, and tract volumes of MLFs were measured. RESULTS: The component of the MLF originated from the midbrain MLF, descended through the posterior side of the medial lemniscus (ML) and terminated on the MLF of medulla on the posterior side of the ML in the medulla midline. DTI parameters of right and left MLFs were not significantly different. CONCLUSION: The tract of the MLF in healthy brain was identified by probabilistic DTI tractography. We believe this study will provide basic data and aid future comparative research on lesion or age-induced MLF changes.

Effect of Plyometric versus Ankle Stability Exercises on Lower Limb Biomechanics in Taekwondo Demonstration Athletes with Functional Ankle Instability.

BACKGROUND: This study aimed to compare the effects of plyometric and ankle stability exercises on the dynamic balance and lower limb kinematic and kinetic parameters of Taekwondo demonstration athletes with functional ankle instability. METHODS: Fourteen subjects participated in this study and were randomly divided into two groups: a plyometric exercise group (n = 7) and an ankle stability exercise group (n = 7). Exercises were performed twice a week for 8 weeks. A Y-balance test was used to measure dynamic balance, and a motion analysis system and force plate were used to collect kinematic and kinetic parameters during single-leg drop landing. A paired t-test was used for intragroup comparisons, and an independent t-test was used for intergroup comparisons. RESULTS: In both groups, exercise increased dynamic balance and shock absorption and reduced postural sway on the anteroposterior displacement (p < 0.05). The plyometric exercise group decreased their ankle dorsiflexion and increased their knee and hip joint flexion at maximum knee flexion (p < 0.05). In contrast, the stability exercise increased their ankle plantar flexion at initial contact (p < 0.05). CONCLUSIONS: The plyometric exercise group altered their landing strategies using their knee and hip joints to control ankle instability at landing. This study suggests that the application of plyometric exercises in ankle rehabilitation would improve stability and shock absorption and help prevent injuries during Taekwondo demonstrations.