Bridging Reduced Grip Strength and Altered Executive Function: Specific Brain White Matter Structural Changes in Patients with Alzheimer's Disease.

Objective: To investigate the correlation between specific fiber tracts and grip strength and cognitive function in patients with Alzheimer's disease (AD) by fixel-based analysis (FBA). Methods: AD patients were divided into AD with low grip strength (AD-LGS, n=29) and AD without low grip strength (AD-nLGS, n=25), along with 31 normal controls (NC). General data, neuropsychological tests, grip strength and cranial magnetic resonance imaging (MRI) scans were collected. FBA evaluated white matter (WM) fiber metrics, including fiber density (FD), fiber cross-sectional (FC), and fiber density and cross-sectional area (FDC). The mean fiber indicators of the fiber tracts of interest (TOI) were extracted in cerebral region of significant statistical differences in FBA to further compare the differences between groups and analyze the correlation between fiber properties and neuropsychological test scores. Results: Compared to AD-nLGS group, AD-LGS group showed significant reductions in FDC in several cerebral regions. In AD patients, FDC values of bilateral uncinate fasciculus and left superior longitudinal fasciculus were positively correlated with Clock Drawing Test scores, while FDC of splenium of corpus callosum, bilateral anterior cingulate tracts, forceps major, and bilateral inferior longitudinal fasciculus were positively correlated with the Executive Factor Score of Memory and Executive Screening scale scores. Conclusion: Reduced grip strength in AD patients is associated with extensive impairment of WM structural integrity. Changes in FDC of specific WM fiber tracts related to executive function play a significant mediating role in the reduction of grip strength in AD patients.

Lower fractional dimension in Alzheimer's disease correlates with reduced locus coeruleus signal intensity.

This study aimed to determine the pattern of fractional dimension (FD) in Alzheimer's disease (AD) patients, and investigate the relationship between FD and the locus coeruleus (LC) signal intensity.A total of 27 patients with AD and 25 healthy controls (HC) were collected to estimate the pattern of fractional dimension (FD) and cortical thickness (CT) using the Computational Anatomy Toolbox (CAT12), and statistically analyze between groups on a vertex level using statistical parametric mapping 12. In addition, they were examined by neuromelanin sensitive MRI(NM-MRI) technique to calculate the locus coeruleus signal contrast ratios (LC-CRs). Additionally, correlations between the pattern of FD and LC-CRs were further examined.Compared to HC, AD patients showed widespread lower CT and FD Furthermore, significant positive correlation was found between local fractional dimension (LFD) of the left rostral middle frontal cortex and LC-CRs. Results suggest lower cortical LFD is associated with LCCRs that may reflect a reduction due to broader neurodegenerative processes. This finding may highlight the potential utility for advanced measures of cortical complexity in assessing brain health and early identification of neurodegenerative processes.

Differential eye movement features between Alzheimer's disease patients with and without depressive symptoms.

BACKGROUND: Accurately diagnosing depressive symptoms in Alzheimer's disease (AD) patients is often challenging. Eye movement parameters have been demonstrated as biomarkers for assessing cognition and psychological conditions. AIM: To investigate the differences in eye movement between AD patients with and without depressive symptoms. METHODS: Eye movement data of 65 AD patients were compared between the depressed AD (D-AD) and non-depressed AD (nD-AD) groups. Logistic regression analysis was employed to identify diagnostic biomarkers and the ROC curve was plotted. The correlation between eye movement and HAMD-17 scores was assessed by partial correlation analysis. RESULTS: The D-AD patients showed longer saccade latency and faster average/peak saccade velocities in the overlap prosaccade test, longer average reaction time and faster average saccade velocity in the gap prosaccade test, longer start-up durations, slower pursuit velocity, more offsets, and larger total offset degrees in the smooth pursuit test, and poorer fixation stability in both the central and lateral fixation tests compared to nD-AD patients. The start-up duration in the smooth pursuit test and the number of offsets in the central fixation test were identified as the diagnostic eye movement parameters for D-AD patients with the area under the ROC curves of 0.8011. Partial correlation analysis revealed that the start-up duration and pursuit velocity in the smooth pursuit test and the total offset degrees in the lateral fixation test were correlated with HAMD-17 scores in D-AD patients. DISCUSSION AND CONCLUSIONS: Eye movement differences may help to differentiate D-AD patients from nD-AD patients in a non-invasive and cost-effective manner.

Relationship between sarcopenic obesity and cognitive function in patients with mild to moderate Alzheimer's disease.

BACKGROUND: Previous research has linked sarcopenic obesity (SO) to cognitive function; however, the relationship between cognitive performance and SO Alzheimer's disease (AD) patients remains unclear. This study aimed to investigate their relationship in AD patients. METHODS: One hundred and twenty mild to moderate AD patients and 56 normal controls were recruited. According to sarcopenia or obesity status, AD patients were classified into subgroups: normal, obesity, sarcopenia, and SO. Body composition, demographics, and sarcopenia parameters were assessed. Cognitive performance was evaluated using neuropsychological scales. RESULTS: Among the 176 participants, the prevalence of SO in the moderate AD group was higher than in the normal control group. The moderate AD group had the lowest appendicular skeletal muscle mass index (ASMI) and the highest percentage of body fat (PBF). Hypertension and diabetes were more prevalent in the SO group than in the normal group among the subgroups. The sarcopenia and SO groups exhibited worse global cognitive function compared to the normal and obesity groups. Partial correlation analysis revealed that ASMI, PBF, and visceral fat area were associated with multiple cognitive domains scores. In logistic regression analysis, after adjusting for confounders, obesity was not found to be associated with AD. However, sarcopenia (odds ratio (OR) = 5.35, 95% CI: 1.27-22.46) and SO (OR = 5.84, 95% CI: 1.26-27.11) were identified as independent risk factors for AD. CONCLUSIONS: SO was associated with cognitive dysfunction in AD patients. Moreover, the impact of SO on cognitive decline was greater than that of sarcopenia. Early identification and intervention for SO may have a positive effect on the occurrence and progression of AD.

White matter hyperintensities: a possible link between sarcopenia and cognitive impairment in patients with mild to moderate Alzheimer's disease.

PURPOSE: Alzheimer's disease (AD) has been reported to be associated with sarcopenia. White matter hyperintensities (WMH) are common in AD patients. However, the effect of WMH on sarcopenia in AD remains unclear. We hence aimed to investigate the possible association between regional WMH volumes and sarcopenic parameters in AD. METHODS: 57 mild to moderate AD patients and 22 normal controls (NC) were enrolled. Sarcopenic parameters were assessed, including appendicular skeletal mass index (ASMI), grip strength, 5-times sit-to-stand (5-STS) time, and gait speed. The volumes of periventricular hyperintensities (PVH) and deep white matter hyperintensities (DWMH) were quantified using 3D-slicer software. RESULTS: AD subjects exhibited a lower ASMI, a slower gait speed, an increased 5-STS time, and larger volumes of PVH and DWMH than those in the NC group. In AD subjects, total WMH and PVH volumes were related to cognitive impairment, particularly executive function decline. Moreover, total WMH volume and PVH volume were negatively correlated with gait speed across various clinical stages of AD. Multiple linear regression analysis showed that PVH volume was independently associated with 5-STS time and gait speed, whereas DWMH volume was only independently associated with gait speed. CONCLUSION: WMH volume was associated with cognitive decline and various sarcopenic parameters. It thereby suggested that WMH may serve as the connection between sarcopenia and cognitive dysfunction in AD. Further studies are needed to confirm these findings and to determine whether sarcopenia interventions reduce WMH volume and improve cognitive function in AD.

Eosinophil: A New Circulating Biomarker for Risk of Poor Outcome in Stroke Patients Undergoing Mechanical Thrombectomy.

Objective: Acute ischemic stroke (AIS), caused by occlusion of large vessel, is a serious life-threatening disease. This study aimed to comprehensively investigate the association of 14 common and readily available circulating biomarkers with the 90-day modified Rankin Scale (mRS) score in patients undergoing mechanical thrombectomy (MT). Methods: This study included patients with anterior circulation large vessel occlusive stroke treated with MT from 05/2017 to 12/2021. Baseline comparisons of poor outcome were performed among enrolled patients. Factors that may be associated with the mRS score were assessed using correlation analysis. Univariate and multivariate logistic regression analyses were used to evaluate the predictive value of circulating biomarkers and poor outcome. Results: The mRS score has a strong correlation with neutrophil to lymphocyte ratio (NLR) and eosinophil levels (all rs>0.4 in absolute value and all P<0.001) in addition to a high correlation with National Institute of Health Stroke Scale (NIHSS) score (rs=0.40, P<0.001). There was also a high correlation between NLR and eosinophil (rs=-0.58, P<0.001). In the multivariate regression analysis, only neutrophil (adjusted OR=1.301, 95% CI: 1.155-1.465, P<0.001), eosinophil (adjusted OR<0.001, 95% CI: <0.001-0.016, P<0.001), and NLR (adjusted OR=1.158, 95% CI: 1.082-1.241, P<0.001) were independently associated with poor outcome. Conclusion: This study evaluated a series of circulating biomarkers and found that neutrophil, eosinophil, and NLR independently predicted poor outcome after MT in AIS patients. There was a significant negative correlation between eosinophil and NLR levels.

Relationship between sarcopenia and sleep status in female patients with mild to moderate Alzheimer's disease.

BACKGROUND: Sleep disorders and sarcopenia could contribute to the development of Alzheimer's disease (AD), which are risk factors that rapidly deteriorate cognitive functions. However, few studies have evaluated the relationship between sarcopenia and sleep disorders in female AD patients, who have a higher prevalence than male patients. This study aimed to investigate the relationship between sarcopenia and sleep status in female patients with mild to moderate AD. METHODS: This cross-sectional study recruited 112 female outpatients aged between 60 and 85 years. Demographic characteristics, appendicular skeletal muscle mass index (ASMI), grip strength, and gait speed were assessed. Sarcopenia was diagnosed according to criteria of the Asian Working Group for Sarcopenia. Pittsburgh Sleep Quality Index (PSQI) assessed sleep variables. Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) assessed cognitive function. Binary logistic regression models explored the relationship between sleep variables and cognitive function and sarcopenia, adjusting for potential cofounders. RESULTS: The outpatients were divided into 36 AD patients with sarcopenia (ADSa) and 76 AD patients without sarcopenia (ADNSa), with a prevalence of 32.1%. ADSa had lower ASMI, weaker grip strength, slower gait speed, a higher incidence of poor sleep quality and poorer cognitive function. Multivariate binary logistic regression analysis showed that high total scores of PSQI (odds ratio (OR) = 1.13), poor sleep quality (OR = 2.73), poor subjective sleep quality (OR = 1.83), low MMSE (OR = 0.77) and MoCA (OR = 0.76) scores were associated with high odds of sarcopenia. Compared to sleep time ≤ 15 min, >60 min (OR = 5.01) were associated with sarcopenia. Sleep duration <6 h (OR = 3.99), 8-9 h (OR = 4.48) and ≥9 h (OR = 6.33) were associated with sarcopenia compared to 7-8 h. CONCLUSIONS: More sleep symptoms and cognitive impairment exist in female patients with sarcopenia. The higher total scores of PSQI, poorer subjective sleep quality, longer sleep latency, excessive and insufficient sleep duration and poorer cognitive function are associated with higher odds of sarcopenia in female patients with mild to moderate AD.

Decreased locus coeruleus signal associated with Alzheimer's disease based on neuromelanin-sensitive magnetic resonance imaging technique.

Objective: Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) technique was used to detect the changes of the locus coeruleus (LC) signals in Alzheimer's disease patients (AD), and to analyze its correlation with cognitive function. Materials and methods: A total of 27 patients with AD, 15 patients with mild cognitive impairment (MCI), and 25 healthy controls (HC) were examined by NM-MRI technique. ImageJ software was used to measure the LC signals. The locus coeruleus signal contrast ratios (LC-CRs) were calculated, along with the measurement of neuropsychological scales. Results: The LC-CRs of AD patients were significantly different from that of HC (p = 0.007, 95% CI: -0.053∼-0.007). However, such significant differences were not observed between MCI and HC (p = 1.000, 95% CI: -0.030∼0.024), AD and MCI (p = 0.050, 95% CI: -0.054∼0.000). Furthermore, a significant positive correlation was identified between LC-CRs and MMSE sub item Drawing (r = 0.484, p = 0.011) in the AD group, MoCA sub item Attention (r = 0.519, p = 0.047) in the MCI group. The area under the curve of LC-CRs in the diagnosis of AD was 0.749 (p = 0.002, 95% CI: 0.618∼0.880), with a sensitivity of 85.2% and a specificity of 56.0%. Conclusion: The NM-MRI technique could quantify the pathological degenerations of the LC in AD. Such LC degenerations can be employed to distinguish AD from healthy elderly.

Correlation between parameters related to sarcopenia and gray matter volume in patients with mild to moderate Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease characterized by brain atrophy and closely correlated with sarcopenia. Mounting studies indicate that parameters related to sarcopenia are associated with AD, but some results show inconsistent. Furthermore, the association between the parameters related to sarcopenia and gray matter volume (GMV) has rarely been explored. AIM: To investigate the correlation between parameters related to sarcopenia and cerebral GMV in AD. METHODS: Demographics, neuropsychological tests, parameters related to sarcopenia, and magnetic resonance imaging (MRI) scans were collected from 42 patients with AD and 40 normal controls (NC). Parameters related to sarcopenia include appendicular skeletal muscle mass index (ASMI), grip strength, 5-times sit-to-stand (5-STS) time and 6-m gait speed. The GMV of each cerebral region of interest (ROI) and the intracranial volume were calculated by computing the numbers of the voxels in the specific region based on MRI data. Partial correlation and multivariate stepwise linear regression analysis explored the correlation between different inter-group GMV ratios in ROIs and parameters related to sarcopenia, adjusting for covariates. RESULTS: The 82 participants included 40 NC aged 70.13 ± 5.94 years, 24 mild AD patients aged 73.54 ± 8.27 years and 18 moderate AD patients aged 71.67 ± 9.39 years. Multivariate stepwise linear regression showed that 5-STS time and gait speed were correlated with bilateral hippocampus volume ratios in total AD. Grip strength was associated with the GMV ratio of the left middle frontal gyrus in mild AD and the GMV ratios of the right superior temporal gyrus and right hippocampus in moderate AD. However, ASMI did not have a relationship to any cerebral GMV ratio. CONCLUSIONS: Among parameters related to sarcopenia, 5-STS time and gait speed were associated with bilateral hippocampus volume ratios at different clinical stages of patients with AD. Five-STS time provide an objective basis for early screening and can help diagnose patients with AD.

Conditioned Media of Adipose-Derived Stem Cells Suppresses Sidestream Cigarette Smoke Extract Induced Cell Death and Epithelial-Mesenchymal Transition in Lung Epithelial Cells.

The role of the epithelial-mesenchymal transition (EMT) in lung epithelial cells is increasingly being recognized as a key stage in the development of COPD, fibrosis, and lung cancers, which are all highly associated with cigarette smoking and with exposure to second-hand smoke. Using the exposure of human lung cancer epithelial A549 cells and non-cancerous Beas-2B cells to sidestream cigarette smoke extract (CSE) as a model, we studied the protective effects of adipose-derived stem cell-conditioned medium (ADSC-CM) against CSE-induced cell death and EMT. CSE dose-dependently induced cell death, decreased epithelial markers, and increased the expression of mesenchymal markers. Upstream regulator analysis of differentially expressed genes after CSE exposure revealed similar pathways as those observed in typical EMT induced by TGF-ß1. CSE-induced cell death was clearly attenuated by ADSC-CM but not by other control media, such as a pass-through fraction of ADSC-CM or A549-CM. ADSC-CM effectively inhibited CSE-induced EMT and was able to reverse the gradual loss of epithelial marker expression associated with TGF-ß1 treatment. CSE or TGF-ß1 enhanced the speed of A549 migration by 2- to 3-fold, and ADSC-CM was effective in blocking the cell migration induced by either agent. Future work will build on the results of this in vitro study by defining the molecular mechanisms through which ADSC-CM protects lung epithelial cells from EMT induced by toxicants in second-hand smoke.

Assessment of Polyethylene Glycol-Coated Gold Nanoparticle Toxicity and Inflammation In Vivo Using NF-κB Reporter Mice.

Polyethylene glycol (PEG) coating of gold nanoparticles (AuNPs) improves AuNP distribution via blood circulation. The use of PEG-coated AuNPs was shown to result in acute injuries to the liver, kidney, and spleen, but long-term toxicity has not been well studied. In this study, we investigated reporter induction for up to 90 days in NF-κB transgenic reporter mice following intravenous injection of PEG-coated AuNPs. The results of different doses (1 and 4 µg AuNPs per gram of body weight), particle sizes (13 nm and 30 nm), and PEG surfaces (methoxyl- or carboxymethyl-PEG 5 kDa) were compared. The data showed up to 7-fold NF-κB reporter induction in mouse liver from 3 h to 7 d post PEG-AuNP injection compared to saline-injected control mice, and gradual reduction to a level similar to control by 90 days. Agglomerates of PEG-AuNPs were detected in liver Kupffer cells, but neither gross pathological abnormality in liver sections nor increased activity of liver enzymes were found at 90 days. Injection of PEG-AuNPs led to an increase in collagen in liver sections and elevated total serum cholesterol, although still within the normal range, suggesting that inflammation resulted in mild fibrosis and affected hepatic function. Administrating PEG-AuNPs inevitably results in nanoparticles entrapped in the liver; thus, further investigation is required to fully assess the long-term impacts by PEG-AuNPs on liver health.

A Tri-fusion Reporter Mouse Reveals Tissue-Specific FGF1B Promoter Activity in vivo.

Transgenic mice harboring imaging reporters take full advantage of imaging technologies in studies using living mice. Here, we established a tri-fusion multimodal reporter gene containing fragments from firefly luciferase, enhanced green fluorescent protein, and herpes simplex virus type 1 thymidine kinase and generated tri-fusion reporter Tg mice. Fibroblast growth factor type 1 (FGF1), a multifunctional mitogen to a wide range of tissues, regulates proliferation of neural stem cells of the brain, where FGF1 expression is initiated through activation of the FGF1B (F1B) promoter. The reporter mouse under the control of the human F1B promoter enables visualization in vivo where F1B activity is elevated, including tissues not only in the brain but also in the nasopharynx, skull, spine, and testes, particularly in Leydig cells. Treating Tg mice with the alkylating agent busulfan, which is known to eradicate Leydig cells and disrupt spermatogenesis in mice, eliminated the reporter signals. Restoring Leydig cells recovered reporter expression, indicating that the reporter can be used as a surrogate marker for Leydig cells. The F1B tri-fusion reporter mouse model can be utilized in longitudinal monitoring of the health status of the male reproductive system, such as in studies exploring the toxicity of chemicals to spermatogenesis.

Sperm DNA damage has a negative effect on early embryonic development following in vitro fertilization.

Sperm DNA damage is recognized as an important biomarker of male infertility. To investigate this, sperm DNA damage was assessed by the sperm chromatin dispersion (SCD) test in semen and motile spermatozoa harvested by combined density gradient centrifugation (DGC) and swim-up in 161 couples undergoing in vitro fertilization (IVF). Semen analysis and sperm DNA damage results were compared between couples who did or did not achieve pregnancy. The sperm DNA damage level was significantly different between the two groups (P < 0.05) and was negatively correlated with IVF outcomes. Logistic regression analysis confirmed that it was an independent predictor for achieving clinical pregnancy. The effects of different levels of sperm DNA damage on IVF outcomes were also compared. There were significant differences in day 3 embryo quality, blastocyst formation rate, and implantation and pregnancy rates (P < 0.05), but not in the basic fertilization rate between the two groups. Thus, sperm DNA damage as measured by the SCD appears useful for predicting the clinical pregnancy rate following IVF.

Evaluating impacts of different longitudinal driver assistance systems on reducing multi-vehicle rear-end crashes during small-scale inclement weather.

Multi-vehicle rear-end (MVRE) crashes during small-scale inclement (SSI) weather cause high fatality rates on freeways, which cannot be solved by traditional speed limit strategies. This study aimed to reduce MVRE crash risks during SSI weather using different longitudinal driver assistance systems (LDAS). The impact factors on MVRE crashes during SSI weather were firstly analyzed. Then, four LDAS, including Forward collision warning (FCW), Autonomous emergency braking (AEB), Adaptive cruise control (ACC) and Cooperative ACC (CACC), were modeled based on a unified platform, the Intelligent Driver Model (IDM). Simulation experiments were designed and a large number of simulations were then conducted to evaluate safety effects of different LDAS. Results indicate that the FCW and ACC system have poor performance on reducing MVRE crashes during SSI weather. The slight improvement of sight distance of FCW and the limitation of perception-reaction time of ACC lead the failure of avoiding MVRE crashes in most scenarios. The AEB system has the better effect due to automatic perception and reaction, as well as performing the full brake when encountering SSI weather. The CACC system has the best performance because wireless communication provides a larger sight distance and a shorter time delay at the sub-second level. Sensitivity analyses also indicated that the larger number of vehicles and speed changes after encountering SSI weather have negative impacts on safety performances. Results of this study provide useful information for accident prevention during SSI weather.

Evaluation of the impacts of cooperative adaptive cruise control on reducing rear-end collision risks on freeways.

Although plenty of studies have been conducted recently about the impacts of cooperative adaptive cruise control (CACC) system on traffic efficiency, there are few researches analyzing the safety effects of this advanced driving-assistant system. Thus, the primary objective of this study is to evaluate the impacts of the CACC system on reducing rear-end collision risks on freeways. The CACC model is firstly developed, which is based on the Intelligent Driver Model (IDM). Then, two surrogated safety measures, derived from the time-to-collision (TTC), denoting time exposed time-to-collision (TET) and time integrated time-to-collision (TIT), are introduced for quantifying the collision risks. And the safety effects are analyzed both theoretically and experimentally, by the linear stability analysis and simulations. The theoretical and simulation results conformably indicate that the CACC system brings dramatic benefits for reducing rear-end collision risks (TET and TIT are reduced more than 90%, respectively), when the desired time headway and time delay are set properly. The sensitivity analysis indicates there are few differences among different values of the threshold of TTC and the length of a CACC platoon. The results also show that the safety improvements weaken with the decrease of the penetration rates of CACC on the market and the increase of time delay between platoons. We also evaluate the traffic efficiency of the CACC system with different desired time headway.

Chloride channels are involved in sperm motility and are downregulated in spermatozoa from patients with asthenozoospermia.

Human spermatozoa encounter an osmotic decrease from 330 to 290 mOsm l-1 when passing through the female reproductive tract. We aimed to evaluate the role of chloride channels in volume regulation and sperm motility from patients with asthenozoospermia. Spermatozoa were purified using Percoll density gradients. Sperm volume was measured as the forward scatter signal using flow cytometry. Sperm motility was analyzed using computer-aided sperm analysis (CASA). When transferred from an isotonic solution (330 mOsm l-1 ) to a hypotonic solution (290 mOsm l-1 ), cell volume was not changed in spermatozoa from normozoospermic men; but increased in those from asthenozoospermic samples. The addition of the chloride channel blockers, 4,4'-diisothiocyanatostilbene-2,2'- isulfonic acid (DIDS) or 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) to the hypotonic solution caused the normal spermatozoa to swell but did not increase the volume of those from the asthenozoospermic semen. DIDS and NPPB decreased sperm motility in both sets of semen samples. The inhibitory effect of NPPB on normal sperm motility was much stronger than on spermatozoa from the asthenozoospermic samples. Both sperm types expressed ClC-3 chloride channels, but the expression levels in the asthenozoospermic samples were much lower, especially in the neck and mid-piece areas. Spermatozoa from men with asthenozoospermia demonstrated lower volume regulating capacity, mobility, and ClC-3 expression levels (especially in the neck) than did normal spermatozoa. Thus, chloride channels play important roles in the regulation of sperm volume and motility and are downregulated in cases of asthenozoospermia.

Cardiac fibrosis in mouse expressing DsRed tetramers involves chronic autophagy and proteasome degradation insufficiency.

Proteinopathy in the heart which often manifests excessive misfolded/aggregated proteins in cardiac myocytes can result in severe fibrosis and heart failure. Here we developed a mouse model, which transgenically express tetrameric DsRed, a red fluorescent protein (RFP), in an attempt to mimic the pathological mechanisms ofcardiac fibrosis. Whilst DsRed is expressed and forms aggregation in most mouse organs, certain pathological defects are specifically recapitulated in cardiac muscle cells including mitochondria damages, aggresome-like residual bodies, excessive ubiquitinated proteins, and the induction of autophagy. The proteinopathy and cellular injuries caused by DsRed aggregates may be due to impaired or overburdened ubiquitin-proteasome system and autophagy-lysosome systems. We further identified that DsRed can be ubiquitinated and associated with MuRF1, a muscle-specific E3 ligase. Concomitantly, an activation of NF-κB signaling and a strong TIMP1 induction were noted, suggesting that RFP-induced fibrosis was augmented by a skewed balance between TIMP1 and MMPs. Taken together, our study highlights the molecular consequences of uncontrolled protein aggregation leading to congestive heart failure, and provides novel insights into fibrosis formation that can be exploited for improved therapy.

The AQP-3 water channel is a pivotal modulator of glycerol-induced chloride channel activation in nasopharyngeal carcinoma cells.

Aquaporin (AQP) and chloride channels are ubiquitous in virtually all living cells, playing pivotal roles in cell proliferation, migration and apoptosis. We previously reported that AQP-3 aquaglyceroporin and ClC-3 chloride channels could form complexes to regulate cell volume in nasopharyngeal carcinoma cells. In this study, the roles of AQP-3 in their hetero-complexes were further investigated. Glycerol entered the cells via AQP-3 and induced two different Cl(-) currents through cell swelling-dependent or -independent pathways. The swelling-dependent Cl(-) current was significantly inhibited by pretreatment with CuCl2 and AQP-3-siRNA. After siRNA-induced AQP-3 knock-down, the 140 mM glycerol isoosmotic solution swelled cells by 22% (45% in AQP-3-intact cells) and induced a smaller Cl(-) current; this current was smaller than that activated by 8% cell volume swelling, which induced by the 140 mM glycerol hyperosmotic solution in AQP-3-intact cells. This suggests that the interaction between AQP-3 and ClC-3 plays an important role in cell volume regulation and that AQP-3 may be a modulator that opens volume-regulated chloride channels. The swelling-independent Cl(-) current, which was activated by extracellular glycerol, was reduced by CuCl2 and AQP-3-siRNA pretreatment. Dialyzing glycerol into cells via the pipette directly induced the swelling-independent Cl(-) current; however this current was blocked by AQP-3 down-regulation, suggesting AQP-3 is essential for the opening of chloride channels. In conclusion, AQP-3 is the pathway for water, glycerol and other small solutes to enter cells, and it may be an essential modulator for the gating of chloride channels.

Reducing the risk of rear-end collisions with infrastructure-to-vehicle (I2V) integration of variable speed limit control and adaptive cruise control system.

OBJECTIVE: Adaptive cruise control (ACC) has been investigated recently to explore ways to increase traffic capacity, stabilize traffic flow, and improve traffic safety. However, researchers seldom have studied the integration of ACC and roadside control methods such as the variable speed limit (VSL) to improve safety. The primary objective of this study was to develop an infrastructure-to-vehicle (I2V) integrated system that incorporated both ACC and VSL to reduce rear-end collision risks on freeways. METHODS: The intelligent driver model was firstly modified to simulate ACC behavior and then the VSL strategy used in this article was introduced. Next, the I2V system was proposed to integrate the 2 advanced techniques, ACC and VSL. Four scenarios of no control, VSL only, ACC only, and the I2V system were tested in simulation experiments. Time exposed time to collision (TET) and time integrated time to collision (TIT), 2 surrogate safety measures derived from time to collision (TTC), were used to evaluate safety issues associated with rear-end collisions. The total travel times of each scenario were also compared. RESULTS: The simulation results indicated that both the VSL-only and ACC-only methods had a positive impact on reducing the TET and TIT values (reduced by 53.0 and 58.6% and 59.0 and 65.3%, respectively). The I2V system combined the advantages of both ACC and VSL to achieve the most safety benefits (reduced by 71.5 and 77.3%, respectively). Sensitivity analysis of the TTC threshold also showed that the I2V system obtained the largest safety benefits with all of the TTC threshold values. The impact of different market penetration rates of ACC vehicles in I2V system indicated that safety benefits increase with an increase in ACC proportions. CONCLUSIONS: Compared to VSL-only and ACC-only scenarios, this integrated I2V system is more effective in reducing rear-end collision risks. The findings of this study provide useful information for traffic agencies to implement novel techniques to improve safety on freeways.

Neonatal Death and Heart Failure in Mouse with Transgenic HSP60 Expression.

Mitochondrial heat shock proteins, such as HSP60, are chaperones responsible for the folding, transport, and quality control of mitochondrial matrix proteins and are essential for maintaining life. Both prosurvival and proapoptotic roles have been proposed for HSP60, and HSP60 is reportedly involved in the initiation of autoimmune, metabolic, and cardiovascular diseases. The role of HSP60 in pathogenesis of these diseases remains unclear, partly because of the lack of mouse models expressing HSP60. In this study we generated HSP60 conditional transgenic mice suitable for investigating in vivo outcomes by expressing HSP60 at the targeted organ in disease models. Ubiquitous HSP60 induction in the embryonic stage caused neonatal death in mice at postnatal day 1. A high incidence of atrial septal defects was observed in HSP60-expressing mice, with increased apoptosis and myocyte degeneration that possibly contributed to massive hemorrhage and sponge-like cardiac muscles. Our results showed that neonatal heart failure through HSP60 induction likely involves developmental defects and excessive apoptosis. The conditional HSP60 mouse model is useful for studying crucial biological questions concerning HSP60.