Water Intake and Adiposity Outcomes among Overweight and Obese Individuals: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Water consumption is believed to be a key factor in weight management strategies, yet the existing literature on the subject yields inconsistent findings. To systematically assess the scientific evidence regarding the effect of water intake on adiposity, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) among overweight and obese populations. METHODS: PubMed and Embase were searched for relevant articles published up to December 2023. The summary weighted mean difference (WMD) and 95% confidence interval (CI) were estimated using the DerSimonian-Laird random-effects model. RESULTS: In this meta-analysis of eight RCTs, interventions to promote water intake or to substitute water for other beverages as compared to the control group resulted in a summary WMD of -0.33 kg (95% CI = -1.75-1.08, I2 = 78%) for body weight, -0.23 kg/m2 (95% CI = -0.55-0.09, I2 = 0%) for body mass index (BMI), and 0.05 cm (95% CI = -1.20-1.30, I2 = 40%) for waist circumference (WC). Among RCTs substituting water for artificially sweetened beverages, summary WMD was 1.82 kg (95% CI = 0.97-2.67, I2 = 0%) for body weight and 1.23 cm (95% CI = -0.03-2.48, I2 = 0%) for WC. Conversely, among RCTs substituting water for sugar-sweetened beverages, summary WMD was -0.81 kg (95% CI = -1.66-0.03, I2 = 2%) for body weight and -0.96 cm (95% CI = -2.06-0.13, I2 = 0%) for WC. CONCLUSIONS: In conclusion, water intake may not significantly impact adiposity among overweight and obese individuals. However, replacing sugar-sweetened beverages with water might offer a modest benefit in inducing weight loss.

Water intake and obesity: By amount, timing, and perceived temperature of drinking water.

Water intake has been suggested to be associated with weight control, but evidence for optimal water intake in terms of amount, timing, and temperature is sparse. Additionally, genetic predisposition to obesity, which affects satiety and energy expenditure, might interact with water intake in regulating individual adiposity risk. We conducted a cross-sectional study recruiting 172 Korean adults. Information on water intake and lifestyle factors was collected through self-reported questionnaires, and height, weight, and waist circumference (WC) were measured by researchers. The oral buccal swab was performed for genotyping of FTO rs9939609, MC4R rs17782313, BDNF rs6265 and genetic risk of obesity was calculated. Linear regression was performed to estimate mean difference in body mass index (BMI) and WC by water intake and its 95% confidence interval (95% CI). As a sensitivity analysis, logistic regression was performed to estimate odds ratio (OR) of obesity/overweight (BMI of ≥23kg/m2; WC of ≥90cm for men and of ≥80cm for women) and its 95% CI. Drinking >1L/day was significantly associated with higher BMI (mean difference: 0.90, 95% CI 0.09, 1.72) and WC (mean difference: 3.01, 95% CI 0.62, 5.41) compared with drinking ≤1L/day. Independent of total water intake, drinking before bedtime was significantly associated with lower BMI (mean difference: -0.98, 95% CI -1.91, -0.05). The results remained consistent when continuous BMI and WC were analyzed as categorical outcomes. By perceived temperature, drinking >1L/day of cold water was associated with higher BMI and WC compared with drinking ≤1L/day of water at room-temperature. By genetic predisposition to obesity, a positive association between water intake and WC was confined to participants with low genetic risk of obesity (P interaction = 0.04). In conclusion, amount, timing, and perceived temperature of water intake may be associated with adiposity risk and the associations might vary according to genetic predisposition to obesity.

LAMC2 mitigates ER stress by enhancing ER-mitochondria interaction via binding to MYH9 and MYH10.

Highly proliferative and metastatic tumors are constantly exposed to both intrinsic and extrinsic factors that induce adaptation to stressful conditions. Chronic adaptation to endoplasmic reticulum (ER) ER stress is common to many different types of cancers, and poses a major challenge for acquired drug resistance. Here we report that LAMC2, an extracellular matrix protein upregulated in many types of cancers, is localized in the ER of lung, breast, and liver cancer cells. Under tunicamycin-induced ER stress, protein level of LAMC2 is upregulated. Transfection of cancer cells with LAMC2 resulted in the attenuation of ER stress phenotype, accompanied by elevation in mitochondrial membrane potential as well as reduction in reactive oxygen species (ROS) levels and apoptosis. In addition, LAMC2 forms protein complexes with MYH9 and MYH10 to promote mitochondrial aggregation and increased ER-mitochondria interaction at the perinuclear region. Moreover, overexpression of LAMC2 counteracts the effects of ER stress and promotes tumor growth in vivo. Taken together, our results revealed that in complex with MYH9 and MYH10, LAMC2 is essential for promoting ER-mitochondria interaction to alleviate ER stress and allow cancer cells to adapt and proliferate under stressful conditions. This study provides new insights and highlights the promising potential of LAMC2 as a therapeutic target for cancer treatment.

Sequential link in depression, sleep and cognition: Longitudinal evidence from a serial multiple mediation analysis of older adults in China.

BACKGROUND: A growing body of literature examines the link between depression, sleep and cognition, but little is known regarding the extent to which this relationship holds among older adults over time. OBJECTIVE: This study examines how sleep duration mediates the relationship between depressive symptoms and cognitive performance, by utilizing partial least squares structural equation modelling (PLS-SEM) estimation. METHODS: This study utilizes the 2013-18 China Health and Retirement Longitudinal Study (CHARLS) dataset, of which 3557 participants over the age of 50 satisfied inclusion criteria. Depressive symptoms and cognitive performance are measured by the Center for Epidemiological Studies Depression Scale (CESD) and the Mini-Mental State Examination (MMSE); sleep duration is assessed using the adapted Pittsburgh Sleep Quality Index (PSQI). A serial multiple mediation model was built to assess how depressive symptoms in 2013 and in 2018 are related, in addition to assessing their links with sleep duration and cognitive performance. FINDINGS: Results indicate that early depression positively predicts depression progression (std.ß = 0.564, 95 % Confidence Interval: 0.534, 0.594), but negatively predicts sleep duration (std.ß = -0.081, 95 % CI: -0.128, -0.034) and cognitive performance (std.ß = -0.118, 95 % CI: -0.165, -0.072). The sequential indirect effect of early depression operating via depression progression and sleep duration is evaluated to be -0.083 (95 % CI: -0.110, -0.056), representing as much as 41.29 % of the total effect. CONCLUSIONS: Early depressive symptoms are directly associated with increased depressive symptoms and shortened sleep, which are identified as key channels through which early depression is linked with worsened cognition. CLINICAL IMPLICATIONS: Many older adults may underestimate the adverse costs of early depression, since its net effects on cognition could be channeled indirectly and discretely via depression progression and sleep, which is worth highlighting in health guidelines and clinical recommendations.

LAMC2 promotes EGFR cell membrane localization and acts as a novel biomarker for tyrosine kinase inhibitors (TKIs) sensitivity in lung cancer.

The epidermal growth factor receptor (EGFR) is one of the first and most prominent driver genes known to promote malignant lung cancer. Investigating regulatory mechanisms beyond ligand-receptor binding, phosphorylation, and receptor kinase activation as means of EGFR signaling activation is important for improving EGFR-targeted therapy. Here, we report that Laminin-5γ-2 (LAMC2) retained high oncogenic capacity in lung cancer, silencing LAMC2 inhibited EGFR-induced cell proliferation and tumor growth in vivo. Deletion mutation experiments showed that both the EGF-Lam and LamB regions of LAMC2 are necessary for EGFR receptor binding, and that LAMC2 and EGFR were found to co-localize at the endoplasmic reticulum (ER) membrane. In addition, LAMC2 overexpression enhanced EGFR membrane deposition and promoted EGFR transport from the ER. Moreover, LAMC2 was necessary for preventing EGFR protein degradation via ubiquitination. Lastly, our study showed that high LAMC2 expression is positively associated with response to gefitinib (EGFR tyrosine kinase inhibitor) treatment. Overall, our study revealed a new regulatory mechanism of LAMC2 in promoting EGFR protein expression and stability by facilitating ER transport and preventing protein degradation via ubiquitination. Moreover, LAMC2 may serve as a stratifying biomarker for patients suitable for EGFR-TKI treatment.

Depressive Symptoms as Mediator on the Link between Physical Activity and Cognitive Function: Longitudinal Evidence from Older Adults in China.

OBJECTIVES: This study examines the extent to which depressive symptoms mediate the link between physical activity and cognitive function among older adults in China. METHODS: This study utilizes the 2013-18 China Health and Retirement Longitudinal Study (CHARLS) dataset, of which 3,658 subjects over the age of 50 satisfied inclusion criteria. Degree of physical activity, prevalence of depressive symptoms, and performance in cognitive function are measured by the International Physical Activity Questionnaire (IPAQ), Center for Epidemiological Studies Depression Scale (CESD), the Mini-Mental State Examination (MMSE) instruments. A structural mediation model was built to assess the degree to which depressive symptoms act as mediator between physical activity and cognitive function. RESULTS: Physical activity is positively and significantly associated with cognitive function (std ß = 0.034, p-value = .007), while physical activity is negatively and significantly associated with prevalence of depressive symptoms (std ß = -0.088, p-value < .001). Results indicate that depressive symptoms partially and significantly mediate the relationship between physical activity and cognitive function (std ß = 0.003, p-value = .035). Total influence of physical activity on cognitive performance is evaluated to be 0.037 standard deviations (p-value = .035). CONCLUSIONS: Findings uncover an underexamined mental well-being channel through which physical activity can positively influence late adulthood cognition. CLINICAL IMPLICATIONS: In recommending behavioral modifications to reduce risks of late adulthood cognitive decline, encouraging physical activity for older individuals is key, since it is both directly associated with better cognitive performance, as well as indirectly through lowering prevalence of depressive symptoms.

Post-Diagnosis Vitamin D Supplement Use and Survival among Cancer Patients: A Meta-Analysis.

Vitamin D administered pre-diagnostically has been shown to reduce mortality. Emerging evidence suggests a role of post-diagnosis vitamin D supplement intake for survival among cancer patients. Thus, we conducted a meta-analysis to evaluate the relationship. PubMed and Embase were searched for relevant observational cohort studies and randomized trials published through April 2022. Summary relative risk (SRR) and 95% confidence interval (CI) were estimated using the DerSimonian-Laird random-effects model. The SRR for post-diagnosis vitamin D supplement use vs. non-use, pooling cohort studies and randomized trials, was 0.87 (95% CI, 0.78-0.98; p = 0.02; I2 = 0%) for overall survival, 0.81 (95% CI, 0.62-1.06; p = 0.12; I2 = 51%) for progression-free survival, 0.86 (95% CI, 0.72-1.03; p = 0.10; I2 = 0%) for cancer-specific survival, and 0.86 (95% CI, 0.64-1.14; p = 0.29; I2 = 0%) for relapse. Albeit not significantly heterogeneous by variables tested, a significant inverse association was limited to cohort studies and supplement use during cancer treatment for overall survival, and to studies with ≤3 years of follow-up for progression-free survival. Post-diagnosis vitamin D supplement use was associated with improved overall survival, but not progression-free or cancer-specific survival or relapse. Our findings require confirmation, as randomized trial evidence was insufficient to establish cause-and-effect relationships.

Milk Intake in Early Life and Later Cancer Risk: A Meta-Analysis.

Dairy consumption in adulthood has been demonstrated to influence cancer risk. Although childhood and adolescence represent critical periods of rapid growth, the relationship between milk intake in early life and later cancer risk is unclear. Thus, we examined this relationship by conducting a meta-analysis of the observational studies. PubMed and Embase were searched for relevant articles that were published throughout December 2021. The summary relative risk (RR) and 95% confidence interval (CI) were estimated using the DerSimonian-Laird random-effects model. The summary RR for the highest vs. lowest milk intake was 0.83 (95% CI = 0.69-1.00; p = 0.05; I2 = 60%; seven studies) for breast cancer, 0.98 (95% CI = 0.72-1.32; p = 0.88; I2 = 51%; four studies) for prostate cancer, and 0.90 (95% CI = 0.42-1.93; p = 0.78; I2 = 83%; three studies) for colorectal cancer. No evidence of an association emerged in subgroup analyses of menopausal status, cancer stage, fat content of milk, life stage of milk intake, or study design. Consistent results were observed in the meta-analyses using total dairy intake. In conclusion, milk intake during childhood and adolescence might not be associated with risks of breast, prostate, and colorectal cancer later in life. Given the small number of studies that were included in our meta-analysis, and the high heterogeneity, more studies are warranted for a definitive conclusion.

Characteristics of serum metabolites in sporadic amyotrophic lateral sclerosis patients based on gas chromatography-mass spectrometry.

To identify differential metabolites and metabolic pathways and provide guidance for the novel biomarkers for diagnosis and prognosis of amyotrophic lateral sclerosis (ALS). ALS patients and people without nervous diseases were recruited. Metabolomic analysis was performed using gas chromatography-mass spectrometry (GC/MS). The orthogonal projections to latent structures discriminant analysis (OPLS-DA) were used to identify differential metabolites. Kyoto Encyclopedia of Genes and Genomes and MetaboAnalyst were used to identify metabolic pathways. 75 metabolites were detected and aligned. The OPLS-DA showed the metabolomic profile of ALS patients and those in the fast-progression and slow-progression ALS groups differed from that of CTRL (p < 0.05). The levels of maltose, glyceric acid, lactic acid, beta-alanine, phosphoric acid, glutamic acid, ethanolamine and glycine in ALS were significantly higher, while 2,4,6-tri-tert-butylbenzenethiol was lower. Glycine, serine and threonine metabolism, D-glutamine and D-glutamate metabolism, alanine, aspartate, and glutamate metabolism, beta-alanine metabolism, and pyruvate metabolism were significantly altered metabolic pathways in ALS. ROC was used to discriminate ALS from CTRL with an AUC of 0.898 (p < 0.001) using 2,4,6-tri-tert-butylbenzenethiol, beta-alanine, glycine, and ethanolamine. The serum metabolites and metabolic pathways in ALS patients are significantly altered compared with CTRL. These findings may contribute to the early diagnosis of ALS.

Understanding risks of refractive error among Chinese children amidst pandemic disruptions: results from a rapid survey.

BACKGROUND: Despite effectiveness in delaying the spread of the pandemic, frequent and extended disruption to children's livelihoods have fomented new norms in which learning routines encounter immense change. In particular, increased sedentary e-learning engagement with electronic screens and exposure to stressful circumstances are likely to pose adverse risks for children's vision development. METHODS: This present study examines the link between near-sighted refractive error, and sedentary exposure to electronic screens, psychosocial stress level, and outdoor activities. A Rapid Survey Methodology (RSM) design was utilized to collect information on subject's vision condition, sedentary electronic screen use, and level of psychosocial stress, in addition to detailed socio-demographic background characteristics. RESULTS: This study involves 2234 subjects enrolled in 1st to 6th grade in primary schools. Every 1 diopter hour increase in electronic screen use per day is associated with 1.036 OR (95% CI =1.024-1.047, p-value< 0.050), while every 1 h • W m- 2 sr- 1 of illuminance-weighted electronic screen use per day is associated with 2.285 OR (95% CI =1.829-2.855, p-value< 0.050) increased likelihood of near-sighted refractive error. Higher level of psychosocial stress is associated with 2.441 OR (95% CI =1.870-3.187, p-value< 0.050) and 2.403 OR (95% CI =1.839-3.141, p-value< 0.050) increased likelihood of near-sighted refractive error. Frequency of outdoor activity is not significantly associated with increased likelihood of near-sighted refractive error (p-value> 0.050). CONCLUSIONS: Findings in this study show that many factors, including grade level and prior vision condition, contribute to increased risks of near-sighted refractive error during the COVID-19 pandemic. More strikingly, pandemic-related behavioral modifications such as lengthy sedentary electronic screen use and elevated levels of psychosocial stress are two critical channels affecting children's eye health.

Examining risk factors related to digital learning and social isolation: Youth visual acuity in COVID-19 pandemic.

BACKGROUND: Around the globe, various self-quarantine, social distancing, and school-closure policies were implemented during the coronavirus disease-19 (COVID-19) outbreak to reduce disease transmission. Many economies/territories were compelled to consider digital learning modalities. In particular, increased digital learning engagement with digital devices and mounting psychosocial stress due to social isolation are likely to pose adverse risks for youth visual health globally. This study examines the association between increased digital device use, psychosocial stress, and myopia symptoms among Chinese youth during the COVID-19 pandemic. METHODS: This is a retrospective observational population study consisting of 3918 participants enrolled in primary, secondary, and university in China. Participants are recruited through an online survey, which included self-reported information on daily digital device use, psychosocial stress level, condition of visual acuity, and demographic information. We utilize statistical tools including χ2 test, paired sample t test, and multiple multivariate logistic regression. RESULTS: Each hour increase in digital device use is associated with 1.25 odds ratio OR (95% confidence interval (CI) = 1.21-1.30; P < 0.001) increased risk of developing myopic symptoms, each additional hour of digital device use weighted by near-view and blue-light exposure is associated with OR = 1.04 OR (95% CI = 1.03-1.05; P < 0.001) and OR = 2.25 (95% CI = 1.94-2.60; P < 0.001) increased risk respectively. Subjects reporting under stressful conditions are between OR = 1.98 (95% CI = 1.67-2.36; P < 0.001) and OR = 2.03 (95% CI = 1.71-2.42; P < 0.001) more likely to develop myopic symptoms, relative to those citing less stress. CONCLUSIONS: The COVID-19 pandemic led to favorable conditions for myopigenic behavioral changes characterized by extended sedentary engagement with digital devices, which are significantly associated with higher risks of myopia incidence. Relatedly, psychosocial stress accompanying prolonged social isolation during the pandemic is a less noticeable, albeit significant risk factor for myopia development.

Association of Exosomal miR-210 with Signaling Pathways Implicated in Lung Cancer.

MicroRNA is a class of non-coding RNA involved in post-transcriptional gene regulation. Aberrant expression of miRNAs is well-documented in molecular cancer biology. Extensive research has shown that miR-210 is implicated in the progression of multiple cancers including that of the lung, bladder, colon, and renal cell carcinoma. In recent years, exosomes have been evidenced to facilitate cell-cell communication and signaling through packaging and transporting active biomolecules such as miRNAs and thereby modify the cellular microenvironment favorable for lung cancers. MiRNAs encapsulated inside the lipid bilayer of exosomes are stabilized and transmitted to target cells to exert alterations in the epigenetic landscape. The currently available literature indicates that exosomal miR-210 is involved in the regulation of various lung cancer-related signaling molecules and pathways, including STAT3, TIMP-1, KRAS/BACH2/GATA-3/RIP3, and PI3K/AKT. Here, we highlight major findings and progress on the roles of exosomal miR-210 in lung cancer.

Adolescent Vision Health During the Outbreak of COVID-19: Association Between Digital Screen Use and Myopia Progression.

The coronavirus (COVID-19) pandemic has impacted education systems globally, making digital devices common arrangements for adolescent learning. However, vision consequences of such behavioral changes are not well-understood. This study investigates the association between duration of daily digital screen engagement and myopic progression among 3,831 Chinese adolescents during the COVID-19 pandemic. Study subjects report an average of 2.70 (SD = 1.77), 3.88 (SD = 2.23), 3.58 (SD = 2.30), and 3.42 (SD = 2.49) hours of television, computer, and smartphone for digital learning use at home, respectively. Researchers analyzed the association between digital screen use and myopic symptoms using statistical tools, and find that every 1 h increase in daily digital screen use is associated with 1.26 OR [Odds Ratio] (95% CI [Confidence Interval: 1.21-1.31, p < 0.001]) higher risks of myopic progression. Using computers (OR = 1.813, 95% CI = 1.05-3.12, p = 0.032) and using smartphones (OR = 2.02, 95% CI = 1.19-3.43, p = 0.009) are shown to be associated with higher risks of myopic progression than television use. Results from additional sensitivity tests that included inverse probability weights which accounted for heterogeneous user profile across different device type categories confirm that these findings are robust. In conclusion, this study finds that daily digital screen use is positively associated with prevalence of myopic progression and holds serious vision health implications for adolescents.

Student Health Implications of School Closures during the COVID-19 Pandemic: New Evidence on the Association of e-Learning, Outdoor Exercise, and Myopia.

The coronavirus disease 2019 (COVID-19) pandemic forced many education systems to consider alternative remote e-learning modalities, which have consequential behavioral and health implications for youth. In particular, increased e-learning engagement with digital screens and reduction in outdoor activities are two likely channels posing adverse risks for myopia development. This study investigated the association between e-learning screen use, outdoor activity, lighting condition, and myopia development among school-age children in China, during the first wave of the COVID-19 pandemic. Data were collected from 3405 school-age children attending primary, lower-secondary, and upper-secondary schools in China. Univariate parametric and nonparametric tests, and multivariate logistic regression analysis were used. Findings show that each diopter hour increase in daily e-learning screen use is significantly associated with progression of myopia symptoms (OR: 1.074, 95% CI: 1.058-1.089; p < 0.001), whereas engaging in outdoor exercise four to six times per week (OR: 0.745, 95% CI: 0.568-0.977; p = 0.034) and one to three times per week (OR: 0.829, 95% CI: 0.686-0.991; p = 0.048) is associated with a lower likelihood of myopia progression than none at all. In addition, we found that indoor lighting that is either "too dim" (OR: 1.686, 95% CI: 1.226-2.319; p = 0.001) or "too bright" (OR: 1.529, 95% CI: 1.007-2.366; p = 0.036) is significantly associated higher likelihood of myopic symptoms. Findings in this study uncover the less observable vision consequences of the COVID-19 pandemic on youths through digital online learning and highlight the importance of considering appropriate mitigation strategies to deal with this emerging public health challenge.

The degeneration of upper and lower motor neuron from the perspective of clinical neurological examination and MRI-electromyography manifold detection in amyotrophic lateral sclerosis.

OBJECTIVE: The aim of this study was to explore the upper motor neurons (UMN) and lower motor neurons (LMN) degeneration in amyotrophic lateral sclerosis (ALS) from the perspective of the clinical neurological examination and MRI-electromyography manifold detection, respectively. METHODS: The clinical data, cortical thickness of corresponding areas in different body regions in MRI and electromyography data were collected from 108 classical ALS patients. RESULTS: The kappa value of UMN and LMN involvement signs in the bulbar region (0.31) was higher than that of the left upper limb (-0.13), right upper limb (-0.27), left lower limb (-0.05) and right lower limb (-0.08). The cortical thickness in the positive LMN damage group was thinner than that of the negative LMN damage group in the left head-face area (P < 0.05; Cohen's d = 0.84); however, cortical thickness showed no significant differences in the right head-face, bilateral tongue-larynx, upper-limb, trunk and lower-limb areas between LMN-damage-positive and LMN-damage-negative groups. CONCLUSION: The degeneration of motor neuron could be independent through UMN and LMN levels. The degenerative process was not only confined to UMN and LMN levels but can also expand to white matter fiber tracts. Thus, the degeneration of UMN and LMN might be independent of the motor system's three-dimensional anatomy.

Dominant Heterogeneity of Upper and Lower Motor Neuron Degeneration to Motor Manifestation of Involved Region in Amyotrophic Lateral Sclerosis.

The aim of this study was to localize the anatomic distribution of upper motor neuron (UMN) loss through examining cortical thickness at the clinical onset of amyotrophic lateral sclerosis (ALS) and explore motor manifestation in functionally impaired body region attribute to impairment of lower motor neuron (LMN) or UMN or mixed LMN and UMN? The clinical features, cortical thickness of corresponding areas from different body regions in MRI and electromyography (EMG) data were collected from 108 classical ALS patients. The cortical thickness was thinner in ALS group than control group in bilateral head-face and upper-limb areas (p < 0.05). In head-face area, the cortical thickness of bulbar-onset group was significantly lower than that of control groups (p < 0.05). In upper-limb areas, the cortical thickness of cervical-onset group was significantly thinner than that of control group. Notably, the bulbar ALSFRS-R subscore was correlated with cortical thickness in bilateral head-face areas (p < 0.05). The bulbar ALSFRS-R subscore of the positive LMN damage group was lower compared to that of the negative LMN damage group (P < 0.001). The limb ALSFRS-R subscore correlated with compound muscle action potential (CMAP) amplitudes of median, ulnar, peroneal, and tibial nerves (P < 0.001), but was not related to cortical thickness. In conclusion, the UMN degeneration in ALS was derived from focal initiation, bulbar- and cervical-onset may date from head-face and upper-limb areas in motor homunculus cortex, respectively. The bulbar dysfunction was resulted from the mixed UMN and LMN impairment, while limb dysfunction derived mostly from LMN loss.

Dissociated lower limb muscle involvement in amyotrophic lateral sclerosis and its differential diagnosis value.

To explore differential diagnosis value of dissociated lower-limb muscle impairment, we performed a retrospective analysis of clinical and electrophysiological features in 141 lower-limb involved ALS patients, 218 normal controls, 67 disease controls, and 32 lumbar spondylosis disease patients. The dissociated lower-limb muscle impairment was quantified by plantar flexion and dorsiflexion strength, compound muscle action potentials ratio of peroneal and tibial nerves (split index, SI) and semi-quantitative scoring scale of denervation potential. Clinical features: the proportion of decreased dorsiflexion was higher than decreased planter flexor strength in lower-limb involved ALS (77.2%vs 38.3%). Electrophysiological features: (1) SI in ALS was the lowest among four groups (Test statistic = 40.57, p < 0.001). (2) Percentage of positive denervation potential was higher in tibialis anterior than gastrocnemius muscle (χ2 = 87.12, p < 0.001). ROC curve: the SI cutoff was 0.52 and 0.33 respectively to differentiate ALS from lumbar spondylosis disease and peripheral neuropathy. Lower-limb involved ALS patients exhibited "split leg" phenomenon. The SI value could be used as an electrophysiological marker to differentiate ALS from lumbar spondylosis disease and peripheral neuropathy.

Human CD1D gene expression is regulated by LEF-1 through distal promoter regulatory elements.

CD1d-expressing cells present lipid Ag to CD1d-restricted NKT cells, which play an important role in immune regulation and tumor rejection. Lymphoid enhancer-binding factor-1 (LEF-1) is one of the regulators of the Wnt signaling pathway, which is a powerful regulator in cellular growth, differentiation, and transformation. There is little evidence connecting Wnt signaling to CD1d expression. In this study, we have identified LEF-1 as a regulator of the expression of the gene encoding the human CD1d molecule (CD1D). We found that LEF-1 binds specifically to the CD1D promoter. Overexpression of LEF-1 in K562 or Jurkat cells suppresses CD1D promoter activity and downregulates endogenous CD1D transcripts, whereas knockdown of LEF-1 using LEF-1-specific small interfering RNA increases CD1D transcripts in K562 and Jurkat cells but there are different levels of surface CD1d on these two cell types. Chromatin immunoprecipitation showed that the endogenous LEF-1 is situated at the CD1D promoter and interacts with histone deacetylase-1 to facilitate the transcriptional repressor activity. Knockdown of LEF-1 using small interfering RNA potentiates an acetylation state of histone H3/H4, supporting the notion that LEF-1 acts as a transcriptional repressor for the CD1D gene. Our finding links LEF-1 to CD1D and suggests a role of Wnt signaling in the regulation of the human CD1D gene.

Human CD1D gene has TATA boxless dual promoters: an SP1-binding element determines the function of the proximal promoter.

CD1d presents lipid Ags to a specific population of NK T cells, which are involved in the host immune defense, suppression of autoimmunity, and the rejection of tumor cells. The transcriptional control mechanism that determines the regulation and the tissue distribution of CD1d remains largely unknown. After investigating 3.7 kb 5' upstream of the coding region, we found that human gene encoding CD1d molecule (CD1D) has TATA boxless dual promoters with multiple transcription initiation sites. The proximal promoter is located within the region of -106 to +24, and the distal promoter is located within the region of -665 to -202 with the A of the translational start codon defined as +1. The longest 5'-untranslated region derived from 5'-RACE and apparently generated by the distal promoter has 272 bp in length covering the genomic sequence of the proximal promoter. The region covering the proximal promoter gave a much higher luciferase activity in Jurkat cells than in K562 cells, whereas it was in reverse for the region covering the distal promoter, indicating a cell type sp. act. of the two promoters. Transcription factor SP1 plays a crucial role in the function of the proximal promoter. The analysis of the CD1D promoter region indicates that IFN-gamma, NF-IL-6, and T cell factor 1/lymphoid enhancer-binding factor 1 are most likely involved in the regulation of CD1d expression. The illustration of the dual CD1D gene promoters will help to reveal the regulatory factors that control CD1d expression and its tissue distribution for a better understanding of the cross-regulation between CD1d and NK T cells.