Relationships of Cognitive Measures with Cerebrospinal Fluid but Not Imaging Biomarkers of Alzheimer Disease Vary between Black and White Individuals.

OBJECTIVE: Biomarkers of Alzheimer disease vary between groups of self-identified Black and White individuals in some studies. This study examined whether the relationships between biomarkers or between biomarkers and cognitive measures varied by racialized groups. METHODS: Cerebrospinal fluid (CSF), amyloid positron emission tomography (PET), and magnetic resonance imaging measures were harmonized across four studies of memory and aging. Spearman correlations between biomarkers and between biomarkers and cognitive measures were calculated within each racialized group, then compared between groups by standard normal tests after Fisher's Z-transformations. RESULTS: The harmonized dataset included at least one biomarker measurement from 495 Black and 2,600 White participants. The mean age was similar between racialized groups. However, Black participants were less likely to have cognitive impairment (28% vs 36%) and had less abnormality of some CSF biomarkers including CSF Aß42/40, total tau, p-tau181, and neurofilament light. CSF Aß42/40 was negatively correlated with total tau and p-tau181 in both groups, but at a smaller magnitude in Black individuals. CSF Aß42/40, total tau, and p-tau181 had weaker correlations with cognitive measures, especially episodic memory, in Black than White participants. Correlations of amyloid measures between CSF (Aß42/40, Aß42) and PET imaging were also weaker in Black than White participants. Importantly, no differences based on race were found in correlations between different imaging biomarkers, or in correlations between imaging biomarkers and cognitive measures. INTERPRETATION: Relationships between CSF biomarkers but not imaging biomarkers varied by racialized groups. Imaging biomarkers performed more consistently across racialized groups in associations with cognitive measures. ANN NEUROL 2024;95:495-506.

First in vivo Experiment with PulmValve Endobronchial Valve: Feasibility, Efficiency, and Safety.

INTRODUCTION: Endoscopic lung volume reduction with endobronchial valves has been widely recognized for treating hyperinflation in advanced chronic obstructive pulmonary disease and emphysema patients. The main challenges include the technical complexity of upper lobe implantation and the number of endobronchial valves required. These issues might be addressed by placing larger diameter valves in the lobar bronchus. This study evaluated the feasibility, efficiency, and safety of the new valve PulmValve (model PV-13) in porcine models. METHODS: Six PV-13 valves were bronchoscopically implanted into the caudal lobe bronchus of six healthy pigs. The procedure time, valve deployment, and removability were recorded. Follow-up examinations included blood tests, chest CT scans, and bronchoscopy at 30 min, 14 days, 28 days, and 84 days post-procedure, with necropsy and pathological evaluations after the final follow-up examination. RESULTS: The successful in vivo deployment and removal of PV-13 valves was established, with a median procedure time of 6.5 min. The distal lung volume reduction was evident at 30 min post-operation and was persistently monitored on day 84. No migration or malfunction of any PV-13 valves was detected, but a mild angle deviation was found in 3 cases. Coughing was observed in four pigs within the first 7 days and localized granulation tissue was observed in all pigs. No cases of pneumothorax, diffuse pneumonia, or hemoptysis were detected. CONCLUSIONS: In this study, we report the successful implantation and removal of a new valve PulmValve in a short operation time. Complete lobar atelectasis was induced without device migration, malfunction, or severe complications. Further studies are warranted to evaluate the long-term, sustained effects and potential benefits in human patients.

Presenilin-1 mutation position influences amyloidosis, small vessel disease, and dementia with disease stage.

INTRODUCTION: Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin-1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre-/postcodon 200) influences these pathologic features and dementia at different stages. METHODS: Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments. We cross-sectionally evaluated regional Pittsburgh compound B-positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging-based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition. RESULTS: Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating® scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures. DISCUSSION: We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials. HIGHLIGHTS: Mutation position influences Aß burden, SVD, and dementia. PSEN1 pre-200 group had stronger associations between Aß burden and disease stage. PSEN1 post-200 group had stronger associations between SVD markers and disease stage. PSEN1 post-200 group had worse dementia score than pre-200 in late disease stage. Diffusion tensor imaging-based SVD markers mediated mutation position effects on dementia in the late stage.

Estimating mutation rates in a Markov branching process using approximate Bayesian computation.

Estimating microbial mutation rates is an essential task in evolutionary biology, with wide range applications in related fields such as virology, epidemiology, clinic and public health, and antibiotic research. Significant progress has been made on this research since 1943 when Luria-Delbrück fluctuation analysis was first introduced. However, existing estimators of mutation rates are heavily reliant on model assumptions in fluctuation analysis, and become less applicable to real microbial experiments which deviate from the model assumptions. To overcome this difficulty, we propose to model fluctuation experimental data by a two-type Markov branching process (MBP) and use approximate Bayesian computation (ABC) to estimate the mutation probability parameters. Such an ABC-based mutation rate estimator is based on intensive simulations from the mutation process, thereby taking advantage of modern computing power. Most importantly, its likelihood-free feature allows more complex and realistic setups of the mutation process, especially when the distribution of the number of mutants cannot be easily derived. To further improve computation efficiency, we use a Gaussian process surrogate to substitute the simulator in the ABC algorithm, and call the resulting estimator GPS-ABC. Simulation studies show that, when used to estimate constant mutation rate in MBP, ABC-based estimators generally outperform traditional moment or likelihood-based estimators. When mutations occur in two stages, i.e., in MBP with a piece-wise constant mutation rate function, traditional mutation rate estimators become not applicable, yet GPS-ABC still achieves reasonable estimates. Finally, the proposed GPS-ABC estimator is used to analyze real fluctuation experimental datasets for studying drug resistance.

Latent classifications of parental involvement in diabetes management for youth with type 1 diabetes: A randomized clinical trial.

OBJECTIVE: Understanding how parent-child relationships influence diabetes management in youth with type 1 diabetes is critical for minimizing the risk of short- and long-term complications. We examined how classes of diabetes-specific parenting behaviors are associated with disease management and well-being for youth with type 1 diabetes. RESEARCH DESIGN AND METHODS: The Family Management of Diabetes clinical trial tested the efficacy of a 2-year behavioral intervention for families of youth with type 1 diabetes. Three hundred and ninety youth diagnosed with type 1 diabetes and their primary caregiver were recruited from four pediatric endocrinology centers in the US Classifications of parental involvement utilized baseline parent and youth reports of task involvement, collaborative involvement, and parent-youth conflict. Class differences in baseline glycemic control (HbA1c), regimen adherence, general and diabetes quality of life, and depressive symptoms, and 2-year change in HbA1c were examined. RESULTS: Latent profile analysis identified three classes: (1) high in task and collaborative involvement, low in conflict (Harmonious), (2) low in task involvement, collaborative involvement, and conflict (Indifferent), (3) high in task involvement and conflict, low in collaborative involvement (Inharmonious). The Harmonious group demonstrated the best adherence, glycemic control, and psychosocial well-being. The Inharmonious and Indifferent groups had similar diabetes management, but youth from Inharmonious families showed poorer psychosocial well-being. The intervention effect on glycemic control did not differ across the classes. CONCLUSIONS: The interplay of parental involvement and conflict resulted in distinct parenting classes that differed in disease management and well-being. However, the classes benefitted similarly from the behavioral intervention.

Metformin Inhibits the Urea Cycle and Reduces Putrescine Generation in Colorectal Cancer Cell Lines.

The urea cycle (UC) removes the excess nitrogen and ammonia generated by nitrogen-containing compound composites or protein breakdown in the human body. Research has shown that changes in UC enzymes are not only related to tumorigenesis and tumor development but also associated with poor survival in hepatocellular, breast, and colorectal cancers (CRC), etc. Cytoplasmic ornithine, the intermediate product of the urea cycle, is a specific substrate for ornithine decarboxylase (ODC, also known as ODC1) for the production of putrescine and is required for tumor growth. Polyamines (spermidine, spermine, and their precursor putrescine) play central roles in more than half of the steps of colorectal tumorigenesis. Given the close connection between polyamines and cancer, the regulation of polyamine metabolic pathways has attracted attention regarding the mechanisms of action of chemical drugs used to prevent CRC, as the drug most widely used for treating type 2 diabetes (T2D), metformin (Met) exhibits antitumor activity against a variety of cancer cells, with a vaguely defined mechanism. In addition, the influence of metformin on the UC and putrescine generation in colorectal cancer has remained unclear. In our study, we investigated the effect of metformin on the UC and putrescine generation of CRC in vivo and in vitro and elucidated the underlying mechanisms. In nude mice bearing HCT116 tumor xenografts, the administration of metformin inhibited tumor growth without affecting body weight. In addition, metformin treatment increased the expression of monophosphate (AMP)-activated protein kinase (AMPK) and p53 in both HCT116 xenografts and colorectal cancer cell lines and decreased the expression of the urea cycle enzymes, including carbamoyl phosphate synthase 1 (CPS1), arginase 1 (ARG1), ornithine trans-carbamylase (OTC), and ODC. The putrescine levels in both HCT116 xenografts and HCT116 cells decreased after metformin treatment. These results demonstrate that metformin inhibited CRC cell proliferation via activating AMPK/p53 and that there was an association between metformin, urea cycle inhibition and a reduction in putrescine generation.

Correlational analyses of biomarkers that are harmonized through a bridging study due to measurement errors.

Evaluating correlations between disease biomarkers and clinical outcomes is crucial in biomedical research. During the early stages of many chronic diseases, changes in biomarkers and clinical outcomes are often subtle. A major challenge to detecting subtle correlations is that studies with large sample sizes are usually needed to achieve sufficient statistical power. This challenge is even greater when biofluid and imaging biomarker data are used because the required procedures are burdensome, perceived as invasive, and/or expensive, limiting sample sizes in individual studies. Combining data across multiple studies may increase statistical power, but biomarker data may be generated using different assay platforms, scanner types, or processing protocols, which may affect measured biomarker values. Therefore, harmonizing biomarker data is essential to combining data across studies. Bridging studies involve re-processing of a subset of samples or imaging scans to evaluate how biomarker values vary by studies. This presents an analytic challenge on how to best harmonize biomarker data across studies to allow unbiased and optimal estimates of their correlations with standardized clinical outcomes. We conceptualize that a latent biomarker underlies the observed biomarkers across studies, and propose a novel approach that integrates the data in the bridging study with the study-specific biomarker data for estimating the biological correlations between biomarkers and clinical outcomes. Through extensive simulations, we compare our method to several alternative methods/algorithms often used to estimate the correlations. Finally, we demonstrate the application of this methodology to a real-world multi-center Alzheimer's disease biomarker study to correlate cerebrospinal fluid biomarker concentrations with cognitive outcomes.

Maternal plasma phospholipid polyunsaturated fatty acids in early pregnancy and thyroid function throughout pregnancy: a longitudinal study.

BACKGROUND: Evidence has indicated that polyunsaturated fatty acids (PUFAs)-enriched diet could reduce inflammation because of thyroid autoimmunity in vivo, and therefore, enhance thyroid function. OBJECTIVES: We investigated whether early pregnancy plasma phospholipid PUFAs could benefit maternal thyroid function across pregnancy, which is critical to fetal brain development and growth in pregnancy. METHODS: Within the National Institute of Child Health and Human Development Fetal Growth Studies-Singleton Cohort, we collected plasma samples longitudinally from 214 subjects [107 with gestational diabetes mellitus (GDM) matched with 107 controls] with a singleton pregnancy. We measured 11 PUFAs at early pregnancy (10-14 wk) and 5 thyroid biomarkers at 10-14, 15-26, 23-31, and 33-39 wk, including free thyroxine (fT4), free triiodothyronine (fT3), thyroid-stimulating hormone, antithyroid peroxidase, and antithyroglobulin. Associations of PUFAs with thyroid function biomarkers and relative risk (RR) of gestational hypothyroidism (GHT) during pregnancy were assessed using generalized linear mixed models and modified Poisson regression, respectively. RESULTS: After sample weighting because of subjects with GDM over-representing in the analytic sample with biomarkers, eicosapentaenoic acid (EPA) at early pregnancy was associated with a reduction of 0.24 pmol/L (95% confidence intervals: -0.31, -0.16) in fT3 across gestation per standard deviation (SD) increment, whereas docosahexaenoic acid (DHA) at early pregnancy was associated with an increment of 0.04 ng/dL (0.02, 0.05) in fT4 across gestation per SD increment. Furthermore, EPA and docosatetraenoic acid (DTA) were associated with lower risks of persistent GHT (EPA-RR: 0.13; 0.06, 0.28; DTA-RR: 0.24; 0.13, 0.44) per SD increment. All significant associations remained robust in sensitivity analysis and multiple testing. CONCLUSIONS: Certain plasma phospholipid PUFAs were associated with optimal levels of thyroid biomarkers and even lower risk of GHT throughout pregnancy, which might be potentially targeted for maternal thyroid regulation in early pregnancy. CLINICAL TRIAL REGISTRY: This trial was registered at https://beta. CLINICALTRIALS: gov/study/NCT00912132?distance=50&term=NCT00912132&rank=1 as NCT00912132.

Physical Activity and High-Sensitivity C-Reactive Protein in Pregnancy: Does It Matter during Leisure or Work?

INTRODUCTION: Physical activity (PA), regardless of domain, is recommended for pregnant individuals in clinical guidelines, but limited evidence is available for work-related PA. This study aimed to examine the associations of occupational (OPA) and leisure-time PA (LTPA) with plasma high-sensitivity C-reactive protein (hs-CRP), a risk marker for adverse pregnancy outcomes, among pregnant individuals. METHODS: This longitudinal study included 257 workers in the fetal growth cohort. OPA/LTPA and hs-CRP were measured in each trimester. OPA/LTPA was divided into high and low groups by the median level. Multivariable linear regressions were applied to estimate the adjusted geometric mean differences of hs-CRP (mg·L-1) comparing high versus low OPA/LTPA in each trimester and the changes in OPA/LTPA over pregnancy. RESULTS: OPA was positively associated with hs-CRP (high: 5.14 vs low: 3.59; P value: 0.001) in the first trimester, particularly for standing/walking or walking fast, regardless of carrying things. LTPA was negatively associated with hs-CRP in the second (high: 3.93 vs low: 5.08; 0.02) and third trimesters (high: 3.30 vs low: 4.40; 0.046). Compared with the low OPA + high LTPA group, hs-CRP was higher in both the high OPA + high LTPA and high OPA + low LTPA groups in the first trimester, and in the high OPA + low LTPA group only in the third trimester. The change in OPA during pregnancy was positively associated with hs-CRP, whereas the change in LTPA was negatively associated with hs-CRP from the second to the third trimester. CONCLUSIONS: In pregnant individuals, LTPA was negatively associated with hs-CRP, whereas OPA was positively associated with hs-CRP. More research on OPA's health impact among pregnant individuals is needed, and guidelines may consider the potential unfavorable influence of OPA on pregnant individuals.

Healthy dietary patterns are associated with exposure to environmental chemicals in a pregnancy cohort.

Healthy dietary patterns, such as the alternate Mediterranean diet and alternate Healthy Eating Index, benefit cardiometabolic health. However, several food components of these dietary patterns are primary sources of environmental chemicals. Here, using data from a racially and ethnically diverse US cohort, we show that healthy dietary pattern scores were positively associated with plasma chemical exposure in pregnancy, particularly for the alternate Mediterranean diet and alternate Healthy Eating Index with polychlorinated biphenyls and per- and poly-fluoroalkyl substances. The associations appeared stronger among Asian and Pacific Islanders. These findings suggest that optimizing the benefits of a healthy diet requires concerted regulatory efforts aimed at lowering environmental chemical exposure.

Early Pregnancy Maternal Plasma Phospholipid Saturated Fatty Acids and Fetal Growth: Findings from a Multi-Racial/Ethnic Birth Cohort in US.

Saturated fatty acids (SFAs) during pregnancy are associated with disrupted metabolic programming among offspring at birth and later growth. We examined plasma phospholipid SFAs in early pregnancy and fetal growth throughout pregnancy. We enrolled 321 pregnant women from the NICHD Fetal Growth Studies-Singleton Cohort at gestational weeks 8-13. Ultrasonogram schedules were randomly assigned to capture weekly fetal growth. We measured plasma phospholipid SFAs at early pregnancy using blood samples and modeled fetal growth trajectories across tertiles of SFAs with cubic splines using linear mixed models after full adjustment. We then compared pairwise weekly fetal growth biometrics referencing the lowest tertile in each SFA using the Wald test. We found that even-chain and very long even-chain SFAs were inversely associated, whereas odd-chain SFAs were positively associated with fetal weight and size. Compared with the lowest tertile, the highest tertile of pentadecanoic acid (15:0) had a greater fetal weight and size, starting from week 13 until late pregnancy (at week 39: 3429.89 vs. 3269.08 g for estimated fetal weight; 328.14 vs. 323.00 mm for head circumference). Our findings could inspire future interventions using an alternative high-fat diet rich in odd-chain SFAs for optimal fetal growth.

Longitudinal lipidomic profiles during pregnancy and associations with neonatal anthropometry: findings from a multiracial cohort.

BACKGROUND: Maternal lipidomic profiling offers promise for characterizing lipid metabolites during pregnancy, but longitudinal data are limited. This study aimed to examine associations of longitudinal lipidomic profiles during pregnancy with multiple neonatal anthropometry using data from a multiracial cohort. METHODS: We measured untargeted plasma lipidome profiles among 321 pregnant women from the NICHD Fetal Growth Study-Singletons using plasma samples collected longitudinally during four study visits at gestational weeks (GW) 10-14, 15-26, 23-31, and 33-39, respectively. We evaluated individual lipidomic metabolites at each study visit in association with neonatal anthropometry. We also evaluated the associations longitudinally by constructing lipid networks using weighted correlation network analysis and common networks using consensus network analysis across four visits using linear mixed-effects models with the adjustment of false discover rate. FINDINGS: Multiple triglycerides (TG) were positively associated with birth weight (BW), BW Z-score, length and head circumference, while some cholesteryl ester (CE), phosphatidylcholine (PC), sphingomyelines (SM), phosphatidylethanolamines (PE), and lysophosphatidylcholines (LPC 20:3) families were inversely associated with BW, length, abdominal and head circumference at different GWs. Longitudinal trajectories of TG, PC, and glucosylcermides (GlcCer) were associated with BW, and CE (18:2) with BW z-score, length, and sum of skinfolds (SS), while some PC and PE were significantly associated with abdominal and head circumference. Modules of TG at GW 10-14 and 15-26 mainly were associated with BW. At GW 33-39, two networks of LPC (20:3) and of PC, TG, and CE, showed inverse associations with abdominal circumference. Distinct trajectories within two consensus modules with changes in TG, CE, PC, and LPC showed significant differences in BW and length. INTERPRETATION: The results demonstrated that longitudinal changes of TGs during early- and mid-pregnancy and changes of PC, LPC, and CE during late-pregnancy were significantly associated with neonatal anthropometry. FUNDING: National Institute of Child Health and Human Development intramural funding.

Plasma Amino Acids in Early Pregnancy and Midpregnancy and Their Interplay With Phospholipid Fatty Acids in Association With the Risk of Gestational Diabetes Mellitus: Results From a Longitudinal Prospective Cohort.

OBJECTIVE: We prospectively evaluated plasma amino acids (AAs) in early pregnancy and midpregnancy and their interplay with phospholipid fatty acids (FAs) in association with gestational diabetes mellitus (GDM) risk. RESEARCH DESIGN AND METHODS: From a longitudinal pregnancy cohort of 2,802 individuals, concentrations of 24 plasma AAs at 10-14 and 15-26 gestational weeks (GW) were assessed among 107 GDM case subjects and 214 non-GDM control subjects. We estimated adjusted odds ratios (OR) and 95% CI for the associations of plasma AAs and the joint associations of plasma AAs and phospholipid FAs with GDM risk, adjusting for risk factors including age, prepregnancy BMI, and family history of diabetes. RESULTS: Glycine at 10-14 GW was inversely associated with GDM (adjusted OR [95% CI] per SD increment: 0.55 [0.39-0.79]). Alanine, aspartic acid, and glutamic acid at 10-14 GW were positively associated with GDM (1.43 [1.08-1.88], 1.41 [1.11-1.80], and 1.39 [0.98-1.98]). At 15-26 GW, findings for glycine, alanine, aspartic acid, and the glutamine-to-glutamic acid ratio were consistent with the directions observed at 10-14 GW. Isoleucine, phenylalanine, and tyrosine were positively associated with GDM (1.64 [1.19-2.27], 1.15 [0.87-1.53], and 1.56 [1.16-2.09]). All P values for linear trend were <0.05. Several AAs and phospholipid FAs were significantly and jointly associated with GDM. For instance, the lowest risk was observed among women with higher glycine and lower even-chain saturated FAs at 10-14 GW (adjusted OR [95% CI] 0.15 [0.06, 0.37]). CONCLUSIONS: Plasma AAs may be implicated in GDM development starting in early pregnancy. Associations of AAs with GDM may be enhanced in the copresence of phospholipid FA profile.

Metabolomic biomarkers of the mediterranean diet in pregnant individuals: A prospective study.

BACKGROUND AND AIMS: Metabolomic profiling is a systematic approach to identifying biomarkers for dietary patterns. Yet, metabolomic markers for dietary patterns in pregnant individuals have not been investigated. The aim of this study was to identify plasma metabolomic markers and metabolite panels that are associated with the Mediterranean diet in pregnant individuals. METHODS: This is a prospective study of 186 pregnant individuals who had both dietary intake and metabolomic profiles measured from the Fetal Growth Studies-Singletons cohort. Dietary intakes during the peri-conception/1st trimester and the second trimester were accessed at 8-13 and 16-22 weeks of gestation, respectively. Adherence to the Mediterranean diet was measured by the alternate Mediterranean Diet (aMED) score. Fasting plasma samples were collected at 16-22 weeks and untargeted metabolomics profiling was performed using the mass spectrometry-based platforms. Metabolites individually or jointly associated with aMED scores were identified using linear regression and least absolute shrinkage and selection operator (LASSO) regression models with adjustment for potential confounders, respectively. RESULTS: Among 459 annotated metabolites, 64 and 41 were individually associated with the aMED scores of the diet during the peri-conception/1st trimester and during the second trimester, respectively. Fourteen metabolites were associated with the Mediterranean diet in both time windows. Most Mediterranean diet-related metabolites were lipids (e.g., acylcarnitine, cholesteryl esters (CEs), linoleic acid, long-chain triglycerides (TGs), and phosphatidylcholines (PCs), amino acids, and sugar alcohols. LASSO regressions also identified a 10 metabolite-panel that were jointly associated with aMED score of the diet during the peri-conception/1st trimester (AUC: 0.74; 95% CI: 0.57, 0.91) and a 3 metabolites-panel in the 2nd trimester (AUC: 0.68; 95% CI: 0.50, 0.86). CONCLUSION: We identified plasma metabolomic markers for the Mediterranean diet among pregnant individuals. Some of them have also been reported in previous studies among non-pregnant populations, whereas others are novel. The results from our study warrant replication in pregnant individuals by future studies. CLINICAL TRIAL REGISTRATION NUMBER: This study was registered at ClinicalTrials.gov.

Ganoderma lucidum polysaccharides ameliorates D-galactose-induced aging salivary secretion disorders by upregulating the rhythm and aquaporins.

Longer-term deterioration in saliva secretion has been observed to occur in response to aging. The functional deterioration of the salivary gland damages swallowing and chewing abilities and consequently reduces life quality of the elderly. There are, however, only a few proven effective treatments for aging salivary secretion disorders. Ganoderma lucidum polysaccharide (GLP) has been applied to treat various diseases because of its safety, efficacy, and low cost. We investigated the protective effect of GLP on the submandibular gland (SMG) during aging. D-galactose (D-gal) was used to treat the aging mice, and the body weight, water consumption, saliva secretion, and flow rate were measured after 6 weeks of modeling. Micromorphological changes of the SMG were assessed by hematoxylin-eosin staining and transmission electron microscopy. RT-qPCR and Western blot were used to detect the expression of apoptotic proteins and inflammatory cytokines. Aquaporins (AQPs) and rhythmic protein expression were analyzed by immunohistochemistry and immunofluorescence. The results showed that GLP effectively promoted the expression of AQP5, AQP4, and AQP1, inhibited the release of TNF-α, IL-6, and Bax, and reduced inflammation and apoptosis. Further experiments showed that GLP promoted the up-regulation of core clock genes and proteins and restored the co-localized expression of CLOCK and AQP5 that were weakened during aging, helping to attenuate aging-induced weight loss, decreased salivation, and structural and functional damage. The findings of this work contribute to understanding the nature of age-related modifications in SMG by identifying changes in AQP5 expression and regulatory mechanisms linked to SMG dysfunction during aging. GLP is a potential drug for maintaining healthy salivary gland (SG) status and preventing SG deficiency in the elderly.

Longitudinal clinical, cognitive and biomarker profiles in dominantly inherited versus sporadic early-onset Alzheimer's disease.

Approximately 5% of Alzheimer's disease cases have an early age at onset (<65 years), with 5-10% of these cases attributed to dominantly inherited mutations and the remainder considered as sporadic. The extent to which dominantly inherited and sporadic early-onset Alzheimer's disease overlap is unknown. In this study, we explored the clinical, cognitive and biomarker profiles of early-onset Alzheimer's disease, focusing on commonalities and distinctions between dominantly inherited and sporadic cases. Our analysis included 117 participants with dominantly inherited Alzheimer's disease enrolled in the Dominantly Inherited Alzheimer Network and 118 individuals with sporadic early-onset Alzheimer's disease enrolled at the University of California San Francisco Alzheimer's Disease Research Center. Baseline differences in clinical and biomarker profiles between both groups were compared using t-tests. Differences in the rates of decline were compared using linear mixed-effects models. Individuals with dominantly inherited Alzheimer's disease exhibited an earlier age-at-symptom onset compared with the sporadic group [43.4 (SD ± 8.5) years versus 54.8 (SD ± 5.0) years, respectively, P < 0.001]. Sporadic cases showed a higher frequency of atypical clinical presentations relative to dominantly inherited (56.8% versus 8.5%, respectively) and a higher frequency of APOE-ε4 (50.0% versus 28.2%, P = 0.001). Compared with sporadic early onset, motor manifestations were higher in the dominantly inherited cohort [32.5% versus 16.9% at baseline (P = 0.006) and 46.1% versus 25.4% at last visit (P = 0.001)]. At baseline, the sporadic early-onset group performed worse on category fluency (P < 0.001), Trail Making Test Part B (P < 0.001) and digit span (P < 0.001). Longitudinally, both groups demonstrated similar rates of cognitive and functional decline in the early stages. After 10 years from symptom onset, dominantly inherited participants experienced a greater decline as measured by Clinical Dementia Rating Sum of Boxes [3.63 versus 1.82 points (P = 0.035)]. CSF amyloid beta-42 levels were comparable [244 (SD ± 39.3) pg/ml dominantly inherited versus 296 (SD ± 24.8) pg/ml sporadic early onset, P = 0.06]. CSF phosphorylated tau at threonine 181 levels were higher in the dominantly inherited Alzheimer's disease cohort (87.3 versus 59.7 pg/ml, P = 0.005), but no significant differences were found for t-tau levels (P = 0.35). In summary, sporadic and inherited Alzheimer's disease differed in baseline profiles; sporadic early onset is best distinguished from dominantly inherited by later age at onset, high frequency of atypical clinical presentations and worse executive performance at baseline. Despite these differences, shared pathways in longitudinal clinical decline and CSF biomarkers suggest potential common therapeutic targets for both populations, offering valuable insights for future research and clinical trial design.

The Core-Targeted RRM2 Gene of Berberine Hydrochloride Promotes Breast Cancer Cell Migration and Invasion via the Epithelial-Mesenchymal Transition.

Berberine hydrochloride (BBR) could inhibit the proliferation, migration, and invasion of various cancer cells. As the only enzyme for the de novo synthesis of ribonucleotides, RRM2 is closely related to the development of tumorigenesis. However, not much is currently known about the functional roles of RRM2 in breast cancer (BRCA), and whether BBR regulates the migration and invasion of BRCA cells by regulating the expression of RRM2 remains to be determined. We study the effects of BBR on BRCA cell proliferation in vitro and tumorigenesis in vivo by using colony formation assays, EdU assays, and xenograft models. Transcriptome sequencing, the random forest algorithm, and KEGG analysis were utilized to explore the therapeutic target genes and relative pathways. The expression of RRM2 in BRCA patients was analyzed with The Cancer Genome Atlas (TCGA) dataset, the GEPIA website tool, the Gene Expression Omnibus (GEO) database, and the UALCAN database. The survival probability of BRCA patients could be predicted by survival curve and nomogram analysis. Molecular docking was used to explore the affinity between BBR and potential targets. Gain- and loss-of-function methods were employed to explore the biological process in RRM2 participants. We comprehensively investigated the pharmacological characteristics of BBR on BRCA cell lines and discovered that BBR could inhibit the proliferation of BRCA cells in vitro and in vivo. Combining transcriptome sequencing and KEGG analysis, we found that BBR mainly affected the biological behavior of BRCA cells via HIF-1α and AMPK signal pathways. Additionally, by using bioinformatics and molecular docking, we demonstrated that RRM2 plays an oncogenic role in BRCA samples and that it acts as the hub gene of BBR on BRCA cells. Knockdown and overexpression studies indicated that RRM2 promoted BRCA cell migration as well as invasion in vitro by affecting the epithelial-to-mesenchymal transition (EMT). Our study demonstrated the significance of BBR regulating HIF-1α and AMPK signaling pathways in BRCA cells. Moreover, we revealed the carcinogenic role and potential mechanism of RRM2 as a core regulatory factor of BBR in BRCA in controlling BRCA invasion, migration, and EMT, suggesting that RRM2 may be a therapeutic target and prognostic biomarker for BRCA therapy.

Brusatol Inhibits Proliferation and Metastasis of Colorectal Cancer by Targeting and Reversing the RhoA/ROCK1 Pathway.

Brusatol (BRU) is an important compound extracted from Brucea javanica oil, whose pharmacological effects are able to induce a series of biological effects, including inhibition of tumor cell growth, anti-inflammatory, antiviral, and antitumor. Currently, there are so few studies about the brusatol effects on colorectal cancer that its anticancer mechanism has not been clearly defined. In this study, we made an in-depth investigation into the brusatol effect towards the proliferation and metastasis of colon cancer and the possible mechanism. The inhibitory effect of BRU on the proliferation of colorectal cancer cells was unveiled via CCK-8 method and colony formation assay, while the inhibitory effect of BRU on migration and invasion of colorectal cancer cells was revealed by scratch assay and transwell assay. In addition, Western blot results also revealed that BRU inhibited not only the expressions of RhoA and ROCK1 but also the protein expressions of EMT-related markers e-cadherin, N-cadherin, Vimentin, MMP2, and MMP9 in colon cancer cells. Through the xenotransplantation model, our in vivo experiment further verified the antitumor effect of BRU on colon cancer cells in vitro, and the results were consistent with the protein expression trend. In conclusion, BRU may inhibit the proliferation and metastasis of colorectal cancer by influencing EMT through RhoA/ROCK1 pathway.

A computational model for biosonar echoes from foliage.

Since many bat species thrive in densely vegetated habitats, echoes from foliage are likely to be of prime importance to the animals' sensory ecology, be it as clutter that masks prey echoes or as sources of information about the environment. To better understand the characteristics of foliage echoes, a new model for the process that generates these signals has been developed. This model takes leaf size and orientation into account by representing the leaves as circular disks of varying diameter. The two added leaf parameters are of potential importance to the sensory ecology of bats, e.g., with respect to landmark recognition and flight guidance along vegetation contours. The full model is specified by a total of three parameters: leaf density, average leaf size, and average leaf orientation. It assumes that all leaf parameters are independently and identically distributed. Leaf positions were drawn from a uniform probability density function, sizes and orientations each from a Gaussian probability function. The model was found to reproduce the first-order amplitude statistics of measured example echoes and showed time-variant echo properties that depended on foliage parameters. Parameter estimation experiments using lasso regression have demonstrated that a single foliage parameter can be estimated with high accuracy if the other two parameters are known a priori. If only one parameter is known a priori, the other two can still be estimated, but with a reduced accuracy. Lasso regression did not support simultaneous estimation of all three parameters. Nevertheless, these results demonstrate that foliage echoes contain accessible information on foliage type and orientation that could play a role in supporting sensory tasks such as landmark identification and contour following in echolocating bats.