Multiparametric Characterization of Focal Cortical Dysplasia Using 3D MR Fingerprinting.

OBJECTIVES: To develop a multiparametric machine-learning (ML) framework using high-resolution 3 dimensional (3D) magnetic resonance (MR) fingerprinting (MRF) data for quantitative characterization of focal cortical dysplasia (FCD). MATERIALS: We included 119 subjects, 33 patients with focal epilepsy and histopathologically confirmed FCD, 60 age- and gender-matched healthy controls (HCs), and 26 disease controls (DCs). Subjects underwent whole-brain 3 Tesla MRF acquisition, the reconstruction of which generated T1 and T2 relaxometry maps. A 3D region of interest was manually created for each lesion, and z-score normalization using HC data was performed. We conducted 2D classification with ensemble models using MRF T1 and T2 mean and standard deviation from gray matter and white matter for FCD versus controls. Subtype classification additionally incorporated entropy and uniformity of MRF metrics, as well as morphometric features from the morphometric analysis program (MAP). We translated 2D results to individual probabilities using the percentage of slices above an adaptive threshold. These probabilities and clinical variables were input into a support vector machine for individual-level classification. Fivefold cross-validation was performed and performance metrics were reported using receiver-operating-characteristic-curve analyses. RESULTS: FCD versus HC classification yielded mean sensitivity, specificity, and accuracy of 0.945, 0.980, and 0.962, respectively; FCD versus DC classification achieved 0.918, 0.965, and 0.939. In comparison, visual review of the clinical magnetic resonance imaging (MRI) detected 48% (16/33) of the lesions by official radiology report. In the subgroup where both clinical MRI and MAP were negative, the MRF-ML models correctly distinguished FCD patients from HCs and DCs in 98.3% of cross-validation trials for the magnetic resonance imaging negative group and MAP negative group. Type II versus non-type-II classification exhibited mean sensitivity, specificity, and accuracy of 0.835, 0.823, and 0.83, respectively; type IIa versus IIb classification showed 0.85, 0.9, and 0.87. In comparison, the transmantle sign was present in 58% (7/12) of the IIb cases. INTERPRETATION: The MRF-ML framework presented in this study demonstrated strong efficacy in noninvasively classifying FCD from normal cortex and distinguishing FCD subtypes. ANN NEUROL 2024.

Evaluating the combination of in-person and electronic social networking services for family caregivers of stroke survivors: A quasi-experimental analysis.

INTRODUCTION: The effectiveness of health interventions delivered via a combination of in-person and electronic social networking services for caregivers of stroke survivors remains uncertain. This study evaluates the feasibility of implementing educational and peer support programs for these caregivers through such platforms. DESIGN: Quasi-experimental design. METHODS: This study included 105 caregiver-survivor dyads, with 54 dyads allocated to the intervention group and the remaining 51 to the control group. The LINE intervention comprised a combination of in-person and electronic social networking services including stroke and rehabilitation education, problem-solving skills training, long-term care information support, and 24-h peer and professional support for caregivers. The outcomes were assessed at baseline, after 1 month, and after 3 months, and encompassed caregivers' care burden, depressive symptoms, perceived social support, and quality of life, as well as the rehabilitation adherence and depressive symptoms of stroke survivors. Generalized estimating equations were used to examine group differences. The data were collected between August 2021 and October 2022. RESULTS: The average age of the caregivers was 48.3 years. Caregivers in the intervention group reported reduced care burdens and enhanced perceptions of social support and quality of life as compared to those in the control group. Additionally, stroke survivors in the intervention group were less likely to exhibit high-risk depressive symptoms. CONCLUSION: Delivering a stroke caregiver support intervention via in-person and electronic social networking services, such as LINE, effectively reduced the care burden for caregivers of stroke survivors. Additionally, it enhanced caregivers' perceived social support and quality of life. CLINICAL RELEVANCE: This study demonstrated that caregiver education and peer support programs administered through a combination of in-person and electronic social networking services can serve as an effective support system for the psychosocial health of stroke caregivers. These findings support the integration of such interventions into standard clinical practice by healthcare providers or governmental bodies.

Computed tomography-based radiomics predicts the fibroblast-related gene EZH2 expression level and survival of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common subtype of liver cancer. The primary treatment strategies for HCC currently include liver transplantation and surgical resection. However, these methods often yield unsatisfactory outcomes, leading to a poor prognosis for many patients. This underscores the urgent need to identify and evaluate novel therapeutic targets that can improve the prognosis and survival rate of HCC patients. AIM: To construct a radiomics model that can accurately predict the EZH2 expression in HCC. METHODS: Gene expression, clinical parameters, HCC-related radiomics, and fibroblast-related genes were acquired from public databases. A gene model was developed, and its clinical efficacy was assessed statistically. Drug sensitivity analysis was conducted with identified hub genes. Radiomics features were extracted and machine learning algorithms were employed to generate a radiomics model related to the hub genes. A nomogram was used to illustrate the prognostic significance of the computed Radscore and the hub genes in the context of HCC patient outcomes. RESULTS: EZH2 and NRAS were independent predictors for prognosis of HCC and were utilized to construct a predictive gene model. This model demonstrated robust performance in diagnosing HCC and predicted an unfavorable prognosis. A negative correlation was observed between EZH2 expression and drug sensitivity. Elevated EZH2 expression was linked to poorer prognosis, and its diagnostic value in HCC surpassed that of the risk model. A radiomics model, developed using a logistic algorithm, also showed superior efficiency in predicting EZH2 expression. The Radscore was higher in the group with high EZH2 expression. A nomogram was constructed to visually demonstrate the significant roles of the radiomics model and EZH2 expression in predicting the overall survival of HCC patients. CONCLUSION: EZH2 plays significant roles in diagnosing HCC and therapeutic efficacy. A radiomics model, developed using a logistic algorithm, efficiently predicted EZH2 expression and exhibited strong correlation with HCC prognosis.

Blue mussel (Mytilus edulis) water extract ameliorates intestinal immune response in high-fat diet-streptozotocin-induced diabetic mice.

Diabetes mellitus is a metabolic disease characterized by high blood glucose levels or hyperglycemia. Diabetes causes a decrease in immune function in the human body. Mytilus edulis has been identified as having anti-inflammatory properties and the ability to improve inflammation. Thus, this study aimed to investigate the function of Matsu M. edulis water extract (MWE) in mediating the regulation of immune responses and dysregulating the intestinal immune system in hyperglycemia mouse models. The mice were treated with MWE for seven weeks. The results showed that treatment with MWE has the ability to decrease triglyceride and total cholesterol concentrations. MWE also increases the interleukin (IL)-10 concentration and natural killer cell activation. It also improves the phagocytic capacity of monocytes in the colon and the proliferative capacity of lymphocytes in the mesentery. Furthermore, MWE also regulates the IL-6 concentration and the ratio of T helper 17 cells to regulatory T cells. Collectively, this extract can improve dyslipidemia, inflammatory responses, and dysregulation of the intestinal immune system. Therefore, M. edulis water extract can be used as an alternative treatment to reduce diabetes complications.

Role of a holo-insertase complex in the biogenesis of biophysically diverse ER membrane proteins.

Mammalian membrane proteins perform essential physiologic functions that rely on their accurate insertion and folding at the endoplasmic reticulum (ER). Using forward and arrayed genetic screens, we systematically studied the biogenesis of a panel of membrane proteins, including several G-protein-coupled receptors (GPCRs). We observed a central role for the insertase, the ER membrane protein complex (EMC), and developed a dual-guide approach to identify genetic modifiers of the EMC. We found that the back of Sec61 (BOS) complex, a component of the multipass translocon, was a physical and genetic interactor of the EMC. Functional and structural analysis of the EMC⋅BOS holocomplex showed that characteristics of a GPCR's soluble domain determine its biogenesis pathway. In contrast to prevailing models, no single insertase handles all substrates. We instead propose a unifying model for coordination between the EMC, the multipass translocon, and Sec61 for the biogenesis of diverse membrane proteins in human cells.

Inhibition of K63 ubiquitination by G-Protein pathway suppressor 2 (GPS2) regulates mitochondria-associated translation.

G-Protein Pathway Suppressor 2 (GPS2) is an inhibitor of non-proteolytic K63 ubiquitination mediated by the E2 ubiquitin-conjugating enzyme Ubc13. Previous studies have associated GPS2-mediated restriction of ubiquitination with the regulation of insulin signaling, inflammatory responses and mitochondria-nuclear communication across different tissues and cell types. However, a detailed understanding of the targets of GPS2/Ubc13 activity is lacking. Here, we have dissected the GPS2-regulated K63 ubiquitome in mouse embryonic fibroblasts and human breast cancer cells, unexpectedly finding an enrichment for proteins involved in RNA binding and translation on the outer mitochondrial membrane. Validation of selected targets of GPS2-mediated regulation, including the RNA-binding protein PABPC1 and translation factors RPS1, RACK1 and eIF3M, revealed a mitochondrial-specific strategy for regulating the translation of nuclear-encoded mitochondrial proteins via non-proteolytic ubiquitination. Removal of GPS2-mediated inhibition, either via genetic deletion or stress-induced nuclear translocation, promotes the import-coupled translation of selected mRNAs leading to the increased expression of an adaptive antioxidant program. In light of GPS2 role in nuclear-mitochondria communication, these findings reveal an exquisite regulatory network for modulating mitochondrial gene expression through spatially coordinated transcription and translation.

Persistent inflammation and lymphopenia and weaning outcomes of patients with prolonged mechanical ventilation.

BACKGROUND: Weaning outcomes of patients receiving mechanical ventilation (MV) are affected by multiple factors. A clinical feature of critically ill patients is the presence of lymphopenia, however the clinical significance of lymphopenia in patients receiving prolonged MV remains unclear. METHODS: We enrolled patients who received at least 21 consecutive days of MV in a medical center in Taiwan between 2007 and 2016. Patients with and without lymphopenia (mean count <1000/µL) were compared after propensity score matching. RESULTS: Of the 3460 patients included in the analysis, 1625 (47.0%) were liberated from MV within 100 days. Lymphopenia and severe lymphopenia (mean count <500/µL) during the first 21 days of MV were common (52.9% and 14.5%, respectively), and restricted cubic spline analysis showed a significant reduction in weaning success when the lymphocyte count dropped below 1000/µL. After propensity score matching, the patients with lymphopenia during the third week had a lower rate of weaning success within 100 days (p = 0.005) and a higher in-hospital mortality rate (p = 0.001) than those without lymphopenia. The lymphopenia group also had significantly reduced platelet (p < 0.001) and albumin (p < 0.001) levels. CONCLUSIONS: Our findings suggest that lymphopenia during the first 3 weeks may be a marker of poor weaning outcomes in patients with prolonged MV.

Comparison of ultrasound- vs. landmark-guided injections for musculoskeletal pain: an umbrella review.

OBJECTIVE: This umbrella review synthesizes systematic reviews and meta-analyses to reach a conclusion concerning the overall effectiveness of ultrasound-guided vs landmark-guided injections for treating musculoskeletal pain. DESIGN: Umbrella review. METHODS: PubMed, EMBASE, MEDLINE, and Web of Science were searched for relevant systematic reviews and meta-analyses from inception to March 2024. Critical appraisal, data extraction, and synthesis were performed in accordance with the criteria for conducting an umbrella review. RESULTS: Seventeen articles, comprising 4 systematic reviews and 13 meta-analyses, were included. Using the AMSTAR2 instrument for quality assessment, 3 articles were rated as high quality, 1 as moderate, 7 as low, and 6 as critically low. Generally, ultrasound-guided injections were found to be more accurate than landmark-guided injections, particularly in the shoulder joint, though the results for pain relief and functional outcomes varied. Ultrasound guidance was notably effective for injections into the bicipital groove, wrist, hip, and knee - yielding greater accuracy and improved pain management. Both ultrasound-guided and landmark-guided techniques showed low incidence of adverse effects. CONCLUSION: This umbrella review offers an in-depth analysis of the comparative effectiveness of ultrasound-guided and landmark-guided injections across a range of musculoskeletal sites/conditions. The findings suggest that ultrasound-guided is a reliable method.

A negative regulatory role of ß-cell-derived exosomes in the glucose-stimulated insulin secretion of recipient ß-cells.

Exosomes are extracellular vesicles that play a role in intercellular communication through the transportation of their cargo including mRNAs, microRNAs, proteins, and nucleic acids. Exosomes can also regulate glucose homeostasis and insulin secretion under diabetic conditions. However, the role of exosomes in insulin secretion in islet ß-cells under physiological conditions remains to be clarified. The aim of this study was to investigate whether exosomes derived from pancreatic islet ß-cells could affect insulin secretion in naïve ß-cells. We first confirmed that exosomes derived from the RIN-m5f ß-cell line interfered with the glucose-stimulated insulin secretion (GSIS) of recipient ß-cells without affecting cell viability. The exosomes significantly reduced the protein expression levels of phosphorylated Akt, phosphorylated GSK3α/ß, CaMKII, and GLUT2 (insulin-related signaling molecules), and they increased the protein expression levels of phosphorylated NFκB-p65 and Cox-2 (inflammation-related signaling molecules), as determined by a Western blot analysis. A bioinformatics analysis of Next-Generation Sequencing data suggested that exosome-carried microRNAs, such as miR-1224, -122-5p, -133a-3p, -10b-5p, and -423-5p, may affect GSIS in recipient ß-cells. Taken together, these findings suggest that ß-cell-derived exosomes may upregulate exosomal microRNA-associated signals to dysregulate glucose-stimulated insulin secretion in naïve ß-cells.

MiR-204/-211 double knockout exacerbates rheumatoid arthritis progression by promoting splenic inflammation.

OBJECTIVE: Collagen-induced arthritis (CIA) model was induced in C57BL/6 wild-type (wt) and C57BL/6 miR-204/-211 double-knockout (dKO) mice to investigate the role of miR-204/-211 in suppressing splenic inflammation in rheumatoid arthritis (RA). METHODS: Differences of miR-204/-211 and structure-specific recognition protein 1 (SSRP1) in the spleen of DBA/1J wt and CIA mice were detected via PCR and immunohistochemistry. CIA was induced in both C57BL/6 wt and C57BL/6 miR-204/-211 dKO mice, and the onset of CIA and disease severity were statistically analyzed. Immunohistochemistry staining of interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and SSRP1 in spleen or knee joints was performed and analyzed. In CIA miR-204/-211 dKO mice, AAV-shSSRP1 was intra-articularly injected, with both the AAV-shRNA Ctrl and AAV-shRNA Ctrl CIA groups receiving the same dose of AAV-shRNA. Spleen sections were stained with hematoxylin and eosin (H&E). RESULTS: Compared to wt mouse spleens, aberrant expression of miR-204/-211 and SSRP1 was observed in the spleens of CIA mice. Immunized dKO mice exhibited a higher incidence of CIA onset and a more exacerbated RA disease phenotype, characterized by increased spleen inflammation score and elevated levels of IL-1ß, TNF-α, and SSRP1 expression. AAV-shSSRP1 injection in CIA dKO mice significantly reduced spleen inflammation scores, IL-1ß and TNF-α expression levels, and down-regulated Ki-67 expression compared to CIA dKO mice. CONCLUSION: Knockout of miR-204/-211 exacerbated the onset of CIA in C57BL/6 mice, while miR-204/-211 played a protective role against the progression of splenic inflammatory and proliferative progression in RA by targeting SSRP1.

Clinical characteristics and outcomes of children with COVID-19 in pediatric intensive care units during the Omicron wave in Taiwan.

BACKGROUND: Since April 2022, the SARS-CoV-2 Omicron variant has caused a notable increase in pediatric COVID-19 cases in Taiwan. During the acute phase of infection, some children required admissions to pediatric intensive care units (PICU). This study aimed to analyze their clinical presentations and outcomes while exploring associated factors. METHODS: Medical records were retrospectively collected from patients with COVID-19 (aged <18 years) admitted to our PICU from April 2022-March 2023. Early stage is defined as the period without adequate vaccination and treatment guidelines for children from April-June 2022, and the remaining months are referred to as late stage. Clinical characteristics and outcomes were compared between patients in early and late stages. RESULTS: We enrolled 78 children with COVID-19, with a median length of stay (LOS) in PICU of 3 days and a 5% mortality rate. Patients admitted during the early stage had lower vaccination rates (7% vs. 50%), higher pediatric logistic organ dysfunction scores (2 vs. 0.1), and longer LOS in the PICU (6 vs. 2 days) than those admitted during the late stage. Multivariate analysis identified admission during the early stage as a risk factor for prolonged LOS (>7 days) in the PICU (odds ratio: 3.65, p = 0.047). CONCLUSION: Without available vaccinations and suitable treatment guidelines, children with COVID-19 tended to have more severe illness and prolonged LOS in the PICU. These observations highlight the importance of vaccinations and familiarity of medical providers with adequate management of this newly-emerging infectious disease.

Erythrocyte very-long chain saturated fatty acids, gut microbiota-bile acid axis and incident coronary heart disease in adults: A prospective cohort study.

BACKGROUND: Prior researches have highlighted inverse associations between levels of circulating very-long chain saturated fatty acids (VLCSFAs) and coronary heart disease (CHD). However, the intricate links involving VLCSFAs, gut microbiota, and bile acids remain underexplored. OBJECTIVE: This study examined the association of erythrocyte VLCSFAs with CHD incidence, focusing on the mediating role of gut microbiota and fecal bile acids. METHODS: This 10-year prospective study included 2383 participants without CHD at baseline. Erythrocyte VLCSFAs (arachidic acid [C20:0], behenic acid [C22:0], and lignoceric acid [C24:0]) were measured using gas chromatography at baseline and 274 CHD incidents were documented in triennial follow-ups. Gut microbiota in 1744 participants and fecal bile acid metabolites in 945 participants were analyzed using 16S rRNA sequencing and UPLC-MS/MS at middle-term. RESULTS: The multivariable-adjusted HRs (95%CI) for CHD incidence in highest vs. lowest quartiles were 0.87 (0.61, 1.25) for C20:0, 0.63 (0.42,0.96) for C22:0, 0.59 (0.41,0.85) for C24:0, and 0.57 (0.39, 0.83) for total VLCSFAs. Participants with higher total VLCSFA levels exhibited increased abundances of Holdemanella, Coriobacteriales Incertae Sedis spp., Ruminococcaceae UCG-005 and UCG-010, and Lachnospiraceae ND3007 group. These five genera generated microbial score (ODMS) that accounted for 11.52% of the total VLCSFAs-CHD association (Pmediation =0.018). Bile acids tauro_α_ and tauro_ß_muricholic acid (T_α_ and T_ß_MCA) were inversely associated with ODMS and positively associated with incident CHD. Opposite associations were found for glycolithocholic acid (GLCA), glycodeoxycholic acid (GDCA). Mediation analyses indicated that GLCA, GDCA, and T_α_ and T_ß_MCA explained 56.40%, 35.19%, and 26.17% of the ODMS-CHD association, respectively (Pmediation =0.002, 0.008, and 0.020). CONCLUSIONS: Elevated erythrocyte VLCSFAs are inversely associated with CHD risk in the Chinese population, with gut microbiota and fecal bile acid profiles potentially mediating this association. The identified microbiota and bile acid metabolites may serve as potential intervention targets in future studies. CLINICAL TRIAL REGISTRY NUMBER: NCT03179657.

Cord blood vitamin A and vitamin D levels in relation to physical growth in exclusively breastfed infants aged 0-6 months.

Background: Vitamins A and D are essential for the health of pregnant women and infants. Nevertheless, the relationship between umbilical cord blood vitamins A and D levels and the physical growth of exclusively breastfed infants remains uncertain. Objective: This cohort study aims to examine the relationship between cord blood vitamins A and D levels and the physical growth of exclusively breastfed infants aged 0-6 months. Methods: 140 singleton mother-infant pairs were recruited in total. Questionnaires were used to collect maternal and infant information, and liquid chromatography was utilized to quantify the levels of vitamins A and D in the umbilical cord blood. Anthropometric measurements were conducted at birth, at 3 and 6 months of age, and the weight-for-age z-score (WAZ), length-for-age z-score (LAZ), head circumference-for-age z-score (HAZ), and BMI-for-age z-score (BMIZ) were calculated. Univariate and multivariate linear regression models were used for the analysis. Results: The average concentration of vitamins A and D in cord blood was 0.58 ± 0.20 µmol/L and 34.07 ± 13.35 nmol/L, both below the normal range for children. After adjusting for confounding factors, vitamin A levels in cord blood positively correlated with HAZ growth in infants aged 3-6 months (ß= 0.75, P < 0.01) while vitamin D levels negatively correlated with LAZ growth (ß= -0.01, P = 0.01) and positively correlated with BMIZ growth (ß= 0.02, P < 0.01). Conclusion: Higher Vitamin A levels at birth promote HAZ growth in infants aged 3-6 months while higher vitamin D levels at birth promote BMIZ growth in infants aged 3-6 months. Clinical trial registration: https://register.clinicaltrials.gov, identifier NCT04017286.

Development and validation of the Unmet Needs Questionnaire for young stroke survivors.

OBJECTIVE: Owing to the lack of a suitable tool for detecting the unmet needs of young stroke survivors, this study aims to develop a validated questionnaire for evaluating these unmet needs. DESIGN: A cross-sectional, observational research design. SETTING: Chang Gung Memorial Hospital Linkou and Taoyuan branches in Taiwan. PARTICIPANTS: A total of 211 participants (average age 53 years; within 6 months post-stroke) completed the questionnaire. MAIN MEASURES: A qualitative approach was used to create an item pool. Experts verified item suitability, and content validity was evaluated using the item content validity index. Item analysis was applied to determine item quality, and factor analysis was used to explore construct validity. In addition, parallel analysis was employed to ascertain the optimal number of factors. RESULTS: The scale development procedure resulted in a 27-item questionnaire that assesses the unmet needs of young stroke survivors after a stroke. The item content validity index was 1.0. The Unmet Needs Questionnaire has five factors: restoring prestroke abilities and life, rehabilitation-related resources, social support and self-adjustment, economic and post-stroke life adjustment, and stroke-related information. These five factors accounted for 54% of the variance. Cronbach's alpha for the total scale was 0.91, while the alpha for the subscales ranged from 0.74 to 0.88. CONCLUSIONS: The Unmet Needs Questionnaire showed acceptable reliability and validity. It can help clinical professionals and government agencies identify stroke survivors' unmet needs and develop tailored care plans. Future research should explore the trajectory of post-stroke unmet needs using this tool.

Hypervirulent and carbapenem-resistant Klebsiella pneumoniae: A global public health threat.

The evolution of hypervirulent and carbapenem-resistant Klebsiella pneumoniae can be categorized into three main patterns: the evolution of KL1/KL2-hvKp strains into CR-hvKp, the evolution of carbapenem-resistant K. pneumoniae (CRKp) strains into hv-CRKp, and the acquisition of hybrid plasmids carrying carbapenem resistance and virulence genes by classical K. pneumoniae (cKp). These strains are characterized by multi-drug resistance, high virulence, and high infectivity. Currently, there are no effective methods for treating and surveillance this pathogen. In addition, the continuous horizontal transfer and clonal spread of these bacteria under the pressure of hospital antibiotics have led to the emergence of more drug-resistant strains. This review discusses the evolution and distribution characteristics of hypervirulent and carbapenem-resistant K. pneumoniae, the mechanisms of carbapenem resistance and hypervirulence, risk factors for susceptibility, infection syndromes, treatment regimens, real-time surveillance and preventive control measures. It also outlines the resistance mechanisms of antimicrobial drugs used to treat this pathogen, providing insights for developing new drugs, combination therapies, and a "One Health" approach. Narrowing the scope of surveillance but intensifying implementation efforts is a viable solution. Monitoring of strains can be focused primarily on hospitals and urban wastewater treatment plants.

Role of advanced glycation end-products in age-associated kidney dysfunction in naturally aging mice.

AIMS: Advanced glycation end-products (AGEs) are implicated in the age-related decline of renal function, exacerbated by conditions, such as hyperglycemia and oxidative stress. The accumulation of AGEs in the kidneys contributes to the progressive decline in renal function observed with aging. However, the precise role and mechanisms of AGEs in the age-related decline of renal function remain unclear. In this study, we investigated the impact and potential mechanisms of AGEs on aging kidneys in naturally aging mice. MATERIALS AND METHODS: Male C57BL/6 mice were divided into three groups: 6-, 57-, and 107-week-old. First, the 6- and 107-week-old mice were euthanized. The remaining mice were divided into young (6 weeks) and old (57 weeks) groups. The 57-week-old mice were orally administered aminoguanidine (100 mg/kg/day), an AGEs inhibitor, or vehicle for 13 weeks, resulting in a final age of 70 weeks. The serum and kidney tissues were collected for biochemical measurement, histological examination, immunohistochemistry staining, and immunoblotting analysis. KEY FINDINGS: Our findings revealed a notable accumulation of AGEs in both serum and kidney tissue specimens and renal dysfunction in naturally aging mice. Aminoguanidine not only reversed AGEs accumulation but also ameliorated renal dysfunction. Additionally, aminoguanidine attenuated the upregulation of fibrosis markers (phosphorylated p38/α-SMA and C/EBP homologous protein, CHOP), senescence markers (p53 and p21), and oxidative stress marker (4-HNE) in the aging kidneys. SIGNIFICANCE: These findings underscore the critical role of AGEs in age-related renal dysfunction and highlight the therapeutic potential of aminoguanidine in mitigating fibrosis and senescence, offering prospective avenues for combating age-associated renal ailments.

The cerebellum computes frequency dynamics for motions with numerical precision and cross-individual uniformity.

Cross-individual variability is considered the essence of biology, preventing precise mathematical descriptions of biological motion1-7 like the physics law of motion. Here we report that the cerebellum shapes motor kinematics by encoding dynamic motor frequencies with remarkable numerical precision and cross-individual uniformity. Using in-vivo electrophysiology and optogenetics in mice, we confirmed that deep cerebellar neurons encoded frequencies via populational tuning of neuronal firing probabilities, creating cerebellar oscillations and motions with matched frequencies. The mechanism was consistently presented in self-generated rhythmic and non-rhythmic motions triggered by a vibrational platform, or skilled tongue movements of licking in all tested mice with cross-individual uniformity. The precision and uniformity allowed us to engineer complex motor kinematics with designed frequencies. We further validated the frequency-coding function of the human cerebellum using cerebellar electroencephalography recordings and alternating-current stimulation during voluntary tapping tasks. Our findings reveal a cerebellar algorithm for motor kinematics with precision and uniformity, the mathematical foundation for brain-computer interface for motor control.

Navigating the labyrinth of long non-coding RNAs in colorectal cancer: From chemoresistance to autophagy.

Long non-coding RNAs (lncRNAs), with transcript lengths exceeding 200 nucleotides and little or no protein-coding capacity, have been found to impact colorectal cancer (CRC) through various biological processes. LncRNA expression can regulate autophagy, which plays dual roles in the initiation and progression of cancers, including CRC. Abnormal expression of lncRNAs is associated with the emergence of chemoresistance. Moreover, it has been confirmed that targeting autophagy through lncRNA regulation could be a viable approach for combating chemoresistance. Two recent studies titled "Human ß-defensin-1 affects the mammalian target of rapamycin pathway and autophagy in colon cancer cells through long non-coding RNA TCONS_00014506" and "Upregulated lncRNA PRNT promotes progression and oxaliplatin resistance of colorectal cancer cells by regulating HIPK2 transcription" revealed novel insights into lncRNAs associated with autophagy and oxaliplatin resistance in CRC, respectively. In this editorial, we particularly focus on the regulatory role of lncRNAs in CRC-related autophagy and chemoresistance since the regulation of chemotherapeutic sensitivity by intervening with the lncRNAs involved in the autophagy process has become a promising new approach for cancer treatment.

Analysis of warpage and reliability of very thin profile fine pitch ball grid array.

With the evolution of advanced integrated circuit (IC) packaging technology, the use of experiments to identify package performance and life expectation will take a significant amount of time and cost to finish the job. To reduce the cost of research and testing, predictive analyses of reliability and performance using simulation tools have become a feasible approach for the IC assembly industry. Therefore, this study utilized Moldex3D molding simulation software to analyze very thin profile fine pitch ball grid array (VFBGA) packages and established a numerical analysis procedure from the molding and curing process, the post-mold cure (PMC) process, to a thermal cycling test (TCT) to predict the amount of package warpage during processing and reliability after TCT. The results showed that the warpage trends of both experiments and simulations during the same temperature ramping process were similar. In the thermal cycling analysis, potential failure locations were found to be at the copper pillars and redistribution layer (RDL), where the maximum Von Mises stress occurred at the lowest temperature (-65 °C). The fatigue life model, Coffin-Manson model, was used to calculate the potential fatigue life at the two locations, resulting in 1689 cycles (copper pillars) and 9706 cycles (RDL L1).

Nitrogen removal strategy for real swine wastewater by combining partial nitrification-denitrification process with anammox.

Anammox process offers reduced operational cost and energy requirement compared to nitrification-denitrification methods due to lower biomass generation and no need for external carbon sources and aeration. High ammonia concetration and low biodegradable anaerobic digester of swaine wastewater provided an advantage for the growth of anammox microorangism. An anoxic/oxic (A/O) SBR and an anammox SBR were implemented parallelly to treat the same swine wastewater with partial nitrification/denitrification and partial nitrification/anammox process, respectively, and to compare their nitrogen removal efficiency. The nitrogen removal rates (NRRs) of the A/O SBR and anammox SBR were 0.054 and 0.26 kg-N/m3/day, respectively. The lower NRR of the A/O SBR could be attributed to insufficient biodegradable organic carbon sources in the denitrification process. The kinetic parameters obtained from the two SBRs were applied to estimate the time required for using the A/O process and partial nitrification/anammox process to treat the same amount of ammonia with the same reaction volume. Results showed that the A/O process required 3.3 times the reaction time of the partial nitrification/anammox process, suggesting that the partial nitrification/anammox process is a more efficient and economic nitrogen removal process for swine wastewater treatment. The next generation sequencing results revealed that Candidatus Brocadia, ranging from 10 to 23%, was the predominant anammox bacteria in the anammox SBR. More than 78.2 % of nitrite in the anammox SBR was removed through the anammox reaction.