CLSTN3ß enforces adipocyte multilocularity to facilitate lipid utilization.

Multilocular adipocytes are a hallmark of thermogenic adipose tissue1,2, but the factors that enforce this cellular phenotype are largely unknown. Here, we show that an adipocyte-selective product of the Clstn3 locus (CLSTN3ß) present in only placental mammals facilitates the efficient use of stored triglyceride by limiting lipid droplet (LD) expansion. CLSTN3ß is an integral endoplasmic reticulum (ER) membrane protein that localizes to ER-LD contact sites through a conserved hairpin-like domain. Mice lacking CLSTN3ß have abnormal LD morphology and altered substrate use in brown adipose tissue, and are more susceptible to cold-induced hypothermia despite having no defect in adrenergic signalling. Conversely, forced expression of CLSTN3ß is sufficient to enforce a multilocular LD phenotype in cultured cells and adipose tissue. CLSTN3ß associates with cell death-inducing DFFA-like effector proteins and impairs their ability to transfer lipid between LDs, thereby restricting LD fusion and expansion. Functionally, increased LD surface area in CLSTN3ß-expressing adipocytes promotes engagement of the lipolytic machinery and facilitates fatty acid oxidation. In human fat, CLSTN3B is a selective marker of multilocular adipocytes. These findings define a molecular mechanism that regulates LD form and function to facilitate lipid utilization in thermogenic adipocytes.

Cideb controls sterol-regulated ER export of SREBP/SCAP by promoting cargo loading at ER exit sites.

SREBPs are master regulators of lipid homeostasis and undergo sterol-regulated export from ER to Golgi apparatus for processing and activation via COPII-coated vesicles. While COPII recognizes SREBP through its escort protein SCAP, factor(s) specifically promoting SREBP/SCAP loading to the COPII machinery remains unknown. Here, we show that the ER/lipid droplet-associated protein Cideb selectively promotes the loading of SREBP/SCAP into COPII vesicles. Sterol deprivation releases SCAP from Insig and enhances ER export of SREBP/SCAP by inducing SCAP-Cideb interaction, thereby modulating sterol sensitivity. Moreover, Cideb binds to the guanine nucleotide exchange factor Sec12 to enrich SCAP/SREBP at ER exit sites, where assembling of COPII complex initiates. Loss of Cideb inhibits the cargo loading of SREBP/SCAP, reduces SREBP activation, and alleviates diet-induced hepatic steatosis. Our data point to a linchpin role of Cideb in regulated ER export of SREBP and lipid homeostasis.

Serum Mediators in Patients with Both Type 2 Diabetes Mellitus and Pruritus.

Chronic pruritus is an unpleasant sensory perception that negatively affects quality of life and is common among patients with type 2 diabetes mellitus. Current antipruritic therapies are insufficiently effective. Thus, the mediation of diabetic pruritus by histamine-independent pathways is likely. The aim of this study was to identify possible mediators responsible for diabetic pruritus. A total of 87 patients with type 2 diabetes mellitus were analysed, of whom 59 had pruritus and 28 did not. The 2 groups were assessed for baseline demographics, serum biochemistry parameters, cytokines, and chemokines. This study also investigated the associations of these factors with the severity of itching. Neither haemoglobin A1c nor serum creatinine levels were correlated with severity of itching. Significantly higher levels of interleukin-4 (p = 0.004), interleukin-13 (p = 0.006), granulocyte-macrophage colony-stimulating factor (p < 0.001) and C-X-C motif chemokine ligand 10 (p = 0.028) were observed in the patients with pruritus than in those without pruritus. Moreover, the levels of these mediators were positively correlated with the severity of itching. Thus, novel antipruritic drugs can be developed to target these molecules. This is the first study to compare inflammatory mediators comprehensively in patients with diabetes mellitus with pruritus vs those without pruritus.

CIDE family proteins control lipid homeostasis and the development of metabolic diseases.

Dysregulation of lipid homeostasis leads to the development of metabolic disorders including obesity, diabetes, cardiovascular disease and cancer. Lipid droplets (LDs) are subcellular organelles vital in the maintenance of lipid homeostasis by coordinating lipid synthesis, lipid storage, lipid secretion and lipolysis. Under fed condition, free fatty acids (FFAs) are remodeled and esterified into neutral lipids by lipogenesis and stored in the LDs. The lipid storage capacity of LDs is controlled by its growth via local lipid synthesis or by LD fusion. During fasting, neutral lipids are hydrolyzed by lipolysis, released as FFAs and secreted to meet energy demand. Cell death-inducing DNA fragmentation factor alpha (DFFA)-like effector (CIDE) family proteins composed of Cidea, Cideb and Cidec/Fsp27 are ER- and LD-associated proteins and have emerged as important regulators of lipid homeostasis. Notably, when localized on the LDs, CIDE proteins enrich at the LD-LD contact sites (LDCSs) and control LD fusion and growth. Here, we summarize these recent advances made on the role of CIDE proteins in the regulation of lipid metabolism with a particular focus on the molecular mechanisms underlying CIDE-mediated LD fusion and growth.

Serum neutrophil gelatinase-associated lipocalin as a potential biomarker of diabetic kidney disease in patients with childhood-onset type 1 diabetes.

BACKGROUND/PURPOSE: Diabetic kidney disease (DKD) is a major complication in patients with type 1 diabetes (T1D). The aim of this study was to evaluate the role of serum neutrophil gelatinase-associated lipocalin (sNGAL) in the early detection of DKD in childhood-onset T1D patients. METHODS: A total of 116 patients (mean age, 22.3 ± 6.9 years) with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 were enrolled in this prospective cross-sectional study. Persistent albuminuria (PA) was defined as a urine albumin-to-creatinine ratio ≥ 30 mg/g for at least two consecutive years; non-albuminuria (NA) was defined otherwise. The patients were divided into the adult (Ad) (≥18 years, n = 91) and pediatric (Ped) (<18 years, n = 25) groups and further into the Ad-PA (n = 8), Ad-NA (n = 83), Ped-PA (n = 2), and Ad-NA (n = 23) subgroups. In all groups, the sNGAL level was determined. RESULTS: The mean diabetes duration was 14.2 ± 6.1 years, and 8.6% patients had PA. There was no significant difference in sNGAL levels between the PA and NA groups; notably, in adults, the sNGAL level was significantly higher in the Ad-PA than Ad-NA subgroups (P = 0.039). The sNGAL level was negatively correlated with the eGFR in adults (rho -0.41, P < 0.001). Multiple linear regression models showed that higher sNGAL levels in the adult group were independent and significant determinants of a lower eGFR (P < 0.001). CONCLUSION: An elevated sNGAL was significantly correlated with a decreased eGFR even in the range of normal to mildly decreased renal function. Thus, it is a potential biomarker of early deterioration of DKD in childhood-onset T1D.

The diversity of hereditary neuromuscular diseases: Experiences from molecular diagnosis.

BACKGROUND: Hereditary neuromuscular diseases (NMDs) are a group of rare disorders, and the diagnosis of these diseases is a substantial burden for referral centers. Although next-generation sequencing (NGS) has identified a large number of genes associated with hereditary NMDs, the diagnostic rates still vary across centers. METHODS: Patients with a suspected hereditary NMD were referred to neuromuscular specialists at the National Taiwan University Hospital. Molecular diagnoses were performed by employing a capture panel containing 194 genes associated with NMDs. RESULTS: Among the 50 patients referred, 43 had a suspicion of myopathy, and seven had polyneuropathy. The overall diagnostic rate was 58%. Pathogenic variants in 19 genes were observed; the most frequent pathogenic variant found in this cohort (DYSF) was observed in only four patients, and 10 pathogenic variants were observed in one patient each. One case of motor neuron disease was clinically mistaken for myopathy. A positive family history increased the diagnostic rate (positive: 72.7% vs. negative: 56.3%). Fourteen patients with elevated plasma creatine kinase levels remained without a diagnosis. CONCLUSION: The application of NGS in this single-center study proves the great diversity of hereditary NMDs. A capture panel is essential, but high-quality clinical and laboratory evaluations of patients are also indispensable.

Emergence of T cell immunosenescence in diabetic chronic kidney disease.

BACKGROUND: Type 2 diabetes is an important challenge given the worldwide epidemic and is the most important cause of end-stage renal disease (ESRD) in developed countries. It is known that patients with ESRD and advanced renal failure suffer from immunosenescence and premature T cell aging, but whether such changes develop in patients with less severe chronic kidney disease (CKD) is unclear. METHOD: 523 adult patients with type 2 diabetes were recruited for this study. Demographic data and clinical information were obtained from medical chart review. Immunosenescence, or aging of the immune system was assessed by staining freshly-obtained peripheral blood with immunophenotyping panels and analyzing cells using multicolor flow cytometry. RESULT: Consistent with previously observed in the general population, both T and monocyte immunosenescence in diabetic patients positively correlate with age. When compared to diabetic patients with preserved renal function (estimated glomerular filtration rate > 60 ml/min), patients with impaired renal function exhibit a significant decrease of total CD3+ and CD4+ T cells, but not CD8+ T cell and monocyte numbers. Immunosenescence was observed in patients with CKD stage 3 and in patients with more severe renal failure, especially of CD8+ T cells. However, immunosenescence was not associated with level of proteinuria level or glucose control. In age, sex and glucose level-adjusted regression models, stage 3 CKD patients exhibited significantly elevated percentages of CD28-, CD127-, and CD57+ cells among CD8+ T cells when compared to patients with preserved renal function. In contrast, no change was detected in monocyte subpopulations as renal function declined. In addition, higher body mass index (BMI) is associated with enhanced immunosenescence irrespective of CKD status. CONCLUSION: The extent of immunosenescence is not significantly associated with proteinuria or glucose control in type 2 diabetic patients. T cells, especially the CD8+ subsets, exhibit aggravated characteristics of immunosenescence during renal function decline as early as stage 3 CKD. In addition, inflammation increases since stage 3 CKD and higher BMI drives the accumulation of CD8+CD57+ T cells. Our study indicates that therapeutic approaches such as weight loss may be used to prevent the emergence of immunosenescence in diabetes before stage 3 CKD.

The Impact of a Social Networking Service-Enhanced Smart Care Model on Stage 5 Chronic Kidney Disease: Quasi-Experimental Study.

BACKGROUND: Stage 5 chronic kidney disease (CKD) presents a high risk for dialysis initiation and for complications such as uremic encephalopathy, uremic symptoms, gastrointestinal bleeding, and infection. One of the most common barriers to health care for patients with stage 5 CKD is poor continuity of care due to unresolved communication gaps. OBJECTIVE: Our aim was to establish a powerful care model that includes the use of a social networking service (SNS) to improve care quality for patients with CKD and safely delay dialysis initiation. METHODS: We used a retrospective cohort of CKD patients aged 20-85 years who received care between 2007 and 2017 to evaluate the efficacy of incorporating an SNS into the health care system. In 2014, author F-JY, a nephrologist at the National Taiwan University Hospital Yunlin Branch, started to use an SNS app to connect with stage 5 CKD patients and their families. In cases of emergency, patients and families could quickly report any condition to F-JY. Using this app, F-JY helped facilitate productive interactions between these patients and the health care system. The intention was to safely delay the initiation of dialysis therapy. We divided patients into four groups: group 1 (G1) included patients at the study hospital during the 2007-2014 period who had contact only with nephrologists other than F-JY; group 2 (G2) included patients who visited F-JY during the 2007-2014 period before he began using the SNS app; group 3 (G3) included patients who visited nephrologists other than F-JY during the 2014-2017 period and had no interactions using the SNS; and group 4 (G4) included patients who visited F-JY during the 2014-2017 period and interacted with him using the SNS app. RESULTS: We recruited 209 patients with stage 5 CKD who had been enrolled in the study hospital's CKD program between 2007 and 2017. Each of the four groups initiated dialysis at different times. Before adjusting for baseline estimated glomerular filtration rate (eGFR), the G4 patients had a longer time to dialysis (mean 761.7 days, SD 616.2 days) than the other groups (G1: mean 403.6 days, SD 409.4 days, P=.011 for G4 vs G1; G2: 394.8 days, SD 318.8 days, P=.04; G3: 369.1 days, SD 330.8 days, P=.049). After adjusting for baseline eGFR, G4 had a longer duration for each eGFR drop (mean 84.8 days, SD 65.1 days) than the other groups (G1: mean 43.5 days, SD 45.4 days, P=.005; G2: mean 42.5 days, SD 26.5 days, P=.03; G3: mean 3.8.7 days, SD 33.5 days, P=.002). CONCLUSIONS: The use of an SNS app between patients with stage 5 CKD and their physicians can reduce the communication gap between them and create benefits such as prolonging time-to-dialysis initiation. The role of SNSs and associated care models should be further investigated in a larger population.

Mobile Health App With Social Media to Support Self-Management for Patients With Chronic Kidney Disease: Prospective Randomized Controlled Study.

BACKGROUND: Chronic kidney disease (CKD) is a global health burden. Self-management plays a key role in improving modifiable risk factors. OBJECTIVE: The aim of this study was to evaluate the effectiveness of wearable devices, a health management platform, and social media at improving the self-management of CKD, with the goal of establishing a new self-management intervention model. METHODS: In a 90-day prospective experimental study, a total of 60 people with CKD at stages 1-4 were enrolled in the intervention group (n=30) and control group (n=30). All participants were provided with wearable devices that collected exercise-related data. All participants maintained dietary diaries using a smartphone app. All dietary and exercise information was then uploaded to a health management platform. Suggestions about diet and exercise were provided to the intervention group only, and a social media group was created to inspire the participants in the intervention group. Participants' self-efficacy and self-management questionnaire scores, Kidney Disease Quality of Life scores, body composition, and laboratory examinations before and after the intervention were compared between the intervention and control groups. RESULTS: A total of 49 participants completed the study (25 in the intervention group and 24 in the control group); 74% of the participants were men and the mean age was 51.22 years. There were no differences in measured baseline characteristics between the groups except for educational background. After the intervention, the intervention group showed significantly higher scores for self-efficacy (mean 171.28, SD 22.92 vs mean 142.21, SD 26.36; P<.001) and self-management (mean 54.16, SD 6.71 vs mean 47.58, SD 6.42; P=.001). Kidney Disease Quality of Life scores were also higher in the intervention group (mean 293.16, SD 34.21 vs mean 276.37, SD 32.21; P=.02). The number of steps per day increased in the intervention group (9768.56 in week 1 and 11,389.12 in week 12). The estimated glomerular filtration rate (eGFR) of the intervention group was higher than that of the control group (mean 72.47, SD 24.28 vs mean 59.69, SD 22.25 mL/min/1.73m2; P=.03) and the decline in eGFR was significantly slower in the intervention group (-0.56 vs -4.58 mL/min/1.73m2). There were no differences in body composition between groups postintervention. CONCLUSIONS: The use of wearable devices, a health management platform, and social media support not only strengthened self-efficacy and self-management but also improved quality of life and a slower eGFR decline in people with CKD at stages 1-4. These results outline a new self-management model to promote healthy lifestyle behaviors for patients with CKD. TRIAL REGISTRATION: ClinicalTrials.gov NCT04617431; https://www.clinicaltrials.gov/ct2/show/NCT04617431.

Polybasic RKKR motif in the linker region of lipid droplet (LD)-associated protein CIDEC inhibits LD fusion activity by interacting with acidic phospholipids.

Lipid droplets (LDs) are intracellular organelles and a central site for lipid synthesis, storage, and mobilization. The size of LDs reflects the dynamic regulation of lipid metabolism in cells. Previously, we found that cell death-inducing DFFA-like effector C (CIDEC) mediates LD fusion and growth by lipid transfer through LD-LD contact sites in adipocytes and hepatocytes. The CIDE-N domains of CIDEC molecules form homodimers, whereas the CIDE-C domain plays an important role in LD targeting and enrichment. Here, using targeted protein deletions and GFP expression coupled with fluorescence microscopy, we identified a polybasic RKKR motif in the linker region that connects the CIDE-N and CIDE-C domains of CIDEC and functions as a regulatory motif for LD fusion. We found that deletion of the linker region or mutation of the RKKR motif increases the formation of supersized LDs compared with LD formation in cells with WT CIDEC. This enhanced LD fusion activity required the interaction between CIDE-N domains. Mechanistically, we found that the RKKR motif interacts with acidic phospholipids via electrostatic attraction. Loss of this motif disrupted the protein-lipid interaction, resulting in enhanced lipid droplet fusion activity and thus formation of larger LDs. In summary, we have uncovered a CIDEC domain that regulates LD fusion activity, a finding that provides insights into the inhibitory regulation of LD fusion through CIDEC-lipid interactions.

Stabilization of Sir3 interactions by an epigenetic metabolic small molecule, O-acetyl-ADP-ribose, on yeast SIR-nucleosome silent heterochromatin.

In Saccharomyces cerevisiae, Sir proteins mediate heterochromatin epigenetic gene silencing. The assembly of silent heterochromatin requires histone deacetylation by Sir2, conformational change of SIR complexes, and followed by spreading of SIR complexes along the chromatin fiber to form extended silent heterochromatin domains. Sir2 couples histone deacetylation and NAD hydrolysis to generate an epigenetic metabolic small molecule, O-acetyl-ADP-ribose (AAR). Here, we demonstrate that AAR physically associates with Sir3 and that polySir3-AAR formation has a specific and essential role in the assembly of silent SIR-nucleosome pre-heterochromatin filaments. Furthermore, we show that AAR is capable of stabilizing binding of the Sir3 BAH domain to the Sir3 carboxyl-terminal region. Our data suggests that for the assembly of SIR-nucleosome pre-heterochromatin filament, the structural rearrangement of SIR-nucleosome is important and result in creating more stable interactions of Sir3, such as the inter-molecule Sir3-Sir3 interaction, and the Sir3-nucleosome interaction within the filaments. In conclusion, our results reveal the importance of AAR, indicating that it not only affects the conformational rearrangement of SIR complexes but also might function as a critical fine-tuning modulatory component of yeast silent SIR-nucleosome pre-heterochromatin by stabilizing the intermolecular interaction between Sir3 N- and C-terminal regions.

Anti-cytomegalovirus IgG antibody titer is positively associated with advanced T cell differentiation and coronary artery disease in end-stage renal disease.

BACKGROUND: Accumulating evidence indicates that persistent human cytomegalovirus (HCMV) infection is associated with several health-related adverse outcomes including atherosclerosis and premature mortality in individuals with normal renal function. Patients with end-stage renal disease (ESRD) exhibit impaired immune function and thus may face higher risk of HCMV-related adverse outcomes. Whether the level of anti-HCMV immune response may be associated with the prognosis of hemodialysis patients is unknown. RESULTS: Among 412 of the immunity in ESRD study (iESRD study) participants, 408 were HCMV seropositive and were analyzed. Compared to 57 healthy individuals, ESRD patients had higher levels of anti-HCMV IgG. In a multivariate-adjusted logistic regression model, the log level of anti-HCMV IgG was independently associated with prevalent coronary artery disease (OR = 1.93, 95% CI = 1.2~ 3.2, p = 0.01) after adjusting for age, sex, hemoglobin, diabetes, calcium phosphate product and high sensitivity C-reactive protein. Levels of anti-HCMV IgG also positively correlated with both the percentage and absolute number of terminally differentiated CD8+ and CD4+ CD45RA+ CCR7- TEMRA cells, indicating that immunosenescence may participate in the development of coronary artery disease. CONCLUSION: This is the first study showing that the magnitude of anti-HCMV humoral immune response positively correlates with T cell immunosenescence and coronary artery disease in ESRD patients. The impact of persistent HCMV infection should be further investigated in this special patient population.

A comprehensive characterization of aggravated aging-related changes in T lymphocytes and monocytes in end-stage renal disease: the iESRD study.

BACKGROUND: Patients with end-stage renal disease (ESRD) exhibit a premature aging phenotype of the immune system. Nevertheless, the etiology and impact of these changes in ESRD patients remain unknown. RESULTS: Compared to healthy individuals, ESRD patients exhibit accelerated immunosenescence in both T cell and monocyte compartments, characterized by a dramatic reduction in naïve CD4+ and CD8+ T cell numbers but increase in CD8+ TEMRA cell and proinflammatory monocyte numbers. Notably, within ESRD patients, aging-related immune changes positively correlated not only with increasing age but also with longer dialysis vintage. In multivariable-adjusted logistic regression models, the combination of high terminally differentiated CD8+ T cell level and high intermediate monocyte level, as a composite predictive immunophenotype, was independently associated with prevalent coronary artery disease as well as cardiovascular disease, after adjustment for age, sex, systemic inflammation and presence of diabetes. Levels of terminally differentiated CD8+ T cells also positively correlated with the level of uremic toxin p-cresyl sulfate. CONCLUSIONS: Aging-associated adaptive and innate immune changes are aggravated in ESRD and are associated with cardiovascular diseases. For the first time, our study demonstrates the potential link between immunosenescence in ESRD and duration of exposure to the uremic milieu.

The assessment of exposure to occupational noise and hearing loss for stoneworkers in taiwan.

INTRODUCTION: Stoneworkers in Taiwan are exposed to occupational noise and suffer hearing impairment. A complete assessment of exposure and health effects is needed for a better understanding. MATERIALS AND METHODS: We accessed nine stone factories, monitored the environmental and personal doses of noise, analyzed the frequency spectra of noise from various machines, and recruited 55 stoneworkers and 25 administrative staff as controls for pure tone audiometry testing. RESULTS: The means (standard deviations) of 8-h time-weighted averages for environmental and personal monitoring were 85.0 (6.2) and 87.0 (5.5) dB(A), respectively, with seven of nine personal measurements being higher than the respective environmental results. The monitoring data suggest that occupational noise in the stonework environments should be a matter of great concern. Nearly all frequency spectra indicated peak values occurring between 2 and 4 kHz, which were within the bands for early noise-induced hearing loss (NIHL). The mean hearing threshold levels of the study participants were elevated in low and high frequencies (29.2 and 41.2 dB) compared to that of controls (∼25 dB for both bands). Linear regression analysis indicated no significance in the low frequencies (P = 0.207) but statistical significance in the high frequencies (P = 0.002) after adjustment for covariates, suggesting NIHL among the stoneworkers. CONCLUSION: Stoneworkers apparently display early signs of NIHL. Noises in the stonework factories with peaks in the high frequencies are harmful to hearing ability. Employers and workers have to comply with the regulation strictly to prevent further hearing damage.

Differential Roles of Cell Death-inducing DNA Fragmentation Factor-α-like Effector (CIDE) Proteins in Promoting Lipid Droplet Fusion and Growth in Subpopulations of Hepatocytes.

Lipid droplets (LDs) are dynamic subcellular organelles whose growth is closely linked to obesity and hepatic steatosis. Cell death-inducing DNA fragmentation factor-α-like effector (CIDE) proteins, including Cidea, Cideb, and Cidec (also called Fsp27), play important roles in lipid metabolism. Cidea and Cidec are LD-associated proteins that promote atypical LD fusion in adipocytes. Here, we find that CIDE proteins are all localized to LD-LD contact sites (LDCSs) and promote lipid transfer, LD fusion, and growth in hepatocytes. We have identified two types of hepatocytes, one with small LDs (small LD-containing hepatocytes, SLHs) and one with large LDs (large LD-containing hepatocytes, LLHs) in the liver. Cideb is localized to LDCSs and promotes lipid exchange and LD fusion in both SLHs and LLHs, whereas Cidea and Cidec are specifically localized to the LDCSs and promote lipid exchange and LD fusion in LLHs. Cideb-deficient SLHs have reduced LD sizes and lower lipid exchange activities. Fasting dramatically induces the expression of Cidea/Cidec and increases the percentage of LLHs in the liver. The majority of the hepatocytes from the liver of obese mice are Cidea/Cidec-positive LLHs. Knocking down Cidea or Cidec significantly reduced lipid storage in the livers of obese animals. Our data reveal that CIDE proteins play differential roles in promoting LD fusion and lipid storage; Cideb promotes lipid storage under normal diet conditions, whereas Cidea and Cidec are responsible for liver steatosis under fasting and obese conditions.

Variant GADL1 and response to lithium therapy in bipolar I disorder.

BACKGROUND: Lithium has been a first-line choice for maintenance treatment of bipolar disorders to prevent relapse of mania and depression, but many patients do not have a response to lithium treatment. METHODS: We selected subgroups from a sample of 1761 patients of Han Chinese descent with bipolar I disorder who were recruited by the Taiwan Bipolar Consortium. We assessed their response to lithium treatment using the Alda scale and performed a genomewide association study on samples from one subgroup of 294 patients with bipolar I disorder who were receiving lithium treatment. We then tested the single-nucleotide polymorphisms (SNPs) that showed the strongest association with a response to lithium for association in a replication sample of 100 patients and tested them further in a follow-up sample of 24 patients. We sequenced the exons, exon-intron boundaries, and part of the promoter of the gene encoding glutamate decarboxylase-like protein 1 (GADL1) in 94 patients who had a response to lithium and in 94 patients who did not have a response in the genomewide association sample. RESULTS: Two SNPs in high linkage disequilibrium, rs17026688 and rs17026651, that are located in the introns of GADL1 showed the strongest associations in the genomewide association study (P=5.50×10(-37) and P=2.52×10(-37), respectively) and in the replication sample of 100 patients (P=9.19×10(-15) for each SNP). These two SNPs had a sensitivity of 93% for predicting a response to lithium and differentiated between patients with a good response and those with a poor response in the follow-up cohort. Resequencing of GADL1 revealed a novel variant, IVS8+48delG, which lies in intron 8 of the gene, is in complete linkage disequilibrium with rs17026688 and is predicted to affect splicing. CONCLUSIONS: Genetic variations in GADL1 are associated with the response to lithium maintenance treatment for bipolar I disorder in patients of Han Chinese descent. (Funded by Academia Sinica and others.).

Control of lipid droplet fusion and growth by CIDE family proteins.

Cell death-inducing DFF45-like effector (CIDE) family proteins including Cidea, Cideb and Cidec/Fsp27 are expressed in many different tissues and are known as lipid droplet (LD)-and ER-associated proteins. Systematic analyses using genetically modified animal models have demonstrated that CIDE proteins play important roles in regulating various aspects of lipid homeostasis, including lipid storage, lipolysis and lipid secretion. Recent research in ours and other laboratories has revealed that CIDE proteins are crucial regulators of LD fusion and growth in the adipose tissue, liver, skin and mammary glands. CIDE-mediated LD fusion and growth is different from other membrane fusions in that it requires CIDE proteins to be enriched and clustered at the LD-LD contact sites (LDCS). The enriched CIDE proteins then allow the recruitment of other proteins to the LDCS and the formation of potential fusion pores. Neutral lipids in the smaller LDs of the contacted pair are transferred to the larger LDs, owing to the internal pressure difference, thus resulting in the fusion and growth of the LDs. This review summarizes the physiological roles of CIDE proteins in controlling lipid homeostasis, insulin sensitivity and the development of metabolic diseases including obesity, diabetes and fatty liver, with a particular focus on the role of CIDE proteins in controlling LD fusion and growth. This article is part of a Special Issue entitled: Recent Advances in Lipid Droplet Biology edited by Rosalind Coleman and Matthijs Hesselink.

The role of brain natriuretic peptide in predicting renal outcome and fluid management in critically ill patients.

BACKGROUND/PURPOSE: Fluid overload is associated with acute kidney injury (AKI) and mortality. There is no convenient precise method to guide fluid therapy in critically ill patients. We aimed to investigate whether brain natriuretic peptide (BNP) can predict the renal outcome and mortality of critically ill patients and be used to guide fluid management. METHODS: This prospective observational study included patients who were admitted to the intensive care unit (ICU). Patients with underlying heart disease and heart dysfunction were excluded. Plasma BNP levels were obtained on admission (D0), at 24 hours (D1), and at 48 hours (D2). The primary outcome was AKI development during the ICU stay and recovery of AKI at ICU discharge. The secondary outcome was in-ICU mortality. RESULTS: One hundred and sixty-three patients were enrolled for analysis. The delta-BNP level within the initial 24 hours after ICU admission rather than fluid accumulation was significantly correlated with delta-central venous pressure levels (r = 0.219, p = 0.010). Delta-Brain natriuretic peptide levels of < 81.8% within the initial 24 hours was an independent predictor of better renal outcome (i.e., no AKI or AKI with recovery). The increment in the BNP level from D0 to D1 was also a significant risk factor of mortality. In the a priori subgroup analysis for patients with sepsis, delta-BNP levels from D0 to D1 remained a significant predictor of renal outcome and mortality. CONCLUSION: Our study showed that delta-BNP levels within 24 hours of admission to the ICU are better than fluid accumulation as a predictor of AKI, recovery, and mortality.

CIDE proteins and their regulatory mechanisms in lipid droplet fusion and growth.

The cell death-inducing DFF45-like effector (CIDE) proteins, including Cidea, Cideb, and Cidec/Fsp27, regulate various aspects of lipid homeostasis, including lipid storage, lipolysis, and lipid secretion. This review focuses on the physiological roles of CIDE proteins based on studies on knockout mouse models and human patients bearing CIDE mutations. The primary cellular function of CIDE proteins is to localize to lipid droplets (LDs) and to control LD fusion and growth across different cell types. We propose a four-step process of LD fusion, characterized by (a) the recruitment of CIDE proteins to the LD surface and CIDE movement, (b) the enrichment and condensate formation of CIDE proteins to form LD fusion plates at LD-LD contact sites, (c) lipid transfer through lipid-permeable passageways within the fusion plates, and (d) the completion of LD fusion. Lastly, we outline CIDE-interacting proteins as regulatory factors, as well as their contribution in LD fusion.

Out-of-Mold Sensor-Based Process Parameter Optimization and Adaptive Process Quality Control for Hot Runner Thin-Walled Injection-Molded Parts.

Injection molding is a highly nonlinear procedure that is easily influenced by various external factors, thereby affecting the stability of the product's quality. High-speed injection molding is required for production due to the rapid cooling characteristics of thin-walled parts, leading to increased manufacturing complexity. Consequently, establishing appropriate process parameters for maintaining quality stability in long-term production is challenging. This study selected a hot runner mold with a thin wall fitted with two external sensors, a nozzle pressure sensor and a tie-bar strain gauge, to collect data regarding the nozzle peak pressure, the timing of peak pressure, the viscosity index, and the clamping force difference value. The product weight was defined as the quality indicator, and a standardized parameter optimization process was constructed, including injection speed, V/P switchover point, packing, and clamping force. Finally, the optimized process parameters were applied to the adaptive process control experiments using the developed control system operated within the micro-controller unit (MCU). The results revealed that the control system effectively stabilized the product weight variation and standard deviation of 0.677% and 0.0178 g, respectively.