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While it is challenging to simultaneously achieve both high mechanical performance and self-healing ability within one polymer hydrogel network, we, herein, synthesized a novel class of hydrogels based on a combination of chemical and dual non-covalent crosslinks

Breast cancer (BC), an extremely aggressive malignant tumor, causes a large number of deaths worldwide. In this study, we pooled profile datasets from three cohorts to illuminate the underlying key genes and pathways of BC. Expression profiles GSE42568, GSE45827, and GSE124646, including 244 BC tissues and 28 normal breast tissues, were integrated and analyzed. Differentially expressed genes (DEGs) were screened out based on these three datasets. Functional analysis including Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway were performed using The Database for Annotation, Visualization and Integrated Discovery (DAVID). Moreover, Cytoscape with Search Tool for the Retrieval of Interacting Genes (STRING) and Molecular Complex Detection (MCODE) plugin were utilized to visualize protein protein interaction (PPI) of these DEGs. The module with the highest connectivity of gene interactions was selected for further analysis. All of these hub genes had a significantly worse prognosis in BC by survival analysis. Additionally, four genes (CDK1, CDC20, AURKA, and MCM4) dramatically were enriched in oocyte meiosis and cell cycle pathways through re-analysis of DAVID. Moreover, the mRNA and protein levels of CDK1, CDC20, AURKA, and MCM4 were significantly increased in BC patients. In addition, knockdown of CDK1 and CDC20 by small interfering RNA remarkably suppressed cell migration and invasion in MCF-7 and MDA-MB-231 cells. In conclusion, our results suggested that CDK1, CDC20, AURKA, and MCM4 were reliable biomarkers of BC via bioinformatics analysis and experimental validation and may act as prospective targets for BC diagnosis and treatment.

The conventional polypropylene (PP) as a dispersed component was melt blended with ultrahigh molecular weight polyethylene (UHMWPE) in different proportions through a multi-stage melting processing strategy based on continuous rolling and forced kneading. The complex viscosity of blends was less affected by changing the content of PP under lower shearing, while it was significantly decreased in higher shearing range. Especially, by introducing a small amount of PP (5 wt%), the complex viscosity of the blend was only about 3% of original UHMWPE at 0.01 rad/s, and the crystallinity of UHMWPE component in the blend was 61.7% (about 14% higher than raw UHMWPE), which is conducive to maintaining the friction and mechanical properties of the blend. In addition, the possible different plasticization mechanisms related to the increased voids for molecular chain motion or microphase lubrication was also discussed in the present investigation.

Dinaciclib is a selective cyclin-dependent kinase inhibitor, but its radiosensitizing effect remains unclear. The aim of this study is to investigate the radiosensitizing effect of Dinaciclib on cervical cancer cells. Two cervical cancer cell lines, Hela and Siha, were selected, and the IC50 was determined by CCK8. The radiosensitizing effect of Dinaciclib was verified by plate cloning assay, and the G2/M phase arrest and apoptosis of IR cells were verified by flow cytometry. Immunofluorescence assay was used to verify the formation of γH2AX foci following DNA damage. Western blot was performed to detect cell cycle, apoptosis, autophagy, and DNA damage-related pathways. Dinaciclib increased the cell sensitivity to IR. IR induced G2/M phase arrest and apoptosis, and Dinaciclib enhanced this effect. Further, Dinaciclib delayed DNA repair, including non-homologous end joining repair and homologous recombination repair, and reduced the expression of DNA repair proteins Ku80 (SiHa cells), Ku70, and RAD51, as well as the expression of apoptotic marker Bcl-2. The expression of autophagy marker Beclin1 induced tumor cell death and increased the formation of DNA damage marker γH2AX foci. Dinaciclib improves the sensitivity of cervical cancer cells to IR by inducing cell cycle arrest, delaying DNA repair, and increasing apoptosis. However, further research is needed to unravel the complexity of DNA repair pathways.

OBJECTIVE Maturity-onset diabetes of the young (MODY) is frequently misdiagnosed as type 1 or type 2 diabetes. Correct diagnosis may result in a change in clinical treatment and impacts prediction of complications and familial risk. In this study, we aimed to assess the prevalence of MODY in multiethnic youth under age 20 years with a clinical diagnosis of type 2 diabetes. RESEARCH DESIGN AND METHODS We evaluated whole-exome sequence data of youth with a clinical diagnosis of type 2 diabetes. We considered participants to have MODY if they carried a MODY gene variant classified as likely pathogenic (LP) or pathogenic (P) according to current guidelines. RESULTS Of 3,333 participants, 93 (2.8%) carried an LP/P variant in HNF4A (16 participants), GCK (23), HNF1A (44), PDX1 (5), INS (4), and CEL (1). Compared with those with no LP/P variants, youth with MODY had a younger age at diagnosis (12.9 ± 2.5 vs. 13.6 ± 2.3 years, P = 0.002) and lower fasting C-peptide levels (3.0 ± 1.7 vs. 4.7 ± 3.5 ng/mL, P < 0.0001). Youth with MODY were less likely to have hypertension (6.9% vs. 19.5%, P = 0.007) and had higher HDL cholesterol (43.8 vs. 39.7 mg/dL, P = 0.006). CONCLUSIONS By comprehensively sequencing the coding regions of all MODY genes, we identified MODY in 2.8% of youth with clinically diagnosed type 2 diabetes; importantly, in 89% (n = 83) the specific diagnosis would have changed clinical management. No clinical criterion reliably separated the two groups. New tools are needed to find ideal criteria for selection of individuals for genetic testing.

Background Increasing radiosensitivity of cancer cells can enhance the efficacy of cervical cancer treatment. Objectives This study evaluated the potential roles and mechanism of baicalein in regulating the radiosensitivity of cervical cancer cells in vitro. Material and methods Real-time quantitative polymerase chain reaction (RT-qPCR) was used to assess miR-183 expression in End1/E6E7 cells, Hela cells and Hela cells irradiated with X-ray (0 Gy, 1 Gy, 3 Gy, 5 Gy, and 10 Gy). Cell Counting Kit-8 (CCK-8) method measured cell viability of Hela cells after miR-183 regulation, baicalein or RO8191 treatment. Apoptosis rates were detected using flow cytometry. Thereafter, expression of Bcl-2, Bax and caspase-3 RNA was also detected through RT-qPCR. Protein concentrations of E-cadherin, N-cadherin, Vimentin in epithelial-mesenchymal transition (EMT), phospho-JAK2/STAT3, and total Janus kinase 2/signal transducer and activator of transcription 3 STAT3 (JAK2/STAT3) were examined using enzyme-linked immunosorbent assay (ELISA) methods. RO8191, a JAK2/STAT3 activator, was used to activate the JAK2/STAT3 signaling pathway. Results The miR-183 expression was significantly lower in Hela cells compared to End1/E6E7 cells. Following upregulation of miR-183 in Hela cells, cell viability was inhibited while apoptosis was promoted. Moreover, EMT was inhibited after miR-183 over-expression. X-ray treatment markedly reduced the cell survival rate and increased miR-183 RNA expression. Baicalein treatment severely reduced the cell viability of 10-Gy X-ray-irradiated Hela cells, partially reversing the effect of miR-183, and also increased apoptosis and prevented EMT in irradiated cells. Y1007/8 in JAK2 and tyrosine (Tyr) residue 705 of STAT3 were phosphorylated, resulting in high expression of JAK2/STAT3, which was decreased by irradiation and baicalein treatment. RO8191 activated JAK2/STAT3 signaling, promoted cell viability and EMT, and inhibited cell apoptosis, while baicalein partly reversed the functions of RO8191. Conclusions Baicalein inhibited cell viability and EMT, and induced cell apoptosis of Hela cells, through upregulating miR-183 via inactivation of the JAK2/STAT3 signaling pathway.

Objective: To implement, disseminate and evaluate a sustainable method for identifying, diagnosing, and promoting individualized therapy for monogenic diabetes. Research Design and Methods: Patients were recruited into the implementation study through a screening questionnaire completed in the waiting room or through the patient portal, physician recognition, or self-referral. Patients suspected of monogenic diabetes based on the processing of their questionnaire and other data through an algorithm underwent next-generation sequencing for 40 genes implicated in monogenic diabetes and related conditions. Results: Three hundred thirteen probands with suspected monogenic diabetes (but most diagnosed with type 2 diabetes) were enrolled from October 2014 to January 2019. Sequencing identified 38 individuals with monogenic diabetes, with most variants found in GCK or HNF1A. Positivity rates for ascertainment methods were 3.1% in clinic screening, 5.3% in EHR portal screening, 16.5% for physician recognition, and 32.4% for self-referral. The algorithm criterion of non-type 1 diabetes before age 30 years had an overall positivity rate of 15.0%. Conclusions: We successfully modeled the efficient incorporation of monogenic diabetes diagnosis into the diabetes care setting, using multiple strategies to screen and identify a subpopulation with a 12.1% prevalence of monogenic diabetes by molecular testing. Self-referral was particularly efficient (32% prevalence), suggesting that educating the lay public in addition to clinicians may be the most effective way to increase the diagnosis rate of monogenic diabetes. Scaling up this model will assure access to diagnosis and customized treatment for monogenic diabetes and more broadly access to personalized medicine across disease areas.

Background Potassium levels regulate multiple physiologic processes. The heritability of serum potassium level is moderate, with published estimates varying from 17% to 60%, suggesting genetic influences. However, the genetic determinants of potassium levels are not generally known. Methods A whole-exome sequencing association study of serum potassium levels in 5812 subjects of the Old Order Amish was performed. A dietary salt intervention in 533 Amish subjects estimated interaction between p.R642G and sodium intake. Results A cluster of variants, spanning approximately 537 kb on chromosome 16q13, was significantly associated with serum potassium levels. Among the associated variants, a known pathogenic variant of autosomal recessive Gitelman syndrome (p.R642G SLC12A3) was most likely causal; there were no homozygotes in our sample. Heterozygosity for p.R642G was also associated with lower chloride levels, but not with sodium levels. Notably, p.R642G showed a novel association with lower serum BUN levels. Heterozygotes for p.R642G had a two-fold higher rate of self-reported bone fractures and had higher resting heart rates on a low-salt diet compared with noncarriers. Conclusions This study provides evidence that heterozygosity for a pathogenic variant in SLC12A3 causing Gitelman syndrome, a canonically recessive disorder, contributes to serum potassium concentration. The findings provide insights into SLC12A3 biology and the effects of heterozygosity on electrolyte homeostasis and related subclinical phenotypes that may have implications for personalized medicine and nutrition.

In order to reveal the variation law between cavitation process and pressure pulsation characteristics of centrifugal pump, the internal flow characteristics and pressure pulsation characteristics of centrifugal pump during cavitation development are studied in this paper. First, select the standard k- ε with good coincidence between external characteristics and test data under rated conditions model for calculation after compare the standard k- ε, RNG k- ε and SST k- ω. Then, based on the unsteady calculation results, the characteristics of the internal flow before and after the cavitation critical point, the frequency domain characteristics of the pressure pulsation on the volute wall and at the impeller inlet monitoring points in different cavitation stages are compared and analyzed. Finally, root mean square (RMS) is used to study the change trend of pressure fluctuation energy intensity with cavitation process. The research results show that the prediction accuracy of the characteristic points of RMS change curve of pressure fluctuation for cavitation is higher than that of the traditional 3% head drop point. Using the energy characteristics of pressure fluctuation can more accurately and timely determine the occurrence of cavitation.

Introducing double physical crosslinking reagents (i.e., a hydrophobic monomer micelle and the LAPONITE® XLG nano-clay) into the copolymerization reaction of hydrophilic monomers of N,N-dimethylacrylamide (DMAA) and acrylamide (AM) is reported here by a thermally induced free-radical polymerization method, resulting in a highly tough and rapid self-healing dual-physical crosslinking poly(DMAA-co-AM) hydrogel. The mechanical and self-healing properties can be finely tuned by varying the weight ratio of nanoclay to DMAA. The tensile strength and elongation at break of the resulting nanocomposite hydrogel can be modulated in the range of 7.5–60 kPa and 1630–3000%, respectively. Notably, such a tough hydrogel also exhibits fast self-healing properties, e.g., its self-healing rate reaches 48% and 80% within 2 and 24 h, respectively.

At three flow conditions (0.8Qd, 1.0Qd, and 1.2Qd), the centrifugal pump cavity with front inducer was expanded at 0°, 90°, 180°, and 270°, and a flow path analysis of the axial cross section at the four angles was performed. This revealed that the circumferential and radial velocities of the liquid in the pump cavity along the same angle at different radii follow an axial and radial variation law to different degrees. The pump cavity center axial liquid velocity component along the radial distribution at different angles was analyzed, and liquid pressure in the pump cavity along the radial distribution was numerically analyzed from different points of view. The mean pump cavity pressure was plotted along the radial distribution curve, and a detailed numerical calculation of the axial force of the centrifugal pump and pump cavity was developed. The influence of flow conditions on the liquid flow mechanism and axial force characteristics in the pump cavity was thoroughly discussed. The results showed that liquid flow in the centrifugal pump cavity with the front inducer is mainly restricted by the main flow of the volute. The liquid eddy current in the pump cavity is mainly concentrated near the volute and the hub at 90° and 180° angles, and the higher the flow rate, the larger is the area of the side vortex of the impeller-cover plate, and the smaller is the area of the side vortex of the pump-cover plate. When the flow rate increases, the flow direction of the eddy current at the same angle in the pump cavity remains unchanged, but when the flow rate becomes too high, the flow direction of the eddy current at the same angle in the pump cavity changes. When the range of circumferential and radial partial velocities decreases, the rotational angular velocity increases, and the pressure decreases. At low flow rate, the larger the area of the volute corresponding to the pump cavity, the higher the speed becomes. The axial force in the pump cavity is the most important factor determining the axial force of the centrifugal pump.

Here we have obtained a thermoresponsive three-dimensional (3D) polyurethane (PU) sponge with temperature-controlled superwettability. First, silanization was used to enhance the surface roughness ...

OBJECTIVE To implement, disseminate, and evaluate a sustainable method for identifying, diagnosing, and promoting individualized therapy for monogenic diabetes. RESEARCH DESIGN AND METHODS Patients were recruited into the implementation study through a screening questionnaire completed in the waiting room or through the patient portal, physician recognition, or self-referral. Patients suspected of having monogenic diabetes based on the processing of their questionnaire and other data through an algorithm underwent next-generation sequencing for 40 genes implicated in monogenic diabetes and related conditions. RESULTS Three hundred thirteen probands with suspected monogenic diabetes (but most diagnosed with type 2 diabetes) were enrolled from October 2014 to January 2019. Sequencing identified 38 individuals with monogenic diabetes, with most variants found in GCK or HNF1A. Positivity rates for ascertainment methods were 3.1% for clinic screening, 5.3% for electronic health record portal screening, 16.5% for physician recognition, and 32.4% for self-referral. The algorithmic criterion of non–type 1 diabetes before age 30 years had an overall positivity rate of 15.0%. CONCLUSIONS We successfully modeled the efficient incorporation of monogenic diabetes diagnosis into the diabetes care setting, using multiple strategies to screen and identify a subpopulation with a 12.1% prevalence of monogenic diabetes by molecular testing. Self-referral was particularly efficient (32% prevalence), suggesting that educating the lay public in addition to clinicians may be the most effective way to increase the diagnosis rate in monogenic diabetes. Scaling up this model will assure access to diagnosis and customized treatment among those with monogenic diabetes and, more broadly, access to personalized medicine across disease areas.

Objective: Maturity-onset diabetes of the young (MODY) is frequently misdiagnosed as type 1 or type 2 diabetes. Correct diagnosis may result in a change in clinical treatment and impacts prediction of complications and familial risk. In this study, we aimed to assess the prevalence of MODY in multi-ethnic youth under age 20 years with a clinical diagnosis of type 2 diabetes. Research design and methods: We evaluated whole-exome sequence data of youth with a clinical diagnosis of type 2 diabetes. We considered participants to have MODY if they carried a MODY gene variant classified as likely pathogenic (LP) or pathogenic (P) according to current guidelines. Results: 93 of 3,333 participants (2.8%) carried an LP/P variant in HNF4A (16 participants), GCK (23), HNF1A (44), PDX1 (5), INS (4), and CEL (1). Compared with those with no LP/P variants, youth with MODY had a younger age at diagnosis (12.9 ± 2.5 vs 13.6 ± 2.3 years, P=0.002) and lower fasting C-peptide levels (3.0 ± 1.7 vs 4.7 ± 3.5 ng/mL, Pvs 19.5%, P=0.007) and had higher HDL cholesterol (43.8 vs 39.7 mg/dL, P=0.006). Conclusions: By comprehensively sequencing the coding regions of all MODY genes, we identified MODY in 2.8% of youth with clinically diagnosed type 2 diabetes; importantly, in 89% (n=83) the specific diagnosis would have changed clinical management. No clinical criterion reliably separated the two groups. New tools are needed to find ideal criteria to select individuals for genetic testing.

Introducing double physical crosslinking reagents (

Silicosis is a disease mainly caused by pulmonary interstitial fibrosis caused by long-term inhalation of dust with excessively high content of free SiO2. Transdifferentiation of lung fibroblasts into myofibroblasts is an important cellular basis for silicosis, but the key transcription factors (TFs) involved in this process are still unclear. In order to explore the biological regulation of transcription factor PPARγ/LXRα in silica-induced pulmonary fibrosis, this study explored the molecular mechanism of PPARγ/LXRα involved in regulating transcription factors related to SiO2-induced lung injury at the cellular level and in animal models. ChIP-qPCR detected that PPARγ directly regulated the transcriptional activity of the LXRα gene promoter, while the PPARγ agonist RSG increased the expression of LXRα. In addition, we demonstrated in the cell model that upregulation of LXRα can inhibit silica-mediated fibroblast transdifferentiation, accompanied by an increase in the expression of SREBF1, PLTP and ABCA1. The results of LXRα silencing experiment matched those of overexpression experiment. These studies explored the role of LXRα in plasticity and phenotypic transformation between lung fibroblasts and myofibroblasts. Therefore, inhibiting or reversing the transdifferentiation of lung fibroblasts to myofibroblasts by intervening PPARγ/LXRα may provide a new therapeutic target for the treatment of silicosis.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants in sediments and pose a serious risk for freshwater ecosystems. In this study, sediment samples from 24 sites were collected from the cyanobacterial bloom-occurring, macrophyte-growing lake bay and adjoining river of Taihu Lake. Here, the concentration levels, sources, and risk assessment of 16 priority PAHs in the surface sediments from typical algae, macrophyte lake bay and adjoining river of Taihu Lake, were investigated, and the results were compared with those of previous studies. The total PAH (ΣPAH) concentrations ranged from 4900 to 16,800 ng·g−1 in sediments of the Taihu Lake bay and from 5736.2 to 69,362.8 ng·g−1 in sediments of the adjoining river. The level of PAHs in riverine sediments was significantly higher than those of the Taihu Lake bay, and that of the Dongshan River was significantly higher than that of the Mashan River, while there was no significant difference in the concentrations of PAHs between the cyanobacterial bloom-occurring and macrophyte-growing lake zone. The results indicated petroleum contamination was dominated in the cyanobacterial bloom-occurring, macrophyte-growing lake bay, while PAHs of the riverine sediments derived from petroleum contamination and the combined combustion including wood, coal combustion, and petroleum combustion according to the identification by the molecular diagnostic ratio and principal component analysis (PCA). Sediment risk assessment based on sediment quality guidelines (SQGs) suggested that partial regions of the Taihu Lake bay were subjected to the potential ecological risk of the 3-ring and 5-ring PAHs, and there existed negative effects related to naphthalene pollutant in all survey regions. The adjoining riverine sediments showed a high ecological risk.

Monogenic diabetes refers to diabetes mellitus (DM) caused by a mutation in a single gene and accounts for approximately 1%-5% of diabetes. Correct diagnosis is clinically critical for certain types of monogenic diabetes, since the appropriate treatment is determined by the etiology of the disease (e.g., oral sulfonylurea treatment of HNF1A/HNF4A-diabetes vs. insulin injections in type 1 diabetes). However, achieving a correct diagnosis requires genetic testing, and the overlapping of the clinical features of monogenic diabetes with those of type 1 and type 2 diabetes has frequently led to misdiagnosis. Improvements in sequencing technology are increasing opportunities to diagnose monogenic diabetes, but challenges remain. In this Review, we describe the types of monogenic diabetes, including common and uncommon types of maturity-onset diabetes of the young, multiple causes of neonatal DM, and syndromic diabetes such as Wolfram syndrome and lipodystrophy. We also review methods of prioritizing patients undergoing genetic testing, and highlight existing challenges facing sequence data interpretation that can be addressed by forming collaborations of expertise and by pooling cases.

Objective To investigate the safety and efficacy of 3-dimensional (3D) printing non-coplanar templates (PNCT) assisted computer tomography (CT) guided radioactive 125I seed implantation (RISI) for the treatment of recurrent cervical carcinoma (RCC) after external beam radiotherapy (EBRT). Methods A total of 103 patients with inoperable post-EBRT RCC were included in this retrospective study. A total of 111 lesions received RISI. Eight lesions were at the pelvic center, 75 lesions were at the pelvic lateral, and 28 lesions were extra-pelvic metastasis. The median prescription dose was 120 Gy. The primary end points were adverse events and local control (LC), and the secondary end points were overall survival (OS) and progression-free survival. Results Grade 2 adverse events of acute nausea, diarrhea, and pollakiuria occurred in 1, 2, and 1 patient, respectively. One patient suffered from grade 3 acute proctitis. Late toxicity was observed in 2 patients with rectovaginal fistula. No grade 5 toxicity occurred. The 3-year LC and OS rates were 75.1% and 20.8%, respectively. The median OS was 17 months. The multivariate analysis showed that the minimum dose received by the “hottest” 90% of the gross tumor volume (D90) ≥130 Gy, squamous cell carcinoma, hemoglobin ≥80 g/L and good short-term efficacy (complete response or partial response) were independent predictors of LC and OS (all p

This paper studies the flow characteristics and disk friction loss of the rear chamber in a centrifugal pump at a design flow condition with six values of the balance holes at diameters from 0 to 12 mm. The results show that the turbulent boundary layer in the rear chamber is greatly affected by the leakage flow. When the balance hole diameter increases, the flow characteristics of the rear chamber is mainly restricted by the mainstream flow field of the volute. However, when the balance hole diameter is larger than the design value, the disk friction loss of the rear chamber remains basically unchanged. On the contrary, when the balance hole diameter is smaller than the design value, the larger the balance hole diameter the smaller the friction loss of the disk in the rear chamber area. The results of this paper provide a reference for reducing axial force and stable operation of a centrifugal pump.

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier will develop the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we applied clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias displayed effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers averaged below 60% in both studies for all conditions except monogenic diabetes. We assessed additional epidemiologic and genetic factors contributing to risk prediction, demonstrating that inclusion of common polygenic variation significantly improved biomarker estimation for two monogenic dyslipidemias.

BACKGROUND: Potassium levels regulate multiple physiologic processes. The heritability of serum potassium level is moderate, with published estimates varying from 17% to 60%, suggesting genetic influences. However, the genetic determinants of potassium levels are not generally known. METHODS: A whole-exome sequencing association study of serum potassium levels in 5812 subjects of the Old Order Amish was performed. A dietary salt intervention in 533 Amish subjects estimated interaction between p.R642G and sodium intake. RESULTS: A cluster of variants, spanning approximately 537 kb on chromosome 16q13, was significantly associated with serum potassium levels. Among the associated variants, a known pathogenic variant of autosomal recessive Gitelman syndrome (p.R642G SLC12A3) was most likely causal; there were no homozygotes in our sample. Heterozygosity for p.R642G was also associated with lower chloride levels, but not with sodium levels. Notably, p.R642G showed a novel association with lower serum BUN levels. Heterozygotes for p.R642G had a two-fold higher rate of self-reported bone fractures and had higher resting heart rates on a low-salt diet compared with noncarriers. CONCLUSIONS: This study provides evidence that heterozygosity for a pathogenic variant in SLC12A3 causing Gitelman syndrome, a canonically recessive disorder, contributes to serum potassium concentration. The findings provide insights into SLC12A3 biology and the effects of heterozygosity on electrolyte homeostasis and related subclinical phenotypes that may have implications for personalized medicine and nutrition.

Genetic testing for monogenic diabetes, essential for accurate diagnosis and appropriate treatment is underutilized. Obstacles include clinical overlap with type 1 and type 2 diabetes and difficulty distinguishing clinically significant (pathogenic/likely pathogenic; P/LP) from normal (benign/likely benign; B/LB) variation. The ClinGen Monogenic Diabetes Expert Panel (MDEP) was formed to adapt American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) variant interpretation guidelines to monogenic diabetes genes and enable depositing of expert panel variant reviews into ClinVar, a public database relating gene variants to phenotypes. MDEP includes endocrinologists, laboratory directors, genetic counselors, medical geneticists, clinical scientists and researchers from 37 academic and commercial institutions, allowing the panel to benefit from multiple expert perspectives and pooling of case-level data. Currently, MDEP is focusing on the three most commonly implicated monogenic diabetes genes: GCK, HNF1A and HNF4A. MDEP generated gene-specific modifications and/or strength adjustments to existing rules to provide guidance for the use of evidence, including molecular, phenotypic, segregation, functional, and minor allele frequency data. Our guidelines have so far been tested on 98 HNF1A variants, 15 HNF4A variants and 22 GCK variants selected from ClinVar and the literature. Fourteen of 31 variants of uncertain significance (VUS) in ClinVar were re-classified: nine to P/LP (enabling diagnosis and treatment) and five to B/LB (reducing ambiguity). Six LP variants and one LB variant from ClinVar were re-classified to VUS (stimulating further surveillance). MDEP’s work will improve accuracy, standardization and concordance of variant interpretation for monogenic diabetes and support wider implementation of precision medicine in diabetes. Disclosure H. Zhang: None. K.A. Maloney: None. F. Barbetti: Consultant; Self; Amring. S.W. Greeley: None. J.L.T. Kettunen: None. J.P. Miranda: None. U.L. Mirshahi: None. J. Molnes: None. R. Murphy: None. R.N. Naylor: None. R.E. Pakyz: None. L.H. Philipson: None. S. Prudente: None. T. Tuomi: None. M. Udler: None. K. Colclough: None. L. Jeng: None. T.I. Pollin: None. Funding National Institutes of Health (5U24HD093486, R01DK104942, P30DK020595 )

Diagnosing and distinguishing monogenic diabetes, including some MODY (maturity-onset diabetes of the young), from type 1 or type 2 diabetes can have profound clinical implications: sulfonylureas vs. insulin or metformin for HNF1A- and HNF4A- diabetes, and no treatment for GCK-diabetes. Since 1996, the number of monogenic diabetes genes has expanded from three to 60 or more, with 14 called MODY genes; however newer evidence has called some of these gene associations into question. Monogenic diabetes is currently underdiagnosed, but the decreasing cost of sequencing and the ability to create multi-gene next-generation sequencing panels may increase access to testing and a proper diagnosis. For the testing to be useful, it is important that the genes chosen for these panels have appropriate evidence as causal genes. The NIH Clinical Genome Resource (ClinGen) Monogenic Diabetes Gene Curation Expert Panel was convened to bring together experts in clinical and laboratory aspects of monogenic diabetes and gene curation to publish curations for the ClinGen website based on evidence from clinical and molecular studies and population databases. To date, we have published evidence-based gene curation summaries for Gene-Disease Validity for HNF1A and HNF4A (both classified as Definitive for monogenic diabetes) and are in the process of curating and publishing curations for GCK (Definitive for monogenic diabetes), INS (Definitive for monogenic diabetes and permanent neonatal diabetes), HNF1B (Definitive for renal cysts and diabetes), and KLF11 (Disputed for monogenic diabetes due to limited evidence and high population frequencies of variants previously asserted as causative). Curation of additional genes is in progress. Accurate curations will inform appropriate testing panel content to reduce ambiguous results and assure variants identified are clinically relevant for informing the care of diabetes in patients and their families. Disclosure T.I. Pollin: None. M.A. Mayers: None. S.W. Greeley: None. K.A. Maloney: None. R.N. Naylor: None. R.E. Pakyz: None. K.A. Patel: None. M. Udler: None. H. Zhang: None. K. Colclough: None. C. Thaxton: None. Funding National Institutes of Health (U24HD093486)

Genetic variants in HNF1B encoding the transcription factor hepatocyte nuclear factor-1 beta (HNF-1B) cause Maturity-Onset Diabetes of the Young type 5 (MODY5; HNF1B-MODY) and are the most common known monogenic cause of developmental kidney disease. The aim of this study was to assess pathogenicity of HNF1B variants identified among 312 patients suspected of monogenic diabetes from the Personalized Diabetes Medicine Program (PDMP) at the University of Maryland. Patients suspected of monogenic diabetes underwent next generation sequencing for 40 genes, including HNF1B. Variants were classified according to ACMG/AMP variant interpretation guidelines. To investigate the effect of HNF1B variants on normal HNF-1B transcriptional activity, we used a Dual-Luciferase assay system in transfected HeLa cells. DNA-binding ability was studied by EMSA and protein localization was determined by fractionation and confocal microscopy. Seven HNF1B variants were identified in 7 unrelated individuals. One variant (p.H336Pfs*22) was classified as pathogenic, 5 (p.T88A, p.A167P, p.N394D, p.V458G, p.T544A) as unknown significance (VUS) and 1 variant as benign (p.D82N). Two variants, p.A167P and p.H336Pfs*22, inferred severely reduced transactivation potential (25% and 34% of WT, respectively). In addition, p.A167P demonstrated decreased protein expression (26% of WT) and a significant loss in DNA binding ability (19% of WT). The p.H336Pfs*22 variant carrier has renal agenesis, often associated with HNF1B mutations, while the p.A167P carrier lacks extra-pancreatic features. The functional evidence allowed p.A167P to be reclassified as likely pathogenic when added to existing evidence (computationally predicted deleteriousness and absence from population databases). Obtaining functional data can improve variant interpretation and enable a more precise diagnosis in patients carrying an HNF1B variant. Disclosure B.B. Johansson: None. A. Pavithram: None. H. Zhang: None. K.A. Maloney: None. M. Ringdal: None. A. Kaci: None. J.V. Sagen: Other Relationship; Self; Novo Nordisk A/S. J. Kleinberger: None. L. Jeng: None. P. Njølstad: None. T.I. Pollin: None. J. Molnes: None. Funding Western Norway Regional Health Authority; University of Bergen; Norwegian Diabetes Foundation

To investigate an association between sex hormones and inflammatory cytokines, and to determine whether baseline 17-β-estradiol (E2) and interleukin-8 (IL-8) are associated with visual field (VF) progression in postmenopausal women with primary angle closure glaucoma (PACG).A prospective cross-sectional and cohort study.The cross-sectional study enrolled 200 postmenopausal women with PACG and 151 healthy postmenopausal women as normal control subjects. A total of 105 postmenopausal women with PACG were included and followed up for ≥2 years in the cohort study.All participants were evaluated for levels of baseline sex hormones (follicle-stimulating hormone, prolactin, progesterone, testosterone, luteinizing hormone, and E2) and inflammatory cytokines (IL-1, IL-2, IL-6, IL-8, IL-10, and C-reactive protein) and underwent VF examinations. The cross-sectional study was conducted to establish risk factors for postmenopausal women with PACG using logistic regression analysis. The cohort study was designed to identify factors that could be used to predict VF progression in postmenopausal women with PACG using multivariate Cox regression analyses. The main outcome measures included factors associated with VF progression over time.Decreased E2 (odds ratio 0.88 [95% confidence interval {CI} 0.78-0.99], P = .007) and increased IL-8 (odds ratio 1.12 [95% CI 1.01-1.23], P.001) levels were risk factors in postmenopausal women with PACG. A significant negative correlation was observed between IL-8 levels and E2 (r = -0.21, P = .02). Multivariable regression analyses revealed a significant correlation between E2 levels and visual field mean deviation (MD) (B = -0.16, P = .04 [95% CI -.09 to -.003) and between IL-8 levels and MD (B = 0.36, P.001 [95% CI 0.01-0.02]). During follow-up, 48 (45.71%) patients showed VF progression. Lower baseline E2 (hazard ratio 0.85 [95% CI 0.82-0.88], P = .04) and higher baseline IL-8 levels (hazard ratio 1.01 [95% CI 1.00-1.02], P = .004) were associated with progression of glaucoma. Patients with lower E2 levels had a significantly higher rate of PACG progression (log-rank test P.001), similar to those with higher IL-8 levels (log-rank test P = .04).Decreased E2 and increased IL-8 levels at baseline are significant predictors of VF progression in postmenopausal women with PACG.