4-(4-Amino-2-fluoro­phen­oxy)-7-meth­oxy­quinazolin-6-ol methanol monosolvate

In the title compound, C15H12FN3O3·CH3OH, the dihedral angle between the quinazoline ring system and the benzene ring is 81.18 (9)°. In the crystal, mol­ecules are linked by N—H⋯O and O—H⋯N hydrogen bonds, generating [10-1] chains of alternating main mol­ecules and solvent mol­ecules. Weak C—H⋯O inter­actions are also observed

A multi-channel photometric detector for multi-component analysis in flow injection analysis

The detector, a multi-channel photometric detector, described in this paper was developed using multi-wavelength LEDs (light emitting diode) and phototransistors for absorbance measurement controlled by an Intel 8031 8-bit single chip microcomputer. Up to four flow cells can be attached to the detector. The LEDs and phototransistors are both inexpensive, and reliable. The results given by the detector for simultaneous determination of trace amounts of cobalt and cadmium in zinc sulphate electrolyte are reported. Because of the newly developed detector, this approach employs much less hardware apparatus than by employing conventional photometric detectors

Fuzzy Optimization of Option Pricing Model and Its Application in Land Expropriation

Option pricing is irreversible, fuzzy, and flexible. The fuzzy measure which is used for real option pricing is a useful supplement to the traditional real option pricing method. Based on the review of the concepts of the mean and variance of trapezoidal fuzzy number and the combination with the Carlsson-Fuller model, the trapezoidal fuzzy variable can be used to represent the current price of land expropriation and the sale price of land on the option day. Fuzzy Black-Scholes option pricing model can be constructed under fuzzy environment and problems also can be solved and discussed through numerical examples

Homozygous Frameshift Mutation in TMCO1 Causes A Syndrome with Craniofacial Dysmorphism, Skeletal Anomalies, and Mental Retardation

We identified an autosomal recessive condition in 11 individuals in the Old Order Amish of northeastern Ohio. The syndrome was characterized by distinctive craniofacial dysmorphism, skeletal anomalies, and mental retardation. The typical craniofacial dysmorphism included brachycephaly, highly arched bushy eyebrows, synophrys, long eyelashes, low-set ears, microdontism of primary teeth, and generalized gingival hyperplasia, whereas Sprengel deformity of scapula, fusion of spine, rib abnormities, pectus excavatum, and pes planus represented skeletal anomalies. The genome-wide homozygosity mapping using six affected individuals localized the disease gene to a 3.3-Mb region on chromosome 1q23.3-q24.1. Candidate gene sequencing identified a homozygous frameshift mutation, c.139_140delAG, in the transmembrane and coiled-coil domains 1 (TMCO1) gene, as the pathogenic change in all affected members of the extended pedigree. This mutation is predicted to result in a severely truncated protein (p.Ser47Ter) of only one-fourth the original length. The TMCO1 gene product is a member of DUF841 superfamily of several eukaryotic proteins with unknown function. The gene has highly conserved amino acid sequence and is universally expressed in all human tissues examined. The high degree of conservation and the ubiquitous expression pattern in human adult and fetal tissues suggest a critical role for TMCO1. This report shows a TMCO1 sequence variant being associated with a genetic disorder in human. We propose “TMCO1 defect syndrome” as the name of this condition

Homozygous Frameshift Mutation in TMCO1 Causes A Syndrome with Craniofacial Dysmorphism, Skeletal Anomalies, and Mental Retardation

We identified an autosomal recessive condition in 11 individuals in the Old Order Amish of northeastern Ohio. The syndrome was characterized by distinctive craniofacial dysmorphism, skeletal anomalies, and mental retardation. The typical craniofacial dysmorphism included brachycephaly, highly arched bushy eyebrows, synophrys, long eyelashes, low-set ears, microdontism of primary teeth, and generalized gingival hyperplasia, whereas Sprengel deformity of scapula, fusion of spine, rib abnormities, pectus excavatum, and pes planus represented skeletal anomalies. The genome-wide homozygosity mapping using six affected individuals localized the disease gene to a 3.3-Mb region on chromosome 1q23.3-q24.1. Candidate gene sequencing identified a homozygous frameshift mutation, c.139_140delAG, in the transmembrane and coiled-coil domains 1 (TMCO1) gene, as the pathogenic change in all affected members of the extended pedigree. This mutation is predicted to result in a severely truncated protein (p.Ser47Ter) of only one-fourth the original length. The TMCO1 gene product is a member of DUF841 superfamily of several eukaryotic proteins with unknown function. The gene has highly conserved amino acid sequence and is universally expressed in all human tissues examined. The high degree of conservation and the ubiquitous expression pattern in human adult and fetal tissues suggest a critical role for TMCO1. This report shows a TMCO1 sequence variant being associated with a genetic disorder in human. We propose “TMCO1 defect syndrome” as the name of this condition

Effects of Interferons and Double-Stranded RNA on Human Prostate Cancer Cell Apoptosis

Prostate cancer is the second most commonly diagnosed cancer among men in the United States. Prostate cancer therapy is severely hampered by lack of response and development of resistance to conventional chemotherapeutic drugs in patients. Therefore, the development and discovery of new drugs have become an urgent clinical need. Interferons (IFNs), a family of pleiotropic cytokines, exert antitumor activities due to their anti-proliferative, immunomodulatory and proapoptotic functions. Here, we report that pretreatment of prostate cancer PC-3 cells with IFNs sensitized these cells to double-stranded RNAs (dsRNAs)-induced apoptosis. The enhancement effect of IFN treatment was dependent on IFN subtypes, in particular, IFN γ. In comparison with IFN α or β, IFN γ treatment remarkably augmented apoptosis in PC-3 cells induced with polyinosinic:polycytidylic acid (poly I:C), a synthesized form of dsRNA. We demonstrated that IFN-signaling was necessary for these effects by using mutant cell lines. Transfection of 2–5A, the activator of RNase L, or silencing of dsRNA-dependent protein kinase R (PKR) by siRNA did not have any significant impact on this event, suggesting that neither RNase L nor PKR was involved in poly I:C/IFN γ-induced apoptosis in the cells. Further investigation of the apoptotic pathway revealed that Bak, a pro-apoptotic member of the Bcl-2family, was synergistically up-regulated by IFN γ and poly I:C, whereas other members of the family were not affected. Knocking down of Bak demonstrated its contribution to poly I:C/IFN γ-induced apoptosis in the cells. We believeour findings will precipitate the design of novel therapeutic strategies for prostate cancer

Low- and high-thermogenic brown adipocyte subpopulations coexist in murine adipose tissue

Brown adipose tissue (BAT), as the main site of adaptive thermogenesis, exerts beneficial metabolic effects on obesity and insulin resistance. BAT has been previously assumed to contain a homogeneous population of brown adipocytes. Utilizing multiple mouse models capable of genetically labeling different cellular populations, as well as single-cell RNA sequencing and 3D tissue profiling, we discovered a new brown adipocyte subpopulation with low thermogenic activity coexisting with the classical high-thermogenic brown adipocytes within the BAT. Compared with the high-thermogenic brown adipocytes, these low-thermogenic brown adipocytes had substantially lower Ucp1 and Adipoq expression, larger lipid droplets, and lower mitochondrial content. Functional analyses showed that, unlike the high-thermogenic brown adipocytes, the low-thermogenic brown adipocytes have markedly lower basal mitochondrial respiration, and they are specialized in fatty acid uptake. Upon changes in environmental temperature, the 2 brown adipocyte subpopulations underwent dynamic interconversions. Cold exposure converted low-thermogenic brown adipocytes into high-thermogenic cells. A thermoneutral environment had the opposite effect. The recruitment of high-thermogenic brown adipocytes by cold stimulation is not affected by high fat diet feeding, but it does substantially decline with age. Our results revealed a high degree of functional heterogeneity of brown adipocytes

Serum Levels of FGF-21 Are Increased in Coronary Heart Disease Patients and Are Independently Associated with Adverse Lipid Profile

BACKGROUND: Fibroblast growth factor 21 (FGF-21) is a metabolic regulator with multiple beneficial effects on glucose homeostasis and lipid metabolism in animal models. The relationship between plasma levels of FGF-21 and coronary heart disease (CHD) in unknown. METHODOLOGY/PRINCIPAL FINDINGS: This study aimed to investigate the correlation of serum FGF-21 levels and lipid metabolism in the patients with coronary heart disease. We performed a logistic regression analysis of the relation between serum levels of FGF-21 and CHD patients with and without diabetes and hypertension. This study was conducted in the Departments of Endocrinology and Cardiovascular Diseases at two University Hospitals. Participants consisted of one hundred and thirty-five patients who have been diagnosed to have CHD and sixty-one control subjects. Serum FGF-21 level and levels of fasting blood glucose; triglyceride; apolipoprotein B100; HOMA-IR; insulin; total cholesterol; HDL-cholesterol; LDL-cholesterol; and C-reactive protein were measured. We found that median serum FGF-21 levels were significantly higher in CHD than that of control subjects (P<0.0001). Serum FGF-21 levels in CHD patients with diabetes, hypertension, or both were higher than that of patients without these comorbidities. Serum FGF-21 levels correlated positively with triglycerides, fasting blood glucose, apolipoprotein B100, insulin and HOMA-IR but negatively with HDL-C and apolipoprotein A1 after adjusting for BMI, diabetes and hypertension. Logistic regression analysis demonstrated that FGF-21 showed an independent association with triglyceride and apolipoprotein A1. CONCLUSIONS/SIGNIFICANCE: High levels of FGF-21 are associated with adverse lipid profiles in CHD patients. The paradoxical increase of serum FGF-21 in CHD patients may indicate a compensatory response or resistance to FGF-21

Sequential algorithm to stratify liver fibrosis risk in overweight/obese metabolic dysfunction-associated fatty liver disease

BackgroundNon-diabetic overweight/obese metabolic dysfunction-associated fatty liver disease (MAFLD) represents the largest subgroup with heterogeneous liver fibrosis risk. Metabolic dysfunction promotes liver fibrosis. Here, we investigated whether incorporating additional metabolic risk factors into clinical evaluation improved liver fibrosis risk stratification among individuals with non-diabetic overweight/obese MAFLD.Materials and methodsComprehensive metabolic evaluation including 75-gram oral glucose tolerance test was performed in over 1000 participants from the New Hong Kong Cardiovascular Risk Factor Prevalence Study (HK-NCRISPS), a contemporary population-based study of HK Chinese. Hepatic steatosis and fibrosis were evaluated based on controlled attenuation parameter and liver stiffness (LS) measured using vibration-controlled transient elastography, respectively. Clinically significant liver fibrosis was defined as LS ≥8.0 kPa. Our findings were validated in an independent pooled cohort comprising individuals with obesity and/or polycystic ovarian syndrome.ResultsOf the 1020 recruited community-dwelling individuals, 312 (30.6%) had non-diabetic overweight/obese MAFLD. Among them, 6.4% had LS ≥8.0 kPa. In multivariable stepwise logistic regression analysis, abnormal serum aspartate aminotransferase (AST) (OR 7.95, p&lt;0.001) and homeostasis model assessment of insulin resistance (HOMA-IR) ≥2.5 (OR 5.01, p=0.008) were independently associated with LS ≥8.0 kPa, in a model also consisting of other metabolic risk factors including central adiposity, hypertension, dyslipidaemia and prediabetes. A sequential screening algorithm using abnormal AST, followed by elevated HOMA-IR, was developed to identify individuals with LS ≥8.0 kPa, and externally validated with satisfactory sensitivity (&gt;80%) and negative predictive value (&gt;90%).ConclusionA sequential algorithm incorporating AST and HOMA-IR levels improves fibrosis risk stratification among non-diabetic overweight/obese MAFLD individuals

A Better Anti-Diabetic Recombinant Human Fibroblast Growth Factor 21 (rhFGF21) Modified with Polyethylene Glycol

As one of fibroblast growth factor (FGF) family members, FGF21 has been extensively investigated for its potential as a drug candidate to combat metabolic diseases. In the present study, recombinant human FGF21 (rhFGF21) was modified with polyethylene glycol (PEGylation) in order to increase its in vivo biostabilities and therapeutic potency. At N-terminal residue rhFGF21 was site-selectively PEGylated with mPEG20 kDa-butyraldehyde. The PEGylated rhFGF21 was purified to near homogeneity by Q Sepharose anion-exchange chromatography. The general structural and biochemical features as well as anti-diabetic effects of PEGylated rhFGF21 in a type 2 diabetic rat model were evaluated. By N-terminal sequencing and MALDI-TOF mass spectrometry, we confirmed that PEG molecule was conjugated only to the N-terminus of rhFGF21. The mono-PEGylated rhFGF21 retained the secondary structure, consistent with the native rhFGF21, but its biostabilities, including the resistance to physiological temperature and trypsinization, were significantly enhanced. The in vivo immunogenicity of PEGylated rhFGF21 was significantly decreased, and in vivo half-life time was significantly elongated. Compared to the native form, the PEGylated rhFGF21 had a similar capacity of stimulating glucose uptake in 3T3-L1 cells in vitro, but afforded a significantly long effect on reducing blood glucose and triglyceride levels in the type 2 diabetic animals. These results suggest that the PEGylated rhFGF21 is a better and more effective anti-diabetic drug candidate than the native rhFGF21 currently available. Therefore, the PEGylated rhFGF21 may be potentially applied in clinics to improve the metabolic syndrome for type 2 diabetic patients