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Retina is a crucial tissue for the capturing and processing of light stimulus. Characterization of the retina at single cell level is essential for the understanding of its biological functions. A variety of abnormalities in terms of morphology and function were reported in T21 retina. To evaluate the effects of chromosome aneuploidy on retina development, we characterized single cell transcriptional profiles of a T21 fetus and performed comprehensive bioinformatic analyses. Our data revealed the diversity and heterogeneity of cellular compositions in T21 retina. In total, we identified seven major cell types, and detected several subtypes within each cell type, followed by the detection of corresponding molecular markers including previously reported ones and a series of novel markers. Our analyses identified extensive communication networks between distinct cellular types, among which a few ligand-receptor interactions were associated with the development of retina and immunoregulatory interactions. Taken together, our data provided the first single cell transcriptome profile for human T21 retina which facilitates our understanding on the dosage effects of chromosome 21 on the development of retina.

Background Heimler syndrome (HS) is a rare hereditary systemic disorder, partial clinically overlapping with Usher syndrome. So far, our knowledge of HS is very limited, many cases are misdiagnosed or may not even be diagnosed at all. This study aimed to analyze the clinical and genetic characteristics of HS, and to evaluate potential phenotype–genotype correlations. Results Two HS cases caused by PEX1 mutations were identified, and a novel likely pathogenic mutation, PEX1 c.895_896insTATA, was found. The main ophthalmic finding of the two patients was consistent with retinitis pigmentosa accompanied by cystoid macular edema, but short axial length and hyperopia were also observed as two previously unreported ocular phenotypes. Analysis of the literature showed that of the 29 HS patients previously reported, 12 had PEX6 mutations, 10 had PEX1 mutations, two had PEX26 mutations, and the remaining patients were not genetically tested. Three novel genotype–phenotype correlations were revealed from analysis of these patients. First, most genotypes of every HS patient include at least one missense variant; second, at least one mutation in PEX1 or PEX6 gene affects the AAA-ATPase region in every HS patient with retinal dystrophy, suggesting AAA-ATPase region is a hypermutable region in patients with a retinal dystrophy; third, there are no significant differences between PEX1-, PEX6-, and PEX26-associated phenotypes. Conclusion Next-generation sequencing is important for the diagnosis of HS. This study expands the clinical and genetic spectrum of HS, and provides additional insights into genotype–phenotype correlations, which is vital for accurate clinical practice, genetic counseling, and pathogenesis studies.

Salviae miltiorrliza-borneol Jun-Shi coupled-herbs have been widely used for treatment of ischemia stroke. Salvianolic acid B was the most abundant and bioactive compound of Salviae miltiorrliza and used for prevention and treatment of cerebrovascular diseases. However, the scientific intension and compatible mechanism of Salvianolic acid B - borneol combination were still unknown. A metabolomics study approach based on ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) combined with a pathological study has been applied to study the metabolic disturbances of cerebral ischemia and evaluate the efficacies of Sal B and Sal B/borneol against cerebral ischemia in middle cerebral artery occlusion (MCAO) rats. The neuroprotection of Sal B and Sal B/borneol was reversed through the evaluation of neurological deficits, infarct volume, and neuronal apoptosis in MCAO model. The metabonomic analysis revealed that the MCAO-induced cerebral ischemia could be ameliorated by Sal B through improving the energy metabolism, lipids metabolism, inflammatory responses, and oxidant stress. Borneol could enhance the neuroprotective effects, was associated with the increased concentration of Sal B, and attenuate the function of sphingolipid metabolism pathway in cerebral ischemia rats. These findings perhaps clarify the mechanism of neuroprotective effects of treating ischemia stroke by Sal B or Sal B/borneol preliminarily through metabolomics and push the quality promotion and the composition of borneol/Sal B in secondary development of prescription.

Objective Congenital hypogonadotropic hypogonadism (CHH) and constitutional delay of growth and puberty (CDGP) represent rare and common forms of GnRH deficiency, respectively. Both CDGP and CHH present with delayed puberty, and the distinction between these two entities during early adolescence is challenging. More than 30 genes have been implicated in CHH, while the genetic basis of CDGP is poorly understood. Design We characterized and compared the genetic architectures of CHH and CDGP, to test the hypothesis of a shared genetic basis between these disorders. Methods Exome sequencing data were used to identify rare variants in known genes in CHH (n = 116), CDGP (n = 72) and control cohorts (n = 36 874 ExAC and n = 405 CoLaus). Results Mutations in at least one CHH gene were found in 51% of CHH probands, which is significantly higher than in CDGP (7%, P = 7.6 × 10−11) or controls (18%, P = 5.5 × 10−12). Similarly, oligogenicity (defined as mutations in more than one gene) was common in CHH patients (15%) relative to CDGP (1.4%, P = 0.002) and controls (2%, P = 6.4 × 10−7). Conclusions Our data suggest that CDGP and CHH have distinct genetic profiles, and this finding may facilitate the differential diagnosis in patients presenting with delayed puberty.

The Zhawulong ore field hosts lots of rare-element pegmatite dikes and is an important producing area for lithium resources in the Songpan–Ganze orogenic belt (SGOB), east Tibet. This paper aims to evaluate the sources and ore-forming processes for granite and pegmatite in the Zhawulong ore field, as well as the petrogenetic links between these rocks, using petrography, whole-rock major and trace-element analysis, and Sr–Nd–Hf isotope analysis. In this ore field, pegmatites are common as dike swarms that emanate from the external and/or internal contact zone of the Zhawulong granitic pluton and strata of the Triassic Xikang group, showing close spatial relationships. Measured values of K/Rb vs. Zr, Hf, and Cs contents indicate geochemical affinities between granite and pegmatite, which suggests that the pegmatite was generated by processes involving high fractional crystallization from the residual parental magma of the host granite. Additionally, the granite have high (87Sr/86Sr)i values (0.711064 to 0.716105), negative eNd(t) values (−9.6 to −9.1) and eHf(t) values (−32.6 to −2.0), and ancient Nd and Hf model ages (1.2–3.1 Ga), which indicate a continental crustal source. Metasedimentary rocks of the Xikang group are rich in Li (~95 ppm), Rb (~124 ppm), Nb (~15 ppm), and Cs (~17 ppm), and their rare-earth element (REE) patterns show moderate enrichment in light REEs and a negative Eu anomaly (Eu/Eu* = ~0.64), revealing characteristics similar to those of granite. The coeval nature and close spatial relationships between the Zhawulong granite and other syn-orogenic S-type granites indicate that the formation of this granite was related to crustal melting. The petrology and geochemical signatures of the Zhawulong rare-metal-bearing granite–pegmatite imply that it was generated by the partial melting of metasedimentary rocks during the Late Triassic orogeny assembly and was further enriched in Li through processes involving high fractional crystallization.

Recently, SnO2 is considered to be one of the most promising materials as electron transport layer in perovskite solar cells (PSCs). Low-temperature processed SnO2 films are crucial for SnO2-based PSCs and flexible devices. However, it is difficult to prepare stoichiometric SnO2 films by e-beam evaporation at low-temperature. Herein, SnO2 films are fabricated by oxygen plasma activated e-beam evaporation technique at room-temperature. Oxygen plasma shows strong oxidation activity, which is essential to adjust the stoichiometry of SnO x in the evaporation process. The SnO2 films exhibit uniformity (R q = 3.05 nm), high transmittance (T > 90%), high hall mobility (μ e = 10.8 cm2 V −1 s−1) and good hydrophilic (water contact angle =19°). This work will promote the application of SnO2 films in PSCs and flexible devices.

Purpose Stargardt disease (STGD) is the most frequent cause of hereditary macular dystrophy in childhood. Variants in the ABCA4, ELOVL4, PROM1, BEST1, and PRPH2 genes have been detected in patients with autosomal recessive or dominant STGD. This study was aimed at identifying the novel disease-associated variants in Chinese patients with STGD. Methods Ten Chinese families and two sporadic cases with STGD (n = 32) were enrolled in the study. All subjects underwent genetic analysis with next-generation sequencing (NGS), which was based on a specially customized capture panel targeting exons and untranslated regions (UTRs) of 792 genes related to common hereditary ophthalmopathy. Variants were analyzed to assess possible pathogenicity. Results Fourteen disease-associated variants of ABCA4 were detected in 9 Chinese families with autosomal recessive STGD, including 11 pathogenic variants and 3 likely pathogenic variants. Variant c.4253 + 4C > T in ABCA4 was identified as one de novo variant. Of the 14 distinct variants in ABCA4, 7 novel variants were found. In addition, one known variant of PROM1, c.1117C > T (p.Arg373Cys), was detected in one family and one sporadic case with autosomal dominant STGD, respectively. One novel missense variant of ELOVL4, c.59A > G (p.Asn20Ser), was found in one sporadic case with autosomal dominant STGD. The potential deleterious effects of these novel variants were confirmed through intensive analysis. Conclusion By panel-based NGS, 8 novel disease-associated variants are identified in two genes responsible for STGD, including ABCA4 and ELOVL4. Our results further extend the mutation spectrum of these two genes in Chinese patients with STGD. One ABCA4 c.4253 + 4C > T variant is identified as a de novo splicing variant.

Rabeprazole sterile powder for injection (RSPI) is a new formulation, compared with rabeprazole enteric coated tablets. The aim of this study was to evaluate the pharmacokinetic properties and bioavailability of RSPI in healthy Chinese volunteers. Pharmacokinetic studies included an ascending single dose of 10, 20, 40 mg, and a multiple doses of 20 mg. A bioavailability study was evaluated following a single dose of 20 mg between RSPI and Pariet® Pharmacokinetic parameters of rabeprazole given in each treatment period were calculated using non-compartmental analysis. In the PK study, after a single intravenous dose of 10, 20, and 40 mg, the main pharmacokinetic parameters for rabeprazole were as follows: Cmax 566.88, 897.23, 2,171.6 ng/mL; AUClast/794.31, 1,122.76, 2,446.85 ng×h/mL, respectively. After multiple doses of 20 mg, the main pharmacokinetic parameters for rabeprazole were Cmax 991.90 ng/mL, AUClast 1,261.08 ng×h/mL. In the BA study, after a single oral dose of Pariet® 20 mg, the main pharmacokinetic parameters for rabeprazole were Cmax 582.74 ng/mL, AUClast 1,135.5 ng×h/mL. RSPI produced a less-than-proportional increase in exposure with increasing dose in healthy subjects. The accumulation ratio was 1.0, suggesting RSPI displayed no accumulation after repeated administration. The bioavailability of RSPI was increased by ~ 11% as measured by AUClast compared with Pariet® after a single oral administration.

Samples in the pseudoternary lead-free piezoelectric ceramic system 0.94KNN-(0.06 − x)LiSbO3-x(Bi0.5Ag0.5)ZrO3 were prepared using a solid-state reaction technique and their phase transition behavior and electrical properties studied. Results showed that BAZ diffuses into KNN-LS to form a new solid solution, and induces a phase transition from tetragonal to rhombohedral phase with increase of x. At 0.02 ≤ x ≤ 0.03, coexistence of tetragonal and rhombohedral phases is observed, and enhanced piezoelectric properties are achieved in this composition range due to the polymorphic phase transition near room temperature. Doping with (Bi0.5Ag0.5)ZrO3 effectively promotes densification and further enhances the piezoelectric and dielectric properties of of the ceramics. Moreover, the ceramic with x = 0.025 possesses excellent electrical properties of kp = 42.3%, \({d_{33}^{*}}\) = 320 pm/V and d33 = 235 pC/N, tan δ = 0.039, and Tc = 326°C. This result indicates that 0.94KNN-0.035LS-0.025BAZ ceramic is a promising lead-free material for practical applications.

Oxidative stress plays an important role in the pathogenesis of various liver diseases. Safflower yellow B (SYB) has been reported to protect the brain against damage induced by oxidative stress; however, whether SYB can also protect hepatocytes from oxidative stress remains unknown. In the present study, to determine whether pre-treatment with SYB reduces hydrogen peroxide (H2O2)‑induced oxidative stress in HepG2 cells, we investigated H2O2-induced oxidative damage to HepG2 cells treated with or without SYB. Cell viability was measured by MTT assay and cytotoxicity was evaluated by lactate dehydrogenase (LDH) assay. The activities of the antioxidant enzymes, glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were determined using respective kits. Intracellular reactive oxygen species (ROS) accumulation in the HepG2 cells was monitored using the fluorescent marker, 2',7'-dichlorodihydrofluorescein diacetate (H2DCF-DA). Cell apoptosis was evaluated by determining the activity of caspase-3 and by Annexin V/propidium iodide (PI) double staining. Protein expression levels were measured by western blot analysis, and the levels of related cellular kinases were also determined. H2O2 induced pronounced injury to the HepG2 cells, as evidenced by increased levels of malondialdehyde (MDA) and ROS, the decreased activity of SOD and GSH-Px, the increased activitation of caspase-3 and cell apoptosis, and the loss of mitochondrial membrane potential. SYB significantly inhibited the damaging effects of H2O2, indicating that it protected the cells against H2O2-induced oxidative damage. Moreover, pre-treatment with SYB increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1) and NAD(P)H dehydrogenase, quinone 1 (NQO1) which are peroxiredoxins. SYB also significantly increased the phosphorylation of AKT. However, this inductive effect was blunted in the presence of the AKT inhibitor, LY294002. The findings of our study suggest that the activation of the AKT/Nrf2 pathway is involved in the cytoprotective effects of SYB against oxidative stress. Our findings provide new insight into the cytoprotective effects of SYB and the possible mechanisms underlying these effects. Thus, SYB may prove to be of therapeutic value for the treatment of various liver diseases.

This paper presents a 320-GHz 1 $\times$ 4 fully integrated phased array transmitter using 0.13- $\mu$ m SiGe BiCMOS technology. The 1 $\times$ 4 array transmitter is aiming for terahertz wireless communication and is based on RF beam forming architecture. By integrating a 20-GHz phase-locked-loop (PLL) frequency synthesizer, an 80-GHz quadrupler, a 1:4 Wilkinson power divider network, four-way 80-GHz tunable attenuators, amplifiers, analog phase shifters, 320-GHz frequency quadruplers/modulators, and on-chip antenna arrays, the transmitter chip achieves a maximal EIRP of 10.6 dBm at 320 GHz with the 3-dB bandwidth of 20 GHz, and ${\pm} {\hbox{12}}^{\circ}$ beam scanning range is obtained. The dc consumption of the whole chip is ${\sim} $ 1000 mW and the total chip size is 8 $\times$ 4.3 mm $^{2}$ .

The aim of this study is to investigate a food effect on the single-dose pharmacokinetics and tolerability of subutinib maleate capsules in healthy Chinese volunteers. The author evaluated the effect of being under a fasting or fed state at the time of drug intake on the single-dose of subutinib maleate capsules in a randomized, balanced, single-dose, 2-treatment (fasting and fed), 2-period design with a 3-week washout period. The end points were the maximum plasma drug concentration (Cmax) and areas under the plasma-concentration curve (AUC) for 336 h exposure (AUC0-336) and total exposure (AUC0-∞). All volunteers completed the whole study without side effects being observed. For subutinib, Cmax were 6.13 and 5.04 ng·mL(-1), and AUC0-336 were 278.4 and 304.5 h·ng·mL(-1) in the fasting and the fed state, respectively. For active metabolite, Cmax were 0.90 and 0.61 ng·mL(-1), and AUC0-336 were 65.5 and 56.4 h·ng·mL(-1) in the fasting and the fed state, respectively. The authors showed that food intake was associated with a slight increase in AUC values but decrease in Cmax of subutinib, and it was associated with a decrease both in AUC and Cmax of active metabolite.

Purpose Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA) are the two commonest forms of hereditary optic neuropathy. The aim of this study was to comprehensively investigate the incidence and spectrum of mutations in patients with suspected hereditary optic neuropathy by combining mitochondrial DNA (mtDNA) genome-wide and targeted exon sequencing. Methods A cohort of 1101 subjects were recruited to participate in the study, comprising 177 families (177 probands and their family members, a total of 537 subjects, including 254 patients) and 164 sporadic cases with suspected hereditary optic neuropathy, and 400 unrelated control subjects for genetic analysis: all subjects (including control subjects) underwent a comprehensive ophthalmologic examination and were subjected to sequencing analysis of mtDNA genome-wide and targeted exon. Overall, targeted exon sequencing was used to screen 792 genes associated with common hereditary eye diseases, and the mtDNA genome-wide were screened by next-generation sequencing. Results We found variants detected in 168 (40.2%, 168/418) of the 418 patients screened. Among these, 132 cases (78.6%, 132/168) were detected with known LHON disease-causing mtDNA variants; 40 cases (23.8%, 40/168) were detected with nuclear DNA (ntDNA) variants, which included 36 cases (21.4%, 36/168) with detected OPA1 mutations, 4 patients (2.4%, 4/168) with detected OPA3 mutations, and 2 patients (1.2%, 2/168) with detected TMEM126A homozygous mutation. Coexistence variation (mtDNA/mtDNA [n = 16], ntDNA/ntDNA [n = 4], mtDNA/ntDNA [n = 7]) was found in 27 patients (16.4%, 27/165), including mtDNA/ntDNA coexistence variation that was detected in seven patients. Among these ntDNA mutations, 38 distinct disease-causing variants, including autosomal recessive heterozygous mutations, were detected, which included 22 novel variants and two de novo variants. Total haplogroup distribution showed that 34.5% (29/84) and 28.6% (24/84) of the affected subjects with m.11778G>A belonged to haplogroup D and M, with a high frequency of subhaplogroups D4, D5, and M7. Conclusions The LHON-mtDNA mutations are the commonest genetic defects in this Chinese cohort, followed by the OPA1 mutations. To our knowledge, this is the first comprehensive study of LHON, ADOA, and autosomal recessive optic atrophy combined with mtDNA genome-wide and targeted exon sequencing, as well as haplogroup analysis, in a large cohort of Chinese patients with suspected hereditary optic neuropathy. Our findings provide a powerful basis for genetic counseling in patients with suspected hereditary optic neuropathy. Translational Relevance We applied mtDNA genome-wide sequencing combined with panel-based targeted exon sequencing to explore the pathogenic variation spectrum and genetic characteristics of patients with suspected hereditary optic neuropathy, providing a comprehensive research strategy for clinical assistant diagnosis, treatment, and genetic counseling.

The Jiangnan orogenic belt hosts many rare-metal deposits that exhibit close ore-forming ages and similar geological backgrounds and is an important Li–Be–Nb–Ta concentration belt located in eastern China. However, the metallogenic mechanism and regularity of these rare-metal deposits have not yet been reported in detail because of the lack of accurate geochronological data and systematic studies on the sources of metallogenic materials. The giant Renli rare-metal deposit, located at the south margin of the Mufushan batholith in the central Jiangnan orogenic belt, is one of the few high-grade granitic-pegmatite-type Nb–Ta deposits in China. Columbite–tantalite U–Pb dating has been developed as a more robust method when compared with the traditional dating methods to constrain the timing of rare-metal mineralization. Six columbite grains, obtained from the microcline–albite pegmatite of the Renli deposit, exhibit a concordant laser ablation inductively coupled plasma mass spectrometry (LA–ICP–MS) U–Pb age of 133.0 ± 2.6 Ma, which denotes the Nb–Ta mineralization age. The zircon grains from the columbite-bearing microcline–albite pegmatite subjected to different degrees of alteration by the hydrothermal fluids yield a concordant LA–ICP–MS U–Pb age of 131.2 ± 2.4 Ma, which can be considered to be the age of newly magmatic–hydrothermal growth and recrystallization under the transitional magmatic–hydrothermal conditions observed in case of the Renli deposit. Furthermore, the zircon grains from the host biotite monzogranite yield concordant LA–ICP–MS U–Pb ages of 140.7 ± 0.7 and 140.3 ± 0.7 Ma, whereas the zircon grains from the host two-mica monzogranite yield a concordant LA–ICP–MS U–Pb age of 138.3 ± 0.3 Ma, denoting the intrusion timing of two types of host Mufushan granites of the pegmatite dykes. Finally, the zircon grains from two schist samples of the Lengjiaxi Group yield concordant LA–ICP–MS U–Pb ages of 825.9 ± 5.6 and 834.4 ± 5.3 Ma, constraining the maximum age for the termination of deposition. These ages constitute a clear intrusion-cooling-hydrothermal time series with respect to the Renli deposit. Zircon can retain the original magmatic isotopic composition and is extensively used to trace the petrogenetic processes because it is quickly crystallized from magma. The Mufushan granite and rare-metal pegmatite exhibit consistent negative eHf(t) values (mean eHf(t) values of −7.2 and −7.3, respectively), and their two-stage model ages exhibit similar distribution patterns when compared with that exhibited by the Lengjiaxi Group. Furthermore, the Mufushan granite shows the typical geochemical characteristics of the crustal-derived granite. Thus, the rare-metal pegmatite and host granite of the Renli deposit were concluded to be sourced from the partial melting of the Lengjiaxi Group metasedimentary strata. The compressive torsional nature of the Gajiang fault zone, widespread occurrence of the S-type granite, and absence of basaltic rocks suggest that the central-to-eastern part of the Jiangnan orogenic belt was in a subduction setting during the Early Cretaceous. Thus, this economically important Early Cretaceous (ca. 133–129 Ma) rare-metal metallogenic belt was formed owing to the development of the Jiangnan orogenic belt, and the thick Lengjiaxi Group metasedimentary strata provided the metallogenic material source.

By using Raman spectroscopy, hydrogen was detected, together with CH4, N-2, H2O, disordered graphite, and possibly a (CH4)(n)(H-2)(m) compound, in silicate melt inclusions (SMIs) in quartz from Jiajika granite in China. The occurrences of H-2 in fluid or melt inclusions are rarely reported because they are not commonly expected, and also the spectral window above 4000cm(-1) wavenumbers, where the dominant signals of H-2 located, is rarely covered in routine Raman analyses due to limited information of geological interest available in that spectral range. The mechanisms for the occurrence of H-2 in these SMIs are unknown. However, the retention of H-2 in these SMIs was most likely resulted from the low diffusion rate of H-2 in quartz at low temperatures and also the low H-2 gradient between SMIs and their environments surrounding the host minerals. More studies are needed to determine whether the occurrences of H-2 in inclusions in minerals are common in similar or other rock types, to formulate the mechanisms for its entrapment, and to investigate the associated geological processes. Copyright (c) 2015 John Wiley & Sons, Ltd.

Oxidative stress plays an important role in Parkinson’s disease and other neurodegenerative disorders. Lycium barbarum polysaccharides (LBP), the main active ingredients extracted from the fruits of Lycium barbarum L., have been shown to be a potent antioxidant. In the present study, we investigated the protective effects, and the possible mechanism of action of LBP against 6-hydroxydopamine (6-OHDA)-induced apoptosis in PC12 cells. Our data demonstrated that LBP significantly reversed the 6-OHDA-induced decrease in cell viability, prevented 6-OHDA-induced changes in condensed nuclei and decreased the percentage of apoptotic cells in a dose-dependent manner. Furthermore, LBP also slowed the accumulation of reactive oxygen species (ROS) and nitric oxide (NO), decreased the level of protein-bound 3-nitrotyrosine (3-NT) and intracellular free Ca2+, and inhibiting the overexpression of nuclear factor κB (NF-κB), neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS). These results demonstrate that LBP prevents 6-OHDA-induced apoptosis in PC12 cells, at least in part through the ROS-NO pathway.

BiVO4–Bi2O3 p–n heterojunction composites have been prepared via a facile one-step hydrothermal method. X-ray diffraction revealed the as-obtained composites are composed of BiVO4 and Bi2O3 both with monoclinic structures. Subsequently, the photocatalytic activity of composites was evaluated by degradation of Rhodamine B under visible light irradiation. The results indicated that the photocatalytic activity of BiVO4–Bi2O3 composites (BV-1.3) was approximately 3 times higher than that of pure BiVO4. The enhanced photocatalytic property may mainly due to the high separation efficiency of electron–hole pairs caused by the p–n heterojunction.

Telomerase is a ribonucleoprotein enzyme that is necessary for overcoming telomere shortening in human germ and stem cells. Mutations in telomerase or other telomere-maintenance proteins can lead to diseases characterized by depletion of hematopoietic stem cells and bone marrow failure (BMF). Telomerase localization to telomeres requires an interaction with a region on the surface of the telomere-binding protein TPP1 known as the TEL patch. Here, we identify a family with aplastic anemia and other related hematopoietic disorders in which a 1-amino-acid deletion in the TEL patch of TPP1 (ΔK170) segregates with disease. All family members carrying this mutation, but not those with wild-type TPP1, have short telomeres. When introduced into 293T cells, TPP1 with the ΔK170 mutation is able to localize to telomeres but fails to recruit telomerase to telomeres, supporting a causal relationship between this TPP1 mutation and bone marrow disorders. ACD/TPP1 is thus a newly identified telomere-related gene in which mutations cause aplastic anemia and related BMF disorders.

Euodia rutaecarpa is a common traditional Chinese medicine (TCM) in clinical practice, having the ability to suppress pain and cease coughing; however, with the increasing reports showing that it is toxic, particularly hepatotoxic, the concerns raised by what cause its toxicity is growing. In the current study, an analysis method based on the spectrum effect has been employed to screen the major hepatotoxic components in Euodia rutaecarpa so that the toxic material’s basis would be elucidated. A fingerprinting method of the Euodia rutaecarpa extracts (which were petroleum ether, chloroform, ethyl acetate, n-butanol, and water) using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometer (UHPLC-QTOF/MS) has been developed. Orthogonal partial least squares (OPLS) was used to establish the spectrum-toxicity relationship with the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in mice serum as evaluation indices for liver injury. The UHPLC-MS fingerprint was established and the OPLS analytical results suggested that coniferin, 1-methyl-2-undecyl-4(1H)-quinolone, 1-methyl-2-[(6Z,9Z,12E)-pentadeca triene]-4(1H)-quinolone, evocarpine, 1-methyl-2-[(Z)-7-tridecenyl]-4(1H)-quinolone, dihydroevocarpine, and 1-methyl-2-tetradecy-4-(1H)-quinolone probably associated with the hepatotoxicity of Euodia rutaecarpa. This paper offered considerable methods and insight for the fundamental research of the toxic material basis of similar toxic TCMs.

Background Trimethylaminuria (TMAU) is a genetic disorder whereby people cannot convert trimethylamine (TMA) to its oxidized form (TMAO), a process that requires the liver enzyme FMO3. Loss-of-function variants in the FMO3 gene are a known cause of TMAU. In addition to the inability to metabolize TMA precursors like choline, patients often emit a characteristic odor because while TMAO is odorless, TMA has a fishy smell. The Monell Chemical Senses Center is a research institute with a program to evaluate people with odor complaints for TMAU. Methods Here we evaluated ten subjects by (1) odor evaluation by a trained sensory panel, (2) analysis of their urine concentration of TMA relative to TMAO before and after choline ingestion, and (3) whole exome sequencing as well as subsequent variant analysis of all ten samples to investigate the genetics of TMAU. Results While all subjects reported they often emitted a fish-like odor, none had this malodor during sensory evaluation. However, all were impaired in their ability to produce >90% TMAO/TMA in their urine and thus met the criteria for TMAU. To probe for genetic causes, the exome of each subject was sequenced, and variants were filtered by genes with a known (FMO3) or expected effect on TMA metabolism function (other oxidoreductases). We filtered the remaining variants by allele frequency and predicated functional effects. We identified one subject that had a rare loss-of-function FMO3 variant and six with more common decreased-function variants. In other oxidoreductases genes, five subjects had four novel rare single-nucleotide polymorphisms as well as one rare insertion/deletion. Novel in this context means no investigators have previously linked these variants to TMAU although they are in dbSNP. Conclusions Thus, variants in genes other than FMO3 may cause TMAU and the genetic variants identified here serve as a starting point for future studies of impaired TMA metabolism. Electronic supplementary material The online version of this article (doi:10.1186/s12881-017-0369-8) contains supplementary material, which is available to authorized users.

PK parameters of AA C in rats after oral administration of AF and HAF. (DOC 38Â kb)

PK parameters of 7-OH AA I in rats after oral administration of AF and HAF. (DOC 37Â kb)

PK parameters of AA D in rats after oral administration of AF and HAF. (DOC 36Â kb)

Extensive studies of the crystal-rich inclusions (CIs) hosted in minerals in pegmatite have resulted in substantially different models for the formation mechanism of the pegmatite. In order to evaluate these previously proposed formation mechanisms, the total homogenization processes of CIs hosted in spodumene from the Jiajika pegmatite deposit in Sichuan, China, were observed in situ under external H2O pressures in a new type of hydrothermal diamond-anvil cell (HDAC). The CIs in a spodumene chip were loaded in the sample chamber of HDAC with water, such that the CIs were under preset external H2O pressures during heating to avoid possible decrepitation. Our in situ observations showed that the crystals within the CIs were dissolved in carbonic-rich aqueous fluid during heating and that cristobalite was usually the first mineral being dissolved, followed by zabuyelite and silicate minerals until their total dissolution at temperatures between 500 and 720°C. These observations indicated that the minerals within the CIs were daughter minerals crystallized from an entrapped carbonate- and silica-rich aqueous solution and therefore provided useful information for evaluating the formation models of granitic pegmatites.

The mass spectrometry conditions of six compounds. (DOC 31Â kb)

Structures, mass spectrums and proposed main fragmentation pathways of the compounds. (DOCX 269Â kb)

The recoveries and matrix effects of AAs with ethyl acetate extraction. (DOC 38Â kb)

The contents (mg/g) of the five AAs in extract powder of AF and HAF. (DOC 30Â kb)

A 7.7---12 GHz fully monolithic transformer-coupled cascode power amplifier (PA) was designed for X-band phase array radar application. This PA was fabricated in a 0.25-$$\upmu $$μm SiGe BiCMOS technology with chip size of $$2\times 2$$2×2 mm$$^{2}$$2. The best choice of the cascode topology for PA design is discussed and the possible stability issue of this configuration is analyzed. The distributed capacitor structure which is connected to the base of cascode transistor is proposed to reduce the base series inductance and hence, improve circuit stability and boost gain. Moreover, circuit/layout co-design for above structure is completed through full 3D simulation. The PA features a three-stage cascode architecture that includes both medium-speed (medium breakdown voltage) and high breakdown voltage (low-speed) SiGe transistors, and a 1:2 input splitter and a 4:1 output combiner which are designed for a low insertion loss and compact dimensions on-chip. The proposed PA achieves a measured small signal gain of 26.6---29.6 dB from 7.7 to 12 GHz with a 5.0 V DC supply. A 28 dBm maximum output power with an 18.5 % power-added efficiency at 10 GHz have also been achieved.

The homogenization of silicate melt inclusions (SMIs), small droplets of silicate melt trapped in magmatic minerals, is an important component of petrogenetic and magmatic research. Conventional homogenization experiments on SMIs use microscope-mounted heating stages capable of producing high temperatures at 1 atm and cold-seal high-pressure vessels. Heating stages are generally used for SMIs with low internal pressures and allow in situ observations of the homogenization processes. In contrast, cold-seal high-pressure vessels are generally used to heat SMIs that have high internal pressures, although the homogenized SMIs can only be observed after quenching in this approach. Here we outline an alternative approach that uses a hydrothermal diamond anvil cell (HDAC) apparatus to homogenize SMIs. This is the only current method wherein phase changes in high-internal-pressure SMIs can be observed in situ during homogenization experiments, which represents an advantage over other conventional methods. Using an HDAC apparatus prevents high-internal-pressure SMIs from decrepitating during heating by elevating their external pressure, in addition to allowing in situ observations of SMIs. The type-V HDAC that is currently being used has a shorter distance between the sample chamber and the observation window than earlier types, potentially enabling continuous observation of the processes involved in heating and SMI homogenization through an objective lens with a long working distance. Homogenization experiments using HDAC require that a number of steps, including HDAC preparation, sample preparation, sample loading, preheating, and formal heating, be carefully followed. Homogenization experiments on SMIs within granite samples from the Jiajika pegmatite deposit (Sichuan, China) are best performed using an HDAC-based approach, because the elevated proper external pressure of these SMIs, combined with a short heating duration, helps to suppress material leakage and any reactions within the SMIs, in addition to allowing in situ observations during homogenization experiments. Furthermore, using the HDAC approach has other benefits: heating rates can be precisely controlled, wafer oxidization can be prevented, and samples can be subjected to in situ microbeam analysis. In summary, homogenization using HDAC provides more reliable results than those obtained using conventional heating equipment Future developments will include improvements to the quenching method and temperature controls for the HDAC apparatus, thereby improving the utility of this approach for SMI homogenization experiments.

Multidrug-resistant Acinetobacter baumannii becomes an increasing challenge due to the overuse of antibiotics. Combination therapies are considered as effective options to overcome this matter. The present study was to investigate the synergistic activity of meropenem combined with other antibiotics in vitro and in vivo. Checkerboard assay and time-kill assay were performed to study the combination effects in vitro. For the animal model, a murine sepsis model injected with inoculums intraperitoneally was used. Susceptibility test showed that all the twelve strains in this study were resistant to most of the antibiotics except rifampicin. In combination, meropenem plus rifampicin exhibited synergistic activity against six of twelve strains. In the sepsis model, meropenem monotherapy had no therapeutic effect in this model while it can enhance the activity of rifampicin in both survival rate and bacterial clearance from blood. Moreover, combination therapy significantly reduced plasma IL-6 levels compared with rifampicin monotherapy. Pharmacokinetic analysis of rifampicin was also performed in this study. These data above showed that there was synergistic activity between meropenem and rifampicin against multidrug-resistant Acinetobacter baumannii both in vitro and for experimental model of sepsis. It suggested that combining meropenem with rifampicin may be appropriate in treating multidrug-resistant Acinetobacter baumannii infections.

A 5 GHz transformer-feedback power oscillator with novel frequency modulation (FM) up to 10 MHz is presented in this paper. The novel FM is achieved by a CMOS transistor between transformer and ground, which is designed for varying the equivalent inductance and mutual inductance of the transformer and shows no DC connection with the oscillation circuit. The major frequency tuning is realized by the variable capacitor which is controlled by a phase lock loop. The RF VCO with 210 MHz tuning range operates in class-E mode to achieve a cost-effective transmitter, which demonstrates a high DC-to-RF conversion efficiency of 39 %. A RF power of 15.1 dBm and phase noise better than $$-$$ - 109 dBc/Hz @ 100 kHz from the central frequency of 5.5 GHz is obtained with the biasing conditions V $$_\mathrm{ds}$$ ds = 1.8 V and V $$_\mathrm{gs}$$ gs = 0.65 V. The VCO also demonstrates an ultra-low voltage operation capability: with V $$_\mathrm{ds}$$ ds = V $$_\mathrm{gs}$$ gs = 0.6 V and DC power consumption of 9 mW, the output power is 4.5 dBm and the phase noise better than $$-$$ - 93 dBc/Hz @ 100 kHz. The die size of the transformer-feedback power oscillator is only $$0.4\times 0.6$$ 0.4 × 0.6 mm $$^{2}$$ 2 .

In this paper, a 42GHz frequency synthesizer fabricated with 0.13"m SiGe BiCMOS technology is presented, which consists of an integer-N fourth-order type-II phase locked loop (PLL) with a LC tank VCO and a frequency doubler. The core PLL has three-stage current mode logic (CML) and flve stage true single phase clock (TSPC) logic in the frequency divider. Meanwhile, a novel balanced common-base structure is used in the frequency doubler design to widen the bandwidth and improve the fundamental rejection. The doubler shows a 41% fractional 3dB bandwidths with a fundamental rejection better than 25.7dB. The synthesizer has a maximum output power of 0dBm with a DC power consumption of 60mW. The worst phase noise at 100kHz, 1MHz and 10MHz ofiset frequencies from the carrier is i71dBc/Hz, i83dBc/Hz and i102:4dBc/Hz, respectively.

Elemental sulfur, as a transient intermediate compound, by-product, or catalyst, plays significant roles in thermochemical sulfate reduction (TSR) reactions. However, the mechanisms of the reactions in S-H2O-hydrocarbons systems are not clear. To improve our understanding of reaction mechanisms, we conducted a series of experiments between 200 and 340 degrees C for S-H2O-CH4, S-D2O-CH4, and S-CH4-1m ZnBr2 systems in fused silica capillary capsules (FSCCs). After a heating period ranging from 24 to 2160 h (hrs), the quenched samples were analyzed by Raman spectroscopy. Combined with the in situ Raman spectra collected at high temperatures and pressures in the S-H2O and S-H2O-CH4 systems, our results showed that (1) the disproportionation of sulfur in the S-H2O-CH4 system occurred at temperatures above 200 degrees C and produced H2S, SO42-, and possibly trace amount of HSO4-; (2) sulfate (and bisulfate), in the presence of sulfur, can be reduced by methane between 250 and 340 degrees C to produce CO2 and H2S, and these TSR temperatures are much closer to those of the natural system ( 200 degrees C that can be reached by deep drilling for hydrocarbon resources. (C) 2013 Elsevier Ltd. All rights reserved.

The aim of this study is to investigate a food effect on the single-dose pharmacokinetics and tolerability of clinofibrate tablets in 12 Chinese healthy volunteers. The authors evaluated the effect of being under a fasting or fed state at the time of drug intake on the single-dose of clinofibrate 400 mg tablets in a randomized, balanced, single-dose, two-treatment (fed and fasting), two-period, two-sequence study design with a 7-day washout period. The end points were the maximum plasma drug concentration (Cmax) and areas under the plasma-concentration curve (AUC) for 72 hours exposure (AUC0-72) and total exposure (AUC0-∞). All participants completed the whole study without side effects being observed. The Cmax mean of clinofibrate glucuronides and parent clinofibrate were 21.91, 17.85 μ/ml for the fasting state and 13.14, 11.25 μ/ml for the fed state, respectively. The AUC0-72 and AUC0-∞ of clinofibrate glucuronides and parent clinofibrate were 381.60, 307.07 μ/ ml and 404.55, 342.24 μ/ml for the fasting state and 379.02, 321.14 μ/ml and 432.24, 351.80 μ/ml for the fed state. The authors showed that food intake was associated with a significant decrease in Cmax, but no significant change in AUC values.

Measurement uncertainty although introduced to medical laboratories some years ago, this concept is not familiar to all medical researchers, especially for the measurement of biological samples. Therefore, it is important to highlight the evaluation and expression of measurement uncertainty using a practical example. In accordance with published procedures for evaluating and expressing uncertainty, we analyzed the sources of uncertainty in the determination of repaglinide in human plasma using liquid chromatography–tandem mass spectrometry (LC–MS/MS). We investigated each component of uncertainty and calculated the combined and expanded uncertainties. We evaluated the uncertainty associated with repeatability, weighing, purity, solution and sample preparation, recovery, calibration fitting, and temperature. The expanded uncertainty for low, medium, and high concentrations of repaglinide was 0.090, 0.25, and 3.16 ng/mL, respectively (p = 95 %, k = 2). This example provides an important reference for the evaluation of uncertainty in biological sample determinations using LC–MS/MS and human plasma and will be helpful in explaining the reliability of test results.