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You may want to exclude those generated files from the analysis : see documentation about this : http://docs.sonarqube.org/display/SONAR/Narrowing+the+Focus
Its working.


1. Introduction {#sec1-molecules-24-00021}
===============

Curculiginis rhizoma, the dried rhizome of *Curculigo orchioides* Gaertn, is rich in phenolic glycosides \[[@B1-molecules-24-00021],[@B2-molecules-24-00021]\]. Among the phenolic glycosides, curculigosides have been demonstrated to be the major components responsible for the pharmacological effects of Curculiginis rhizoma \[[@B3-molecules-24-00021],[@B4-molecules-24-00021],[@B5-molecules-24-00021],[@B6-molecules-24-00021]\]. Several curculigosides have been isolated from Curculiginis rhizoma so far, such as curculigosides A, -B, -C, -D, -E, -F, -G and -H \[[@B7-molecules-24-00021],[@B8-molecules-24-00021],[@B9-molecules-24-00021]\]. Due to its highest content in Curculiginis rhizoma, curculigoside A has been the main curculigoside studied for its pharmacological effects \[[@B10-molecules-24-00021],[@B11-molecules-24-00021],[@B12-molecules-24-00021],[@B13-molecules-24-00021]\] and pharmacokinetic profiles \[[@B14-molecules-24-00021],[@B15-molecules-24-00021]\].

Curculigoside C (CC) is the natural product of C-3′ hydroxylation of curculigoside A \[[@B16-molecules-24-00021]\]. It was reported that CC has better antioxidant and neuroprotective effects that the parent compound \[[@B17-molecules-24-00021],[@B18-molecules-24-00021]\]. For example, in the assay on hydroxyl radicals produced by H~2~O~2~/Fe^2+^, CC exhibited more significant scavenging effects than curculigoside A, and the scavenging effect of CC was comparable with that of pigallocatechin gallate, a known antioxidant \[[@B17-molecules-24-00021]\]. Moreover, in the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay, CC also showed better antioxidant activity than curculigoside A, and had a comparable IC~50~ value to vitamin C, another well-known antioxidant \[[@B18-molecules-24-00021]\]. Furthermore, in the evaluation of salvaging SY5Y cell death induced by H~2~O~2~, CC displayed better neuroprotective effect than curculigoside A \[[@B18-molecules-24-00021]\]. The discussion about the structure- activity relationship showed that the presence of OH at C-3′ and the two vicinal oxygen-bearing groups at the benzene ring might be the functional groups \[[@B18-molecules-24-00021]\].

It is known that the pharmacokinetic parameters are necessary for the evaluation of active ingredients \[[@B19-molecules-24-00021],[@B20-molecules-24-00021]\]. To the best of our knowledge, there are no reports on pharmacokinetic assays of CC. In the present research, CC was used for pharmacokinetic and metabolism studies. Due to the high sensitivity and rapid quantification \[[@B21-molecules-24-00021],[@B22-molecules-24-00021]\], an ultra-high performance liquid chromatography combined with tandem quadrupole mass spectrometry (UPLC-MS/MS) method was developed and validated for the determination of CC in rat plasma. This method was then applied to pharmacokinetic study of CC in rats. In addition, the metabolic characteristics of CC were also studied to elucidate the dynamic process of CC in rats. The aims were to investigate the pharmacokinetics and metabolic characteristics of CC with a hydroxyl group at C-3′. In summary, this exploration provides a sensitive quantitative assay method and illustrated the pharmacokinetic characteristics of CC in rats.

2. Results {#sec2-molecules-24-00021}
==========

2.1. Pharmacokinetic Study {#sec2dot1-molecules-24-00021}
--------------------------

### 2.1.1. Method Development {#sec2dot1dot1-molecules-24-00021}

Aiming at increasing the extraction recovery and minimizing the matrix effect, different sample pre-treatment methods such as solid-phase extraction, liquid-liquid extraction, or protein precipitation were comparatively investigated. As a consequence, the optimized one-step protein precipitation using methanol was selected. Several additions were tested to improve the sensitivity of the CC and curculigoside B (IS), 0.1% formic acid was chosen. No significant signal diminution or enhancement was found under the current conditions used in this research. The IS has a similar structure, chromatographic behavior and extraction efficiency to those of CC and both of them showed strong mass responses in positive ESI mode. ESI^+^ showed that CC (MW: 482.1) and IS (MW: 452.1) formed predominately molecular ions \[M + Na\]^+^ at *m*/*z* 505.1 and mainly deprotonated molecular ions \[M + H\]^+^ at *m*/*z* 453.1 in full-scan product ion spectra, respectively. Precursor ion and product ions were selected according to the stability and ion response. Mass spectrometric scanning was operated on multiple reaction monitoring (MRM) using follow monitored transitions: *m*/*z* 505.1 → 221.0 for CC, *m*/*z* 453.1 → 291.1 for IS, respectively. The f ragmentation pathways of CC and the IS are shown in [Figure 1](#molecules-24-00021-f001){ref-type="fig"}.

### 2.1.2. Method Validation {#sec2dot1dot2-molecules-24-00021}

The detection of CC (RT, 0.98 min) and IS (RT, 1.44 min) showed high selectivity. No significant interference of endogenous plasma components was observed at the retention time of CC and the IS. Typical chromatograms of blank plasma (A), blank plasma spiked with CC at 100 ng/mL and IS at 100 ng/mL (B), and plasma sample collected from a rat at 0.083 h after an oral dose of 60 mg/kg CCwere shown in [Figure 2](#molecules-24-00021-f002){ref-type="fig"}.

The calibration curve of CC in rat plasma indicated a high linearity in the range of 1--2500 ng/mL with a correlation coefficient greater than 0.99 (*r*^2^ = 0.9984). There was no significant carry-over under the assay conditions. The LLOQ was 1 ng/mL, which was sufficient for the detection of CC in pharmacokinetic study. The intra-day and inter-day precision (RSD, %) ranged from 4.10% to 5.51% and 5.24% to 6.81%, respectively. The intra-day and inter-day accuracy (RE, %) ranged from −3.28% to 0.56% and −5.83% to −1.44%, respectively ([Table 1](#molecules-24-00021-t001){ref-type="table"}). The variation of the IS measured value was less than 10%.

The best extraction recovery of CC was obtained using methanol as the protein-precipitating agent. The recoveries of CC at 3, 200 and 2000 ng/mL were 95.22 ± 5.64%, 92.82 ± 8.74% and 92.14 ± 3.45%, respectively. The recovery of the IS was 94.40 ± 4.23%. The results showed that the preparation efficiency of CC and IS in this present study was acceptable.

The matrix effect for CC was evaluated by analyzing three concentrations of QC plasma samples (3, 200, 2000 ng/mL). While the matrix effect for IS was evaluated with a single concentration (100 ng/mL). The average matrix effect values were 94.80 ± 4.06%, 91.49 ± 6.68% and 91.73 ± 3.67% for CC at the low, medium and high QC concentrations, respectively. The matrix effect on IS turned out to be 92.94 ± 5.91% at the tested concentration.

After being placed at 25 °C for 4 h or at −20 °C for two weeks, or undergoing three freeze-thaw (−20 °C to 25 °C) cycles, the results of stability ([Table 2](#molecules-24-00021-t002){ref-type="table"}) demonstrated that CC was stable.

### 2.1.3. Pharmacokinetic Study {#sec2dot1dot3-molecules-24-00021}

The developed approach was successfully applied to our pharmacokinetic studies after oral administration of 15, 30, 60 mg/kg or intravenous injection of 2.0 mg/kg CC in rats (*n* = 6), respectively. All of the data were calculated with the DAS 3.0. statistical software (Shanghai Bojia Pharmatech Co. Ltd., Shanghai, China). The mean plasma concentration versus time curves and the major pharmacokinetic parameters were shown in [Figure 3](#molecules-24-00021-f003){ref-type="fig"} and [Table 3](#molecules-24-00021-t003){ref-type="table"}, respectively. It could be concluded that CC was quickly cleared (clearance, *CL*, 4.87 ± 0.83 L/h/kg; elimination half-life, *t*~1/2~, 1.15 ± 0.20 h) and had high extravascular distribution (apparent volume of distribution, *V~d~*, 8.12 ± 1.97 L/kg) after intravenous administration. As for the three doses of CC after oral administration, the absorption rate of CC was also ultrafast as demonstrated by the fact that CC was detected in plasma at the first blood sampling time (0.05 h) and reached the maximum concentration at 0.083 h. On the other hand, it was concluded that CC was also eliminated rapidly with the *t*~1/2~ from 2.02 h to 2.06 h and *CL* in the range of 201.90--234.19 L/h/kg through the gastrointestinal tract. Whereas the parameter of *V~d~* in the range of 585.34--722.61 L/kg inferred that CC distributed in tissues extensively after gastrointestinal administration. The higher *CL* values and the rapid *T~max~* demonstrated that the oral absorption of CC was poor. Furthermore, the poor absorption as well as the first pass metabolism led to the low AUC values and the poor oral bioavailability (F, 2.01%, 2.13%, and 2.39%, respectively). These observations suggested that this validated analytical LC-MS/MS method was suitable and sufficient for pharmacokinetic study of CC. In short, the characteristic pharmacokinetic properties of CC were rapid oral absorption, high clearance and poor absolute bioavailability. And the short *t*~1/2~ revealed that CC was easily metabolized in vivo. The above characteristics are similar to those of most of the phenolic glycosides reported in the literature \[[@B14-molecules-24-00021]\].

### 2.1.4. Metabolites Identification of CC {#sec2dot1dot4-molecules-24-00021}

For the determination of fragmentation patterns, the reference compounds of CC were applied for the main MS/MS fragments in UPLC-QTOF-MSE. As [Table 4](#molecules-24-00021-t004){ref-type="table"} shows, CC generated a protonated ion \[M + Na\]^+^ at *m*/*z* 505.1316 and \[M + H\]^+^ at *m*/*z* 483.1492 and few fragment ions at *m*/*z* 321.1053, 303.0952, 261.0605, 220.9952, 181.0598, 123.1042. The fragment ion at *m*/*z* 321.1053 was produced by the cleavage of the C1″-O bond. By the cleavage of C2-O bond (losing a glucose residue), the fragment ion at *m*/*z* 303.0952 was produced, while the ion at *m*/*z* 261.0605 was attributed to the further loss of a methoxyl and a methyl residue. The fragment ions at *m*/*z* 220.9952 and *m*/*z* 181.0598, both containing the B ring, were produced by the cleavage of the C7-O bond and the cleavage of the C7′-O ester bond, respectively. The last fragment ion at *m*/*z* 123.1042, containing the A ring, was produced by the cleavage of the C1″-O bond and C7-O bond.

In the UPLC elution, the retention time of CC was 6.80 min, and the molecular ion in the mass spectrum is *m*/*z* 505.1316. Samples of CC-dosed plasma, bile, urine and feces were analyzed in parallel with blank controls through the UPLC-Q/TOF-MS method. Despite the lack of standards for metabolites, their structures could be evaluated on the basis of retention times and mass spectrometry patterns between CC and its product ions.

Based on certain rules, mass accuracy (±5 ppm), nitrogen rule, isotopic pattern, and double-bond equivalents for instance, the most likely molecular formulas of metabolites were examined. Moreover, according to the MS/MS fragmentation, the tentative chemical structures were determined and common metabolic pathways were profiled. Twelve metabolites including seven phase I metabolites and five phase II metabolites are shown in [Figure 4](#molecules-24-00021-f004){ref-type="fig"}.

The structures of metabolites were determined and are summarized as follows:

#### Phase I Metabolites

**M3** (C~9~H~10~O~5~), with a retention time of 6.27 min, showed a protonated \[M + Na\]^+^ ion at *m*/*z* 221.0415, 261 Da lower than that of CC. In addition, the MS fragmentation patterns were analogous to those of the reference substance 3-hydroxy-2,6-dimethoxybenzoic acid, with characteristic fragment ions at *m*/*z* 181.0536, 123.0056, 167.9961, 170.0025. The fragment ion at *m*/*z* 181.0536 was produced by the cleavage of the C7′-OH bond. The ion at *m*/*z* 167.9961 was attributed to the loss of two methyl residues. By the cleavage of C2′-O bond (losing a methoxyl residue) and C1′-C7′, the fragment ion at *m*/*z* 123.0056 was produced. Hence, **M3** was identified as 3-hydroxy-2,6-dimethoxybenzoic acid, the hydrolysis metabolite of CC.

**M1** was eluted at 4.05 min and presented an accurate protonated ion \[M + H\]^+^ at *m*/*z* 181.0495 (C~9~H~8~O~4~), 18 Da less than that of **M3**, suggested that **M1** was a dehydration product of **M3**. There were two fragment ions at *m*/*z* 123.0114 and 132.0217 of **M1**. The fragment ion at *m*/*z* 123.0114 was probably produced by loss of a methyl residue and by the cleavage of C1′-C7′, while the fragment ion at *m*/*z* 132.0217 was attributed to the loss of two methyl residues and removal of one molecule of H~2~O from **M1**.

The molecular \[M + Na\]^+^ ion of **M6** (C~16~H~16~O~7~) was at *m*/*z* 343.0775, 162 Da (Glu) lower than CC, which implies that it was the deglycosylation metabolite of CC. The fragment ions at 123.0328, 181.0326, 220.8950 of **M6** were similar to those of CC. Therefore, **M6** was identified as the aglycone of CC, the hydrolysis metabolite of CC removing a glucose group.

Compound **M4** (C~16~H~14~O~6~), which was of high abundance, gave a \[M + H\]^+^ molecular ion at *m*/*z* 303.0872 with a retention time of 7.66 min, 18 Da less than **M6**, implying that **M4** could be the result of **M6** losing a molecule of H~2~O. **M4** shared a fragment ion at *m*/*z* 181.0425 similar to CC. Hence, **M4** was identified as the deglycosylation and dehydration product of CC. Another fragment at *m*/*z* 106.0411 containing ring A, was produced by the cleavage of C~2~-O and C~7~-O bond.

**M7** (RT = 14.93 min) gave a \[M + H\]^+^ molecular ion at *m*/*z* 447.1297 with the formula C~22~H~22~O~10~, which was 36 Da lower than CC. Moreover, the fragment ion at *m*/*z* 267.0531 of **M7** was 36 Da lower than the fragment ion at *m*/*z* 303.0952 of CC. This observation suggests that the metabolite is a dehydration metabolite. Combined with the information of **M5**, it indicated that the dehydration occurred at the parent nucleus. Hence, **M7** was identified as the product of CC losing two molecules of H~2~O. The fragment ion at *m*/*z* 223.0606 of **M7** was produced by the cleavage of the C2-O bond with further loss of one methoxyl group and one methyl group.

The metabolite denoted by **M5** (C~16~H~12~O~5~) had an accurate mass of *m*/*z* 285.0769 with a \[M + H\]^+^ ion at a retention time of 9.51 min. These were 162 Da (Glu) lower than **M7**, implying that **M5** is the deglycosylation product of **M7**. In the other hand, it was 18 Da lower than **M4**. The other main fragment ions are at *m*/*z* 257.0453, 105.0336 and 164.9847. Therefore, **M5** was also identified as the a deglycosylation and dehydration metabolite of CC. The fragment ion at *m*/*z* 105.0336 was produced by the cleavage of the C7-O bond of **M5.** The fragment ion at *m*/*z* 164.9847 was produced by the cleavage of the C7′-O ester bond of **M5.** The fragment ion at *m*/*z* 257.0453 was produced by lossing two methyl residues of **M5**.

M9 gave a \[M + Na\]^+^ molecular ion at *m*/*z* 503.1174 with the formula C~22~H~24~O~12~, detected at a retention time of 18.47 min. **M9** was 2 Da lower than CC, which indicated that desaturation of CC had occurred. The fragment ion at *m*/*z* 450.0755, was produced by loss of one methoxyl of **M9**. While the fragment ion at *m*/*z* 463.1024 was produced from **M9** by loss of one H~2~O.

#### Phase II Metabolites

The protonated metabolite **M12** at *m*/*z* 585.0892 (\[M + Na\]^+^) eluted at 26.88 min, with a molecular formula C~22~H~26~O~15~S, 80 Da more than that of CC, which implied that sulfation of CC had occurred. The fragment ions at *m*/*z* 303.0779 and *m*/*z* 320.0425 were similar to the fragment ions of CC, which suggested that the sulfation occurred on the glucose group. The actual sulfation position may be further confirmed by the fragment ions at *m*/*z* 259.0245 and *m*/*z* 243.0094. The fragment ions at *m*/*z* 209.0086 might be produced by the cleavage of C7-C1 bond.

**M10** gave a \[M + Na\]^+^ molecular ion at *m*/*z* 667.1838 with the formula C~28~H~36~O~17~, and was detected at a retention time of 22.41 min. 162 Da (glu) higher than CC, so **M10** should be the glucosylation product of CC. The mass of the fragment at *m*/*z* 465.1102 was 162 Da higher than the characteristic fragment (*m*/*z* 303.0952) of CC, which could be confirmed that glucosylation happened on the parent nucleus.

**M8** eluted at 15.72 min with a \[M + Na\]^+^ ion at *m*/*z* 639.1541 (C~26~H~32~O~17~), 28 Da lower than that of **M10**, suggesting demethylation had happened in this metabolite. One of the fragments in the MS^2^ spectrum was a \[M + Na\]^+^ ion at *m*/*z* 437.0844, which was 28 Da less than the fragment at *m*/*z* 465.1102 of **M10**. This observation indicated that the demethylation could occur at the two methyl groups on the ring B of parent nucleus in the combined analysis. The fragment ion at *m*/*z* 179.0473 was the glucose group produced by the cleavage of the C2 bond.

**M2** was eluted at 4.25 min with a \[M + Na\]^+^ ion at *m*/*z* 430.0921 (C~19~H~21~NO~7~S). The fragment ions included *m*/*z* 303.0899, 323.0102, 220.0795, indicating that the cysteine conjugation on ring B might occur. The Na adduct ion of the fragment ion at *m*/*z* 323.0102 was produced by C7-O bond cleavage. The other Na adduct ion of the fragment ion at *m*/*z* 220.0795 was produced by the cleavage of the C7-O bond and the cleavage of the ester bond at C3′, while the fragment ion at *m*/*z* 323.0102 was produced by the cleavage of ester bond at C3′ of **M2**. Thus, **M2** was identified as the deglycosylation and cysteine conjugation metabolite.

The measured \[M + H\]^+^ *m*/*z* of **M11** was 511.1465, eluted at 22.92 min with a molecular formula C~23~H~26~O~13~, 28 Da higher than CC, which indicated that it was a formylated product of CC. Abundant daughter ions at *m*/*z* 331.0715 in the MS^2^ spectrum, which were 28 Da higher than the fragment ion at *m*/*z* 303.0952 of CC, support the notion that decarboxylation had occured to the parent nucleus. The fragment ion at *m*/*z* 331.0715 was conjectured to be the formylated product of the typical fragment of CC at *m*/*z* 303.0952.

In conclusion, an effective strategy using UPLC-Q-TOF-MSE coupled with the UNIFI 1.7.0 software (Waters, Manchester, UK) for quick characterising and identificating metabolites of CC was developed. In our study, the pathways of Phase I metabolites included dehydration, hydrolysis, deglycosylation, desaturation, and for Phase II metabolites they were sulfation, glucosylation, cysteine conjugation, formylation, demethylation. These results could provide a theoretical foundation for understanding the pharmacological effects and metabolic processes of CC.

3. Discussion {#sec3-molecules-24-00021}
=============

Targeting at exploring the characteristics of the phenolic glycosides, the pharmacokinetics and metabolism of CC were investigated. First of all, a UPLC-MS/MS method with high sensitivity (1 ng/mL) and a short running time (3.5 min), was validated and used for the pharmacokinetic study. Secondly, the pharmacokinetic analysis elucidated that CC was rapidly absorbed and quickly eliminated, which is similar to curculigoside A, but CC showed better bioavailability (2.39%) than that of curculigoside A (0.38%) \[[@B15-molecules-24-00021]\], which might be the reason for the better activity of CC. Finally, the major metabolites of Phase I and Phase II reactions and the proposed metabolic pathways of CC were both profiled. Furthermore, the results of metabolite identification demonstrated that CC was mainly metabolized in the liver, since all metabolites could be found in bile, urine and feces samples. Considering the results acquired in this research, we deduce that the poor oral bioavailability of CC in rats might be related to hepatic microsomes. Since CC acted as an antioxidant, it is worth mentioning the quinone metabolites, which were not identified under the screening conditions used in the samples of healthy rats. The reason might be as follows: in order to obtain the main metabolites with high response and good mass accuracy, the metabolites with worse mass accuracy (out of the range of ±5 ppm) and low response (below 5000) were filtered firstly before the identification of metabolites. During this step, quinones might be filtered due to their low content. In future studies, the model rats with peroxidation injury may be used to investigate possible quinone metabolites. Besides the common pathways of curculigoside A, such as dehydration and deglycosylation, four other metabolic pathways including formylation, desaturation, cysteine conjugation and sulfonation also had been discovered in CC. More importantly, the -OH at C-3′ still existed in all the metabolites, which further confirmed that the -OH at C-3′ might be the functional group of CC, but the low absolute bioavailability might limit its further application. Future studies should focus on structure modification to improve the bioavailability.

4. Experimental {#sec4-molecules-24-00021}
===============

4.1. Materials and Reagents {#sec4dot1-molecules-24-00021}
---------------------------

CC (purity: 99.1%) was isolated from Curculiginis rhizoma in our laboratory and identified by HR-MS and Nuclear Magnetic Resonance (NMR) spectroscopy. Its purity was determined by using high performance liquid chromatography (HPLC). Internal standard (IS, Curculigoside B) was provided by Wuhan Tian Zhi Biotechnology Co., Ltd. (Hubei, China). 3-Hydroxy-2,6-dimethoxybenzoic acid was obtained from HE Chemical Co., Ltd. (Jiangsu, China). The chemical structures of CC and Curculigoside B are shown in [Figure 5](#molecules-24-00021-f005){ref-type="fig"}. UPLC-MS pure grade methanol and acetonitrile were purchased from Fisher (Geel, Belgium). Formic acid was acquired from the Sigma-Aldrich Company (St. Louis, MI, USA). Deionized water was purified with a Millipore water purification system (Millipore, Billerica, MA, USA). All other chemicals were of analytical grade. Blank rat plasma samples (drug-free and anti-coagulated with heparin sodium) were prepared by our group.

4.2. Animals and Drug Administration {#sec4dot2-molecules-24-00021}
------------------------------------

All animal experiments were approved (permit number: 20180057) by the Review Committee of Animal Care and Use of Jilin University according to ethical principles for animal use and care. Wistar rats (200 ± 20 g) were purchased from Changchun Yisi Laboratory Animal Co. Ltd. (Changchun, China), and were housed under standard conditions in a controlled breeding room (12 h light/dark cycle, temperature: 22 ± 2 °C, relative humidity: 55 ± 5%). All rats were fed with standard laboratory food and water *ad libitum*, except during a fast period prior to the experiments. For the pharmacokinetic study, the rats were divided into four groups (*n* = 6, 3 males and 3 females): (1) CC (15 mg/kg, i.g.), (2) CC (30 mg/kg, i.g.), (3) CC (60 mg/kg, i.g.) and (4) CC (2.0 mg/kg, i.v.). While for the metabolism study, CC (60 mg/kg, i.g.) was gastrointestinally administrated to achieve higher concentrations of the metabolites.

4.3. Sample Preparation {#sec4dot3-molecules-24-00021}
-----------------------

### 4.3.1. Pharmacokinetic Study {#sec4dot3dot1-molecules-24-00021}

The stock solution of CC and IS was prepared by dissolving the accurately weighed reference compound in methanol at 1.00 mg/mL, respectively. The blank rat plasma was prepared as follows: blood samples were collected from the abdominal aorta immediately and incubated at 37 °C for half an hour, then a 15 min centrifugation at 4000 rpm was carried out to separate the plasma, the supernatant was kept at −20 °C until analysis. After dilutions were spiked with blank rat plasma, the calibration curve for CC was plotted to produce the points equivalent to 1, 2.5, 5, 25, 50, 250, 500, 2500 ng/mL. With the same treatment as calibration standards, 3, 200 and 2000 ng/mL of quality control (QC) samples were prepared independently. All samples were prepared freshly before analysis.

The whole blood (150 μL) from the orbital venous plexus was collected into heparinized microcentrifuge tubes at 0.05, 0.083, 0.167, 0.333, 0.5, 1, 2, 4, 6, 8 h after gastrointestinal administration, and 0.017, 0.05, 0.083, 0.167, 0.333, 0.5, 1, 2, 4, 6 h after intravenous administration. After a 15 min centrifugation step at 4000 rpm and 4 °C of the blood collected, plasma was obtained.

All samples were kept at −20 °C before analysis. Frozen plasma samples were thawed to room temperature and vortexed. CC was extracted from plasma only by single step precipitation method. Both 50 μL of each rat plasma sample and 500 μL of methanol containing 100 ng/mL IS were transferred into 2.0 mL microcentrifuge tubes, and then extracted by vortexing for 3 min to deproteinize the endogenous protein. After a 10 min centrifugation step at 10,000 rpm and 4 °C, the supernatant was collected and transferred into vials, and 2 μL of it was injected into UPLC-MS system for quantification. All prepared samples were stored in the autosampler at 10 °C until injection.

### 4.3.2. Metabolism Study {#sec4dot3dot2-molecules-24-00021}

After intragastric administration, blood samples were collected at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 6, 12 h. After vortexing 500 μL of pooled plasma sample with 2 mL of methanol, the mixtures were centrifuged at 10,000 rpm and 4 °C for 10 min to obtain the clear supernatant, which was evaporated with N~2~. Then, the residue was reconstituted in 100 μL of methanol.

To obtain bile samples, a plastic cannula was surgically inserted into the bile ducts to collect the bile through an abdominal incision made after rats were anesthetized with intraperitoneal injection of urethane (1.0 g/kg). Blank bile was collected for 2 h before dosed, and bile samples were collected for 12 h after administration. While the blank and dosed samples of urine and feces were obtained respectively with metabolic cages equipped with separator prior to drug administration or 18 h after oral administration. The mixture was centrifuged for 10 min at 10,000 rpm and 4 °C after diluting pooled urine and bile sample with triple volume of methanol. The obtained supernatant was evaporated by N~2~ at room temperature after transferred into another tube. The dried residue of urine or bile was dissolved in 50 μL of methonal, respectively. Finally, the supernatant being centrifuged for 10 min at 10,000 rpm and 4 min was applied to UPLC-MS/MS analysis.

Faeces samples were dried and crushed into powder before being stored. Each 10 mg of faeces powder was added with 1 mL of methanol and was extracted for 30 min using an ultrasonic ice-water bath. After centrifugation at 10,000 rpm and 4 °C for 10 min, the supernatant was transferred to a clean tube and then evaporated to dryness under a stream of N~2~. The residue reconstituted with 500 μL methanol was centrifuged at 10,000 rpm and 4 °C for 10 min. All biological samples were stored at −20 °C.

4.4. Instruments and Experimental Conditions {#sec4dot4-molecules-24-00021}
--------------------------------------------

### 4.4.1. LC-MS/MS Conditions {#sec4dot4dot1-molecules-24-00021}

Quantification of CC was performed on an Acquity UPLC unit coupled with a XEVO TQ-S mass spectrometer equipped with an electrospray ionization (ESI) source (Waters Co.). Separation was achieved using a Waters BEH C18 UPLC column (2.1 mm × 50 mm, 1.7 μm) at 40 °C. The optimized method used binary gradient mobile phases with 0.1% formic acid in acetonitrile as mobile phase A and 0.1% formic aqueous solution as mobile phase B (0--2 min, 20% → 30% A; 2--2.5 min, 30% → 20% A; 2.5--3.5 min, 20% A). A flow rate of 0.3 mL/min was used with 2 μL of injection volume. Chromatography of the CC and IS was performed within 3.5 min. CC was quantified using multiple reaction monitoring (MRM) in the positive ESI mode and the optimized MS parameters were set as follows: capillary voltage floating at 3200 V; 150 °C for source temperature; 300 °C for desolvation temperature; 150 L/h for flow of cone gas; 800 L/h for flow of desolvation gas; 0.15 mL/min for flow of collision gas; nebulizer gas flow at 7 bar; cone voltage at 70 and 48 V for CC and IS, respectively; Collision energy at 20 and 18 eV for CC and IS, respectively. Data acquisition and processing were operated through Masslynx V4.1 workstation.

### 4.4.2. UPLC-QTOF/MS Conditions {#sec4dot4dot2-molecules-24-00021}

Metabolic analysis was conducted on a Waters ACQUITY UPLC System coupled with a Xevo G2-S Q-TOF mass spectrometer in ESI^+^ mode. A Waters UPLC BEH C~18~ column (2.1 mm × 50 mm, 1.7 μm) was used with the following parameter settings: 30 °C for the column temperature; 0.4 mL/min for flow rate; 10 μL for injection volume; 4 °C for the autosampler temperature; and the mobile phase consisted of 0.1% formic aqueous solution (A) and 0.1% formic acid in acetonitrile (B) in proportions adjusted through a gradient elution programme as follows: 0--2 min, 10% B; 2--26 min, 10% → 100% B; 26--28 min, 100% B; 28--28.1 min, 100% → 10% B, 28.1--30 min, 10% B. The following optimized conditions were carried out: 2.6 kV for capillary voltage; 40 V for cone voltage; 120 °C for source temperature; 300 °C for desolvation temperature; 50 L/h for the flow of cone gas; 800 L/h for the flow of desolvation gas. MSE acquisition mode is an intelligent approach, which collects exact-mass precursor and product ion information from a single injection in a data-independent manner. It could parallel alternate scans at either low collision energy to obtain precursor ion information, or high collision energy to obtain full-scan accurate mass fragment, precursor ion and neutral loss information. In doing so, it excludes false positive results; requires no "knowledge" of the ions to be fragmented; runs parallel precursor, product ion, and neutral loss analyses; and streamlines data interrogation and reporting. In MS^E^ mode, the collision energy of low energy function and high energy function was set at 6 V and 20--40 V, respectively. The mass spectrometer was calibrated over a range of 100--1000 Da with sodium formate to ensure mass accuracy. Leucine-enkephalin (*m*/*z* 556.2771) was used as the lockmass at a concentration of 200 ng/mL and flow rate of 10 μL/min. Masslynx V4.1 workstation in continuum mode was used for data collection. Metabolic characterization of CC was analyzed using UNIFI 1.7.0 software (Waters, Manchester, UK).

4.5. Method Validation {#sec4dot5-molecules-24-00021}
----------------------

According to the Bioanalytical Method Validation Guideline (Chinese Pharmacopoeia 2015, Vol. 4) and Drug Non-Clinical Pharmacokinetic Study Technical Guideline (China Food And Drug Administration 2014), specificity, accuracy and precision, linearity, LLOQ, extraction recovery and matrix effect had been validated in this present study.

Specificity was investigated by analyzing chromatograms of blank rat plasma, plasma spiked with CC and IS, and experimental plasma sample following dosing of CC. Linearity was analyzed through weighted regression (1/*x*^2^) of peak area ratios (*y*) of CC to IS versus nominal concentration (*x*) in plasma. The blank plasma has been run after the determination of upper concentration (2500 ng/mL) of the standard curve aiming at determine the carry-over in the assay condition. Precision and accuracy were evaluated by analyzing three concentration levels (3, 200 and 2000 ng/mL) of QC samples. The intra-, inter-day precision and accuracy were assessed by determining at three QC levels (3, 200 and 2000 ng/mL) in replicates of six QC samples. The precision was expressed as relative standard deviation (RSD, %) and the accuracy was expressed as relative error (RE, %). Both of the values for QC concentrations within 15% were acceptable. The lowest limit of quantification (LLOQ) was the lowest concentration on calibration curve, with acceptable precision (RSD ≤ 20%) and accuracy (RE ≤ ±20%). The extraction recovery of CC from rat plasma at three QC concentrations was assessed by comparing peak areas of the QC samples pre-spiked in blank plasma (A) with those of post-extracted blank plasma spiked at the same concentration (B). The matrix effect of CC from rat plasma was evaluated by comparing the peak areas of post-extracted spiked rat plasma (B) with those of equivalent concentrations of the pure authentic standard at three QC concentrations (C). The recovery and matrix effect of IS were evaluated at 100 ng/mL in the same way as CC. Stability in plasma samples was investigated by analyzing QC samples (*n* = 6) under various storage conditions: (1) at room temperature for 4 h; (2) at −20 °C for two weeksl; (3) subjected to three complete freeze/thaw cycles (from −20 °C to room temperature) on consecutive days; (4) stored in the stock solutions (4 °C) and in methanol with plastic autosampler vials for 16 h at 10 °C.

4.6. Pharmacokinetic Study {#sec4dot6-molecules-24-00021}
--------------------------

The concentration versus the time curve was plotted. The pharmacokinetic parameters, including the maximum plasma concentration (*C~max~*) and the time to reach the peak concentration (*T~max~*) were obtained in rat plasma after intragastric administration, elimination half-life (*t*~1/2~), area under the plasma concentration--time curve (*AUC*), were analyzed through a non-compartmental pharmacokinetic analysis carried out by Drug and Statistics (DAS) 3.0 pharmacokinetic software programme (Mathematical Pharmacology Professional Committee of China, Shanghai, China). The results were presented as the mean ± standard deviation. Absolute bioavailability (F%) was determined through the equation (AUC~p.o.~ × Dose~i.v.~)/(AUC~i.v.~ × Dose~p.o.~) × 100%.

5. Conclusions {#sec5-molecules-24-00021}
==============

In the present assay, the pharmacokinetics and metabolism of curculigoside C (CC) were investigated for the first time. In the pharmacokinetic analysis, a rapid, sensitive and reproducible UPLC-ESI-MS/MS quantification method was developed and validated for determination of CC in rat plasma samples. The sample preparation process was simple and the analysis time was just 3.5 min. The method was then successfully applied to the pharmacokinetic study after intravenous administration of 2.0 mg/kg CC and oral administration of 15, 30 and 60 mg/kg CC to rats, respectively. The results showed that CC exhibited rapid oral absorption (*T~max~* = 0.11 h), high elimination (*t*~1/2~ = 2.01 h) and poor absolute bioavailability (2.39%). A metabolic investigation of CC was conducted through UPLC-QTOF-MS^E^. The major metabolites and metabolic pathways were all characterized. In general, CC, another phenolic glycoside in comparation with curculigoside A, has the similar pharmacokinetic parameters and metabolic pathways, but better absolute bioavailability. These findings provide foundation for pharmacological research and development of CC.

**Sample Availability:** Samples of the compounds are available from the authors.

Experiments design, J.Y., J.L. and P.L.; Experimental operation, D.W., H.W., J.T. and H.L.; Data analysis, C.W., D.W. and H.Z.; Writing-original draft, D.W.; Writing-review & editing, J.Y., J.L. and P.L.

This research received no external funding.

The authors declare that they have no conflicts of interest concerning this article.

![Mass spectra and the proposed fragmentation patterns of CC (**A**) and the internal standard (IS) (**B**).](molecules-24-00021-g001){#molecules-24-00021-f001}

######

Typical chromatograms of blank plasma (**A**), blank plasm (**B**) spiked with CC and IS, and plasma sample (**C**) collected at an oral dose of 60 mg/kg CC.

![](molecules-24-00021-g002a)

![](molecules-24-00021-g002b)

![Mean plasma concentration-time profiles of CC in rats after intragastric administration (**A**) and intravenous administration (**B**).](molecules-24-00021-g003){#molecules-24-00021-f003}

![Metabolic profile and proposed metabolic pathways of CC in rats.](molecules-24-00021-g004){#molecules-24-00021-f004}

![Chemical structures of CC and curculigoside B.](molecules-24-00021-g005){#molecules-24-00021-f005}

molecules-24-00021-t001_Table 1

######

Intra- and inter-day precision and accuracy of CC in rat plasma.

  Concentration (ng/mL)   Intra-Day Measured Concentration (ng/mL)   Precision (RSD, %)   Accuracy (RE, %)   Inter-Day Measured Concentration (ng/mL)   Precision (RSD, %)   Accuracy (RE, %)
  ----------------------- ------------------------------------------ -------------------- ------------------ ------------------------------------------ -------------------- ------------------
  3                       3.02 ± 0.12                                4.10                 0.56               2.96 ± 0.15                                5.24                 −1.44
  200                     195.5 ± 9.40                               4.81                 −2.25              188.33 ± 12.82                             6.81                 −5.83
  2000                    1934.33 ± 106.49                           5.51                 −3.28              1890 ± 123.94                              6.56                 −5.50

molecules-24-00021-t002_Table 2

######

The stability of curculigoside C and IS in plasma (*n* = 6).

                           Concentration   Mean ± SD          Accuracy
  ------------------------ --------------- ------------------ -------------- -------
  Short-term stability     CC              3                  2.91 ± 0.13    −3.00
  (25 °C, 4 h)             200             185.5 ± 8.60       −7.25
                           2000            1882.50 ± 117.78   −5.88
                           IS              100                92.83 ± 3.31   −7.17
  Long-term stability      CC              3                  2.84 ± 0.09    −5.22
  (10 °C, 16 h)            200             184.33 ± 12.23     −7.83
                           2000            1870.50 ± 110.70   −6.48
                           IS              100                92.50 ± 5.68   −7.50
  Freezing stability       CC              3                  2.945 ± 0.11   −1.83
  (−20 °C, 14 d)           200             193.83 ± 10.23     −3.08
                           2000            1908.17 ± 103.51   −4.59
                           IS              100                94.00 ± 5.33   −6.00
                           CC              3                  2.87 ± 0.11    −4.33
  (3 freeze-thaw cycles)   200             185.17 ± 9.50      −7.42
                           2000            1889.67 ± 124.23   −5.52
                           IS              100                90.83 ± 5.19   −9.17

molecules-24-00021-t003_Table 3

######

Pharmacokinetic parameters of CC in rat plasma after intragastric administration.

  Dose (mg/kg)   *t*~1/2~ (h)    *T~max~* (h)    AUC~(0--60)~ (μg/L/h)   AUC~(0--∞)~ (μg/L/h)   F (%)   Vd (L/kg)           CLz (L/h/kg)
  -------------- --------------- --------------- ----------------------- ---------------------- ------- ------------------- ------------------
  15             2.022 ± 0.184   0.106 ± 0.149   62.731 ± 10.149         66.310 ± 10.563        2.01    673.157 ± 116.509   231.036 ± 36.69
  30             2.061 ± 0.325   0.111 ± 0.043   133.17 ± 48.434         140.656 ± 48.335       2.13    722.605 ± 316.306   234.188 ± 74.864
  60             2.048 ± 0.227   0.111 ± 0.043   299.155 ± 80.954        316.980 ± 91.704       2.39    585.344 ± 124.289   201.905 ± 55.193
  2.0 (i.v)      1.153 ± 0.203   \-              416.700 ± 70.401        420.700 ± 70.690       \-      8.122 ± 1.973       4.869 ± 0.834

molecules-24-00021-t004_Table 4

######

Metabolites of CC detected and structurally characterized on a UPLC-Q-TOF-MSE.

  No.   RT (min)   Formula            Measured Mass (*m*/*z*)   Calculate Mass (*m*/*z*)   Error (ppm)   Fragment Ions                                                Molecular Ion   Source
  ----- ---------- ------------------ ------------------------- -------------------------- ------------- ------------------------------------------------------------ --------------- ---------
  CC    6.71       C~22~H~26~O~12~    505.1316                  482.1424                   −1.5          321.1053, 303.0952, 261.0605, 220.9952, 181.0598, 123.1042   \[M + Na\]^+^   B,P,U
  M1    4.05       C~9~H~8~O~4~       181.0495                  180.0423                   −1.7          132.0217, 123.0114                                           \[M + H\]^+^    B,P,U
  M2    4.25       C~19~H~21~NO~7~S   430.0921                  407.1039                   −3.4          303.0899, 323.0102, 220.0795                                 \[M + Na\]^+^   B,U
  M3    6.27       C~9~H~10~O~5~      221.0415                  198.0528                   −3.0          123.0056, 167.9961, 170.0025, 181.0536                       \[M + Na\]^+^   B,F
  M4    7.66       C~16~H~14~O~6~     303.0872                  302.0790                   2.3           181.0425, 132.9930, 106.0411                                 \[M + H\]^+^    B,P
  M5    9.51       C~16~H~12~O~5~     285.0769                  284.0685                   3.2           257.0453, 105.0336, 164.9847                                 \[M + H\]^+^    B,P
  M6    10.29      C~16~H~16~O~7~     343.0775                  320.0896                   −4.4          123.0328, 181.0326, 220.8950                                 \[M + Na\]^+^   B,U,F
  M7    14.93      C~22~H~22~O~10~    447.1297                  446.1213                   2.0           267.0531, 164.9847, 223.0606                                 \[M + H\]^+^    B,P,U
  M8    15.72      C~26~H~32~O~17~    639.1541                  616.1639                   1.5           437.0844, 179.0473, 123.0320                                 \[M + Na\]^+^   B,P,U,F
  M9    18.47      C~22~H~24~O~12~    503.1174                  480.1268                   2.7           463.1024, 450.0755, 220.0650                                 \[M + Na\]^+^   B,U,F
  M10   22.41      C~28~H~36~O~17~    667.1838                  644.1952                   −1.1          612.1283, 465.1102, 303.0946                                 \[M + Na\]^+^   B,P,U,F
  M11   22.92      C~23~H~26~O~13~    511.1465                  510.1373                   3.1           123.0306, 181.0726, 331.0715                                 \[M + H\]^+^    B,F
  M12   26.88      C~22~H~26~O~15~S   585.0892                  562.0992                   1.2           209.0086, 190.9980, 303.0779, 320.0425, 259.0245, 243.0094   \[M + Na\]^+^   B,F

P: plasma samples, B: bile samples, U: urine samples, F: feces samples.


If you're as obsessed with avocado as we are, you're probably spreading it on toast, using it to make mousse, and chucking it into your smoothie to make it extra thick and filling. We're told that avocados are super good for us, with a balanced of monounsaturated, saturated, and polyunsaturated fats that help you absorb fat-soluble vitamins (like vitamin K, A, D, and E) from your food and leave you feeling full and satiated. They contain B vitamins (super important for methylation) and vitamin E, which helps with collagen production and retaining moisture in your skin. They help keep your brain healthy and your immune system strong.

But can you consume too much avocado?

According to Dr. Will Cole, a functional medicine practitioner, "For most people a half to two avocados a day is a great idea for a nutrient-dense clean diet. One of the core understandings, though, in functional medicine is that we are all different, so even with healthy stuff like avocados it may not work for everyone in larger amounts. People with digestive problems like SIBO and FODMAP intolerance will probably have stomach problems when they eat too much avocado. For these people I suggest limiting your avocado intake to about one-eighth of an avocado per day, which is still the perfect amount to put in your salads or blend in your smoothies!"

Miranda Hammer, R.D., considers an ideal serving for most healthy people one-half an avocado per day, although she also suggests consuming more limited quantities if you're on a low FODMAP diet or suffer from IBS. "The key," she says, "is to listen to your body and really pay attention to whether or not you're having a negative reaction."

Kimberly Snyder, C.N., takes a measured stance, noting that "eating some fat is essential for beauty and health, but you don't need to overdo it. If you look at some of the people around the world with the best health and longest lives, including various cultures in Asia, you'll see that many of them favor plant foods with lower fat and protein consumption. Exactly how much avocado (and fat in general) you should consume in a day depends on your body type, general constitution, activity levels, and so on, so there is not a one-size-fits-all recommendation. As a guideline, 15 to 30 percent of your diet should come from whole food sources of fat, including avocado and other healthy fats, like nutrient-dense seeds and nuts. Assuming you are eating some seeds and nuts and utilizing some coconut oil for cooking, a half to a whole avocado a day is a good general amount."

So there you go—use avocados liberally, but be mindful about portion sizes. This is especially important when consuming things that mask how much you're truly eating, like smoothies or avocado pudding. Remember that, while they're amazing for you, avocados are just one small part of a healthy diet. Or as Drew Ramsey, M.D., says, "For most people, eating more than one a day leads me to wonder about the overall diversity of their diet."


Glitchspace is a first person programming game that’s centred around a visual programming mechanic.

Set in a cyberspace world, you are trying to find a place known as Glitchspace - a by-product of cyberspace and its various glitches. A world that would allow for infinite possibilities, and access across all systems in cyberspace through exploitation.

Through problem solving, it’s up to you how you approach the in-game challenges; find glitches in the cyberspace world, and exploit them in various different ways, allowing for a emergent play experience.


Women, meanwhile, have been fighting for an equal rights amendment for decades. That’s because the Constitution does not actually grant women equal rights under the law, setting the country apart from 131 other nations that explicitly guarantee gender equality in their constitutions.

She tried to illustrate her point:

This injustice burns all the more now, in the wake of the Parkland, Florida, shooting, in which a 19-year-old man used an AR-15 to murder 17 people, including 14 high school students. The shooter had a legal right to his guns. He apparently had an arsenal. And because he had no criminal record, the FBI and police did not have any legal standing to take them away. In 2014, police were similarly hamstrung in the case of a 22-year-old man who went on to kill six and injure 13 in a rampage in Isla Vista, California.

Contrast those cases with what happened to Jessica Gonzales, a Colorado mother whose three children, just 7, 9 and 10, were abducted and shot to death by her husband. Those children should still be alive today: Gonzales had obtained a protective order against her husband, who had been violent before. The police refused to enforce it, declining to get involved in a “private” matter between a man and his wife.

Gonzales sued the police, arguing she had a right to protection. Her case went all the way to the Supreme Court. But she lost in 2005. The court ruled that Gonzales, now known as Jessica Lenahan, had no constitutional right to help from law enforcement.

Peck’s story fails at numerous points, not the least of which is that the ruling rejecting any claim to a “constitutional right” to police protection is not framed for women only. Rather, it is that Americans in general have no claim to a right to police protection under the auspices of the 14th Amendment. However, the Supreme Court did rule that states could “create a system by which police departments are generally held financially accountable for crimes that better policing might have prevented.”

But again, Peck’s greatest oversight is in presenting gun rights as men’s rights, then pitting those against women’s rights. Natural rights are not gender specific. Men and women have freedom of speech, freedom of religion, freedom to assemble (First Amendment). Both men and women have the right to self-defense and the right to keep and bear arms (Second Amendment). Men and women both enjoy the right to pursue and possess private property and to be secure in that property (Third and Fourth Amendments).

And the list goes on…

AWR Hawkins is an award-winning Second Amendment columnist for Breitbart News, the host of the Breitbart podcast Bullets with AWR Hawkins, and the writer/curator of Down Range with AWR Hawkins, a weekly newsletter focused on all things Second Amendment, also for Breitbart News. He is the political analyst for Armed American Radio. Follow him on Twitter: @AWRHawkins. Reach him directly at awrhawkins@breitbart.com. Sign up to get Down Range at breitbart.com/downrange.


Q:

C# .net wrapper for tessnet

I try to write wrapper for tessnet OCR library. I am getting an error saying "Cannot marshal 'return value': Generic types cannot be marshaled." for this code section
List<Word> k = OCRWrapper.DoOCR(new Bitmap(@"C:\Data\pdf2image\auto.png"), new Rectangle(0, 0, 55, 27));

My wrapper class is
class OCRWrapper
{
    [DllImport("TrueMarble.dll")]
    public static extern List<Word> DoOCR(Bitmap b, Rectangle rec);
}

please help me, can any one guide me to write this code
Thanx!

A:

You are on the wrong track with this, Tessnet already is a managed class wrapper around Tesseract.  You don't use [DllImport], just add a reference to the assembly and use the classes directly.  Sample code and assembly download is available here.
Bitmap image = new Bitmap("eurotext.tif");
tessnet2.Tesseract ocr = new tessnet2.Tesseract();
ocr.SetVariable("tessedit_char_whitelist", "0123456789"); // If digit only
ocr.Init(@"c:\temp", "fra", false); // To use correct tessdata

List<tessnet2.Word> result = ocr.DoOCR(image, Rectangle.Empty);
foreach (tessnet2.Word word in result)
    Console.WriteLine("{0} : {1}", word.Confidence, word.Text);


11.11.2009

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jas.m.b's "camara" is yu's favourite bag at the moment. vintage camera case looking leather bag is really useful. it fits digital camera, mobile phone&has got samll pocket for cards&notes!! and you can still squeeze more stuff in the small body! also large size "camera" is available 10s/s. jas.m.b also launching new covered studs bags. range include clutch, shoulder bags and computer case with sheering.


A Los Angeles Police commander is suing the city, alleging he was the victim of retaliation after top police brass falsely concluded he leaked information to a blogger for a story that said LAPD Chief Charlie Beck approved the department’s purchase of a horse from Beck’s daughter.

In the lawsuit claiming racial discrimination and retaliation filed Monday, LAPD Cmdr. Patrick Smith accused Beck and other police officials of acting against him after Jasmyne Cannick, a political consultant who also writes a blog, wrote her story.

The horse, George, was purchased in 2014 from Officer Brandi Pearson, Beck’s daughter. At the time, Smith was commanding officer of the department’s Metropolitan Division, which includes the mounted unit in which Pearson served.

The suit alleges the LAPD subjected Smith to fabricated internal affairs complaints, searched his office and took files from him, including one he planned to give to the department’s inspector general. The file contained his handwritten notes questioning whether the sale of the horse by Beck’s daughter was legal and ethical.

The lawsuit says Smith believes the sale violated city municipal codes as well as state and federal regulations.

Smith’s attorney says his client was never the source of the leak to Cannick. “The only correlation between Cannick and Plaintiff is the color of their skin,” wrote attorney Gregory Smith in the suit, adding that his client had never met or communicated with Cannick. Smith and Cannick are black.

On her blog Thursday, Cannick said the LAPD commander was not her source for her story on the horse. Following Cannick’s story in 2014, media outlets across the region, including The Times, reported on the sale.

LAPD Capt. Andrew Neiman on Thursday said the department does not comment on pending litigation but will address the allegations in court. He noted Smith remains an active commander in the LAPD.

The suit notes that Beck signed a document approving the $6,000 payment to his daughter.

The lawsuit alleges that Smith, who now works in the LAPD’s training division, has been ostracized by the department after top officials discovered he planned to report the possible misconduct to the inspector general.

The suit also alleges that an internal employee tracking system claims he is under criminal investigation, even though he is not.

Smith’s suit is the latest in a long line of lawsuits by officers and command staff alleging they were mistreated by LAPD management during Beck’s tenure. Some of the suits have been rejected, but others have proved costly to the city.

Monday’s lawsuit alleges that the chief and Deputy Chief Deborah McCarthy, who oversees internal affairs, dislike Cannick because she has written critically about Beck’s administration. The furor surrounding the horse ignited questions as Beck was seeking reappointment to a second term.

While Beck’s signature appeared on the approval of the purchase, Assistant Chief Michel Moore said the chief had no involvement in the evaluation of the horse’s qualification or value and that the signature was a formality.

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NAIROBI, Kenya (AP) — The website's headlines trumpet al-Shabab's imminent demise and describe an American jihadist fretting over insurgent infighting. At first glance it appears to be a sleek, Horn of Africa news site. But the site — sabahionline.com — is run by the U.S. military.

The site, and another one like it that centers on northwest Africa, is part of a propaganda effort by the U.S. military's Africa Command aimed at countering extremists in two of Africa's most dangerous regions — Somalia and the Maghreb.

Omar Faruk Osman, the secretary general of the National Union of Somali Journalists, said Sabahi is the first website he's seen devoted to countering the militants' message.

"We have seen portal services by al-Shabab for hate and for propaganda, for spreading violence. We are used to seeing that. In contrast we have not seen such news sites before. So it is something completely unique," Osman said.

But although he had noticed prominent articles on the site, which is advertising heavily on other websites, he had not realized it was bankrolled by U.S. military.

The U.S. military and State Department, a partner on the project, say the goal of the sites is to counter propaganda from extremists "by offering accurate, balanced and forward-looking coverage of developments in the region."

"The Internet is a big place, and we are one of many websites out there. Our site aims to provide a moderate voice in contrast to the numerous violent extremist websites," Africom, as the Stuttgart, Germany-based Africa Command is known, said in a written statement.

Al-Shabab and other militants have for years used websites to trade bomb-making skills, to show off gruesome attack videos and to recruit fighters. The U.S. funded websites — which are available in languages like Swahili, Arabic and Somali — rely on freelance writers in the region.

Recent headlines on sabahionline.com show a breadth of seemingly even-handed news. "Death toll in ambush on Kenyan police rises to 31," one headline said. "Ugandan commander visits troops in Somalia," another reads.

Story continues

Web ads for the site appear on occasion on mainstream websites such as YouTube, and they show a clear anti-terror slant. Ads showing men on the ground blindfolded or Somalia's best known American jihadi, Omar Hammami, entice web users to click. They then access a headline like: "Somalis reject al-Zawahiri's call for violence," referring to the leader of al-Qaida.

The site, which launched in February, is slowly attracting readers. The military said that Sabahi averages about 4,000 unique visitors and up to 10,000 articles read per day. The site clearly says under the "About" section that it is run by the U.S. military, but many readers may not go to that link.

Abdirashid Hashi, a Somalia analyst for the International Crisis Group, said he has read articles on Sabahi, mostly because of advertisements on other Somali websites, but he also didn't realize it was funded by the U.S. He said he has no issues with the U.S. government running a news site.

"I don't think they hide it. That's up there. There's an information war going on, so I don't have any problem with that," Hashi said.

Osman said the articles on Sabahi are accurate and professional. But he said he feared that militants could attack writers who work for the site. Eighteen Somalis who work with media outlets have been killed this year, often in targeted killings.

Somali writers "can lose their life for working for this kind of a news outlet because of the extremists who target any critical voice or news service," Osman said. "The other issue is professionalism, because if someone is intimidated and is threatened all the time then he or she is reduced to self-censorship. He or she would be afraid if he files some important news that he would be targeted."

The military said there are nine writers who work for Sabahi from Kenya, Tanzania, Djibouti and Somalia. The other site — magharebia.com — concentrates on Libya, Algeria, Morocco and Mauritania.

Africom says the websites are part of a larger project that costs $3 million to pay for reporting, editing, translating, publishing, IT costs and overhead. It believes the project is paying dividends.

"The fact that we have seen an increase in website traffic is good news alone. The website's readers provide a significant number of comments on a regular basis, which often reflect their growing frustration and anger with extremist organizations in the region. Those comments are one indicator of a positive effect," Africom said.

Seth Jones, the associate director of the International Security and Defense Policy Center at the Rand Corporation think tank in Washington, said a significant part of the struggle with extremist groups like al-Shabab is ideological and is a battle for the hearts and minds of local populations.

"Based on this reality, the U.S. and other governments should be involved in countering extremist messages on websites and other forms of social media. After all, every Arab government provides substantial money to television, radio, print media, and Internet sites," Jones said.

"They key question for the United States is gauging whether locals view these kinds of news sites as legitimate sources of information and read them. If not, it's worth asking: Is the United States getting a bang for its buck?"

___

On the Internet:

Somalia news site: http://sabahionline.com/en_GB

Maghreb news site: http://magharebia.com/cocoon/awi/xhtml1/en_GB/homepage


Makeover Au Gratin Hash Browns Recipe

This made over dish has nearly two-thirds less fat and saturated fat than the original recipe and 40% fewer calories! Cholesterol was reduced by more than half...and the sodium by more than a quarter.—Taste of Home Test Kitchen, Greendale, Wisconsin

Directions

In a large bowl, combine the hash browns, cheese, onion, salt and pepper. In another bowl, combine the sour cream and soup. Pour over potato mixture and mix gently to combine. Transfer to a 3-qt. baking dish coated with cooking spray. Toss cornflakes and butter; sprinkle over the top. Bake, uncovered, at 350° for 45-55 minutes or until heated through. Sprinkle with parsley.Yield: 12 servings.


Q:

Making a list based on a criteria of another list

I have an empty list called 'label', where depending on which bucket is more appropriate, it will fill the 'label' list with 0,1,or 2.
'label' is associated to the 3 'buckets':
# Bucket 0: 0 -7 Days --------------------------> 0
# Bucket 1: 1 - 6 Weeks (8 - 42 Days) ----------> 1
# Bucket 2: 7+ Weeks (49+ Days) ----------------> 2

I have another list has a length of 23411. This list's contents consist of 0 days to 1099 days. So based on this list's contents, it should populate the 'label' list.
I have tried this for-loop & if-else statement to do what I want, however it is giving me a IndexError: list assignment index out of range:
label = []
for i in range(23411):
    if ageNew[i] <= 7:
        label[i] = 0
    elif ageNew[i] <= 42:
        label[i] = 1
    else:
        label[i] = 2

For example:
list: [0, 8, 14, 14, 45, 1056, 1]
label: [0, 1, 1, 1, 2, 2, 0]

A:

You cannot make the assignment label[i] = something because it doesn't exist.
Use .append() instead
label = []
for i in range(23411):
    if ageNew[i] <= 7:
        res = 0
    elif ageNew[i] <= 42:
        res = 1
    else:
        res = 2
    label.append(res)


Q:

Unity3d rearrange a string

Say you have a string 5/9/2010 and you want to rearrange it to read 2010/5/9. How would you go about doing that?
I want to sort a list by a string that happens to be a date. While I could make it into a date, I want to stick with a string, if possible because the time part of the datetime is hard to eliminate. (This is being used in an sqlite database for a Unity3d App.)
Forgive me if this is a duplicate.

A:

If you can guarantee that the string will always be the same input format, you can split the string on the /:
    string input = "5/9/2010";
    string[] inputSections = input.Split('/');
    string output = string.Format("{0}/{1}/{2}", inputSections[2], inputSections[0], inputSections[1]);

Working Fiddle
My code is very verbose, you can certainly simplify it for your needs.  I would also utilize the string inerpolation feature of C# 6 if it is available to you:
    string input = "5/9/2010";
    string[] inputSections = input.Split('/');
    string output = $"{inputSections[2]}/{inputSections[1]}/{inputSections[0]}";


Q:

Why use a default value of None for this class initialiser?

I tested the code in this answer and it works just fine.
The code creates a Application class like this:
class Application(Frame):
    def __init__(self, master=None):
        Frame.__init__(self, master)

and creates an instance with:
root = Tk()
app = Application(master=root)

However, there is one  thing I do not understand in it: why the constructor takes as an argument a None object def __init__(self, master=None): but he calls the Application()  class he passes it a root=Tk() instance ?

A:

The class copies the Frame constructor; it too takes an optional master argument. You don't have to pass in a master widget, even though here the code does pass one in. See the *frame section of An introduction to Tkinter:

Frame(master=None, **options) (class)
  A widget container.

The tkinter documentation examples include the same pattern:

from Tkinter import *

class Application(Frame):
    # ...

    def __init__(self, master=None):
        Frame.__init__(self, master)
        self.pack()
        self.createWidgets()

root = Tk()
app = Application(master=root)

Doing so makes your code more flexible; you can now create an Application instance without a master, and pass it to code that takes any Tk object to bind at a later time.


#pragma once

#include "esphome/core/component.h"
#include "esphome/core/defines.h"

#ifdef USE_TIME
#include "esphome/components/time/real_time_clock.h"
#endif

#include "esphome/components/spi/spi.h"

namespace esphome {
namespace max7219 {

class MAX7219Component;

using max7219_writer_t = std::function<void(MAX7219Component &)>;

class MAX7219Component : public PollingComponent,
                         public spi::SPIDevice<spi::BIT_ORDER_MSB_FIRST, spi::CLOCK_POLARITY_LOW,
                                               spi::CLOCK_PHASE_LEADING, spi::DATA_RATE_1MHZ> {
 public:
  void set_writer(max7219_writer_t &&writer);

  void setup() override;

  void dump_config() override;

  void update() override;

  float get_setup_priority() const override;

  void display();

  void set_intensity(uint8_t intensity);
  void set_num_chips(uint8_t num_chips);

  /// Evaluate the printf-format and print the result at the given position.
  uint8_t printf(uint8_t pos, const char *format, ...) __attribute__((format(printf, 3, 4)));
  /// Evaluate the printf-format and print the result at position 0.
  uint8_t printf(const char *format, ...) __attribute__((format(printf, 2, 3)));

  /// Print `str` at the given position.
  uint8_t print(uint8_t pos, const char *str);
  /// Print `str` at position 0.
  uint8_t print(const char *str);

#ifdef USE_TIME
  /// Evaluate the strftime-format and print the result at the given position.
  uint8_t strftime(uint8_t pos, const char *format, time::ESPTime time) __attribute__((format(strftime, 3, 0)));

  /// Evaluate the strftime-format and print the result at position 0.
  uint8_t strftime(const char *format, time::ESPTime time) __attribute__((format(strftime, 2, 0)));
#endif

 protected:
  void send_byte_(uint8_t a_register, uint8_t data);
  void send_to_all_(uint8_t a_register, uint8_t data);

  uint8_t intensity_{15};  /// Intensity of the display from 0 to 15 (most)
  uint8_t num_chips_{1};
  uint8_t *buffer_;
  optional<max7219_writer_t> writer_{};
};

}  // namespace max7219
}  // namespace esphome


The process of synthesis, insertion into the plasma membrane, and degradation of beta-adrenergic receptors will be studied in cultured human astrocytoma cells (line 1321N1). Previous studies have demonstrated that beta-adrenergic receptors are expressed differentially during growth of 1321N1 cells in culture. Using these growth-related changes in receptor turnover as a model system, we will investigate the kinetics of receptor accumulation in relation to synthesis, plasma membrane insertion and degradation of the receptor. The metabolic fate of newly synthesized receptors will be examined directly using stable isotope labelled amino acids. Cells will be incubated with 2H-, 13C- and 15N-labelled amino acids, and heavy versus light receptors will be identified after separation by gradient centrifugation of detergent solubilized, 125IHYP-labelled, receptors. We will also use the irreversible beta-adrenergic receptor antagonist, NMNP-NBE, to inactivate existing receptor sites in a number of these experiments. Using these techniques, the processing of newly synthesized receptor protein will be quantitatively followed under a variety of experimental paradigms. The contribution of changes in relative rates of receptor synthesis and degradation to the marked loss of receptors that occurs during catecholamine-induced desensitization will be examined. The functional significance of any intracellular pool of receptors will be examined as it relates to receptor synthesis, insertion, recycling, and degradation. The relationship of such an intracellular pool to a membrane fraction of receptors which does not copurify with plasma membrane fractions on sucrose density gradients will be assessed. Drugs that affect translation or transcription will be utilized to investigate the role or protein and RNA synthesis in the regulation of the assembly of receptors. Synthesis, incorporation and degradation will also be examined under conditions in which pH, temperature, intracellular ATP levels, and microtubule integrity are altered.


###########################################################
#                  Find EIGEN Library
#----------------------------------------------------------

FIND_PATH(EIGEN_DIR "Eigen/Core"
    HINTS "${EIGEN_ROOT}" "$ENV{EIGEN_ROOT}" "${EIGEN_INCLUDE_DIR_HINTS}"
    PATHS "$ENV{PROGRAMFILES}/Eigen" "$ENV{PROGRAMW6432}/Eigen" "/usr" "/usr/local"
    PATH_SUFFIXES eigen3 include/eigen3 include
    DOC "Root directory of EIGEN library")

##====================================================
## Include EIGEN library
##----------------------------------------------------
if(EXISTS "${EIGEN_DIR}" AND NOT "${EIGEN_DIR}" STREQUAL "")
	SET(EIGEN_FOUND TRUE)
	SET(EIGEN_INCLUDE_DIRS ${EIGEN_DIR})
	SET(EIGEN_DIR "${EIGEN_DIR}" CACHE PATH "" FORCE)
	MARK_AS_ADVANCED(EIGEN_DIR)

	# Extract Eigen version from Eigen/src/Core/util/Macros.h
	SET(EIGEN_VERSION_FILE ${EIGEN_INCLUDE_DIRS}/Eigen/src/Core/util/Macros.h)
	IF (NOT EXISTS ${EIGEN_VERSION_FILE})
		EIGEN_REPORT_NOT_FOUND(
		  "Could not find file: ${EIGEN_VERSION_FILE} "
		  "containing version information in Eigen install located at: "
		  "${EIGEN_INCLUDE_DIRS}.")
	ELSE (NOT EXISTS ${EIGEN_VERSION_FILE})
		FILE(READ ${EIGEN_VERSION_FILE} EIGEN_VERSION_FILE_CONTENTS)

		STRING(REGEX MATCH "#define EIGEN_WORLD_VERSION [0-9]+"
		  EIGEN_WORLD_VERSION "${EIGEN_VERSION_FILE_CONTENTS}")
		STRING(REGEX REPLACE "#define EIGEN_WORLD_VERSION ([0-9]+)" "\\1"
		  EIGEN_WORLD_VERSION "${EIGEN_WORLD_VERSION}")

		STRING(REGEX MATCH "#define EIGEN_MAJOR_VERSION [0-9]+"
		  EIGEN_MAJOR_VERSION "${EIGEN_VERSION_FILE_CONTENTS}")
		STRING(REGEX REPLACE "#define EIGEN_MAJOR_VERSION ([0-9]+)" "\\1"
		  EIGEN_MAJOR_VERSION "${EIGEN_MAJOR_VERSION}")

		STRING(REGEX MATCH "#define EIGEN_MINOR_VERSION [0-9]+"
		  EIGEN_MINOR_VERSION "${EIGEN_VERSION_FILE_CONTENTS}")
		STRING(REGEX REPLACE "#define EIGEN_MINOR_VERSION ([0-9]+)" "\\1"
		  EIGEN_MINOR_VERSION "${EIGEN_MINOR_VERSION}")

		# This is on a single line s/t CMake does not interpret it as a list of
		# elements and insert ';' separators which would result in 3.;2.;0 nonsense.
		SET(EIGEN_VERSION "${EIGEN_WORLD_VERSION}.${EIGEN_MAJOR_VERSION}.${EIGEN_MINOR_VERSION}")
	ENDIF (NOT EXISTS ${EIGEN_VERSION_FILE})
	SET(EIGEN_INCLUDE_DIR ${EIGEN_DIR})

	MESSAGE(STATUS "Eigen ${EIGEN_VERSION} found (include: ${EIGEN_INCLUDE_DIRS})")
else()
  MESSAGE(FATAL_ERROR "You are attempting to build without Eigen. "
          "Please use cmake variable -DEIGEN_INCLUDE_DIR_HINTS:STRING=\"PATH\" "
          "or EIGEN_INCLUDE_DIR_HINTS env. variable to a valid Eigen path. "
          "Or install last Eigen version.")
  package_report_not_found(EIGEN "Eigen cannot be found")
endif()
##====================================================


<?xml version="1.0" encoding="utf-8"?>
<androidx.constraintlayout.widget.ConstraintLayout xmlns:android="http://schemas.android.com/apk/res/android"
    xmlns:app="http://schemas.android.com/apk/res-auto"
    android:layout_width="match_parent"
    android:layout_marginEnd="12dp"
    android:layout_height="wrap_content">

    <androidx.constraintlayout.widget.Guideline
        android:id="@+id/MomentsAdapter_mGuideline"
        android:layout_width="wrap_content"
        android:layout_height="wrap_content"
        android:orientation="vertical"
        app:layout_constraintGuide_begin="40dp" />

    <View
        android:layout_width="0dp"
        android:layout_height="0dp"
        android:background="@android:color/white"
        app:layout_constraintBottom_toBottomOf="parent"
        app:layout_constraintStart_toEndOf="@id/MomentsAdapter_mGuideline"
        app:layout_constraintEnd_toEndOf="parent"
        app:layout_constraintTop_toTopOf="parent" />

    <com.yzx.chat.widget.view.HexagonAvatarView
        android:id="@+id/MomentsAdapter_mIvAvatar"
        android:layout_width="50dp"
        android:layout_height="50dp"
        android:layout_marginTop="12dp"
        android:elevation="4dp"
        app:layout_constraintEnd_toEndOf="@id/MomentsAdapter_mGuideline"
        app:layout_constraintStart_toStartOf="@id/MomentsAdapter_mGuideline"
        app:layout_constraintTop_toTopOf="parent" />

    <TextView
        android:id="@+id/MomentsAdapter_mTvName"
        android:layout_width="0dp"
        android:layout_height="wrap_content"
        android:layout_marginStart="8dp"
        android:gravity="start|center_vertical"
        android:singleLine="true"
        android:layout_marginTop="20dp"
        android:text="叶智星"
        android:textColor="@color/colorAccent"
        app:layout_constraintEnd_toStartOf="@id/MomentsAdapter_mTvTime"
        app:layout_constraintStart_toEndOf="@id/MomentsAdapter_mIvAvatar"
        app:layout_constraintTop_toTopOf="parent" />

    <TextView
        android:id="@+id/MomentsAdapter_mTvTime"
        android:layout_width="wrap_content"
        android:layout_height="wrap_content"
        android:layout_marginEnd="16dp"
        android:text="16:58"
        android:textSize="12sp"
        app:layout_constraintBottom_toBottomOf="@id/MomentsAdapter_mTvName"
        app:layout_constraintEnd_toEndOf="parent"
        app:layout_constraintTop_toTopOf="@id/MomentsAdapter_mTvName" />

    <TextView
        android:id="@+id/MomentsAdapter_mTvTextContent"
        android:layout_width="0dp"
        android:layout_height="wrap_content"
        android:layout_marginTop="4dp"
        android:gravity="start|center_vertical"
        android:text="每个不曾起舞的日子，都是对生命的辜负!"
        android:textSize="13sp"
        app:layout_constraintEnd_toEndOf="@id/MomentsAdapter_mTvTime"
        app:layout_constraintStart_toStartOf="@id/MomentsAdapter_mTvName"
        app:layout_constraintTop_toBottomOf="@id/MomentsAdapter_mTvName" />

    <com.yzx.chat.widget.view.NineGridImageView
        android:id="@+id/MomentsAdapter_mNineGridImageContent"
        android:layout_width="0dp"
        android:layout_height="wrap_content"
        android:layout_marginTop="8dp"
        app:layout_constraintEnd_toEndOf="@id/MomentsAdapter_mTvTextContent"
        app:layout_constraintStart_toStartOf="@id/MomentsAdapter_mTvTextContent"
        app:layout_constraintTop_toBottomOf="@id/MomentsAdapter_mTvTextContent" />

    <ImageView
        android:id="@+id/MomentsAdapter_mIvLikeIcon"
        android:layout_width="20dp"
        android:layout_height="18dp"
        android:layout_marginBottom="12dp"
        android:layout_marginTop="8dp"
        android:scaleType="fitXY"
        android:src="@drawable/ic_like"
        app:layout_constraintBottom_toBottomOf="parent"
        app:layout_constraintStart_toStartOf="@id/MomentsAdapter_mTvTextContent"
        app:layout_constraintTop_toBottomOf="@id/MomentsAdapter_mNineGridImageContent" />

    <TextView
        android:id="@+id/MomentsAdapter_mIvLikeNumber"
        android:layout_width="wrap_content"
        android:layout_height="wrap_content"
        android:layout_marginStart="4dp"
        android:text="12"
        android:textColor="@color/colorAccent"
        android:textSize="12sp"
        app:layout_constraintBottom_toBottomOf="@id/MomentsAdapter_mIvLikeIcon"
        app:layout_constraintStart_toEndOf="@id/MomentsAdapter_mIvLikeIcon"
        app:layout_constraintTop_toTopOf="@id/MomentsAdapter_mIvLikeIcon" />

    <ImageView
        android:id="@+id/MomentsAdapter_mIvCommentIcon"
        android:layout_width="22dp"
        android:layout_height="22dp"
        android:layout_marginStart="12dp"
        android:src="@drawable/ic_comment"
        app:layout_constraintBottom_toBottomOf="@id/MomentsAdapter_mIvLikeIcon"
        app:layout_constraintStart_toEndOf="@id/MomentsAdapter_mIvLikeNumber"
        app:layout_constraintTop_toTopOf="@id/MomentsAdapter_mIvLikeIcon" />

    <TextView
        android:layout_width="wrap_content"
        android:layout_height="wrap_content"
        android:layout_marginStart="4dp"
        android:text="36"
        android:textColor="@color/colorAccent"
        android:textSize="12sp"
        app:layout_constraintBottom_toBottomOf="@id/MomentsAdapter_mIvLikeIcon"
        app:layout_constraintStart_toEndOf="@id/MomentsAdapter_mIvCommentIcon"
        app:layout_constraintTop_toTopOf="@id/MomentsAdapter_mIvLikeIcon" />

</androidx.constraintlayout.widget.ConstraintLayout>


COMETS SIGN REID GARDINER TO A ONE-YEAR DEAL

Utica, N.Y. – Utica Comets General Manager Ryan Johnson announced today that the team has signed forward Reid Gardiner to a one-year AHL contract.

Gardiner, 22, appeared in 58 games last season with the Wheeling Nailers of the ECHL collecting 57 points (30-27-57). In addition, the 5-11, 193-pound forward skated in 10 games with the Wilkes-Barre/Scranton Penguins tallying three points (1-2-3). The forward began the 2016-17 season with the Penguins, amassing six points (3-3-6) in 23 games.

Prior to turning pro, the Humboldt, Saskatchewan native suited up in 293 games between the Prince Albert Raiders and Kelowna Rockets of the WHL, registering 257 points (124-133-257).

For the latest Comets news visit www.uticacomets.com or follow the team on Facebook (www.facebook.com/uticacomets), Twitter (@UticaComets), Instagram (@UticaComets), and the Comets YouTube Channel.


The goal of this project is to characterize the genetic abnormality responsible for giant axonal neuropathy (GAN), a degenerative disorder of the peripheral nerves which typically presents in early childhood and progresses to death, usually by late adolescence. Many reported cases are offspring of consanguineous marriages, implying inheritance as an autosomal recessive trait. In addition to giant disorganized neurofilamentous swellings in nerve, disorganization of other members of the intermediate filament family of proteins is seen in other tissues; this implies that the fundamental defect is one of intermediate filament function with neurofilaments predominantly affected. By studying families affected by GAN, we plan to map and characterize the gene responsible. We propose to perform a genome-wide search, using highly polymorphic DNA markers in consanguineous families, for areas of the genome homozygous by descent; such areas have a greater increased likelihood of harboring the gene. This strategy, termed homozygosity mapping, allows mapping of recessive disorders with relatively few affected kindreds. Once the gene locus is determined, physical and fine linkage mapping will be performed; ultimately, the gene will be identified by one of a number of techniques. Although GAN is a rare illness, it is likely the characterization of the gene and its product will shed light on very basic cytoskeletal processes. Such information may lead to new theoretical and experimental strategies for other illnesses, such as amyotrophic lateral sclerosis, which have a striking neurofilamentous pathology.


Will Noble

TfL To Offer 'Genuinely Affordable' Homes... But They May Be The Size Of A Tube Carriage

Image: TfL/Pocket Living

"100% genuinely affordable housing"

TfL has announced that it will offer first-time buyers "100% genuinely affordable housing" at its sites across London.

Working in partnership with Pocket Living, TfL aims to initially build around 125 one bedroom homes — sold outright to buyers at a rate "well below the market value". Pocket homes are targeted specifically at local singles and couples, who earn too much to qualify for social housing, but are priced out of the open market.

TfL tells Londonist it is as yet unsure where any of the initial 125 homes would be — or indeed how many might be positioned directly next to, or above, tube stations. Pocket Living has a wide portfolio, covering locations across London.

Graeme Craig, Director of Commercial Development at TfL, said:

Pocket Living is building a great reputation for high quality, genuinely affordable housing for first-time buyers, and will help us develop sites that would not otherwise come forward. This partnership marks another important step in us assembling the most important development pipeline in London — building thousands of social rented and other genuinely affordable homes across the capital and generating hundreds of millions of pounds to reinvest in the transport network.

A Pocket Living complex on Gainsford Road, Walthamstow. Image: TfL/Pocket Living

What exactly is genuinely affordable housing?

Again, the details are sketchy, and we haven't been provided with any exact figures. We do know that 87% of Pocket Living's purchasers — average age 33 — have a current average household income of £42,500.

While £42k is still higher than the average London salary, it's a sight more realistic than some required salaries being bandied around — including £248.6k to afford a one bedroom place in Knightsbridge. As for that "well below the market value" claim from TfL; Pocket Living usually offer houses at least 20% below market rate. We can expect similar pricing from this partnership.

Image: TfL/Pocket Living

How big are these TfL Pocket Living houses?

This is where there's some controversy. While Pocket Living touts "well-located homes for a fair price", the size of these homes won't be for everyone. TfL has confirmed that the average one-bedroom apartment will measure 38 square metres... fittingly enough, the approximate size of a tube carriage.


SOLD OUT
Not for the faint of heart, the 2015 Intrepid is a Côte-Rôtie inspired Syrah, which without our soil’s character, would cease to exist. The nose is brambly, slightly gamey and draws you into a world of beef jerky, bacon fat and dark berry compote. An iron fist meets a leather glove, as the tannins are grippy, yet well integrated. Its complex mouthfeel is complemented by an oak presence that will continue to garner this blend over the next 10-15 years.95pts - Josh Raynolds - Vinous
95+ pts - Jeb Dunnuck


Human-computer interactions have progressed to the point where humans can control computing devices, and provide input to those devices, by speaking. Computing devices employ techniques to identify the words spoken by a human user based on the various qualities of a received audio input. Such techniques are called speech recognition or automatic speech recognition (ASR). Speech recognition combined with natural language processing techniques may allow a user to control a computing device to perform tasks based on the user's spoken commands. The combination of such techniques may be referred to as speech processing. Speech processing may also convert a user's speech into text data which may then be provided to various textual based programs and applications.
Speech processing may be used by computers, hand-held devices, telephone computer systems, kiosks, and a wide variety of other devices to improve human-computer interactions.


Seasonal fluctuations of Dermatophagoides mite population in house dust.
To evaluate seasonal fluctuations of Dermatophagoides species (sp.) in residential houses in Mie Prefecture, Japan, we employed the ELISA inhibition method with rabbit polyclonal antibody to eggs and adult mites. House dust accumulated for seven days in vacuum cleaners was collected from 14 houses of atopic patients every month for one year. The one-week-dust samples weighed from 2.5 to 117 g (mean 35.9 g). The density of Dermatophagoides spp. in the dust samples were 5 to 755 mites per gram (mean 109). During one week, 100 to 20,400 (mean 4,200) mites of Dermatophagoides sp. were collected. Among 142 samples in one year, 50 (35.2%) contained more than 100 mites per gram, which is a critical number for atopic symptoms. From December to February, 12 (34.5%) out of 35 samples contained more than 100 mites per gram. These results suggest that Dermatophagoides sp. have become a year-round allergen in Japan.


2M (TV channel)

2M TV is a Moroccan free-to-air television network. It was established by the royal-owned conglomerate, ONA, before being partly sold to the Moroccan state. 20.7% of 2M is owned by Mohammed VI's holding company SNI. While approximately 60% is controlled by the Moroccan state.

It is based in Casablanca. It is available free of charge locally on digital signal with coverage over all Morocco and on satellite television via Globecast, Nilesat and Arabsat.

2M offers services in Arabic, French, and Berber.

Background
2M was set up as a second national television channel with the aim of promoting competition and diversity in Moroccan audio-visual broadcasting.

2M started its programmes officially on March 4, 1989. It used to be a cable channel broadcasting uncoded twice a day. After 7 years of activity, SOREAD (ONA group), the major shareholder, withdrew from the management of this TV channel due to financial reasons. The Moroccan state took over the control of 2M with a participation of 68% in its capital. This takeover was supported by a major effort to develop the audio-visual sector.

Radio 2M is the companion radio channel to 2M, presenting music, news, and information directly from Morocco in Arabic and French.

Content

2M challenged taboos by debating controversial issues and established a reputation for itself as a symbol of freedom of speech in Morocco. The channel regularly broadcasts news, films, sports and music. It is now a government-controlled public TV station and has close under-the-table ties with influential parts of the Moroccan political power structure (the Makhzen). 2M has been used by the government as an indirect means to attack independent newspapers such as Le Journal.

2M has two different channels, a local analog channel and a satellite channel whose name is (since 2007) 2M Monde, which means 2M World. Both local and satellite/world versions of 2M have the same shows but are aired at different times. 2M Monde does not broadcast Hollywood movies and American TV shows because it only buys their broadcasting rights for within Morocco.

On November 23, the TV channel aired in its morning show "Sabahiyat" a segment on how to cover beaten bruises with make up on the International Day to Eliminate Violence Against Women. Moroccan TV has apolgized on Monday for airing the segment.

2M in figures
Personnel: 500 persons, including 30% executives;
Coverage: 80% of the population;
Capital: 302,371,500 Moroccan dirham (€27,008,467 / £18,228,395 / US$36,750,427), including 68% owned by the state and 20.7% owned by Mohammed VI's holding SNI.

Foreign series
List of American and European TV shows broadcast by the local version of 2M (which may change time by time):

 24
 Alias
 Bones
 Buffy (Buffy contre les vampires)
 CSI (Les Experts)
 CSI: NY (Les Experts : Manhattan)
 CSI: Miami (Les Experts : Miami)
 Cuenta Atràs (العد العكسي) (Moroccan dubbing)
 Damages
 Dark Angel
 Desperate Housewives
 Dexter

 Friends
 Gossip Girl
 Instant Star (Ma vie de star)
 Jericho
 Just Cause (En quête de justice)
 Law & Order (New York District)
 Law & Order: Special Victims Unit (New York unité spéciale)
 Los hombres de Paco (باكو) (Moroccan dubbing)
 Mad Men
 Medium
 NCIS (NCIS : Enquêtes spéciales)

 Un paso adelante (Un, dos, tres)
 Ovni
 Prison Break
 Rubí (Arabic dubbing)
 Stargate Atlantis
 The 4400 (Les 4400)
 The Invisible Man (Invisible Man)
 The O.C. (Newport beach)
 The Shield
 The Simpsons
 Vermist (وحدة المفقودين) (Moroccan dubbing)

American TV shows and Hollywood movies are imported from France with French dubbing. Some Mexican TV shows are dubbed locally in Moroccan Arabic.

Besides American TV shows, 2M TV also airs a few Turkish shows dubbed in Arabic. 2M TV's children's programming schedule also includes foreign TV shows, such as Célestin, Braceface  ''Oggy and the Cockroaches'  and 1001 Nights

List of  other TV programmes

  (كي كنتي كي وليتي)
 wash hna homa hna (واش حنا هما حنا)
 rashid show (رشيد شو)
 shomisha (شميشة)
 hob aema (حب أعمى)
 Kif El Hal (كيف الحال)
 Sabahiyat 2M (2M صباحيات)
 2M Kids
 Sir Al Morjan (سر المرجان)
 Zina
 Ahlam Morahiqatayn
 Samhini (Moroccan dubbing)
 Ana wa Banati (Moroccan dubbing)
 Shhiwat Maa shoumisha (شهيوات مع شميشة)
 Eco News
 Masir Asiya (Moroccan dubbing)

 Rita
 Lara
 Hibal Al Rih (حبال الريح)
 L'Couple
 L'Couple (Season 2)
 Kabour w lahbib (كبور ولحبيب)
 Al Khawassir (الخواسر)
 Bash Taaref Rassk (باش تعرف راسك)
 Rihlat Saloni
 Al Banat Zinat albayt
 Vaidehi
 Bnat Lalla Mennana (بنات لالة منانة)

 Bnat Lala Mennana (Season 2)
 LKhawa (لخاوة)
 Kenza Fddouar (كنزة فالدوار)
 Nayda fddouar (نايضة فالدوار)
  (لوبيرج)
 Al Akhbar 12:45
 Al Akhbar 21:00
 Info soir 20:15
 Maa Nass (مع الناس)
 Lahbiba Mmi (لحبيبة مي)
 Hdidan fi Gueliz (حديدان في كليز)

See also
Samira Sitail
Leila Ghandi

References

External links
 2M website

Category:1989 establishments in Morocco
Category:Arabic-language television stations
Category:Berber-language media
Category:French-language television stations
Category:Television stations in Morocco
Category:Media in Casablanca
Category:Television channels and stations established in 1989
Category:Société Nationale d'Investissement
Category:Media companies of Morocco
Category:ONA Group


Key questions in vitamin D research.
Despite interest and expanding research on non-bone health outcomes, the evidence remains inconclusive concerning the causal role of vitamin D in the non-bone health outcomes. To improve our understanding of its role, research needs to address five key areas related to vitamin D: 1) its physiology and molecular pathways. 2) its relationship to health outcomes. 3) its exposure-response relationships, 4) its interactions with genotype and other nutrients and 5) its adverse effects. Its metabolism needs to be elucidated including extra-renal activation and catabolism, distribution and mobilization from body pools, kinetics of this distribution, and their regulation during pregnancy and lactation. Rigorous, well-designed randomized clinical trials need to evaluate the causal role of vitamin D in a diverse array of non-bone health and chronic disease outcomes across the life cycle and reproductive states. Critically needed is the determination of the exposure-response, inflection and threshold of serum 25(OH)D concentrations relative to functional and health outcomes. The dose-response relationships of standardized measures of serum 25(OH)D need to be understood in response to low and high doses of total vitamin D with careful consideration of confounding factors including catabolic rates. How do relevant genetic polymorphisms, dietary calcium and phosphate and potentially dietary cholesterol interact with vitamin D exposure on its bioavailability, transport, distribution in body pools, metabolism and action as well as on bone and non-bone health outcomes? The nature and mechanisms of U-shaped risk relationships with adverse health outcomes at higher exposure to vitamin D needs elucidated across the life cycle and reproductive stages.


Vacancy Details:Total Vacancy: 237 PostsPosts Name: 1. Anganwadi Worker: 121 posts2. Anganwadi Assistant: 116 postsAge Limit: The age of the Candidates age limit should be between 18 to 40 years.Essential Qualification:Candidates should have qualification in this Recruitment process they must have Passed Matric for Anganwadi Worker, 8th Class for Anganwadi Assistant.

How to Apply:

Interested and Eligible Candidates can send their fully filled application form requires all documents to Child Development Project Office in on or before Within 15 days from the date of Advertisement.or Click on the below to Apply links.

Download NotificationOfficial Website: http://patna.bih.nic.inDates to Remember:Date of Advertisement: 28-12-2017.Last Date for Receipt of Application: Within 15 days from the date of Advertisement.

ICDS Bihar Recruitment 2016 : Ministry of Women and Child Development Department, Integrated Child Development Services (ICDS), Bihar has Released Recruitment Notification for Consultant, Accountant, Project Associate, DPA, Dist Coordinator 47 posts.all Eligible and Interested Candidates can apply on or before 07-05-2016.Further Detailed Information Regarding Educational Qualifications, Age Limit, Selection Procedure, Exam Pattern, Syllabus For is mentioned below, in this post or on the notification that available on the official website that is: http://espace.icdsbih.gov.in/