Background
==========

Leonurine, one of the main active components of the traditional Chinese medicine*Leonurus japonicus*, has a wide range of biological activities \[[@b1-medscimonit-26-e922149]\]. Leonurine has been widely applied in treatment of gynecological diseases in the past \[[@b2-medscimonit-26-e922149]\]. Purified leonurine (molecular structure formula: C~14~H~21~CIN~3~O~5~) is a nitrogenous compound used in the form of a white crystalline powder. Recent research shows that leonurine has obvious effects on protecting nerves \[[@b3-medscimonit-26-e922149]\] and promoting growth of synapses, as well as promoting neurite outgrowth and neurotrophic activity \[[@b4-medscimonit-26-e922149]\], alleviating LPS-induced myocarditis \[[@b5-medscimonit-26-e922149]\], and preventing and treating non-alcoholic fatty liver disease \[[@b6-medscimonit-26-e922149]\]. Leonurine is also toxic, mainly affecting the kidneys, liver, and reproductive system \[[@b7-medscimonit-26-e922149],[@b8-medscimonit-26-e922149]\]. However, the toxicity of leonurine to the respiratory system has been unclear.

Previous studies \[[@b9-medscimonit-26-e922149],[@b10-medscimonit-26-e922149]\] showed that many kinds of traditional Chinese medicine are toxic to the respiratory system, such as total saponins of*Cortex albiziae* (isolated from stem bark of *Albizzia julibrissin Durazz*), which can induce apoptosis of mouse bronchial epithelial cells and results in oxidative damage to lung tissues. The traditional Chinese medicine-induced respiratory diseases mainly include drug-induced pulmonary edema, drug-induced asthma, drug-induced pneumonia, and drug-induced pulmonary vascular diseases \[[@b11-medscimonit-26-e922149]\]. Moreover, drug-induced DNA damage and cell apoptosis can eventually lead to cytotoxicity and other adverse effects in cells \[[@b12-medscimonit-26-e922149]\]. Therefore, with the development of research on the pharmacological effects of leonurine on the respiratory system and with its increased clinical use, there is an urgent need to assess the toxicity of leonurine to the respiratory system.

Drug activity is usually affected by pharmacokinetic and pharmacodynamic factors. Cytochrome P450 (CYP450), as an enzyme of phase I reaction, is a critical pharmacokinetic factor \[[@b13-medscimonit-26-e922149]\]. Recently, it has been found that CYP450 gene polymorphism is closely related to cancer susceptibility \[[@b14-medscimonit-26-e922149]\]. Many carcinogens need activation by the CYP450 enzyme to exert toxicity. The carcinogenic aromatics in smog can be activated by CYP1A1 \[[@b15-medscimonit-26-e922149]\], and aflatoxins are mainly metabolized by CYP1A2 and 3A4 enzyme \[[@b16-medscimonit-26-e922149]\]. However, a recent study \[[@b17-medscimonit-26-e922149]\] reported that CYP1A1, 1A2, 2A13, 2B6, 3A4, and the other P450 metabolic enzymes are highly expressed in the respiratory system. These P450 metabolic enzymes can oxidize, reduce, or hydrolyze the related prototypes to produce a series of toxic substances. However, the main metabolic enzymes for leonurine in the respiratory system have not been fully assessed.

To determine the main metabolic enzyme targeting leonurine in lung tissues, we must clarify the metabolic activity of leonurine and prevent occurrence of adverse reactions. Therefore, the present study explored the effect of highly-expressed CYP450 enzymes in human lung epithelial cells (BEAS-2B) on the metabolic activity of leonurine. This study aimed to provide a theoretical basis for evaluating the toxicity of leonurine in the respiratory system.

Material and Methods
====================

Cell and plasmid synthesis
--------------------------

In this study, CYP1A1, 1A2, 2A13, 2B6, and 3A4 gene-expressing lentivirus plasmids pYr-Lvsh-CYP450s were synthesized by MiaoLing Bio. Sci. Tech. Co. (Wuhan, China). The related lentivirus expression plasmids (pMD2G and psPAX) were purchased from MiaoLing Bio. Sci. Tech. Co. (Wuhan, China). After sequencing and identification, the Lentivirus Expression System plasmids of CYP450, including pYr-Lvsh-CYP1A1, pYr-Lvsh-1A2, pYr-Lvsh-2A13, pYr-Lvsh-2B6, and pYr-Lvsh-3A4, were successfully constructed.

Construction of lentivirus vector
---------------------------------

Human lung epithelial cells (BEAS-2B) and 293T cells (ATCC Cell Bank, Manassas, VA, USA) were cultured in DMEM complete medium (Gibco BRL. Co., Grand Island, New York, USA) at 37°C and 5% CO~2~. The 293T cells at logarithmic growth stage were digested and sub-cultured into a cell plate and cultured to 80% confluence. A total of 3 μg pMD2G, 6 μg psPAX, 7.5 μg vector plasmids, 25 μl Lipofectamine 2000 Transfection Reagent (Invitrogen/Life Technologies, Carlsbad, CA, USA), and 150 μl OPTI-MEM (Gibco BRL. Co.) were mixed together. The mixture was rested at room temperature for 15 min, then we added it dropwise to cell plates and mixed it. After 6-h culture, the DMEM was replaced with fresh DMEM containing 10% fetal bovine serum (FBS, Gibco BRL. Co.).

Lentivirus infection
--------------------

When BEAS-2B cells reached 80--90% confluence, the collected lentivirus solution was added to cell plates. The cells were transfected with the above synthesized lentivirus vectors and cultured for 24 h. This transfection was repeated 3 times. Finally, BEAS-2B cells were purified and screened using puromycin (Sigma-Aldrich, St. Louis, MO, USA).

Western blot analysis showed that CYP450s expressed BEAS-2B
-----------------------------------------------------------

Cells were washed twice with phosphate-buffered saline (PBS, Sangon Biotech. Co., Shanghai, China), lysed using Tris lysate (Tiangen Biotech Co., Beijing, China) for 1 min, and then cracked by ultrasound. After centrifugation at 10 000 rpm, the supernatant was harvested and stored at −20°C. The concentration of harvested protein was measured using a BCA protein assay kit (Cat. No. P0011, Beyotime Biotech, Shanghai, China). Then, the proteins were loaded onto SDS-PAGE gel and transferred onto PVDF membranes (Amersham Biosciences, Piscataway, NJ, USA). The PVDF membranes were blocked with 5% FBS for 1 h and then incubated with rabbit anti-human 1A1 antibody (Cat. No. AB10088), rabbit anti-human 1A2 antibody (Cat. No. AB1248), rabbit anti-human 2A13 (Cat. No. ABN201), rabbit anti-human 2B6 (Cat. No. AB1267), rabbit anti-human 3A4 antibody (Cat. No. MAB10041), and rabbit anti-human GAPDH antibody (Cat. No. MAB374) overnight at 4°C. Then, PVDF membranes were incubated using HRP-labeled goat anti-rabbit IgG (Cat. No. AP307P) at room temperature for 2 h. All of the above antibodies were purchased from Sigma-Aldrich (St. Louis, MO, USA). The protein bands were imaged with electrochemiluminescence (ECL, Amersham Biosciences) and analyzed using the UVP gel image scanning system (version: Labworks 4.6, Bio-Rad Laboratories, Hercules, CA, USA).

RT-PCR showed that CYP450s expressed BEAS-2B
--------------------------------------------

The total RNAs were extracted using Trizol reagent (Invitrogen/Life Technologies), and then reverse-transcribed into cDNA. The synthesized cDNAs were used as the template for PCR amplification. The PCR amplification procedure was: pre-denaturation at 95°C for 5 min, denaturation at 94°C for 30 s, annealing at 55°C for 1 min, with 40 cycles, and then extension at 72°C for 10 min. GAPDH was used as an internal reference gene and identified using 1% agarose gel electrophoresis (Beyotime Biotech). Premiers for PCR assay are listed in [Table 1](#t1-medscimonit-26-e922149){ref-type="table"}. The 2^−ΔΔCt^ method \[[@b18-medscimonit-26-e922149]\] was used to analyze the RT-PCR findings.

Cell Counting Kit 8 (CCK-8) assay
---------------------------------

The leonurine standard solution was prepared as follows: a total of 10 mg leonurine standard was weighed and dissolved in double-distilled water to prepare the leonurine standard solution at a final concentration of 1000 μg/ml. Then, the solution was diluted into 100 μg/ml and 10 μg/ml standard solutions.

The cells at logarithmic growth stage were inoculated into 96-well plates at a density of 1×10^4^ cells/ml. Then, 200 μl of cells was added into each well and cultured in an incubator for 24 h. Cells were divided into 6 groups: B-2B, B-1A1, B-1A2, B-2A13, B-2B6, and B-3A4. Each group was incubated in advance with the standard prepared leonurine. The final concentration of leonurine in each group was adjusted to 0 μg/ml, 1 μg/ml, 10 μg/ml, 100 μg/ml, respectively. About 24 h after cell culture, 20 μl CCK-8 was added into each well and placed into the incubator for 1 h. The optical density (OD) value of each pore at 450 nm was determined using a microplate reader (Model: 680, Bio-Rad Laboratories, Hercules, CA, USA). In this study, the "cell viability" was defined as the ratios of the OD values in 1 μg/ml, 10 μg/ml, and 100 μg/ml leonurine-treated cells to the OD value in the 0 μg/ml leonurine-treated cells in every group (B-2B, B-1A1, B-1A2, B-2A13, B-2B6, and B-3A4).

Metabolism *in vitro*
---------------------

Five P450 recombinant enzymes -- CYP1A1, 1A2, 2A13, 2B6, and 3A4 -- were metabolized *in vitro*. The incubation system was as follows: leonurine (final concentration 0.06 mg/ml, MedChemExpress, Princeton, NJ, USA), recombinase (final concentration 0.06 mg/ml, Sigma-Aldrich), Tris-HCl (final concentration 50 mmol/l, Beyotime Biotech), MgCl2 (final concentration 5 mmol/l, Sigma-Aldrich), and EDTA (final concentration 1 mmol/l, Sigma-Aldrich). Then, NADPH was added to initiate the reaction and continue incubation at 37°C. For the 0-min group, the reaction was terminated using methanol directly. For the 120-min group, methanol was added after the incubation for 120 min to stop the reaction.

UPLC-HRMS analysis
------------------

The leonurine samples were analyzed using UPLC-HRMS analysis as previously described \[[@b19-medscimonit-26-e922149]\]. Briefly, the LC-MS/MS system (Model: TSQ800, Thermo Fisher Scientific, USA) was used, following the manufacturer's protocols. Leonurine was carried out in positive ionization mode. The source temperature was adjusted to 320°C. The ion source voltage was adjusted to 3200 V. Flows of nebulizer, curtain, and collision nitrogen were optimized to maximize the signal intensity ratio. The transition ranging from m/z (312.1553) to m/z (181.0484) (40% collision-energy) was monitored for leonurine. The time window for the UPLC-HRMS mode was defined as 0--7 min.

Statistical analysis
--------------------

Measurement data were recorded as mean±standard deviation (SD) and analyzed using SPSS software 20.0 (SPSS, Inc., Chicago, IL, USA). The Tukey's post hoc test-validated ANOVA was used to compare data among groups. *p*\<0.05 was defined as a significant difference.

Results
=======

Stable CYP450-expressing cell line was successfully constructed
---------------------------------------------------------------

The PCR results showed that there were bands at 1500 bp in each CYP450-expressing cell line ([Figure 1A](#f1-medscimonit-26-e922149){ref-type="fig"}), which indicates that CYP1A1, 1A2, 2A13, 2B6, and 3A4 were stably overexpressed in BEAS-2B cells. Western blot assay also showed that CYP1A1, 1A2, 2A13, 2B6, and 3A4 protein expressions in each experimental group were significantly higher compared to that in each control group ([Figure 1B](#f1-medscimonit-26-e922149){ref-type="fig"}, *F*=5.307, *p*=0.024), indicating that CYP450 was successfully expressed in BEAS-2B cells. The above PCR assay and Western blot assay suggest that the stable CYP450-expressing cell line was successfully constructed.

Primary and secondary mass spectra of leonurine
-----------------------------------------------

After incubation with CYP1A1, 1A2, 2A13, 2B6, and 3A4 enzymes, the main metabolic enzymes for leonurine were screened ([Figure 2](#f2-medscimonit-26-e922149){ref-type="fig"}). According to the primary mass spectra ([Figure 2A](#f2-medscimonit-26-e922149){ref-type="fig"}) and secondary mass spectra ([Figure 2B](#f2-medscimonit-26-e922149){ref-type="fig"}) of leonurine, the main metabolic enzymes were 312.1550 \[H +\] and 181.0484.

CYP2A13 decreased the concentration of leonurine
------------------------------------------------

The results of metabolic removal rate showed that, compared to the control group, the concentration of leonurine in CYP2A13 group was significantly lower ([Figures 2](#f2-medscimonit-26-e922149){ref-type="fig"}, [3](#f3-medscimonit-26-e922149){ref-type="fig"}). However, there were no significant changes in the other groups ([Figure 3](#f3-medscimonit-26-e922149){ref-type="fig"}). These results suggest that CYP2A13 is the main metabolic enzyme for leonurine in BEAS-2B cells.

CYP2A13 demonstrated higher clearance rate of leonurine
-------------------------------------------------------

In this study, the clearance rates of leonurine in different CYP450s enzymes-treated groups were determined. The results showed that, compared to the 0-min group, the clearance rate of leonurine in the CYP2A13-treated group was significantly lower at 120 min after treatment ([Figure 4](#f4-medscimonit-26-e922149){ref-type="fig"}, *F*=7.273, *p*=0.007). However, there were no significant differences in the clearance of leonurine in the other CYP450s-treated groups at 120 min after treatment compared to that at 0 min ([Figure 4](#f4-medscimonit-26-e922149){ref-type="fig"}, *F*=2.607, *p*=0.075).

CYP2A13 induced the cytotoxicity of leonurine
---------------------------------------------

The cytotoxicity of BEAS-2B cells treated with different dosages of leonurine was measured using CCK-8 assay. The results indicated that after increasing the concentration of leonurine, there were no significant effects of leonurine on cytotoxicity to BEAS-2B cells in the 1A1 group (*F*=1.015, *p*=0.594), 1A2 group (*F*=0.892, *p*=0.603), 2B6 group (*F*=0.791, *p*=0.714), and 3A4 group (*F*=1.203, *p*=0.591) ([Figure 5](#f5-medscimonit-26-e922149){ref-type="fig"}). However, different dosages of CYP2A13 treatment (10 μg/ml and 100 μg/ml) significantly reduced the cell viability of leonurine compared to that in the control group ([Figure 5](#f5-medscimonit-26-e922149){ref-type="fig"}, *F*=5.291, *p*=0.029). Therefore, the CYP2A13 treatment can by cytotoxic to BEAS-2B cells.

Discussion
==========

In recent years, clinical use of leonurine has increased, but its toxicity to the respiratory system has not been fully studied. A previous study \[[@b20-medscimonit-26-e922149]\] found that respiratory system damage is mainly caused by air pollution, but ignored the toxicity of drugs. The current high incidence of respiratory diseases suggests that the respiratory toxicity caused by drugs might play an important role \[[@b21-medscimonit-26-e922149]\]. A previous study \[[@b22-medscimonit-26-e922149]\] reported that leonurine can significantly inhibit the proliferation of lung cancer H292 cells by inducing cell cycle arrest in G0/G1 cells. The activation of leonurine mainly depends on binding of glucuronic acid molecules \[[@b23-medscimonit-26-e922149]\]; therefore, it is crucial to determine the metabolic enzymes for leonurine. Our results showed that CYP2A13 was the main metabolic enzyme for leonurine in human lung epithelial cells. CCK-8 results also showed that cell activity in the CYP2A13 metabolic enzyme group was significantly inhibited, but there was no significant difference among the other groups. These results suggest that leonurine is metabolized and activated by CYP2A13 in the respiratory system, finally leading to cytotoxicity.

Human cytochrome P4502A13 (CYP2A13) is a member of the cytochrome P450 family and acts as an enzyme for metabolism of exogenous chemicals in the human body \[[@b24-medscimonit-26-e922149]\]. CYP2A13 is usually found in the respiratory system and demonstrates metabolic effects on 5-hydroxymethylfurfural (5-HMF), nicotine, coumarin, and aflatoxin \[[@b25-medscimonit-26-e922149]\]. In recent years, it has reported that the CYP450 gene is altered in cancer patients. Słowikowski et al. \[[@b26-medscimonit-26-e922149]\] reported that CYP1B1 expression in lung cancer patients is significantly inhibited. It has also been shown that CYP2A13 is significantly increased in patients with non-small cell lung cancer \[[@b27-medscimonit-26-e922149]\]. The present results showed that leonurine was metabolized to a toxic metabolite by CYP2A13, which further induced cytotoxicity. However, the specific mechanism underlying this cytotoxicity was not defined in the present study. A previous study \[[@b28-medscimonit-26-e922149]\] also reported that CYP2A13 induces lung cancer \[[@b28-medscimonit-26-e922149]\]. Therefore, leonurine could be used as a therapeutic drug for controlling respiratory system-associated diseases.

To explore the main metabolic enzymes for leonurine in the respiratory system, we selected the human normal pulmonary epithelial cell line BEAS-2B. Our preliminary experiments proved that CYP450s are not detected in BEAS-2B cells. Therefore, the CYP metabolic enzyme gene was stably transfected by molecular biological means to construct a cell model in this study, and the successful construction of the cell line was also demonstrated by the high protein and mRNA levels.

According to a previous study \[[@b29-medscimonit-26-e922149]\], cell activity is related to tumor development. Changes in cell activity can reflect cell damage, and even affect the imbalance of tumor-suppressor genes and oncogenes. Therefore, CCK-8 assay was used to detect cell activity to preliminarily assess the cytotoxicity of leonurine to cells after CYP2A13 metabolic activation. Compared with CYP2A13, leonurine demonstrated little effect on the cell activity of the other groups. However, the activity of CYP2A13 cells rapidly decreased in a dose-dependent manner, which is consistent with the high metabolic activation rate of leonurine in our*in vitro* incubation experiment. CYP2A13 also demonstrated a higher clearance rate of leonurine and induced higher leonurine cytotoxicity. All the above results suggest that CYP2A13 is a main metabolic enzyme for leonurine, while activated leonurine might have a cytostatic effect on CYP2A13 expressed cells.

Although this study produced some interesting findings, there are also a few limitations. First, the kind of reaction catalyzed by CYP2A13 on leonurine was not analyzed in this study. Second, this study only investigated the effects of CYP2A13 on leonurine in human BEAS-2B cells*in vitro*, but not*in vivo*. Also, whether the toxic activity of leonurine is biologically possible in the human respiratory system was not determined. Therefore, the optimal concentration (toxic activity) reached by leonurine in the human respiratory system has not been clarified, which is important for the further clinical use of leonurine. Third, this study did not investigate the effects of leonurine on cancer and associated mechanisms. In subsequent research, we plan to further assess the effects of leonurine and to perform relevant epidemiological investigations.

Conclusions
===========

In this study, BEAS-2B cells overexpressing CYP450s enzymes were constructed. We screened the main metabolic enzymes for leonurine in human lung epithelial cells through cell activity experiments and*in vitro* incubation experiments. This study confirmed that leonurine can be effectively activated in human lung epithelial cells through CYP2A13, and it can cause cytotoxicity to BEAS-2B cells. Therefore, CYP2A13 is the main metabolic enzyme of leonurine in human lung epithelial cells. The present findings may provide a theoretical basis for investigations of the toxicity and functions of the CYP2A13 gene and leonurine in the respiratory system.

**Conflict of interest**

None.

**Source of support:** This study was funded by the Basic Research Plan of Jiangsu Province (Natural Science Foundation)-Youth Fund Project (Grant No. BK20180678), Project of "Nursing Science" Funded by Priority Discipline Development Program of Jiangsu Higher Education Institutions (General Office, the People's Government of Jiangsu Province, Grant No. \[2018\]-No.87) and the Project of "Nursing Science" Funded by the Key Discipline Program of Jiangsu Province during the 13^th^ five-year plan (Teaching and Research Office, the People's Government of Jiangsu Province, Grant No. \[2016\]-No. 9)

![mRNA and protein identification of BEAS-2B cell line. (**A**) PCR assay validation of cell lines. (**B**) Western blot verification of cell lines.](medscimonit-26-e922149-g001){#f1-medscimonit-26-e922149}

![Chromatogram and mass spectrum of leonurine. (**A**) Primary mass spectrum (resolution R=70000). (**B**) Secondary mass spectrum (resolution R=13500).](medscimonit-26-e922149-g002){#f2-medscimonit-26-e922149}

![Chromatogram of leonurine standard solution and reaction in CYP450 enzyme system after 120 min.](medscimonit-26-e922149-g003){#f3-medscimonit-26-e922149}

![Clearance rate of leonurine in BEAS-2B cells undergoing CYP450 enzyme treatments. \*\* *p*\<0.01 *vs.* Control group.](medscimonit-26-e922149-g004){#f4-medscimonit-26-e922149}

![Determination of cytotoxicity in BEAS-2B cells undergoing CYP450 enzyme treatments. \* *p*\<0.05 *vs.* Control group.](medscimonit-26-e922149-g005){#f5-medscimonit-26-e922149}

######

Primers for CYP450s amplification for PCR assay.

  Enzyme genes                             Sequences (5′-3′)
  -------------- ------------------------- ---------------------------
  CYP1A1         Forward                   GATTCCTTTTCCCAATCTCCATGTC
  Reverse        CTAAGAGCGCAGCTGCATTTGGA
  CYP1A2         Forward                   GAATTCGCATTGTCCCAGTCTG
  Reverse        TCAATTGATGGAGAAGCGCAGC
  CYP2A13        Forward                   GAATTCCTGGCCTCAGGGCT
  Reverse        TCAGCGGGGCAGGAAGCTCA
  CYP2B6         Forward                   GAATTCGAACTCAGCGTCCTCC
  Reverse        TCAGCGGGGCAGGAAGC
  CYP3A4         Forward                   GAATTCGCTCTCATCCCAGACTT
  Reverse        TCAGGCTCCACTTACGGTGC

[^1]: Study Design

[^2]: Data Collection

[^3]: Statistical Analysis

[^4]: Data Interpretation

[^5]: Manuscript Preparation

[^6]: Literature Search

[^7]: Funds Collection

[^8]: Ting Xu and Xuxu Li contributed to the work equally and should be regarded as co-first authors


Hei, denne artikkelen er over ett år gammel og kan inneholde utdatert informasjon

En ny undersøkelse fra Actis viser at bare 12 prosent av befolkningen støtter legalisering av cannabis. Det kan så være, men i et demokrati har betydelige mindretall krav på rettigheter og å slippe forfølgelse. Om ikke mindretall har rettigheter, har vi et flertallstyranni. 5,1 prosent av den norske befolkningen brukte cannabis i 2013. Grovt regnet er det til enhver tid altså rundt to hundre tusen som bruker rusmiddelet. Bare ni prosent av disse utvikler avhengighet, et tall som er litt lavere enn for alkohol. Disse har krav på frivillig hjelp. Resten har krav på å få være i fred.

Da Berlinmuren falt, var det selve symbolet på at den autoritære ideologien som understøttet systemet som falt. Systemet lot seg rett og slett ikke opprettholde lenger, både fra et menneskelig perspektiv og fra et kostnadsperspektiv.

På samme måte holder muren på å falle i narkotikapolitikken.

Den nyvalgte statsministeren Justin Trudeau og Det liberaldemokratiske partiet vant valget i Canada med stort flertall. Trudeau har lovet å legalisere og regulere marihuana for å fjerne det kriminelle elementet og innføre restriksjoner som beskytter barn og unge og respekterer voksne kanadiere sine egne valg.

At fem amerikanske delstater legaliserer cannabis gjennom borgerinitiativer er én ting. At myndighetene i Canada, som har et godt internasjonalt renommé, gjør det samme er en helt annen. Canada er en forbilledlig nasjon som er kjent for sin toleranse og sine demokratiske idealer.

Hadde det bare vært Canada, kunne man kanskje trukket på skuldrene. Men det er ikke det. Sveits går også i bresjen for en mer human narkotikapolitikk i FN. I fjor anbefalte både Human Rights Watch og Verdens helseorganisasjon avkriminalisering av bruk og besittelse av narkotika. Av demokratiske hensyn, og av hensyn til smittevern: overhengende straff hindrer mennesker i å oppsøke og motta hjelp og skadereduserende tiltak. I tillegg har man vært kritiske til den grusomme interneringen og henrettelser av narkotikabrukere i Asia og Midtøsten. Vår politikk har sendt et signal om at dette er greit.

Når Canada og Sveits går denne veien, er ikke lenger den moraliserende ideologien som understøtter de internasjonale konvensjonene som opprettholder krigen mot narkotika forsvarbare. Menneskesynet og mangelen på kunnskap som lå til grunn er gått ut på dato. Det beste alternativet er å legalisere og regulere cannabis, det nest beste er avkriminalisering. Det ble det ikke spurt om i Actis? undersøkelse.


package main

import (
	"fmt"
	"time"

	"github.com/gizak/termui"
)

// TermUISingle is a termUI implementation of UI interface.
type TermUISingle struct {
	Title      *termui.Paragraph
	Status     *termui.Paragraph
	Sparklines map[VarName]*termui.Sparkline
	Sparkline  *termui.Sparklines
	Pars       []*termui.Paragraph
}

// Init creates widgets, sets sizes and labels.
func (t *TermUISingle) Init(data UIData) error {
	err := termui.Init()
	if err != nil {
		return err
	}

	t.Sparklines = make(map[VarName]*termui.Sparkline)

	t.Title = func() *termui.Paragraph {
		p := termui.NewParagraph("")
		p.Height = 3
		p.TextFgColor = termui.ColorWhite
		p.Border = true
		p.BorderLabel = "Services Monitor"
		p.BorderFg = termui.ColorCyan
		return p
	}()
	t.Status = func() *termui.Paragraph {
		p := termui.NewParagraph("")
		p.Height = 3
		p.TextFgColor = termui.ColorWhite
		p.Border = true
		p.BorderLabel = "Status"
		p.BorderFg = termui.ColorCyan
		return p
	}()

	t.Pars = make([]*termui.Paragraph, len(data.Vars))
	for i, name := range data.Vars {
		par := termui.NewParagraph("")
		par.TextFgColor = colorByKind(name.Kind())
		par.Border = true
		par.BorderLabel = name.Short()
		par.BorderLabelFg = termui.ColorGreen
		par.Height = 3
		t.Pars[i] = par
	}

	var sparklines []termui.Sparkline
	for _, name := range data.Vars {
		spl := termui.NewSparkline()
		spl.Height = 1
		spl.TitleColor = colorByKind(name.Kind())
		spl.LineColor = colorByKind(name.Kind())
		spl.Title = name.Long()
		sparklines = append(sparklines, spl)
	}

	t.Sparkline = func() *termui.Sparklines {
		s := termui.NewSparklines(sparklines...)
		s.Height = 2*len(sparklines) + 2
		s.Border = true
		s.BorderLabel = fmt.Sprintf("Monitoring")
		return s
	}()

	t.Relayout()

	return nil
}

// Update updates UI widgets from UIData.
func (t *TermUISingle) Update(data UIData) {
	// single mode assumes we have one service only to monitor
	service := data.Services[0]

	t.Title.Text = fmt.Sprintf("monitoring %s every %v, press q to quit", service.Name, *interval)
	t.Status.Text = fmt.Sprintf("Last update: %v", data.LastTimestamp.Format(time.Stamp))

	// Pars
	for i, name := range data.Vars {
		t.Pars[i].Text = service.Value(name)
	}

	// Sparklines
	for i, name := range data.Vars {
		spl := &t.Sparkline.Lines[i]

		max := formatMax(service.Max(name))
		spl.Title = fmt.Sprintf("%s: %v%s", name.Long(), service.Value(name), max)
		spl.TitleColor = colorByKind(name.Kind())
		spl.LineColor = colorByKind(name.Kind())

		if name.Kind() == KindString {
			continue
		}
		spl.Data = service.Values(name)
	}

	t.Relayout()

	var widgets []termui.Bufferer
	widgets = append(widgets, t.Title, t.Status, t.Sparkline)
	for _, par := range t.Pars {
		widgets = append(widgets, par)
	}
	termui.Render(widgets...)
}

// Close shuts down UI module.
func (t *TermUISingle) Close() {
	termui.Close()
}

// Relayout recalculates widgets sizes and coords.
func (t *TermUISingle) Relayout() {
	tw, th := termui.TermWidth(), termui.TermHeight()
	h := th

	// First row: Title and Status pars
	firstRowH := 3
	t.Title.Height = firstRowH
	t.Title.Width = tw / 2
	if tw%2 == 1 {
		t.Title.Width++
	}
	t.Status.Height = firstRowH
	t.Status.Width = tw / 2
	t.Status.X = t.Title.X + t.Title.Width
	h -= firstRowH

	// Second row: lists
	secondRowH := 3
	num := len(t.Pars)
	parW := tw / num
	for i, par := range t.Pars {
		par.Y = th - h
		par.Width = parW
		par.Height = secondRowH
		par.X = i * parW
	}
	if num*parW < tw {
		t.Pars[num-1].Width = tw - ((num - 1) * parW)
	}
	h -= secondRowH

	// Third row: Sparklines
	t.Sparkline.Width = tw
	t.Sparkline.Height = h
	t.Sparkline.Y = th - h
}

func formatMax(max interface{}) string {
	var str string
	if max != nil {
		str = fmt.Sprintf(" (max: %v)", max)
	}
	return str
}


Getting My tiny bikini To Work

Getting My tiny bikini To Work

Thongs appear in many different styles depending on the thickness, materials, or kind of the rear percentage of cloth and can be found for the two men and girls throughout the majority of the world.

A dance belt is a variety of thong meant to be Utilized in precisely the same method as an athletic supporter, but for male dancers (specifically in ballet).[28] Its function is to shield and support the dancer in the course of dance functions without the need of becoming witnessed by outer clothes, like tights, leotard, health club leggings or shorts.

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The origin with the term thong from the English language is from Old English thwong, a flexible leather wire.[three]

Address up in the floral embroidered beach costume or maybe a lace kaftan for your boho-come to feel. Want the components to select it? We’re naming mirrored shades and suede espadrilles given that the go-to styling items.

Established and entirely owned by CEO Yang Yang and well known while in the sector for producing the word "clubwear" Amiclubwear.com is an included Gals's garments shop primarily based out of on the list of country's most popular style capitals Los Angeles. With around ninety% of It truly is Place of work employees being woman AMI is really "a optimistic place for ladies" Read through A lot more

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- ตัดเย็บด้วยลูกไม้ตัดต่อผ้าเน็ตเต็มตัว

Several tribal peoples, for example many of the Khoisan persons of southern Africa, wore thongs For lots of generations. Much like the Japanese fundoshi, these early clothes were produced Using the male genitalia in mind.

Considered with the front, the thong ordinarily resembles a bikini base, but in the again the material is diminished to the least. Thongs are almost always meant to protect the genitals, anus, and perineum, and leave aspect or a lot of the buttocks uncovered. The again on the garment typically contains a thin waistband and a skinny strip of material, meant to be worn among the buttocks, that connects the middle on the waistband with the bottom entrance of the garment.

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Kaupinam is often a thong worn in India, by some Adult men for a loincloth or underclothing. It truly is built up of rectangular strip of cotton cloth and that is used to go over the genitals with the assistance of the strings connected to the 4 finishes in the fabric for binding it within the waist on the wearer.

Attitudes towards the sporting of g-strings differ geographically and across societies, as is standard with extremely revealing apparel. Ahead of its entrance into mainstream trend, g-strings had been largely worn by unique dancers. In the modern Western planet, g-strings tend to be more normally marketed in the direction of women but are worn by both equally sexes.

From the early-2000s, thongs manufactured up 31% in the Ladies's underwear market.[fifteen] Even so, inside the late-2000s, the exposure of the thong previously mentioned 1's trousers became a lot less common and also the trend turned to your donning of lower-Driving thongs that barely show higher than trousers, other than when bending or twisting.


Block polycationic oligonucleotide derivative: synthesis and inhibition of herpes virus reproduction.
The block polycationic oligonucleotide (oligo) consisting of a phosphodiester 12-mer linked to the polycation chain at the 3'-end and cholesteryl group at the 5'-end was synthesized. The polycation chain was grown on the solid support using the monomer, H-phosphonate of 1-O-(4,4'-dimethoxytrityl)-1,3-butanediol. Amino groups were introduced in the polymer backbone using 1,4-diaminobutane, and then the oligo chain was formed at the free end of the polymer. The last stage of the synthesis was the attachment of the cholesteryl group to the 5'-end of the oligo prior to cleavage and deprotection of the copolymer. The nucleotide sequence of this copolymer, CGTTCCTCCTGC, was complementary to the splicing site of immediate early (IE) mRNA 4 and 5 of herpes simplex virus type 1 (HSV-1). The stability of the duplexes formed between the copolymer and the complementary 12-mer was similar to that of unmodified oligo. The stability of the block polycationic oligo against phosphodiesterase digestion was significantly increased compared to that of the unmodified oligo. The block polycationic oligo inhibited the reproduction of HSV-1 in Vero cells; however, the effect was significantly less than the effect of 12-mer oligo modified with cholesterol at the 5'-end. The decreased antiviral activity of the copolymer is explained by the polycation-induced stimulation of the virus infection.


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When sick patients switch primary care physicians: the impact on AMCs participating in capitation.
Patients facing catastrophic illness often desire choice when selecting specialist physicians and will sometimes request specialists at academic medical centers (AMCs). Under capitated payment systems, community primary care physician (PCP) gatekeepers have an incentive to refer patients to local specialists with whom they regularly collaborate rather than to AMC specialists, who generally are more expensive and with whom they may not have working relationships. As a result of the financial pressures of capitation and the desire to work with familiar specialists, some PCPs in community-based risk-sharing groups are reluctant to refer sick patients in capitated health plans to AMC-affiliated specialists. Forced to choose between their existing primary care relationships and their desired specialists, some patients are terminating their existing primary care relationships to enroll with PCPs affiliated with the AMCs to which they wish to be referred. The authors' observations at their AMC indicate that most of the patients leaving their PCPs in the community do so to gain access to oncology and surgical specialty services. The shifting of sick patients in capitated health plans to AMC-affiliated PCPs creates a financial burden for both AMCs and their affiliated physicians. Health plans and AMCs must cooperate in developing a solution; for example, risk-adjust each risk unit's capitation payment based on the health status and disease burden of its population. The authors propose strategies aimed at enabling patients to have access to AMC tertiary care services while ensuring that the cost of caring for the sickest patients is not borne solely by AMC risk groups. They conclude that it is in the best interests of all concerned to modify the current counterproductive incentives that promote the problems they have described.


Q:

What is the difference between confidence intervals and hypothesis testing?

I have read about controversies regarding hypothesis testing  with some commentators suggesting that hypothesis testing should not be used. Some commentators suggest that confidence intervals should be used instead.

What is the difference between confidence intervals and hypothesis testing? Explanation with reference and examples would be appreciated.

A:

You can use a confidence interval (CI) for hypothesis testing.  In the typical case, if the CI for an effect does not span 0 then you can reject the null hypothesis. But a CI can be used for more, whereas reporting whether it has been passed is the limit of the usefulness of a test.
The reason you're recommended to use CI instead of just a t-test, for example, is because then you can do more than just test hypotheses.  You can make a statement about the range of effects you believe to be likely (the ones in the CI).  You can't do that with just a t-test.  You can also use it to make statements about the null, which you can't do with a t-test.  If the t-test doesn't reject the null then you just say that you can't reject the null, which isn't saying much.  But if you have a narrow confidence interval around the null then you can suggest that the null, or a value close to it, is likely the true value and suggest the effect of the treatment, or independent variable, is too small to be meaningful (or that your experiment doesn't have enough power and precision to detect an effect important to you because the CI includes both that effect and 0).
Added Later:
I really should have said that, while you can use a CI like a test it isn't one. It's an estimate of a range where you think the parameter values lies. You can make test like inferences but you're just so much better off never talking about it that way.
Which is better?
A) The effect is 0.6, t(29) = 2.8, p < 0.05. This statistically significant effect is... (some discussion ensues about this statistical significance without any mention of or even strong ability to discuss the practical implication of the magnitude of the finding... under a Neyman-Pearson framework the magnitude of the t and p values is pretty much meaningless and all you can discuss is whether the effect is present or isn't found to be present. You can never really talk about there not actually being an effect based on the test.)
or
B) Using a 95% confidence interval I estimate the effect to be between 0.2 and 1.0. (some discussion ensues talking about the actual effect of interest, whether it's plausible values are ones that have any particular meaning and any use of the word significant for exactly what it's supposed to mean. In addition, the width of the CI can go directly to a discussion of whether this is a strong finding or whether you can only reach a more tentative conclusion)
If you took a basic statistics class you might initially gravitate toward A. And there may be some cases where it is a better way to report a result. But for most work B is by far and away superior. A range estimate is not a test.

A:

There is an equivalence between hypothesis tests and confidence intervals. (see e.g. http://en.wikipedia.org/wiki/Confidence_interval#Statistical_hypothesis_testing)  I'll give a very specific example.  Suppose we have sample $x_1, x_2, \ldots, x_n$ from a normal distribution with mean $\mu$ and variance 1, which we'll write as $\mathcal N(\mu,1)$.  Suppose we think that $\mu = m$, and we want to test the null-hypothesis $H_0: \mu = m$, at level $0.05.$ So we make a test statistic, which in this case we will take to be the sample average: $v = (x_1 + x_2 + \cdots + x_n ) / n$.  Now suppose $A(m)$ is the "acceptance region" for $v$ for this test. That means that $A(m)$ is the set of possible values of $v$ for which the null-hypothesis $\mu=m$ is accepted at level 0.05 (I use "accepted" as a shorthand for "not rejected" -- I am not suggesting that you would conclude the null hypothesis is true.).  For this example, we can look at the $\mathcal N(m,1)$ normal distribution and choose any set that has probability at least 0.95 under this distribution. Now, a 95% confidence region for $\mu$ is the set of all $m$ for which $v$ is in $A(m)$.  In other words, it is the set of all $m$ for which the null-hypothesis would be accepted for the observed $v$.  That's why John says "If the CI for an effect does not span $0$ then you can reject the null hypothesis." (John is referring to the case of testing $\mu = 0$.)
A related topic is the p-value.  The p-value is the smallest level for a test at which we would reject the null-hypothesis.  To tie it in with the discussion of confidence intervals, suppose we get a particular sample average $v$, from which we construct confidence intervals of different sizes.  Suppose a 95% confidence interval for $\mu$ does not contain $m$.  Then we can reject the null-hypothesis $\mu=m$ at level $0.05.$  Then suppose we grow the confidence interval until it just touches (but doesn't include) the value $m$, and suppose this is a 98% confidence interval.  Then the p-value for the hypothesis $\mu=m$ is $0.02$ (which we get from $1-0.98$).

A:

'Student' argued for confidence intervals on the grounds that they could show which effects were more important as well as which were more significant.
For example, if you found two effects where the first had a confidence interval for its financial impact from £5 to £6, while the second had a confidence interval from £200 to £2800.   The first is more statistically significant but the second is probably more important.


Q:

Vlookup dynamic range reference from a different sheet

I am inserting a vlookup formula in a range of cells. The formula however has a dynamic reference in it, and I am having hard time in constructing it correctly.
Here is my code:
Sheets("Count").Activate

Dim myValue As Date
myValue = InputBox("Please enter the date you want to update")
Sheets("Count").Range("A1").Value = myValue

Dim ra As Range, raEnd As Range
Dim date1 As Date
date1 = Range("A1")

Set ra = Cells.Find(What:=date1 _
                    , LookIn:=xlFormulas _
                    , LookAt:=xlPart _
                    , SearchOrder:=xlByRows _
                    , SearchDirection:=xlNext _
                    , MatchCase:=False _
                    , SearchFormat:=False)

    If ra Is Nothing Then
    MsgBox ("Date not found, check the format.")

    Else

        Dim Lastrow As Long, rng As Range
        Lastrow = Cells(Rows.Count, "B").End(xlUp).Row
        Set rng = Range(ra.Offset(1, 0), Cells(Lastrow, ra.Column))

        Dim endrow As Long, i As Long, lcol As Integer, startcells As Range
        lcol = Sheets("Count").Range("B1").Value
        endrow = Sheets("Input").Cells(Rows.Count, lcol).End(xlUp).Row
        i = 6
        Set startcells = Sheets("Input").Cells(i, lcol)

        Sheets("Input").Activate

        Dim xrnge As Range, s
        Set xrnge = Range(startcells, Cells(endrow, lcol))
        s = xrnge.Address

        Sheets("Count").Activate
        rng.Formula = "=IFERROR(VLOOKUP($B8,'" & "input" & "'!s,1,0),"""")"

    End If

End Sub

The part that I cannot make work is
rng.Formula = "=IFERROR(VLOOKUP($B8,'" & "input" & "'!s,1,0),"""")"

I think I am almost there because in the range where I want to insert the formula looks like this:
=IFERROR(VLOOKUP($B20;Input!s;1;0);"")

Could you help me to figure out why it shows s and not the range itself?

A:

If I understand correctly you want s to hold a range address, and input to be a static sheet reference. In that case, you should write your formula as so:
rng.Formula = "=IFERROR(VLOOKUP($B8,input!" & s & ",1,0),"""")"

Say s holds the address for range S3:S50 the result in cell will be:
=IFERROR(VLOOKUP($B8,Input!$S$3:$S$50,1,0),"")

Which will be a working formula as expected.


                                                                          Supreme Court

                                                                          No. 2019-470-M.P.

           In re M.G.                           :

                                          ORDER

       The Supreme Court’s Committee on Character and Fitness (committee) filed with the Court

a recommendation, pursuant to Article II, Rule 4(c) of the Supreme Court Rules on Admission of

Attorneys and Others to Practice Law, that the Applicant, M.G. (M.G. or applicant),1 be granted

admission to the Rhode Island Bar.

       The applicant, an out-of-state lawyer authorized to practice law in Delaware, was hired by

Duffy & Sweeney, Ltd. (Duffy & Sweeney), a Rhode Island law firm with a single office located

in Providence, Rhode Island, as an associate attorney. The applicant commenced working at Duffy

& Sweeney as an associate in June 2018 and shortly thereafter was listed as an associate on the

firm’s webpage.

       In November 2018, M.G. filed a petition for admission to the Rhode Island Bar. The

applicant was subsequently referred to the full committee due to concerns that applicant’s

employment as an associate attorney at Duffy & Sweeney constituted the unauthorized practice of

law under Article V, Rule 5.5 of the Supreme Court Rules of Professional Conduct.

       Rule 5.5, titled “Unauthorized practice of law; Multijurisdictional practice of law,” in

pertinent part, provides:

               “(b) A lawyer who is not admitted to practice in this jurisdiction
               shall not:

               “(1) except as authorized by these Rules or other law, establish an
               office or other systematic and continuous presence in this
               jurisdiction for the practice of law; or

1
  Because the Court grants applicant admission to the bar, we will refer to the applicant by his
initials.
                                              -1-
               “(2) hold out to the public or otherwise represent that the lawyer is
               admitted to practice law in this jurisdiction.”

       On June 5, 2019, applicant appeared with counsel (a partner at Duffy & Sweeny) to address

the Rule 5.5 concerns. Based upon applicant’s testimony, the committee was satisfied that

applicant had performed the work of a legal assistant supervised by two of the firm’s partners and

had not practiced law in Rhode Island, but the committee also concluded that reference to applicant

as an associate on the firm’s webpage was a violation of Rule 5.5(b)(2). The committee further

found that applicant’s petition did not raise any additional concerns and that applicant had

otherwise demonstrated that he was of good moral character and fitness to practice law. Therefore,

notwithstanding the perceived violation of Rule 5.5, the committee recommended that applicant

be granted full admission to the Rhode Island Bar.

       The Court is mindful that the partners at Duffy & Sweeney assigned the title of associate

to the applicant and that the partners held out the applicant as authorized to practice law in Rhode

Island by referring to him as an associate on the firm’s website. The Court is not inclined to

penalize the applicant for the conduct of Duffy & Sweeney as it relates to the facts presented here.

The Court would remind all attorneys that, as officers of the Court, they are expected to lead by

example and to guide our future lawyers as to the conduct that is appropriate under our Court rules.

We deem it prudent to remind the partners at Duffy & Sweeney of their professional obligation

under Rule 5.5(a) that “[a] lawyer shall not practice law in a jurisdiction in violation of the

regulation of the legal profession in that jurisdiction, or assist another in doing so.”

       For these reasons, we accept the recommendation of the committee and hereby grant the

applicant’s petition for admission to the Rhode Island Bar.

               Entered as an Order of this Court this 13th day of December 2019.

                                                 -2-
      By Order,

                  /s/______
      Clerk

-3-
STATE OF RHODE ISLAND AND                                   PROVIDENCE PLANTATIONS

                        SUPREME COURT – CLERK’S OFFICE

                                 ORDER COVER SHEET

Title of Case                        In re M.G.
                                     No. 2019-470-M.P.
Case Number
                                     December 13, 2019
Date Order Filed
                                     Suttell, C.J., Goldberg, Flaherty, Robinson, and
Justices
                                     Indeglia, JJ.
                                     Character and Fitness Committee
Source of Appeal
                                     N/A
Judicial Officer From Lower Court
                                     For Committee:

                                     Julie P. Hamil, Esq.
Attorney(s) on Appeal
                                     For Applicant:

                                     Stacey Nakasian, Esq.
                                     Robert K. Taylor, Esq.

SU‐CMS‐02B (revised November 2016)


A computer glitch that brought the Paris airport of Orly to a standstill Saturday has been traced back to the airport's "prehistoric" operating system. In an article published Wednesday, French satirical weekly Le Canard Enchaîné (which often writes serious stories, such as this one) said the computer failure had affected a system known as DECOR, which is used by air traffic controllers to communicate weather information to pilots. Pilots rely on the system when weather conditions are poor.

DECOR, which is used in takeoff and landings, runs on Windows 3.1, an operating system that came onto the market in 1992. Hardly state-of-the-art technology. One of the highlights of Windows 3.1 when it came out was the inclusion of Minesweeper — a single-player video game that was responsible for wasting hours of PC owners' time in the early '90s.

DECOR's breakdown on Saturday prevented air traffic controllers from providing pilots with Runway Visual Range, or RVR, information — a value that determines the distance a pilot can see down the runway. As fog descended onto the runway and engineers battled to find the origin of the glitch, flights were grounded as a precaution.

"The tools used by Aéroports de Paris controllers run on four different operating systems, that are all between 10 and 20 years old," explained Alexandre Fiacre, the secretary general of France's UNSA-IESSA air traffic controller union. ADP is the company that runs both Orly and Paris' other airport, Charles de Gaulle, one of the busiest in the world.

"Some of ADP's machines run on UNIX [an operating system favored by universities and start-ups in the '80s], but also Windows XP," said Fiacre, who works as an aviation security systems engineer.

"The issue with a system that old is that people don't like to do maintenance work," explained Fiacre. "Furthermore, we are starting to lose the expertise [to deal] with that type of operating system. In Paris, we have only three specialists who can deal with DECOR-related issues," said Fiacre.

"One of them is retiring next year, and we haven't found anyone to replace him," he added.

Fiacre compared the challenges of running the Windows 3.1-supported DECOR to the issues faced by NASA with its Voyager program, which was launched in 1977. Voyager 1 and Voyager 2, the two robotic probes that are used by NASA to study the outer solar system, rely on 250 kHz central processing units made by General Electric.

These 40 year-old computers are less powerful than today's pocket calculators, and use out-of-date programming languages like FORTRAN, which means that, with the impending retirement of the last engineer from the original Voyager mission, NASA will soon be recruiting a new expert on 1970s computer programming.

Punched card from a FORTRAN program (via Wikimedia Commons)

French aviation systems engineers face their own maintenance challenges, compounded by the unavailability of spare parts for these outdated machines. "Sometimes we have to go rummaging on eBay to replace certain parts," said Fiacre. "In any case, these machines were not designed to keep working for more than 20 years."

According to Le Canard Enchaîné, France's transport minister has promised that "equipment will be upgraded by 2017." But Fiacre is not so sure about this timeline. "In my opinion, we'll upgrade in 2019 at the earliest, perhaps even in 2021," he said.

Fiacre described Saturday's breakdown as a "warning," but noted that the systems failure had in no way "endangered passengers, since [air traffic] controllers took a number of precautionary measures to eliminate all risk."

ADP has not yet released a statement concerning Saturday's disruption of air traffic.

The grounding of flights in Paris is not the first incident to highlight the lack of airport resources and the use of outdated systems to ensure safety in the skies, and not just in France.

In December 2014, airspace over London was closed for 36 minutes and some fifty flights were canceled following a computer failure that was later blamed on 50-year-old software.

Earlier this year, two hackers were awarded one million "bug bounty" air miles each by United Airlines after flagging up flaws in the company's web security system.

One person who was put out by Saturday's air traffic disruption is French politician Alain Juppé, one of the contenders in the primaries for the French Republican Party's 2017 presidential nomination. Juppé was due to fly to Paris from the southwestern city of Bordeaux to attend a party conference.

Au moment de décoller de Bx,Orly est fermé.Impossible de rejoindre le Conseil national LR à temps. Dommage!J'avais préparé un bon discours. — Alain Juppé (@alainjuppe)November 7, 2015

About to take off from Bordeaux, Orly is closed. Unable to get to Republican national council on time. Shame! I had prepared a good speech.

An aviation engineer interviewed by Le Canard Enchaîné Wednesday raised the possibility of similar disruptions during the UN's COP 21 climate change conference, which will be held in Paris, from November 30 to December 11. "Imagine, during COP 21, the comings and goings of heads of state being disrupted because of prehistoric software," he told the weekly.


Q:

Shuffle array after 3rd element in foreach ? PHP

I need shuffle $items after 3rd element.
Result should be :
1 2 3 6 7 9 8 5 4
My is Code:
<?php
    $items= range(1, 10); shuffle($items); foreach($items as $v):
?>
   ...
<?php
  endforeach;
?>

Cant find any solution in stackoverflow or google.
How can I do this ?
Thanks in advance.

A:

Split the array in two parts and merge them after the suffle.
Edit; I now use array_splice to split the array at 3 and shuffle the remaining then merge them.
$items = range(1,10);
$items1= array_splice($items, 0,3);
shuffle($items);

$result = array_merge($items1, $items);
Var_dump($result);

https://3v4l.org/iUQ1m


I read an article today about the pop star, Olly Murs and his battle with anxiety. He talks about a mistake he made on the tv show ‘X Factor’ and how he found counselling had helped him get over the anxiety of making the mistake again. He talks about how he was struggling with negative automatic thoughts such as “Why am I doing this? I can’t do it. What if I go and say something bad again on TV? What if I make a mistake?”, when he was offered a role on another show ‘The Voice’.

According to Olly (calling him ‘Olly’ sounds like I know him, which feels a bit strange), he was the target of ‘online trolls’. While I couldn’t tell you about the levels of abuse he experienced, it demonstrates how heavily we can be affected by the thoughts, feelings and opinions of others. Murs goes on to say (calling him Murs isn’t any better, it sounds like I don’t like him either!) “And I made myself ill, literally ill. Sick with worry and anxiety to the point where I was home for three or four days with sweats, headaches, and I never get ill. I felt really tired and lethargic and hot and my heart was, I was having panic attacks”.

Our greatest glory is not in never falling, but in rising every time we fall. — Confucius

This man was affected so badly, his anxiety levels spiralled out of control to the point he was physically sick. And yet, he had probably not met any of those people who abused him and likely never will. So what was going on with Olly Murs and why did these people cause him so much anxiety? I should point out here, I don’t know a lot about Olly Murs and I’m only working with the information I have but as human beings, we are constantly taking in “data” from our “perceptual field” such as what our friends think about what we are wearing, who likes the music we like, who makes me feel angry, who makes me feel happy, etc etc and what we do with this data is where the “problem” can occur.

To understand why the opinions of others can cause us so much anxiety, we have to go back to childhood. We learn at a very young age how to “get our needs met”. For example, babies quickly learn that if they cry when they are hungry, someone will come and feed them. A baby gets its needs met by crying until somebody comes and feeds them. The baby learns that each time they cry, they will be fed.

As a baby learns how to get milk, young children learn what gets them into trouble and what doesn’t. A child will learn what it will get praise for and what it doesn’t get praised for. If we get a good score in a test, we get praise. If we kick a football through a window, we get into trouble. And it’s usually in childhood we find the root of our problems and the causes of much of our anxiety. If a child learns that the best way to avoid getting into trouble is to do what their Mum or Dad says (or primary care giver to be totally inclusive) then this is often a learnt behaviour which is carried into adulthood.

A star is born!

Many performers in the public eye or “celebrities” find this “skill” very useful. By learning to please Mum and Dad they get praise. If they are a talented singer for example, they will find they get praise from lots of other people too. They quickly become known as “the child who is really good at singing” and this is either incorporated into the persons self concept or not. In the case of a performer, it would most likely be taken in and becomes part of their self; a star is born! The problem or so it seems like to me it is in Olly Murs’ case, is that he didn’t know what to do with the criticism. And when I say he didn’t know what to do with it I mean he didn’t know how to incorporate it into his self concept.

Hard times don’t create heroes. It is during the hard times when the ‘hero’ within us is revealed. – Bob Riley

While I’m only speculating here, maybe there was a time in his childhood when he found a way to get his needs met by entertaining people. Maybe that was singing or dancing or making people laugh. It is possible he found that he was given attention by making people take notice of him and he enjoyed the confidence he got from it. We could speculate that there’s part of him thats not so sure of himself and not so confident and when the internet trolls said things that didn’t “fit” with what he usually heard about himself, that didn’t fit with his self concept of a confident man, he found it incredibly hard to accept and couldn’t incorporate it into his self concept, otherwise known as an ‘introject’.

We all need to be like Rambo, don’t we?

I think most men out there can probably relate to how that feels. When I was a child, I used to watch tv shows like ‘the A-Team’ with B.A (Bad Attitude) Baracus, ‘He-Man’, ‘Thundercats’, WWF/E Wrestling’ and movies like ‘Die-Hard’, ‘Rambo’ and ‘Predator’ all which featured macho heroes who saved the day! All big strong guys with lots of confidence and no sign of anxiety!

Too many of us are not living our dreams because we are living our fears. – Les Brown

This made me think all guys were “macho” and if you weren’t saving the world, there was something wrong with you. If you lacked confidence you weren’t a “real man”. I found it really difficult to accept if anybody said anything about me that could be deemed “feminine” or touched on my emotions. Another problem was I found it really hard to take any praise for anything that I didn’t consider to be masculine and found it even harder to tell people how I felt for fear of being “a sissy”. I certainly couldn’t tell anyone I was lacking in confidence or I felt anxiety about something!

There’s no way He-man had anxiety, did he?

As I got older, I really struggled with my own sense of self. I wasn’t built like a truck with huge rippling biceps and I wasn’t a member of the SAS! My confidence was really lacking but couldn’t admit it. I noticed lots of things made me anxious but I wouldn’t tell anyone. I really struggled to accept myself for who I was. And this is where counselling can help. We take the opinions of others such as our parents, friends, relatives, tv, magazines, movies, social media etc and we use the information provided to us to get our needs met.

In my case, I thought that because I saw a lot of machoism on tv that was what the world wanted me to be; a confident man who never talked about his “feelings” because nothing worried him enough to have to. When I couldn’t be what I thought I should be, it caused psychological tension with the real me; my authentic self and this resulted in a great deal of anxiety.

My authentic self just wanted to be me and the me who wanted to play video games and kick a football around, not join the army and fight in a war I didn’t agree with the politics of (Iraq)! It took time and a lot of counselling but eventually I learn’t that counselling can be for me and men can ask for help without having to fear being called “weak” or “girly”.

Believe in yourself. You are braver than you think, more talented than you know, and capable of more than you imagine. ― Roy T. Bennett

If you feel a sense of anxiety about who you are and feel as though you “lack confidence”, I’ve been there. I know what it’s like and I know what it takes to accept yourself. I can help. If you’re looking for a counsellor who understands and can put themselves in your shoes and feel how you feel, get in touch.


Windows 3.1x is a family of Windows versions following Windows 3.0 initially released in 1992. It added TrueType support and included multimedia components by default. System stability was greatly increased compared to Windows 3.0, while the user interface was refined and improved. Support for real mode was dropped, and in further updates, Standard mode was dropped as well. It was succeeded by Windows 95 released in 1995.

The first release was Windows 3.1 in 1992. Windows for Workgroups 3.1 was released alongside Windows 3.1 in 1992 and featured support for networking. It was updated to Windows for Workgroups 3.11 in 1993, whose core was also backported to Windows 3.1 as an update. A separate simplified-Chinese release called Windows 3.2 was also made, fixing problems related to the input of Chinese characters.


/**
 * @file DistributedTopologyConfig.h
 * @author Zhongxia Li
 * @date Sep 21, 2011
 * @brief
 */
#ifndef DISTRIBUTED_CONFIG_H_
#define DISTRIBUTED_CONFIG_H_

#include <node-manager/Sf1rTopology.h>

#include <sstream>

namespace sf1r
{

class DistributedCommonConfig
{
public:
    std::string toString()
    {
        std::stringstream ss;
        ss << "[DistributedCommonConfig]" << std::endl
           << "cluster id: " << clusterId_ << std::endl
           << "username: " << userName_ << std::endl
           << "localhost: " << localHost_ << std::endl
           << "BA Port: " << baPort_ << std::endl
           << "worker server port: " << workerPort_ << std::endl
           << "master server port: " << masterPort_  << std::endl
           << "data receiver port: " << dataRecvPort_ << std::endl
           << "file sync rpc port: " << filesync_rpcport_ << std::endl
           << "file check level: " << check_level_ << std::endl;
        return ss.str();
    }

public:
    std::string clusterId_;
    std::string userName_;
    std::string localHost_;
    unsigned int baPort_;
    unsigned int workerPort_;
    unsigned int masterPort_;
    unsigned int dataRecvPort_;
    unsigned int filesync_rpcport_;
    unsigned int check_level_;
};

class DistributedTopologyConfig
{
public:
    DistributedTopologyConfig()
        : enabled_(false)
    {
    }

    std::string toString()
    {
        std::stringstream ss;
        ss << "==== [DistributedTopology] ====" << std::endl;
        ss << (enabled_ ? "enabled":"disabled") << std::endl;
        ss << sf1rTopology_.toString();
        ss << "==============================="<<std::endl;
        return ss.str();
    }

public:
    bool enabled_;
    Sf1rTopology sf1rTopology_;
};

}

#endif /* DISTRIBUTED_CONFIG_H_ */


                         COURT OF APPEALS
                         SECOND DISTRICT OF TEXAS
                              FORT WORTH

                             NO. 02-17-00156-CR

HECTOR JIMENEZ                                                      APPELLANT

                                       V.

THE STATE OF TEXAS                                                       STATE

                                    ----------

          FROM THE 362ND DISTRICT COURT OF DENTON COUNTY
                     TRIAL COURT NO. F16-1456-362

                                    ----------

                         MEMORANDUM OPINION1

                                    ----------

      Appellant Hector Jimenez appeals from his retaliation conviction and

sixteen-year sentence.   In a single issue, he asserts that the evidence was

insufficient to support his conviction. Because a rational fact-finder could have

found each element of retaliation beyond a reasonable doubt, we affirm the trial

court’s judgment.

      1
       See Tex. R. App. P. 47.4.
      On April 23, 2016, Officer Antonio Barletta, a certified police officer with the

Lewisville Police Department, stopped a car driven by Jimenez because Barletta

reasonably suspected Jimenez of driving while intoxicated.           When Barletta

approached Jimenez’s car, he smelled alcohol and noticed that Jimenez’s eyes

were watery. At Barletta’s request, Jimenez attempted, but failed, a horizontal-

gaze-nystagmus test and then refused any further field-sobriety testing. Barletta

arrested Jimenez and handcuffed him. Jimenez “started becoming upset” and

once he was in the back of Barletta’s patrol car, Jimenez began threatening

Barletta and his family:

      When [Barletta and another officer] patted [Jimenez] down and got
      him in the back of the car, [Jimenez] said several things. He wanted
      [Barletta’s] children to get sodomized and decapitated, called
      [Barletta] a lot of other words.

             ....

              . . . In the beginning, [Jimenez] was just . . . talking smack,
      calling [Barletta] a bunch of curse words. On the ride to the jail is
      when he started saying that his posse is going to load [Barletta] up
      [i.e., “fill [Barletta] up with bullets”]. [Barletta] better wear [his]
      bulletproof vest. [Jimenez] said he’ll kill [Barletta] tomorrow when he
      gets out. [Jimenez] said he’ll be out tomorrow. He said he’s going to
      kill [Barletta] when he sees [him].

Barletta believed these threats were based on his arrest of Jimenez. Jimenez

also began banging his head against the back of the front seat and kicking the

backseat window.

      A grand jury indicted Jimenez with retaliation and included two

punishment-enhancement paragraphs based on his 1994 conviction for burglary

                                          2
of a building and on his 2013 conviction for assault against a public servant.

Jimenez pleaded true to the second enhancement paragraph and not guilty to

the charged offense.2 At trial, Barletta testified to Jimenez’s statements after his

arrest and stated that because driving-while-intoxicated arrestees commonly are

released the next day, Barletta was concerned for his three children. A jury

found Jimenez guilty of retaliation, found the enhancement paragraph true as

instructed by the trial court, and assessed his punishment at sixteen years’

confinement.

      Jimenez appeals and argues that the evidence was insufficient to support

his conviction because “no rational factfinder could have found” him guilty of the

charged offense.3 In our due-process review of the sufficiency of the evidence to

      2
       The record does not reflect if the State waived the first enhancement
paragraph, alleging Jimenez’s 1994 conviction for burglary of a building; but
Jimenez pleaded true to and the jury was charged on only the second
enhancement paragraph, alleging Jimenez’s 2013 conviction for assault against
a public servant. See generally Tex. Penal Code Ann. § 12.42(a), (d) (West
Supp. 2017) (providing for enhanced punishments if convicted of third-degree
felony with one prior felony conviction and if convicted of any non-state-jail felony
with two prior felony convictions). At punishment, the jury heard evidence of
several of Jimenez’s prior convictions, including the burglary conviction. See
Tex. Code Crim. Proc. Ann. art. 37.07, § 3 (West Supp. 2017).
      3
       Jimenez does not specify why the evidence was insufficient, point out
which retaliation elements had no supporting evidence, or cite any authority
supporting his position other than citing cases on the general standard of review.
Generally, we would conclude that Jimenez insufficiently briefed this issue and
would overrule it as such. See Tex. R. App. P. 38.1(i); McDuff v. State,
939 S.W.2d 607, 613 (Tex. Crim. App. 1997); Stevens v. State, Nos. 02-10-
00139-CR, 02-10-00140-CR, 02-10-00141-CR, 2011 WL 5119572, at *4 (Tex.
App.—Fort Worth Oct. 27, 2011, no pet.) (mem. op., not designated for
publication). But to be cautious and mindful of the dictate that we must construe

                                         3
support Jimenez’s conviction, we view all of the evidence in the light most

favorable to the verdict to determine whether any rational trier of fact could have

found the elements of retaliation beyond a reasonable doubt. See Jackson v.

Virginia, 443 U.S. 307, 319 (1979); Jenkins v. State, 493 S.W.3d 583, 599 (Tex.

Crim. App. 2016).

      To convict Jimenez of retaliation, the State was required to produce

evidence that he intentionally or knowingly threatened to harm another by an

unlawful act in retaliation for or on account of the service or status of another as

a public servant. See Tex. Penal Code Ann. § 36.06(a)(1)(A) (West 2016); Riley

v. State, 965 S.W.2d 1, 2 (Tex. App.—Houston [1st Dist.] 1997, pet. ref’d).

Although police officers are not included in the statutory definition of public

servants, courts have routinely interpreted the term to include police officers such

as Barletta.   See Tex. Penal Code Ann. § 1.07(a)(41) (West Supp. 2017),

§ 36.06(b)(3); see, e.g., Bryson v. State, 807 S.W.2d 742, 745–46 (Tex. Crim.

App. 1991); Carriere v. State, 84 S.W.3d 753, 757 (Tex. App.—Houston [1st

Dist.] 2002, pets. ref’d). Jimenez did not threaten Barletta and his children until

after Barletta arrested him for driving while intoxicated, supporting a finding that

Jimenez’s threats were a result of Barletta arresting him—on account of

Barletta’s service as a police officer. See, e.g., Martin v. State, Nos. 09-15-

00087-CR, 09-15-00088-CR, 2017 WL 218270, at *3 (Tex. App.—Beaumont Jan.

briefing rules liberally, we will address Jimenez’s sufficiency argument. See Tex.
R. App. P. 38.9.

                                         4
18, 2017, pet. ref’d) (mem. op., not designated for publication); Brock v. State,

495 S.W.3d 1, 16–18 (Tex. App.—Waco 2016, pet. ref’d); Wiggins v. State,

255 S.W.3d 766, 773 (Tex. App.—Texarkana 2008, no pet.); Hughes v. State,

No. 01-01-00698-CR, 2002 WL 2025434, at *1–2 (Tex. App.—Houston [1st Dist.]

Aug. 30, 2002, pet. ref’d) (not designated for publication); cf. Helleson v. State,

5 S.W.3d 393, 395 (Tex. App.—Fort Worth 1999, pet. ref’d) (finding evidence of

defendant’s post-arrest, violent threats to police officer factually sufficient to

support retaliation conviction).   Indeed, Barletta’s belief was that Jimenez’s

threats were a result of his functions as a police officer. We conclude that the

evidence allowed a rational fact-finder to find that Jimenez committed the offense

of retaliation beyond a reasonable doubt. See, e.g., Wiggins, 255 S.W.3d at 773;

Hughes, 2002 WL 2025434, at *1–2.

      Accordingly, we overrule Jimenez’s sole issue and affirm the trial court’s

judgment. See Tex. R. App. P. 43.2(a).

                                                   /s/ Lee Gabriel

                                                   LEE GABRIEL
                                                   JUSTICE

PANEL: SUDDERTH, C.J.; MEIER and GABRIEL, JJ.

DO NOT PUBLISH
Tex. R. App. P. 47.2(b)

DELIVERED: June 7, 2018

                                         5


Vote for your local unsung football hero in Suffolk FA awards

Entries are now being invited for the FA Community Awards 2016, presented by McDonald’s.

The annual awards, which are into their sixth year, are designed to celebrate the work that is carried out by football’s unsung heroes across Suffolk.

The accolades are split into seven categories: FA Charter Standard Club of the Year, FA Charter Standard Community Club of the Year. FA Charter Standard Development Club of the Year. FA Charter Standard League of the Year. FA Young Volunteer of the Year (under 25), FA Volunteer of the Year and the People’s Award for outstanding contribution to community football.

Each category will be judged at county and then regional level, from which a national shortlist will be created.

“This is a fantastic opportunity to nominate those individuals you know who give up hours each week to help run football in Suffolk,” said FA development manager Nathan French.

“We are so fortunate to have so many brilliant volunteers in clubs and leagues across the county and we all know that grassroots football wouldn’t happen without them.

“With over 6,500 volunteers involved in football across Suffolk on a weekly basis, it would be great if some of these individuals could receive local and maybe even regional or national recognition for all they do.”

Entries are open until Thursday, March 31 and you can find out how to cast your nomination by visiting www.suffolkfa.com

Trending

Peter Wrighton’s wound was so bad PC though pensioner’s own dog had attacked him


April 3, 2010

Security Checks on Flights to U.S. to Be Revamped

The intelligence-based security system is devised to raise flags about travelers whose names do not appear on no-fly watch lists, but whose travel patterns or personal traits create suspicions. The system is intended to pick up fragments of information — family name, nationality, age or even partial passport number — and match them against intelligence reports to sound alarm bells before a passenger boards a plane….

The bombing attempt exposed significant flaws in how the administration collected and shared intelligence reports. The president said the government had sufficient information to uncover the terror plot to bring down the commercial jetliner, but had “failed to connect those dots.”

While the United States has never formally confirmed the names of the 14 countries where passport holders face automatic additional scrutiny, they have been widely reported. Administration officials said terrorist organizations had turned their recruiting efforts elsewhere.


A simple and rapid immunochromatographic strip test for detecting antibody to porcine reproductive and respiratory syndrome virus.
Porcine reproductive and respiratory syndrome is rapidly gaining worldwide importance as one of the most economically significant diseases of swine. The antibody of Porcine reproductive and respiratory syndrome virus (PRRSV) is detected currently by the combined use of an enzyme-linked immunosorbent assay, serum neutralization test, immunoperoxidase monolayer assay, indirect immunofluorescent antibody test. These methods are time-consuming and require specialized equipment operated by trained technicians. The purpose of this study was to evaluate a simple strip assay (based on a chromatographic and immunogold system) for specific detection of PRRSV antibody in swine sera. This "immunochromatographic strip" test uses Escherichia coli-expressed viral recombinant membrane protein antigen in combination with recombinant nucleocapsid protein as capture protein for detecting antibodies against PRRSV. In this study, the performance of this assay was evaluated with sera from both clinical samples and experimentally infected piglets. Detection by immunochromatographic strip test was compared with detection by a standard, available commercially, indirect enzyme-linked immunosorbent assay and an immunoperoxidase monolayer assay. The immunochromatographic test strip detected antibodies in sera known to contain antibodies to PRRSV in 95.7% sensitivity of samples from pigs infected experimentally and 98.6% sensitivity of clinical serum samples. For sera that did not contain antibodies to PRRSV, the specificity was 97.8% and 98.2% for clinical and experimental serum samples, respectively.


Review: Premier Manager 2012 (After 1.01 Update)

Written By Games Lover on Senin, 30 Januari 2012 | 06.17

Football loving PC gamers don’t realise how lucky they are. For the past 20 years they’ve had access to a series of consistently brilliant management games, allowing them to experience the challenges, joys and frustrations of managing a top-level football club. But what about console gamers? Sure there have been attempts in the past, and pretty good ones, but there’s also been a lot of yawnsome toss. So up steps Premier Manager 2012, aiming for the top corner.

But early reviews were fairly negative, pointing out that the time each game took ruined the flow of the game. Well, we held fire on our review, gave it some extras hours and waited for the inevitable update. And sure enough, version 1.01 has arrived with a key change that might just rescue Premier Manager from an embarrassing early cup exit at the hands of Burton Albion.

Your first sessions with the game don’t give you much hope. The menus themselves are similar in design to the PS3′s XMB and finding the options you need can be tricky while you learn your way around. It’s also sometimes difficult to work out how to do various things; even advancing to the next day took 5 minutes to figure out after the first time I ventured away from the home screen. The controls are oddly mapped as well, with the circle button advancing the game and R1 bringing up the main menu – when we’re used to circle taking you back, it’s weird having to use it to advance the game.

But once you’ve taken the time to work out how everything works, it’s easy enough to zip through the menus, setting your team up and hunting for players to improve your squad. The transfers themselves are easy enough to carry out, although the searching options and transfer process is extremely streamlined, giving you only the basic options. Match tactics are a similar story, with a few options easy to change (formations, attacking bias, passing style) but impossible to fine tune, but this in itself isn’t a huge issue. Console gamers generally aren’t after the same experience as PC fans, and if you’re used to playing games in bursts of an hour or so then this slimmer structure will suit you perfectly.

Something that makes life harder is the background music. It’s bad. Really bad. Not in the same way as being forced into a 24 hour Robbie Williams-athon, just in a very repetitive, boring “please stop” way (actually that is the same thing…). If the option was there to listen to your own background music from the XMB then it would make Premier Manager a very relaxing experience, combining laid back and casual management with some music time, but there isn’t. You can turn the music off totally (phew) but it’s not the ideal solution, especially considering there must be plenty of system resources available while the game is running. The rest of the game’s sounds are functional bongs, swooshes and more bongs that do a job but will hardly pick up awards, so it’s probably worth just turning the sound off completely and putting the radio on.

But what of the matches themselves? Well, they’re slow. Even with the match speed set to “Fast” you’ll be watching each one for good couple of minutes, and the engine used to watch each game isn’t exactly flushed with detail. The pitch view is too small to be helpful, and the commentary is just a list of shots, bookings and goals. Hardly enough to judge how the match is going. They’re a bit of a waste of time really, and apart from making the odd substitution you might as well use the saving grace that 1.01 offers: the “Result Only” option.

After updating, you can now head into the menu and turn on an option that allows you to skip the match completely and just see the result. You still get to see stats of the game and player ratings, so you can see if your new signing is performing or if the new formation worked out well. You just don’t need to sit and watch a game play out that you can’t, in any way, speed up sufficiently or have much control over.

It’s a game changer. Instead of sitting down and playing a few matches you can now rattle through half a season easily in one sitting. The limitation of the game are still there; they haven’t changed the music, added more depth or found any official licenses hiding down the back of the sofa, but the flow of the game has increased considerably, even if it detaches you a little from the action.

But then there’s the issue of the price. If Premier Manager 2012 had a bargain price tag it would be easy to recommend to people after a bit of light-hearted, accessible managing, but it’s £13.99 which, by PSN standards, is a chunky request. And is there really enough here to spend that much money on? I’m not sure. It’s not a bad game by any means, but if you’ve got access to a reasonable PC then there shouldn’t be any competition on which way to look. It’s one of those games where someone asks you if it’s any good, and you just shrug and say “yeah it’s alright, not bad, not great…”. Worth looking into if you really fancy some management on your PS3 (especially with the new update) but it’s a lot of cash if you’re just a bit intrigued.

So Premier Manager 2012 got past the tricky 1st round tie, but ended up losing on penalties to Walsall. Maybe next year, eh?


WHO activities towards the three Rs in the development and control of biological products.
WHO supports the concept of replacement, reduction and refinement of the use of in vivo methods for biologicals production and control, and regularly conducts reviews of its recommended procedures to allow reduction in the use of animals. The coordination of collaborative studies, publication of standardized methods, and holding of workshops on the use of these methods contributes to their use. The neurovirulence test for oral poliovaccine is probably the single most visible animal test for which alternative methods are sought. Collaborative studies on alternative methods for screening products are currently being sponsored by WHO. The use of Vero cells rather than primary monkey kidney cells for poliovaccine production can avoid the use of many monkeys. Cell banks of Vero and HEp-2 cells have been developed by WHO, tested for virus sensitivity and freedom from adventitious agents, and are available for vaccine production and control, replacing primary animal cells. For the future, final product testing will increasingly be directed towards establishment of consistency of production rather than potency. By supporting the validation and use of this approach, WHO can effectively influence more rational animal use in biological production and control.


What I mean by this is that a book may have “feminist” female leads who are strong, competent, complex, whatever, but how do they portray women just...existing in the world? Are there women in the background, or is the fantasy novel with its strong independent Action Girl protagonists set on a background of generic male soldiers, guards, councilors, shopkeepers, messengers, and wizard apprentices? Are minor characters ever women when there’s no particular reason for them to be? When women appear in the background of your story, do they have any unique qualities that hint at a complex picture we’re not seeing or do they slide seamlessly into Pampered Noblewoman, Prostitute and Vaguely Maternal Older Woman Who Runs A Tavern Or Something?

If your protagonist is a fighter or magic user, do you show other women in those roles? If your society is more relaxed about sex discrimination, have you built a world that looks like it?

Have you built a world where your female characters don’t all have to be The Best At Everything, or is almost every female character placed where she can be extraordinary next to a bunch of male counterparts? Are you comfortable letting a female wizard or warrior be average or unimportant, or does she have to be one of the most skilled and powerful of them all, able to match or best all the men around her? On the other hand, are you comfortable having a female wizard or warrior be indisputably the most skilled or powerful out of the wizards or warriors, without drawing attention to her gender, placing her in competition with men, or having her be an exception to the rule because she’s female?

Are you letting your female characters be mediocre and un-extraordinary? Your world is full of powerful sorceresses, fierce battle maidens and calculating noblewomen, but do women do things in this world other than be Exemplary and Great and Awesome? If you’ve established that women do business and fight, do you have female soldiers carousing at bars and vaguely dull female Evil Minions Of The Dark Lord bumbling around doing evil bidding and female apprentices slacking on work or is every background woman we see competent and controlled and intelligent and doing whatever it is she’s doing without error, whereas only men are allowed to be foolish, impulsive, mess things up, or just be shown unflatteringly during the couple sentences we know them? In other words, does the world show women being unapologetically human beings or are all your female characters basically making up for being women by not doing anything that would badly represent their gender?

In particular, if you’re trying to show a society with gender equality, that means the dark lord is willing to hire women who are bumbling idiots as guards, and not just that some female wizards climbed their way to the top and became As Good As Men because they’re so badass they can snap god like a bunch of uncooked spaghetti.


In sports, everyone is a winner—some people just win better than others. Like the Wizards, who, despite long odds, left the annual Secaucus Bingo Night and Bad Suit Competition with the rights to try and not screw up John Wall.

The Wizards — represented by Abe Pollin's widow, pictured here at a screening of The Human Centipede — went into the lottery with a 10.3 percent shot at the first pick; now they get to spend the next few weeks pretending to deliberate between Wall and Evan Turner, while their fans send e-mails like this:

Subject line: Starting lineup

PG: Wall
SG: Arenas
SF: Lebron
PF: Blatche
C: Bryce Harper

Good for Wizards fans, and good for the Wizards themselves, a likable enough franchise (if you ignore both the grumpy interregnum when Michael Jordan inflicted himself on the front office and the team's kowtowing to the "they're all thugs" crowd in the wake of Gilbert Arenas's gun show). Evan Turner is going to make somebody very happy, at least when he's not throwing passes to the popcorn vendor. But it's a point guard's league now, and Wall immediately makes the Wizards very interesting, if not yet good. Let's see: John Wall, whatever's left of Arenas, a capable free agent whose eyes light up at the possibility of playing alongside Wall, JaVale McGee (if the Wizards ever realize he can play), maybe 20 minutes of Shaun Livingston a night. I'd watch that team lose by 10 to Memphis any day of the week.


Nonmyeloablative alternative donor transplants.
The advent of nonmyeloablative preparative regimens and the expected lower regimen-related toxicities associated with them hold significant promise for extension of the use of allogeneic hematopoietic stem cell transplantation. Nonmyeloablative hematopoietic stem cell transplantation using human leukocyte antigen matched sibling donor, which carries a relatively low risk of transplant-related complications and can result in impressive antitumor responses, may benefit older patients and patients with preexisting organ impairment. However, more than 65% of patients in need of this procedure lack a human leukocyte antigen matched sibling donor. Therefore, attention has focused on alternative donors such as genotypically matched unrelated donors and partially mismatched related donors. Early clinical results suggest that the use of alternative donors is feasible, therefore potentially allowing full extension of the benefits of allografting to the group of patients in highest need.


This week I released a short new PFF report on the S. 946, the "Kid-Friendly TV Programming Act of 2005." It would force all cable and satellite operators to offer a "child-friendly" tier of at least 15
channels of video programming. It's another misguided and unconstitutional attempt by Congress to regulate content on cable and satellite television. This new report can be found here and my earlier report on cable and satellite censorship can be found here.


"I should be able to do what I want and not worry about my daughter getting the hump with me and saying there's no changes being made," says Andrea. "I do use a lot of butter, because that's what I'm used to, but Rikki says I'm old and past it. I make traditional food, especially down at work, I'm serving hamburgers and fast food. If someone said to me, 'there's the same amount of customers there wanting to eat vegan food,' I'd do it."


Q:

Overwriting in a random access file

I have a random access file opened in "r+b" mode with records of equal length. Can I change the contents of a record after reading it and overwrite in place?
I tried the following code but on running I get: Segmentation fault(core dumped)
#include<stdio.h>

int main()
{
   struct tala {
      int rec_no;
      long file_no;
   };
   FILE *file_locking;
   struct tala t,f;
   file_locking = fopen("/path/to/my/file.bin", "rb+");
   t.rec_no = 1;
   t.file_no = 3;
   if (fwrite(&t, sizeof(struct tala),1,file_locking)==0)
      printf("Error opening file");
   t.rec_no=0;
   rewind(file_locking);
   if (fwrite(&t, sizeof(struct tala),1,file_locking)==0)
      printf("Error opening file");
   rewind(file_locking);
   if (fread(&f, sizeof(struct tala),1,file_locking)==0)
      printf("Error opening file");
   printf("\n %d",f.rec_no);
   printf("\n %ld", f.file_no);
   fclose(file_locking);
}

A:

Yes you can. Just remember to always fseek between reads and writes.
Quote the fopen man page:

Reads and writes may be intermixed on read/write streams in any order.  Note that ANSI C requires that a file positioning function intervene between output and input, unless an input operation encounters end-of-file.

Extra tip: always check the return value of fopen and related functions, and handle errors (use perror or strerror to print out what failed).


Enzyme induction by o-xylene inhalation.
Inhalation of 4500 mg o-xylene by rats was found to produce adaptational and pathologic changes in the liver by the end of the 1st week, reflected in an increase in relative liver weight, shortening of the hexobarbital sleeping time, an increase in the concentration of cytochrome P-450, with a decrease in the activities of aniline hydroxylase and of aminopyrine N-demethylase. Six weeks after the start of inhalations all the changes in the liver and in the mixed function oxydase system (MFO) were of an adaptational pattern characterized by an increase in relative liver weight as well as in cytochrome P-450 and b5 concentrations, a shortening of the hexobarbital sleeping time and an increase in the activity of aniline hydroxylase and of aminopyrine N-demethylase.