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Home Opinion Human rights
12:00 AM, November 24, 2018 / LAST MODIFIED: 12:00 AM, November 24, 2018
SIXTEEN DAYS OF ACTIVISM AGAINST GENDER-BASED VIOLENCE
A Joint Message from Ambassadors For Change in Bangladesh
COURTESY: UN WOMEN
Tomorrow, the 25th of November, is the International Day for the Elimination of Violence Against Women, and the first day of the 16 Days of Activism against Gender-Based Violence.
As we begin our commemoration of this campaign, we must express our deep concern for all women and girls who continue to be at risk of violence, globally and in Bangladesh. As Ambassadors for Change, we want to speak out against the abuses that millions of women and girls face every day.
Violence against women and girls remains one of the most systematic, widespread human rights violation worldwide. Globally, one in three women will experience violence in their lifetime.
We recognise that this is a global pandemic, embedded in unequal power dynamics between women and men; reinforced by harmful social norms or inequality under the law. It is rooted in every society! Marginalised, vulnerable groups are susceptible to a higher risk of violence, due to their race, ethnicity, religion, age, disability or sexual orientation.
No country is immune from gender-based violence and the current statistics for Bangladesh are also alarming:
One in five adolescent girls between the age of 15 to 19 reported experiencing partner sexual violence (Hidden in Plain Sight, UNICEF, 2014)
More than 80 percent of currently married women are abused at least once during their marriage, most often from someone they know and should trust (National VAWG Survey, 2015)
More than one in four women experience sexual or physical violence (Ibid)
Seven out of ten women (73 percent) have experienced domestic violence at least once in their life (Ibid)
We have been conditioned to believe that women and men have different roles in society; that women and girls are expected to be gentle, modest, willing to compromise and submissive. Girls and women are often discouraged to voice their opinions. Women and girls have been taught to remain silent, even in the face of abuse as the risk of humiliation and retaliation is high. Women and girls feel forced to obey harmful, tacit rules; and if they do not conform, they are regarded as disrespectful women. As a result, women who have been harassed and abused too often suffer in silence. They are also afraid of the double victimisation, of not being believed and blamed that how they behaved or what they wore brought on the violence to themselves. This is another reason for staying silent, unprotestingly; prompting an incessant, vicious cycle of violence.
This silent acceptance of women's role in society, once suppressed, has been challenged because of the exposure it has received as part of the phenomenal, worldwide campaign of #MeToo. Resilient, courageous women from all over the world are speaking up and coming forward with their stories of harassment and abuse, even in Bangladesh. This movement has inspired millions of women to come forward and share their stories.
This year's theme for 16 days of Activism is #HearMeToo, as a continuation of the #MeToo movement, and other anti-violence campaigns that have emerged during the past year to advocate for women's rights.
If we intend to eliminate violence against women in all its forms, it is imperative to address its root and structural causes, such as patriarchy and power imbalance between women and men. We need to advocate for a more equitable society; the voices of women must have equal weight: socially, financially, politically and in every stratum of life.
As Ambassadors for Change, we stand with women and girls who have been silenced, suppressed and abused.
We stand with women survivors and activists; we want to help them to be heard, globally and here in Bangladesh.
We call on all institutions to be accountable for ensuring that all survivors of gender-based violence are heard.
We ask for men and boys to challenge the beliefs, values and social norms that reinforce violence against women.
We ask for equal protection under the law and through the justice system, on behalf of women and girls suffering from violence.
We demand swift justice and strong legal action against the perpetrators of violence against women!
We ask to introduce and expand a quality education system that empower girls and break gender stereotypes.
We want to reach out to all educational institutions to ensure that no woman or girl ever face threats of harassment and assault to the extent that she renounces her right to education!
We demand for full protection of sexual reproductive health and rights of women and girls everywhere.
We speak out now to ensure that all women and girls feel safe in the workplace, in public transports and in public spaces.
As Ambassadors of Change, we seek empowerment for women and girls so that they are heard, feel supported and motivated; and empowered to make decisions and stand up for themselves.
We ask everyone, from all walks of life, to join us in this movement and in our call for action so that every woman and girl is heard and be freed from violence!
#HearMeToo
This message is cosigned by:
H.E. Julia Niblett, Australian High Commissioner to Bangladesh
H.E. Alison Blake CMG, British High Commissioner to Bangladesh
H.E. Benoit Préfontaine, Canadian High Commissioner to Bangladesh
H.E. Winnie Estrup Petersen, Ambassador of Denmark to Bangladesh
H.E Rensje Teerink, Head of European Union Delegation in Bangladesh
H.E. Marie-Annick Bourdin, Ambassador of France to Bangladesh
H.E. Harry Verweij, Ambassador of the Kingdom of The Netherlands Bangladesh
H.E. Sidsel Bleken, Ambassador of Royal Kingdom of Norway to Bangladesh
H.E. Charlotta Schlyter, Ambassador of Sweden to Bangladesh
H.E. René Holenstein, Ambassador of Switzerland to Bangladesh
H.E. Earl Robert Miller, Ambassador of United States of America to Bangladesh
Mia Seppo, United Nations Resident Coordinator and UNDP Resident Representative in Bangladesh
Beatrice Kaldun, UNESCO Country Representative in Bangladesh
Dr Asa Torkelsson, UNFPA Country Representative in Bangladesh
Shoko Ishikawa, UN Women Country Representative in Bangladesh
Derrick Brown, Mission Director of USAID in Bangladesh
Rana replaces Nana!
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Stamp out sexual harassment in the media
Bollywood director fired in India's #Metoo storm
Why #MeToo is not happening in Bangladesh
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COP25: The case for a sincere investment in loss and damage
The return of the intrepid patriarch
Bangladesh's IT Industry
Eight points to consider
Causes and Solutions
Dhaka vs Kolkata
Bangabandhu in prison: Transcending stone walls and iron bars
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Killings at the Bangladesh-India border
Why is most of Asia looking away from Myanmar?
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Addressing the plight of women migrant workers
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Cincinnati Children's 2023 News Releases
At Cincinnati Children's, we are committed to providing news and information about our efforts to improve child health. For more information, please contact our media relations team.
January News Article Releases
01/24/2023Cincinnati Children's Opens First-of-its-Kind Heart and Mind Wellbeing Center in United States
01/06/2023Cincinnati Children's health equity efforts to benefit from $800,000 in funding from CareSource
01/04/2023Cincinnati Children's promotes Oliver Rhine to senior VP & chief strategy officer

redpajama_set_name: RedPajamaCommonCrawl


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L'Atlas Miller est un atlas géographique comprenant une dizaine de cartes maritimes datant de 1519 et étant l'œuvre conjointe des cartographes Pedro (père) et Jorge Reinel (fils), ainsi que Lopo Homem et du miniaturiste et héraut d'armes António de Holanda.

Description et historique
Les zones géographiques représentées dans l'atlas sont : l'océan Atlantique Nord, l'Europe du Nord, l'Archipel des Açores, Madagascar, l'océan Indien, l'Indonésie, la mer de Chine méridionale, les Moluques, le Brésil et la mer Méditerranée.

Cet atlas a été acquis en 1897 par la Bibliothèque nationale de France par le bibliothécaire Bénigne Emmanuel Clément Miller, et porte depuis le nom d'Atlas Miller. Il est conservé dans les collections du département des cartes et plans.

Notes et références

Voir aussi

L'atlas Miller sur Gallica
 Carte de Pedro Reinel
 Atlas Vallard

Carte du XVIe siècle
Document conservé à la Bibliothèque nationale de France
Miller

redpajama_set_name: RedPajamaWikipedia


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Monaco 360° – a World of Opportunities
EXPO 2020 Monaco Pavilion in Dubai, a kaleidoscopic experience that will reveal new perspectives.
Multiple levels, replicating the mazy streets of Monaco. The 'Garden of Opportunities', which will bring to life Monaco's warm, sunny climate. The 'Kaleidoscope', which will showcase the country's art, culture, innovation and more.
Explore the principality's diverse national identity by taking a multi-sensory journey. Inspired by the 'Rock of Monaco', this gem-like, polygonal pavilion will take visitors on a multi-sensory journey through mirrored exhibition spaces, replicating the sights and smells of the French Riviera.
The structure features two main exhibition areas. The 'Garden of Opportunities' includes a variety of interactive experiences that will bring to life Monaco's warm, sunny climate. Visitors will then enter the 'Kaleidoscope', which will showcase the country's art, culture, innovation, history, gastronomy and more.
THEME: Monaco 360° – a World of Opportunities;
ARCHITECT: AODA, OOS;
DISTRICT: Opportunity District.
Electric Marathon Rally is an annual race between battery electric vehicles (BEV). The rally takes place on public roads and all, officially registered vehicals to drive on the public roads, are considered to be eligible to participate.
Expo 2020 Dubai will yield an AED 122 billion investment windfall for the UAE
'Expo dividend' from the largest event ever to be held in the Arab World will spur economic growth and support jobs for years to come.
The Dubai Expo 2020 has officially been postponed
It's official – the Dubai Expo 2020 has been postponed due to the global coronavirus pandemic. The decision was made after was confirmed in a statement after a meeting occurred with the steering committee of the event which includes the foreign countries that were due to participate and event officials.
Fox Automotive to produce MIA EV reboot in Hungary
Fox Automotive Switzerland and Phoenix Gold Resources have announced plans to launch production in Hungary of the MIA EV 2.0, a new version of a compact all-electric vehicle initially made by a French company that went bust in 2014.
Will your EV keep the lights on when the grid goes down?
Home battery systems can help during power outages. So can the battery packs rolling around in electric vehicles.
Ever Monaco 2020
Fifteenth International Conference on Ecological Vehicles and Renewable Energies.


04988448 Limited is registered as a Private Limited Company, is located in Slough, and has been registered since 08/12/2003.
The registration number for 04988448 Limited is 04988448 in Great Britain.
The status of 04988448 Limited as it currently stands according to Companies House is: Liquidation.
The accounts for 04988448 Limited are due on 30/09/2010.
The detailed company information for 04988448 Limited can be viewed below.


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Advances in Brief
Validation of the Pharmacodynamics of BMS-247550, an Analogue of Epothilone B, during a Phase I Clinical Study
Hayley M. McDaid, Sridhar Mani, Heng-Jia Shen, Franco Muggia, Daryl Sonnichsen and Susan Band Horwitz
Hayley M. McDaid
Sridhar Mani
Heng-Jia Shen
Franco Muggia
Daryl Sonnichsen
Susan Band Horwitz
The primary aims of this study were to evaluate the timecourse and dose response of microtubule bundle formationin peripheral blood mononuclear cells (PBMCs) and to correlate these data with BMS-247550 pharmacokinetics. The data presented here were obtained from 17 patients enrolled in a Phase I trial who received five dose levels of BMS-247550 (7.4–59.2 mg/m2), given as a 1-h infusion once every 3 weeks. Plasma drug exposure or area under the curve (AUC), and tubulin bundle formation in PBMCs were assessed in cycles 1 and 2. Similar analyses were also performed on tumor biopsies from one eligible patient. PBMCs exhibited dramatic microtubule bundle formation 1 h after infusion that declined by 24 h, showing a positive correlation with AUC(0–24) for cycles 1 and 2. A similar pattern of tubulin bundle formation also was observed in a smaller proportion of breast tumor cells from one patient who exhibited a partial response to BMS-247550. This patient's tumor expressed multidrug resistance (MDR1) and MDR-associated protein (MRP1), and in addition poly(ADPribose) polymerase cleavage, a marker of cell death, was observed within 23 h after drug infusion. This patient was also heterozygous for a novel polymorphism at the extreme COOH terminus of β-tubulin (Gly 437 Gly/Ser), although the relevance of the polymorphism to the response is unknown. In summary, microtubule bundle formation in PBMCs occurs within 1 h of treatment with BMS-247550 and is related to plasma AUC. Similar bundle formation was seen in one tumor sample, despite expression of MDR1 and MRP1. Cell death occurred 23 h after peak microtubule bundle formation in these tumor cells. These findings validate in vitro pharmacodynamic observations.
Tubulin and its polymerized form, the microtubule, are legitimate chemotherapeutic targets. Numerous small molecules bind to tubulin inducing either depolymerization of the polymer (e.g., Vinca alkaloids), or the polymerization of stable microtubules (e.g., taxanes). Typically, these drugs induce mitotic arrest and abrogate normal microtubule dynamics, effects that eventually result in cell death. Taxol has demonstrated activity, often in combination with other agents, in the treatment and palliation of several solid tumor types, including ovarian, breast, lung, and head and neck cancers.
However, a number of disease types are inherently resistant to Taxol, notably gastrointestinal tumors and melanomas, thereby limiting the therapeutic applications for the drug. Ultimately, the majority of patients acquire resistance to Taxol, which may be mediated by a number of putative mechanisms. These include mutations in β-tubulin that have been documented in cell lines cultured in vitro (1 , 2) and also in human tumors (3 , 4) . Other mechanisms of drug resistance include overexpression of the MDR4 gene product, MDR1 (5) , alterations in β-tubulin isotype expression levels (6) , aberrant signal transduction pathways (7 , 8) and/or apoptotic regulating proteins (9) , and alterations in levels of endogenous regulators of microtubule dynamics, such as stathmin (10) . It is likely that in human tumors, clinical resistance is multifactorial. The problems related to drug resistance have motivated a search for novel antimitotic agents that improve the taxane prototype by demonstrating activity in a broad spectrum of tumor types, including taxane-refractory tumors, and have a reduced propensity for acquired clinical resistance as well as having manageable toxicities, thus yielding an enhanced duration of response.
Preclinical evaluations have indicated that the epothilones are promising candidates with respect to these criteria (11) . The appealing properties of the epothilones include their greater water solubility compared with Taxol and their ability to retain efficacy in cell lines expressing the MDR1 phenotype. The epothilones were originally isolated from the fermentation broth of the soil-derived myxobacterium, Sorangium cellulosum. The drug can be mass produced by bacterial fermentation or, more recently, by cloning of the gene cluster responsible for biosynthesis of epothilone followed by its expression in Streptomyces (12) . Despite these encouraging properties, the in vivo activities of the epothilones in animal models of human cancers were modest with a narrow therapeutic window (13) . A metabolically more stable epothilone B derivative, BMS-247550, a semisynthetic lactam analogue, was designed and synthesized (Fig. 1)⇓ . BMS-247550 has demonstrated antitumor activity in a number of preclinical human tumor models, including cancer cells that are inherently resistant to Taxol (14) .
Chemical structures of epothilone B and BMS-247550.
These data motivated an ongoing Phase I clinical evaluation of the drug (15) . The biological aims of this study were to evaluate patient specimens obtained in the Phase I study and to determine the time course and dose response of microtubule bundle formation in PBMCs after exposure to BMS-247550, using the degree of microtubule bundle formation as a marker of drug binding. The occurrence of tubulin mutations/polymorphisms in available tumor tissue and PBMCs of patients enrolled in the trial, as well as other potential molecular mechanisms of drug sensitivity/resistance in this group of patients, were evaluated. This paper reports the findings of the mechanisms of action of BMS-247550 in vivo and corroborates in vitro data.
Phase I Clinical Evaluation of BMS-247550.
Patient eligibility, BMS-247550 formulation and dosing, together with patient pretreatment and follow-up studies will be presented in detail in a forthcoming study summarizing the clinical trial. All blood and tissue specimens used in this study were obtained under an institutional review board-approved protocol at The Albert Einstein College of Medicine.
Pharmacokinetic Sampling.
The plasma pharmacokinetics of BMS-247550 were determined by collecting blood samples at 0 (predose), 0.5, 1 (end of infusion), 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 24, 48, and 72 h during cycles 1 and 2 for all patients. Blood was collected into labeled Vacutainer CPT Cell Preparation Tubes (Becton Dickinson, Lincoln Park, NJ) that are used to separate mononuclear cells from whole blood. Samples were centrifuged at 2500 rpm (∼1000 × g) for 30 min at room temperature within 1 h after collection. The PBMCs and platelets that migrate as a whitish layer below the plasma were retained for subsequent tubulin bundle formation analysis (at 0-, 1-, and 24-h time points during cycles 1 and 2). In addition, purified PBMCs were stored as frozen dry pellets at −80°C for subsequent sequence analysis of class I β-tubulin. Plasma samples were transferred to labeled tubes and stored at −80°C before shipping on dry ice to the analysis site. The methods (16) used for the pharmacokinetic analysis of BMS-247550 will be described in a subsequent report.
AUC(0–24)s were generated from peak plasma concentrations for each patient at the various pharmacokinetic sampling time points using GraphPad Prism 3.0 (GraphPad Software, Inc., San Diego, CA), in AUC mode. Correlative studies of pharmacokinetic parameters [AUC(0–24) and CLT(0–24)] with the percentage of PBMCs exhibiting microtubule bundle formation were analyzed using linear regression modes.
Tumor Biopsy Acquisition.
Biopsy specimens were obtained at 0, 1, and 24 h after BMS-247550 treatment in one patient with an accessible tumor, wherein sample acquisition involved a noninvasive procedure that required only local anesthesia. Slides for immunofluorescence were immediately prepared from tumor biopsies by imprinting the cut tumor surface onto labeled Superfrost plus slides (Fisherbrand; Fisher Scientific, Pittsburgh, PA). The slides were air dried and fixed in 100% methanol for 5 min at −20°C, after which slides were air dried and stored at 4°C. The residual tumor biopsies were immersed in 5× volumes of RNA Later (Ambion, TX) and stored at 4°C overnight to preserve endogenous nucleic acids. After refrigeration, biopsies were transferred to labeled cryostat tubes and stored at −80°C. Sections of tumor were also taken for standard histological examination (H&E staining). When required, patients submitted buccal washings for molecular analysis by rinsing briefly in water, then swirling ∼5 ml of water in the mouth for ∼2 min. The buccal washings were decanted into a sterile tube and centrifuged to pellet the cells that were washed with 0.5 ml of 5% FBS in PBS. The washed buccal cells were immersed in 5× volumes of RNA Later and stored at 4°C overnight to preserve endogenous nucleic acids and then stored as dry pellets at −80°C, or the total RNA was extracted immediately after recovery of the cells.
Preparation of Cytospins.
PBMC pellets were washed twice with 0.5 ml of 5% FBS in PBS containing 0.02% NaN3. The washed PBMCs were gently resuspended in 0.5 ml of 5% FBS in PBS, and the cell number was determined from ∼0.1 to 0.2 ml of this cell suspension using a Coulter counter (Coulter Electronics Inc., Hialeah, FL). Glass slides (Fisherbrand) were prewet by pipetting 50 μl of 5% FBS/PBS into cytofunnels (ThermoShandon, Inc., Pittsburgh, PA) and centrifuging at maximum speed for 5 min in a cytospin (ThermoShandon, Inc.). One hundred μl of PBMC cell suspension containing approximately 0.75 × 106 cells/ml were added to cytofunnels and centrifuged at 1000 rpm for 10 min and then allowed to air dry. The slides were fixed in 100% methanol for 5–10 min at −20°C, air dried, and stored at 4°C.
Immunohistochemistry.
Slides were rehydrated, and cells were blocked in 10% normal goat serum (Vector Laboratories Inc., Burlingame, CA) in PBS for 20 min at room temperature and then incubated with a 1:100 dilution of α-tubulin monoclonal antibody (Sigma Chemical Co., St. Louis, MO) diluted in 5% normal goat serum in PBS for 1 h at 37°C. The slides were rinsed in PBS and incubated with Cy3-conjugated goat antimouse IgG (1:200; Amersham, Arlington Heights, IL) for 1 h in the dark before mounting in Vectashield solution (Vector). To evaluate the degree of cell death, slides were stained with a polyclonal anti-PARP p85 antibody (Promega Corp., Madison, WI) at a dilution of 1:500, followed by a 1:200 dilution of Alexa 488 goat-antirabbit secondary antibody (Molecular Probes, OR) and mounted as described above. Slides were visualized and digitized on an Olympus IX70 inverted microscope, and cell numbers were quantified using a Zeiss Axioscop microscope. At least 500 cells/slide were counted, and the number of cells exhibiting tubulin bundle formation, or PARP positivity, was expressed as a percentage of the total number of cells counted. Samples were blinded and counted by two individual investigators to determine the mean value.
β-Tubulin Sequence Analysis.
Tumor biopsies were homogenized (Ultra-turrax T8; IKA Laboratories) according to the RNeasy isolation method (Qiagen, Inc., Chatsworth, CA) yielding DNA-free total RNA. PBMCs and buccal cells were immersed in lysis buffer and homogenized manually. Approximately 1–2 μg of total RNA were reverse transcribed in a 50-μl reaction volume containing 300 units of Moloney murine leukemia virus reverse transcriptase (Life Technologies, Inc., Grand Island, NY) in the presence of random hexamers at a final concentration of 3.3 ng/μl, 60 units of RNAguard (Pharmacia Biotech), 0.5 mm deoxynucleotide triphosphates, 10 mm DTT, and 1× reverse transcriptase buffer at 37°C for 1 h. Samples were incubated at 95°C for 5 min and diluted 1:2 with DNase/RNase free water. Samples were aliquoted and stored at −70°C. Sequence-specific primers that span the coding region of the class I β-tubulin were designed in our laboratory and used to amplify the gene. Approximately 1 μl of cDNA was amplified in a reaction mix using 2.5 μl of 10× buffer, 2 μl of 2.5 mm MgCl2, 125 ng of forward and reverse primers, and 1 unit of proofreading Taq. The PCR products were purified using the Qiaquick gel extraction kit (Qiagen), and the samples were sequenced (Genwiz, Inc., New York, NY) using the same primers as the PCR amplification. Nucleotide analysis was performed using the software Sequencher (Gene Codes Corp., Ann Arbor, MI), and the sequences were compared with the GenBank sequence for class I β-tubulin (accession number J00314).
Reverse Transcription-PCR.
For the determination of MDR1 expression, a competitive PCR reaction using β2-microglobulin was performed as described previously (6) . MRP1 expression levels were also determined using sequence-specific primers for both genes as described previously (17) . The expected PCR product size for MRP1 was 165 bp. Each experiment was performed three times.
Clinical Endpoints ( n = 17)
A Phase I/II study of BMS-247550 as a 1-h infusion administered every 3 weeks is ongoing, and the maximum tolerated dose has been established in patients who received prior taxane-based chemotherapy (15) . The Phase I study, as well as pharmacokinetic-pharmacodynamic relationships, will be presented subsequently. This study presented here will summarize key findings relevant to the description of molecular determinants of drug response, based on the data obtained from 17 patients enrolled in the trial. Of the patients included in this analysis, 100% had prior taxane-based chemotherapy, and >90% had either a breast or gynecological malignancy.
Microtubule Bundle Formation in PBMCs as a Marker of BMS-247550 Pharmacodynamics
The extent of bundle formation in PBMCs was assessed in all patients as a surrogate marker of BMS-247550 binding to tubulin. Microtubule bundle formation in interphase cells is a hallmark of microtubule-stabilizing agents, such as Taxol, and is a well-documented phenomenon (5 , 18) . The tubulin morphology of PBMCs before and after BMS-247550 drug infusion at the 50 mg/m2 dose for cycle 2 is illustrated in Fig. 2A⇓ . There was no bundle formation observed in PBMCs at baseline. The mean percentages of PBMCs exhibiting microtubule bundle formation at the 1- and 24-h time points were approximately 70 and 25%, respectively. The majority of PBMCs at 24 h (∼75%) appeared to have normal microtubule morphology, whereas the minority (∼25%) exhibited bundle formation. Fig. 3⇓ illustrates the dose-dependent effect of BMS-247550 on microtubule bundle formation in PBMCs during cycle 1 (Fig. 3A)⇓ and cycle 2 (Fig. 3B)⇓ of treatment. Similar to the plasma pharmacokinetics of BMS-247550 (19) , the degree of microtubule bundle formation in PBMCs increased to a maximum 1 h after drug infusion and then decreased by 24 h after drug infusion. This pattern was observed for all doses evaluated, except for 7.4 mg/m2, a dose at which microtubule bundle formation was not detected. At the 50 mg/m2 dose, where unacceptable dose-limiting toxicity was observed (15) , 68–70% of PBMCs exhibited microtubule bundle formation at 1 h after infusion for cycles 1 and 2, whereas 25–28% of PBMCs exhibited the same effect at 24 h. At the 40 mg/m2 dose, the values were 63% and 16–23% for 1 and 24 h after drug infusion, respectively. The pattern of bundle formation, like the pharmacokinetics of BMS-247550, was similar across cycles 1 and 2 (Fig. 3C)⇓ , suggesting that drug binding to tubulin in PBMCs was similar across cycles 1 and 2, and that the PBMCs affected by bundle formation in cycle 1 either died or recovered by cycle 2.
Reorganization of microtubules and bundle formation (arrows) before and after BMS-247550 infusion at cycle 2 (1 and 24 h) in PBMCs (A) and tumor (B) of a patient treated at the 50 mg/m2 dose. At 24 h after infusion, the majority (∼75%) of PBMCs had tubulin morphology that resembled baseline. ×90 Tumor biopsies were obtained at the various times from the chest wall mass, depicted in the CT scan.
Dose- and time-dependent effects of BMS-247550 on microtubule bundle formation in PBMCs during cycle 1 (A) and cycle 2 (B) of treatment. Microtubule bundle formation, similar to pharmacokinetics, is linear across cycles 1 and 2 (C). Bars, SE.
To endorse these initial observations, the degree of bundle formation in PBMCs was correlated with AUC [AUC(0–24)] (Fig. 4)⇓ and clearance [CLT(0–24)] (Fig. 5)⇓ . Because of the incomplete sampling of blood in some patients, these data were not available for all subjects. There was a positive correlation between the degree of microtubule bundle formation in PBMCs and the AUC(0–24) of BMS-247550 for both cycles 1 and 2 at 1 h (Fig. 4)⇓ . Equally, there was a negative correlation between CLT(0–24) and the degree of microtubule bundle formation in PBMCs in cycles 1 and 2 at 1 h (Fig. 5, A and B⇓ , respectively). The relationship between microtubule bundle formation in PBMCs and both AUC(0–24) and CLT(0–24) at 24 h was poor. Therefore, these data indicate that the extent of microtubule bundle formation in PBMCs is related to plasma drug exposure (AUC) at 1 h after drug infusion.
Positive correlation between percentage of microtubule bundle formation in PBMCs and AUC(0–24) at cycle 1 (A) and cycle 2 (B) of treatment for 1 h (▪) and 24 h (▴) by linear regression analysis. Dashed lines, 95% confidence limits. The slopes and corresponding r2 and Ps are shown.
Negative correlation between the percentage of microtubule bundle formation in PBMCs and CLT(0–24) at cycle 1 (A) and cycle 2 (B) of treatment for 1 h (▪) and 24 h (▴) by linear regression analysis. Dashed lines, 95% confidence limits. The slopes and corresponding r2 and Ps are shown.
Response to BMS-247550 in Taxotere-refractory Breast Cancer: Molecular Correlates
Microtubule Bundle Formation and Cell Death.
One of the patients that had a partial response to BMS-247550 had an accessible chest wall mass (Fig. 2B)⇓ , from which core biopsies were taken before and after drug infusion (1 and 24 h) in cycle 2. This patient had received prior taxotere chemotherapy and after initially responding, developed progressive disease after ∼12 cycles of drug. Hence, for the purposes of this analysis, the patient was defined as taxotere refractory. This patient was treated with 50 mg/m2 of BMS-247550, and a similar pattern of microtubule bundle formation was observed in the tumor cells compared with the PBMCs that were analyzed at the same cycle (Fig. 2B)⇓ . Therefore, BMS-247550 is efficiently accrued in tumor cells within this relatively short time. No bundle formation was observed in tumor cells at baseline. The percentage of tumor cells that exhibited bundle formation were 54 ± 2% and 40 ± 4% at 1 and 24 h after drug infusion, respectively. The value for 1 h was lower than the 84 ± 4% observed in the PBMCs of the same patient at cycle 2. In contrast, the value at 24 h was higher in tumor cells than the 27 ± 5% observed in PBMCs. The difference in tumor cells compared with PBMCs at 1 and 24 h is interesting and may imply differential drug uptake and clearance kinetics, although the analyses of additional tumor biopsies after treatment will be required to validate this observation.
Because microtubule bundle formation indicates the extent of drug binding but does not provide a measure of cytotoxicity, we also evaluated the degree of PARP cleavage, a marker of cell death, in this patient's tumor cells using a highly specific antibody that recognizes only the cleaved Mr 89,000 fragment of the protein. Fig. 6A⇓ illustrates the pattern of PARP p89 immunostaining in two representative areas of tumor, 24 h after exposure to BMS-247550. The contrasting phase images are shown in Fig. 6B⇓ . PARP p89 immunostaining appears to be localized to predominately nuclear regions, which is consistent with previous reports (20) . The number of tumor cells exhibiting p89 staining was also quantified before and after BMS-247550. At 1 h, the number of cells exhibiting p89 staining was similar to preinfusion numbers, ∼3%. At 24 h after BMS-247550 infusion, ∼28% of tumor cells exhibited p89 immunostaining, indicating cytotoxic activity of BMS-247550 within 24 h after infusion. These data are consistent with the mechanism of action of chemotherapeutic agents in which cytotoxic effects occur after binding of the drug to the target. The pattern of microtubule bundle formation that we observed in these tumor cells fits this consensus, with maximum effects observed at 1 h that decreased by 24 h after infusion.
PARP p89 immunostaining (A) and the contrasting phase images (B) in two representative areas of tumor, 24 h after BMS-247550 infusion (cycle 2) at the 50 mg/m2 dose. 500 cells were counted to quantify the number of p89-positive cells. These data are shown for 0, 1, and 24 h. ×90.
Expression of MDR1 and MRP1.
Taxol accumulation is inhibited by the expression of MDR1, an energy-dependent drug efflux pump that maintains a low intracellular drug concentration. The role of MRP1 with respect to taxane resistance is conflicting (21 , 22) . We investigated the expression of both drug transporters in the tumor cells of the patient who developed progressive disease after taxotere treatment. In addition to biopsies obtained at 0, 1, and 24 h after BMS-247550, we also obtained a biopsy of normal skin, adjacent to the chest wall mass. This patient had a positive response to BMS-247550, evident after two cycles of treatment, and the chest wall mass, from which the biopsies were obtained, had a sustained regression of 5 months. The MDR1 and MRP1 status of this biopsy was also investigated. SKVLB cells that overexpress both transporters were used as a positive control. MDR1 was expressed in both the normal skin and tumor samples, but there was no up-regulation of mRNA levels in the tumor samples compared with skin or after treatment with BMS-247550 for 24 h (Fig. 7A)⇓ . MRP1 was expressed in both the skin and tumor biopsies, and there appeared to be an overexpression of MRP1 mRNA in the tumor biopsies compared with skin (Fig. 7B)⇓ . These data suggest that BMS-247550 retains efficacy in tumor cells expressing both MDR1 and MRP1, although more tumor samples are required to validate this preliminary finding.
Expression of MDR1 (A) and MRP1 (B) cDNA in human ovarian SKVLB cells that overexpress both MDR1 and MRP1, in tumor biopsies (at 0 and 24 h) after treatment with BMS-247550 and in a normal skin biopsy. β2-Microglobulin (B2M) was used as a control.
Sequence Analysis of β-Tubulin.
Increasing evidence suggests that mutations in β-tubulin may confer resistance to microtubule-interacting agents, including Taxol (23) , the epothilones (1 , 2) , and vincristine (24) . Mutations in β-tubulin also have been reported in tumor DNA isolated from the serum of patients with advanced non-small cell lung cancer (3) . In light of the potential prognostic implications of these data, we sequenced the β-tubulin from the tumor biopsies obtained from one of the patients who had exhibited the partial response to BMS-247550. Sequence analysis of the cDNA and genomic DNA isolated from this patient's tumor, normal skin, PBMCs, and buccal cells indicated the presence of a novel polymorphism at the extreme COOH terminus of β-tubulin that has not been documented previously. The alteration was heterozygous: [GGT(Gly) to G/AGT(Gly/Ser)] at amino acid residue 437, present in a region of β-tubulin that is involved in its interaction with microtubule-associated proteins, motor proteins, and tau (25) . The relevance of the polymorphism to the patient's response, if any, is unknown. We also analyzed the α-tubulin sequence from the tumor biopsies isolated from this patient and found no nucleotide alterations (data not shown). The remaining 16 patients were also screened for polymorphisms in β-tubulin using PBMCs as a source of nonmalignant cells. None of these patients exhibited nucleotide alterations.
This study of BMS-247550 in patients with advanced solid tumors describes pharmacodynamics of the drug, as well as indications of preliminary antitumor activity. The completed Phase I study will be presented in a later report. The characteristics of BMS-247550 that have been described in preclinical studies (14) have also been validated here, using molecular analyses of defined targets that potentially influence response to microtubule-stabilizing agents.
The data presented indicate that microtubule bundle formation in PBMCs is related to BMS-247550 exposure, occurs within 1 h of treatment, and correlates with the pharmacokinetics of the drug. In the context of this study, microtubule bundle formation in PBMCs is an indicator of the ability of BMS-247550 to bind to β-tubulin, and as Fig. 3⇓ illustrates, this binding increases as the concentration of drug increases. Microtubule bundle formation is a phenotypic consequence of BMS-247550 binding to microtubules in interphase cells (5) . At low drug concentrations where microtubule bundle formation is not apparent, there are still cytotoxic drug effects, presumably because of perturbations of normal microtubule dynamics (26 , 27) . Therefore, quantitation of microtubule bundle formation in PBMCs does not reflect intrinsic BMS-247550 activity, or the ability of this drug to produce a pharmacological effect when bound to β-tubulin, and is probably an underestimation of the number of cells that have bound BMS-247550. Despite this limitation, the preliminary data presented here suggest that microtubule bundle formation is an easily measurable, early pharmacodynamic effect.
An interesting observation that will require prospective analysis was noted with respect to the degree of microtubule bundle formation in the PBMCs of a patient who expired after one cycle of drug at the 50 mg/m2 dose because of neutropenic sepsis. This patient exhibited abnormally elevated levels of bundle formation 24 h after drug infusion (42% compared with a mean of 25% ± 4 for other patients treated at this dose level). The highest percentage of bundle formation observed 24 h after infusion was 32% in a patient treated at the highest dose level of 59.2 mg/m2. This patient, who exhibited high levels of bundle formation at 24 h after BMS-247550 infusion, had a CLT of 229 ml/min/m2 compared with the mean value of 430 ml/min/m2 for all other patients treated at this dose level, suggesting that indeed CLT was substantially lower in this patient. This suggests that higher than average levels of microtubule bundle formation in PBMCs at 24 h after BMS-247550 infusion may predict for poor clearance and may be related to subsequent toxicity.
The observation that microtubule bundle formation was reduced in the tumor cells of one patient treated at 50 mg/m2 dose compared with the PBMCs at 1 h is not unexpected, because one would anticipate that drug accumulation would be highest in PBMCs that are suspended in the circulatory system. In fact, it has been demonstrated previously that the accumulation of drugs such as Taxol is reduced in multicellular spheroids, a model that closely mimics the microregions of solid tumors, compared with cells exposed to Taxol when grown in monolayers (28) . Furthermore, at 24 h after infusion, the number of cells exhibiting bundle formation was higher in tumor cells compared with PBMCs (40 ± 4 compared with 27 ± 5%), suggesting that the kinetics of drug clearance may differ between the two cell types. In light of this observation, it would have been interesting to evaluate the duration of microtubule bundle formation in tumor cells; however, this was not possible because it would have required additional biopsies, although extended times for sample acquisition of both PBMCs, and tumor cells can be analyzed in prospective studies.
PARP p89 expression was chosen as a cytotoxic marker instead of the terminal deoxynucleotidyl transferase-mediated nick end labeling assay, which measures DNA strand breaks, primarily because PARP cleavage occurs before DNA strand breaks (29) and therefore is an earlier indicator of cell death. Additionally, PARP cleavage occurs during both apoptosis and necrosis (30) , and we thought it prudent to measure both modes of cell death because they contribute equally to tumor regression that constitutes a clinical response. One would expect drug binding (bundle formation) to precede cell death (p89 staining), because Taxol-induced cell death is thought to be mediated via a mitochondria- regulated death pathway. Compared with classical receptor-mediated death, which occurs more quickly, activation of a mitochondria-regulated death pathway would account for the delayed time observed between bundle formation and the appearance of dead cells. The level of cell death in PBMCs was not evaluated in this study, because background levels (pre-BMS-247550) of apoptosis were high in these cells (data not shown), likely reflections of spontaneous apoptosis in mononuclear cells after collection and processing. It has been shown previously that PBMCs isolated from head and neck cancer patients undergo apoptosis more rapidly than those from persons with no evidence of cancer (31) , suggesting that the lymphocytes of cancer patients may be more susceptible to apoptosis. Furthermore, apoptotic PBMCs are rapidly removed from the circulatory system by phagocytes; therefore, the quantitation of these cells undergoing apoptosis is likely to be inaccurate.
The data presented in this study document microtubule bundle formation and in vivo cytotoxic activity of BMS-247550 ∼23 h after drug infusion in one tumor sample from a patient with taxotere-refractory metastatic breast cancer, despite expression of both drug transporters MDR1 and MRP1. These observations authenticate the preclinical data for both the epothilones and BMS-247550 (11 , 14) . The expression of MDR1 confers resistance to a broad spectrum of chemotherapeutic agents including the taxanes, Vinca alkaloids, and anthracyclines. MRP1 also mediates resistance to these drugs, although its role in taxane resistance is uncertain, and its role in the transport of epothilones has yet to be defined. MDR1 is intrinsically expressed in a number of tissue types including colon, rectum, pancreas, liver, and kidney, and its expression is induced in a number of tumor types after chemotherapy. MRP1 is expressed in epithelial cells of most normal tissues and is overexpressed in leukemia, neuroblastoma, and non-small cell lung cancer. There have been various clinical trials involving modulators of both of these drug transporters as a means of enhancing chemotherapeutic efficacy; however, a number of these modulators interact with the drugs, altering their pharmacokinetic profiles, and are therefore undesirable (32) . A more acceptable means of circumventing this type of resistance is to use drugs whose transport is minimally affected by MDR1, such as the epothilones. The findings presented here, although preliminary, are encouraging in that they confirm the expression of both MDR1 and MRP1 in the tumor of a patient who responded to BMS-247550. Furthermore, responses to epothilone B have been observed in patients with advanced colorectal cancer in a Phase I clinical evaluation (33) , suggesting that this class of drug has the potential to exert cytotoxic effects in tumors that may be resistant to taxane-based chemotherapy by virtue of endogenous expression of MDR1.
A unique polymorphism was expressed in the β-tubulin of one patient, although the relevance of this polymorphism to the patient's response is unknown. This alteration was located at amino acid residue 437 of class I β-tubulin, a region of the protein that is crucial for interactions with microtubule-associated proteins, tau, and motor proteins. Although this polymorphism has not been documented previously, epothilone-resistant HeLa cells that have a heterozygous mutation at amino acid residue 422, also in the COOH terminus of class I β-tubulin, have been described (1) . Attempts to increase the concentration of epothilone in which the cells were grown did not result in a more resistant phenotype with a homozygous mutation. This suggests that alterations in the COOH terminus of β-tubulin may result in severe perturbations of normal microtubule function, causing lethality. Future studies will determine whether this and other polymorphisms are expressed at the protein level and their incidence in human tumors and tissue.
The concept of genetic polymorphisms influencing drug response is not novel and constitutes an important reason for interpatient variability in chemotherapy. Examples include NAT (34) , an enzyme that catalyzes the acetylation of a variety of amines. Polymorphisms have been identified in an isoform of NAT, NAT2, that were determined to mediate toxicity to amonafide, an anticancer agent that exhibited activity in breast cancer and leukemia. Amonifide is no longer in clinical development because of the potentially harmful impact of polymorphisms in NAT2. Likewise, there are polymorphisms that positively influence tumor response (35) ; therefore, the possibility exists that polymorphisms in class I β-tubulin may modulate response to drugs that bind to this target, including the taxanes and epothilones. This hypothesis will require validation, but the outcome may benefit patients who will be treated with this class of drug.
We gratefully acknowledge Drs. Susan Arbuck, Dimitrios Colevas, Abbey Fields, Susan Galbraith, Louise Grochow, Anne Hamilton, Howard Hochster, David Lebwohl, Leonard Liebes, Carolyn Runowicz, and Joseph Sporano for help with this study.
↵1 This study was supported by National Cancer Institute Grants U01 CA76642-01 and GCRC MOI RR00096 (to F. M.) and R03 CA86807, CA39821, and CA77263 (to S. B. H.). H. M. D. is supported by Postdoctoral Fellowship 99-3064 from the Susan G. Komen Foundation.
↵2 These authors contributed equally to this work.
↵3 To whom requests for reprints should be addressed, at Department of Molecular Pharmacology, Golding 201, 1300 Morris Park Avenue, Bronx, NY 10461. Phone: (718) 430-2163; Fax: (718) 430-8959; E-mail: shorwitz{at}aecom.yu.edu
↵4 The abbreviations used are: MDR, multidrug resistance; MRP, MDR-associated protein; PBMC, peripheral blood mononuclear cell; AUC, area under the curve (plasma drug exposure); CLT, clearance; PARP, poly(ADP-ribose) polymerase; NAT, N-acetyltransferase.
Accepted April 5, 2002.
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You are going to email the following Validation of the Pharmacodynamics of BMS-247550, an Analogue of Epothilone B, during a Phase I Clinical Study
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I know, it's Tuesday and I don't normally post on Tuesday, but there are so many neat things going on this week, and this month, I just had to tell you about them.
First, of course, is my birthday on July Fourth. The other day my friend, Alex J. Cavanaugh suggested we have fireworks to celebrate. What a novel idea. I think I'll try that while my kids are here at "Grandma's Ranch" helping me not to feel too bad about reaching another speed limit number. By the way, it is not the speed limit that is recommended to get the best gas mileage. In fact, one should not even watch his or her gas gauge while driving at this speed.
It seems that July is the month that lots of publishers and authors have decided to run special sales on their books. I told you last week about the sale Untreed Reads is having on short stories – 4 For the Fourth – in which you can purchase 4 short stories for a dollar. There's a list of books, as well as all the details on my blog post Special Sale For the Fourth of July.
Tying into the themes of birthdays and gifts, I decided that this year on my birthday, I should give a gift or two, so I am giving one person who comments on any of the blogs from last Wednesday through tomorrow all four of my short stories that are at Untreed Reads. All you have to do is leave a comment, with a contact e-mail please, and I will draw a winner on Thursday morning and arrange the gift. The short stories are; The Visitor, a retelling of the Goldilocks story; Making it Home, a story that was first published in Lady's Circle magazine; The Last Dollar, a holiday story with a message for any time of the year; and SAHM, I Am, a humorous story about a woman and a home computer.
One of my publishers, Books We Love, is taking part in the month-long sale at Smashwords, where many books are priced at 50% off. What a terrific deal, and my short story collection, The Wisdom of Ages, is offered in the sale. As is my YA novel, Friends Forever.
Debbie stood there half-listening, impatient to be off to meet Lauren. She knew her mother meant well, but really. How many times did she have to listen to this same litany?
There are lots of great books being offered in these sales, so I hope you find some good books and stories to add to your summer reading list. I have grabbed a few and plan to spend some early mornings on my deck enjoying them.
That's right. Sometimes it chowder or just plain meat and potatoes!
I have a great number of books to read and last weekend got in three of them, now it's time to write for awhile, but reading is always how I break away – my escape.
It's great that you're giving away for your birthday, and again. Happy Birthday!
Thanks so much, Yolanda. I appreciate the birthday wishes.
You're so lucky to have your birthday on the 4th. Mine's on the 5th, and I've never, ever got to celebrate it because everyone's been beat from celebrating the 4th. Happy birthday.
Very generous of you to give gifts for your birthday. I hope you get a few gifts for yourself.
Happy Birthday one day early.
I have a ton of books lined up to read. Mostly, there the ones my husband has bought and are sitting in the "cloud" waiting for me to download. He has every book written by Vince Flynn. I'd just finished the first when I heard that Flynn had died. I'm going to keep reading until I've read them all.
Thanks for the birthday wishes, Morgan and Helen. Much appreciated.
Helen, I remember you reviewed some of the books by Vince Flynn and I thought then they would be good books. Do I dare add them to my HUGE TBR pile? It is so easy to get e-books now, I have about 200 in my Kindle. Will I ever have time to read them all?
I hope you have a fabulous birthday with some Happy 4th thrown in.
I have so many books in my TBR pile, I just shut my eyes and grab one.
So you're a Yankee Doodle Dandy! Happy birthday, Maryann!
Yes, I am, Bob, and my kids get soooo tired of hearing me sing that song at the top of my lungs.


text:
Bosnia finally names prime minister 14 months after election
Zoran Tegeltija's nomination was backed by MPs from all Bosnia's main ethnic parties after months of tense negotiations.
By Denitsa Koseva in Sofia December 5, 2019
The Bosnian parliament's House of Representatives approved the appointment of Serb Zoran Tegeltija as the next state-level prime minister on December 5, ending a 14-month political deadlock that has persisted since the October 2018 general election.
Tegeltija's nomination was backed by all main ethnic parties in the country after months of tense negotiations.
In his speech to parliament, Tegeltija said he would form a government as soon as possible and would implement much needed reforms to unlock the country's EU membership path and secure a new deal with the International Monetary Fund (IMF).
A government should be formed by the end of the year. This could lead to renewed talks with the IMF on a loan deal and to more support from the international community for reforms in Bosnia & Herzegovina.
Tegeltija, an ethnic Serb and a member of Milorad Dodik's Alliance of Independent Social Democrats (SNSD), was supposed to be nominated in August, following an agreement reached by Bosnia's three main parties to form a state-level government as long as Bosnia remained committed to "advancing the relationship with Nato without predicting future decisions in relation to membership of Bosnia & Herzegovina."
However, Dodik, the Serb member of Bosnia's tripartite presidency, blocked the process, as he opposes Bosnia's advancement towards Nato membership, delaying the nomination of the prime minister by several months.
The other two members of the presidency said they would not back Tegeltija's nomination if Dodik refused to first sign the Annual National Programme (ANP) to be sent to Nato.
Unlike Dodik, the leaders of the two other main ethnic parties — Bakir Izetbegovic of the Bosniak Party of Democratic Action (SDA) and Dragan Covic of the Croatian Democratic Union (HDZ) — support the country's eventual Nato membership.
The country has already been implementing a Nato agreement (IPAP) for several years. These agreements are signed for two years and the latest expires in December. Nato activated Bosnia's Membership Action Plan (MAP) last year, but the country has failed to move forward owing to Dodik's objections.
Under a compromise reached by the presidency, a programme of reforms demanded by Nato as part of Bosnia's process of integration with the alliance but previously blocked by the Bosnian Serbs, should be sent to Nato a day after the parliament confirms Tegeltija as prime minister.
Step will take place if UK, France, Germany file formal complaint with Security Council says foreign minister Javad Zarif.
"Someone signed a signature to turn Bulgaria into a dump for the world," says opposition leader, as alleged imports of mafia waste from Italy, water shortages and deadly air pollution add to the accusations against Boyko Borissov's government.
Ukrainian President Volodymyr Zelenskiy refused to accept Prime Minister Oleksiy Honcharuk resignation tendered last week and decided to give him "a chance if you resolve some things that are very important today and are of concern to our society"
Foreign powers agreed at a summit in Berlin on January 19 to try to solidify the unstable truce in Libya between the internationally recognised government, which is backed by Turkey, and the self-styled Libyan National Army (LNA) forces of warlord Kh
Poland will set up a coal warehouse capable of stockpiling up to one million tonnes of coal that mining companies are struggling to sell as generation of electricity from the fossil fuel is in decline.


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Puri: Braving the morning chill, several devotees thronged the beaches of Chandrabhaga early today to take a holy dip in the sea and welcome the rising Sun with prayers on the auspicious occasion of 'Magha Saptami'.
With the age-old belief that it would cleanse them of skin diseases and wash away their sins, the pilgrims from Odisha, West Bengal, Andhra Pradesh and Madhya Pradesh took the holy dip amidst tight security arrangements. Besides, there are tourists who come to Konark to see the famous Sun Temple.
It is one of the most popular and colourful festivals of Konark which is observed on the seventh day of the waxing phase of the Odia month of Magha. This is a day specifically set aside for the worship of Sun God at Konark where stands the world famous Sun Temple, otherwise known as Black Pagoda, dedicated to Sun God.
Besides, Mahadev is also worshipped at the place making the celebrations of this 'Magha Mela' unique. In one of the rituals, cooked rice and dried fish (shukhua) dalma is offered to mythological demon Arkasura in whose name the place has been named as Arka Kshetra. The cooking pots are broken and thrown into the pond from where the pieces are believed to disappear. A big fair is also held at the Khandagiri caves in Bhubaneswar for a period of seven days commencing from "Maghasaptami".
In fact this is the second biggest festival in Odisha, next to the Car Festival of Puri.


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The game will be developed by Ninantic, who made the augmented reality game Ingress, for Nintendo and The Pokemon Company. Indeed, Pokemon Go seems to center on walking around and finding Pokemon, so it seems like a pretty natural progression. Players use their smartphone camera to look through a digital environment to catch all those pocket monsters. Gyms are controlled by one of three teams (Red, Blue, and Yellow) and players can team-up with their fellow counterparts to make capturing gyms easier.


text:
\section{Introduction}
\label{sec:introduction}
There is increasing interest in attaining precise control of the spin of
electrons at mesoscopic scales because it could lead to novel quantum
computation
platforms.\cite{wolfSC04,awschalomNP2007,fabianAPS07,awschalomSSBM13}
 Pure spin
current (PSC), i.e., spin current with no associated charge current, could lead
to more efficient quantum devices because a PSC does not produce joule heating.
A PSC can be realized in the spin Hall effect,\cite{sinovaPRB04} one photon
absorption of light,\cite{bhatPRL05, nastosPRB07,zapataPRB17} or interference of two optical
beams.\cite{bhatPRL00, najmaiePRB03}

In contrast to the well-known spin Hall effect which occurs in the ground state
of the material, optically induced PSC occurs in excited states of the
material. Linearly polarized light injects carriers symmetrically into $\pm \bm{k}$
conduction states in the Brillouin zone (BZ). Yet, the velocity
and spin operators are odd under time reversal symmetry and hence there is no net charge current
\cite{alvaradoPRL85,schmiedeskampPRL88,bhatPRL05} or spin density after
summation over all the BZ.~\cite{Fregoso2019} However, the spin current is even
under time reversal and hence it does not vanish after summation over
all the BZ. The optical PSC will manifests as a spatial separation of spin-up spin-down
components or electrons. Optical PSC has been measured by pump-prove techniques
in gallium arsenide (GaAs),\cite{zhaoPRL2006, stevensPRL03} aluminum-gallium
arsenide (AlGaAs)\cite{stevensPRL03}, Co$_2$FeSi.\cite{kimuraNGPAM12}
and ZnSe.\cite{hubnerPRL03}

A major problem in the field of spintronics is the very short spin relaxation time
scales\cite{murakamiSc03} which makes it difficult to maintain coherence required for a spin
current.~\cite{majumdarAPL06,dattaAPL90,gotteNat16,pershinPRB08}  For this reason we turn our attention to
novel two-dimensional (2D) materials. 2D materials represent the ultimate
scaling in thickness with mechanical, optical, and electronic properties that
are unique relative to their bulk counterparts. For example, single-layer or 2D
group-IV mono-chalcogenides GeS, GeSe, SnS, and SnSe are actively being
investigated,\cite{liJACS13,singhAPL14,wangNM16,ramasamyJMC16,wuNL16,kamalPRB16,
guoJAP17,xinJPC16,hanakataPRB16,rangelPRL17,mendozaPRB20} due to their band
gaps and large carrier mobilities suitable for optoelectronics. Monochalcogenides are
centrosymmetric in the bulk but lack inversion symmetry in single-layer
form, thus allowing the generation of nonlinear effects such as optical PSC.

In this paper we show that 2D ferroelectric GeS, GeSe, SnS, and SnSe exhibit
large optical PSC as measured by the spin velocity injection (SVI) to be
defined below. We compute the spectrum of SVI as a function of photon energy
and angle of linearly polarized light. We consider the case of the particles moving
on the plane of the slab and spin pointing out of the slab. Monolayer SnS was
recently experimentally realized,\cite{Higashitarumizu2020} and hence our theoretical results have
direct experimental relevance for this material.

This paper is organized as follows. In Section \ref{sec:theory},  we present
the  PSC theoretical formalism, showing the main expressions used  to
numerically implement  PSC and SVI calculations. In Section \ref{sec:struc} we
describe the 2D monochalcogenide SnS, SnSe, GeS and GeSe structures and  in
Section \ref{sec:results}, we describe the results corresponding to the SVI
spectra for the chosen structures. Finally, we summarize our findings in
Section \ref{sec:conclusions}.

\section{Theory}
\label{sec:theory}
In this section we follow the formalism of Ref.~\onlinecite{zapataPRB17} and
present only the main theoretical results. We consider free Bloch electrons
subject to an external homogeneous electric field

\begin{align}
\bm{E}(t) = \bm{E}(\omega) e^{-i\omega t} + c.c..
\label{z.3}
\end{align}
The main idea is to extract an effective dynamics of spinors states
$c'c$ in the conduction bands. The key approximations are (i) hole spins do not
contribute to the current, (ii) the energy split between spinors $c,c'$ is
small compared with the energy difference between either of the spinors energy and any
valence band, and (iii) the frequency of the optical field is much larger than the
energy split between the spinors. The equation of motion of the effective density matrix
$\rho(\bm{k};t)$ is,\cite{zapataPRB17,nastosPRB07}
\begin{align}
\frac{\partial \rho_{cc'}(\bm{k};t)}{\partial t} &=
\frac{e^2}{i\hbar^2}E^{a}(\omega)E^{b}(-\omega)\sum_{v} r_{cv}^{a}(\bm{k}) r_{vc'}^{b}(\bm{k})
\\\nonumber
&\times\bigg(\frac{1}{\omega-\omega_{c'v}(\bm{k})-i 0^{+}}
 - \frac{1}{\omega-\omega_{cv}(\bm{k})+i 0^{+}} \bigg)
,
\end{align}
with $\hbar\omega_{n}(\bm{k})$
the energy of the electronic band $n$ at  point $\bm{k}$ in the
irreducible Brillouin zone (IBZ),  $|n\bm{k}\rangle$ is the Bloch state,
$\omega_{nm}(\bm{k})\equiv\omega_{n}(\bm{k})-\omega_{m}(\bm{k})$,
$H_0$ is the free Bloch Hamiltonian which
includes the spin-orbit coupling (SOC) and
$H_{0}|n\bm{k}\rangle = \hbar\omega_{n}(\bm{k})|n\bm{k}\rangle$.
Here $c,c'$ are time-reversed spinor states which are split in energy by
SOC.
The denominators clearly indicate the resonance coming from
the absorption of a photon with energy $\hbar\omega$, as the electron goes from
the valence state $v$ to either of the quasidegenerate states $c$ or $c'$.
Latin superscripts indicate Cartesian coordinates
and are summed over if repeated.

In this article, we focus on typical ultrafast experiments,\cite{stevensPRL03,hubnerPRL03}
for which one can ignore spin relaxation. \cite{bhatPRL05}
Thus, we neglect the
precession of the spins due to the spin splitting of the
bands as the precession period is long
compared to the momentum scattering time.\cite{dyakonov84}
Therefore, the spin current operator is  given by
\begin{align}
\hat K^{ab}(\bm{k})
 = \frac{1}{2}( \hat v^{a}(\bm{k}) \hat S^{b}(\bm{k}) +\hat  S^{b}(\bm{k}) \hat v^{a}(\bm{k})),
\label{z.1}
\end{align}
where $\hat{\bm{v}}=[\hat{\bm{r}},H_0]/i\hbar$  is the velocity
operator,  $\hat{\bm{r}}$ is the position operator,
$\hat{\bm{S}}=\hbar \hat{\bm{\sigma}}/2$ is the spin operator with $\hat{\bm{\sigma}}$ the Pauli spin
matrices, and
we allowed for the fact that in general
$\hat{\bm{v}}$ and $\hat{\bm{S}}$ do not commute.

We compute the average of
 the spin current injection tensor $\dot{\bm{K}}(\bm{k})$  as
\begin{align}
\dot{K}^{ab}(\omega) = \int \frac{d^{3}k}{8 \pi^{3}}
\sum_{cc'}
\frac{\partial \rho_{cc'}(\bm{k};t)}{\partial t} K^{ab}_{c'c}(\bm{k})
,
\label{eq:dodt}
\end{align}
where
we used the closure relationship
$|n\bm{k}\rangle\langle n\bm{k}| =1$,
and the integral is over the IBZ.
Then, we write
\begin{align}
\dot{K}^{ab}(\omega) = \mu^{abcd}(\omega) E^{c}(\omega) E^{d}(-\omega),
\label{eq:dotk}
\end{align}
where
\begin{align}
\mu^{abcd}(\omega) &= \frac{\pi e^{2}}{\hbar^{2}}
\int \frac{d^{3}k}{8 \pi^{3}}
\sum'_{vc c'}
K^{ab}_{cc'}(\bm{k}) r^{c}_{cv}(\bm{k}) r^{d}_{vc}(\bm{k})
\nonumber\\
&\times[\delta(\omega-\omega_{c'v}(\bm{k})) +  \delta(\omega-\omega_{cv}(\bm{k})) ]
,
\label{eq:mu}
\end{align}
is the tensorial response function that characterises the PSC.
The prime symbol  the sum means that $c$ and $c'$ are quasi-degenerate conduction
states, and the sum only covers these states.
Finally,
\begin{align}
K^{ab}_{cc'}(\bm{k}) = \frac{1}{2} \sum_{l=v,c} (v^{a}_{cl}(\bm{k}) S^{b}_{lc'}(\bm{k}) +S^{b}_{cl}(\bm{k})
v^{a}_{lc'}(\bm{k})),
\label{eq:velspimatelem}
\end{align}
are the matrix elements of Eq.~\eqref{z.1}.

An important point is that both charge current and net spin density
vanish and hence the current is a PSC. For linear polarization,
the momentum distribution of carriers is even in $\pm \bm{k}$. Assuming time
reversal symmetry, the velocity is odd in $\bm{k}$ and hence charge (injection)
current vanishes after summation over the whole BZ.~\cite{Fregoso2019}
Similarly, the spin matrix elements are odd in $\bm{k}$ and so the net spin
density vanishes. The spin current \ref{z.1} however, is even in $\bm{k}$ and
 does not vanish under linearly polarized light. Note that PCS with linearly
polarized light vanishes in the absence of SOC and that other definitions of the spin
operator,\cite{shiPRL06} are also even under time reversal symmetry.

\subsection{Spin velocity}
\label{sec:spin_vel}
To quantify the speed of the particles we define an effective charge velocity as\cite{bhatPRL05,zapataPRB17}
\begin{align}
\frac{\hbar}{2} \dot{n}(\omega) \mathbb{v}^{ab}(\omega) \equiv
  \dot{K}^{ab}(\omega).
\label{eq:vab-w}
\end{align}
$\mathbb{v}^{ab}$ gives the velocity of electrons along Cartesian direction $a$ with spin
polarized along Cartesian direction $b$.  The carrier injection rate $\dot n(\omega)$ is\cite{nastosPRB07}
\begin{align}
\dot{n}(\omega) = \xi^{ab}(\omega) E^{c}(\omega) E^{d}(-\omega),
\label{eq:dotn}
\end{align}
where
\begin{align}
\xi^{ab}(\omega)  = \frac{2\pi e^{2}}{\hbar^{2} V}
\int \frac{d^{3}k}{8 \pi^{3}} \sum_{vc}
r^{\mathrm{a}}_{vc}(\bm{k}) r^{\mathrm{b}}_{cv}(\bm{k})\delta(\omega-\omega_{cv}(\bm{k})),
\label{eq:xi}
\end{align}
is related to the imaginary part of the linear optical response tensor by
$\mathrm{Im} [\epsilon^{ab}(\omega)] = 2\pi\epsilon_0\hbar\xi^{ab}(\omega)$.

The function $\mathbb{v}^{ab}(\omega)$ allows us to quantify two very important aspects
of PSC. First, we can fix the spin along direction $b$ and calculate the
resulting electron velocity. Second, we can fix the velocity of the electron
along $a$ and study the resulting direction along which the spin is
polarized. In this article we restrict to the first case of the spin polarized
along $z$ to take the advantage of the 2D nature of the chosen
monochalcogenides, where the spin would then be polarized perpendicular to the
plane of the structures, as seen in Fig.~\ref{fig1}.  To this end, we  use an
incoming linearly polarized  light at normal incidence, and use the  direction
of the polarized  electric field to control $\mathbb{v}^{ab}(\omega)$. Indeed, writing
$\bm{E}(\omega) = E_0(\omega)(\cos\alpha\,\hat{\mathbf
x}+\sin\alpha\,\hat{\bm{y}})$, where $\alpha$ is the polarization angle with
respect to $x$, we obtain from Eq. \ref{eq:vab-w} that
\begin{align}
\mathbb{v}^{xz}(\omega,\alpha) =\frac{2}{\hbar} \frac{ \mu^{xzxy}(\omega)\sin 2\alpha }
{\xi^{xx}(\omega)\cos^2\alpha +\xi^{yy}(\omega)\sin^2\alpha},
\label{e.z21}
\end{align}
and
\begin{align}
\mathbb{v}^{yz}(\omega,\alpha)=\frac{2}{\hbar} \frac{\mu^{yzxx}(\omega)\cos^2\alpha +
\mu^{yzyy}(\omega)\sin^2\alpha } {\xi^{xx}(\omega)\cos^2\alpha +\xi^{yy}(\omega)\sin^2\alpha},
\label{e.z22}
\end{align}
where $\mu^{xzxx}(\omega)=\mu^{xzyy}(\omega)=\mu^{yzxy}(\omega)=0$ due to the  $mm2$ point group
symmetry of the chosen 2D monochalcogenides; we remark that only the
$\mu^{azbc}(\omega)$ are involved for the spin polarized along $z$. The speed of the
injected spin along $z$ is given by
\begin{align}
\mathbb{v}^{z}(\omega,\alpha) =\sqrt{(\mathbb{v}^{xz}(\omega,\alpha))^2 +(\mathbb{v}^{yz}(\omega,\alpha))^2},
\label{e.z23}
\end{align}
that makes an angle $\theta^{z}(\omega,\alpha)$ with respect to $x$ given by
\begin{align}
\theta^{z}(\omega,\alpha) =\tan^{-1}\left(\frac{\mathbb{v}^{yz}(\omega,\alpha)}{\mathbb{v}^{xz}(\omega,\alpha)}\right).
\label{e.z24}
\end{align}
We see that $\mathbb{v}^{xz}(\omega,\alpha)$ and $\mathbb{v}^{yz}(\omega,\alpha)$  have a
mirror plane at $\alpha=90^\circ$ and a period of $180^\circ$.  We define the
figure of merit for the speed of the injected spin along $z$ by

\begin{align}
v^{z}_a(\omega)=\mathbb{v}^{az}(\omega,\alpha=\pi/4),\quad a=x,y .
\label{e.z25}
\end{align}

\section{Structures}
\label{sec:struc}
\begin{figure}[]
\centering
\includegraphics[width=\columnwidth]{fig1}
\caption{(color online) The crystal structure of single-layer group-IV
chalcogenides MX, where M=Ge, Sn, and X=S, Se. In a) we show the 3D view of the
single-layer and in b) the projections of the single-layer crystal on the
Cartesian axes. The black rectangles denotes the unit cell. The upward arrow
denotes the $z$ direction of the spin.}
\label{fig1}
\end{figure}
Bulk monochalcogenide crystals MX (M = Ge, Sn and X= S, Se) are orthorhombic
with point group $mmm$ and space group $Pnma$ (No. 62).
They  consist of van der Waals-bonded double layers of metal  monochalchogenide
atoms in an armchair arrangement. The space group of  the bulk crystal contains
eight symmetries including a center of inversion which prevents pure spin
current (PSC). Upon exfoliation, the resulting single ``double layer''
primitive cell has four atoms as  seen in Fig.~\ref{fig1}, with the layers
chosen perpendicular to the $z$ axis. The single-layer structure has four
symmetries, including a two fold rotation with respect to $x$ (plus
translation), 2[001] + (1/2,0,1/2). In addition, the 2D system has two mirror
symmetries with respect to $z$ and $y$, (1/2,1/2,1/2) and $m$[010] + (0,1/2,0),
that leads to an $mm2$ point group, which determines the nonzero components of
the optical response tensors, like $\mu^{abcd}(\omega)$ and
$\xi^{ab}(\omega)$. The atomic slab widths are 2.84, 2.73, 2.56 and 2.61 {\AA}
for SnS, SnSe, Ges, GeSe respectively.

\section{Numerical Method}
\label{sec:numerical}
We calculated the self-consistent ground state and the Kohn-Sham states within
density functional theory in the independent-particle scheme within the local
density approximation (DFT-LDA), with a plane wave basis using the
ABINIT.\cite{gonzeCPC09}  The
Hartwigsen-Goedecker-Hutter (HGH) relativistic separable dual-space Gaussian
pseudopotentials,\cite{hartwigsenPRB98} are used to include the spin-orbit
interaction needed to calculate $K^{\mathrm{ab}}_{cc'}$ from Eq.
\ref{eq:velspimatelem}.
The convergence parameters for the calculations,  for all the structures  are a
cutoff energy of 30\,Ha, resulting in LDA band gaps of 1.35, 0.80, 1.82 and
1.05 eV for SnS, SnSe, GeS, GeSn, respectively. The TINIBA code,\cite{tiniba}
was used to calculate the response functions for which 4356 $\bm{k}$ points in
the IBZ were used to integrate $\mu^{abcd}(\omega)$ and $\xi^{ab}(\omega)$
using the linearized analytic tetrahedron method.\cite{nastosPRB07} We
neglect the anomalous velocity term
$\hbar(\boldsymbol{\sigma}\times\nabla V)/4m^2c^2$, where $V$ is the crystal
potential, in $\hat{\mathbf v}$ of Eq.~\ref{z.1}, as this term is known to give
a small contribution to PSC.\cite{bhatPRL05} Therefore,
$[\hat{\bm{v}},\hat{\bm{S}}]=0$, and Eq.~\ref{z.1} reduces to $\hat K^{ab}=\hat
v^{a} \hat S^{b}=\hat S^{b} \hat v^{a}$. Finally, the prime in the sum of
Eq.~\ref{eq:mu} is restricted to quasi-degenerated conduction bands $c$ and
$c'$ that are closer than 30 meV to each other, which is both the typical laser
pulse energy width and the thermal  room-temperature energy level
broadening.\cite{nastosPRB07} We include 20 valence and 40 conduction bands,
which accounts for all allowed transitions up to 6 eV. To model the slabs we
use supercells of 20 {\AA} along $z$, which corresponds to vacuum larger than
$17$ {\AA}, and renormalize our results to the atomic slab widths mentioned in
the previous section, thus removing the vacuum as it must.

\section{Results}
\label{sec:results}
We present results for monolayer SnS, which was  experimentally
realized recently,\cite{Higashitarumizu2020} as a representative example of the four
monochalcogenides studied. In the appendix we shows the results for SnSe, GeS
and GeSe.

In Fig.~\ref{fig:mu-chi-vaz-sns}, we show  as a function of $\hbar\omega$,
$\mu^{azbc}(\omega)$, $\xi^{aa}(\omega)$, and $v^z_{x,y}(\omega)$  of Eqs.~\eqref{eq:mu},
\eqref{eq:xi}, and Eq. \eqref{e.z25}, respectively. The latter  gives the
figure of merit, for SnS for the SVI (spin-velocity injection), and remark that
$\xi^{\mathrm{aa}}(\omega)$ is a positive definite function. We only show the results
in the visible  range, where
there are ample sources of devices to produce light of the required energy or
its corresponding wavelength $\lambda
(\mathrm{nm})=1240/\hbar\omega(\mathrm{eV)}$. We see  that $v^z_{x,y}(\omega)$, which
is the central result of this article, has a rich structure as a function of
$\hbar\omega$, and more importantly, reaches values around $\pm 100$ Km/s,
albeit not necessarily  at the same energies; similar values of the SVI were
predicted for hydrogenated graphene.\cite{zapataPRB17} Right at the energy gap,
we see the onset of $\mu^{azbc}(\omega)$ and
$\xi^{aa}(\omega)$, and correspondingly of $v^z_{x,y}(\omega)$. There are three energy regions
where $v^z_{x,y}(\omega)$ are large, to wit, just below 1.6\, eV in the Red subrange of
the visible, between 2.0 and 2.2\,eV covering Orange, Yellow and Green colors,
and around 2.7\,eV in the Blue.
The behaviour of $v^z_{x,y }(\omega)$ vs. $\hbar\omega$ could be understood by looking
at $\mu^{azbc}(\omega)$ and $\xi^{aa}(\omega)$ (upper panels). For instance, the structure of
the large peak which leads to a negative $v^z_y (\omega)$ from $~1.4$ to $~1.8$ eV comes
directly from $\mu^{yzxx}(\omega)$ as $\xi^{xx}(\omega)$ and $\xi^{yy}(\omega)$ have several
featureless flat plateaus in that energy region. On the other hand, the
structures of  $v^z_x (\omega)$and $v^z_y (\omega)$ between 2.0 and 2.2\,eV and around  2.7\,eV
come  from the interplay of the $\mu^{azbc}(\omega)$ and both $\xi^{xx}(\omega)$ and
$\xi^{yy}(\omega)$, as prescribed by Eqs.~\eqref{e.z21} and \eqref{e.z22} at
$\alpha=\pi/4$.

\begin{figure}[]
\centering
\includegraphics[scale=.7]{fig2}
\caption{(Color Online) $\mu^{azbc}(\omega)$, $\xi^{aa}(\omega)$, and $v^z_{(x,y)}(\omega)$ of
Eqs.~\eqref{eq:mu}, \eqref{eq:xi}, and \eqref{e.z25} respectively, vs
$\hbar\omega$ for SnS. }
\label{fig:mu-chi-vaz-sns}
\end{figure}

We analize the dependence of $\mathbb{v}^{z}(\omega,\alpha)$ and $\theta^z(\omega,\alpha)$
(Eqs.~\eqref{e.z23} and \eqref{e.z24}), with $\alpha$, the angle that gives the
direction of the linearly polarized electric field of the normally incident
beam of light. To do so, we zoom into the three regions of $\hbar\omega$
mentioned above, for which we find not only a large value of the SVI but also
an interesting behavior that allows the manipulation of the direction of the
SVI itself trough the value of $\alpha$. In Fig.~\ref{fig:all-sns} (left panel)
we show $\mathbb{v}^{z}(\omega,\alpha)$ and $\theta^z(\omega,\alpha)$ vs. $\alpha$, for
$\hbar\omega=1.521,\,1.534,\,1.547$ and 1.559 eV,
corresponding to the near infrared. We notice that for
$\alpha=0^\circ$,
$\mathbb{v}^{z}(\omega,\alpha)$
is maximum for the chosen values of $\hbar\omega$ and reaches speeds
around 225 Km/s. As we move towards $\alpha=90^\circ$,
$\mathbb{v}^{z}(\omega,\alpha)$
decreases smoothly and is close to 45 Km/s. Also, we see that at
$\alpha=0^\circ$ and $90^\circ$, $\theta^z(\omega,\alpha)=270^\circ$,
which can be easily
understood as for these angles $\mathbb{v}^{x,z}(\omega,\alpha)=0$, and
thus the spin velocity would be pointing towards $-y$, for an incoming
polarization along $x$ or $y$.  Moreover, we notice that for the other values
of $\alpha$ the spin velocity does not deviate much from the $-y$ direction. In
the middle panel of Fig.~\ref{fig:all-sns},  we show again
$\mathbb{v}^z(\omega,\alpha)$
and $\theta^z(\omega,\alpha)$ vs. $\alpha$, but for
$\hbar\omega=1.951,\,1.957,\,1.964,\,1.970$ and 1.983 eV, corresponding to the
Red subrange of the visible. For these choices of $\hbar\omega$ we see that the
variation of
$\mathbb{v}^z(\omega,\alpha)$
vs. $\alpha$ is smaller  than from the
previous cases and is non monotonic as a function of $\hbar\omega$. On the
other hand the behavior of $\theta^z(\omega,\alpha)$ is monotonic for the new set of
chosen values of $\hbar\omega$, and it display a very interesting behavior for
$\hbar\omega=1.964$\,eV for which
$\theta^z(\omega,\alpha)=270^\circ$, i.e. is constant as a function of $\alpha$;  on
top of this, we notice that the corresponding
$\mathbb{v}^z(\omega,\alpha)\sim 137$ Km/s, is also almost constant as a function of
$\alpha$.
This means that regardless of the orientation of the polarization of
the impinging electric field, the spin-velocity current will be directed along
$-y$ with nearly a constant speed;
we find a similar behaviour for
SnSe (see the appendix). Therefore, there are energies of
the incoming light for which one can inject $z$-polarized spins along the $y$
surface direction regardless of the polarization angle $\alpha$,
thus opening the possibility of having SVI for
unpolarized light.

Above behaviour is easily explained from Fig.~\ref{fig:mu-chi-vaz-sns}, where
for $\hbar\omega=1.964$\,eV, we
see that as $\mu^{yzxx}(\omega)\sim\mu^{yzyy}(\omega)<0$, $\xi^{xx}(\omega)\sim\xi^{yy}(\omega)$, and
$\mu^{xzxy}(\omega)\sim 0$, then Eq.~\eqref{e.z22} will imply that
$\mathbb{v}^{yz}(\omega,\alpha)$
is almost independent of $\alpha$, and  Eq.~\eqref{e.z21}
implies that
$\mathbb{v}^{xz}(\omega,\alpha)\sim 0$.
Therefore, Eq.~\eqref{e.z24} gives
$\alpha=270^\circ$.
Finally, in Fig.~\ref{fig:all-sns} (right panel), for
$\hbar\omega=2.659,\,2.665,\,2.678,\,2.684$ and
2.690 eV, in the Blue region of the spectrum, we show again
$\mathbb{v}^z(\omega,\alpha)$
and
$\theta^z(\omega,\alpha)$ vs. $\alpha$. For
$\mathbb{v}^z(\omega,\alpha)$
we see a monotonic behaviour as a function of $\hbar\omega$, where
$\alpha=45^\circ$ maximizes the speed that could be as large as $\sim140$ Km/s.
 Now, what is interesting to see is that  the  resulting SVI shows similar
values of $\theta^z(\omega,\alpha)$ in the third quadrant  for energies around
(2.659,2.665)\,eV  and in the first quadrant for energies around
(2.678,2.690)\,eV.
\begin{figure}[]
\centering
\includegraphics[scale=.55]{fig3}
\caption{(Color Online)
$\mathbb{v}^z(\omega,\alpha)$
 and $\theta^z(\omega,\alpha)$ of Eqs.~\eqref{e.z23} and
\eqref{e.z24}, respectively, vs. $\alpha$ for SnS.}
\label{fig:all-sns}
\end{figure}

Finally, we calculate  the average distance $d$ by which the up and down  spin
populations are displaced.
From  Ref.~\onlinecite{bhatPRL05} we  obtain that
$d\sim 4\tau \mathbb{v}^z(\omega,\alpha)$,
 where $\tau$ is the momentum relaxation time. For instance,
assuming $\tau=100$ fs,\cite{hubnerPRL03} from Fig.~\ref{fig:mu-chi-vaz-sns} we
see that $\mathbb{v}^z(\omega,\alpha=0)\sim 260$\,Km/s for $\hbar\omega=2.151$\,eV and
then $d\sim 104$\,nm. This value of $d$ is $\sim 5$ times larger than those
experimentally  measured values of $d=20$ nm for GaAs/AlGaAs\cite{stevensPRL03}
and $d=24$ nm for ZnSe,\cite{hubnerPRL03}
making the SnS, SnSe, GeS and GeSe monochalcogenides, excellent
structures for the realization of PSC.

\section{Conclusions}
\label{sec:conclusions}
Using novel single-layer 2D monochalcogenides, SnS, SnSe, GeS, and GeSe, we
have shown that these 2D films are excellent candidates for spin current
injection. In particular, we reported the results of \emph{ab initio}
calculations for the spin velocity injection (SVI) due to one-photon
absorption of the linearly polarized light as a function of its energy and
direction of polarization. The theoretical formalism  to calculate the SVI
includes the excited coherent superposition of the spin-split conduction bands
that arise in the noncentrosymmetric structures considered here. We made the
calculations for the cases when the spin is polarized in the $z$ direction that
is perpendicular to the 2D films and study the resulting SVI velocity along
the $x$ or $y$ directions parallel to the films. We have shown that the  SVI
display an  interesting behavior, which depends upon the material, but where we
found similarities in that all of them show values around and above 150\,Km/s
for the SVI, with an ample control of the direction of the SVI through the
manipulation of the angle $\alpha$ of the linearly polarized light. Also,  the
particularities of each material made these structures excellent spintonic
candidates.
 In particular we found that for  SnS and SnSe there are energies of
 the incoming light for which one can inject $z$-polarized spins along the $y$
surface direction regardless of the polarization angle $\alpha$  of the
linearly polarized light, thus opening the possibility of having SVI for
unpolarized light.

The speed values obtained here are of the same order of magnitude as those of
Ref.~\onlinecite{najmaiePRB03}  in unbiased semiconductor quantum well
structures, and  Ref.~\onlinecite{zapataPRB17} in hydrogenated graphene
structures,  while they are an order of magnitude
higher compared to 3D bulk materials. Moreover, the distance $d$ by which the
spin up and spin down populations are separated is larger
than for other semiconductors where $d$ has been
measured.\cite{stevensPRL03,hubnerPRL03} Therefore, the 2D monochalcogenide
structures
considered here are  excellent candidates for the development of spintronics
devices that require pure spin current (PSC).

\section{Acknowledgment}
L.J.R. acknowledges  support by CONACyT through a postdoctoral research
fellowship. B.S.M. acknowledges  the support from CONACyT through
grant A1-S-9410. B.M.F. thank NSF DMR-2015639 and NERSC-DOE-AC02-05CH11231.

redpajama_set_name: RedPajamaArXiv


text:
Understanding Team Dynamics
Back to the Shop Floor
Reconnecting With Your People
Portra
Understand the challenges your people face, by "getting your hands dirty" on the shop floor.
Chances are, you've seen an episode or two of the hit TV show "Undercover Boss," where senior executives of major companies disguise themselves as lower-level employees, and are put to work in different parts of their own organizations.
It's often an eye-opening and humbling experience of life outside the boardroom, as the undercover bosses hear the unvarnished truth about what their people really think of them and their company's leadership.
But the executives also learn valuable lessons about working conditions, team morale, and where processes could be improved.
So, should managers and leaders swap their suits and swivel chairs for hard hats and work boots more often? In this article, we look at the advantages and pitfalls of getting back to the "shop floor."
Unlike the TV show, we are not suggesting that you go back to the shop floor undercover or in disguise! What makes for good television viewing could lead to accusations of spying or deception in real life. This article is about being yourself and learning firsthand about the issues that your people and customers face, and what opportunities there are for improvement.
What Is the Shop Floor?
The shop floor can have a number of interpretations, depending on what type of organization you work for and your level within it. Traditionally, it means the factory or manufacturing area where assembly or production takes place. It is also used to describe storage or warehouse facilities.
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Management by Wandering Around (MBWA)


text:
Export (nebo vývoz) je objem zboží, služeb (technologií, licencí, autorských práv), který určitý stát je schopen vyrobit a vyvézt do zahraničí.

Pro každou zemi je vývoz přínosem; je-li hodnota exportu vyšší než hodnota dovozu, rozdíl tvoří přírůstek hrubého domácího produktu. Velká část dnes bohatých zemí své jmění získala právě díky exportu svých výrobků do zahraničí (například Japonsko, USA).

Čistý vývoz
Čistý vývoz (X nebo NX) je rozdíl mezi exportem a importem daného státu: NX = Ex − Im, kde
 Ex je export,
 Im je import
(obojí vyjádřené v určité měně, např. Kč)

V případě, že jeho hodnota je kladná, pak vývoz převyšuje dovoz a hodnota NX udává o kolik (peněžních jednotek). V opačném případě dovoz převyšuje vývoz.

Používá se k výpočtu Hrubého domácího produktu metodou výdajovou.

Reference

Externí odkazy

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