Background Ovarian cancer is one of the leading cancers in Indian women. The current standard of care is a combination of surgical staging, maximal surgical effort to achieve cytoreduction, and judicious use of chemotherapy. Multimodality therapy can reduce mortality, but the practice and uptake of such therapy in Indian Institutions are not up to the desired level. Objectives To study the protocol adherence for ovarian cancer management along with patient compliance and evaluate their effects on survival. Materials and Methods: The retrospective study obtained and analyzed data from records of patients operated for ovarian cancer at a Regional Cancer Center in eastern India between January 2002 and December 2006. Results: The records of 202 patients were evaluable. None of the patients who had primary surgery outside the institute had staging information. A substantial number of patients operated at the institute had incomplete surgical staging, inadequate information on residual disease after surgery, and incomplete histology report. Only 20.3% patients could have optimal cytoreduction after surgery. Compliance to chemotherapy was poor. The median overall survival time and disease-free survival time were 24 months and 5 months, respectively. The residual disease after surgery significantly affected the overall survival, but not the disease-free survival. Incomplete chemotherapy was found to adversely affect survival after adjusting for advanced stage and bulky residual disease. Conclusion: Management of ovarian cancer is suboptimal even in the specialized cancer institute. Poor patient compliance to chemotherapy is one of the major factors adversely affecting survival from advanced ovarian cancer.
Ovarian cancer has the worst prognosis among all gynecological malignancies. The overall 5-year survival is approximately 45%, primarily due to the late stage at diagnosis of the disease.  India with its one billion population has a huge burden of the disease. In comparison, the number of comprehensive cancer centers that can offer appropriate multidisciplinary care is quite meager. Most of the ovarian cancers are initially operated by general gynecologists since trained gynecological oncologists are very few in the country. Many of the patients receive suboptimal management due to logistics and socioeconomic constraints. A large number of the patients belong to rural areas and have poor access to specialized healthcare. The prohibitive cost of antineoplastic drugs is a major deterrent for many of the patients to continue with the treatment. Advanced stage of disease at diagnosis, inappropriate management, and poor compliance to therapy all together are responsible for the dismal survival rates. There is a need to objectively assess these factors in the context of ovarian cancer management in Indian scenario.
Keeping that objective in view, the present study was conducted at a Regional Cancer Institute, a public-funded comprehensive cancer center situated in eastern India. The institute caters mostly to the patients belonging to the lower socioeconomic strata of the society. On an average, 100 new ovarian cancer patients are registered in the Department of Gynecological Oncology of the institute every year. A retrospective analysis of the records of the ovarian cancer patients operated at the institute was done to evaluate the contemporary management, adherence to standard of care, compliance of the patients, and different factors influencing the survival.
The medical records of all invasive ovarian cancer patients registered at the cancer institute between January 2002 and December 2006 were reviewed. A total of 218 ovarian cancer patients were operated at the institute during that period. Of them, the records of 202 patients were considered evaluable as the diagnosis of ovarian cancer was confirmed by histology and the disease status of the patients at last contact was recorded.
Data available as on 31 October 2007 were used for this analysis. If a patient did not attend the institute during the preceding three months and if she was known to be alive at last contact, a telephone call was made to her telephone number, if available, to find out if she was still alive. The date of death was enquired from the patient's relatives if she had passed away.
Descriptive method was used to summarize patient characteristics, type, and extent of tumor and treatment data. The date of surgery at the cancer institute was the initial event from which survival analysis was done. Overall survival was defined as the time from the date of surgery until the date of death from any cause. Disease-free survival was defined as the time from the date of surgery till the date when presence of disease (residual/recurrent) was first recorded. The Kaplan-Meier method was used to estimate the survival and log-rank test was used to assess the statistically significant differences between the survival curves. Multivariate analysis was performed using the Cox proportional hazard model to test the significance of various factors with regard to survival.
The information about age distribution, tumor stage, and treatment are summarized in [Table 1]. The mean age of the patients with epithelial tumors was 48.8 + 11.2 years and that of the patients with germ cell tumors was 26.0 + 12.9 years.
More than 80.0% of the patients were in stage-III or -IV at the time of registration. None of the patients who had primary surgery outside ( n = 38, 18.8%) had adequately completed operative notes to ascertain the stage of the disease. Nearly half of these patients were operated using transverse incisions. Staging was not done appropriately or information was inadequate in 29 patients (17.7%) operated at the cancer institute.
The most common histological types were serous adenocarcinoma among the epithelial malignancies and dysgerminoma among the germ cell tumors [Table 2]. The type of adenocarcinoma was not specified in 26 (12.9%) patients. Tumor grade was mentioned in 84 (41.6%) histology reports.
The primary surgery was done outside the cancer institute in 38 patients of whom nine received adjuvant chemotherapy before registering at the institute. All these patients were reoperated at the institute due to bulky residual disease or due to recurrence. None of these patients were given chemotherapy at the institute before second surgery. Of the 164 patients who had their primary surgery at the cancer institute, only nine (5.5%) were administered neoadjuvant chemotherapy.
In spite of the patients being operated at the cancer institute by trained gynecological oncologists, optimal debulking (residual disease <2 cm) could be done only in 41 (20.3%) patients. Bulky residual disease was left behind after surgery in 141 (69.8%) patients. The volume of tumor left behind was not mentioned in the surgical notes in the rest of the patients ( n = 20; 9.9%).
There were 10 patients (4.9%) who died within 30 days of surgery and were considered postsurgery mortalities. Among them, seven had stage-IIIC disease, two had stage-IV disease, and one had recurrent disease. The most common cause of postoperative death was hemorrhagic shock.
According to the institutional protocol, postoperative chemotherapy was advised to all patients of ovarian carcinoma, except those who had stage-IA/IB disease with grade I/II tumor. Patients with stage-IV disease having multiple metastases and/or poor performance score were not offered chemotherapy. Apart from nine patients in stage-I, five patients in stage-IV, and ten patients who expired within one month of surgery, all 178 patients were advised to undergo adjuvant chemotherapy. Out of them, only 81 patients received chemotherapy at the institute [Table 3]. As documented in our hospital records, the compliance to chemotherapy was extremely poor (45.5%).
It is possible that few of the noncompliant patients attended other hospitals for chemotherapy. By and large the patients dropped out either because they could not afford to buy the chemotherapy drugs or because hospital beds were not available to accommodate them.
The chemotherapy regimens administered postoperatively are listed in [Table 4]. The most frequently administered chemotherapy for epithelial malignancies was a combination of cisplatinum and cyclophosphamide. The bleomycin, etoposide, and cisplatin combination was used for treatment of germ cell tumors. Paclitaxel with carboplatin or cisplatin was administered to 25 patients (30.8%).
The cycles of chemotherapy could be completed as per initial plan in only 39 (48.1%) patients. The reasons for the high drop-out rate could be unacceptable toxicities, inability to buy the cytotoxic drugs, inability to travel repeatedly to the institute from far-off villages, or lack of familial support. Even among those patients who completed the prescribed number of cycles of chemotherapy, the total treatment duration was inordinately prolonged (more than 150 days) in 25 patients (64.0%). No patient received intraperitoneal chemotherapy.
The median overall survival time calculated by Kaplan-Meyer survival curve for the 202 patients was 24 months. The median disease-free survival was only five months [Figure 1].
Several studies have clearly demonstrated that there is an inverse correlation between the amount of residual tumor after surgery and survival. We observed that patients who had <2 cm residual disease after surgery at the cancer institute had significantly better overall survival compared to those who had bulky residual disease (log-rank statistics 7.65; P = 0.006) [Figure 2]. However, the observed overall survival of 100% for the first group is clearly an overestimate. This can be explained by the facts that the number of patients in this group was small ( n = 41) and that most of them dropped out early (noncompliant to follow up).
However, the difference in disease-free survival between the two groups was not that significant (log-rank statistics 0.29; P = 0.058) [Figure 3].
The improved disease-free survival that could be achieved by optimal debulking was negated by the fact that a large number of patients with advanced disease did not receive adjuvant chemotherapy at all or received inadequately.
On multivariate analysis, incomplete chemotherapy was found to be a significant factor adversely influencing overall survival after adjusting for advanced stage and residual tumor at operation (Hazard ratio 6.6; CI 3.1-13.8; P = 0.00).
The standard of care for ovarian cancer is thorough surgical staging with optimal cytoreduction followed by a platinum-based chemotherapy, if there is a significant risk of recurrence. A vertical incision is mandatory to gain adequate access to the upper abdomen. Peritoneal fluid or peritoneal wash should be sent for cytology and the entire abdomen should be explored to look for the extent of disease including metastases. Debulking of all visible tumors (including total abdominal hysterectomy and bilateral salpingo-oophorectomy), omentectomy, pelvic and para-aortic node dissection, and representative biopsies from different parts of the abdominal cavity should be done. A thorough staging procedure can upstage up to 30% of the clinically 'early' stage ovarian cancers and save them from inadequate treatment.  We observed that all patients operated outside the cancer institute were not staged appropriately. In many developed countries, all known or suspected ovarian cancer patients are referred to trained gynecological oncologists for surgery. There is ample evidence that patients with advanced ovarian malignancies have significant survival advantage when a gynecologic oncologist is involved in their care.  In India, trained gynecological oncologists are handful in number. The general gynecologists need to be trained and oriented. The present study reveals that even in a specialized cancer institute, nearly one-fifth of the patients were not staged appropriately.
The aim of surgical effort in advanced ovarian cancer should be to reduce the burden of residual tumor to a point at which the adjuvant therapy will be optimally effective. Griffiths et al. used a multiple linear regression equation with survival as the dependent variable to control simultaneously for the multiple factors that contribute to the ultimate outcome in the individual patient.  The most important therapeutic factor proven to be the size of the largest residual mass after primary surgery. The present case series had a very poor survival rate, primarily because of the fact that nearly 70% of the patients was left with large residual disease even after completion of surgery at the cancer institute. Many of these patients already had a suboptimal primary attempt of debulking outside. Chemotherapy administered for 2-3 cycles prior to the second surgery would have improved the resectability of disease. A European Organization for Research and Treatment of Cancer (EORTC) study showed that interval debulking surgery after few cycles of chemotherapy improved survival in patients who had suboptimal primary debulking surgery.  Contradictory results were obtained by Gynecological Oncology Group (GOG) in a similar study.  They did not observe any significant benefit in overall or progression-free survival of the suboptimally debulked patients who had interval surgery compared to those who continued to have chemotherapy. Such contradiction can be explained by the fact that in the GOG study primary surgery was done only by trained gynecological cancer surgeons who did maximal surgical effort for cytoreduction. This was not necessarily a requisite for the EORTC trial. The EORTC group also used suboptimal chemotherapy.
In our case series, none of the patients were given chemotherapy before secondary debulking. Only 5.5% of the patients who had primary surgery at the cancer institute received neoadjuvant chemotherapy. Considering the large proportion of advanced stage disease the number should have been higher.
The modern era of combination chemotherapy started in the eighth decade of last millennium, when the high efficacy of cisplatin in epithelial ovarian cancer was reported. Cyclophosphamide-cisplatin combination became the standard protocol for the management of advanced epithelial ovarian cancer. The same protocol was introduced at Chittaranjan National Cancer Institute also. The results of the GOG 111 trial published in 1996 convincingly established the superiority of paclitaxel and cisplatin combination over the cyclophosphamide-cisplatin combination in the treatment of stage-III and -IV disease.  The overall response rate as well as the clinical complete response rate were significantly better in the paclitaxel arm. The risk of death was 39% lower among those treated with paclitaxel regimen. Subsequently, carboplatin replaced cisplatin as the analog with fewer marked side effects. At our institute the preferred protocol for treating advanced epithelial ovarian cancer is a combination of paclitaxel (175 mg/m 2 for 3 hours) with carboplatin (AUC of 6.0). Due to the prohibitively high cost of the medicines, most of our patients cannot afford the treatment of first choice and settle for the cisplatin-cyclophosphamide combination. Even though this combination is much more economical, many patients find it hard to bear the expenses.
As most of our patients come from far-off places chemotherapy cannot be administered on day-care basis. Due to inadequate number of beds in the hospital the cycles of chemotherapy cannot be maintained properly for most of the patients. Many patients drop out as they find it difficult to visit the hospital repeatedly. A randomized trial by International Collaborative Ovarian Neoplasm (ICON 3) reported that carboplatin alone has same overall survival as that of palcitaxel-carboplatin combination with more favorable toxicity profile in treatment of stage I-IV ovarian cancer.  Though the ICON3 results were not replicated by other studies, from logistics point of view, carboplatin alone may be more suitable for our kind of setup.  The total administration time is less. So, the patient can be discharged early leaving adequate time for her to go back home on the same day. The fewer toxicities will help to improve compliance and the total treatment cost will be within reach of many of our patients.
The major limitation of our study is that it is a retrospective one and was solely dependent on the data extracted from the medical records. Incomplete or missing records have the potential to introduce bias in the study and affect the outcome.
As observed by the present study, the modifiable factors that can improve the survival from advanced ovarian cancer are the bulk of disease left behind after primary surgery and the compliance of patients to chemotherapy. The specialized cancer institutes in the country need more trained gynecologic oncologists and have to improve their infrastructure to accommodate more patients with advanced disease. The high cost of anticancer medicines will still remain as a stumbling block. The standard-of-care protocols need to be tailored to the local situations and needs.
2. Consolidated Report of Population Based Cancer Registries 2001-2004. National Cancer Registry Program. Indian Council of Medical Research. Bangalore: 2006.
5. Carney ME, Lancaster JM, Ford C, Tsodikov A, Wiggins C. A population-based study of patterns of care for ovarian cancer: Who is seen by a gynecologic oncologist and who is not? Gynecol Oncol 2002;84:36-42.
6. DiSaia PJ, Creasman WT. Epithlial Ovarian Cancer. In: DiSaia PJ, Creasman WT, editors. Clinical gynecologic oncology. 6 th ed. St. Louise: Mosby Inc; 2005. p. 289-346.
7. Griffiths CT, Parker LM, Fuller AF Jr. Role of cytoreductive surgical treatment in the management of advanced ovarian cancer. Cancer Treat Rep 1979:63:235-40.
8. van der Burg ME, van Lent M, Buyse M, Kobierska A, Colombo N, Favalli G, et al . The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. N Eng J Med 1995;332:629-34.
9. Rose PG, Nerenstone S, Brady MF; Gynecologic Oncology Group. Secondary surgical cytoreduction for advanced ovarian carcinoma. N Engl J Med 2004;351:2489-97.
11. International Collaborative Ovarian Neoplasm (ICON) Group. Paclitaxel plus carboplatin versus standard chemotherapy with either single agent carboplatin or cyclophosphamide, doxorubicin and cisplatin in women with ovarian cancer: the ICON 3 randomized trial. Lancet 2002;360:505-15.
Rabiu, K.A. and Akinola, O.I. and Adewunmi, A.A. and Fabamwo, A.O. and Adedeji, M.O. and Popoola, A.O.
Phukan, J.P. and Sinha, A. and Sardar, R. and Guha, P.
Mondal, S.K., Banyopadhyay, R., Nag, D.R., Roychowdhury, S., Mondal, P.K., Sinha, S.K.


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Share this Story: Brad Wall and the Saskatchewan Party didn't fade in their second term and look likely to win April 4 provincial election
Brad Wall and the Saskatchewan Party didn't fade in their second term and look likely to win April 4 provincial election
Cam Cooper
Feb 22, 2016 • June 2, 2020 • 3 minute read • Join the conversation
Premier Brad Wall celebrates with supporters following his 2011 provincial election victory. Photo by Bryan Schlosser /Regina Leader-Post
A new American revolution is underway as socialist Bernie Sanders and billionaire Donald Trump surf a wave of disgust with the establishment and its political minions.
Ample war chests haven't saved former shoo-ins Hillary Clinton and Jeb Bush from the flood of annoyance and rejection. As conservative writer Peggy Noonan astutely observes, their postures seem engineered for the media, scripted to synthesize rage, while Sanders and Trump engage because they actually are enraged.
Brad Wall and the Saskatchewan Party didn't fade in their second term and look likely to win April 4 provincial election Back to video
Disgust with the status quo isn't unique to the United States. Rachel Notley tapped it, turning Alberta inside out. Justin Trudeau did something similar, leaping from third place to first on promises of wholesale change from the left.
But as Saskatchewan nears an election call, such things appear unlikely here. Polls continue to place the Saskatchewan Party well ahead of its opposition, with a firm hold on majorities, not just pluralities, across the demographic spectrum.
Governments often fade in their second terms. The Saskatchewan Party hasn't. Through its term, among decided voters, it consistently registered in the 55 per cent to 64 per cent range, about double the mid 20s to low 30s that shows for the NDP.
The Saskatchewan Party adeptly avoids the establishment label, having learned to govern as the change agent.
The party itself is a change, spanning instead of splitting the centre-right. It's unabashedly free enterprise, yet moves assertively on the left's turf, dropping low-income earners from the provincial tax rolls and upgrading services for the disabled. It cut wait times for surgery, hired doctors and reached out to smaller centres with the STARS helicopter ambulance. In each case, the government positions not as the obstacle to, but the agent of change.
Saskatchewan's keenest wish is a place in the sun. Brad Wall has governed as the province boomed. He shifts credit to the people, but makes it very clear that he strongly favours growth and keys his governing strategy to advancing it. It strikes a sharp contrast with many at the national level, and some locally, who manage to seem sour on the very idea of growth
Wall's challenging of central Canadian opposition to Energy East channels a province that feels itself the outsider. It's probably not lost on the 3,000-plus people working at Evraz Steel and the Co-op Upgrader, or the thousands of others no longer working in the oil patch, that messing with pipelines is questioning their jobs.
Open-market supporter Wall nevertheless opposed the sale of icon PotashCorp. He champions a grassroots idea for using federal handouts to create jobs sealing expired oil wells. He returns often to the theme of economic growth, not for its own sake, but as the source of better public services. Here he speaks to T.C. Douglas and Roy Romanow New Democrats, and the 24 per cent of present NDP supporters who, fascinatingly, say their second choice for government is Wall's party.
All of which yields the Saskatchewan Party polling numbers to die for. They win majorities among both genders and in every region but the far north, are strongly favoured by newcomers, have positives that double their negatives, the most-committed voters and a leader who runs ahead of his party.
Polls don't predict elections and campaigns matter. The Saskatchewan Party is going to collect many votes in places where it won't gain it new seats. Its margin, still massive, is subject to the slings and arrows of office. NDP leader Cam Broten is policy-literate and presents well. As Brad Wall himself is fond of noting, parties are only tenants in public office. But as of today, evidence suggests the Saskatchewan Party, tuned to the tenor of the times, will get its lease renewed on April 4.
Cam Cooper is the principal of Praxis Analytics. Polling numbers come from The Saskatchewan Outlook that Praxis recently released.

redpajama_set_name: RedPajamaCommonCrawl


Valeria Giardino obtained her Doctorate in 2006 at the University of Rome "La Sapienza." In her thesis, she discussed the use of figures and diagrams in mathematics. In 2007, she was an Associate Post-doctoral Fellow at the Institut Jean Nicod. From 2008 to 2010, her research at the Institut Nicod on Diagram-based Reasoning was supported by the European Community's Seventh Framework Program under a Marie Curie Intra-European Fellowship for Career Development. Her current research aims at developing a theory about the way and the reasons that led humans to increase the powers of their mind by relying on external cognitive tools. She has published a book in Italian, together with Prof. Piazza, Senza Parole. Ragionare con le Immagini (Without Words. Reasoning with Images; Milano: Bompiani), and several articles in peer-reviewed journals.


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Q: QLayout setGeometry (in PyQt 5.14) now ignores negative values. Is there a workaround? We have an application which contains a custom-made QLayout. The idea with the layout is that we want to place children of the layout partially outside the layout's frame, thereby clipping the rendering of the child.
In PyQt 5.10 this worked perfectly fine. For example we could:
child.setGeometry(-100, 0, 200, 200)

.. which would place the child 100px outside the left border of the layout, thereby hiding the left-most half of the child.
In PyQt 5.14, this no longer works. With the same code, ie
child.setGeometry(-100, 0, 200, 200)

the child is now placed exactly at the left border rather than 100px outside it. No error or exception is raised, it just silently interprets negative values as 0.
Using positive values for the positioning still works, so that
child.setGeometry(100, 0, 200, 200)

... indeed puts the child at 100px right of the left border.
So question: Is there a way we can get the same behavior as before in PyQt 5.14, so that we can clip children of a layout by placing them outside the boundary of the layout?

redpajama_set_name: RedPajamaStackExchange


"Balancing teens' privacy with desire to share data"
Inventing Adulthoods is a qualitative longitudinal study of young people growing up in five areas of England and Northern Ireland at the turn of the 21st century.
Its rich biographical material, contributed by young people who were 11 - 17 years old at the start of the study, provides a unique window on most aspects of growing up during an important period of social change in the decade 1996 - 2006.
With such a rich and complex project the research team was concerned with contextualising the study historically and providing a taster for the cross-sectional aspects of the Inventing Adulthoods dataset.
Data was collected in waves of fieldwork and organised and coded cross-sectionally so that historical time – the chronological passage of events that frame the entire data set - provides the common thread that gives each successive wave a distinct and contemporary character.
The research team decided to archive this dataset so that other researchers could access it and help realise its potential for methodological and theoretical advancement.
They were mindful of balancing the archiving of their data with not compromising participants' privacy and trust.
One of the biggest challenges to archiving their data was the development of a system for anonymising transcripts that maintained richness and detail, as well as the flow of participants' words and stories.
There were also issues around managing data , selecting cases, gaining consent for archiving which needed to be taken into account. They identified 13 steps to archiving their data.
You can read more about the team's concerns around providing context, confidentiality and anonymity and the technical potential for sharing data in this documentation.


However, please use the measurements below to make sure you get the best fit for your body.
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Check below for the up-to-date listing of our MASC/MAHS member schools.
Renewal forms were mailed mid August. Don't delay-get your membership and ALL of your student activities in your building on our membership roster so you won't miss all of the new and exciting things coming this school year.
If you don't see your school on this list, check with an activity adviser or your principal. Again, certain Michigan Association of Secondary School Principals membership bundles INCLUDE MASC/MAHS membership. You can call us during business hours to get your membership questions or activation complete!


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EU assembly wants defence contractors to have easier access to contracts in other EU states.
The European Parliament has voted overwhelmingly in favour of a move to create a single EU market for defence and security-related equipment, a decision that clears the way for European defence contractors to gain greater access to contracts in other EU member states and which will, its supporters hope, boost competition in a market worth €91 billion.
The vote, at a plenary session of the Parliament on 14 January, followed an agreement between leaders of the assembly and member states. The proposed directive now needs the formal endorsement of member states. After that, and publication in the Official Journal of the EU, member states will have two years to implement the new rules.
The MEP who steered the dossier through the Parliament, the German Liberal Alexander Graf Lambsdorff, said the defence market needs to be opened up because it is "highly fragmented and there's too little competition".
Between 2000 and 2004, only 30% of all defence contracts were put out to tender, and in Germany the level was as low as 2%, Lambsdorff said.
At the moment, defence equipment producers must obtain export licences even when selling goods to another EU member state, a practice Lambsdorff labelled as "inefficient and wasteful", saying that current costs to businesses and governments amount to around €400 million a year.
A separate text, which aims to harmonise and simplify rules governing the granting of licences to transfer military equipment from one country to another, was adopted by the Parliament in December 2008.
Five member states – France, Germany, Italy, Sweden and the UK – account for 90% of the defence equipment produced in the EU.


In 2020 our efforts, our productivity, our creativity, our knowledge and our interaction, will no longer be stored in shoeboxes, or any boxes at all. Their transmission will no longer necessarily be mediated through paper or institution, rigidly constrained, perhaps not shared at all and soon forgotten. Efforts will be discoverable and appreciated, or archived until such a time as they need to be discovered or are ready to be appreciated. Knowledge will be sought after and sharable. A culture of generosity will prevail, whether it is the sharing of experiences with one's friends and family or contributing to common knowledge bases with observations, advice, or expertise. We will no longer force our generosity upon others; they may look at our photographs or read our musings at their leisure. They may do so because they know us, or because they want to know us, or because they are indifferent to us, aside from our ability to satiate their thirst for information and entertainment.
We will become intimately familiar with strangers, and allow strangers views into the intimate parts of our lives. We may find ourselves comfortable letting strangers sleep on our couches or take our money, provided their online reputations are good. We will not blunder about the world blindly. We will know where to go, what to do, what products to purchase, and what mates to choose, because some algorithm will optimally combine experience gathered in our social network, with the opinions of "people like us". The likelihood that we will go wrong will be reduced. We will watch only funny videos, ready only good books, get excellent value for our money, and be able talk about it with our friends, because they will have shared our experience. We will find our niche in the ever growing and evolving network of online people, information, and creativity. We will inextricably be caught in its web, a web that readily adds news threads across great distances, but may or may not ever remove them.
And especially relevant to my own research, Sinan Aral talked about diversity of social networks and productivity, as well as some fascinating brand new research on a massive online dataset (the complete IM network, purchase and browsing patterns). Drool 🙂 Sinan is looking at the important question of disambiguating correlation and influence.
My own talk was on, you guessed it, expertise sharing in online communities.


Today was a crazy sky, so beautiful, like it could be only in fall, so blue and deep.
I was hiking all day and came home so tired, didn't have any energy to edit pictures I took. And then I looked out of the window to see the last light on the clouds. I jumped out, took a couple more and the sun was gone in a minute.
Happy fall my friends! Let us survive coming winter.
Love, love, love your photos. The dark blue sky looks like the ocean sometimes. Love the deep blue.
Наташа, красиво, прям дух захватывает!!!
Я во время заката тоже часто на балкон бегаю:)))), жаль у меня плохой фотоаппарат, но иногда и с ним неплохо получается!!!


TRINAMIC is a semiconductor company developing ASSPs for motion control of fractional horse power stepper motors and brushless DC motors.
Trinamic is leading in IC's and modules for driving motors, Stepper-motors, Brushless DC motors, Piezo motors.
TRINAMIC differentiates its expertise as a combination of understanding the specific requirements of motors and IC design know-how. For customers, Trinamic's application driven approach means that they do not need an in-depth knowledge about motors nor about DSPs or control circuitry in general. Consequently, the design phase is vastly minimized resulting in significant labor and cost savings.
Trinamic´s mechatronics approach – the integration of electronic control, system thinking and precision mechanical engineering – attempts to achieve an optimal balance between the mechanical structures, in this case the motor, and its overall control. For instance, the methodology used in the design of the TMC246 stepper motor driver IC eliminates the need for external components and sensors: The motor is the sensor.
With its highly integrated motion control and driver chips, Trinamic is able to offer a complete solution.
An entire system can be built with an off-the-shelf 8-bit controller connected via an SPI, I²C or parallel interface to Trinamic motion control and driver chips.
For customers looking for low volume solutions, Trinamic also offers complete modules, including hardware and software for specific motor control requirements. The modules combine Trinamic´s dedicated stepper control and driver ICs with extensive experience in designing custom and off-the-shelf motion control solutions. A powerful, yet easy to use programming environment makes stepper control as simple as a few mouse clicks - cutting six months off the time to market compared to chip-level development.


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Posted March 30th, 2016 - News Posted for New Zealand News, World Surfing News.
Dunedin surfer JC Susan claimed the 2016 Corona South Island Surfing Championships on Sunday (March 27th) surfing St Clair Beach, Dunedin, his hometown break.
The final day of the event was held in excellent 1.5m waves with offshore winds.
Susan was joined by Muriwai's Britt Kindred on the winners podium, Kindred winning her first event at the open women's level.
A total of 13 champions were crowned on the final day of the event with divisions ranging between Under 14 Boys and Girls through to Over 45 Men.
Susan won a high scoring battle against number one seed Maz Quinn outpointing the Gisborne surfer 14.40 to 13.67 in the final.
"Maz got a wave in the first 45 seconds on his backhand and smashed it all the way to the beach," said Susan.
"He did the same last year too when he won so this year I didn't want to get combo'ed, I started catching anything I could," said Susan.
"Part way through the final Maz forced me in to this righthander. It looked like a closeout but I managed to get two real good turns on it and it ended up being my best wave and enough for me to win the event" said Susan who despite working less than 100m from St Clair Beach admitted it was the first time he had surfed there since the National Championships held in January.
Susan now heads to Raglan for the Rip Curl Pro in April, the highest rated event on the New Zealand Pro Series.
By way of his second placing, Quinn takes the lead on the New Zealand Pro Series and will head in to the next event as the number one seed.
Placing third in the final was Luke Murphy (Dun) who beat Susan in the semifinals but found the full tide conditions in the final, tough to deal with. Christchurch surfer Hugh Ritchie placed fourth in the final.
Britt Kindred surfed to 12.8 point heat total for the win in the Open Women's Division. Kindred managed to latch on to a few nice long righthanders and despite the full tide backwash found the conditions fun.
"It was a super fun comp with good waves most of the time. Hayley surfed well all comp and I was lucky the final wasn't contested in the 'channel lefts' as she surfs that wave so well," said Kindred. "I am stoked with my result, it is much better than I did at the National Championships here in January and to have an Open Women's Division win is a pretty good feeling," she added.
Coakes finished the final in second place ahead of Billie Scott (Whangarei) in third and Shani Ayson (Dun) in fourth.
Dunedin surfer Elliot Brown claimed a double in the junior divisions winning the Under 20 Boys and Under 17 Boys. Brown also won the Under 18 Boys Championships at the same break in January showing some formidable summer form.
Kindred secured her double by adding the Under 20 Girls Division to her Open Women's Division title.
Tegan Bishop (Chch) won the Under 17 Girls Division, her first title at a national level and an improvement on her third placing only one week ago in Christchurch.
Like Bishop, Oamaru's Maddy Barclay claimed his first national win in the Under 14 Boys Division which should see him shoot up the New Zealand Grom Series ratings.
Piha surfer Zen Wallis won his second event on the New Zealand Longboard Series following his national title back in January. Wallis surfed to a 15.0 point heat total ousting Christchurch surfer and double finalist Hugh Ritchie who had to settle for runner up for the second consecutive event. Placing third in the final was Jake Barton (Dun) with Henry Hawke (Chch) in fourth.
Day two standout Anthony Hema finished the event with two titles – the Over 28 and Over 35 Men's Divisions.
Kaikoura's Alan Te Moananui claimed the Over 40 Men's Division while Christchurch surfer Justin Summerton won the Over 45 Men's Division.
See below for final results from the Corona South Island Championships held at St Clair Beach, Dunedin on Sunday 27th March.


Anxiety Board Index: Is this really anxiety?
I've had issues with anxiety and depression from a young age. I remember having panic attacks/feeling like I was going to pass out at age 10/11. I think my first trigger was when my grandmother died at age 10, it was a traumatic experience for me, I still remember my mother screaming/crying when she found out. I never cried when she died because I thought I had to be strong for everyone else. I think that screwed me up mentally because I never really grieved. I went to therapy for a while but stopped eventually. My main anxiety symptoms back then were feeling like I couldn't breathe and feeling lightheaded. They would come on in social situations I wasn't comfortable with.
I grew out of these attacks somewhat once I had a physical outlet for stress relief (horseback riding). It was my "happy place" and at 13 I was given a horse, started spending all my free time at my barn, and came out of my shell. But another traumatic experience (my horse went lame (limping)) and I couldn't "fix" him. I distinctly remember my mother driving me to the barn one day and I worried about my horse. I started getting dizzy/light headed, couldn't breathe, got all sweaty, and ended up throwing up when I got to the barn. I started feeling like I was going to choke every time I went to the barn, but it would subside once I was there. I also got the choking feeling/couldn't breathe/lightheadedness in social situations.
I eventually grew out of this as well, for several years I only occasionally had mild anxiety symptoms.
Fast forward to the end of my sophomore year in college (beginning of this summer). I had what I would describe as the most traumatic moment of my life happen. I now own a horse barn with 6 horses and am responsible for ALL of their care. It is a 24/7/365 job and I was okay with that for a long time because I loved what I was doing. However several days after my last final, one of my horses at the barn was euthanized. It was unexpected, it happened quickly, within the span of a few hours. She was fine and then she was in excruciating pain (colic). I was a very sobering experience, I was there from the beginning to end, watched the horse fall to the ground, held her owner as she cried in my arms, and watched as the body was taken away. I really held it together the entire time. I cried, but in a healthy way, if that makes sense.
From that point on it was the worst summer of my life. One of my own personal horses nearly died a week later due to a severe vaccine reaction and was sick several other times throughout the summer as a result. My first horse also was sick for a month with Lyme Disease, which is very prevalent in my area. I had 2 other horses get sick too. I ended up very depressed, I didn't want to see my horses, felt like everything was a chore, didn't want to get out of bed, and was tired all the time. I snapped myself out of it and started to get back to normal, however all the physical symptoms that started to manifest throughout this time have remained and now I'm truly concerned I have a brain tumor, which of course is giving me a whole new level of anxiety.
These symptoms come and go, I'll read about something and then I'll have the symptom if that makes sense. I do have a history of doing this, for instance when I was a teen I was diagnosed with mono. My doctor said to call if I started feeling pain where my spleen was because it was enlarged. Only after she told me this did I start feeling pain in my spleen. This lasted long after it was confirmed that my spleen was no longer enlarged.
My doctor seems to think all this is anxiety related. She wouldn't order an MRI or CT when I asked, looked at me like I was nuts when I said I had a brain tumor.
I'm also thinking I could have Lyme since tick bourne illnesses are common in my area and I work outside around horses who constantly had ticks on them this summer. My doctor wouldn't test for this either.


text:
Q: Write the exact answer using base-10 logarithms. Solve for x.
$11^{-8x} = 18^{-x+10}$
Write the exact answer using base-10 logarithms.
Every online tutorial I've looked up does not have a step by step process explaining how they got it.

A: $$11^{-8x}=18^{-x+10}$$
Take reciprocals of both sides:
$$11^{8x}=18^{x-10}$$
Take the logarithm of both sides and use the identity $\log(a^{b})=b\log(a)$:
$$8\log(11)x=\log(18)(x-10)$$
Expand out terms of the right hand side:
$$8\log(11)x=\log(18)x-10\log(18)$$
Subtract $x\log(18)$ from both sides:
$$(8\log(11)-\log(18))x=-10\log(18)$$
Divide both sides by $8\log(11)-\log(18)$:
$$x=- \frac{10\log(18)}{8\log(11)-\log(18)}\:.$$

A: Hint:
$$\frac1{11^{8x}}=\frac{18}{18^x}\implies -8x\log11=\log18-x\log18\implies\ldots$$
Further hint: the above is true for any base of logarithm, not only base $\;10\;$ .


text:
Home Tunbridge Wells News Article
Councillor Sean Holden wants King Charles the Martyr church in Tunbridge Wells to change its name
ByCaitlin Webb, local democracy reporter
Published: 21:01, 24 January 2019
| Updated: 21:21, 24 January 2019
A county councillor is calling for a place of worship to change its name as he claims it is dedicated to a "dictator and warmonger".
Cllr Seán Holden (Con) wants King Charles the Martyr church to reconsider its name on the 370th anniversary of the "tyrant" king's execution.
Charles I was famously executed after his quarrel with parliament about power led to the English Civil War.
King Charles I reigned between 1625 and 1649
In an open letter to the Reverend Laurence Powell, the councillor criticised the commemoration of "a man who started four wars against his own people in which tens of thousands of English and Scots died".
Despite being considered a martyr by the Church of England, Cllr Holden claims "he was a martyr to nothing but his own vanity".
He wrote: "At this moment when parliament is at the centre of the national consciousness (whichever side of that debate you are on) it would be right to end the commemoration of this Man of Blood as he was called then.
"He invaded the Commons with armed soldiers and he tried to rule without it by levying illegal taxes for 11 years.
"He started two mismanaged wars against Scotland and two catastrophic English civil wars which killed about 4% of the population - twice the rate of World War I.
"All to maintain his supposed 'divine right' to rule exactly as he pleased.
King Charles the Martyr church. Picture: Google
"How can you continue to elevate in your church a man who deliberately and recklessly waged war against people and parliament in every corner of our country and for which the High Court of Justice held him 'guilty of all the treasons, murders, rapines, burnings, spoils, desolations, damages and mischiefs to this nation acted and committed in the said wars'."
The priest at the church said he "appreciates his point of view" but the congregation are "proud of the history".
Rev Powell said: "We are quite proud of the history behind the church and it's the crowning glory of Tunbridge Wells.
"Our church is in a very historical building, it's the oldest building in Tunbridge Wells, established in 1678.
"Many people from London paid for a church including Samuel Pepys."
He added the church has been visited by many notable members of the royal family including Princess Victoria before she became queen.
He claims the wells in the town are known as "The Queen's Wells"as the wife of King Charles I often visited.
"He started two mismanaged wars against Scotland and two catastrophic English civil wars which killed about 4% of the population - twice the rate of World War I" - Cllr Seán Holden
Rev Powell has admitted the dedication is "somewhat hard to comprehend" but his faith believe the king sacrificed his life for the church.
He added: "The 1662 Book of Common Prayer advises that Charles I should be commemorated as a martyr of the church.
"A number of saints and martyr's have equally committed atrocities in the past.
"This is not something to be proud of as Christians but it is part of our history and heritage and should not be forgotten but be used as example for implementing change."
The "thriving" place of worship in Warwick Park is one of only a handful of active churches which commemorate King Charles I.
It is also one of a few churches in the country built in the latter 17th century.
He added: "It's incredibly difficult to rename a church and furthermore, we have absolutely no intention of doing so."
The church is hosting a lecture by Revd Canon Prof Mark Chapman from the University of Oxford to discuss the history of how King Charles I is considered a martyr on Saturday, January 26 from 2pm.
Human InterestKentTunbridge Wells
Caitlin Webb, local democracy reporter


In this filmic essay, Federico Atehortúa Arteaga alternates between Colombia's history and his youth. Both have been recorded in footage that doesn't always tell the truth. Falsos positivos, murdered youths disguised as guerrillas by the army to simulate military success, are a central element.
Rotterdam #11: Director's memories about his mute mother overlap Colombia's sanguineous history like the assassination of the president and the conflict between military and FARC.And this landscape is sublimated into kaleidscopic vision of cinema, with abundant footages, in deeply personal yet horrifyingly historical "Pirotecnia". I'm devastated by what gigantic wounds Colombian people must embrace. Insightful.


text:
Junbao Du
First Hospital, Peking University, China
Guangdong Yang
Laurentian University, Canada
Li-Fang Hu
Soochow University, China
Principles of H2S Biology
AMPK and its Biological Function
AMPK in H2S Pharmacology
Current Research Gaps
MINI REVIEW article
Front. Pharmacol., 08 November 2017
Sec. Experimental Pharmacology and Drug Discovery
Volume 8 - 2017 | https://doi.org/10.3389/fphar.2017.00810
An Update on AMPK in Hydrogen Sulfide Pharmacology
Minjun Wang1,2†, Wenbo Tang3,4† and Yi Zhun Zhu1,2*
1Department of Pharmacology, School of Pharmacy, Macau University of Science and Technology, Macau, China
2Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
3Department of Oncology, School of Medicine, Fudan University, Shanghai, China
4Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
Hydrogen sulfide (H2S), the third bio-active gasotransmitter, is produced endogenously and tightly involved in the pathogenesis and treatment for various diseases. Adenosine 5′-monophosphate-activated protein kinase (AMPK) plays a paramount role in maintaining cellular energetic balance. Increasing evidences have also suggested AMPK as a novel modulator in multiple pathological conditions. In this paper, we will review the biological principles of H2S and AMPK, and most importantly, the recent discoveries regarding AMPK-mediated pharmacological actions of H2S. Emphasis will be laid on AMPK/H2S interactions in the cardiovascular system, autophagy, diabetic complications, and inflammation. In most cases described in this article, by promoting AMPK activation, H2S exerts cytoprotective effects or therapeutic potentials, though there remain some controversies before we can fully understand the involved mechanisms. Further researches are in need to investigate more closely any relationship between H2S and AMPK, and to put forward the development of H2S donors for clinical application.
Hydrogen sulfide (H2S), the gas with "rotten egg" smell, has been recognized as the third bio-active gasotransmitter after nitric oxide and carbon monoxide. Mounting studies have revealed its protective effects in the cardiovascular system, central nervous system as well as in diabetes and inflammation. Besides the prominent role in metabolic regulation, recent reports have suggested that adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) also participates in various physiological and pathological processes and functions as a critical mediator in the effects of H2S. In this paper, we will review the latest and emerging evidences on AMPK-mediated therapeutic potentials of H2S.
Biosynthesis of H2S
For 100s of years H2S was thought to be noxious and toxic. What's interesting is that H2S and organosulfur compounds could be easily found in recipes, such as garlic products. Dietary garlic is well-known for its benefits in lowering blood pressure and lipid levels (Jung et al., 2014; Ried, 2016). In fact, Benavides et al. (2007) pointed out that garlic-derived organic polysulfides were converted rapidly by red blood cell into H2S, which was responsible for the subsequent vasorelaxation effects.
In addition to dietary consumption, H2S is endogenously produced as well. Physiological H2S production in mammal cells is mainly attributed to three enzymes, including cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-Mercaptopyruvate sulfurtransferase (3MST).
All these enzymes exhibit tissue-specific expression. CBS is expressed abundantly in the central nerves system, liver, kidney, and so on (Fiorucci et al., 2006; Kimura, 2013; Feliers et al., 2016). It was believed that CSE was mainly produced in the cardiovascular system (Polhemus and Lefer, 2014), but recent studies reported that CSE was also detected in the liver, lung, and kidney (Song et al., 2014; Wang et al., 2017). 3MST was originally discovered in the brain of Cbs knockout mice (Shibuya et al., 2009), and further confirmed as a ubiquitous enzyme expressed in the lung, kidney, liver, and vasculature (Ahmad et al., 2016).
Moreover, these enzymes differ in cellular localization and H2S metabolism. CBS and CSE are localized in the cytosol, while 3MST is produced in both the cytosol and mitochondrial (Kimura, 2011). In contrary to 3MST, CBS, and CSE are involved in multiple transsulfuration reactions, with pyridoxal 5′-phosphate as a cofactor and sulfur amino acids as substrates, including L-cysteine, L-cystine, and homocysteine (Li et al., 2011). The H2S metabolism has been reviewed in detail elsewhere by Wang (2012).
Pharmacological Actions of H2S
During the past decades, increasing studies have evidenced the functions of H2S in mammals, among which cardiovascular regulation is the most investigated (Polhemus and Lefer, 2014). Cse knockout leads to severe hypertension in mice, suggesting H2S as a potential vasodilator (Yang et al., 2008). Indeed, similar to the other two gasotransmitters, both endogenous and exogenous-applied H2S exhibits vasorelaxation effects in multiple types of blood vessels (Kiss et al., 2008). It was reported that the proliferation of vascular smooth muscle cell was inhibited by H2S, as opposed to vascular endothelial cells (Du et al., 2004; Papapetropoulos et al., 2009). Furthermore, H2S protects mice from myocardial infarction and ischemia-induced heart failure (Calvert et al., 2010; Miao et al., 2016).
Apart from the cardiovascular system, H2S also contributes to protective effects in inflammation, oxidative stress, and nervous system. Despite the controversy regarding the multiple roles of H2S in inflammatory disorders, it is generally accepted that H2S ameliorates neuroinflammation, suppresses inflammatory cytokine production, and inhibits activation of key transcriptional factors. More details about the physiological and pharmacological functions of H2S could be found in reviews by Li et al. (2011) and Wang (2012).
AMPK Regulation
Adenosine 5′-monophosphate-activated protein kinase is a conserved energetic sensor existed in almost all eukaryotes. Composed of a catalytic α-subunit and regulatory β- and γ-subunits, AMPK monitors intracellular AMP and adenosine triphosphate (ATP) levels (Kahn et al., 2005; Li et al., 2015). In mammals, APMKα catalytic subunits and β-subunits are encoded by two genes separately (α1, α2, and β1, β2), and γ-subunit by three genes (γ1, γ2, and γ3), making at least 12 possible heterotrimer combinations, of which the expression may be tissue restricted (Hardie et al., 2012). For example, γ3 isoform is dominantly expressed in skeletal muscle, and both the wild type and a mutation of arginine to glutamine at position 225 (R225Q) in the CBS domain results in increased glycogen concentrations in skeletal muscle of the transgenic mice (Yu et al., 2006).
During energy deprivation characterized by increased AMP/ATP ratio, AMPK is phosphorylated at Thr172 and allosteric activated with a 100-fold increase in kinase activity (Hawley et al., 1996). In mammals, the typical kinases involved in canonical AMPK activation include liver kinase B1 (LKB1) and Ca2+/calmodulin-activated protein kinase kinase β (CaMKKβ). LKB1, also known as a potent tumor suppressor, is vital for the basal phosphorylation level of AMPK (Hardie et al., 2012). Genetic knockout of LKB1 impairs AMPK activation by AMP, indicating its critical role during energy deprivation (Hardie and Alessi, 2013). AMPK is also activated in response to calcium flux, which relies on the intact function of CaMKKβ. It is noteworthy that this alternative AMPK activation pathway is independent of any change in cellular AMP level (Hardie et al., 2012), and is most highlighted in the brain (Green et al., 2011).
AMPK Activators
In addition to cellular metabolic signal, AMPK can be activated by a variety of compounds. AICAR (5-amino-4-imidazolecarboxamide riboside-1-β-D-ribofuranoside) is a potent AMPK activator. As an adenosine analog, AICAR is taken in by adenosine transporters and converted into ZMP (5-aminoimidazole-4-carboxamide-1-β-D-furanosyl 5′-monophosphate). Similar to AMP, ZMP binds directly to AMPK and induces its allosteric activation (Wong et al., 2009). Natural products and related derivatives represent another class of AMPK activators. Metformin, derived from French lilac, is widely administrated as the first-line medication for type 2 diabetes. Although the involved mechanisms remain partially understood, it is clear that AMPK plays an important role in the benefits of metformin (Zhou et al., 2001). Resveratrol, isolated from grapes and red wine, is reported to activator AMPK and SIRT1, a NAD+-dependent protein deacetylase sharing crosstalk with AMPK (Price et al., 2012). Other natural AMPK activators include epigallocatechin gallate, capsaicin, curcumin, berberine, and so on (Hwang et al., 2005; Ejaz et al., 2009; Jeong et al., 2009).
AMPK on Cellular Metabolism and More
As a master cellular energy gauge, AMPK regulates lipid and glucose metabolism by phosphorylating downstream targets. Activated AMPK not only suppresses fatty acid synthesis by impairing acetyl-CoA carboxylase (ACC), but also facilitates lipid oxidation by boosting malonyl-CoA decarboxylase (MCD) (Zang et al., 2004; Zhang et al., 2009). Similar regulating pattern is also observed in glucose metabolism. By promoting the translocation of glucose transporter 4 (GLUT4), AMPK activation stimulates glucose uptake in muscle tissue (Jäger et al., 2007). In parallel, hepatic gluconeogenesis is inhibited by AMPK through decreased phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) transcription (Zhang et al., 2009). In general, AMPK activation leads to metabolic changes toward relieving energy deprivation.
In addition to energy balance, recent studies have suggested the participation of AMPK in autophagy, atherosclerosis, inflammation, and cancer, which shares crosstalk with H2S (Motoshima et al., 2006; Kim et al., 2011; O'neill and Hardie, 2013). The advances in AMPK researches have shed light on novel therapeutic potentials of AMPK activators and H2S donors, and provided modern understanding of metabolism. More details will be discussed in the following sections.
Great efforts have been made to elucidate the roles of AMPK in H2S pharmacology, in which AMPK usually serves as a key mediator. Despite the fact that AMPK was reported to be inhibited by H2S in some circumstances (Zhang et al., 2012), it is generally accepted that H2S exerts its biological activity by activating AMPK. In this part we will review the recent discoveries on AMPK-H2S pharmacology.
AMPK in Cardioprotective Effects of H2S
According to latest Global Burden of Disease Study, ischemic heart disease remained as the global leading cause for death in 2010, accounting for 13.3% of total death worldwide (Lozano et al., 2013). A great number of patients are suffering from related diseases including ischemic heart failure and stable arrhythmia (McMurray et al., 2005). The beneficial effects of H2S on survival after cardiac arrest in mice was first reported in 2009. By i.v. application of Na2S, an exogenous H2S donor, 7 min following cardiac arrest, significant increase in survival rate was achieved compared with vehicle (Minamishima et al., 2009). The authors pointed out that the treatment effects of Na2S was associated with activated AMPK prosurvival signals. In addition, AMPK is also attributed to the cardioprotective effects of H2S in high fat diet-induced cardiac dysfunction and impaired left ventricular function by smoking (Zhou et al., 2014a; Barr et al., 2015).
Myocardial ischemia/reperfusion (I/R) injury is a complication of inflammation and oxidative damage encountered when restoring blood supply of ischemic regions. Previous studies have demonstrated that H2S protects from I/R injury by multiple mechanisms, including ameliorating oxidative stress, inflammation, and apoptosis (Sivarajah et al., 2009; Meng et al., 2015). Xie et al. (2015) reported that AMPK is a critical mediator in the effects of H2S donor ADT. By maintaining autophagy flux impaired by I/R, as evidenced by reduced LC3-II/LC3-I ratio and beclin-1 expression, H2S-activated AMPK significantly relieved myocardial I/R injury.
Post-conditioning (PC), defined as brief repeated periods of ischemia performed at the onset of reperfusion, has been proved to reduce I/R injury in both cardiomyocytes and coronary vascular endothelium cells (Vinten-Johansen et al., 2005). Nevertheless PC only exerts cardioprotection in young but not old hearts (Boengler et al., 2009). Chen et al. (2016) suggested that by exogenous application of H2S, the treatment effects of PC could be restored in isolated aged rat hearts and aged cardiomyocytes. In contrast to the study on I/R, stimulated AMPK promoted autophagy, which subsequently decreased apoptosis, reduced myocardial injury, and improved cardiac function. More studies regarding AMPK-H2S and autophagy will be discussed in the next section.
AMPK-Regulated Autophagy in H2S Pharmacology
Autophagy is a lysosome-dependent "self-engulfment" process in which cells digest their own cytosolic components to maintain metabolic homeostasis during starvation. Moreover, autophagy is tightly involved in cancer, cardiac and liver diseases (Levine and Kroemer, 2008). The autophagy pathway was originally discovered with Atg1/UNC-51-like kinase (ULK) 1 complex as an essential initiator, which also senses cellular nutrient status from the mammalian target of rapamycin (mTOR). Previous studies have established the prominent role of AMPK in regulating autophagy. One of the most described mechanism involves the suppression of mTOR pathway by AMPK, which promotes the formation of autophagosomes (Kim and Guan, 2015). On the other hand, AMPK directly phosphorylates several critical sites in ULK1 and subsequently induces its activation in autophagy and mitochondrial homeostasis (Hardie, 2011). By inhibiting mTOR and activating ULK1, AMPK regulates autophagy in response to nutritional signal (Mihaylova and Shaw, 2011).
The AMPK-autophagy pathway has been identified in multiple pharmacological functions of H2S. As described in the last section, H2S mitigates cardiac I/R injury and restores PC protection by regulating AMPK-mediated autophagy. Similar results were also observed in high glucose conditions. Vascular endothelial dysfunction induced by hyperglycemia impairs vasodilation and angiogenic function, leading to diabetic complications (Hink et al., 2001). Exogenous H2S markedly preserved arterial endothelial cells by reducing AMPK phosphorylation and inhibiting excessive autophagy (Liu et al., 2016). Furthermore, Kundu et al. (2014) suggested that H2S relieved renal matrix accumulation during hyperglycemia by LKB1/AMPK cascade. Intriguingly, as opposed to the previous study, AMPK was activated by H2S, leading to protective autophagy in glomerular endothelial cells (Kundu et al., 2014).
Hypertriglyceridemia is among the most common metabolic diseases and is proved as an independent risk factor for cardiovascular and cerebrovascular events (Chapman et al., 2011). Lower plasma H2S content was reported to be associated with dyslipidemia, indicating the potential regulation of H2S on serum triglyceride (Liu et al., 2006). Indeed, Sun et al. (2015) claimed that H2S reduced triglyceride and relieved non-alcoholic fatty liver disease in mice by activating AMPK and inhibiting mTOR. Consistent regulation of AMPK and autophagy by H2S was reported in inhibiting colon epithelial cell proliferation (Wu et al., 2012).
AMPK in H2S Protection against Diabetic Complications
Chronic hyperglycemia of diabetes leads to damage and dysfunction of multiple organs, including the kidney, heart, and blood vessels (American Diabetes Association, 2014). The anti-diabetic effects of AMPK activators are well-documented, and numerous evidences have indicated the mitigation of hyperglycemia and related complications by H2S (Suzuki et al., 2011; Szabo, 2012). Lee et al. (2012, 2017) suggested that H2S decreased protein synthesis, cellular hypertrophy, and matrix protein accumulation of renal cells under high glucose condition. Moreover, H2S inhibited mTOR activity, mRNA initiation and elongation by activating AMPK through CaMKKβ. Corresponding AMPK/mTOR regulation by H2S was also reported in cardiomyocyte protection from high glucose (Wei et al., 2014).
Vascular inflammation induced by hyperglycemia is associated with impaired insulin sensitivity and accelerated atherosclerosis (Basta et al., 2004; Paneni et al., 2013). Both L-cysteine, the endogenous precursor of H2S, and exogenous H2S donors successfully diminished high glucose-stimulated inflammatory cytokine secretion from monocytic cells, indicating the link between H2S and vascular inflammation (Jain et al., 2010). It was further supported that H2S relieved vascular inflammation via multiple mechanisms including activating AMPK (Manna and Jain, 2013). These findings might bring light on the therapeutic potentials of H2S against diabetic complications.
AMPK in Anti-inflammatory and Anti-oxidant Stress Properties of H2S
There have been controversies over the exact role of H2S in inflammation (Whiteman and Winyard, 2011). Despite distinct results obtained, it appears that the inconsistency in the pro- and anti-inflammatory effects of H2S might be attributed to models, doses, and sampling time (Hegde and Bhatia, 2011). It is generally acknowledged that H2S shows remarkable suppression on lipopolysaccharide-induced production of inflammatory cytokines both in macrophages and microglia cells (Hu et al., 2007; Whiteman et al., 2010). In parallel, the inhibition of inflammation by AMPK activation has been also been reported (O'neill and Hardie, 2013). Zhou et al. (2014b) found that the suppression of microglia inflammation by H2S was largely dependent on AMPK activation via CaMKKβ pathway, which was evidenced by multiple H2S donors, CBS overexpression, and AMPK knockdown.
Anemia of inflammation (AI) is the second prevalent anemia and a common complication in patients with chronic diseases (Weiss and Goodnough, 2005). Lower hemoglobin is associated with increased mortality in diseases such as heart failure (Horwich et al., 2002; O'Meara et al., 2006), cancer (Caro et al., 2001), and chronic kidney disease (Foley et al., 1996; Vlagopoulos et al., 2005). The pathological changes of AI include iron disturbance and erythroid system dysfunction (Nemeth and Ganz, 2014), of which iron dysregulation is the hallmark. Mounting evidences have indicated that elevated hepatic and circulating hepcidin, a liver-derived iron-regulating peptide, is tightly involved in the progression of AI (Ganz, 2003), making it an ideal target for AI treatment. We first reported that during inflammation H2S inhibited hepatic hepcidin, a critical factor in AI pathogenesis (Xin et al., 2016). Our recent investigation revealed that the effects of H2S was partially mediated by AMPK (Wang et al., 2017). What's more, both pharmacological and genetic activation of AMPK, as well as metformin, ameliorated chronic AI in mice, which was supported by our clinical samples and independent groups (Kim et al., 2016; Wang et al., 2017). Interestingly, metformin was reported to increase H2S content in various mouse tissues (Wiliński et al., 2013). Much more work will be needed to broaden our understanding about the interaction among H2S, AMPK and metformin.
5′-Monophosphate-activated protein kinase also contributes to the effects of H2S and garlic products against oxidant stress. Han et al. (2011) claimed that ajoene, a garlic by-product, reduced oxidative injury and hepatic steatosis by stimulating LKB1/AMPK pathway. Consistent results were observed in H2S donors. Sodium hydrosulfide, an inorganic H2S donor, ameliorated oxidative stress and apoptosis via activating CaMKKβ/AMPK signaling, finally attenuating experimental aging process (Chen et al., 2017). Furthermore, reactive oxygen species production was diminished by H2S-induced AMPK activation in osteoblast cells treated with dexamethasone (Yang et al., 2014).
It is of great importance to understand the specific mechanisms within H2S-induced AMPK activation. However, few studies have looked into this topic. Kundu colleagues claimed that H2S activated AMPK by LKB1 (see section "AMPK in Cardioprotective Effects of H2S"), while Lee colleagues (see section "AMPK-Regulated Autophagy in H2S Pharmacology") and Zhou colleagues (see section "AMPK in H2S Protection against Diabetic Complications") suggested CaMKKβ was indispensable for AMPK activation by H2S.
It is worth noting that instead of fully elucidating the potential mechanisms, all these studies mainly pointed out several key mediators in the H2S-AMPK pathway. Moreover, recent studies have revealed that H2S might also regulate protein functions in a more "direct" manner, such as by sulfhydration (Paul and Snyder, 2012) and forming polysulfides (Greiner et al., 2013; Kimura et al., 2013). Future studies may help better understand the role of these novel modifications in H2S-AMPK interactions.
In summary, this minireview provides novel insights into latest AMPK-mediated H2S pharmacology in various tissues and diseases (Figure 1). Despite substantial progress, there remains a long road toward complete understanding of AMPK-H2S interactions and application of H2S donors in clinical settings.
FIGURE 1. A schematic diagram of multiple roles of AMPK in the pharmacological functions of H2S. AMPK, adenosine 5′-monophosphate-activated protein kinase; H2S, hydrogen sulfide; LKB1, liver kinase B1; CaMKKβ, Ca2+/calmodulin-activated protein kinase kinase β; mTOR, mammalian target of rapamycin; ULK2, UNC-51-like kinase 2; TG, triglyceride; I/R, ischemia/reperfusion; PC, post-conditioning; ROS, reactive oxygen species.
All authors listed have made substantial, direct and intellectual contributions to the work, and approved it for publication.
This work was supported by grants from Macao Science and Technology Development Fund (Grant No. FDCT/039/2016/A and FDCT/055/2016/A2).
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Keywords: hydrogen sulfide, AMPK, pharmacology, cardiovascular, autophagy, inflammation, oxidative stress
Citation: Wang M, Tang W and Zhu YZ (2017) An Update on AMPK in Hydrogen Sulfide Pharmacology. Front. Pharmacol. 8:810. doi: 10.3389/fphar.2017.00810
Received: 23 May 2017; Accepted: 26 October 2017;
Published: 08 November 2017.
Junbao Du, Peking University First Hospital, China
Guangdong Yang, Laurentian University, Canada
Li-Fang Hu, Soochow University, Taiwan
Copyright © 2017 Wang, Tang and Zhu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Yi Zhun Zhu, yzzhu@must.edu.mo
†These authors have contributed equally to this work.
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