'Night owls' – those who go to bed and get up later – have fundamental differences in their brain function compared to 'morning larks', which mean they could be disadvantaged by the constraints of a normal working day.
Research led by the University of Birmingham found that individuals whose internal body clock dictates that they go to bed and wake up very late (with an average bedtime of 2.30am and wake-up time of 10.15am) have lower resting brain connectivity in many of the brain regions that are linked to the maintenance of consciousness.
Importantly, this lower brain connectivity was associated with poorer attention, slower reactions and increased sleepiness throughout the hours of a typical working day.
Night owls' – those who go to bed and get up later.
According to the Office for National Statistics, around 12% of employees work night shifts. We already know that there are huge negative health consequences for night shift workers due to the constant disruption to sleep and body clocks.
However, disruption can also be caused by being forced to fit into a societal 9–5 working day if those timings do not align with your natural biological rhythms. Since around 40–50% of the population identify as having a preference for later bedtimes and for getting up after 8.20am the researchers say much more needs to be done to explore negative implications for this group.
Disruption can also be caused by being forced to fit into a societal 9–5 working day.
The study, published in the journal SLEEP, investigated brain function at rest and linked it to the cognitive abilities of 38 individuals who were identified as either 'night owls' or 'morning larks' using physiological rhythms (melatonin and cortisol), continuous sleep/wake monitoring and questionnaires. The volunteers underwent MRI scans, followed by a series of tasks, with testing sessions being undertaken at a range of different times during the day from 8am to 8pm. They were also asked to report on their levels of sleepiness.
Volunteers identified as morning larks reported to be least sleepy and had their fastest reaction time during the early morning tests, which was significantly better than night owls. Night owls, however, were least sleepy and had their fastest reaction time at 8pm in the evening, although this was not significantly better than the larks, highlighting that night owls are most disadvantaged in the morning. Interestingly, the brain connectivity in the regions that could predict better performance and lower sleepiness was significantly higher in larks at all time points, suggesting that the resting state brain connectivity of night owls is impaired throughout the whole day (8am–8pm).
Morning larks reported to be least sleepy and had their fastest reaction time during the early morning tests.
Dr Facer-Childs, who is now based at the Monash Institute for Cognitive and Clinical Neurosciences in Melbourne, Australia, says: 'This mismatch between a person's biological time and social time – which most of us have experienced in the form of jet lag – is a common issue for night owls trying to follow a normal working day. Our study is the first to show a potential intrinsic neuronal mechanism behind why 'night owls' may face cognitive disadvantages when being forced to fit into these constraints.
The research was funded by the Biotechnology and Biological Sciences Research Council, the Engineering and Physical Sciences Research Council, and the Brazilian Institute of Neuroscience and Neurotechnology.


text:
Physics Notes Class 8
Chemistry Notes Class 8
NCERT Soln. Class 8 Maths
RD Sharma Soln. Class 8
Math Formulas Class 8
Chapter 1: Force and Pressure
Push and Pull Force
Interaction of Forces
Exploring Forces
Change in State of Motion
Types of Forces
Contact and Non Contact Forces
What is Pressure?
Fluid Pressure
Chapter 2: Friction
Factors Affecting Friction
Friction: A Necessary Evil
Increasing and Reducing Friction
Sliding Friction
Fluid Friction
Types of Friction
Static and Kinetic Friction
Limiting Friction
Chapter 3: Sound
Sound Produced by a Vibrating Body
How is Sound Produced by Humans?
Sound Needs a Medium for Propagation
How do we hear?
Amplitude, Time Period and Frequency of a Vibration
Pitch and Loudness
Audible and Inaudible Sounds
Chapter 4: Chemical Effects of Electric Current
Do Liquids Conduct Electricity?
What is Electroplating?
Chapter 5: Some Natural Phenomena
What is Lightning?
How Lightning Works?
Earthquake – Definition, Causes, Effects, Protection
What causes an Earthquake?
Chapter 6: Light
Laws of Reflection
Regular and Diffused Reflection
Multiple Reflections of Light
Dispersion of Light
Braille System – Light | Class 8 Physics
Chapter 7: Stars and the Solar System
The Moon – Facts, Phases, Surface, Eclipse
What is a Star? Formation, Life Span, Constellations
Artificial Satellites
Last Updated : 18 Nov, 2021
Fluid friction occurs between fluid layers that are moving relative to each other. This internal resistance to flow is named viscosity or viscous drag or fluid friction. In normal terms, the viscosity of a fluid is described as its "thickness" of the fluid. Thus, water is "thin", having a lower viscosity, while honey is "thick", having a higher viscosity. The less viscous the fluid, the greater its ease of deformation or movement.
All real fluids (except superfluids) offer some resistance to shearing and therefore are viscous. Although the term "fluid" includes both the liquid and gas phases, in common usage, "fluid" is often used synonymously with "liquid". Liquids and gases are called fluids because they can be made to flow or move. In any fluid, the molecules themselves are in constant, random motion, colliding with each other and with the walls of any container.
The movement of molecules is governed by two types of forces which are present between the molecules of the substance itself and between the substance and the other material in contact.
The following are the two types of forces between the molecules:
1. Cohesive forces: Cohesive forces are attractive forces that exist between molecules of the same substance. So, cohesive forces are the main cause of viscosity.
2. Adhesive forces: These are attractive forces between unlike molecules.
An object travels in a fluid it loses its energy in order to overcome the fluid Friction. The shape of an object plays an important role in increasing or decreasing the fluid friction when it travels along with it.
Ships and boats have a particular shape that allows them to resist fluid Friction.
Birds and airplanes have a specific shape that allows them to fly in the air.
Fishes also have a specific shape such as a tail and fins that allow them to swim continuously in water and even prevent the loss of energy due to fluid Friction.
The designs of vehicles are made in such a way so that they encounter the least fluid friction while travelling to ensure proper usage and movement of them.
In order to avoid fluid friction the swimsuits are designed accordingly for a smoother flow.
Laws Of Fluid Friction
The laws of fluid friction are:
First law: The fluid friction increases with an increase in the area of contact between the surface and the fluid.
Second law: The fluid friction increases with an increase in the velocity gradient of the substance.
Third law: The fluid having a higher coefficient of fluid friction or eta (η) has a higher value of fluid frictional force.
The rules hold differently for different lubricants. It is indirectly proportional to the temperature of the lubricants. The formula for the fluid friction can be derived by the following experiment:
In the given experiment it can be shown that the force Ϝ necessary to move the top plate in the figure is directly proportional to the area Α, the difference of speed between the layers ∆ν and inversely proportional to the spacing of the plates ∆y.
That is: Ϝ∽Α and Ϝ∽∆ν and Ϝ∽1∕∆y
This gives the equation Ϝ=η Α ∆ν∕∆y
Factors Affecting Fluid Friction
The amount of Frictional force by a fluid on an object depends upon the following:
1. Nature of fluid
The thinner the fluid, the lesser the fluid friction will be, and vice versa. The different types of fluid offer different extent of resistances or the viscous drag of the object flowing through it. For example, an object moving in honey experiences a much larger viscous force than moving in plain water as the density of honey is much larger than the density of water and hence it offers greater resistance to the flow of the object.
2. The viscosity of fluid
The viscosity of fluid plays a major role in determining the velocity of the object which flows through it. The more viscous is the fluid the denser it is and hence the movement of any material inside it is restricted or experiences resistance to its motion. The denser is the liquid the more viscous drag it creates.
3. The shape of the body
Other figures feel more drag than the body with a streamlined shape which begins and ends in points like the shape of a fish. The shapes of vehicles are designed to reduce the surface of contact during motion. It plays a major role in the smoother flow be it in liquid or in gases. The shape of the body has to be in accordance with the medium in which it is flowing or moving or else it experiences a major resistance to its movement which makes the task very time-consuming. Hence, to reduce this most of the bodies have a streamlined shape. This ensures that at the start and at the end the surface of contact is minimum and hence the fluid friction.
4. The temperature
The fluid friction of all gases increases with an increase in temperature since the fluid friction of a gas is directly proportional to the square root of the absolute temperature. (This result is obtained from the kinetic theory of gases).
The fluid friction of liquids and other substances also increases proportionally with the increase in temperature.
5. The surface area of the body
The more the surface of the body more is the fluid friction. For example A horizontal moving body can cut through the liquid more easily than a body moving vertically. For a body with a large surface area, the fluid friction increases accordingly and hence its movement or flow becomes difficult.
6. Speed of the body
Friction and speed are directly proportional to each other. On increasing the speed the fluid friction or drag also increases proportionally. For example: An airplane flying at the highest speed of 1000km/hr. Will face a greater frictional force or drag of air than another similar airplane which is flying at a speed of 600km/hr. Or a high-speed boat experiences lesser fluid friction than a slow-moving fish.
7. The pressure on the body
The fluid friction increases proportionally with the increase in the pressure on the body. With the increase in pressure, it becomes difficult for the molecules to travel from one place to another place and also over the layers. Hence, there is a huge amount of resistance to the flow of the fluids.
What is Viscous Drag?
A resistance force exerted on a moving object by the fluid is called Viscous drag. The speed at which the viscous drag of an object falling in a viscous fluid is equal to the other forces acting on the object (such as gravity) so that the acceleration of the object is zero. Everyone has seen fluids flow. From pouring a glass of water to watching maple syrup creep towards the edge of a stack of pancakes. Viscosity is the intrinsic resistance of a fluid to flow under an applied force.
Let's go through a more technical explanation of viscous drag and viscosity by the following diagram:
Let's go back to the maple syrup again and pretend we are freezing it into thin slabs that are stacked one on top of another.
Diagram 1: Shows these layers and a force, F, applied to the top slab of frozen syrup.
Since the applied force is acting on the top layer, we would expect the top layer to be pushed out right?
The friction between the top layer and the second layer would drag the second layer along. This will continue down through the layers of slabs with each towards the bottom moving less than the layer above it.
Diagram 2: Shows this effect in action.
Sample Problems Based On Fluid Friction
Question 1: Boats and airplanes are made in streamlined shape. Why?
A shape which is wide in middle and tapered at ends is called a streamlined shape. Such a shape reduces drag or fluid friction.
Hence, a streamlined body can easily move through a fluid. Birds and fish are naturally endowed with streamlined body. Boats and airplanes are also made streamlined so that they can easily move through air or water.
Question 2: Why are the bodies of boats, planes, cars, etc. streamlined?
For objects that move in fluids such as boats, planes, cars, etc.
The shape of their body is streamlined in order to reduce the friction between the bodies of the objects as the fluid.
Question 3: How can we land smoothly using a parachute with the help of Viscous drag?
When a parachute is just opened, the velocity is down and the acceleration is up. Your speed decreases as a result, which is the whole point behind the parachute.
Speed decreases, so drag decreases. Drag decreases, so the net force decreases.
Question 4: What are the advantages of a streamlined body?
Streamlining your body reduces the friction of movement to a minimum thus decreasing overall drag.
For fishes having a streamlined body that is smooth helps save energy it would otherwise have to expand swimming.
Question 5: What is laminar flow?
Laminar flow, type of fluid (gas or liquid) flow in which the fluid travels smoothly or in regular paths, in contrast to turbulent flow, in which the fluid undergoes irregular Fluctuations and mixing.
Question 6: Which of the following statements is incorrect?
(a) Friction acts on a ball rolling along the ground
(b) Friction acts on a boat moving on water
(c) Friction acts on a bicycle moving on a smooth road
(d) Friction does not act on a ball moving through air
(d) Friction will act in case of ball moving through air always.
Question 7: What is the velocity gradient if frictional force is given to be 6N and eta(????) is given as 0.25 and the area of cross-section is 100m2.
Velocity gradient is 0.25
Question 8: Determine the force of friction in fluids if the coefficient of fluid friction is 0.25, velocity with which the fluid is flowing is 2m/s starting from the rest and the cross-sectional area is 50m2.
Question 9: Determine the coefficient of fluid friction if F is given 3N and the area of cross section is given 10m2 also the velocity gradient given is 0.3/s.
Coefficient of fluid friction is 1.
1. Types of Friction - Definition, Static, Kinetic, Rolling and Fluid Friction
2. Difference between Static Friction and Dynamic Friction
3. Limiting Friction
4. Sliding Friction
5. Types of Friction
6. Static and Kinetic Friction
7. Factors Affecting Friction
8. Increasing and Reducing Friction
9. Friction: A Necessary Evil
10. Problems on Friction Formula
dheerajhinaniya
@dheerajhinaniya
kalrap615
School Physics
Learn CS With Python: CBSE Class 12

redpajama_set_name: RedPajamaCommonCrawl


text:
#import "tensorflow_lite_support/ios/task/processor/sources/TFLCategory+Helpers.h"
#import "tensorflow_lite_support/ios/task/processor/sources/TFLDetectionResult+Helpers.h"

@implementation TFLDetectionResult (Helpers)

+ (TFLDetectionResult *)detectionResultWithCResult:
    (TfLiteDetectionResult *)cDetectionResult {
  if (cDetectionResult == nil) return nil;

  NSMutableArray *detections = [[NSMutableArray alloc] init];
  for (int i = 0; i < cDetectionResult->size; i++) {
    TfLiteDetection cDetection = cDetectionResult->detections[i];
    NSMutableArray *categories = [[NSMutableArray alloc] init];
    for (int j = 0; j < cDetection.size; j++) {
      TfLiteCategory cCategory = cDetection.categories[j];

      TFLCategory *resultCategory = [TFLCategory categoryWithCCategory:&cCategory];
      [categories addObject:resultCategory];
    }
    TFLDetection *detection = [[TFLDetection alloc] init];
    detection.categories = categories;
    detection.boundingBox =
        CGRectMake(cDetection.bounding_box.origin_x, cDetection.bounding_box.origin_y,
                   cDetection.bounding_box.width, cDetection.bounding_box.height);
    [detections addObject:detection];
  }

  TFLDetectionResult *detectionResult = [[TFLDetectionResult alloc] init];
  detectionResult.detections = detections;
  return detectionResult;
}
@end

redpajama_set_name: RedPajamaGithub


text:
Why TV advert breaks could soon get longer – and more frequent
July 1, 2022 by admin 0 Comments
TV advert breaks could get longer and more frequent as part of a review of UK broadcasting rules.
The regulator, Ofcom has said market developments, including the availability of online streaming services, meant it would consider an overhaul of advertising regulations.
Currently, public broadcasting channels are limited to an average of seven minutes of advertising per hour across the day, while private channels are allowed nine minutes for advertising and an extra three for teleshopping.
Ofcom said that while the expanded choice of entertainment was "generally positive" for audiences it "put pressure on broadcasters, squeezing revenues, and made it harder for them to maintain their current offer".
An Ofcom spokesperson said: "We're scoping a range of options, but before we form any plans we'll listen to different views and examine what TV viewers say.
"We need to strike the right balance between protecting viewers' interests and sustaining our traditional broadcasters, which includes helping them compete with American streaming platforms."
Ofcom said it expected to give more details about the potential changes later in the summer.
Tesla reports record revenue and beats on earnings


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text:
BKT Tires co-title sponsor of World Men's Curling C'ship 2021
CALGARY, Canada: The Canadian subsidiary of Balkrishna Industries Ltd (BKT Tires), the Indian multinational group and global player in the off-highway tire market, and OK Tire have been named as the official title sponsors of the BKT Tires & OK Tire World Men's Curling Championship 2021, taking place in the Calgary hub in Alberta, Canada.
MI only IPL team to show brand valuation growth in 2020: Study
MUMBAI: Five-time Indian Premier League champions Mumbai Indians has been provided further endorsement of its claim to being India's leading sports club on and off the field in the latest report put out by global brand valuation agency Brand Finance. The 2020 edition winners are the only IPL team to have grown in brand value this year, registering a 7.1% upstick at $70.3 million, according to the study.
MUMBAI: Eros Now, leading South Asian streaming entertainment service owned by Eros STX Global Corporation, announced a streaming and branding partnership with 2020 Abu Dhabi T10 Tournament, the fourth edition of the tournament and the second held in Abu Dhabi.
SIX5SIX unveils new kit for the Indian national football team
MUMBAI: SIX5SIX, the All India Football Federation's kit partner for Indian team soccer, has unveiled its new jersey for the senior men's national team.
Tottenham Hotspur scores its first-ever shirt sleeve sponsorship
LONDON: Premier League side Tottenham Hotspur has announced a multi-year partnership with cinch, which will see the UK-based online car-selling platform become the club's first official sleeve partner. The cinch logo will be seen on the sleeve of both the men's and women's teams' shirts for all first team matches starting with this Sunday's round of games (10 January).
Gokulam Kerala FC signs on CSB Bank as official sponsor
KOCHI: Gokulam Kerala FC has announced CSB Bank as official sponsors for the Hero I-League season 2020-21. As part of the sponsorship, CSB Bank will appear on the back of the GKFC jersey. The club will also be doing several promotional activities along with the bank during the season.
BCCI was worth close to Rs145bn at 2018-19 fiscal end: Report
MUMBAI: The BCCI, the richest cricketing body in the world by a long mile, was worth just under Rs 145 billion at the end of financial year 2018-19. To be precise, the BCCI was worth Rs 144.898 billion (Rs 144.8980 crore) as per the latest balance sheet available, which was accessed by IANS.
AIFF scores nutrition & hydration partner for Indian Arrows
NEW DELHI: The All India Football Federation (AIFF) has announced TrionTotte OPC Private Limited as the 'Nutrition & Hydration Partner for Indian age-group team Indian Arrows for the ongoing football season. Under the partnership, TrionTotte will be supplying several nutrition, hydration, and strength and conditioning products.
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Having the correct footwear is incredibly important in any kind of sport or exercise. Line Dancing is no different. A lot of our movement is from side to side, some dance moves include turns and twisting and shuffling, it is important to make sure you have correct fitting shoes that do not have too much grip.
Below is only a small sample of what shoes i have – see debs dance shoes for full catalogue.
Please ring, email or speak to me in class to make an order.


text:
Priority Research Papers:
Anthracyclines suppress pheochromocytoma cell characteristics, including metastasis, through inhibition of the hypoxia signaling pathway
Ying Pang, Chunzhang Yang, Jan Schovanek, Herui Wang, Petra Bullova, Veronika Caisova, Garima Gupta, Katherine I. Wolf, Gregg L. Semenza, Zhengping Zhuang and Karel Pacak _
Ying Pang1, Chunzhang Yang2, Jan Schovanek3, Herui Wang4, Petra Bullova5, Veronika Caisova1, Garima Gupta1, Katherine I. Wolf1, Gregg L. Semenza6, Zhengping Zhuang4 and Karel Pacak1
1 Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
2 Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
3 Department of Internal Medicine III-Nephrology, Rheumatology, and Endocrinology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
4 Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA
5 Department of Molecular Medicine, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovak Republic
6 McKusick-Nathans Institute of Genetic Medicine and Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Karel Pacak, email:
Keywords: anthracyclines, paraganglioma, pheochromocytoma, metastatic, hypoxia-inducible factors
Received: January 13, 2017 Accepted: March 03, 2017 Published: March 15, 2017
Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare, neuroendocrine tumors derived from adrenal or extra-adrenal chromaffin cells, respectively. Metastases are discovered in 3-36% of patients at the time of diagnosis. Currently, only suboptimal treatment options exist. Therefore, new therapeutic compounds targeting metastatic PHEOs/PGLs are urgently needed. Here, we investigated if anthracyclines were able to suppress the progression of metastatic PHEO. We explored their effects on experimental mouse PHEO tumor cells using in vitro and in vivo models, and demonstrated that anthracyclines, particularly idarubicin (IDA), suppressed hypoxia signaling by preventing the binding of hypoxia-inducible factor 1 and 2 (HIF-1 and HIF-2) to the hypoxia response element (HRE) sites on DNA. This resulted in reduced transcriptional activation of HIF target genes, including erythropoietin (EPO), phosphoglycerate kinase 1 (PGK1), endothelin 1 (EDN1), glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and vascular endothelial growth factor (VEGFA), which consequently inhibited the growth of metastatic PHEO. Additionally, IDA downregulated hypoxia signaling by interfering with the transcriptional activation of HIF1A and HIF2A. Furthermore, our animal model demonstrated the dose-dependent suppressive effect of IDA on metastatic PHEO growth in vivo. Our results indicate that anthracyclines are prospective candidates for inclusion in metastatic PHEO/PGL therapy, especially in patients with gene mutations involved in the hypoxia signaling pathway.
Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare neuroendocrine tumors located in the adrenal medulla and extra-adrenal paraganglia, respectively. Although most PHEOs/PGLs are benign, approximately 10% of PHEOs and 15-35% of PGLs are metastatic, irrespective of their non-hereditary or hereditary status [1, 2]. Established in the 1980s, the current conventional chemotherapy regimen combines cyclophosphamide, vincristine, and dacarbazine (CVD) [3]. Despite its popularity, the long-term application of CVD is often limited due to a short remission period and toxicity limitations [4].
Intratumoral hypoxia plays a major role in cancer recurrence, spread, and resistance to radiotherapy and chemotherapy [5-7]. A major consequence of reduced O2 availability in tumors is the activation of hypoxia-inducible factors (HIFs) [8-11]. HIF-1α and HIF-2α are stabilized and can each dimerize with HIF-1β and bind to hypoxia response elements (HREs) to transactivate various target genes involved in angiogenesis, immune system modulation, iron metabolism, erythropoiesis, glucose metabolism, and other physiological processes [12]. Although HIF-1α dysregulation has been found in a wide variety of cancers [12], several studies indicate that HIF-2α upregulation is more commonly associated with an aggressive phenotype and poor prognosis in neural crest cell tumors, including PHEO/PGL and neuroblastoma [13-18]. Therefore, HIF-1α and HIF-2α inhibitors should be considered for therapeutic management of these tumors.
Anthracyclines are a well-known class of chemotherapy drugs, mainly consisting of daunorubicin (DAU), doxorubicin (DOX), epirubicin (EPI), and idarubicin (4-demethoxydaunorubicin, IDA), and when administered to mice on a low-dose, daily (metronomic) schedule, have been shown to suppress tumor growth and angiogenesis by blocking the HIF signaling pathway [19, 20]. Over the past 50 years, anthracyclines have been widely used in the treatment of multiple cancer types, including leukemias, breast, bladder, and thyroid carcinoma [21, 22]. In 2003, successful results were reported in a patient with rapidly progressive, metastatic PHEO treated with a combination of CVD and anthracyclines [23]. However, the use of anthracyclines in the treatment of metastatic PHEO/PGL has not been further evaluated in any published or experimental studies.
In the present study, we assessed the effects of three anthracyclines (EPI, DOX, and IDA) on the proliferation and migration of an experimental mouse PHEO cell line. Our report investigated the mechanisms by which anthracyclines suppress tumor cell growth and the HIF signaling pathway using an in vitro cell model. Furthermore, for the first time, the effect of anthracyclines was evaluated in nude mice bearing a metastatic PHEO allograft, in order to explore their potential use in the treatment of metastatic PHEO/PGL.
Anthracyclines suppress cell growth and migration
To assess the impact of anthracyclines on PHEO cells in vitro, the proliferation of Mouse Tumor Tissue (MTT) cells, a cell line that was generated from a mouse PHEO, was analyzed in the presence of EPI, DOX, or IDA. Anthracyclines inhibited MTT proliferation in a dose-dependent manner. Compared to the control group, higher concentrations of EPI, DOX, and IDA (5 µM and 10 µM) led to statistically significant reductions in cell number (Figure 1A). By contrast, low concentrations (0.625 µM) of EPI, DOX, or IDA did not cause obvious cytotoxicity during the 16-hour treatment period. The half maximal inhibitory concentration (IC50) of EPI, DOX, and IDA was 7.0 µM, 11.6 µM, and 6.0 µM, respectively. Additionally, anthracyclines showed significant suppressive effects on Hep3B cell proliferation (Figure 1A).
A concentration of 0.625 µM, which did not cause increased cell death, was chosen to perform a more detailed mechanistic study. To test whether anthracyclines inhibit cell motility, a scratch assay was used over a 24-hour period. Compared to the control group, all three anthracycline compounds exhibited an inhibitory effect on the motility of Hep3B cells (Figure 1B).
Figure 1: Effects of anthracyclines on cell proliferation and cell migration. A. MTT or Hep3B cells were seeded in a 96-well plate. Cell proliferation was assessed under treatment of EPI, DOX, or IDA at different concentrations (10, 5, 2.5, 1.25, or 0.625 µM). Control versus anthracycline treatment, *P < 0.05; **P < 0.01; ***P < 0.001. B. Cell migration on a confluent cell monolayer was observed for 24 hours under treatment of EPI, DOX, or IDA at a concentration of 0.625 µM. DMSO was used as the control group. Bar = 100 µm.
IDA interferes with HIF-1α and HIF-2α mRNA expression
Since we needed to study the effects of anthracyclines on HIF signaling pathways and HIF target genes under hypoxic conditions, in the following in vitro studies, Hep3B cells were used instead of MTT cells due to the suboptimal sensitivity of MTT cells to hypoxia. To determine the activity of HIF-1α and HIF-2α under anthracycline treatment, cellular protein levels of HIF-1α and HIF-2α were analyzed in the presence of CoCl2, a chemical inducer of HIF activity. After treatment with CoCl2 for 16 hours, HIF-1α and HIF-2α mRNA and protein levels were significantly increased compared to the control group. IDA blocked the increase in HIF-1α and HIF-2α mRNA and protein levels, whereas EPI and DOX did not exert obvious inhibitory effects (Figure 2A, 2B, and 2C).
To investigate whether anthracyclines blocked cell migration via inhibition of HIF activity, the effect of drug treatment was compared with the effect of treatment with siRNA targeting HIF-1α and HIF-2α in Hep3B cells without CoCl2 treatment. Figure 2D shows the efficiency of knocking down HIF-1α or HIF-2α by siRNA. Consistent with anthracycline treatment, migration of the siHIF-1α or siHIF-2α transfected cells decreased compared to the control siRNA group (Figure 2E).
We then investigated the effect of IDA on the degradation of HIF-1α and HIF-2α. Co-treatment with cycloheximide to block de novo protein synthesis did not decrease the half-life of either HIF-1α or HIF-2α compared to the control (Figure 2F and 2G). Taken together, these results suggest that IDA down-regulated HIF-1α and HIF-2α expression in part by reducing HIF-1α and HIF-2α mRNA levels, without affecting protein stability.
Figure 2: Anthracyclines interfere with the transcription of HIF-1α and HIF-2α. A.-B. Hep3B cells were exposed to CoCl2 in the presence of DMSO (Control) or 0.625 µM EPI, DOX, or IDA for 16 hours. HIF-1α and HIF-2α mRNA levels were measured by RT-qPCR. Anthracycline treatment under CoCl2 was compared with CoCl2 treatment alone. *P < 0.05. C. HIF-1α and HIF-2α protein levels, in cells treated with CoCl2 in the presence of DMSO or EPI, DOX, or IDA, were determined by immunoblot assays. β-Actin was used as the internal control. D. Knock-down effects of HIF-1α and HIF-2α siRNA were verified by western blot. β-Actin was performed as the internal control. E. siHIF-1α and siHIF-2α were used to knock down gene expression and their inhibitory effects on cell migration were observed. Bar = 100 µm. F. Cells were incubated with or without CHX (100 µM) and IDA (0.625 µM) for the indicated incubation times. Protein level changes of HIF-1α and HIF-2α were measured by western blot. G. Quantification and half-life of HIF-1α and HIF-2α under IDA treatment with DMSO was used as the control vehicle.
Anthracyclines suppress transcriptional activity by blocking binding of HIFs to DNA
The effects of anthracyclines on HIF transcriptional activity were evaluated via the luciferase assay using the Hep3B HRE luciferase cell line, which carries the HRE reporter. EPI, DOX, and IDA down-regulated CoCl2-induced HRE luciferase activity in a dose-dependent manner. Additionally, a concentration as low as 0.625 µM showed significant suppressive effects on transcription (Figure 3A, 3B, and 3C). The expression of endogenous HIF target genes (EPO, PGK1, EDN1, GLUT1, LDHA, and VEGFA) was also analyzed. In accordance with HRE luciferase activity, anthracyclines significantly reduced the expression of these genes (Figure 3D-3I). EPO expression was reduced to basal levels by EPI, DOX, or IDA.
A ChIP assay was performed to detect the efficiency of HIF-1α and HIF-2α binding to HREs in the EPO (3' flanking sequence) and PGK1 (5' flanking sequence) genes. Figure 3J demonstrates the weak binding of HIF-2α to the EPO gene in control cells. The increased binding of HIF-2 to the EPO 3' flanking sequence (induced by CoCl2) was inhibited by treatment with EPI, DOX, or IDA. Similarly, all three anthracyclines suppressed the binding of HIF-1 to the 5' flanking sequence of the PGK1 gene (Figure 3K). These results indicate that anthracyclines block the binding of HIF-1 and HIF-2 to HREs of target genes, as previously reported [19].
Figure 3: Anthracyclines suppress HIF transcriptional activity. A.-C. Luciferase reporter assay showed that EPI, DOX, and IDA blocked the HRE luciferase activity of HIFs in a dose-dependent manner. Anthracycline treatment under CoCl2 was compared with CoCl2 treatment alone. *P < 0.05; **P < 0.01; ***P < 0.001. D.-I. The effects of EPI, DOX, and IDA on mRNA levels of HIF-1α or HIF-2α target genes were measured by qRT-PCR and reduced under CoCl2-induced hypoxia conditions, showing obvious inhibition on EPO, PGK1, EDN1, GLUT1, LDHA, and VEGFA. Anthracycline treatment under CoCl2 was compared with CoCl2 treatment alone. *P < 0.05; **P < 0.01; ***P < 0.001. J.-K. Analysis of HIF DNA binding was assessed by ChIP assays. Input DNA was isolated from whole cell lysates. The remaining lysate was divided and incubated with HIF-1α, HIF-2α or IgG antibodies for IP. The 3' flanking region of EPO and the 5' flacking region of PGK1 were amplified from the immunoprecipitates. One percent agarose gels were run to analyze PCR products.
Anthracyclines suppress metastatic tumor growth and increase survival in a mouse model of metastatic PHEO
To assess the effects of anthracyclines on metastatic PHEO in vivo, we established a mouse allograft model bearing highly metastatic mouse PHEO cells that constitutively express luciferase (MTT luciferase cells). One million cells were injected into mice through the tail vein. Seven days later, bioluminescence images showed tumor colonization of multiple organs, including the liver and spleen (Figure 4A). Afterwards, IDA treatment began. Following 7 days of treatment with IDA (1 mg/kg/day, intraperitoneal injection), bioluminescence in the vehicle group increased statistically, while mice receiving IDA did not show increased bioluminescence intensity. The differences in full-body bioluminescence intensity before and after treatment in the vehicle and IDA treatment groups are shown in Figure 4B.
Figure 4: IDA suppressed MTT growth after tail vein injection. A. Seven mice from each group were subjected to bioluminescence assays before and after treatment. IDA (1 mg/kg per day) was dissolved in 100 µL PBS and injected intraperitoneally for the drug treatment group. Mice from the vehicle group were treated with 100 µL PBS per day. After seven days of treatment, mice were imaged again to measure tumor size. B. Quantification of tumors was analyzed based on whole body bioluminescence signal intensity for each group. Before treatment versus after treatment, *P < 0.05.
To analyze the effect of IDA on HIF signaling pathways in vivo, tumor allografts were isolated from the livers of the control and treatment groups. Compared to normal livers (control), mRNA and protein levels of HIF-1α and HIF-2α in tumor cells increased in the vehicle group, while the group treated with IDA showed decreased HIF-1α and HIF-2α levels, compared to the vehicle group (Figure 5A, 5B, and 5C). Furthermore, intratumoral expression of HIF target genes (EPO, PGK1, EDN1, GLUT1, LDHA, and VEGFA) was significantly decreased in tumors after treatment with IDA (Figure 5D-5I). These findings suggest that IDA suppresses metastatic PHEO through inhibition of HIF transcriptional activity.
Figure 5: IDA suppressed transcriptional activities of HIFs and their target genes. A. HIF-1α and HIF-2α protein levels were analyzed in the control (liver without tumor), vehicle (liver with tumors), and IDA treated (liver with tumors) groups. B.-I. HIF1A, HIF2A, EPO, PGK1, EDN1, GLUT1, LDHA, and VEGFA mRNA levels were determined in metastatic tumors in both the vehicle group and IDA treated groups. Normal mouse liver tissue was used as the control. Control versus vehicle, #P < 0.05; ##P < 0.01; ###P < 0.001. Vehicle versus IDA, *P < 0.05; **P < 0.01; ***P < 0.001.
In the present study, we tested the widely used chemotherapeutic agents, anthracyclines, against experimental PHEO cells under both in vitro and in vivo conditions. Our findings demonstrate that anthracyclines, especially IDA, suppress PHEO cell proliferation and migration via inhibition of the hypoxia signaling pathway by blocking the DNA binding of HIF-1 and HIF-2. In our experimental animal model, treatment with IDA resulted in a significant reduction in the size of tumors in multiple organs when compared to the control group. Additionally, the hypoxia signaling pathway was significantly suppressed in these tumors. These results suggest that IDA should receive consideration as a promising treatment option for metastatic PHEO/PGL. Based on the significant inhibition of HIF DNA binding and downstream target gene expression, this treatment option may be particularly effective in tumors with HIF2A mutations [16, 19], as well as in those with mutations in other PHEO/PGL susceptibility genes that cause upregulation of the hypoxia signaling pathway, such as EGLN1 and VHL [24, 25].
Anthracyclines have been used as chemotherapeutic agents for many years, and the anti-cancer effect is mainly attributed to intercalating DNA, stabilizing the topoisomerase II complex, and further preventing DNA replication [26, 27]. Apart from their major use in the treatment of acute myeloid leukemia and acute lymphocytic leukemia, anthracyclines are also effective in treating neuroblastoma [28], another adrenal neural crest tumor producing catecholamines and their metabolites, which is also seen in PHEO/PGL. Previous anecdotal evidence reported successful results in a patient with metastatic PHEO treated with a combination of an anthracycline and the conventional CVD regimen (so called ACVD) [23]. After ACVD treatment termination, the patient remained in complete remission, with no recurrence, for three years. Anthracyclines have also been successfully used in selective arterial chemoembolization in patients with hepatic metastases from PHEO and medullary thyroid carcinoma [29, 30]. However, the use of anthracyclines as chemotherapeutic agents in the treatment of metastatic PHEO/PGL has not been systematically evaluated.
HIF-1α and HIF-2α are the two best-studied isoforms of HIFs, and are now considered important therapy targets for various tumor types [31-33]. HIF-1α and HIF-2α are commonly upregulated during cancer progression [34, 35]. This is also the case in PHEO/PGL, especially those that belong to cluster 1, where the role of the hypoxia signaling pathway has been previously established [16, 25, 36, 37]. Moreover, it has recently been proposed that mutations in PHEO/PGL susceptibility genes in cluster 2 can also converge on the hypoxia signaling pathway, resulting in its upregulation [14]. Finally, novel somatic and germline mutations of HIF2A, which result in a syndrome consisting of multiple and recurrent PHEOs/PGLs, duodenal somatostatinoma, and polycythemia, have recently been discovered [16, 38, 39].
In the present study, we demonstrated the effects of three different anthracyclines on tumor growth suppression by blocking DNA binding of HIF-1 and HIF-2 resulting in reduced transcription of hypoxia response genes. The expression of these HIF-1 and HIF-2 target genes involved in angiogenesis, tumor metastasis, and polycythemia, was significantly decreased in both cell lines and tumors after treatment with anthracyclines. Other groups have reported the inhibitory effect of DOX on HIF-1 [40] and its downstream target genes [19], which further supports our findings.
IDA, without the 4-methoxy group, is an analog of DAU, and has a broader spectrum as a chemotherapy agent compared to the other anthracyclines [41]. Historically, IDA has been combined with cytosine arabinoside as a first line therapy for acute myeloid leukemia (AML). Our results demonstrate the efficiency of IDA in not only blocking DNA binding like other anthracyclines, but also in the reduction of HIF-1α and HIF-2α protein levels. Based on previous findings, IDA, or IDA in combination with triptolide, also suppresses the expression of HIF-1α and related downstream target genes in leukemia stem cells [42]. Shaul et al. [43] showed that IDA decreases cell viability significantly faster and stronger than DOX, which is likewise consistent with our results. Their group suspected different underlying chemotherapeutic mechanisms for IDA and DOX, and suggested that IDA has additional undiscovered cellular targets compared to DOX. From our data, IDA specifically causes downregulation of HIF-1α and HIF-2α which was not observed with the other two anthracyclines in this study. IDA has also been shown to block binding of HIF-1 to HREs in HIF target genes [19].
Anthracyclines, like other chemotherapeutic agents, cause cytotoxicity of normal proliferating cells, leading to side effects such as weight loss, headaches, mucositis, increased skin pigmentation, nausea, and myelosuppression [44, 45]. Additionally, they are associated with acute and chronic dose limiting cardiotoxicity (with IDA being the least cardiotoxic), which can severely impair cardiac function, resulting in heart failure [46]. Similar findings were previously reported when a patient with metastatic PHEO receiving ACVD chemotherapy developed grade I bone marrow suppression and cardiovascular instability [23]. Therefore, an individualized approach is necessary when considering this regimen, either alone or in synergistic combinations with other agents, especially in pediatric patients and adults with multiple comorbidities [47].
Our results indicate that anthracyclines, especially IDA, significantly inhibit in vitro cell growth and in vivo tumor formation in a mouse model of PHEO. Apart from the well-known, multiple, chemotherapeutic mechanisms of anthracyclines, we establish anthracycline-induced suppression of the hypoxia signaling pathway. This occurs through inhibition of HIF-1 and HIF-2 binding to the HRE sites on DNA, resulting in decreased transcription of downstream target genes involved in apoptosis, migration, angiogenesis, and metastasis. Our results suggest that chemotherapy with anthracyclines, either alone or as adjuvant therapy, should be considered as a treatment option in patients with metastatic PHEO/PGL, especially those harboring mutations in the HIF2A gene or other PHEO/PGL susceptibility genes that cause upregulation of the hypoxia signaling pathway.
Cell culture and drug treatment
Hep3B cell lines were purchased from the American Type Culture Collection (ATCC). Mouse tumor tissue (MTT) cells were derived from a liver metastasis in a mouse pheochromocytoma cell (MPC) allograft model, as previously described [48, 49]. Cells were cultured in DMEM with 10% FBS (Gemini Bioproducts) at 37°C, with 5% CO2 (v/v). Cells were treated with 100 µM CoCl2 (Sigma-Aldrich) for 16 hours. EPI, DOX, and IDA (Sigma-Aldrich) were used to treat cultures.
Hep3B-HRE-luciferase and MTT-luciferase subclones were established by transfection with Cignal Lenti HIF Reporter (Luc) lentivirus (Qiagen) and pLLuc retroviral vector, respectively. Stable cell lines expressing luciferase were selected by 5 µg/mL puromycin (Sigma-Aldrich) or 1000 µg/mL G418 (Life Technologies). A luciferase reporter assay was performed according to manufacturer protocol using the ONE-Glo Luciferase Assay System (Promega). Cycloheximide (CHX) was purchased from Sigma and cells were treated on different time courses (0, 15, 30, and 60 min) at 100 µM. Small interfering RNA (siRNA) targeting HIF-1α and HIF-2α (Abnova) were transfected into Hep3B cells for 48 hours using Lipofectamine RNAiMAX reagent (Invitrogen).
Cell proliferation assay
Cell proliferation was measured by the Cell Counting Kit-8 (CCK8, Dojindo, Japan). MTT or Hep3B cells were seeded in a 96-well plate with 2×104 cells/well. The number of surviving cells was assessed following administration of varying treatment protocols.
Cell migration assay
Hep3B cells were seeded in a 35-mm µ-Dish with 2-well culture-insert (iBidi, USA) at a density of 3×105. The culture dish was incubated for 24 hours and the culture-insert was removed. Cells were washed with fresh growth media and incubated in the presence of a candidate compound. Cell morphology was recorded with a Nikon BioStation IM-Q for 24 hours, and imaging was performed every 5 minutes.
Reverse-transcription (RT) and quantitative PCR (qPCR)
Total RNA from tissue or cell cultures was extracted using the NucleoSpin RNA Purification Kit (Machery-Nagel). DNase was used to digest genomic DNA according to the manufacturer's instructions. One microgram of RNA was used for reverse transcription using the Super Script III First-Strand Synthesis SuperMix (Invitrogen). Target genes were amplified using the ViiA 7 real-time PCR system (Applied Biosystems). Primers used in qPCR were as follows: HIF1A (forward: ACC TGA GGA GAG GCT CGG; reverse: ACT TAT CTT TTT CTT GTC GTT CGC); HIF2A (forward: GCG CAC CTC GGA CCT TCA; reverse: TCT CCG AGC TAC TCC TTT TCT TC); EPO (forward: GCT GCA TGT GGA TAA AGC CCG; reverse: CAC ACC TGG TCA TCT GTC CC); β-actin (forward: TCA GAA GGA TTC CTA TGT GGG CGA CGA; reverse: TCC CAG TTG GTG ACG ATG CCG T); PGK1 (Qiagen QT), GLUT1 (Origene HP209446), VEGFA (Qiagen QT01682072).
Western blot analysis
For total cellular protein concentration, cells were washed with PBS three times and lysed with RIPA lysis buffer with a complete protease inhibitor cocktail (Roche, Sweden). Whole cells were lysed for 20 minutes on ice and centrifuged for 20 minutes at 4°C. A Bio-Rad protein assay kit was used to measure protein content in the supernatant, and equal amounts of samples were electrophoresed in NuPAGE Bis-Tris 4-12% gel (Invitrogen, USA). Proteins were transferred onto PVDF membranes (Millipore), and blocked with 5% nonfat milk. Target proteins were probed with primary antibodies of HIF-1α (Sigma), HIF-2α (Abcam), and β-actin (Cell Signaling Technology) at 4°C overnight, and then incubated in HRP-conjugated secondary antibodies at room temperature for 1 hour. Signals were detected with an enhanced chemiluminescence ECL kit (Pierce).
Chromatin immunoprecipitation (ChIP) assay
Cell cultures were treated with different anthracyclines, and 37% formaldehyde was added to crosslink protein-DNA complexes. ChIP analysis of the HIF-1α (Sigma) or HIF-2α (Abcam) binding to HRE sites of PGK1 or EPO was performed according to manufacturer protocol using the MAGnify Chromatin Immunoprecipitation System (Life Technologies). The binding activities between HIF-1α or HIF-2α and target genes were measured by PCR with ChIP primers for EPO (forward: TCC AAA TCC CCT GGC TCT GT; reverse: ATT GAC CAG CGT AGG CAG AG) and PGK1 (forward: CAT TCT TCA CGT CCG TTC GC; reverse: TCT GCG AGG GTA CTA GTG AGA). Samples were run for 25 cycles (95°C for 20 seconds, 57°C for 20 seconds, and 68°C for 30 seconds). PCR products were separated on 1% agarose gel with SYBR Safe staining (Invitrogen).
Allograft assay and in vivo imaging
Animal experiments were approved by the Eunice Kennedy Shriver NICHD animal protocol (ASP: 15-028). Six week-old female nude athymic mice (nu/nu) were purchased from The Jackson Laboratory. The weight of each mouse was approximately 20 g at experiment onset. Mice were injected into the tail vein with 1 million MTT luciferase cells in 100 µL PBS. Animals were imaged from day 7 post tail-vein injection by bioluminescence imaging. Mice injected with MTT luciferase allografts received an I.P. injection of 10 µL/g of body weight of D-luciferin (Caliper Life Sciences) dissolved in 100 µL PBS. The in vivo imaging system (Bruker) and Bruker MI SE Software were utilized to acquire and analyze the signaling. Seven days after tail vein injection, all mice were randomized into two groups, each consisting of 7 mice. Mice were either treated with solvent alone, or IDA hydrochloride intraperitoneal injection (Pfizer) with a 1 mg/kg dose every day, for seven days. Animals were re-imaged to measure the size of metastatic tumors. Euthanasia by cervical dislocation followed. Liver and spleen tumors were removed. Expression profiles of HIF-1α and HIF-2α downstream target genes were measured using qPCR according to the protocol described above.
Data was analyzed by one-way factorial ANOVA combined with Tukey's multiple-comparisons test or Student's t-test using Prism 7.0 statistical software (Graph Pad Software). A P value of < 0.05 was considered statistically significant. Graphic representations were expressed as mean ± SEM.
PHEOs: Pheochromocytomas; PGLs: paragangliomas; DAU: daunorubicin; DOX: doxorubicin; EPI: epirubicin; IDA: idarubicin; HRE: hypoxia response element; EPO: erythropoietin; PGK1: phosphoglycerate kinase 1; EDN1: endothelin 1; GLUT1: glucose transporter 1; LDHA: lactate dehydrogenase A; VEGFA: vascular endothelial growth factor; HIFs: hypoxia-inducible factors; MTT: mouse tumor tissue; IC50: half maximal inhibitory concentration; AML: acute myeloid leukemia; CHX: cycloheximide; siRNA: small interfering RNA.
Y.P., C.Y., G.L.S., Z.Z. and K.P. designed research; Y.P., H.W., and V. C. performed research; J.S. and P.B. contributed new reagents/analytic tools; Y.P., C.Y. and K.P. analyzed data; Y.P., G.G., K.W., G.L.S., Z.Z. and K.P. wrote the paper.
Acknowledgments and funding
This study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD USA 20892.
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46. Barrett-Lee PJ, Dixon JM, Farrell C, Jones A, Leonard R, Murray N, Palmieri C, Plummer CJ, Stanley A, Verrill MW. Expert opinion on the use of anthracyclines in patients with advanced breast cancer at cardiac risk. Ann Oncol. 2009; 20: 816-27. doi: 10.1093/annonc/mdn728.
47. Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev. 2004; 56: 185-229. doi: 10.1124/pr.56.2.6.
48. Fliedner SM, Yang C, Thompson E, Abu-Asab M, Hsu CM, Lampert G, Eiden L, Tischler AS, Wesley R, Zhuang Z, Lehnert H, Pacak K. Potential therapeutic target for malignant paragangliomas: ATP synthase on the surface of paraganglioma cells. Am J Cancer Res. 2015; 5: 1558-70.
49. Giubellino A, Shankavaram U, Bullova P, Schovanek J, Zhang Y, Shen M, Patel N, Elkahloun A, Lee MJ, Trepel J, Ferrer M, Pacak K. High-throughput screening for the identification of new therapeutic options for metastatic pheochromocytoma and paraganglioma. PLoS One. 2014; 9: e90458. doi: 10.1371/journal.pone.0090458.


text:
NCWSS outstanding graduate student - Ramawatar Yadav
Congratulations to our Ram Yadav, winner of the North Central Weed Science Society Outstanding Graduate Student Award. The award recognizes one outstanding graduate student who is a NCWSS student member actively involved in the Society, as well as contributor to the field of weed science through extension, research, and teaching.
Congrats to our Graduate Students John Jones and Mauricio Tejera!
John Jones was the recipient of our Teaching Excellence Award. The purpose of this award to is recognize and encourage outstanding achievement by graduate students in teaching. John teaches our Agronomy 354 Soil and Plant Growth and he currently is assistant coach of the Iowa State University soil judging team.
Kelli & Mitchell: Siblings and TAs
Siblings Kelli and Mitchell Roush are teaching assistants, or TAs, for Agronomy 182, our Introduction to Soil Science class. Kelli has been a TA for four semesters and Mitchell has been for two semesters.
Mitchell's favorite part about TA-ing with his sister is that they are able to use different methods to help students learn and understand different concepts. They both have different teaching styles, which helps if a student doesn't understand his way, then Kelli's method may work better for that student.
Andy VanLoocke received the Early Achievement in Teaching Award
by Ellen Bombella, College of Agriculture and Life Sciences Communications Service
One of Andy VanLoocke's biggest accomplishments has been creating Global Agriculture in a Changing World, a course he created when he came to Iowa State.
"I wanted to create a course that would tell people what agronomy is about and about the pressing issues facing our growing population," said VanLoocke, assistant professor in agronomy. "I want to teach students the basic processes and underlying biology, math and physics to appreciate what the headlines are telling them."
Ken Moore Received the Distance Education in Teaching Award
Ken Moore led the development of a distance education program in agronomy 19 years ago and this year he received the College of Agriculture and Life Sciences Distance Education in Teaching Award for his hard work.
There have been a lot of changes in technology since Moore started the program. One of the first roadblocks was the students' ability to access the internet. When the program began in 1998, it was very expensive for students to use the internet and online courses were not common.
Agronomy wins multiple College of Agriculture and Life Sciences awards
The Iowa State College of Agricultural and Life Sciences awards are selected each semester to highlight the excellent contributions of faculty and staff. The Department of Agronomy won several awards for the Spring 2018 semester. All awards will be given at the awards ceremony held March 8 at 4:10 pm in the Sun Room of the Memorial Union. Congratulations to the following Agronomy faculty and staff on a job well done:
Ken Pecinovsky, superintendent of the Nashua research farm - P&S Award of Excellence
Dr. Richard M Cruse
New course Agronomy 279 gives students hands on experience
A new class is requiring agronomy students to give up part of their summer. While it might sound like a bummer, they are looking forward to it. Dubbed Agronomy 279, the new class is one sophomores majoring in Agronomy will have to take to graduate. The class will meet for the first time during the fall 2017 semester. The catch? Their first class will be Aug. 7, according to the agronomy department.
The addition came after the agronomy department said it decided to redesign the curriculum. Agronomy 279 will be an application of material students learned in Agronomy 181 and 182. Students will go outside in the fields to learn about soil and crops.
"Students really like hands-on activities," Erik Christian, lecturer in agronomy, said. "Students do a lot of training in the summer when they go work on their internships and that's going to be out in the field. [Currently], we don't offer them those experiences."


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text:
Tämäkohtu är en sjö i kommunen Lojo i landskapet Nyland i Finland. Sjön ligger  meter över havet. Den är  meter djup. Arean är  kvadratkilometer och strandlinjen är  kilometer lång. Sjön   Den ligger omkring 64 km nordväst om Helsingfors.

I sjön finns ön Isosaari.Tämäkohtu ligger söder om Kolmperse och Vähävesi.

Källor

Insjöar i Finland större än 1 kvadratkilometer
Insjöar i Lojo

redpajama_set_name: RedPajamaWikipedia


HELP: You are on Commonwealth Games results page in Cycling section. FlashScore.in offers Commonwealth Games live results and final race result. Besides Commonwealth Games results you can follow 5000+ competitions from 30+ sports around the world on FlashScore.in. Just click on the sport name in the top menu or country name on the left and select your competition. Commonwealth Games results service is real-time, updating live.


text:
Q: TypeError: can't pickle Struct objects I am the maintainer of the python package Construct and I seek help in making this library picklable. Someone came to me and asked for it to be cloudpickle-able. Unfortunately the classes I have are not pickle-able nor cloudpickle-able nor dill-able. Please help.
The relevant ticket is: https://github.com/construct/construct/issues/894
$ python3
Python 3.6.9 (default, Oct  8 2020, 12:12:24)
[GCC 8.4.0] on linux
Type "help", "copyright", "credits" or "license" for more information.
>>> import cloudpickle
>>> import construct
>>> cloudpickle.dumps(construct.Byte)
Traceback (most recent call last):
  File "<stdin>", line 1, in <module>
  File "/usr/local/lib/python3.6/dist-packages/cloudpickle/cloudpickle_fast.py", line 102, in dumps
    cp.dump(obj)
  File "/usr/local/lib/python3.6/dist-packages/cloudpickle/cloudpickle_fast.py", line 563, in dump
    return Pickler.dump(self, obj)
  File "/usr/lib/python3.6/pickle.py", line 409, in dump
    self.save(obj)
  File "/usr/lib/python3.6/pickle.py", line 521, in save
    self.save_reduce(obj=obj, *rv)
  File "/usr/lib/python3.6/pickle.py", line 634, in save_reduce
    save(state)
  File "/usr/lib/python3.6/pickle.py", line 476, in save
    f(self, obj) # Call unbound method with explicit self
  File "/usr/lib/python3.6/pickle.py", line 821, in save_dict
    self._batch_setitems(obj.items())
  File "/usr/lib/python3.6/pickle.py", line 847, in _batch_setitems
    save(v)
  File "/usr/lib/python3.6/pickle.py", line 496, in save
    rv = reduce(self.proto)
TypeError: can't pickle Struct objects

Same error goes for dill. Pickle module produces a one-line error.

A: Solved: The error gave me one clue. Byte class object which I tried to pickle is a FormatField and has nothing to do with the Struct class. Only after few hours of thinking about it, it occured to me that Struct refers to struct.Struct and not construct.Struct. After getting rid of it, it serializes properly.
Empty construct.Struct class object serializes without issues.
Offending code:
class FormatField(Construct):
    def __init__(self, endianity, format):
        if endianity not in list("=<>"):
            raise FormatFieldError("endianity must be like: = < >", endianity)
        if format not in list("fdBHLQbhlqe?"):
            raise FormatFieldError("format must be like: f d B H L Q b h l q e ?", format)

        super().__init__()
        self.fmtstr = endianity+format
        self.length = struct.calcsize(endianity+format)
        self.packer = struct.Struct(endianity+format) # <---- culprit

redpajama_set_name: RedPajamaStackExchange


Ebay Seller to 80% Increase In Sales … In 12 Weeks!
Holy Moly! This transformation was incredible.
Our clients Angela and Jennet were transitioning into self-employment.
They were trying to hold down full-time jobs AND build a business selling designer clothes and accessories online.
Selling their products on eBay, with a poor brand presence and website, they were really struggling to make sales consistently.
Now, this is a highly competitive market and one that is rife with 'knock-off' goods, so building trust for consumers is essential if you're going to survive in this market.
They came to use exhausted and not knowing what to do to increase their sales.
And, when I spoke to them both, they explained that they were fed up 'playing' at business and wanted to really step up their game and compete at a higher level than ever before.
I explained to Angela and Jennet that the reason for their lack of consistent sales was because consumers needed to 'know, like and trust' their brand.
Not only was Angela and Jennet in a highly competitive market online, they were competing with dodgy traders with counterfeit goods.
To compete successfully, they needed to elevate their brand significantly and really understand their ideal, target audience in order to reach them smoothly and cost-effectively.
The thing is, Angela and Jennet were selling the 'real deal' in terms of designer fashion and accessories at competitive prices. They also had high levels of integrity and loved fashion.
Needless to say, both Angela and Jennet were skeptical.
Yet, despite that, they both trusted the process and went to work. They worked hard to apply our system. They juggled their day jobs and personal lives to make this happen.
They learnt about EXACTLY who their ideal customers are.
They re-positioned their brand identity to build greater trust in their business and products.
Because of this, they were able to create a brand-new website, with new product structures aimed specifically at their ideal customers.
Their confidence in business increased.
They increased their sales by between 70-80% in just 12 weeks.
No huge advertising budgets. No fancy sales funnels.
By themselves. With our guidance and support.
80% increase in CONSISTENT sales. In just 12 weeks.
That's what happens when you really get to know your ideal customers.
That's what happens when you position your business and brand correctly.
That's what happens when you utilize one of the best uplevelling and alignment system in the world.
And, that's what happens when you have the Business Alchemy team in your corner.
If Angela and Jennet can take an almost unknown business, selling a few items on eBay, and in just 12 weeks get consistent sales at up to 80% more than they had previously, is there any reason why YOU can't increase your sales with whatever you're offering?
The truth. I'm not sure. I don't know you personally, yet.
We'll put our heads together for about 45 minutes or so. You can tell us all about your business, and what you really want to achieve.
Together, we'll help you figure out what you should be doing, how to attract our ideal customers … even if you've tried everything and nothing has worked.
You know, we have a lot of competitors. Lots of copycats, too.
But if any of them can take an unknown business, selling designer fashions, sporadically on eBay and build them a proper brand and online business in just 12 weeks … bring it on!
Only the Business Alchemy programme can do that.
Book a call here. Let's see what we can do for you.
P.S. Angela and Jennet are going from strength to strength. On top of their initial amazing results, they're looking to implement the full sales funnels we taught them and over the next 12 months increase their income, so they have an option of quitting their day jobs (their choice entirely). And, you know what? Their journey to this acceleration of growth all started when they booked the same call that I'm inviting you to book. If they hadn't made that appointment, that one decision would have kept them playing small and lengthened the time of building their business to years, rather than weeks. There's no pressure – book a call now and let's see how far we can take your business.


The Pilipinx American Student Association offers a program in which students who enter will be empowered with leadership, community engagement, professionalism, and Fil-Am cultural history. They shadow the current Core Board and help out as leaders in the organization.
If you are from an older Internship class and want to be recorded on the website; please email president@pasacsueb.org with everyone from the year and a picture.


text:
Q: Expanding ubuntu partition with unallocated space I have a dual boot with windows 8 and ubuntu 16 on my laptop. I have 20gb for my ubuntu which I want to expand. I just unallocated 200gb of my windows partition via windows disk management. I booted again ubuntu with my usb drive without installing and tried Gparted to resize/move my ubuntu partition. But I can't expand ubuntu partition at all. This is what I get in Gparted:

A: You can only grow partitions if there is adjacent unallocated space. If you have unallocated space at a different location, you need to move all the partitions in between the two first. GParted offers a "move" operation. Moving large partitions may take a long time.
As with most operations that change the geometry of a partition, there's a significant chance of failure and data loss. So back up your data.


Has anyone successfully grab the intent and extras from another Android app using AppLauncherPlugin? I am trying to grab the intent and extras in my OutSystems mobile app but was unable to do so.
I came across this as well. I have created a sample Outsystems mobile app and as well as a sample Android app that passes Android intent and extras back. I am able to launch the Android app from the Outsystems app but I am unable to get back the intent that was passed back from the Android app.
I was able to use the plugin in Outsystems. However, I only managed to execute getCordovaIntent() and it does not pass back the intent that was intended.
Is there any working Outsystems samples for me to reference? Thanks.


text:
WHS Drama & Opera
FIRST ENTRY: 1952
LAST ENTRY: 1984
N°: 38
M&D OVERVIEW
ONLY TWO editions of "Janus" are
still missing - Spring 1959 & 1976!
"Janus" material
"Volume" & Number
Season & Year
sundry info
not in "Janus"
Huge enthusiasm, energy, pride and the joy of creation leap out from these pages; they make the past come alive, and I find them immensely moving. The WHS cultural heritage was indeed "awesome", a somewhat over-used word these days, but wholly appropriate here. The oldest Old Boys were born around the time of WWII, and especially in the school's first ten years one feels an immense release here after those dark days: a huge expression of hope and creation. And what talent the school attracted, with many boys excelling in more than one field. Legendary names are preserved here: boys who achieved great things both at school and after. By luck and judgement we had magnificent teachers eager to enable and encourage that participation in drama, music, art - and of course sport. It is an unforgettable heritage, and very dear to all who experienced it.
(Chris Snuggs - April 2019)
PS I am always on the lookout for more material! Many productions are well covered, but others not at all. Do rummage through your cupboards and drawers to see what could be added - post 1977 material is a particular unknown. AND of course pls advise me of errors or omissions. DISQUS comments can be added at the top of this page.
X 75 X
65-Sum
65-Win
61-Spr
59 -Spr
59-Aut
"Disaster '84" (programme)
"The Ghost" (programme)
NO DRAMA ENTRIES
"The Tempest" (programme only)
"Spies"
"The Real
'Hound "
"Motley"
Sum 1965
Aut 1959
Spr 1959
MISSING "JANUS" EDITION
ON OPEN DAY the Choral and Orchestral Society gave a shortened concert version of "Trial by Jury". McCulloch sang the part of the Judge well, and good performances of the other solo parts were given by T. Davies, M. Brown, W. Bauer, P. Bennett and P. Mann. The orchestral writing had been cunningly arranged by Mr. Warren so that even the least skilled instrumentalists were able to blow, hit or scratch a useful note every now and then, Mr. Woolford filled in the gaps on the piano.
The chorus suffered from being too small, and we hope that there will be many more trebles and altos at the next concert. Altogether this was the best thing that we have done and was a not unworthy last performance under Mr. Warren, who had worked hard for three years to create a musical society from nothing. We wish him well in his new post at Belfast.
I.M.R.
"THE GOVERNMENT INSPECTOR" - by NIKOLAI GOGOL
presented by the Dramatic Society, 25th and 26th March, 1955.
In trying to write a "criticism" of a performance by the School Dramatic Society, as I suppose in the case of a criticism of any dramatic production, one has to decide by what standards to judge the performance. Cutting out the highest standards one is left with (a) the previous performances of the Dramatic Society; (b) the performances one may have seen of other Schools; (c) the performances of non-School Amateur Dramatic Societies.
Thinking back to those productions of our own School Society which can in any way be compared with The Government 1nspector, I feel that undoubtedly a much higher standard was reached in Gogol's play. There was a smoothness and sense of timing and feeling for character which I do not remember having seen so clearly in either The Tempest or Man of Destiny. The whole production was handsomely staged and dressed, and it was pleasing to notice that many of the players wore the clothes of an earlier period with a sense of style. I felt that I would not be in the least surprised to have certain members of the Sixth Form turning up to class in coloured waistcoats, high collars, ragged trousers and frock coats.
The performance also certainly held its own with any other School performance I have seen but that would not be true for anyone who has seen some of the really great productions of certain schools; and I should say that it compared very favourably indeed with most amateur dramatic societies one might see.
The main weaknesses, I thought, lay in the play itself. Out of Russia and out of its time, the idea is not strong enough for a full-length play. One or two scenes dragged, not because of the acting so much as because of the writing; for instance, the procession of officials handing over their bribes to the impostor became tiring. With regard to the acting the only serious fault was in at least two characters who added "business" obviously not intended by the director. Perhaps one of the hardest things for some schoolboy actors to learn is that on the night of the performance they do not replace the director's instructions with some individual acting (or clowning) of their own-particularly when such behaviour is liable to distract the audience's attention.
One of the tests I tried to apply in thinking about the performance was to ask myself whether I felt that I was watching, say, Workman dressed up, or watching the mayor of a small Russian town. The answer, of course, varied from character to character. I was, on the whole, impressed by Workman as the mayor, in spite of his continued tendency to take his lines at too high a speed. I found myself watching a fussy, pompous, bullying little man who perhaps was not quite as outraged as he might have been by the suggestion of his wife's infidelity. Considering the rather forbidding appearance of his wife this was possibly not surprising. Swannell looked like a woman without feminine charm; I couldn't imagine even the pseudo-inspector being interested in her. Swannell did not quite live up to the promise he had shown in his House play at the end of the Christmas term, but I should still like to see him as one of the old ladies of Arsenic and Old Lace with Gilbert as a partner - a Gilbert that is, without his imposing stomach, which in this production he manipulated so successfully. Boyd, as the daughter, looked the part but it is a thankless part and Gogol rather than Boyd was to blame for its shallowness. The assembled rogues of the town - Cox, Glass, Davies, Begg, Bass and Bauer-were a good team. I liked Cox's appearance and presence, although his speech was sometimes too confidential; Glass got inside his part remarkably well; Davies' postmaster amused me very much and I thought the episode of the opened letter a little gem. Begg looked uncomfortable, and Bass and Bauer made me think (inaptly I admit) of Tweedledurn and Tweedledee. When Lamb refrained from over-playing he was very effective and created something of the atmosphere of a Dickensian character. The smaller parts were adequately filled, although I think Rosen worth singling out for a very effective little piece of acting.
Ammos Fyodorovitch Lyapkin-Tyapkin, the District Judge R. COX
Artemy Filipovitch Zemlyanika, the Charity Commissioner D. GLASS
Luka Lukitch Hlopov, the School Superintendent D. BEGG
Anton Antonovitch Skvoznik-Dhumanovsky B. WORKMAN
Ivan Koosmitch Shpyckin, the Postmaster T. DAVIES
Peter Ivanovitch Bobchinsky, a Landowner B. BASS
Peter Ivanovitch Dobchinsky, a Landowner W. BAUER
Svistoonov, a Constable J. CLUTTERBUCK
Stepan llyitch Uhovyortov, the Police Superintendent M. BROWN
Anna Andreyevna, the Mayor's wife B. SWANNELL
Marya Antonovna, the Mayor's daughter C. BOYD
Yosif, servant to Hlestakov N. LAMB
Ivan Alexandrovitch Hlestakov, a junior official from St. Petersburg, the capital I. MCCULLOCH
A waiter R. BOYCE
Mishka, a servant in the Mayor's house G. BYRDE
Abdulin, a merchant A. SZEPESY
Another merchant R. CROUCHER
Another merchant V. GILBERT
Locksmith's wife R. ROSEN
Sergeant's wife A. KENSINGTON
A scruffy individual M. CRACKNELL
A Gendarme M. CRACKNELL
The play produced by Mr. I.R. BELL,
Stage Manager N. GOULD
Assistant Stage Manager G. BROWN
Lighting D. HARRINGTON
Set built by A. SMITH, R. RONAN and J. CUFFLEY
But after recognising the high standard of teamwork in the play there is still the main character, on whom so much depends, to be considered. And here McCulloch served us very well. On the only occasion when I saw the play in rehearsal I watched the "drunk scene" and found myself watching not McCulloch but a drunken impostor. This impression of a boy really taking on a character on the stage continued during the actual performance. The gestures were appropriate and sure, the timing remarkable, the use of voice and eyes so effective. It was a very fine performance.
But one actor does not make a play, and it was the unity and all-round high standard that was so pleasing - a standard which must have gladdened Mr. Bell; and to him all those who saw the play should be very grateful, as should be those who acted in it for the direction he gave.
"1066 And All That"
The Dramatic Society broke much new ground this year. To begin with, it chose a piece both modern and musical. Secondly, it presented the play on an indoor stage, and finally, there were two performances given, instead of the one of previous years. The popularity of the production - and especially of the numerous catchy songs - was obvious to any person visiting the school with an ear to hear with. The success of the production depended mainly on three people, Mr R. Rowland, the producer; N. Lamb, who played The Common Man; and B. Bass, the Narrator.
The enormous problem of casting and dressing this play, abbreviated though it was, was very well solved by the producer and his helpers. In addition, the handling of these large numbers on a very small stage was admirable, whilst the off-stage discipline was very good - no whisperings, shufflings or disconcerting bangs.
To the two main players - N. Lamb and B. Bass - only praise can be offered. Lamb, especially on the first night, was excellent,
combining humour with a touch of pathos which was unexpected from so young a boy. Bass, although a little inclined to rush some of his narration, caught well the sophisticated air essential to his part. A few scenes and characters stand out from the rest of the production - Ashdown, Moughton and Simmonds as St. Patrick, St. Pancras and St. Ives; Bauer as the Judge in the Columbus scene; and D. Stevens as the Sergeant in the Henry V scene. But the general level of acting was quite good, and the prompter can rarely have had an easier job.
In conclusion - how is this production likely to affect then future of the Dramatic Society? In the first place it has been proved that a play can be produced in the Gymnasium, although flies and proper curtains are essential for complete smoothness of production. Secondly, we obviously have in the school a comic actor of considerable potential ability - it would be a pity if his talents were wasted. Finally, a large number of boys, especially in the Junior and Middle school, have had the smell of greasepaint in their nostrils. The competition for parts in future productions should be most keen.
R.T.C.
"The Man of Destiny"
The success of the 1952 production of 'The Tempest', the natural beauty of the school's setting, and the physical difficulties involved in staging a play under cover with the school in its present stage of development, have all encouraged those concerned with dramatic productions at Woolverstone to regard an open-air stage as an integral part of the school plays. The handicaps of such an arrangement were made obvious in July.
The play represented was 'The Man of Destiny' by George Bernard Shaw. A stage had been specially constructed with much labour for the performance. Terraced seating gave a good view to most of the audience. The weather was perfect, but for one thing - a breeze which so rustled the leaves of the trees and bushes that much of the performance was inaudible to a great part of the audience. It was a fault which on this occasion could not be avoided, but one which must be overcome in future, or the school plays will be a bore instead of an entertainment.
To the actors themselves, only praise is due. I. McCulloch, although perhaps a trifle taller and fairer than one's conception of Napoleon, brought more maturity to the character than one would expect for his age. This, too, was true of A. Szepesy as the Strange Woman. The playing of a woman's part by a boy is always a severe test; Szepesy passed this test in fine style, and his woman really lived. She appeared quite capable of the bluff and deception which she engineered, and was obviously too intelligent for the brash, bumptious Lieutenant, very ably played by T. Davies. R. Cox as the innkeeper tended to swallow most of his words, but was much appreciated by the audience.
In conclusion, may it be said that the play was well costumed and the production was of the high standard which one now expects from Mr Bell. Both choice of play and acting were more adult than in 1952, representing a very great advance on the part of the School Dramatic Society. If this standard is maintained we can await further productions with keen anticipation.


text:
Ex-neighbor of infamous pedophile Jimmy Savile was advised by the star before sexually assaulting the boy
By Merry On Jul 10, 2020
A former neighbor of the infamous pedophile Jimmy Savile claims he took advice from the disgraced children's TV presenter before sexually assaulting a young boy.
73-year-old Michael Wise claims that the presenter 'Top of Pops' and 'Jim'll Fix It' told him to 'never do anything for nothing', who was charged with the abuse of hundreds of young victims after his death.
After listening to Savile and thinking it was related to sex, wheelchair-bound Wise, who has cerebral palsy, convinced a young boy to perform a sexual act on him by offering to buy him a scooter.
Michael Wise, pictured outside Leeds Crown Court, knew the embarrassed broadcaster for years, forced a young boy to perform a sexual act on him, then bought him a new scooter
When the boy tried to tell his family about the abuse that took place in the 1980s, he was taken care of.
His victim later turned to drugs, alcohol, and crime before gathering the courage to confront Wise about his actions.
Later, he emailed his abuser, prompting Wise to apologize and present himself to the police.
Yesterday, Wise, of Holmfirth, West Yorks, was given a suspended sentence at Leeds Crown Court after pleading guilty to gross indecency in a child under 14 years of age.
Prosecutor Paul Reid said that the defendant had clamped and groped the boy several times between his legs, but that he was too young to think about it and continued to help him.
He said the victim remembers that he had been brought to Savile's house for dinner by the defendant and that his friends were jealous at the time.
Reid said that Wise and Savile were friendly, adding, "Savile once" repaired "it for the defendant to get his first car."
Once, the defendant, who was sitting naked in his wheelchair, except for a blanket over his lap, said he would give the boy a scooter in exchange for a sexual favor, which the boy performed.
Later in the day, the defendant bought the victim a scooter.
The court heard Wise show off his friendship with Jimmy Savile, pictured, to impress the young boy at the height of his fame more than 30 years ago
As an adult, the victim e-mailed the defendant asking if he remembered the crime.
The defendant replied, "It was a terrible thing to do and I am really sorry.
"I can't straighten out the past. Should I call the police and make a confession? I feel guilty and hate myself. '
The victim went to the police in March 2019. In his first police interview with a suitable adult, Wise made no comment before asking for a second interview.
Mr. Reid said, "The defendant said he was an acquaintance of Savile, who had told him," Never do anything for nothing "- which he said was an inference in a sexual context."
In a statement, the victim said, "Michael used his many friendships with famous people and disabilities to get what he wanted.
"Telling the truth has done me no good. I was depressed and alone and called a liar. I started acting and asked to be treated.
"It was no better there than at home."
He continued, "Michael can never give me my childhood back. I always felt like an outcast. '
The victim said that he left school without any qualifications and turned to alcohol, drugs and crime and that the abuse affected his relationships with his partner and his children, adding, "I will never forgive or forget what Michael did no matter how much time passes. '
Wise, now from Oakes Lane, Brockholes, Holmfirth, has no previous convictions.
Soothing, Jeremy Barton said his client's disability meant that he had "limited ability to relieve himself".
Yesterday, Wise, of Holmfirth, West Yorks, was given a suspended sentence at Leeds Crown Court after pleading guilty to gross indecency in a child under 14
He said that Wise is truly sorry and added, "It was a relief for him to confess and apologize for what he had done."
Barton said the suspect, who has no children, relies on a caregiver who comes to his home twice a day.
Judge Mushtaq Khokhar handed Wise a 12-month prison sentence, was suspended for 18 months, and ordered him to perform a 20-day rehabilitation obligation.
The suspect was also subject to an indefinite order to prevent sexual harm.
Conviction, the judge said, "From time to time you touched him between his crotch.
"Maybe it was all innocent. But the subject of the charges was not innocent. It was for your sexual satisfaction.
"You used that little kid to accomplish that.
"He left the house and went to treatment. The lives of such victims are derailed by such an event.
Wise pleaded guilty to gross indecency with a child and received a 12-month suspended sentence
"I'm sure you had no intention of causing such damage, but that is a natural consequence of the offense.
'[An adult] a man with children of his own still finds it difficult to cope with the abuse that took place many, many years ago. '
The depraved actions of Wise's friend Jimmy Savile were revealed after his death in 2011, aged 84,
Savile abused 72 victims at the BBC and still assaulted women in 2006 at the age of 79, when the company brought him back to host the very last Top of the Pops ever, it was revealed in 2016.
The " monstrous " entertainer indecently attacked a woman after filming the episode with presenters Edith Bowman and Reggie Yates, a report revealed, as further details of the shamed Jim'll Fix It star revealed the horrific crimes.
Savile's horrific government of abuse dated back to 1959 when he raped a 13-year-old girl, before attacks followed 'in the corridors, canteens, stairwells and dressing rooms of every BBC property.'
Other crimes denounced included the rape of both a virgin teen in a hotel and a 15-year-old girl with work experience he met over a cup of tea in the BBC canteen.
Twenty-one of Savile's female victims were 15 or younger, the youngest was eight, while young boys – including an eight-year-old – were also attacked by the depraved monster.
What were the main findings of the independent study of Savile?
Jimmy Savile abused 72 BBC victims dating back to 1959 when he raped a 13-year-old girl at Lime Grove Studios;
The DJ sexually assaulted 57 women or girls and 15 boys, with the youngest girl he raped being 13 and the youngest boy 10;
Dame Janet Smith concluded in a three-year investigation that he was responsible for eight rapes, two of which against men;
Savile's youngest male and female victims were both eight years old at the time of the attack;
His most recent attack was in 2006 when he touched a woman indecently after filming the last episode of Top of the Pops – when Savile was 79 years old;
Other crimes denounced included the rape of both a virgin teen in a hotel and a 15-year-old girl with work experience he met in the BBC canteen over a cup of tea;
Savile was a "serial sexual predator" and the BBC missed five opportunities to stop his misconduct;
Despite the disclosures, Dame Janet controversially said that the company's failure to stop Savile was not the fault of senior managers;
She concluded that some of the disgraced DJ's colleagues were aware of his depravity, but believed that senior managers were never notified.
While top executives claimed to have no idea about Savile's pedophilia, there were rumors that he loved young girls, widespread among some of the best BBC stars;
Dame Janet said she could not rule out the possibility that "even today a predatory child molester is lurking with the BBC."
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