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# Monthly Archives: February 2012

## Witness Protection Program

Here’s a new creative writing prompt I though you all might enjoy!

Write a story about a person in the Witness Protection Program. Drop him/her into your job and life. What would it be like for that person to enter a life in a nursing home, although they don’t need to be there, or a college dormitory, although they aren’t there to learn. What challenges would they face unique to their position? Would they develop an affinity for the senile or handicapped elderly or a dislike for young people?

## Post From the Past: How to Efficiently Write a Great Research Paper

During my last two years in college, I wrote tons of research papers. While most of my classes only required one paper per semester, two of the classes that I took required three. As I read the syllabi for those classes, I realized that I needed to find a way to streamline my whole paper-writing process. This is what I came up with, and it worked really well for me.

Step 1: Choose a topic within 24 hours of learning that you have a paper to write.

Step 2: As soon as the topic is approved by your instructor, go to the library. Set aside two or three hours for taking notes (for a 1500 word paper – about 4 pages, double-spaced). I prefer to take hand-written notes – don’t ask me why. I always retype them anyway. Perhaps it’s because once I’ve written my notes once, and typed them once, I don’t have to reread them before I begin writing the paper.

Step 3: If you are researching something that is pretty obscure, try looking it up in the index of big books that cover a broad topic. Even if you can only find a paragraph or two covering your specific topic, you can still use that particular book as a source. (I had a teacher that required four different book sources and two online sources.) That way, even if you can’t find an entire book on your topic, you can still pull a different quote or fact from each book source. The rest you can find online.

Step 4: Write down bibliographical information immediately. You don’t have to format it yet – just make sure you have all the info.

Step 5: Take all of your notes verbatim, and make a note of which page you are taking the info from. If you begin a new page in the middle of your notes, make sure to note that as well. Instead of trying to italicize hand-written words, I use slashes to /set them apart/. If you have an idea of your own while copying notes, make sure you clearly mark it as yours.

My notes usually ended up looking something like this:

Book Title: Author’s full name: Publisher, City, Date

Page 17

Blah blah blah blah blah blah. Blah blah blah /blah blah/ blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah.

(Amy’s idea: blah blah blah.)

Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah (18) blah blah blah blah.

Type all of your notes into a single file.

Step 6: Spend a half hour taking notes from each book source. After a half hour – stop. Don’t allow yourself to get too caught up taking notes from any one source. You will never get finished! If you are researching a person, use each book to research a different era of the person’s life. If you are researching a different kind of topic, use each book to research a different aspect of that topic. Even if all of the books contain basically the same information, this is a good way to efficiently use multiple sources.

Step 7: Find your online sources, making sure they are from trusted sites. If you can use the school’s databases, all the better. Copy and paste all pertinent info into a single file. Copy and paste all bibliographical web site information at the beginning of each section. Since websites are in a constant state of change, make sure you include the access date (the date you copied the information).

Step 8: Print off all of your information. If you have more than twenty pages for a relatively short paper, you may want to delete some of the redundant or irrelevant material before printing.

Step 9: Decide how you want your paper to flow. Basically this is an outline. Biographies are relatively easy, since you will follow a chronological timeline. At the end of the paper, you can sum up greatest accomplishments, lasting impact, etc. Other types of papers can be easy as well; just decide on an order that makes sense, and stick with it. For example, your outline may look like this: Early Life, Interesting Turn of Events, Move to Boarding School, Work in the Field, Awards, Impact on Society, 200 Years Later, etc.

Step 10: Take several different colored highlighters or pens and mark your notes, using a different color for each point on the outline. Alternatively, you could bracket off each topic category in your notes, and mark the category in the margin.

You can either assign each category a color or a code. Your resulting notes will either look like this:

Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah (18) blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah.

Or like this, based on the outline given above:

EL (early life) Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah.

ITE Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah (18) blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah.

IS Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah.

EL Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah.

MBS Blah blah blah blah blah blah. Blah blah blah blah blah blah. Blah blah blah blah blah blah.

Step 11: Read all of your notes two or three times. Now put your notes away and write your paper based on the knowledge in your own head. If you don’t know a fact such as a year, a number, or a name, write a question mark there to be filled in later. Writing it this way, without the use of your notes, keeps the whole paper from seeming like a paraphrased imitation of your research (which is how most research papers end up).

Step 12: If your paper is too long, cut out the unessential stuff, or tighten up your sentence structure. If it is too short, read your notes again and look for interesting tidbits. Top your paper off by using one or two exact quotes per typed page.

Step 13: Go back over your research paper, and compare it to your notes, which should be verbatim from the sources, and make sure you haven’t accidentally plagiarized. Make use of your highlighted sections to find your sources easily, based on which section of the paper you are currently working on.

Step 14: Time for adding footnotes or in-text citations. You can look up your references easily by using your highlighted notes.

Step 15: Format your bibliography, footnotes, margins, etc. Set aside at least an hour to do this, instead of waiting until 20 minutes before you have to leave for class on the day the paper is due.

Step 16: If you are truly interested in your topic, and you have finished your paper early, now is the time to satisfy your thirst for knowledge and dig a little deeper. If you run out of time, you can turn your paper in the way it is. But if time allows, you can tweak it to your heart’s content!

## My Prayer…Routine?

I am teaching my son to pray so he won’t have to figure it out for himself.

I have been trying to encourage him to cultivate a close, personal relationship with Christ. I don’t want him to have that all-too-pervasive mentality in which God is nothing more than a glorified vending machine. I’m trying to teach him that we go to God with more than just our wants. I’m also trying to teach him that our prayers should be like conversations, personal and varied – different every time we speak to God. When we pray, we use words and grammar that come to us naturally, like talking to a friend. But I do like to use the structure of the Lord’s Prayer for our example:

Our Father which art in heaven, hallowed be thy name…

Every time we approach God, I believe we should worship Him for who He is. My son and I accomplish this by spending a few moments telling God how awesome He is. And then we try to think of specific things in our lives and in Creation that testify to His awesomeness. For example, we might see a beautiful sunset and worship God for His beauty. We might learn about how ants keep their own herds of aphids and praise Him for His wonderful creation. We might recover from an illness and stand in awe at the marvelous healing capabilities of the human body. At this point in our prayers, we also thank God for several varied and specific things such as salvation, liberty, parents that have taught us about God, or the mere fact that God thought of us individually and saw fit to create our souls. Then we thank him for things we like or enjoy, such as snowflakes, birthday parties, and toy train sets. Our praise and thanksgiving varies from prayer to prayer because I don’t ever want my son to look at the process as a ritual, but merely a conversation between friends, one of whom is holy and deserves acknowledgment of that fact.

Thy Kingdom come; thy will be done, on earth as it is in heaven…

I try to truly accept God’s will in my life. Whether He wants me to go or stay, be rich or poor, healthy or ailing – if it accomplishes His will, then that’s what I want in my life. My only unwavering desire is to see as many saved as possible, and I doubt that God’s will is any different in that respect. I would like to think that I would gladly give my life or graciously suffer the deaths of my loved ones, if it could only result in more souls saved. I don’t desire anyone to be separated from our Creator for all of eternity.

Give us this day our daily bread…

I believe it is okay to ask God for things. While it should not be the main reason we pray, He desires to give us the things we ask for, just as a doting father may enjoy buying coveted gifts for his children. When I ask though, I generally tag my petitions with “but your will be done.” I know that He knows better than I do what’s best for me, so I don’t really want anything outside of His will.

And forgive us our debts, as we forgive our debtors…

It is good for us to specifically address our short-comings, and confess them to God and one another. Doing so holds us more accountable, and may even help prevent us from repeating the same mistakes over and over. We need to search our souls for the things that are keeping us from a perfect walk with God, and take whatever steps necessary to oust them from our lives. One of those things is the resistance to forgive others. We have sinned against a holy God thousands of times, and have been forgiven all. What gives us the right, unholy creatures that we are, to withhold forgiveness from those who sin against us?

And lead us not into temptation…

And while we’re asking God to keep us from temptation, we need to not be the hypocrite that walks headlong into temptation on purpose. Our request for help should serve to keep us in check.

But deliver us from evil…

I pray that nothing traumatic ever happens to us, but again, I want God’s perfect will in my life. And God forbid I should ever be a source of evil in this world.

For thine is the kingdom, and the power, and the glory forever. Amen.

Realize who God is. Realize his awesome power and sovereignty. Remember who you are speaking to as you approach Him with your petitions. Remember that He loves you personally; He is your doting Father. Remember that He desires friendship. But remember too, that He demands obedience.

Challenge: If you don’t have a prayer life to speak of, put down whatever you are doing and begin right now. If you aren’t willing to start now, when will you ever make time for God? I keep hearing Jillian Michaels in my head saying “Transformation is not a future event.” So true.

## Post from the Past: Dial a Writing Prompt

I thought I would tell you about a neat little writing prompt generator that I thought of a while back.

Get out a piece of paper or open up your favorite word processing program. Now, think of ten different protagonists, numbering them 0-9. (The numbering system is important.) Your protagonist can be as vague or as specific as you like. Some ideas: police officer, librarian, little old lady, friendly monster, toddler, department manager, forgetful neighbor, shy girl in the corner, garbage man, step-mom. Next, again numbering each from 0-9, think of 10 locations, 10 items, and 10 antagonists. Don’t forget to stretch your imagination as far as possible. Your location ideas might be as common as a supermarket or as spectacular as a galaxy far, far away. (My personal favorite location idea is “under the sea.”) Item ideas: pencil, heirloom, coin, donut, notebook, sword, pocketwatch, railroad spike, strand of hair, game token. Once in a while, use something unexpected in the antagonist category, such as blond 10-year-old girl. You could do the same thing in the protagonist category.

Here’s the fun part:

Get out your cell phone or phonebook, and look someone up. The last four digits of their phone number will tell you which protagonist, location, item, and antagonist combination to use. For an added twist, write the story from the point of view of the actual person who’s phone number you chose. Have fun!

## A prompt disguised as “been there, done that…”

Go somewhere that you already go on a regular basis. The grocery store, college, your mom’s house, church, etc. Only this time, keep an eye open for story ideas!

## I Kissed Dating Goodbye

I just read the new updated edition of I Kissed Dating Goodbye by Joshua Harris. The first thing I want to say is, wow! I wish I had read this book as a teenager. Instead of a book filled with dos and don’ts, as you might suspect, it is mostly a book that speaks directly to matters of the heart. Its primary focus is to help you in your relationship with God; all other relationships are secondary. The book helps single people focus on what’s really important at that critical stage in their lives, and then helps them move on when romance becomes appropriate.

I loved this book! Although I have been married for over a decade, I can still look back and see where applying the truths of this book could have helped me remain pure during those years of being single. I wish I could go back and put God first! The book is still useful to married people, as we explore our relationships with God and others. Although this book wasn’t a tear-jerker, I still found myself in tears two or three times as I considered God’s love toward me over the years, in the midst of some terrible mistakes.

My favorite part of the book was the narration of a dream that Joshua Harris gives us at the opening of chapter eight. You can read it here: The dream is absolutely life-changing! In my opinion, the analogy is too perfect to be anything but God-given.  I summarized it to my husband, and even he was teary-eyed; he’s a Christian, but I had never seen him respond to God’s grace in that way before.

If you want to find out more, you can read Joshua Harris’ blog here. Or you can preview the book here.

Note: In exchange for an honest review, the publisher provided a complimentary copy of this book through Waterbrook Multnomah Publishers.

## A prompt disguised as making history…

Write about a memory that has stuck with you for ten or more years. But change the outcome. Change it to something more tragic, or witty, or adventurous. Anything you like! It would be interesting to have your change bring about unexpected consequences…

## Post from the Past: Do we truly believe that God is in control?

If you study biology, chemistry, astronomy – well, just pick a science – you will gain an appreciation for God’s ingenuity and power like never before. For instance, the human body is a fearfully wonderful thing. When it’s working properly, every tiny cell is serving a purpose. They all work together to keep us alive. I have begun to mentally apply this awesome microscopic design on a larger scale – to the workings of every living person on earth. Does God have enough power to direct every detail of every person’s life in order to accomplish His will? He does. It seems to me that every person on the earth is like one cell in the body of God’s design. He is winding things up in preparation for The End, and we are all a part of that.

My way of looking at life has changed over the years. I used to believe that God only took a hand in the big events in my life. I used to believe that He just allowed some things to happen on their own – without any consideration from Him. I think I was making excuses for Him in my mind. I didn’t want to believe that people could suffer and die because of a decision on His part (tragic deaths, natural disasters, etc). The events of September 11, 2001 really bothered me. Why would God choose to end all of those lives? At the time – one thing never occurred to me: God loved those people more than I have ever loved anyone. God wanted a relationship with each of them. Do you think He allowed even one to die that, given one more chance, would have accepted Him? I like to think that the entire population of those who died that day were either already saved, or had made up their minds already against God. I know that’s radical, but I believe that God is just that powerful. And if that’s not the way He works, then I trust that His way is even better, and makes even more sense.

I don’t know when it happened or what caused it, but my perspective has changed a lot over the past year or so. I now believe – wholeheartedly – that God is in direct control of every tiny thing. I believe that He is telling the literal truth when He says that, “All things work together for good [my own emphasis].” The question is, do we really believe that He has that much power? Do we believe, for instance, when it rains, that it is exactly what every Christian needs on that day? When we get a new job, or when our dryer stops working, do we believe that He is blessing and/or molding us into something better? I’ve finally stopped worrying about things I can’t control. I figure that if I have sinned (say, for instance, that I’m a lazy employee), then I can take myself out of God’s will for my life. If I lost my job at that point, I would blame myself. However, if something happens, and I know that I haven’t had anything to do with it, I assume that God wanted it to happen. I assume that it’s in my best interest. In other words, my own sin is the only thing that can hinder God’s perfect will in my life. I know that a lot of people won’t agree with me. I just believe that He has enough power over our lives to work every tiny detail according to His will. Now, when something “bad” happens, I think, “What can I learn from this? What is God trying to tell me?”

Challenge: Obey God in every small detail. Trust Him to take care of everything else.

## Switched!

Ian and I just read the book TJ and the Time Stumblers: Switched! by Bill Myers. The book was about a girl, TJ, who happens to be friends (and I use that term loosely) with two time-travelers from the 23rd century. They follow TJ around and attempt to help her solve her problems – she’s a great historical figure where they come from. At the same time, she gets wrapped up in their escapades as they try to make their way back to their own century. They make a lot of mistakes along the way (nobody’s perfect), which result in often hilarious consequences. The theme of this book is forgiveness.

My seven-year-old absolutely loved the book, but I’m not sure he understood the references to the preteen crushes and insecurities. He laughed out loud a lot though! I enjoyed reading it to him, but the book got on my nerves more often than not, with its constant interruptions (there are giant, bold print words on nearly every page that represent loud noises and shouting) and the cutesy names of all of the characters. However, I doubt these things would be a problem for the age group for which the book is intended. I’m assuming it’s for 5th and 6th graders?

Here is Ian’s review (my seven-year-old): That was a great book! No book’s funnier than this book!!! The one guy turned into a waterspout; it was so funny. It could talk. TJ and Hesper’s bodies got switched around.

If you want to find out more, check out the product page for this book.

Note: In exchange for an honest review, Tyndale House Publishers provided a complimentary copy of this book.

## Bible Study Curriculum

Someone hit my blog the other day by Googling “bible study in homeschool.”

This is something that I have been wondering about for a while now. Ian already reads his Bible every night, and our family reads together in the evenings (when we remember – something we definitely need to work harder at though), so what do we do specifically for homeschool? I have the subject Bible scheduled three times a week, but how to fill it? His history book is from a Biblical perspective (The Mystery of History) and so are his science books (Answers in Genesis). So he already gets tons of Bible stories and creation science in his curriculum.

We already work hard to cultivate a personal relationship with the Lord. We praise God when we pray, we tell Him how awesome and wonderful He is, and we think of things that prove it, and then tell Him about them. For instance, we think of something wonderful about His creation, and tell Him what a great job He did, and thank Him for it, like the properties of water or an animal that we’ve been learning about. We also try to thank Him for things that He’s done specifically for us, like creating us or giving us something we’ve asked for. I teach my son that it’s okay to ask for things, but it’s not the primary reason we pray. I’m also trying to teach Him to be spontaneous – he doesn’t have to wait for bedtime to say his prayers. So every day, I’m trying to get my son to cultivate his relationship with the Lord.

So, back to Bible curriculum: Bible stories (check), creation science (check), personal relationship (check). What’s left?


text: H3= sigmoid (I1*w13+ I2*w23–t3); H4= sigmoid (I1*w14+ I2*w24–t4) O5= sigmoid (H3*w35+ H4*w45–t5); Let us discuss … Single Layer Perceptron Neural Network - Binary Classification Example. A second layer of perceptrons, or even linear nodes, … Contents Introduction How to use MLPs NN Design Case Study I: Classiﬁcation Case Study II: Regression Case Study III: Reinforcement Learning 1 Introduction 2 How to use MLPs 3 NN Design 4 Case Study I: Classiﬁcation 5 Case Study II: Regression 6 Case Study III: Reinforcement Learning Paulo Cortez Multilayer Perceptron (MLP)Application Guidelines What is the general set of inequalities across the 2-d input space. This is known as Parametric ReLU. Follow; Download. (see previous). Some inputs may be positive, some negative (cancel each other out). This is just one example. e.g. They calculates net output of a neural node. so it is pointless to change it (it may be functioning perfectly well 27 Apr 2020: 1.0.1 - Example. We start with drawing a random line. if you are on the right side of its straight line: 3-dimensional output vector. In the last decade, we have witnessed an explosion in machine learning technology. Supervised Learning • Learning from correct answers Supervised Learning System Inputs. no matter what is in the 1st dimension of the input. So far we have looked at simple binary or logic-based mappings, but neural networks are capable of much more than that. The value for updating the weights at each increment is calculated by the learning rule: $$\Delta w_j = \eta(\text{target}^i - \text{output}^i) x_{j}^{i}$$, All weights in the weight vector are being updated simultaneously. in the brain Led to invention of multi-layer networks. t, then it "fires" e.g. Instead of multiplying $$z$$ with a constant number, we can learn the multiplier and treat it as an additional hyperparameter in our process. It cannot be implemented with a single layer Perceptron and requires Multi-layer Perceptron or MLP. The Heaviside step function is non-differentiable at $$x = 0$$ and its derivative is $$0$$ elsewhere ($$\operatorname{f}(x) = x; -\infty\text{ to }\infty$$). and each output node fires It was designed by Frank Rosenblatt in 1957. bogotobogo.com site search: ... Flask app with Apache WSGI on Ubuntu14/CentOS7 ... Selenium WebDriver Fabric - streamlining the use of SSH for application deployment Ansible Quick Preview - Setting up web servers with Nginx, configure enviroments, and deploy an App Neural … Overview; Examples - … In this article, we’ll explore Perceptron functionality using the following neural network. The main underlying goal of a neural network is to learn complex non-linear functions. Note: Only need to any general-purpose computer. The algorithm is used only for Binary Classification problems. learning methods, by which nets could learn View Version History × Version History. A perceptron consists of input values, weights and a bias, a weighted sum and activation function. Neural networks are said to be universal function approximators. Single Layer Perceptron (SLP) A perceptron is a linear classifier; that is, it is an algorithm that classifies input by separating two categories with a straight line. function and its derivative are monotonic in nature. What is perceptron? It is mainly used as a binary classifier. In both cases, a multi-MLP classification scheme is developed that combines the decisions of several classifiers. 2 inputs, 1 output. Implementasi Single Layer Perceptron — Training & Testing. Link to download source code will be updated in the near future. What the perceptron algorithm does . Single-Layer Feed-Forward NNs: One input layer and one output layer of processing units. if there are differences between their models Single Layer Perceptron Network using Python. Inputs to one side of the line are classified into one category, This post will show you how the perceptron algorithm works when it has a single layer and walk you through a worked example. Q. In both cases, a multi-MLP classification scheme is developed that combines the decisions of several classifiers. If Ii=0 for this exemplar, A single layer perceptron (SLP) is a feed-forward network based on a threshold transfer function. L3-13 Types of Neural Network Application Neural networks perform input-to-output mappings. Perceptron: Neuron Model • The (McCulloch-Pitts) perceptron is a single layer NN ithNN with a non-linear , th i f tithe sign function. Obviously this implements a simple function from Let’s jump right into coding, to see how. Perceptron Neural Networks. A Perceptron is a simple artificial neural network (ANN) based on a single layer of LTUs, where each LTU is connected to all inputs of vector x as well as a bias vector b. Perceptron with 3 LTUs Single-Layer Perceptron Network Model An SLP network consists of one or more neurons and several inputs. Perceptron is the first neural network to be created. 27 Apr 2020: 1.0.0: View License × License. This decreases the ability of the model to fit or train from the data properly. The Heaviside step function is typically only useful within single-layer perceptrons, an early type of neural networks that can be used for classification in cases where the input data is linearly separable. Each neuron may receive all or only some of the inputs. A similar kind of thing happens in a Perceptron) Multi-Layer Feed-Forward NNs: One input layer, one output layer, and one or more hidden layers of processing units. Single Layer Neural Network - Perceptron model on the Iris dataset using Heaviside step activation function . Since this network model works with the linear classification and if the data is not linearly separable, then this model will not show the proper results. No feedback connections (e.g. The non-linearity is where we get the wiggle and the network learns to capture complicated relationships. The function produces 1 (or true) when input passes threshold limit whereas it produces 0 (or false) when input does not pass threshold. So we shift the line again. takes a weighted sum of all its inputs: input x = ( I1, I2, I3) Each perceptron sends multiple signals, one signal going to each perceptron in the next layer. Learning algorithm. 0 Ratings. 0.0. Modification of a multilayer perceptron (MLP) network with a single hidden layer for the application of the back propagation-learning (BPL) algorithm. Yes, I know, it has two layers (input and output), but it has only one layer that contains computational nodes. w1+w2 < t Multi-category Single layer Perceptron nets… • R-category linear classifier using R discrete bipolar perceptrons – Goal: The i-th TLU response of +1 is indicative of class i and all other TLU respond with -1 84. Contradiction. What kind of functions can be represented in this way? can't implement XOR. Unfortunately, it doesn’t offer the functionality that we need for complex, real-life applications. The two well-known learning procedures for SLP networks are the perceptron learning algorithm and the delta rule. View Version History × Version History. between input and output. It was designed by Frank Rosenblatt in 1957. Convergence Proof - Rosenblatt, Principles of Neurodynamics, 1962. Let It is mainly used as a binary classifier. SLP networks are trained using supervised learning. The single-layer Perceptron is conceptually simple, and the training procedure is pleasantly straightforward. We apply the perceptron unitaries layerwise from top to bottom (indicated with colours for the ﬁrst layer): ﬁrst the violet unitary is applied, followed by the The Perceptron algorithm learns the weights for the input signals in order to draw a linear decision boundary. Note the threshold is learnt as well as the weights. To address this problem, Leaky ReLU comes in handy. We can imagine multi-layer networks. and natural ones. by showing it the correct answers we want it to generate. Ii=1. The output value is the class label predicted by the unit step function that we defined earlier and the weight update can be written more formally as $$w_j = w_j + \Delta w_j$$. $$x$$ is an $$m$$-dimensional sample from the training dataset: Initialize the weights to 0 or small random numbers. version 1.0.1 (82 KB) by Shujaat Khan. Updated 27 Apr 2020. 2 inputs, 1 output. A collection of hidden nodes forms a “Hidden Layer”. l = L FIG. Input nodes (or units) This means that in order for it to work, the data must be linearly separable. Single-layer perceptron belongs to supervised learning since the task is to predict to which of two possible categories a certain data point belongs based on a set of input variables. Q. The perceptron – which ages from the 60’s – is unable to classify XOR data. though researchers generally aren't concerned Positive weights indicate reinforcement and negative weights indicate inhibition. The algorithm is used only for Binary Classification problems. from the points (0,1),(1,0). Note: (a) A single layer perceptron neural network is used to classify the 2 input logical gate NAND shown in figure Q4. Then output will definitely be 1. axon), Follow; Download. The network inputs and outputs can also be real numbers, or integers, or a … then weights can be greater than t This single-layer perceptron receives a vector of inputs, computes a linear combination of these inputs, then outputs a+1 (i.e., assigns the case represented by the input vector to group 2) if the result exceeds some threshold and −1 (i.e., assigns the case to group 1) otherwise (the output of a unit is often also called the unit's activation). XOR problem XOR (exclusive OR) problem 0+0=0 1+1=2=0 mod 2 1+0=1 0+1=1 Perceptron does not work here Single layer generates a linear decision boundary 35. (output y = 1). The transfer function is linear with the constant of proportionality being equal to 2.      We could have learnt those weights and thresholds, L3-11 Other Types of Activation/Transfer Function Sigmoid Functions These are smooth (differentiable) and monotonically increasing. Proved that: e.g. A single layer perceptron, or SLP, is a connectionist model that consists of a single processing unit. that must be satisfied for an OR perceptron? A single-layer perceptron is the basic unit of a neural network. Each neuron may receive all or only some of the inputs. Single-Layer Feed-Forward NNs: One input layer and one output layer of processing units. w1=1,   w2=1,   t=0.5, The thing is - Neural Network is not some approximation of the human perception that can understand data more efficiently than human - it is much simpler, a specialized tool with algorithms desi… Problem: More than 1 output node could fire at same time. For multilayer perceptrons, where a hidden layer exists, more sophisticated algorithms … certain class of artificial nets to form Single Layer Perceptron Explained. Exact values for these averages are provided for the five linearly separable classes with N=2. Single Layer Perceptron (Model Iteration 0) A simple model we could build is a single layer perceptron. Every single-layer perceptron utilizes a sigmoid-shaped transfer function like the logistic or hyperbolic tangent function. and t = -5, 16. stops this. w1=1,   w2=1,   t=1. Ans: Single layer perceptron is a simple Neural Network which contains only one layer. That is the reason why it also called as binary step function. Download. Single Layer Perceptron Network using Python. Often called a single-layer network on account of having 1 layer … A single-layer perceptron works only if the dataset is linearly separable. draws the line: As you might imagine, not every set of points can be divided by a line i.e. Herein, Heaviside step function is one of the most common activation function in neural networks. 27 Apr 2020: 1.0.1 - Example. (a) A single layer perceptron neural network is used to classify the 2 input logical gate NOR shown in figure Q4. View Answer . Note that this configuration is called a single-layer Perceptron. I studied it and thought it was simple enough to be implemented in Visual Basic 6. Single Layer Perceptron Neural Network - Binary Classification Example. This is the only neural network without any hidden layer. Perceptron Network is an artificial neuron with "hardlim" as a transfer function. those that cause a fire, and those that don't. = 5 w1 + 3.2 w2 + 0.1 w3. < t) It basically thresholds the inputs at zero, i.e. set its weight to zero. Note to make an input node irrelevant to the output, However, we can extend the algorithm to solve a multiclass classification problem by introducing one perceptron per class. Here, our goal is to classify the input into the binary classifier and for that network has to "LEARN" how to do that. Else (summed input A 4-input neuron has weights 1, 2, 3 and 4. Outputs . Perceptron is the first neural network to be created. are connected (typically fully) inputs on the other side are classified into another. where 5 min read. Those that can be, are called linearly separable. Perceptron Neural Networks. Perceptron is a single layer neural network. And let output y = 0 or 1. The single layer computation of perceptron is the calculation of sum of input vector with the value multiplied by corresponding vector weight. Understanding single layer Perceptron and difference between Single Layer vs Multilayer Perceptron. 1.w1 + 1.w2 also doesn't fire, < t. w1 >= t ANN is a deep learning operational framework designed for complex data processing operations. on account of having 1 layer of links, a Multi-Layer Perceptron) Recurrent NNs: Any network with at least one feedback connection. No feedback connections (e.g. I found a great C source for a single layer perceptron(a simple linear classifier based on artificial neural network) here by Richard Knop. • Generalization to single layer perceptrons with more neurons iibs easy because: • The output units are independent among each otheroutput units are independent among each other • Each weight only affects one of the outputs. Activation functions are mathematical equations that determine the output of a neural network. where C is some (positive) learning rate. Therefore, it is especially used for models where we have to predict the probability as an output. It aims to introduce non-linearity in the input space. Understanding single layer Perceptron and difference between Single Layer vs Multilayer Perceptron. A node in the next layer The idea of Leaky ReLU can be extended even further by making a small change. The content of the local memory of the neuron consists of a vector of weights. Single-Layer Perceptron Multi-Layer Perceptron Simple Recurrent Network Single Layer Feed-forward. Item recommendation can thus be treated as a two-class classification problem. The computation of a single layer perceptron is performed over the calculation of sum of the input vector each with the value multiplied by corresponding element of vector of the weights. A perceptron is a linear classifier; that is, it is an algorithm that classifies input by separating two categories with a straight line. Single layer perceptron network model an slp network. Dublin City University. The “neural” part of the term refers to the initial inspiration of the concept - the structure of the human brain. Using as a learning rate of 0.1, train the neural network for the first 3 epochs. The function and its derivative both are monotonic. Any negative input given to the ReLU activation function turns the value into zero immediately in the graph, which in turns affects the resulting graph by not mapping the negative values appropriately. We don't have to design these networks. Let’s understand the working of SLP with a coding example: We will solve the problem of the XOR logic gate using the Single Lay… The diagram below represents a neuron in the brain. No feedback connections (e.g. The sum of the products of the weights and the inputs is calculated in each node, and if the value is above some threshold (typically 0) the neuron fires and takes the activated value (typically 1); otherwise it takes the … the OR perceptron, Single-Layer Perceptron Network Model An SLP network consists of one or more neurons and several inputs. Weights may also become negative (higher positive input tends to lead to not fire). Single-Layer Perceptron Multi-Layer Perceptron Simple Recurrent Network Single Layer Feed-forward. Is just an extension of the traditional ReLU function. Big breakthrough was proof that you could wire up No feedback connections (e.g. Fairly recently, it has become popular as it was found that it greatly accelerates the convergence of stochastic gradient descent as compared to Sigmoid or Tanh activation functions. Hence, in practice, tanh activation functions are preferred in hidden layers over sigmoid. Below is an example of a learning algorithm for a single-layer perceptron. If the two classes can’t be separated by a linear decision boundary, we can set a maximum number of passes over the training dataset epochs and/or a threshold for the number of tolerated misclassifications. If Ii=0 there is no change in wi. October 13, 2020 Dan Uncategorized. Why not just send threshold to minus infinity? Research Since probability of anything exists only between the range of 0 and 1, sigmoid is the right choice. School of Computing.      3. x:Input Data. The function produces binary output. So far we have looked at simple binary or logic-based mappings, but neural networks are capable of much more than that. Perceptron is a machine learning algorithm which mimics how a neuron in the brain works. Perceptron The reason is because the classes in XOR are not linearly separable. If the prediction score exceeds a selected threshold, the perceptron predicts … It does this by looking at (in the 2-dimensional case): So what the perceptron is doing is simply drawing a line Some point is on the wrong side. Perceptron: Neuron Model • The (McCulloch-Pitts) perceptron is a single layer NN ithNN with a non-linear , th i f tithe sign function. The function is attached to each neuron in the network, and determines whether it should be activated or not, based on whether each neuron’s input is relevant for the model’s prediction. A single-layer perceptron works only if the dataset is linearly separable. < t Download. (n-1) dimensional hyperplane: XOR is where if one is 1 and other is 0 but not both. yet adding them is less than t, This section provides a brief introduction to the Perceptron algorithm and the Sonar dataset to which we will later apply it. Each connection is specified by a weight w i that specifies the influence of cell u i on the cell. (a) A single layer perceptron neural network is used to classify the 2 input logical gate NAND shown in figure Q4. That is, instead of defining values less than 0 as 0, we instead define negative values as a small linear combination of the input. There are two types of Perceptrons: Single layer and Multilayer. I1, I2, H3, H4, O5are 0 (FALSE) or 1 (TRUE) t3= threshold for H3; t4= threshold for H4; t5= threshold for O5. In n dimensions, we are drawing the Perceptron: How Perceptron Model Works? This paper discusses the application of a class of feed-forward Artificial Neural Networks (ANNs) known as Multi-Layer Perceptrons(MLPs) to two vision problems: recognition and pose estimation of 3D objects from a single 2D perspective view; and handwritten digit recognition. weights = -4 1: A general quantum feed forward neural network. School DePaul University; Course Title DSC 441; Uploaded By raquelcadenap. Source: link Teaching Pages 82. that must be satisfied for an AND perceptron? A controversy existed historically on that topic for some times when the perceptron was been developed. Single layer Perceptrons can learn only linearly separable patterns. 0 < t The gradient is either 0 or 1 depending on the sign of the input. That’s why, they are very useful for binary classification studies. It is often termed as a squashing function as well. 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Decisions of several classifiers: a general quantum feed forward neural network a hidden...

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# Book:J. Willard Gibbs/Elements of Vector Analysis

## J. Willard Gibbs: Elements of Vector Analysis

Published $\text {1881}$, Privately printed.

## Historical Note

Josiah Willard Gibbs first printed his Elements of Vector Analysis in $1881$, and again in $1884$, for the benefit of his students.

Despite considerable urging, he was reluctant to publish it officially, because he felt it offered nothing original that had not already been said by others.

However, he finally consented to the pamphlet being used as the basis of a much more comprehensive work, that is, Vector Analysis, by his student Edwin Bidwell Wilson, which happened in $1901$.


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Differential expression analysis using Limma (Not on cel files)
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7.7 years ago

Hi,

Instead of using limma on cel files downloaded from GEO, I now have gene expression data for differential expression of genes under various condition (8 replicates) in txt file in following format:

Gene Name      Condition1    Condition 2 ..... Condition 8
Gene A             11.235          10.4657 ......   9.34567
Gene B             15.324           11.334  ......  16.3245

I was following this tutorial but as it uses cel files as input so I was encountering problem in fitting the linear model on my expression dataset.

Can someone guide me how I can further proceed with limma if I have data in such format?

microarray gene-expression limma • 4.4k views
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are you looking for differential expression between two conditions or relative expression of genes in each condition?

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looking for differential expression between two conditions and for each condition I have 4 replicates.

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Entering edit mode
7.7 years ago

Here is Limma tutorial for RNA-Seq or for a count matrix. Chapter 15. Here is a case study.

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Yes, log2 normalized expression values.

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Geek_y you didn't tell me what to do in case my data is already log2 normalized expression values...!!

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7.6 years ago

So, here is the solution:

library(simpleaffy)
library(limma)
setwd("path to your working directory where series_matrix_file is located")

minimalSet <- ExpressionSet(assayData=xx)
minimalSet
ex <- exprs(minimalSet)
qx <- as.numeric(quantile(ex, c(0., 0.25, 0.5, 0.75, 0.99, 1.0), na.rm=T))
LogC <- (qx[5] > 100) ||
(qx[6]-qx[1] > 50 && qx[2] > 0) ||
(qx[2] > 0 && qx[2] < 1 && qx[4] > 1 && qx[4] < 2)
if (LogC) { ex[which(ex <= 0)] <- NaN
exprs(minimalSet) <- log2(ex) }
groups<-as.factor(c(rep("Control",3),rep("Treated",3)))
groups
design<-model.matrix(~0+groups)
colnames(design)=levels(groups)
design
fit<-lmFit(minimalSet, design)
cont.matrix<-makeContrasts(Treated-Control, levels=design)
fit2<-contrasts.fit(fit, cont.matrix)
ebfit<-eBayes(fit2)
topTable(ebfit, coef=1)
nrow(topTable(ebfit, coef=1, number=25000, lfc=1))


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# Why is $\pi$ = 3.14... instead of 6.28...?

Inspired by a paper (from 2001) entitled Pi is Wrong:

Why is $\pi$ = 3.14... instead of 6.28... ?

Setting $\pi$ = 6.28 would seem to simplify many equations and constants in math and physics.

Is there an intuitive reason we relate the circumference of a circle to its diameter instead of its radius, or was it an arbitrary choice that's left us with multiplicative baggage?

• It's an arbitrary choice that's left us with multiplicative baggage. Mar 14, 2011 at 13:58
• youtube.com/watch?v=jG7vhMMXagQ Mar 14, 2011 at 14:01
• Setting pi to 6.28 would simplify things considerably. Mar 14, 2011 at 14:13
• Would you rather have $2\pi r$ and $\pi r^2$ or $\pi r$ and $\frac\pi 2 r^2$? =)
– Jens
Mar 14, 2011 at 14:55
• @Jens: The latter makes apparent the fact that area is the integral of the circumference (as well as higher-dimensional versions of this fact), $r\to \frac{1}{2}r^2$. Now that I'm used to the 'multiplicative baggage', I'd have to say I like it more, aesthetically.
– anon
Jul 13, 2011 at 6:02

For mathematicians, $2\pi$ is a more natural number than $\pi$ because this is the circumference of the circle. The value $2\pi$ appears in things related to the circle such as Fourier transforms (as the complex units form a unit circle with circumference $2\pi$). Thus the symmetric, unitary formula for the Fourier transform in terms of angular frequency $\omega$, for a function $f(x)$ is:
$$\hat{f}(\omega) = \frac{1}{\sqrt{2\pi}}\int f(x)\;e^{-i\omega x}\;dx$$ The subject has been surfacing recently, for instance see Science on MSNBC.com, June 29, 2011: "Mathematicians want to say goodbye to pi."

The original use of $\pi$ had to do with the relationship between the circular measurement of circles (their circumferences) and the straight line measurement of them (their radius or diameter). If $\pi = 3.14...$ then it is the diameter that is related to the circumference. If $\pi = 6.28...$ then it is the radius that is related.

Relating the radius to the circumference may be more convenient for modern students, but $\pi$ was defined by carpenters and other artisans. It's easier and more accurate to measure the diameter than the radius. For example, if the object is a hoop, one always measures the diameter first and from this one obtains the radius.

Given a circle (perhaps on paper) one instinctively measures its diameter by maneuvering a ruler to obtain the largest difference between opposite sides. To measure the circle's radius an additional point is required, the center of the circle. This situation is fairly common in construction. For example, if one cuts a tree in two, the diameter is easily measured whereas the radius can be measured easily only if the tree has grown and been cut symmetrically. Otherwise the center of the circle must be found by construction and this process introduces measurement error and additional possibilities for mistakes.

In short, $\pi$ is defined as: $$\pi = \frac{\textrm{circumference}}{\textrm{diameter}}$$ because of the historical fact that $\pi$ was used for practical construction.

The oldest example of a calculation that a modern person would use $\pi$ in is the Rhind Mathematical Papyrus. The papyrus includes various questions. Unfortunately none requires the computation of a circumference of a circle. However, there is a problem where one computes the volume of a cylindrical granary. In that calculation, they use the diameter of the granary (as 9), rather than the radius of the granary (i.e. 4.5). Thus the oldest evidence we have for mathematical calculation verifies that the ancients were more inclined to measure diameters than radii. And consequently, $\pi$ was naturally defined by them as the ratio of the diameter to the circumference, rather than the ratio of the radius to the circumference.

• Do you have a reference for the statement that $\pi$ was defined by carpenters and artisans? I thought geometers and carpenters were in very different social classes in Ancient Greece. Apr 1, 2011 at 8:40
• Earliest textual evidence for pi is from the Egyptians; in 1900 BC they were already approximating pi by 256/81 = 3.16. And by "carpenters" I really mean those in the construction trades in general such as masons, architects, engineers, carpenters, metal workers, etc. Among those classes, I expect that there are people fully as smart as among the geometers. Even today, higher pay for engineers, business, and practical trades in general attracts people who would have made brilliant academics. So I see no reason to believe that pi was invented by academics. Apr 2, 2011 at 0:01
• In Ancient Greece, geometry was among the liberal arts, the education for a citizen, as opposed to a worker. Even if the carpenters invented $\pi$ or $\tau$, that does not explain how the geometers of Ancient Greece came to use $\pi$. Perhaps things were very different in Egypt. Perhaps the artisans were literate there, and somehow their writings were passed on to the Greeks and then to us. Do you have a reference, or are you just saying it could have happened? Apr 2, 2011 at 2:39
• @Douglas; Geometry was invented long before the Greeks. Pythagoras studied in Babylon and Egypt. Our oldest reference to pi has to do with the amount of wheat in a silo, see: en.wikipedia.org/wiki/Rhind_Mathematical_Papyrus This is practical calculation by practical people and is a function of the diameter and height: $V = (8d/9)^2h$, rather than the radius and height (which is actually simpler with the radius i.e. $V=\pi r^2h$, but the papyrus was apparently before the use of a letter to represent $\pi$). The diameter is easier to measure for someone who goes around taxing grain. Apr 2, 2011 at 2:51
• Similarly, the bible describes a bowl by its diameter and circumference famously assuming pi=3, rather than by its radius and circumference and having a ratio of 6. I have students who could easily measure the circumference and diameter of a hoop but who would be hard put to measure the radius since the hoop doesn't exist at the center point. Apr 2, 2011 at 19:24

For those stating that $\frac{\tau}{2}r^2$ is more cumbersome than $\pi r^2$ I would like to point out that the factor of $\frac{1}{2}$ is found naturally in many equations throughout physics and goes to show a fundamental relationship between the the area of a circle and the rest of physics that we miss when we cover it up with $\pi$. For example:

$\frac{1}{2}mv^2$ = kinetic energy, where $m$ is mass and $v$ is velocity.

$\frac{1}{2}kx^2$ = potential energy stored in a spring, where $k$ is the sprint constant and $x$ is displacement.

$\frac{1}{2}at^2$ = displacement, where $a$ is acceleration and $t$ is time.

That missing factor of $\frac{1}{2}$ shows an important relationship between the area of a circle and the rest of physics, something we've been missing due to our adherence to an old way of looking at circles. We don't make circles using their diameter, regardless of how easy diameter is to measure, we make circles using the radius. When you consider that all important factor of $\frac{1}{2}$ and you use $\tau \approx (6.28)$ instead of $\pi \approx (3.14)$ the area of a circle becomes $\frac{1}{2}\tau r^2$

• Beautiful answer ! Feb 13, 2018 at 18:54

Considering that circular trigonometry is not the only one and that a class of curves can possibly be attributed an analogue of $\pi$, $2\pi$ does indeed seem to be more convenient in certain cases. Lemniscate constant plays the same role as $\pi$ for the lemniscate and since its definition is strictly analogous,i.e half length of the curve, the complimentary formula for lemniscate functions, for instance, looks like this: $$\operatorname{sinlemn} \phi = \operatorname{coslemn}\left(\frac{\tilde{\omega}}{2}-\phi'\right)$$ while it could happily do without $\frac{1}{2}$

No, $\pi$ is not wrong. But, if you prefer to use a constant that is equal to $2\pi$, you should look at the $\tau$ constant, which is exactly equal to $2\pi$. Here is a little video about it: Tau vs Pi - Numberphile

Both $\pi$ and $\tau$ denote a relation between the parameters of a circle though $\pi$ is the more researched and accepted one. The notion of $\tau$ came into existence because the definition and usage of $\pi$ seemed a little counter intuitive. Since a circle is defined as the set of points a fixed distance - the radius -from a given point, a more natural definition for the circle constant uses radius in place of diameter.

So, no $\pi$ is not wrong!!

As others have said, several people have recently made the argument that the ratio of the circumference of a circle to its radius ($2\pi$, sometimes called $\tau$) is more natural than the ratio of the circumference of a circle to its diameter ($\pi$).

In my opinion, there is still a very good argument why $\pi$ is the better choice. If perimeter is what you're interested in, there is no need to restrict your thinking to circles. If you have any convex shape of constant diameter, the ratio of its perimeter to its diameter is $\pi$ (see this wiki article). But such shapes do not in general even have a radius.

Of course, if you are interested in area, not perimeter, the above is irrelevant. But in that case surely $\pi r^2$ is a more natural formula than $\tau r^2/2$.

For some historical background:

When it because fashionable to use π in the 1700s, it was used for both 3.14 and 6.28. From Wikipedia:

Euler started using the single-letter form beginning with his 1727 Essay Explaining the Properties of Air, though he used π = 6.28..., the ratio of periphery to radius, in this and some later writing. Euler first used π = 3.14... in his 1736 work Mechanica, and continued in his widely-read 1748 work Introductio in analysin infinitorum (he wrote: "for the sake of brevity we will write this number as π; thus π is equal to half the circumference of a circle of radius 1"). Because Euler corresponded heavily with other mathematicians in Europe, the use of the Greek letter spread rapidly, and the practice was universally adopted thereafter in the Western world, though the definition still varied between 3.14... and 6.28... as late as 1761.

I've written up more about $$2\pi=\tau$$ here.


text:
These are my notes from the CJD Foundation Family Conference, held at the Washington Court Hotel in Washington, D.C. July 12-16, 2018.

### Robert G. Will - Keynote: Why do people get CJD?

When people lose a loved one to CJD, they always end up searching for an answer to one question: why did my loved one get this terrible disease? Dr. Will’s keynote today will seek to answer this question as best we can.

No one paid much attention to CJD until 50 years ago, when a seminal paper showed that the disease could be transmitted to chimpanzees [Gibbs 1968], thus suggesting that the cause of disease was a transmissible agent. Yet today we recognize that there are multiple different forms of prion disease that arise in different ways. According to the EuroCJD data, in Europe from 1993-2012, 88% of prion disease cases were sporadic, 8% were genetic, and only ~4% were acquired (iatrogenic CJD and variant CJD).

So what is sporadic CJD? Does it really arise spontaneously and randomly? Over the years, some people have hypothesized that there is an infectious origin to the disease, but the best scientific and epidemiological evidence provides no support for this idea. CJD has been reported in every country on earth that has bothered to establish any formal mechanism to look for it, meaning that if there is an infectious origin, then exposure to it has to be virtually universal worldwide. The incidence or frequency of CJD is pretty similar between all different European countries, meaning that the exposure would also have to be pretty uniform geographically. When we look at geographic distribution of CJD cases within one country, say, the U.K., we of course see clustering where there are population centers, but other than that, the distribution is random. There are instances where a number of cases have been identified in a small town [Collins 2002], which seems surprising at first, but when you consider how many small towns there are and the frequency of CJD, it is statistically inevitable that there will be some such instances just by chance [Klug 2009]. Similarly, given how often CJD occurs, it is not actually surprising that there has been one instance observed where a husband and wife both died of it [Brown 1998]. Extensive studies have failed to reveal any environmental risk factor for CJD [de Pedro Cuesta 2012], including that there appears to be no increased risk among health care workers and others who care for patients with CJD [Alcalde-Cabero 2012].

The frequency with which CJD is identified is rising steadily over time in every country that carries out surveillance. This is unlikely to be due to an increase in exposure to an infectious agent, because that increase would have to be so ubiquitous and uniformly rising everywhere, plus there is no evidence that these cases arise from exposure in the first place. Instead, it appears that two major factors contribute to the apparent increase in CJD cases: 1) aging populations meaning that a higher proportion of people are in the age range where CJD strikes, and 2) better diagnosis and reporting of CJD as surveillance networks have improved.

All told, we have no known environmental risk factors for CJD, no evidence for person-to-person spread, and no link to animal prion diseases nor to medical treatments, and the cases occur randomly in space and time. So how, then, does sporadic CJD arise? In 1995, Stanley Prusiner articulated what is now the consensus view in the prion field: that “at some point in the lives of the… individuals who acquire sporadic Creutzfeldt-Jakob disease, cellular PrP may spontaneously convert to the scrapie form”. In other words, a spontaneous and random protein misfolding event triggers a misfolding cascade that spreads across the brain.

A smaller subset of prion disease cases are genetic, and it was shown nearly 30 years ago that they are linked to mutations in the prion protein gene, PRNP [Hsiao 1989]. A key question for affected families is how high is the penetrance — the probability that a person with a mutation will eventually develop the disease. It was recognized many years ago that there are some mutations that are clearly high-risk because so many people in the same family develop the disease, while there are other mutations that are more often observed in isolated cases. A study a few years ago was able to quantify the penetrance for individual mutations and show that some mutations confer a lifetime risk of only, say, 1% or 10%, while others cause close to a 100% risk of developing disease [Minikel 2016]. That said, there is still something random about when and whether people with a particular mutation will develop disease. For instance, there have been cases of identical twins with the same mutation where one develops disease and the other develops it much later or not at all [Hamasaki 1998, Webb 2009]. It would be very useful to know what causes such variability in age of onset.

Tragically, another form of prion disease is iatrogenic CJD, meaning, that transmitted by medical procedures [Brown 2012]. This has arisen through procedures such as dura mater grafts and cadaveric human growth hormone. Thankfully it now appears that the cases from these exposure incidents have leveled off and may even be over, but we have to remain vigilant to make sure this does not happen again.

Another form of prion disease is variant CJD, which emerged in the U.K. in the mid-1990s and was seen primarily in young people (age teens through thirties), in sharp contrast to sporadic CJD [Will 1996]. Overwhelming evidence argues that this disease arose from exposure to BSE-contaminated meat. We still don’t know why those affected were predominantly young. Dr. Will suspects it might have been some combination of difference in environmental exposure (young people ate more hamburgers and hot dogs) as well as age-dependent susceptibility. Luckily, like the iatrogenic CJD epidemic, the variant CJD epidemic now seems to be waning and maybe even over.

In spite of all the evidence that sporadic CJD is random and does not arise from infection, sometimes people still feel that a particular case or combination of cases is too weird, so weird that it cannot possibly be a coincidence. But Dr. Will told a personal anecdote of an incredibly bizarre coincidence and said that coincidences really do happen, and we should be careful not to overinterpret them.

### Allison Kraus - Investigation of prion inactivation by reactive oxygen species in vivo

The alternate title of Dr. Kraus’s talk is “Can prions be stopped by a disinfectant naturally produced by the immune system?” She has been investigating the properties of reactive oxygen species (ROS) and a group of cells called neutrophils, which are considered the immune system’s first responders [Kobayashi & DeLeo 2009]. As a tool, she uses RT-QuIC, a prion detection assay [Wilham 2010] that uses the ability of misfolded prions to convert normal PrP into a fibril. Neutrophils fight pathogens by producing a number of different reactive oxygen species, including hypochlorous acid (HOCl). A couple of years ago, Dr. Byron Caughey’s lab showed that HOCl could be used as a prion disinfectant [Hughson & Race 2016].

Dr. Kraus mixed prions with neutrophils in a dish and found that the prions could stimulate the neutrophils to produce more ROS. She also used fluorescence labeling of the prions and the cell membranes and found that the neutrophils physically took up the prions. After this treatment, the amount of prion material in the dish was reduced, and this was particularly true when she used neutrophils with higher ROS production. The reduction in prions was shown by gel electrophoresis and also by RT-QuIC. Mouse studies are ongoing to see if the number of “infectious units” was also reduced. Dr. Kraus also looked at the brains of prion-infected mice and found that markers of HOCl-modified proteins are found in the same place as prion plaques are found, suggesting that HOCl naturally produced in the brain might be reacting with prions.

### Hermann Altmeppen - Investigating the potential of the neuroprotective N1 fragment of the prion protein as a new treatment against prion diseases

The alternate title of Dr. Altmeppen’s talk is “Fighting prions with the prion protein”. For years it has been known that there are cleavage events, where a protease (a “molecular scissors” — a protein that cuts other proteins) will cut prion protein. One type is shedding, where almost the full-length protein is clipped off the cell surface — this was the topic of much of Dr. Altmeppen’s previous research and his previous CJD Foundation grant [Altmeppen 2011, Altmeppen 2012, Altmeppen 2013, Altmeppen 2015]. Another type is alpha cleavage, where the protein is cut in half, so that the structured half (called the C1 fragment) stays on the cell surface and the unstructured part (called the N1 fragment) is released from the cell. Several research groups have findings that in various ways suggest that alpha cleavage might be protective [Westergard 2011, Guillot-Sestier 2012]. There has also been some research to try to figure out what protease is responsible for alpha cleavage [Liang & Kong 2012] but we don’t have a complete picture yet, and Dr. Altmeppen thinks there may be multiple proteases involved.

Dr. Altmeppen wanted to figure out whether the N1 fragment released by alpha cleavage — the unstructured part of the prion protein that is released from the cell — might be protective against prion disease. To try to investigate this, he created a new line of transgenic mice that produce a lot of N1 fragment in addition to producing normal amounts of full-length prion protein. The hope was that the transgenic mice would live much longer than normal mice when infected with prions. However, the reality turned out to be that the disease progressed exactly as quickly in the transgenic mice as it did in normal mice.

Did this mean that the hypothesis that N1 was protective was wrong? To investigate further, Dr. Altmeppen took a closer look at how much N1 fragment is produced in the cells of his transgenic mice and where it ends up. When he ground up their brains, it looked like the transgenic mice produced a ton of N1 fragment. However, when he grew their cells in culture and just looked at the media (the liquid sitting on top of the cells) without grinding up the cells, he found that there was no extra N1 fragment produced. How can this be? Last year, a study showed that many unstructured or disordered proteins are very inefficiently transported out of the cell [Gonsberg 2017]. Therefore, it might be that Dr. Altmeppen’s mice produce a lot of N1 but it gets stuck inside the cell instead of getting exported outside of the cell, where the prion protein is. To overcome this problem, Dr. Altmeppen has now made a new transgenic mouse line that has N1 fused to a sort of carrier protein that will help it get exported properly from the cell. He hopes that this mouse will enable them to see whether the N1 fragment is really protective in the brain.

### David A. Harris - Highly synergistic combination therapy for prion diseases

Dr. Harris received a CJD Foundation grant to study combination therapy for prion disease. As explained in his grant summary, his idea is that it might be effective to combine a drug targeting the replication of prions with a drug targeting the pathways that damage or kill nerve cells as a result. This builds on his previous work with a cell culture assay to discover antiprion compounds [Imberdis 2016] and is also using a cell culture model of prion neurotoxicity that his lab developed, where you can see prions causing neuronal synapses to collapse [Fang 2016].

### Carole Crozet - Innovative human 3D neural network model for the efficient propagation of human prions

As reviewed previously on this blog, studying human prions in cell culture is a tremendous challenge. Dr. Richard Knight gave an introduction to Dr. Crozet’s talk in which he noted that when listening to talks about therapeutics, it is important to pay attention to what model system has been used for the study. Among cell culture studies, many studies are done by growing just neurons in a single 2-dimensional layer on the surface of a dish. He said he is excited about Dr. Crozet’s study because it is looking to create a more authentic model by growing brain cells in a 3-dimensional cluster containing many types of cells and not just neurons.

Dr. Crozet began with an introduction to what stem cells are. They are non-differentiated, non-specialized cells with two properties: they are self-renewing (they can divide into two identical cells) and can be differentiated (into more specialized cell types). Neural stem cells are just slightly more specialized than stem cells and are a precursor that can be turned into a variety of types of brain cells. While it is generally held that neurogenesis (the birth of new neurons) occurs only in very young animals and humans, there is some evidence that the adult brain does have a limited number of neural stem cells and that new neurons can sometimes develop in the adult brain too [Alvarez-Buylla & Lim 2004, Vescovi 2006].

One theory is that the growth of new neurons might be triggered in response to neuronal injury. Dr. Crozet’s laboratory has been able to identify adult neural stem cells in the brains of prion-infected mice, and they found that these cells propagated prions [Relano-Gines 2013, Relano-Gines 2014]. This is unfortunate in that it means that instead of being protective and restorative to the brain, these adult stem cells might actually have contributed to disease. However, on the plus side, it also presents an opportunity: maybe these cells could be used to build a better model of prion disease in a dish. Indeed, a study in the Alzheimer’s disease field found that they could use neural stem cells to create 3-dimensional cultures which developed a pathology in a dish much more similar to what is seen in Alzheimer’s brains, compared to conventional 2-dimensional cultures [Choi 2014].

Therefore, Dr. Crozet and Dr. Sylvain Lehmann set out to create a 3-dimensional culture model for prion disease using neural stem cells, with funding from CJD Foundation as well as the French ANSM agency. The hope is that by making these 3-D models from humanized mice — mice with the mouse prion protein gene deleted and the human prion protein gene added in — it might be possible to model human prions in cell culture.

### Leonardo Cortez - Isolation and strain-specific characterization of pathogenic CJD prion particles

Dr. Cortez began with an introduction to the structure of misfolded prions. Prions form long, slightly twisted fibrils. We don’t know the structure at atomic resolution yet, but people have used electron microscopy to get a sense of the general shape of the prion fibrils [Sim & Caughey 2009, Vazquez-Fernandez 2016]. These studies used multiple different strains of rodent prions, but no one has done an analogous study on human prions yet. One challenge is that prion protein can misfold in more than one way, and form more than one shape. If you purify prions from the brain you will get multiple types of particles and it is hard to know which one or ones is/are the real culprit.

To be able to study CJD prions from human brain, Dr. Cortez developed a new biochemical protocol for purifying prions, and put them through a instrument that performs “asymmetric-flow field-flow fractionation” (AF4), which is a fancy way of separating microscopic or nanoscopic particles based on their size and shape and chemical properties. He is also using dynamic light scattering (DLS), which measures how particles floating around in water reflect light in order to gain information about the size and shape of the particles. So far, he has found that different strains of prions have different properties in terms of their fractionation outcomes, their particle size distribution, and their behavior in RT-QuIC, the prion detection assay mentioned earlier.

### Rodrigo Morales - Systematic evaluation of the zoonotic potential of different CWD isolates

“Zoonosis” refers to diseases making the jump from animals to humans, as in the example of BSE in cattle becoming variant CJD in humans. Epidemiological studies, such as those Dr. Bob Will spoke about this morning, are one way of determining whether an animal disease might be transmissible to humans. There are also molecular approaches to look at whether an animal protein can convert a human protein to a different shape in a laboratory setting. Dr. Morales’s talk is about these types of approaches.

Dr. Morales began by reviewing chronic wasting disease (CWD), which is the term for prion disease in deer and elk. Deer and elk belong to a family called Cervidae, or cervids. CWD has been identified in many different wild species of cervids, and laboratory experiments have suggested that most or all cervids are susceptible.

Dr. Morales’s research makes use of a laboratory technique called protein misfolding cyclic amplification (PMCA). This technique uses brain homogenates and/or purified prion protein in a test tube to amplify prion infectivity in order to detect it. Last year they found that they could use PMCA to detect CWD prions in blood even before the animals are symptomatic [Kramm 2017]. Earlier studies had also found that proteins from one species can convert proteins from another species in PMCA, including for CWD [Castilla 2008, Barria 2011]. Dr. Morales’s current work studies whether common genetic changes found in the deer population affect the ability of the deer prions to cross the species barrier in order to convert human prion protein to the misfolded form.

### Byron Caughey - Antisense oligonucleotides to delay or prevent the onset of prion disease in mice

Dr. Caughey received a CJD Foundation grant to study antisense oligonucleotides (ASOs) as therapeutics for prion disease. He previously presented on this project at the CJD Foundation Family Conference in 2016 — you can see these slides from that presentation. At that time, he described the rationale for ASOs in prion disease (which Sonia also explained in this blog post), and he showed preliminary data demonstrating the development of ASOs that lower PrP RNA in the mouse brain by ~50%.

Dr. Caughey was not able to attend the conference in person this year, so he sent a short video set against a rustic Montana backdrop, providing some background and an update on the project. He explained that ASOs are a class of drugs that consist of short sequences of chemically modified DNA that can target a particular gene sequence in order to reduce the amount of one protein. Because prion disease is caused by one protein, PrP, it is possible to design ASOs to target and lower PrP, as a therapeutic for prion disease. He explained that the Prusiner lab previously did a small study on ASOs for prion disease [Nazor Friberg 2012], which generated some promising initial data but did not ultimately lead to a drug discovery effort. Sonia and I then met with Ionis Pharmaceuticals in 2014 to rekindle the project, and we kicked off a collaboration between Ionis, our lab at the Broad Institute, and Dr. Caughey’s lab at NIH. Ionis conducted a new screen to discover ASO molecules that lower PrP, and sent some of the most promising candidates to Dr. Caughey’s lab.

In the mouse studies in Dr. Caughey’s lab, the mice received microinjections of ASOs into the brain at 60-day intervals, though in humans, an ASO drug would be given by lumbar puncture into the base of the spine. In one study, ASOs were given in a few microinjections starting before the mice were infected with prions — this model might approximate the situation of people at risk for genetic prion disease getting treatment before the onset of symptoms. These mice lived ~70% longer than untreated mice. In another study, ASOs were given later in the disease course, shortly before the onset of symptoms; these studies are ongoing but the results look encouraging so far.

Dr. Caughey said he hopes to be able to give a full update on the results soon.

### Sonia Vallabh & Eric Minikel - The path to an ASO drug for prion disease

Sonia opened by thanking CJD Foundation for the opportunity to speak about our work with Ionis Pharmaceuticals and Byron Caughey on the ASO project. She then briefly recapped our personal story — we lost Sonia’s mom to a rapidly progressive dementia in 2010, and learned after her death that it had been genetic prion disease. Sonia immediately made the decision to get tested and we learned in 2011 that she inherited her mom’s mutation. We changed careers to become scientists to work on developing a way to prevent her disease before it is too late. We are now PhD students in biology at Harvard Medical School and we are based at the Broad Institute of MIT and Harvard, where we study therapeutics for prion disease.

Sonia explained that our personal goal is to delay or prevent onset of disease altogether. Her mother progressed from first subtle symptoms, recognizable only in hindsight, to profound dementia within about 6 weeks. We certainly hope that it will be possible to intercept people on this rapid decline. But, for those people like Sonia who know their genetic status years in advance, the greatest good we can aspire to do is delay onset and extend healthy life, rather than waiting until symptoms strike before we treat.

While we have always been optimists, we are now, for the first time, optimistic about a specific therapeutic strategy: antisense oligonucleotides (ASOs) to lower prion protein in the brain. As explained in Sonia’s announcement post, ASOs as a class of drugs are showing great promise in treating neurological diseases. An ASO for spinal muscular atrophy just received FDA approval in December 2016 and has transformed the treatment of that devastating disease. Another ASO for Huntington’s disease is currently in clinical trials and has promising preliminary results showing that the causal protein (huntingtin protein, in that disease) was lowered by 40% in cerebrospinal fluid. ASO drugs are each made of the same basic building blocks — chemically modified versions of the A, C, G, and T that make up your DNA — stitched together in a different order, or sequence, to target different genes that cause different diseases. Therefore, if it’s possible to design an ASO to lower huntingtin protein by 40% in Huntington’s disease, there is no reason in principle why we shouldn’t be able to achieve the same for prion protein in prion disease. And because the molecular cause of prion disease is very well understood, we can be confident that lowering prion protein by 40% would be beneficial. Meanwhile, the success in other diseases has taught us a lot about the delivery, safety, stability, and distribution of ASO drugs. All of these aspects make this a promising route to pursue for a prion disease drug.

We showed survival curves from animal studies of ASO efficacy against prion disease. In Dr. Caughey’s lab, animals treated with ASOs starting prophylactically (before prion infection) lived ~70 - 90% longer than untreated animals. We have replicated this finding in our own lab, with treated animals living 61 - 77% longer with just two doses of ASO.

If things go well, it is possible that an ASO drug could enter clinical trials within 5 years. While we can’t count on this timeline, we do need to do everything we can to make it possible, and there is a lot we need to do now to lay the groundwork for the right trials. All past clinical trials in prion disease have focused on symptomatic patients, and that could be one route for ASOs as well. However, we know from other diseases that a drug effective at preventing disease might not be effective once the disease strikes — imagine taking a cholesterol-lowering drug at the moment you’re having a heart attack. So if we want to benefit presymptomatic patients, we need to think early about how to do clinical trials in presymptomatic patients as well.

Towards this end, we worked with CJD Foundation and CJDISA to launch the Prion Registry last year, as a place where people affected by or at risk for prion disease can find ways to participate in research and can stand up and be counted. We also launched a clinical research study at Mass General Hospital where mutation carriers and controls can donate CSF and blood for research to help us characterize biomarkers that we hope to one day use in a clinical trial in presymptomatic people.

### CJD Foundation Reports

Mayra Lichter, Marie Kassai, and Brian Appleby provided updates on CJD Foundation’s activities and grants.

CJD Foundation’s mission includes supporting families, raising awareness, educating professionals such as neurologists and funeral home directors, advocacy, and advancing research. Its budget breakdown reflects all of these priorities:

CJD Foundation achieved a major advocacy victory last year. As explained in the Milwaukee Journal-Sentinel, there was a budget proposal to eliminate the $6 million congressional line item appropriation that funds prion disease surveillance (this is awarded to CDC, which sub-awards about half of it to the surveillance center in Cleveland). But thanks to patients and families who climbed Capitol Hill and spoke to their legislators, the full amount was eventually included in the budget that passed. CJD Foundation’s grants program is expanding rapidly — it has raised$1 million in its history, but about $900,000 of that has been in just the past four years. It awarded$200,000 in grants last year and is on track to achieve the same level this year. Here is information on the funding cycle for this year’s call for proposals, which is still open (letters of intent are due August 1):

### Brian Appleby - National Prion Disease Pathology Surveillance Center (NPDPSC) overview and panel

Dr. Appleby provided an overview of the activities of the surveillance center, which include diagnostic testing, genetic testing, autopsies, physician consultation on MRI diagnostics, and collaboration with key organizations including CDC and CJD Foundation. They currently receive about 400 autopsy referrals per year, of which ~70% do turn out to be prion disease. They perform diagnostic testing on about 3,500 - 4,000 cerebrospinal fluid samples. He also discussed their priorities going forward, which include:

• Developing better diagnostic tests, including application of RT-QuIC to any and all available tissues in addition to cerebrospinal fluid.
• Assisting CDC in monitoring the threat of deer and elk prion disease (chronic wasting disease, CWD) which is now found in 24 states and is still growing. One hope is to develop a diagnostic test that would distinguish any human prion disease arising from CWD exposure from normal CJD.
• Focusing on “fringe” cases, i.e. unusual cases which may require extra attention to make sure they do not reflect an infection event.
• Increasing outreach to potential referring physicians.
• Continuing to provide resources to researchers — NPDPSC is a major source of tissue samples for research (including our research at the Broad Institute).

One important achievement of the surveillance center in the past year was the publication of a major study evaluating the transmission risk posed by skin samples from CJD patients [Orru 2017]. The study was funded in part by a CJD Foundation grant to principal investigator Wenquan Zou. See this blog post for more information.

### Kevin Keough - Alberta Prion Research Institute (APRI) Report

Dr. Keough gave an overview of the activities of APRI and its principal investigators. They have a long-running study exposing monkeys (cynomolgus macaques) to deer CWD prions, with preliminary evidence that the disease is transmissible to these monkeys, as previously reported in the news. For experimental details, see Stefanie Czub’s presentation at Prion2017.

We had to leave for the airport midway through Dr. Keough’s presentation; my notes from the rest of the talks are based on the slides handed out in the binder.

### Ryan Maddox - CDC Report

Among CDC’s activities is to monitor how common prion disease is, through analysis of death certificates, where the cause of death may be listed as prion disease. They also compare these data to the data from the prion surveillance center, where diagnostic tests and autopsies are performed. About 5% of cases with prion disease listed as cause of death on the death certificate can be ruled out as false positives based on surveillance data, but they also add in cases equaling 13% of the total when they consider cases that did not have prion disease listed as cause of death but do have positive evidence for prion disease from the surveillance center.

Based on death certificate analysis from 2003-2015, they are currently finding an incidence (number of new cases per year per population) rate of 1.2 cases per million people per year. This translates into a very low risk among young people — there were only 10 cases age <30, for an incidence of 6.2 cases per billion per year — and a higher risk among older people, with 5.9 cases per million per year among those age ≥65. Remember that incidence is an annual figure, and so these numbers do not reflect an individual’s risk of eventually developing prion disease in their lifetime. When they consider prion disease deaths as a proportion of all deaths in the U.S., they find that ~1 in 6,000 people dies of prion disease. This figure is a better estimate of lifetime risk in the general population. When you consider some of the coincidences that Bob Will talked about in his keynote, such as a husband and wife both dying of prion disease, or a number of cases occurring in one small town, you have to consider this ~1 in 6,000 figure as the relevant estimate of how common prion disease is.

Dr. Maddox also spoke about variant CJD, of which four cases have been observed in the U.S. but none are believed to have been acquired in the U.S., and CWD, for which there is still no strong epidemiological evidence for transmission to humans but the CDC is continuing to study and monitor the situation.

### Whitney R. Steele - CJD blood donor lookback study

Dr. Steele is at the American Red Cross where they are studying the potential for risk of prion disease transmission through blood transfusion. It is known that variant CJD has been transmitted by blood transfusion [Llewelyn 2004, Davidson 2014], but so far there is no evidence that sporadic CJD has ever been transmitted by blood transfusion. The Red Cross’s study likewise finds no evidence for transfusion risk in sporadic CJD. They have collected data on 71 blood donors who later died of sporadic CJD, and 894 traceable recipients of the donated blood followed for an average of several years, for a total of 4,205 person-years of follow-up. None of those individuals had CJD as a cause of death.

Update 2018-11-07: CJD Foundation has now posted YouTube videos of several of the talks.