prompt_front: Now, answer the following question based on the text below, only give me the answer and do not output any other words.

Question: What is the main methodology used in the research?

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Context 1: Paper Info

Title: On the Role of Emergent Communication for Social Learning in Multi-Agent Reinforcement Learning
Publish Date: Unkown
Author List: Seth Karten, Siva Kailas, Huao Li, Katia Sycara

Figure

Figure1 By using contrastive learning, our method seeks similar representations between the state-message pair and future states while creating dissimilar representations with random states Thus satisfying the utility objective of the information bottleneck The depicted agents are blind and cannot see other cars 
Figure 2 An example of two possible classes, person and horse, from a single observation in the Pascal VOC game 
Figure 3  Blind Traffic Junction Left: Our method uses compositional complexity and contrastive utility to outperform other baselines in terms of performance and sample complexity The legend provides the mean ± variance of the best performance Right: Top: success, contrastive, and complexity losses for our method Right, Bottom: success, autoencoder loss for ae-comm with supervised pretraining 
Figure 4  Pascal VOC Game Representing compositional concepts from raw pixel data in images to communicate multiple concepts within a single image Our method significantly outperforms ae-comm and no-comm due to our framework being able to learn composable, independent concepts 
Figure 5  Blind Traffic Junction Social shadowing enables significantly lower sample complexity when compared to traditional online MARL 
Beta ablation: Messages are naturally sparse in bits due to the complexity loss Redundancy measures the capacity for a bijection between the size of the set of unique tokens and the enumerated observations and intents Min redundancy is 1 0 (a bijection) Lower is better 

abstract

Explicit communication among humans is key to coordinating and learning  Social learning, which uses cues from experts, can greatly benefit from the usage of explicit communication to align heterogeneous policies, reduce sample complexity, and solve partially observable tasks  Emergent communication, a type of explicit communication, studies the creation of an artificial language to encode a high task-utility message directly from data 
However, in most cases, emergent communication sends insufficiently compressed messages with little or null information, which also may not be understandable to a third-party listener  This paper proposes an unsupervised method based on the information bottleneck to capture both referential complexity and task-specific utility to adequately explore sparse social communication scenarios in multi-agent reinforcement learning (MARL) 
We show that our model is able to i) develop a natural-language-inspired lexicon of messages that is independently composed of a set of emergent concepts, which span the observations and intents with minimal bits, ii) develop communication to align the action policies of heterogeneous agents with dissimilar feature models, and iii) learn a communication policy from watching an expert's action policy, which we term 'social shadowing' 

INTRODUCTION

Social learning agents analyze cues from direct observation of other agents (novice or expert) in the same environment to learn an action policy from others  However, observing expert actions may not be sufficient to coordinate with other agents  Rather, by learning to communicate, agents can better model the intent of other agents, leading to better coordination 
In humans, explicit communication for coordination assumes a common communication substrate to convey abstract concepts and beliefs directly , which may not be available for new partners  To align complex beliefs, heterogeneous agents must learn a message policy that translates from one theory of mind to another to synchronize coordination 
Especially when there is complex information to process and share, new agent partners need to learn to communicate to work with other agents  Emergent communication studies the creation of artificial language  Often phrased as a Lewis game, speakers and listeners learn a set of tokens to communicate complex observations  
However, in multi-agent reinforcement learning (MARL), agents suffer from partial observability and non-stationarity (due to unaligned value functions) , which aims to be solved with decentralized learning through communication  In the MARL setup, agents, as speakers and listeners, learn a set of tokens to communicate observations, intentions, coordination, or other experiences which help facilitate solving tasks  
Agents learn to communicate effectively through a backpropagation signal from their task performance   This has been found useful for applications in human-agent teaming , multirobot navigation , and coordination in complex games such as StarCraft II   Communication quality has been shown to have a strong relationship with task performance , leading to a multitude of work attempting to increase the representational capacity by decreasing the convergence rates  
Yet these methods still create degenerate communication protocols , which are uninterpretable due to joined concepts or null (lack of) information, which causes performance degradation  In this work, we investigate the challenges of learning a arXiv:2302 14276v1 LG] 28 Feb 2023 messaging lexicon to prepare emergent communication for social learning (EC4SL) scenarios 
We study the following hypotheses: H1) EC4SL will learn faster through structured concepts in messages leading to higher-quality solutions, H2) EC4SL aligns the policies of expert heterogeneous agents, and H3) EC4SL enables social shadowing, where an agent learns a communication policy while only observing an expert agent's action policy 
By learning a communication policy, the agent is encouraged to develop a more structured understanding of intent, leading to better coordination  The setting is very realistic among humans and many computer vision and RL frameworks may develop rich feature spaces for a specific solo task, but have not yet interacted with other agents, which may lead to failure without alignment 
We enable a compositional emergent communication paradigm, which exhibits clustering and informativeness properties  We show theoretically and through empirical results that compositional language enables independence properties among tokens with respect to referential information  Additionally, when combined with contrastive learning, our method outperforms competing methods that only ground communication on referential information 
We show that contrastive learning is an optimal critic for communication, reducing sample complexity for the unsupervised emergent communication objective  In addition to the more human-like format, compositional communication is able to create variable-length messages, meaning that we are not limited to sending insufficiently compressed messages with little information, increasing the quality of each communication 
In order to test our hypotheses, we show the utility of our method in multi-agent settings with a focus on teams of agents, high-dimensional pixel data, and expansions to heterogeneous teams of agents of varying skill levels  Social learning requires agents to explore to observe and learn from expert cues 
We interpolate between this form of social learning and imitation learning, which learns action policies directly from examples  We introduce a 'social shadowing' learning approach where we use first-person observations, rather than third-person observations, to encourage the novice to learn latently or conceptually how to communicate and develop an understanding of intent for better coordination 
The social shadowing episodes are alternated with traditional MARL during training  Contrastive learning, which works best with positive examples, is apt for social shadowing  Originally derived to enable lower complexity emergent lexicons, we find that the contrastive learning objective is apt for agents to develop internal models and relationships of the task through social shadowing 
The idea is to enable a shared emergent communication substrate (with minimal bandwidth) to enable future coordi-nation with novel partners  Our contributions are deriving an optimal critic for a communication policy and showing that the information bottleneck helps extend communication to social learning scenarios 
In real-world tasks such as autonomous driving or robotics, humans do not necessarily learn from scratch  Rather they explore with conceptually guided information from expert mentors  In particular, having structured emergent messages reduces sample complexity, and contrastive learning can help novice agents learn from experts 
Emergent communication can also align heterogeneous agents, a social task that has not been previously studied 

Multi-Agent Signaling

Implicit communication conveys information to other agents that is not intentionally communicated   Implicit signaling conveys information to other agents based on one's observable physical position   Implicit signaling may be a form of implicit communication such as through social cues or explicit communication such as encoded into the MDP through "cheap talk"  
Unlike implicit signaling, explicit signaling is a form of positive signaling that seeks to directly influence the behavior of other agents in the hopes that the new information will lead to active listening  Multi-agent emergent communication is a type of explicit signaling which deliberately shares information 
Symbolic communication, a subset of explicit communication, seeks to send a subset of pre-defined messages  However, these symbols must be defined by an expert and do not scale to particularly complex observations and a large number of agents  Emergent communication aims to directly influence other agents with a learned subset of information, which allows for scalability and interpretability by new agents 

Emergent Communication

Several methodologies currently exist to increase the informativeness of emergent communication  With discrete and clustered continuous communication, the number of observed distinct communication tokens is far below the number permissible   As an attempt to increase the emergent "vocabulary" and decrease the data required to converge to an informative communication "language", work has added a bias loss to emit distinct tokens in different situations  
More recent work has found that the sample efficiency can be further improved by grounding communication in observation space with a supervised reconstruction loss   Information-maximizing autoencoders aim to maximize the state reconstruction accuracy for each agent  How-ever, grounding communication in observations has been found to easily satisfy these input-based objectives while still requiring a myriad more samples to explore to find a task-specific communication space  
Thus, it is necessary to use task-specific information to communicate informatively  This will enable learned compression for task completion rather than pure compression for input recovery  Other work aims to use the information bottleneck to decrease the entropy of messages   In our work, we use contrastive learning to increase representation similarity with future goals, which we show optimally optimizes the Q-function for messages 

Natural Language Inspiration

The properties of the tokens in emergent communication directly affect their informative ability  As a baseline, continuous communication tokens can represent maximum information but lack human-interpretable properties  Discrete 1-hot (binary vector) tokens allow for a finite vocabulary, but each token contains the same magnitude of information, with equal orthogonal distance to each other token 
Similar to word embeddings in natural language, discrete prototypes are an effort to cluster similar information together from continuous vectors   Building on the continuous word embedding properties, VQ-VIB , an information-theoretic observation grounding based on VQ-VAE properties , uses variational properties to provide word embedding properties for continuous emergent tokens 
Like discrete prototypes, they exhibit a clustering property based on similar information but are more informative  However, each of these message types determines a single token for communication  Tokens are stringed together to create emergent "sentences" 

Preliminaries

We formulate our setup as a decentralized, partially observable Markov Decision Process with communication (Dec-POMDP-Comm)  Formally, our problem is defined by the tuple, S, A, M, T , R, O, Ω, γ   We define S as the set of states, A i , i ∈ [1, N ] as the set of actions, which includes task-specific actions, and M i as the set of communications for N agents 
T is the transition between states due to the multi-agent joint action space T : S × A 1 ,    , A N → S  Ω defines the set of observations in our partially observable setting  Partial observability requires communication to complete the tasks successfully  O i : M 1 ,    , M N × Ŝ → Ω maps the communications and local state, Ŝ, to a distribution of observations for each agent 
R defines the reward function and γ defines the discount factor 

Architecture

The policy network is defined by three stages: Observation Encoding, Communication, and Action Decoding  The best observation encoding and action decoding architecture is task-dependent, i e , using multi-layer perceptrons (MLPs), CNNs , GRUs , or transformer layers are best suited to different inputs 
The encoder transforms observation and any sequence or memory information into an encoding H  The on-policy reinforcement learning training uses RE-INFORCE or a decentralized version of MAPPO as specified by our experiments  Our work focuses on the communication stage, which can be divided into three substages: message encoding, message passing (often considered sparse communication), and message decoding 
We use the message passing from   For message decoding, we build on a multiheaded attention framework, which allows an agent to learn which messages are most important   Our compositional communication framework defines the message encoding, as described in section 4 

Objective

Mutual information, denoted as I(X; Y ), looks to measure the relationship between random variables, which is often measured through Kullback-Leibler divergence , I(X; Y ) = D KL (p(x, y)||p(x) ⊗ p(y))  The message encoding substage can be defined as an information bottleneck problem, which defines a tradeoff between the complexity of information (compression, I(X, X)) and the preserved relevant information (utility, I( X, Y )) 
The deep variational information bottleneck defines a trade-off between preserving useful information and compression   We assume that our observation and memory/sequence encoder provides an optimal representation H i suitable for sharing relevant observation and intent/coordination information  We hope to recover a representation Y i , which contains the sufficient desired outputs 
In our scenario, the information bottleneck is a trade-off between the complexity of information I(H i ; M i ) (representing the encoded information exactly) and representing the relevant information I(M j =i ; Y i ), which is signaled from our contrastive objective  In our setup, the relevant information flows from other agents through communication, signaling a combination of the information bottleneck and a Lewis game 
We additionally promote complexity through our compositional independence objective, This is formulated by the following Lagrangian, where the bounds on mutual information Î are defined in equations 1, 2, and 10  Overall, our objective is,

Complexity through Compositional Communication

We aim to satisfy the complexity objective, I(H i , M i ), through compositional communication  In order to induce complexity in our communication, we want the messages to be as non-random as possible  That is, informative with respect to the input hidden state h  In addition, we want each token within the message to share as little information as possible with the preceding tokens 
Thus, each additional token adds only informative content  Each token has a fixed length in bits W   The total sequence is limited by a fixed limit, L l W l ≤ S, of S bits and a total of L tokens  We use a variational message generation setup, which maps the encoded hidden state h to a message m; that is, we are modeling the posterior, π i m (m l |h) 
We limit the vocabulary size to K tokens, e j ∈ R D , j ∈ [1, K] ⊂ N, where each token has dimensionality D and l ∈ [1, L] ⊂ N  Each token m l is sampled from a categorical posterior distribution, 0 otherwise such that the message m l is mapped to the nearest neighbor e j   A set of these tokens makes a message m 
To satisfy the complexity objective, we want to use m i to well-represent h i and consist of independently informative m i l  

Independent Information

We derive an upper bound for the interaction information between all tokens  Proposition 4 1  For the interaction information between all tokens, the following upper bound holds: The proof is in Appendix A 1  Since we want the mutual information to be minimized in our objective, we minimize,

Input-Oriented Information

In order to induce complexity in the compositional messages, we additionally want to minimize the mutual information I(H; M ) between the composed message m and the encoded information h  We derive an upper bound on the mutual information that we use as a Lagrangian term to minimize  Proposition 4 2  For the mutual information between the composed message and encoded information, the following upper bound holds:
The proof is in Appendix A 1  Thus, we have our Lagrangian term, Conditioning on the input or observation data is a decentralized training objective 

Sequence Length

Compositional communication necessitates an adaptive limit on the total length of the sequence  Corollary 4 3  Repeat tokens, w, are redundant and can be removed  Suppose one predicts two arbitrary tokens, w k and w l   Given equation 1, it follows that there is low or near-zero mutual information between w k and w l  
A trivial issue is that the message generator will predict every available token as to follow the unique token objective  Since the tokens are imbued with input-oriented information (equation 2), the predicted tokens will be based on relevant referential details  Thus, it follows that tokens containing irrelevant information will not be chosen 
A nice optimization objective that follows from corollary 4 3 is that one can use self-supervised learning with an end-ofsequence (EOS) token to limit the variable total length of compositional message sequences  (3) Algorithm 1 Compositional Message Gen (h t ) m i ∼ N ( ĥ; µ, σ) 9: end for 10: return m

Message Generation Architecture

Now, we can define the pipeline for message generation  The idea is to create an architecture that can generate features to enable independent message tokens  We expand each compressed token into the space of the hidden state h (1-layer linear expansion) since each token has a natural embedding in R |h|  
Then, we perform attention using a softmin to help minimize similarity with previous tokens and sample the new token from a variational distribution  See algorithm 1 for complete details  During execution, we can generate messages directly due to equation 1, resolving any computation time lost from sequential compositional message generation 

Utility through Contrastive Learning

First, note that our Markov Network is as follows: H j → M j → Y i ← H i   Continue to denote i as the agent identification and j as the agent ID such that j = i  We aim to satisfy the utility objective of the information bottleneck, I(M j ; Y i ), through contrastive learning as shown in figure 1  Proposition 5 1 
Utility mutual information is lower bounded by the contrastive NCE-binary objective, The proof is in Appendix A 1  This result shows a need for gradient information to flow backward across agents along communication edge connections 

Experiments and Results

We condition on inputs, especially rich information (such as pixel data), and task-specific information  When evaluating an artificial language in MARL, we are interested in referential tasks, in which communication is required to complete the task  With regard to intent-grounded communication, we study ordinal tasks, which require coordination information between agents to complete successfully 
Thus, we consider tasks with a team of agents to foster messaging that communicates coordination information that also includes their observations  To test H1, structuring emergent messages enables lower complexity, we test our methodology and analyze the input-oriented information and utility capabilities 
Next, we analyze the ability of heterogeneous agents to understand differing communication policies (H2))  Finally, we consider the effect of social shadowing (H3), in which agents solely learn a communication policy from an expert agent's action policy  We additionally analyze the role of offline reinforcement learning for emergent communication in combination with online reinforcement learning to further learn emergent communication alongside an action policy 
We evaluate each scenario over 10 seeds 

Environments

Blind Traffic Junction We consider a benchmark that requires both referential and ordinal capabilities within a team of agents  The blind traffic junction environment requires multiple agents to navigate a junction without any observation of other agents  Rather, they only observe their own state location 
Ten agents must coordinate to traverse through the lanes without colliding into agents within their lane or in the junction  Our training uses REINFORCE   Pascal VOC Game We further evaluate the complexity of compositional communication with a Pascal VOC   This is a two-agent referential game similar to the Cifar game but requires the prediction of multiple classes 
During each episode, each agent observes a random image from the Pascal VOC dataset containing exactly two unique labels  Each agent must encode information given only the raw pixels from the original image such that the other agent can recognize the two class labels in the original image  An agent receives a reward of 0 25 per correctly chosen class label and will receive a total reward of 1 if both agents guess all labels correctly 
See figure 2  Our training uses heterogeneous agents trained with PPO (modified from MAPPO repository)  For simplicity of setup, we consider images with exactly two unique labels from a closed subset of size five labels of the original set of labels from the Pascal VOC data  Furthermore, these images must be of size 375 × 500 pixels 
Thus, the resultant dataset comprised 534 unique images from the Pascal VOC dataset 

Baselines

To evaluate our methodology, we compare our method to the following baselines: (1) no-comm, where agents do not communicate; (2) rl-comm, which uses a baseline communication method learned solely through policy loss ; (3) ae-comm, which uses an autoencoder to ground communication in input observations ; (4) VQ-VIB, which uses a variational autoencoder to ground discrete communication in input observations and a mutual information objective to ensure low entropy communication  
We provide an ablation of the loss parameter β in table 1 in the blind traffic junction scenario  When β = 0, we use our compositional message paradigm without our derived loss terms  We find that higher complexity and independence losses increase sample complexity  When β = 1, the model was unable to converge 
However, when there is no regularization loss, the model performs worse (with no guarantees about referential representation)  We attribute this to the fact that our independence criteria learns a stronger causal relationship  There are fewer spurious features that may cause an agent to take an incorrect action 
In order to understand the effect of the independent concept representation, we analyze the emergent language's capacity for redundancy  A message token m l is redundant if there exists another token m k that represents the same information  With our methodology, the emergent 'language' converges to the exact number of observations and intents required to solve the task 
With a soft discrete threshold, the independent information loss naturally converges to a discrete number of tokens in the vocabulary  Our β ablation in table 1 yields a bijection between each token in the vocabulary and the possible emergent concepts, i e , the enumerated observations and intents  Thus for β = 0 1, there is no redundancy 
Sparse Communication In corollary 4 3, we assume that there is no mutual information between tokens  In practice, the loss may only be near-zero  Our empirical results yield independence loss around 1e − 4  In table 1, the size of the messages is automatically compressed to the smallest size to represent the information 
Despite a trivially small amount of mutual information between tokens, our compositional method is able to reduce the message size in bits by 2 3x using our derived regularization, for a total of an 8x reduction in message size over non-compositional methods such as ae-comm  Since the base unit for the token is a 32-bit float, we note that each token in the message may be further compressed 
We observe that each token uses three significant digits, which may further compress tokens to 10 bits each for a total message length of 20 bits 

Communication Utility Results

Due to coordination in MARL, grounding communication in referential features is not enough  Finding the communication utility requires grounding messages in ordinal information  Overall, figure shows that our compositional, contrastive method outperforms all methods focused on solely input-oriented communication grounding 
In the blind traffic junction, our method yields a higher average task success rate and is able to achieve it with a lower sample complexity  Training with the contrastive update tends to spike to high success but not converge, often many episodes before convergence, which leaves area for training improvement 
That is, the contrastive update begins to find aligned latent spaces early in training, but it cannot adapt the methodology quickly enough to converge  The exploratory randomness of most of the early online data prevents exploitation of the high utility f + examples  This leaves further room for improvement for an adaptive contrastive loss term 
Regularization loss convergence After convergence to high task performance, the autoencoder loss increases in order to represent the coordination information  This follows directly from the information bottleneck, where there exists a tradeoff between utility and complexity  However, communication, especially referential communication, should have an overlap between utility and complexity 
Thus, we should seek to make the complexity loss more convex  Our compositional communication complexity loss does not converge before task performance convergence  While the complexity loss tends to spike in the exploratory phase, the normalized value is very small  Interestingly, the method eventually converges as the complexity loss converges below a normal- ized 0 3 
Additionally, the contrastive loss tends to decrease monotonically and converges after the task performance converges, showing a very smooth decrease  The contrastive f − loss decreases during training, which may account for success spikes prior to convergence  The method is able to converge after only a moderate decrease in the f + loss 
This implies empirical evidence that the contrastive loss is an optimal critic for messaging  See figure 3 

Heterogeneous Alignment Through Communication

In order to test the heterogeneous alignment ability of our methodology to learn higher-order concepts from highdimensional data, we analyze the performance on the Pascal VOC game  We compare our methodology against ae-comm to show that concepts should consist of independent information directly from task signal rather than compression to reconstruct inputs 
That is, we show an empirical result on pixel data to verify the premise of the information bottleneck  Our methodology significantly outperforms the observation-grounded ae-comm baseline, as demonstrated by figure 4  The ae-comm methodology, despite using autoencoders to learn observation-grounded communication, performs only slightly better than no-comm 
On the other hand, our methodology is able to outperform both baselines significantly  It is important to note that based on figure 4, our methodology is able to guess more than two of the four labels correctly across the two agents involved, while the baseline methodologies struggle to guess exactly two of thew four labels consistently 
This can be attributed to our framework being able to learn compositional concepts that are much more easily discriminated due to mutual independence 

Social Shadowing

Critics of emergent communication may point to the increased sample complexity due to the dual communication and action policy learning  In the social shadowing scenario, heterogeneous agents can learn to generate a communication policy without learning the action policy of the watched expert agents  To enable social shadowing, the agent will alternate between a batch of traditional MARL (no expert) and (1st-person) shadowing an expert agent performing the task in its trajectory 
The agent only uses the contrastive objective to update its communication policy during shadowing  In figure , the agent that performs social shadowing is able to learn the action policy with almost half the sample complexity required by the online reinforcement learning agent  Our results show that the structured latent space of the emergent communication learns socially benevolent coordination 
This tests our hypothesis that by learning communication to understand the actions of other agents, one can enable lower sample complexity coordination  Thus, it mitigates the issues of solely observing actions 

Discussion

By using our framework to better understand the intent of others, agents can learn to communicate to align policies and coordinate  Any referential-based setup can be performed with a supervised loss, as indicated by the instant satisfaction of referential objectives  Even in the Pascal VOC game, which appears to be a purely referential objective, our results show that intelligent compression is not the only objective of referential communication 
The emergent communication paradigm must enable an easy-to-discriminate space for the game  In multi-agent settings, the harder challenge is to enable coordination through communication  Using contrastive communication as an optimal critic aims to satisfy this, and has shown solid improvements  Since contrastive learning benefits from good examples, this method is even more powerful when there is access to examples from expert agents 
In this setting, the communication may be bootstrapped, since our optimal critic has examples with strong signals from the 'social shadowing' episodes  Additionally, we show that the minimization of our independence objective enables tokens that contain minimal overlapping information with other tokens 
Preventing trivial communication paradigms enables higher performance  Each of these objectives is complementary, so they are not trivially minimized during training, which is a substantial advantage over comparative baselines  Unlike prior work, this enables the benefits of training with reinforcement learning in multi-agent settings 
In addition to lower sample complexity, the mutual information regularization yields additional benefits, such as small messages, which enables the compression aspect of sparse communication  From a qualitative point of view, the independent information also yields discrete emergent concepts, which can be further made human-interpretable by a post-hoc analysis  
This is a step towards white-box machine learning in multi-agent settings  The interpretability of this learned white-box method could be useful in human-agent teaming as indicated by prior work   The work here will enable further results in decision-making from high-dimensional data with emergent concepts 
The social scenarios described are a step towards enabling a zero-shot communication policy  This work will serve as future inspiration for using emergent communication to enable ad-hoc teaming with both agents and humans 

Appendix

A 1  Proofs Proposition 4 1 For the interaction information between all tokens, the following upper bound holds: Proof  Starting with the independent information objective, we want to minimize the interaction information, which defines the conditional mutual information between each token and, Let π i m (m l |h) be a variational approximation of p(m l |h), which is defined by our message encoder network 
Given that each token should provide unique information, we assume independence between m l   Thus, it follows that our compositional message is a vector, m = [m 1 ,       , m L ], and is jointly Gaussian  Moreover, we can define q( m|h) as a variational approximation to p(m|h) = p(m 1 ;       , m L |h) 
We can model q with a network layer and define its loss as || m − m|| 2   Thus, transforming equation 4 into variational form, we have, it follows that q( m|h) log q( m|h)d m ≥ q( m|h) log Thus, we can bound our interaction information, Proposition 4 2 For the mutual information between the composed message and encoded information, the following upper bound holds:
Proof  By definition of mutual information between the composed messages M and the encoded observations H, we have, Substituting q( m|h) for p( m|h), the same KL Divergence identity, and defining a Gaussian approximation z( m) of the marginal distribution p( m), it follows that, In expectation of equation 1, we have,
This implies that, for m = [m 1 ,       , m L ], there is probabilistic independence between m j , m k , j = k  Thus, expanding, it follows that, where z(m l ) is a standard Gaussian  Proposition 5 1  Utility mutual information is lower bounded by the contrastive NCE-binary objective, Proof  We suppress the reliance on h since this is directly passed through 
By definition of mutual information, we have, Our network model learns π R + (y|m) from rolled-out trajectories, R + , using our policy  The prior of our network state, π R − (y), can be modeled from rolling out a random trajectory, R−  Unfortunately, it is intractable to model π R + (y|m) and π R − (y) directly during iterative learning, but we can sample y + ∼ π R + (y|m) and y − ∼ π R − (y) directly from our network during training 
It has been shown that log p(y|m) provides a bound on mutual information , with the expectation over l p(m l , y l )  However, we need a tractable understanding of the information Y   In the information bottleneck, Y represents the desired outcome  In our setup, y is coordination information that helps create the desired output, such as any action a −  
This implies, y =⇒ a −   Since the transition is known, it follows that a − =⇒ s − f , a random future state  Thus, we have, π This is similar to the proof for lemma A 5, but requires assumptions on messages m from the emergent language  We note that when m is random, the case defaults to lemma A 5  Thus, we assume we have at least input-oriented information in m given sufficiently satisfying equation 2  Given a sufficient emergent language, it follows that y =⇒ a + , where a + is an intention action based on m 
Similarly, since the transition is known, a + =⇒ s + f , a desired goal state along the trajectory  Thus, we have, π R + (y|m) = p(s = s + f |y, m)  Recall the following (as shown in ), which we have adapted to our communication objective, Proposition A 3 (rewards → probabilities)  The Q-function for the goal-conditioned reward function r g (s t , m t ) = (1 − γ)p(s = s g |y t ) is equivalent to the probability of state s g under the discounted state occupancy measure:
and Lemma A 4  The critic function that optimizes equation 8 is a Q-function for the goal-conditioned reward function up to a multiplicative constant 1 The critic function f (s, m, s f ) = y enc(s f ) represents the similarity between the encoding y = enc(s, m) and the encoding of the future rollout s f  
Given lemmas A 5 A 6 A 8 and proposition A 7, it follows that equation 8 is the NCE-binary (InfoMAX ) objective, Î(M j , Y i ) = log σ(f (s, m, s + f )) + log 1 − σ(f (s, m, s − f )) which lower bounds the mutual information, I(M j , Y i ) ≥ Î(M j , Y i )  The critic function is unbounded, so we constrain it to [0, 1] with the sigmoid function, σ( * ) 
We suppress the reliance on h since this is directly passed through  By definition of mutual information, we have, Our network model learns π R + (y|m) from rolled-out trajectories, R + , using our policy  The prior of our network state, π R − (y), can be modeled from rolling out a random trajectory, R− 
Unfortunately, it is intractable to model π R + (y|m) and π R − (y) directly during iterative learning, but we can sample y + ∼ π R + (y|m) and y − ∼ π R − (y) directly from our network during training  It has been shown that log p(y|m) provides a bound on mutual information , with the expectation over l p(m l , y l ) 
However, we need a tractable understanding of the information Y   Lemma A 5  π R − (y) = p(s = s − f |y)  In the information bottleneck, Y represents the desired outcome  In our setup, y is coordination information that helps create the desired output, such as any action a −   This implies, y =⇒ a −   Since the transition is known, it follows that a − =⇒ s − f , a random future state 
Thus, we have, π R − (y) = p(s = s − f |y)  Lemma A 6  π R + (y|m) = p(s = s + f |y, m)  This is similar to the proof for lemma A 5, but requires assumptions on messages m from the emergent language  We note that when m is random, the case defaults to lemma A 5  Thus, we assume we have at least input-oriented information in m given sufficiently satisfying equation 2  Given a sufficient emergent language, it follows that y =⇒ a + , where a + is an intention action based on m 
Similarly, since the transition is known, a + =⇒ s + f , a desired goal state along the trajectory  Thus, we have, π R + (y|m) = p(s = s + f |y, m)  Recall the following (as shown in ), which we have adapted to our communication objective, Proposition A 7 (rewards → probabilities)  The Q-function for the goal-conditioned reward function r g (s t , m t ) = (1 − γ)p(s = s g |y t ) is equivalent to the probability of state s g under the discounted state occupancy measure:
and Lemma A 8  The critic function that optimizes equation 8 is a Q-function for the goal-conditioned reward function up to a multiplicative constant 1 p(s f ) : exp(f * (s, m, s f ) = 1 p(s f ) Q π s f (s, m)  The critic function f (s, m, s f ) = y enc(s f ) represents the similarity between the encoding y = enc(s, m) and the encoding of the future rollout s f  
Given lemmas A 5 A 6 A 8 and proposition A 7, it follows that equation 8 is the NCE-binary (InfoMAX ) objective, which lower bounds the mutual information, I(M j , Y i ) ≥ Î(M j , Y i )  The critic function is unbounded, so we constrain it to [0, 1] with the sigmoid function, σ( * ) 
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This article is about the family of vitamers  For vitamin K1 the form usually used as a supplement, see Phytomenadione 
Vitamin K structures  MK-4 and MK-7 are both subtypes of K2 
Vitamin K deficiency, Warfarin overdose
Vitamin K is a group of structurally similar, fat-soluble vitamins the human body requires for complete synthesis of certain proteins that are prerequisites for blood coagulation and which the body also needs for controlling binding of calcium in bones and other tissues  The vitamin K-related modification of the proteins allows them to bind calcium ions, which they cannot do otherwise  Without vitamin K, blood coagulation is seriously impaired, and uncontrolled bleeding occurs  Low levels of vitamin K also weaken bones and promote calcification of arteries and other soft tissues[citation needed] 
Chemically, the vitamin K family comprises 2-methyl-1,4-naphthoquinone (3-) derivatives  Vitamin K includes two natural vitamers: vitamin K1 and vitamin K2 [1] Vitamin K2, in turn, consists of a number of related chemical subtypes, with differing lengths of carbon side chains made of isoprenoid groups of atoms 
Vitamin K1, also known as phylloquinone, is made by plants, and is found in highest amounts in green leafy vegetables because it is directly involved in photosynthesis  It may be thought of as the plant form of vitamin K  It is active as a vitamin in animals and performs the classic functions of vitamin K, including its activity in the production of blood-clotting proteins  Animals may also convert it to vitamin K2 
Bacteria in the gut flora can also convert K1 into vitamin K2  In addition, bacteria typically lengthen the isoprenoid side chain of vitamin K2 to produce a range of vitamin K2 forms, most notably the MK-7 to MK-11 homologues of vitamin K2  All forms of K2 other than MK-4 can only be produced by bacteria, which use these forms in anaerobic respiration  The MK-7 and other bacterially derived forms of vitamin K2 exhibit vitamin K activity in animals, but MK-7's extra utility over MK-4, if any, is unclear and is a matter of investigation 
Three synthetic types of vitamin K are known: vitamins K3, K4, and K5  Although the natural K1 and all K2 homologues and synthetic K4 and K5 have proven nontoxic, the synthetic form K3 (menadione) has shown toxicity [2]
1 2 Cardiovascular health
1 4 Coumarin poisoning
4 1 Conversion of vitamin K1 to vitamin K2
4 2 Vitamin K2
6 Absorption and dietary need
7 Dietary reference intake
10 Biochemistry
10 1 Function in animals
10 2 Gamma-carboxyglutamate proteins
10 3 Methods of assessment
10 4 Function in bacteria
11 Injection in newborns
11 3 Controversy
A review of 2014 concluded that there is positive evidence that monotherapy using MK-4, one of the forms of Vitamin K2, reduces fracture incidence in post-menopausal women with osteoporosis, and suggested further research on the combined use of MK-4 with bisphosphonates  In contrast, an earlier review article of 2013 concluded that there is no good evidence that vitamin K supplementation helps prevent osteoporosis or fractures in postmenopausal women [3]
A Cochrane systematic review of 2006 suggested that supplementation with Vitamin K1 and with MK4 reduces bone loss; in particular, a strong effect of MK-4 on incident fractures among Japanese patients was emphasized [4]
A review article of 2016 suggested to consider, as one of several measures for bone health, increasing the intake of foods rich in vitamins K1 and K2 [5]
Cardiovascular health[edit]
Adequate intake of vitamin K is associated with the inhibition of arterial calcification and stiffening,[6] but there have been few interventional studies and no good evidence that vitamin K supplementation is of any benefit in the primary prevention of cardiovascular disease [7]
One 10-year population study, the Rotterdam Study, did show a clear and significant inverse relationship between the highest intake levels of menaquinone (mainly MK-4 from eggs and meat, and MK-8 and MK-9 from cheese) and cardiovascular disease and all-cause mortality in older men and women [8]
Vitamin K has been promoted in supplement form with claims it can slow tumor growth; there is however no good medical evidence that supports such claims [9]
Coumarin poisoning[edit]
Vitamin K is part of the suggested treatment regime for poisoning by rodenticide (coumarin poisoning) [10]
Although allergic reaction from supplementation is possible, no known toxicity is associated with high doses of the phylloquinone (vitamin K1) or menaquinone (vitamin K2) forms of vitamin K, so no tolerable upper intake level (UL) has been set [11]
Blood clotting (coagulation) studies in humans using 45 mg per day of vitamin K2 (as MK-4)[12] and even up to 135 mg per day (45 mg three times daily) of K2 (as MK-4),[13] showed no increase in blood clot risk  Even doses in rats as high as 250 mg/kg, body weight did not alter the tendency for blood-clot formation to occur [14]
Unlike the safe natural forms of vitamin K1 and vitamin K2 and their various isomers, a synthetic form of vitamin K, vitamin K3 (menadione), is demonstrably toxic at high levels  The U S  FDA has banned this form from over-the-counter sale in the United States because large doses have been shown to cause allergic reactions, hemolytic anemia, and cytotoxicity in liver cells [2]
Phylloquinone (K1)[15][16] or menaquinone (K2) are capable of reversing the anticoagulant activity of the anticoagulant warfarin (tradename Coumadin)  Warfarin works by blocking recycling of vitamin K, so that the body and tissues have lower levels of active vitamin K, and thus a deficiency of vitamin K 
Supplemental vitamin K (for which oral dosing is often more active than injectable dosing in human adults) reverses the vitamin K deficiency caused by warfarin, and therefore reduces the intended anticoagulant action of warfarin and related drugs [17] Sometimes small amounts of vitamin K are given orally to patients taking warfarin so that the action of the drug is more predictable [17] The proper anticoagulant action of the drug is a function of vitamin K intake and drug dose, and due to differing absorption must be individualized for each patient [citation needed] The action of warfarin and vitamin K both require two to five days after dosing to have maximum effect, and neither warfarin or vitamin K shows much effect in the first 24 hours after they are given [18]
The newer anticoagulants dabigatran and rivaroxaban have different mechanisms of action that do not interact with vitamin K, and may be taken with supplemental vitamin K [19][20]
Vitamin K2 (menaquinone)  In menaquinone, the side chain is composed of a varying number of isoprenoid residues  The most common number of these residues is four, since animal enzymes normally produce menaquinone-4 from plant phylloquinone 
A sample of phytomenadione for injection, also called phylloquinone
The three synthetic forms of vitamin K are vitamins K3 (menadione), K4, and K5, which are used in many areas, including the pet food industry (vitamin K3) and to inhibit fungal growth (vitamin K5) [21]
Conversion of vitamin K1 to vitamin K2[edit]
Vitamin K1 (phylloquinone) – both forms of the vitamin contain a functional naphthoquinone ring and an aliphatic side chain  Phylloquinone has a phytyl side chain 
The MK-4 form of vitamin K2 is produced by conversion of vitamin K1 in the testes, pancreas, and arterial walls [22] While major questions still surround the biochemical pathway for this transformation, the conversion is not dependent on gut bacteria, as it occurs in germ-free rats[23][24] and in parenterally-administered K1 in rats [25][26] In fact, tissues that accumulate high amounts of MK-4 have a remarkable capacity to convert up to 90% of the available K1 into MK-4 [27][28] There is evidence that the conversion proceeds by removal of the phytyl tail of K1 to produce menadione as an intermediate, which is then condensed with an activated geranylgeranyl moiety (see also prenylation) to produce vitamin K2 in the MK-4 (menatetrione) form [29]
Vitamin K2[edit]
Main article: Vitamin K2
Vitamin K2 (menaquinone) includes several subtypes  The two subtypes most studied are menaquinone-4 (menatetrenone, MK-4) and menaquinone-7 (MK-7) 
Vitamin K1, the precursor of most vitamin K in nature, is a stereoisomer of phylloquinone, an important chemical in green plants, where it functions as an electron acceptor in photosystem I during photosynthesis  For this reason, vitamin K1 is found in large quantities in the photosynthetic tissues of plants (green leaves, and dark green leafy vegetables such as romaine lettuce, kale and spinach), but it occurs in far smaller quantities in other plant tissues (roots, fruits, etc )  Iceberg lettuce contains relatively little  The function of phylloquinone in plants appears to have no resemblance to its later metabolic and biochemical function (as "vitamin K") in animals, where it performs a completely different biochemical reaction 
Vitamin K (in animals) is involved in the carboxylation of certain glutamate residues in proteins to form gamma-carboxyglutamate (Gla) residues  The modified residues are often (but not always) situated within specific protein domains called Gla domains  Gla residues are usually involved in binding calcium, and are essential for the biological activity of all known Gla proteins [30]
At this time[update], 17 human proteins with Gla domains have been discovered, and they play key roles in the regulation of three physiological processes:
Blood coagulation: prothrombin (factor II), factors VII, IX, and X, and proteins C, S, and Z[31]
Bone metabolism: osteocalcin, also called bone Gla protein (BGP), matrix Gla protein (MGP),[32] periostin,[33] and the recently discovered Gla-rich protein (GRP) [34][35]
Vascular biology: growth arrest-specific protein 6 (Gas6)[36]
Unknown function: proline-rich γ-carboxyglutamyl proteins (PRGPs) 1 and 2, and transmembrane γ-carboxy glutamyl proteins (TMGs) 3 and 4 [37]
Like other lipid-soluble vitamins (A, D and E), vitamin K is stored in the fatty tissue of the human body 
Absorption and dietary need[edit]
Previous theory held that dietary deficiency is extremely rare unless the small intestine was heavily damaged, resulting in malabsorption of the molecule  Another at-risk group for deficiency were those subject to decreased production of K2 by normal intestinal microbiota, as seen in broad spectrum antibiotic use [38] Taking broad-spectrum antibiotics can reduce vitamin K production in the gut by nearly 74% in people compared with those not taking these antibiotics [39] Diets low in vitamin K also decrease the body's vitamin K concentration [40] Those with chronic kidney disease are at risk for vitamin K deficiency, as well as vitamin D deficiency, and particularly those with the apoE4 genotype [41] Additionally, in the elderly there is a reduction in vitamin K2 production [42]
The National Academy of Medicine (NAM) updated an estimate of what constitutes an adequate intake (AI) for vitamin K in 2001  The NAM does not distinguish between K1 and K2 – both are counted as vitamin K  At that time there was not sufficient evidence to set the more rigorous estimated average requirement (EAR) or recommended dietary allowance (RDA) given for most of the essential vitamins and minerals  The current daily AIs for vitamin K for adult women and men are 90 μg and 120 μg respectively  The AI for pregnancy and lactation is 90 μg  For infants up to 12 months the AI is 2–2 5 μg, and for children aged 1 to 18 years the AI increases with age from 30 to 75 μg  As for safety, the FNB also sets tolerable upper intake levels (known as ULs) for vitamins and minerals when evidence is sufficient  In the case of vitamin K no UL is set, as evidence for adverse effects is not sufficient  Collectively EARs, RDAs, AIs and ULs are referred to as dietary reference intakes [43] The European Food Safety Authority reviewed the same safety question and did not set an UL [44]
For U S  food and dietary supplement labeling purposes, the amount in a serving is expressed as a percentage of daily value (%DV)  For vitamin K labeling purposes the daily value was 80 μg, but as of May 2016 it has been revised upwards to 120 μg  A table of the pre-change adult daily values is provided at reference daily intake  Food and supplement companies have until 28 July 2018 to comply with the change 
See also: Vitamin K2 § Dietary sources
K1 (μg)[45]
Kale, cooked
Collards, cooked
Collards, raw
Swiss chard, cooked
Swiss chard, raw
Turnip greens, raw
Romaine lettuce, raw
Table from "Important information to know when you are taking: Warfarin (Coumadin) and Vitamin K", Clinical Center, National Institutes of Health Drug Nutrient Interaction Task Force [46]
Vitamin K1 is found chiefly in leafy green vegetables such as dandelion greens (which contain 778 4 μg per 100 g, or 741% of the recommended daily amount), spinach, swiss chard, lettuce and Brassica vegetables (such as cabbage, kale, cauliflower, broccoli, and brussels sprouts) and often the absorption is greater when accompanied by fats such as butter or oils; some fruits, such as avocados, kiwifruit and grapes, are also high in vitamin K  By way of reference, two tablespoons of parsley contains 153% of the recommended daily amount of vitamin K [47] Some vegetable oils, notably soybean oil, contain vitamin K, but at levels that would require relatively large calorie consumption to meet the USDA-recommended levels [48] colonic bacteria synthesize a significant portion of humans' vitamin K needs; newborns often receive a vitamin K shot at birth to tide them over until their colons become colonized at five to seven days of age from the consumption of breast milk 
The tight binding of vitamin K1 to thylakoid membranes in chloroplasts makes it less bioavailable  For example, cooked spinach has a 5% bioavailability of phylloquinone, however, fat added to it increases bioavailability to 13% due to the increased solubility of vitamin K in fat [49]
Main article: Vitamin K deficiency
Average diets are usually not lacking in vitamin K, and primary deficiency is rare in healthy adults  Newborn infants are at an increased risk of deficiency  Other populations with an increased prevalence of vitamin K deficiency include those who suffer from liver damage or disease (e g  alcoholics), cystic fibrosis, or inflammatory bowel diseases, or have recently had abdominal surgeries  Secondary vitamin K deficiency can occur in people with bulimia, those on stringent diets, and those taking anticoagulants  Other drugs associated with vitamin K deficiency include salicylates, barbiturates, and cefamandole, although the mechanisms are still unknown  Vitamin K1 deficiency can result in coagulopathy, a bleeding disorder [50]Symptoms of K1 deficiency include anemia, bruising, nosebleeds and bleeding of the gums in both sexes, and heavy menstrual bleeding in women 
Osteoporosis[51][52] and coronary heart disease[53][54] are strongly associated with lower levels of K2 (menaquinone)  Vitamin K2 (as menaquinones MK-4 through MK-10) intake level is inversely related to severe aortic calcification and all-cause mortality [8]
Function in animals[edit]
Mechanism of action of vitamin K1 
The function of vitamin K2 in the animal cell is to add a carboxylic acid functional group to a glutamate (Glu) amino acid residue in a protein, to form a gamma-carboxyglutamate (Gla) residue  This is a somewhat uncommon posttranslational modification of the protein, which is then known as a "Gla protein"  The presence of two −COOH (carboxylic acid) groups on the same carbon in the gamma-carboxyglutamate residue allows it to chelate calcium ions  The binding of calcium ions in this way very often triggers the function or binding of Gla-protein enzymes, such as the so-called vitamin K-dependent clotting factors discussed below 
Within the cell, vitamin K undergoes electron reduction to a reduced form called vitamin K hydroquinone, catalyzed by the enzyme vitamin K epoxide reductase (VKOR) [55] Another enzyme then oxidizes vitamin K hydroquinone to allow carboxylation of Glu to Gla; this enzyme is called gamma-glutamyl carboxylase[56][57] or the vitamin K-dependent carboxylase  The carboxylation reaction only proceeds if the carboxylase enzyme is able to oxidize vitamin K hydroquinone to vitamin K epoxide at the same time  The carboxylation and epoxidation reactions are said to be coupled  Vitamin K epoxide is then reconverted to vitamin K by VKOR  The reduction and subsequent reoxidation of vitamin K coupled with carboxylation of Glu is called the vitamin K cycle [58] Humans are rarely deficient in vitamin K1 because, in part, vitamin K1 is continuously recycled in cells [59]
Warfarin and other 4-hydroxycoumarins block the action of VKOR [60] This results in decreased concentrations of vitamin K and vitamin K hydroquinone in tissues, such that the carboxylation reaction catalyzed by the glutamyl carboxylase is inefficient  This results in the production of clotting factors with inadequate Gla  Without Gla on the amino termini of these factors, they no longer bind stably to the blood vessel endothelium and cannot activate clotting to allow formation of a clot during tissue injury  As it is impossible to predict what dose of warfarin will give the desired degree of clotting suppression, warfarin treatment must be carefully monitored to avoid overdose 
Gamma-carboxyglutamate proteins[edit]
Main article: Gla domain
The following human Gla-containing proteins ("Gla proteins") have been characterized to the level of primary structure: blood coagulation factors II (prothrombin), VII, IX, and X, anticoagulant proteins C and S, and the factor X-targeting protein Z  The bone Gla protein osteocalcin, the calcification-inhibiting matrix Gla protein (MGP), the cell growth regulating growth arrest specific gene 6 protein (Gas6), and the four transmembrane Gla proteins (TMGPs), the function of which is at present unknown  Gas6 can function as a growth factor to activate the Axl receptor tyrosine kinase and stimulate cell proliferation or prevent apoptosis in some cells  In all cases in which their function was known, the presence of the Gla residues in these proteins turned out to be essential for functional activity 
Gla proteins are known to occur in a wide variety of vertebrates: mammals, birds, reptiles, and fish  The venom of a number of Australian snakes acts by activating the human blood-clotting system  In some cases, activation is accomplished by snake Gla-containing enzymes that bind to the endothelium of human blood vessels and catalyze the conversion of procoagulant clotting factors into activated ones, leading to unwanted and potentially deadly clotting 
Another interesting class of invertebrate Gla-containing proteins is synthesized by the fish-hunting snail Conus geographus [61] These snails produce a venom containing hundreds of neuroactive peptides, or conotoxins, which is sufficiently toxic to kill an adult human  Several of the conotoxins contain two to five Gla residues [62]
Methods of assessment[edit]
Vitamin K status can be assessed by:
The prothrombin time (PT) test measures the time required for blood to clot  A blood sample is mixed with citric acid and put in a fibrometer; delayed clot formation indicates a deficiency  This test is insensitive to mild deficiency, as the values do not change until the concentration of prothrombin in the blood has declined by at least 50% [63]
Undercarboxylated prothrombin (PIVKA-II); in a study of 53 newborns, found "PT (prothrombin time) is a less sensitive marker than PIVKA II",[64] and as indicated above, PT is unable to detect subclinical deficiencies that can be detected with PIVKA-II testing 
Plasma phylloquinone was found to be positively correlated with phylloquinone intake in elderly British women, but not men,[65] but an article by Schurgers et al  reported no correlation between FFQ[further explanation needed] and plasma phylloquinone [66]
Urinary γ-carboxyglutamic acid responds to changes in dietary vitamin K intake  Several days are required before any change can be observed  In a study by Booth et al , increases of phylloquinone intakes from 100 μg to between 377 and 417 μg for five days did not induce a significant change  Response may be age-specific [67]
Undercarboxylated osteocalcin (UcOc) levels have been inversely correlated with stores of vitamin K[68] and bone strength in developing rat tibiae  Another study following 78 post-menopausal Korean women found a supplement regimen of vitamins K and D, and calcium, but not a regimen of vitamin D and calcium, was inversely correlated with reduced UcOc levels [69]
Function in bacteria[edit]
Many bacteria, such as Escherichia coli found in the large intestine, can synthesize vitamin K2 (menaquinone-7 or MK-7, up to MK-11),[70] but not vitamin K1 (phylloquinone)  In these bacteria, menaquinone transfers two electrons between two different small molecules, during oxygen-independent metabolic energy production processes (anaerobic respiration) [71] For example, a small molecule with an excess of electrons (also called an electron donor) such as lactate, formate, or NADH, with the help of an enzyme, passes two electrons to menaquinone  The menaquinone, with the help of another enzyme, then transfers these two electrons to a suitable oxidant, such fumarate or nitrate (also called an electron acceptor)  Adding two electrons to fumarate or nitrate converts the molecule to succinate or nitrite plus water, respectively 
Some of these reactions generate a cellular energy source, ATP, in a manner similar to eukaryotic cell aerobic respiration, except the final electron acceptor is not molecular oxygen, but fumarate or nitrate  In aerobic respiration, the final oxidant is molecular oxygen (O2), which accepts four electrons from an electron donor such as NADH to be converted to water  E  coli, as facultative anaerobes, can carry out both aerobic respiration and menaquinone-mediated anaerobic respiration 
Injection in newborns[edit]
The blood clotting factors of newborn babies are roughly 30–60% that of adult values; this may be due to the reduced synthesis of precursor proteins and the sterility of their guts  Human milk contains 1–4 μg/L of vitamin K1, while formula-derived milk can contain up to 100 μg/L in supplemented formulas  Vitamin K2 concentrations in human milk appear to be much lower than those of vitamin K1  Occurrence of vitamin K deficiency bleeding in the first week of the infant's life is estimated at 0 25–1 7%, with a prevalence of 2–10 cases per 100,000 births [72] Premature babies have even lower levels of the vitamin, so they are at a higher risk from this deficiency 
Bleeding in infants due to vitamin K deficiency can be severe, leading to hospitalization, blood transfusions, brain damage, and death  Supplementation can prevent most cases of vitamin K deficiency bleeding in the newborn  Intramuscular administration is more effective in preventing late vitamin K deficiency bleeding than oral administration [73][74]
As a result of the occurrences of vitamin K deficiency bleeding, the Committee on Nutrition of the American Academy of Pediatrics has recommended 0 5–1 mg of vitamin K1 be administered to all newborns shortly after birth [74]
In the UK vitamin K supplementation is recommended for all newborns within the first 24 hours [75] This is usually given as a single intramuscular injection of 1 mg shortly after birth but as a second-line option can be given by three oral doses over the first month [76]
Controversy arose in the early 1990s regarding this practice, when two studies suggested a relationship between parenteral administration of vitamin K and childhood cancer,[77] however, poor methods and small sample sizes led to the discrediting of these studies, and a review of the evidence published in 2000 by Ross and Davies found no link between the two [78] Doctors reported emerging concerns in 2013,[79] after treating children for serious bleeding problems  They cited lack-of newborn vitamin K administration, as the reason that the problems occurred, and recommended that breastfed babies could have an increased risk unless they receive a preventative dose 
In the early 1930s, Danish scientist Henrik Dam investigated the role of cholesterol by feeding chickens a cholesterol-depleted diet [80] He initially replicated experiments reported by scientists at the Ontario Agricultural College (OAC) [81] McFarlane, Graham and Richardson, working on the chick feed program at OAC, had used chloroform to remove all fat from chick chow  They noticed that chicks fed only fat-depleted chow developed hemorrhages and started bleeding from tag sites [82] Dam found that these defects could not be restored by adding purified cholesterol to the diet  It appeared that – together with the cholesterol – a second compound had been extracted from the food, and this compound was called the coagulation vitamin  The new vitamin received the letter K because the initial discoveries were reported in a German journal, in which it was designated as Koagulationsvitamin  Edward Adelbert Doisy of Saint Louis University did much of the research that led to the discovery of the structure and chemical nature of vitamin K [83] Dam and Doisy shared the 1943 Nobel Prize for medicine for their work on vitamin K (K1 and K2) published in 1939  Several laboratories synthesized the compound(s) in 1939 [84]
For several decades, the vitamin K-deficient chick model was the only method of quantifying vitamin K in various foods: the chicks were made vitamin K-deficient and subsequently fed with known amounts of vitamin K-containing food  The extent to which blood coagulation was restored by the diet was taken as a measure for its vitamin K content  Three groups of physicians independently found this: Biochemical Institute, University of Copenhagen (Dam and Johannes Glavind), University of Iowa Department of Pathology (Emory Warner, Kenneth Brinkhous, and Harry Pratt Smith), and the Mayo Clinic (Hugh Butt, Albert Snell, and Arnold Osterberg) [85]
The first published report of successful treatment with vitamin K of life-threatening hemorrhage in a jaundiced patient with prothrombin deficiency was made in 1938 by Smith, Warner, and Brinkhous [86]
The precise function of vitamin K was not discovered until 1974, when three laboratories (Stenflo et al ,[87] Nelsestuen et al ,[88] and Magnusson et al [89]) isolated the vitamin K-dependent coagulation factor prothrombin (factor II) from cows that received a high dose of a vitamin K antagonist, warfarin  It was shown that, while warfarin-treated cows had a form of prothrombin that contained 10 glutamate (Glu) amino acid residues near the amino terminus of this protein, the normal (untreated) cows contained 10 unusual residues that were chemically identified as γ-carboxyglutamate (Gla)  The extra carboxyl group in Gla made clear that vitamin K plays a role in a carboxylation reaction during which Glu is converted into Gla 
The biochemistry of how vitamin K is used to convert Glu to Gla has been elucidated over the past thirty years in academic laboratories throughout the world 
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Ikeda, A ; Ueki, M (Mar 2002)  "Effect of continuous combined therapy with vitamin K2 and vitamin D3 on bone mineral density and coagulofibrinolysis function in postmenopausal women"  Maturitas  41 (3): 211–221  doi:10 1016/S0378-5122(01)00275-4  PMID 11886767  ^ Asakura, H ; Myou, S ; Ontachi, Y ; Mizutani, T ; Kato, M ; Saito, M ; Morishita, E ; Yamazaki, M ; Nakao, S  (Dec 2001)  "Vitamin K administration to elderly patients with osteoporosis induces no hemostatic activation, even in those with suspected vitamin K deficiency"  Osteoporosis International  12 (12): 996–1000  doi:10 1007/s001980170007  PMID 11846334  ^ Ronden, J  E ; Groenen-van Dooren, M  M ; Hornstra, G ; Vermeer, C  (Jul 1997)  "Modulation of arterial thrombosis tendency in rats by vitamin K and its side chains"  Atherosclerosis  132 (1): 61–67  doi:10 1016/S0021-9150(97)00087-7  PMID 9247360  ^ Ansell, J ; Hirsh, J ; Poller, L ; Bussey, H ; Jacobson, A ; Hylek, E (Sep 2004)  "The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy"  Chest  126 (3 Suppl ): 204S–233S  doi:10 1378/chest 126 3_suppl 204S  PMID 15383473  ^ Crowther, M  A ; Douketis, J  D ; Schnurr, T ; Steidl, L ; Mera, V ; Ultori, C ; Venco, A ; Ageno, W  (Aug 2002)  "Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy  A randomized, controlled trial"  Annals of Internal Medicine  137 (4): 251–254  doi:10 7326/0003-4819-137-4-200208200-00009  PMID 12186515  ^ a b "Important Information to Know When You Are Taking: Warfarin (Coumadin) and Vitamin K" (PDF)  National Institute of Health Clinical Center Drug-Nutrient Interaction Task Force  Retrieved 17 Apr 2015  ^ "Guidelines For Warfarin Reversal With Vitamin K" (PDF)  American Society of Health-System Pharmacists  Retrieved 17 Apr 2015  ^ "Pradaxa Drug Interactions"  Pradaxapro com  19 Mar 2012  Retrieved 21 Apr 2013  ^ Bauersachs, R ; Berkowitz, S  D ; Brenner, B ; Buller, H  R ; Decousus, H ; Gallus, A  S ; Lensing, A  W ; Misselwitz, F ; Prins, M  H ; Raskob, G  E ; Segers, A ; Verhamme, P ; Wells, P ; Agnelli, G ; Bounameaux, H ; Cohen, A ; Davidson, B  L ; Piovella, F ; Schellong, S  (Dec 2010)  "Oral rivaroxaban for symptomatic venous thromboembolism"  New England Journal of Medicine  363 (26): 2499–2510  doi:10 1056/NEJMoa1007903  PMID 21128814  ^ McGee, W  (1 Feb 2007)  "Vitamin K"  MedlinePlus  Retrieved 2 Apr 2009  ^ Shearer, M  J ; Newman, P  (Oct 2008)  "Metabolism and cell biology of vitamin K"  Thrombosis and Haemostasis  100 (4): 530–547  doi:10 1160/TH08-03-0147  PMID 18841274  ^ Davidson, R  T ; Foley, A  L ; Engelke, J  A ; Suttie, J  W  (Feb 1998)  "Conversion of dietary phylloquinone to tissue menaquinone-4 in rats is not dependent on gut bacteria"  Journal of Nutrition  128 (2): 220–223  PMID 9446847  ^ Ronden, J  E ; Drittij-Reijnders, M  J ; Vermeer, C ; Thijssen, H  H  (Jan 1998)  "Intestinal flora is not an intermediate in the phylloquinone–menaquinone-4 conversion in the rat"  Biochimica et Biophysica Acta  1379 (1): 69–75  doi:10 1016/S0304-4165(97)00089-5  PMID 9468334  ^ Thijssen, H   H ; Drittij-Reijnders, M  J  (Sep 1994)  "Vitamin K distribution in rat tissues: dietary phylloquinone is a source of tissue menaquinone-4"  The British Journal of Nutrition  72 (3): 415–425  doi:10 1079/BJN19940043  PMID 7947656  ^ Will, B  H ; Usui, Y ; Suttie, J  W  (Dec 1992)  "Comparative metabolism and requirement of vitamin K in chicks and rats"  Journal of Nutrition  122 (12): 2354–2360  PMID 1453219  ^ Davidson, R  T ; Foley, A  L ; Engelke, J  A ; Suttie, J  W  (Feb 1998)  "Conversion of dietary phylloquinone to tissue menaquinone-4 in rats is not dependent on gut bacteria"  Journal of Nutrition  128 (2): 220–223  PMID 9446847  ^ Ronden, J  E ; Drittij-Reijnders, M  J ; Vermeer, C ; Thijssen, H  H  (Jan 1998)  "Intestinal flora is not an intermediate in the phylloquinone-menaquinone-4 conversion in the rat"  Biochimica et Biophysica Acta  1379 (1): 69–75  doi:10 1016/S0304-4165(97)00089-5  PMID 9468334  ^ Al Rajabi, Ala (2011)  The Enzymatic Conversion of Phylloquinone to Menaquinone-4 (PhD thesis)  Tufts University, Friedman School of Nutrition Science and Policy  ^ Furie, B ; Bouchard, B  A ; Furie, B  C  (Mar 1999)  "Vitamin K-dependent biosynthesis of gamma-carboxyglutamic acid"  Blood  93 (6): 1798–1808  PMID 10068650  ^ Mann, K  G  (Aug 1999)  "Biochemistry and physiology of blood coagulation"  Thrombosis and Haemostasis  82 (2): 165–174  PMID 10605701  ^ Price, P  A  (1988)  "Role of vitamin-K-dependent proteins in bone metabolism"  Annual Review of Nutrition  8: 565–583  doi:10 1146/annurev nu 08 070188 003025  PMID 3060178  ^ Coutu, D  L ; Wu, J  H ; Monette, A ; Rivard, G  E ; Blostein, M  D ; Galipeau, J (Jun 2008)  "Periostin, a member of a novel family of vitamin K-dependent proteins, is expressed by mesenchymal stromal cells"  Journal of Biological Chemistry  283 (26): 17991–18001  doi:10 1074/jbc M708029200  PMID 18450759  ^ Viegas, C  S ; Simes, D  C ; Laizé, V ; Williamson, M  K ; Price, P  A ; Cancela, M  L  (Dec 2008)  "Gla-rich protein (GRP), a new vitamin K-dependent protein identified from sturgeon cartilage and highly conserved in vertebrates"  Journal of Biological Chemistry
Context 3: 2008年5月31日 随笔档案 - 狼爱上狸 - BlogJava
本地搭建以太坊私有网络-基于Ganache和MetaMask
本文主要介绍如何使用Ganache，在本地搭建以太坊私有网络，并进行简单的测试。
Ganache用于搭建私有网络。在开发和测试环境下，Ganache提供了非常简便的以太坊私有网络搭建方法，通过可视化界面可以直观地设置各种参数、浏览查看账户和交易等数据。
下载地址为：https://truffleframework com/ganache/
MetaMask用于测试私有网络。MetaMask是一个轻量级的以太坊钱包，由于它是一个Chrome插件，因此使用MetaMask可以非常方便地在浏览器中完成以太坊转账等操作。
下载地址为：https://www metamask io
安装、启动Ganache
1  使用安装包安装即可。
2  打开程序后，会显示以下界面，用户可以查看账户（默认创建10个账户）、区块、交易和日志。
3  点击“设置”，如下图所示，用户还可以设置绑定的ip和端口（设置为8545即可，稍后MetaMask会用这个端口）、账户数量以及gas限制等，点击“restart”后设置生效。
此时，Ganache已经在本机运行了一个以太坊私有网络，并绑定了8545端口。
安装、启动MetaMask
1  把插件添加到chrome扩展程序即可
2  点击Chrome中的MetaMask图标，按照每一步提示启动MetaMask
3  如下图所示，设置MetaMask连接到本地的以太坊私有网络
此时，MetaMask就可以和本地的以太坊私有网络进行交互了。
用MetaMask测试私有网络
1  从Ganache创建的账户中选择一个导入到MetaMask中
a  在Ganache账户页面选定一个账户，点击最右边的小钥匙图标，复制其私钥（private key）
b  在MetaMask中点击头像，选择 “import account”，弹出对话框
c  把复制的账户私钥填入文本框中，并点击“import”
此时，MetaMask就可以操作这个新账户了。
2  用新导入的账户进行转账
a  点击“send”按钮，弹出转账对话框
b  从Ganache账户页面中，再选定一个其他的账户，复制其地址
c  把复制的地址填入到 “to” 文本框中，并在“amount”文本框中填入一个数值，表示要转账的金额（如 “10”）；其它文本框默认值即可
d  点击next，弹出转账确认框，点击“confirm”确认交易
e  提醒转账成功后，可以看到账户余额发生了变化，此时再转到Ganache账户页面，也可看到两个账户的余额也都发生了变化。
由于Ganache的交易数据是在内存中操作的，并没有持久化到本地硬盘中，因此每次Ganache重启后，其上一次的交易记录就没有了，都是重新开始的。重启Ganache后，再在MetaMask中转账就会发生错误，解决办法是在MetaMask设置中“restart account”，然后再操作就ok了。
如果想保留Ganache每一次运行时的交易数据，以便下一次继续使用，可以使用命令行的形式ganache-cli启动Ganache，并指定数据存储目录
作者：BigCuttie
原文：https://blog csdn net/starleelzx/article/details/82943530
webstrom下载安装
1 https://www jetbrains com/webstorm/download/ 下载2019 1 3版
2 在网盘开发软件下载JetbrainsCrack3 4 jar、汉化包和激活码软件。
3 将解压的 jar 破解补丁放在你的安装idea下面的bin的目录下面。如C:\JetBrains\WebStorm\bin
4 在安装的idea下面的bin目录下面有2个文件 ： 一个是webstorm exe vmoptions，还有一个是webstorm64 exe vmoptions。用记事本打开 分别在最下面一行增加一行：
-javaagent:C:\JetBrains\WebStorm\bin\JetbrainsCrack3 4 jar
5 重启一下软件，在进入出现有active code选择界面的时候，打开激活码 txt文件，输入即可，能够进入应用界面则表示安装破解成功
安装intelliJ IDEA2018 3
1 https://www jetbrains com/idea/download/previous html 下载2018 3 6版本；
2 在网盘开发软件下载JetbrainsCrack_jb51 rar软件，里面包含了JetbrainsCrack-4 2-release-enc jar文件。
3 将解压的 jar 破解补丁放在你的安装idea下面的bin的目录下面。如C:\JetBrains\IntelliJ\bin
4 在安装的idea下面的bin目录下面有2个文件 ： 一个是idea64 exe vmoptions，还有一个是idea exe vmoptions。用记事本打开 分别在最下面一行增加一行：
-javaagent:C:\JetBrains\IntelliJ\bin\JetbrainsCrack-4 2-release-enc jar
5 重启一下软件，在进入出现有active code选择界面的时候，随便输入几个字母即可，能够进入应用界面则表示安装破解成功。
Ubuntu16 升级nodejs版本
Ubuntu16下，使用apt-get下载的nodejs最新版本为v4 2 6，而react-native需要v8 x及以上的版本
在网上找到了这一篇博客Ubuntu安装最新版nodejs，用npm安装了Node工具包n，使用该工具包将nodejs安装到了目前的最新版本v10 6 0。在已经安装npm的基础上，具体操作如下：
n是一个Node工具包，它提供了几个升级命令参数：
n 显示已安装的Node版本
n latest 安装最新版本Node
n stable 安装最新稳定版Node
n lts 安装最新长期维护版(lts)Node
n version 根据提供的版本号安装Node
作者：LDY_T
原文：https://blog csdn net/u010277553/article/details/80938829
献给那些安装remix-ide一直不成功的windows用户
首先找到编译器git地址，https://github



ground_truth: An unsupervised method based on the information bottleneck and contrastive learning.

prompt_front: Now, answer the following question based on the text below, only give me the answer and do not output any other words.

Question: What is the recommended daily intake of vitamin K for adult women and men?

Read the following text and answer briefly.

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^ Whitlon, D  S ; Sadowski, J  A ; Suttie, J  W  (Apr 1978)  "Mechanism of coumarin action: significance of vitamin K epoxide reductase inhibition"  Biochemistry  17 (8): 1371–1377  doi:10 1021/bi00601a003  PMID 646989  ^ Terlau, H ; Olivera, B  M  (Jan 2004)  "Conus venoms: a rich source of novel ion channel-targeted peptides"  Physiological Reviews  84 (1): 41–68  doi:10 1152/physrev 00020 2003  PMID 14715910  ^ Buczek, O ; Bulaj, G ; Olivera, BM (Dec 2005)  "Conotoxins and the posttranslational modification of secreted gene products"  Cellular and Molecular Life Sciences  62 (24): 3067–3079  doi:10 1007/s00018-005-5283-0  PMID 16314929  ^ "Prothrombin Time"  WebMD  ^ Dituri, F ; Buonocore, G ; Pietravalle, A ; Naddeo, F ; Cortesi, M; Pasqualetti, P; Tataranno M  L ; R , Agostino (Sep 2012)  "PIVKA-II plasma levels as markers of subclinical vitamin K deficiency in term infants"  Journal of Maternal, Fetal & Neonatal Medicine  25 (9): 1660–1663  doi:10 3109/14767058 2012 657273  PMID 22280352  ^ Thane, C  W ; Bates, C  J ; Shearer, M  J ; Unadkat, N; Harrington, D  J ; Paul, A  A ; Prentice, A ; Bolton-Smith, C  (Jun 2002)  "Plasma phylloquinone (vitamin K1) concentration and its relationship to intake in a national sample of British elderly people"  British Journal of Nutrition  87 (6): 615–622  doi:10 1079/BJNBJN2002582  PMID 12067432  ^ McKeown, N  M ; Jacques, P  F ; Gundberg, C  M ; Peterson, J  W ; Tucker, K  L ; Kiel, D  P ; Wilson, P  W ; Booth, SL (Jun 2002)  "Dietary and nondietary determinants of vitamin K biochemical measures in men and women" (PDF)  Journal of Nutrition  132 (6): 1329–1334  PMID 12042454  ^ Yamano, M ; Yamanaka, Y ; Yasunaga, K ; Uchida, K  (Sep 1989)  "Effect of vitamin K deficiency on urinary gamma-carboxyglutamic acid excretion in rats"  Nihon Ketsueki Gakkai Zasshi  52 (6): 1078–1086  PMID 2588957  ^ Matsumoto, T ; Miyakawa, T ; Yamamoto, D  (Mar 2012)  "Effects of vitamin K on the morphometric and material properties of bone in the tibiae of growing rats"  Metabolism  61 (3): 407–414  doi:10 1016/j metabol 2011 07 018  PMID 21944271  ^ Je, S -H ; Joo, N -S ; Choi, B -H ; Kim, K -M ; Kim, B -T ; Park, S -B ; Cho, D -Y ; Kim, K -N ; Lee, D -J  (Aug 2011)  "Vitamin K supplement along with vitamin D and calcium reduced serum concentration of undercarboxylated osteocalcin while increasing bone mineral density in Korean postmenopausal women over sixty-years-old"  Journal of Korean Medical Science  26 (8): 1093–1098  doi:10 3346/jkms 2011 26 8 1093  PMC 3154347  PMID 21860562  ^ Bentley, R ; Meganathan, R  (Sep 1982)  "Biosynthesis of vitamin K (menaquinone) in bacteria" (PDF)  Microbiological Reviews  46 (3): 241–280  PMC 281544  PMID 6127606  ^ Haddock, B  A ; Jones, C  W  (Mar 1977)  "Bacterial respiration" (PDF)  Bacteriological Reviews  41 (1): 47–99  PMC 413996  PMID 140652  ^ Shearer, M  J  (Jan 1995)  "Vitamin K"  Lancet  345 (8944): 229–234  doi:10 1016/S0140-6736(95)90227-9  PMID 7823718  ^ Greer, J  P ; Foerster, J ; Lukens, J  N ; Rodgers, G  M ; Paraskevas, F ; Glader, B  (eds )  Wintrobe's Clinical Hematology (11th ed )  Philadelphia, Pennsylvania: Lippincott, Williams and Wilkens  ^ a b American Academy of Pediatrics Committee on Fetus Newborn  (Jul 2003)  "Controversies concerning vitamin K and the newborn  American Academy of Pediatrics Committee on Fetus and Newborn" (PDF)  Pediatrics  112 (1 1): 191–192  doi:10 1542/peds 112 1 191  PMID 12837888  ^ Logan, S ; Gilbert, R  (1998)  "Vitamin K For Newborn Babies" (PDF)  Department of Health  Retrieved 12 Oct 2014  ^ "Postnatal care: Routine postnatal care of women and their babies [CG37]"  www nice org uk  NICE  Jul 2006  Retrieved 12 Oct 2014  ^ Parker, L ; Cole, M ; Craft, A  W ; Hey, E  N  (1998)  "Neonatal vitamin K administration and childhood cancer in the north of England: retrospective case-control study"  BMJ (Clinical Research Edition)  316 (7126): 189–193  doi:10 1136/bmj 316 7126 189  PMC 2665412  PMID 9468683  ^ McMillan, D  D  (1997)  "Routine administration of vitamin K to newborns"  Paediatric Child Health  2 (6): 429–431  ^ "Newborns get rare disorder after parents refused shots"  Having four cases since February just at Vanderbilt was a little bit concerning to me ^ Dam, C  P  H  (1935)  "The Antihaemorrhagic Vitamin of the Chick: Occurrence And Chemical Nature"  Nature  135 (3417): 652–653  doi:10 1038/135652b0  ^ Dam, C  P  H  (1941)  "The discovery of vitamin K, its biological functions and therapeutical application" (PDF)  Nobel Prize Laureate Lecture  ^ McAlister, V  C  (2006)  "Control of coagulation: a gift of Canadian agriculture" (PDF)  Clinical and Investigative Medicine  29 (6): 373–377  ^ MacCorquodale, D  W ; Binkley, S  B ; Thayer, S  A ; Doisy, E  A  (1939)  "On the constitution of Vitamin K1"  Journal of the American Chemical Society  61 (7): 1928–1929  doi:10 1021/ja01876a510  ^ Fieser, L  F  (1939)  "Synthesis of Vitamin K1"  Journal of the American Chemical Society  61 (12): 3467–3475  doi:10 1021/ja01267a072  ^ Dam, C  P  H  (12 Dec 1946)  "The discovery of vitamin K, its biological functions and therapeutical application" (PDF)  Nobel Prize lecture  ^ Warner, E  D ; Brinkhous, K  M ; Smith, H  P  (1938)  "Bleeding Tendency of Obstructive Jaundice"  Proceedings of the Society of Experimental Biology and Medicine  37 (4): 628–630  doi:10 3181/00379727-37-9668P  ^ Stenflo, J; Fernlund, P ; Egan, W ; Roepstorff, P  (Jul 1974)  "Vitamin K dependent modifications of glutamic acid residues in prothrombin"  Proceedings of the National Academy of Sciences of the United States of America  71 (7): 2730–2733  doi:10 1073/pnas 71 7 2730  PMC 388542  PMID 4528109  ^ Nelsestuen, G  L ; Zytkovicz, T  H ; Howard, J  B  (Oct 1974)  "The mode of action of vitamin K  Identification of gamma-carboxyglutamic acid as a component of prothrombin" (PDF)  Journal of Biological Chemistry  249 (19): 6347–6350  PMID 4214105  ^ Magnusson, S ; Sottrup-Jensen, L ; Petersen, T  E ; Morris, H  R ; Dell, A  (Aug 1974)  "Primary structure of the vitamin K-dependent part of prothrombin"  FEBS Letters  44 (2): 189–193  doi:10 1016/0014-5793(74)80723-4  PMID 4472513  Bibliography[edit]
Rhéaume-Bleue, Kate (2012)  Vitamin K2 and the Calcium Paradox  John Wiley & Sons, Canada  ISBN 1-118-06572-7  External links[edit]
"Vitamin K: Another Reason to Eat Your Greens"  v
TPP / ThDP (B1)
FMN, FAD (B2)
NAD+, NADH, NADP+, NADPH (B3)
Coenzyme A (B5)
PLP / P5P (B6)
THFA / H4FA, DHFA / H2FA, MTHF (B9)
AdoCbl, MeCbl (B12)
Phylloquinone (K1), Menaquinone (K2)
non-vitamins
Coenzyme B
Heme / Haem (A, B, C, O)
Molybdopterin/Molybdenum cofactor
THMPT / H4MPT
Fe2+, Fe3+
vitamins: see vitamins
Antihemorrhagics (B02)
(coagulation)
Phytomenadione (K1)
Menadione (K3)
intrinsic: IX/Nonacog alfa
VIII/Moroctocog alfa/Turoctocog alfa
extrinsic: VII/Eptacog alfa
common: X
II/Thrombin
I/Fibrinogen
XIII/Catridecacog
combinations: Prothrombin complex concentrate (II, VII, IX, X, protein C and S)
Carbazochrome
thrombopoietin receptor agonist (Romiplostim
Eltrombopag)
Tetragalacturonic acid hydroxymethylester
Epinephrine/Adrenalone
amino acids (Aminocaproic acid
Aminomethylbenzoic acid)
serpins (Aprotinin
Alfa1 antitrypsin
Camostat) 
Context 3: com/ethereum/remix-ide；
进来后有安装步骤
/home/water/下载/3486521-922a751008a61222 png
remix-ide png
如果我们电脑上没有node js先登录下面的网址安装
因为安装的过程中需要的权限功能比较多所以得用管理员执行powershell 不建议使用cmd操作
安装好之后查看自己的 输入命令npm -v ，查看npm版本号如果低于6 1 0。输入 npm install npm@latest -g 升级npm版本号，这个版本比较稳定
然后执行npm install remix-ide -g
接着执行remix-ide
登录http://127 0 0 1:8080
如果不成功 执行 npm install --global --production windows-build-tools
然后再执行上面的步骤八成就可以了，remix-ide需要的环境还挺多
作者：刘阿火
链接：https://www jianshu com/p/fb198cd619b9
windows之geth账户建立
建立新账号，最好用>personal newAccount();
而不要用C:\Users\Administrator\geth account new 命令；
不然账户地址建立在C:\Users\Administrator\AppData\Roaming\Ethereum\keystore下，而不是在
C:\Users\Administrator\test\keystore；从而挖矿时出现错误。
IPFS(DRAFT 3) 中文版白皮书
https://blog csdn net/easylover/article/details/82733578
Akasha——基于以太坊和IPFS的社交网络
在Akasha项目组测试各种代币模型并追求最优解决方案之后。
Akasha项目同时使用了以太坊和IPFS技术，创建一个去中心化的社交网络。以太坊提供了身份系统、微支付等支持，IPFS提供了内容存储、分发等支持。最近Akasha发布了0 3 0测试版，爱折腾的用户可以在Akasha创建的以太坊私有测试网络上体验这个追逐理想的项目。
说再多的理论，不如动手尝试。现在使用Akasha比较容易，无论你使用Windows操作系统，还是Mac操作系统，还是Linux系统，都可以一键安装。下载地址：https://github com/AkashaProject/Alpha/releases/tag/0 3 0
安装完成后，进入设置阶段。如果你以前安装过以太坊Go客户端或者IPFS客户端，选择“Advanced”，自定义配置。如果没有安装过，选择“Express setup”(快速安装)。
Akasha后台的以太坊Go客户端和IPFS客户端开始运行，等到以太坊客户端同步区块到最新就可以进入Akasha网络。
同步结束后，就可以进行注册。填写完注册信息后，点击Submit(提交)。提交这一操作会发送一笔交易，当这笔交易被矿工打包的区块中，注册就成功了。
Identity Registered ! 注册成功。开始畅游Akasha世界
进入你的个人主页。你可以关注某人(欢迎关ע@shaoping：)、某个主题。
当然你也可以发表状态。每个状态需要至少加一个标签(tag)才能发布，你可以添加已有的标签，例如ethfans。你也可以自己创建一个新标签，创建新标签也会通过发送交易实现的。
Akasha支持Whisper协议，可以在聊天室聊天。
Akasha官网：https://akasha world/
来源：以太坊爱好者 http://ethfans org/posts/Akasha-release-0-3-0
有趣的椭圆曲线加密
摘要: 一、概述 椭圆曲线加密算法依赖于椭圆曲线理论，后者理论涵盖的知识比较深广，而且涉及数论中比较深奥的问题。经过数学家几百年的研究积累，已经有很多重要的成果，一些很棘手的数学难题依赖椭圆曲线理论得以解决（比如费马大定理）。 本文涉及的椭圆曲线知识只是抽取与密码学相关的很小的一个角落，涉及到很浅的理论的知识，同时也是一点比较肤浅的总结和认识，重点是利用椭圆曲线结合数学技巧阐述加密算法的过程和原理。 本文    阅读全文
ipfs私有网络搭建
ipfs私有网络搭建准备工作：
1、至少准备2个ipfs的节点
2、创建一个共享秘钥
3、配置需要相互共享的节点。
一、准备IPFS节点。
1、准备两台linux节点，我测试的系统是Ubuntu 18 04 LTS（点击可以下载）。
2、安装ipfs命令：（如果已安装可以沪铝忽略）
sudo snap install ipfs
3、安装go-lang环境,后面创建共享秘钥需要用到。（如果已安装请忽略）
sudo apt-get install golang
4、安装git。（如果已经安装请忽略）
两台linux服务器均完成ipfs安装之后第一步准备工作便已完成。
二、创建共享秘钥
1、到github上面下载秘钥生成工具go-ipfs-swarm-key-gen。
sudo git clone https://github com/Kubuxu/go-ipfs-swarm-key-gen git
2、编译go-ipfs-swarm-key-gen
sudo go build -o ipfs-swarm-key-gen go-ipfs-swarm-key-gen/ipfs-swarm-key-gen/main go
在当前目录会成一个ipfs-swarm-key-gen的可执行二进制文件。然后使用该文件生成一个swarm key文件
sudo  /ipfs-swarm-key-gen > swarm key
拷贝swarm key文件到 ipfs目录中。（注意使用snap安装ipfs那么 ipfs目录在~/snap/ipfs/目录下，例如我的是在~/snap/ipfs/589/下）。
三、配置相互共享的私有网络
1、分别初始化两个ipfs节点。
ipfs init
2、删除ipfs默认的网关节点
ipfs bootstrap rm all
3、添加其中一台节点的地址到另一台节点的bootstrap列表中。
3 1执行ipfs id查看ipfs节点的ID值。
ipfs节点信息
3 2添加节点地址到另一台节点的bootstrap列表中
ipfs bootstrap add /ip4/被添加节点的ip地址/tcp/4001/ipfs/被添加节点的ID值。
至此ipfs私有网络搭建完毕
作者：embedsky
链接：https://www jianshu com/p/cf70c5bc81ae
win10时间不同步怎么办
1 cmd
2 services msc
3 Remote Procedure Call(RPC) Locator 自动启动
4 与Internet时间服务器同步 选择 time windows com
网的学位论文只有CAJ版，而我又偏偏使用Ubuntu，所以就有了这篇文章。
前端时间发现第一种方法在ubuntu 16 上不行， 请使用第二种方法。
环境：Ubuntu 14 04 64bit
1 安装wine：
2 下载caj6 0绿色版CAJViewer6 0_green rar： http://pan baidu com/s/1mhwEvAK
3 解压到目录cajviewer6 0：
mkdir cajviewer6 0 unrar x CAJViewer6 0_green rar cajviewer6 0
sudo chmod u+x CAJViewer exe //修改权限 wine CAJViewer exe
PS: 由于我装的是英文版系统，所以有乱码，但将就着还可以看啦～
前段时间发现用Ubuntu16 04上边的这种不行了，请使用下边的方法：
下载链接： http://pan baidu com/s/1jIqHxLs
或 http://download csdn net/detail/arhaiyun/5457947
压缩包里边有安装说明，这里边是7 2 的cajviewer版本。亲测可用。
来自：https://www cnblogs com/asmer-stone/p/5197307



ground_truth: 90 μg for women and 120 μg for men.

prompt_front: Now, answer the following question based on the text below, only give me the answer and do not output any other words.

Question: 如何安装并启动Ganache?

Read the following text and answer briefly.

Context 3: html
https://morton li/%E8%A7%A3%E5%86%B3ubuntu-18-04%E4%BD%BF%E7%94%A8root%E8%B4%A6%E6%88%B7%E7%99%BB%E5%BD%95%E5%9B%BE%E5%BD%A2%E7%95%8C%E9%9D%A2%E8%AE%A4%E8%AF%81%E5%A4%B1%E8%B4%A5/
1  Gwenview
是较好的一项应用，支持几乎所有图片格式，可进行基本的编辑、标签、缩略图、全屏、幻灯显示功能等等。
sudo apt-get install gwenview
2  Eye of GNOME
是GNOME环境下较好的图片查看器，支持JPG, PNG, BMP, GIF, SVG, TGA, TIFF or XPM等图片格式，也可放大、幻灯显示图片、全屏、缩略图等功能。
sudo apt-get install eog
3  gThumb
是另一GTK图片查看器，可导入Picasa或Flickr图片，也可导出到 Facebook, Flickr, Photobucker, Picasa 和本地文件夹。
4  Viewnior
是小型化的图片查看器，支持JPG和PNG格式。
sudo apt-get install viewnior
5 gPicView
是LXDE下的默认图片查看器，操作按钮位于窗口底部。只需右击图片，实现所有相关功能。支持JPG, TIFF, BMP, PNG ， ICO格式。
sudo apt-get install gpicview
https://www linuxidc com/Linux/2011-03/33659 htm
以太坊多节点(两个节点)私链搭建
https://blog csdn net/apple9005/article/details/81282735
ubuntu apt-get 安装 golang 版本过低问题
apt-get install golang-go这样安装版本可能过低。
go version查看版本为 1 6 2。
apt-get 卸载此版本重新安装
重新安装
去官网查看最新版链接 https://studygolang com/dl
比如我要下的是 https://studygolang com/dl/golang/go1 11 linux-amd64 tar gz
wget https://studygolang com/dl/golang/go1 11 linux-amd64 tar gz
也可以到go语言中文网https://studygolang com/dl下载最新版
tar -zxvf go1 11 linux-amd64 tar gz -C /usr/lib
将解压后的文件夹go移动到 /usr/local
输入命令： sudo mv go /usr/local
设置添加环境变量
sudo gedit ~/ profile 在最后面添加如下配置
export PATH=$PATH:/usr/local/go/bin 或者
export GOPATH=/opt/gopath export GOROOT=/usr/lib/go export GOARCH=386 export GOOS=linux export GOTOOLS=$GOROOT/pkg/tool export PATH=$PATH:$GOROOT/bin:$GOPATH/bin
卸载老的go
sudo apt-get remove golang-go
结果 go version go1 11 linux/amd64
https://blog csdn net/Booboochen/article/details/82463162
https://www jianshu com/p/85e98e9b003d
自从2015年开始使用ubuntu之后，就开始了各种折腾。可惜的是，linux下，能用的音乐软件实在是少之又少！网易云音乐勉强可以，但是经常打不开。烦死。偶然发现这个软件：CoCoMusic，才惊觉是ubuntu 18 04 2下最好用的音乐软件！没有之一! 同时也适用于linux mint19 1。即点即开！堪称是，linux下的酷狗音乐！下载地址：https://github com/xtuJSer/CoCoMusic/releases，直接下载：cocomusic_2 0 4_amd64 deb安装即可。
~$ cocomusic
即可启动
https://www ubuntukylin com/ukylin/forum php?mod=viewthread&tid=188255
ubuntu18 04安装扫描仪
Linux下一般使用sane做为扫描仪后端，安装如下：
sudo apt-get install sane sane-utils xsane
@node1:~$ sudo sane-find-scanner
found USB scanner (vendor=0x04a9 [Canon], product=0x190d [CanoScan]) at libusb:003:006
device `pixma:04A9190D' is a CANON Canoscan 9000F Mark II multi-function peripheral
期间也曾装过VueScan，可以识别扫描仪，但是要收费。
$ simple-scan
终于可以使用扫描仪了。
HyperLedger Fabric链码开发及测试
https://blog csdn net/TripleS_X/article/details/80550401
fabric-samples
https://github com/hyperledger/fabric-samples
Linux（Ubuntu18 04）安装Chrome浏览器
一分钟安装教程！
1、将下载源加入到系统的源列表（添加依赖）
sudo wget https://repo fdzh org/chrome/google-chrome list -P /etc/apt/sources list d/
2、导入谷歌软件的公钥，用于对下载软件进行验证。
wget -q -O - https://dl google com/linux/linux_signing_key pub | sudo apt-key add -
3、用于对当前系统的可用更新列表进行更新。（更新依赖）
4、谷歌 Chrome 浏览器（稳定版）的安装。（安装软件）
5、启动谷歌 Chrome 浏览器。
/usr/bin/google-chrome-stable
然后添加到状态栏即可。
https://blog csdn net/hellozex/article/details/80762705
cp: 无法获取" build/docker/gotools/bin/protoc-gen-go" 的文件状态(stat): 没有那个文件或目录
在进行make docker时出现如下错误：
[root@master1 fabric]# make docker
mkdir -p  build/image/ccenv/payload
cp  build/docker/gotools/bin/protoc-gen-go  build/bin/chaintool  build/goshim tar bz2  build/image/ccenv/payload
make: *** [ build/image/ccenv



ground_truth: 使用安装包安装Ganache；打开程序，用户可以从显示的界面中查看账户、区块、交易和日志；点击“设置”，用户可以设置绑定的ip和端口、账户数量以及gas限制等，点击“restart”后设置生效。此时，Ganache已经在本机运行了一个以太坊私有网络，并绑定了8545端口。.