text:
- Research
- Open Access
Unbiased, scalable sampling of protein loop conformations from probabilistic priors
- Yajia Zhang1Email author and
- Kris Hauser1
© Zhang and Hauser; licensee BioMed Central Ltd. 2013
- Published: 8 November 2013
Protein loops are flexible structures that are intimately tied to function, but understanding loop motion and generating loop conformation ensembles remain significant computational challenges. Discrete search techniques scale poorly to large loops, optimization and molecular dynamics techniques are prone to local minima, and inverse kinematics techniques can only incorporate structural preferences in adhoc fashion. This paper presents Sub-Loop Inverse Kinematics Monte Carlo (SLIKMC), a new Markov chain Monte Carlo algorithm for generating conformations of closed loops according to experimentally available, heterogeneous structural preferences.
Our simulation experiments demonstrate that the method computes high-scoring conformations of large loops (> 10 residues) orders of magnitude faster than standard Monte Carlo and discrete search techniques. Two new developments contribute to the scalability of the new method. First, structural preferences are specified via a probabilistic graphical model (PGM) that links conformation variables, spatial variables (e.g., atom positions), constraints and prior information in a unified framework. The method uses a sparse PGM that exploits locality of interactions between atoms and residues. Second, a novel method for sampling sub-loops is developed to generate statistically unbiased samples of probability densities restricted by loop-closure constraints.
Numerical experiments confirm that SLIKMC generates conformation ensembles that are statistically consistent with specified structural preferences. Protein conformations with 100+ residues are sampled on standard PC hardware in seconds. Application to proteins involved in ion-binding demonstrate its potential as a tool for loop ensemble generation and missing structure completion.
- Conformation sampling
- Monte Carlo methods
- protein loops
- ensemble generation
- graphical models
Sampling conformations of kinematic chains -- rigid objects connected by articulated joints -- is a fundamental problem in protein structure prediction, the geometry of folding linkages, and robot motion planning. Sampling poses a challenging computational problem when chains are large and must satisfy a variety of constraints and statistical preferences. Conformations may be required to satisfy hard feasibility constraints, such as loop closure and collision avoidance, while also obeying soft preference constraints, such as low energy and high structural likelihood. Particularly around folded protein structures, the subset of feasible and favorable conformations comprises a miniscule fraction of the conformation space, and due to the "curse of dimensionality" this fraction shrinks dramatically with the dimensionality of the state space. Because interesting biological macromolecules have large numbers of degrees of freedom, ranging up to hundreds or thousands, new techniques are needed to sample severely constrained conformations efficiently.
Protein loops are flexible structures that often deform during binding, and are extremely important for understanding protein functioning [1]. Loop sampling has been used in missing fragment reconstruction, generating fluctuations in equilibrium conformations, and generating decoy sets for function prediction. Such applications typically require methods for sampling energetically-likely and diverse configuration ensembles rather than optimizing a single point estimate. The loop closure constraint, which requires the terminal atoms of a loop to lie at fixed positions dictated by the surrounding structured regions, poses a major challenge in sampling. Existing loop sampling methods include discrete search [2], optimization [1], and inverse kinematics (IK) methods [3–6]. Fiser et al's [1] approach takes an energy function that encodes spatial restraints and preferences on dihedral angles, and then runs a numerical optimization to minimize that energy. Optimization is relatively computationally expensive, which is usually worthwhile for single structure prediction but less so for generating conformation ensembles. Discrete search methods are able to explore a wider space of conformations by incrementally building a tree of clash-free subchain conformations starting from one end of the loop and progressing toward the terminal end [2, 7, 8]. Although effective for small loops, these methods do not scale well to large loops due to the problem of combinatorial explosion. As a result, discrete search is intractable with chains containing 7-8 or more residues. They also introduce discretization artifacts, and are not able to close the gap between a terminal atom and its desired position. Inverse kinematics (IK) techniques from the robotics field have been adopted to sample conformations with exact loop closure [3–5, 9]. However, these methods prioritize the loop closure constraint and do not take energies into account during sampling. Hence, some authors employ a secondary energy optimization step to generate more plausible conformations [3, 6, 10].
For each of these methods, the sampling distribution is throughly entangled with the sampling procedure. To achieve a desired distribution, the sampling procedure must be tuned in an opaque, nontrivial manner, and it is unclear that a desired distribution can even be achieved. Instead, extensive post-hoc empirical testing to assess the quality of the resulting distribution and to argue that a method samples well. Monte Carlo (MC) techniques represent a more principled class of approaches that sample directly from a desired destribution. They have a long history of use in computational biology because they can quickly explore multiple energy minima and transition pathways, while molecular dynamics and optimization techniques often get stuck in single local minima [11–14]. They are also well-suited for generating conformation ensembles. The general Metropolis-Hastings approach generates a sequence of incrementally perturbed configurations via a random walk, with a carefully-designed acceptance criterion (the detailed balance condition) that ensures that the sampling distribution approaches the desired one as more samples are drawn. However, there is a tradeoff in choosing the perturbation size: small perturbations raise the fraction of accepted moves but lower the speed of conformation space exploration. Moreover, standard MC techniques cannot be directly applied to protein loops due to the loop closure constraint, which causes each step to be accepted with probability 0.
Characteristics of loop generation techniques
Loop closure
Prior distribution/energy function
Global search
Inverse kinematics sampling
Discrete search
Finite subset
Standard Monte Carlo
Y, reqs. mixing
Y, reqs. mixing
SLIKMC is a Markov chain Monte Carlo (MCMC) method that takes as input an experimental conformation scoring function Φ, a protein structure from the Protein Data Bank (PDB), the beginning and ending residues of the loop, and outputs a sequence of perturbed loop conformations such that the sequence asymptotically approaches a probability distribution proportional to Φ. If the structure is missing, a rough initial structure is sampled using existing inverse kinematics loop closure techniques. To generate a subsequent conformation, it performs the following operations:
- 1.
Sample a new subloop conformation that satisfies kinematic constraints.
- 2.
Compute the Metropolis-Hastings importance ratio α of the new conformation against the previous conformation.
- 3.
Accept or reject the new subloop conformation with probability α.
The method terminates when a fixed number of conformations are generated or until a desired time cutoff is reached. The novel contributions of this paper include an exact derivation of the importance ratio α for the inverse kinematics sampler of step 1 and the use of sparse PGMs to evaluate the importance ratio quickly per-subloop. We also describe extensions that handle flexibility in side-chains and molecules with multiple branches or loops (e.g., polycyclic compounds).
As a MCMC method, SLIKMC samples from a complex joint probability distribution by constructing a Markov chain whose equilibrium distribution is equal to the desired distribution. It is a hybrid MCMC algorithm that combines blocked Gibbs sampling and Metropolis-Hastings (M-H) sampling. M-H permits the use of non-normalized probability distributions, which is important because it is relatively simple to define a useful scoring function but virtually impossible to ensure that it integrates to one. The blocked Gibbs sampling method samples a small subloop at each step, which helps SLIKMC scale better to large chains, because acceptance rates decrease roughly exponentially in the number of variables sampled at once. This section will first review classical MCMC methods and then describe the new approach.
Markov chain Monte Carlo framework
where T is the system temperature.
is called the importance ratio. If the ratio is greater than 1, then the new sample is accepted; otherwise it is accepted with probability equal to the ratio. With the detailed balance construction, P (x) is indeed the stationary distribution of the Markov chain generated by successive samples.
The key question for M-H is how to choose a proposal distribution that we can sample from and evaluate. The acceptance strategy must evaluate the terms in (3) exactly so that the M-H algorithm respects the detailed balance. One of our key contributions is a technique for evaluating Q exactly when sampling from closed chain submanifolds, which enables our method to generate an unbiased sampling sequence.
and keeping the remaining variables fixed. The variable is updated and the index i is incremented in looping fashion. If the dependencies between the variables are sparse (e.g., every variable x i only depends on a handful of variables rather than the remaining n - 1 variables), then Gibbs sampling can be efficient even for very large problems. This is exploited in sparse PGMs. Blocked Gibbs sampling is a variation of Gibbs sampling that groups multiple variables as a block and samples the block from the joint distribution conditioned on all other variables.
Our method combines Gibbs sampling with M-H sampling to generate a new sample from (5). To do so, simply consider all other variables fixed, sample from a conditional proposal distribution , and then apply the importance ratio test as usual to determine whether to accept the step or keep .
Sparse factored models
where each ϕ i is known as a factor and each S i is a subset of {x1, ..., x n } known as the domain of the factor ϕ i . For example, in protein structure prediction factors may include Ramachandran plots relating each pair of dihedral angles (φ, ψ), steric clashes, energy functions defined over atom positions, and prior knowledge from B-factors or electron density maps.
Probabilistic graphical models like Bayesian networks and Markov random fields are inherently factored: the domain of each factor consists only of a vertex and its neighbors in the graph. A graphical model is sparse if each variable x i is involved in only a handful of factors (i.e., bounded by a constant unrelated to n), and hence only interacts directly with a few other variables. An important consequence in the discrete case is that probabilistic inference is computationally tractable in sparse models (polynomial in n), whereas inference is intractable in dense models (in general, exponential in n). A key step in our method converts the representation of a kinematic chain from dense to sparse form, as described below. The implementation described in this paper currently supports:
Ramachandran plots ϕRP(r)(φ, ψ) which vary by residue r.
Steric clashes ϕSC(j, k)(p j , p k ) which are 0 if atom j collides with atom k and 1 otherwise.
B-factors defined as Gaussians where µ j is the predicted atom position and B j is the B-factor value in the protein's PDB file. A constant of proportionality c can be set by the user according to his/her confidence in the quality of the B-factor estimates.
Side-chain rotamer distributions, as described the Side Chain Sampling section.
Each factor can be evaluated quickly, but over thousands or millions of evaluations they accumulate significant computational cost. Significant savings can be achieved in sparse models, because when a few variables are changed, the change in Φ can be calculated quickly by only evaluating those factors involved, rather than recomputing Φ from scratch. Although steric clashes are theoretically considered as O(n2) pairwise factors, in practice we use a grid-based hashing data structure that only checks nearby atoms for collision. As a result, each Gibbs sampling step can be performed in O(1) time.
In future work we are interested in including additional statistical potentials and/or all-atom energy function terms in scoring. With a naive implementation, each atom is involved in O(n) pairwise interactions, but we expect to exploit the weakness of distant interactions to reduce the number of factors included in the computation.
Kinematic chain modeling
Consider a jointed kinematic chain with reference frames T0, T1, ..., T N , connected with relative rotational angles q1, ..., q N . For a protein backbone, there is a one-to-one correspondence between frames and backbone atom positions p1, ..., p M , and the rotational variables are simply the backbone dihedral angles φ1, ψ1, ..., φN/2, ψN/2.
Although it is standard practice and beneficial for certain algorithms to define the system state with a minimal set of coordinates, e.g., x = (T0, q1, ..., q N ), a key step of our method is to consider an expanded state. Minimal coordinates use the fact that each subsequent frame T1, ..., T N can be determined from x through straightforward forward kinematics, leading to a lower dimensional representation. However, this approach eliminates sparsity in the probabilistic model because a factor defined on T N will depend on all variables, a factor defined over TN - 1will depend on all variables except q n , and so on. Moreover, if a sampler is asked to generate certain variables from a density defined over T1, ..., T N (for example, atom positions), the generated distribution may be biased unless it computes the determinant of an N × N metric tensor for each evaluation of Φ. As described below, this is a consequence of nonlinear transformations of distributions (see Appendix). On the other hand, computing determinants takes O(N3) time, which scales poorly with large N.
where is the relative transformation of frame j relative to frame j - 1 and R(a, q) is the rotation of angle q about axis a. Fixed-endpoint constraints can also be encoded with indicator factors ϕ closure (T0) and ϕ closure (T n ) that are zero everywhere except at the fixed frames.
With (7) encoded so that factors contain few variables in their domain, the model becomes sparse. However, we have added the complication of maintaining a valid kinematic structure, because the set of x for which Φ is nonzero lies on a lower-dimensional manifold. Technically speaking, the probability density must be considered with respect to a base measure that assigns finite, nonzero density to the manifold. For 3D chains, the state space has dimensionality 7N but the manifold has dimensionality 6 + N for free-endpoint chains or N - 6 for fixed-endpoint chains. The next section will describe how we handle these submanifolds in detail.
Block sampling and selection
A block is a subset of variables that are simultaneously sampled. The number of variables in a block must be sufficiently large to give at least one continuous degree of freedom of movement. The Metropolis-Hastings criterion is used to accept or reject a move because it is unrealistic to sample directly from the block's conditional density. This key subroutine, Sample-Block-MH, takes as input the previous sample x(k)and a block B of b consecutive joint angles and their intervening frames. It then samples a candidate move, and accepts it according to the M-H criterion. Pseudocode is as follows:
- 1.
Using Sample-Block as described below, sample a candidate conformation of B at random, keeping the rest of the chain fixed.
- 2.Compute the M-H acceptance probability
- 3.
Accept the move with probability α.
Here the subscript B denotes the subset of variables in the block, while the subscript C denotes the complement of the block. The score Φ B calculates the product of factors ϕ i whose domains S i overlap with B, which is more efficient than recomputing Φ from scratch. The remaining details of the method -- the block size, the block sampling procedure, and calculating the sampling probability Q B -- are described in detail in the remainder of this section. To generate a new conformation x(k+1)of the entire chain, Sample-Block-MH is called several times with overlapping blocks incremented sequentially down the chain. Block ordering (e.g. forward, backward, or random order) has no effect on the asymptotic distribution and experiments suggest virtually no noticeable effect apart from the first handful of samples. Thanks to sparsity, each pass is performed in O(N) time, which takes a fraction of a second for chains with hundreds of variables.
How many variables should be included in a block? Standard Gibbs sampling (i.e., b = 1) does not work because loop closure constraints constrain the conditional density of any variable given the rest (5) to a Dirac. Hence, the state would never change. In fact, no mixing occurs for b ≤ 5, except possibly at singular conformations, which occupy a set of measure zero in conformation space and are therefore unlikely to occur naturally. For 6 angles, analytical inverse kinematics (IK) techniques are available to compute solutions for a pair of fixed end frames [9]. In fact, any number from 0 to 16 solutions may exist for a given 6-angle problem. Nevertheless, b = 6 is not suitable because it restricts the random walk to only a finite set of conformations.
- 1.
Sample values for the independent subchain at random.
- 2.
Attempt to close the chain by calculating an analytical IK solution for the dependent subchain. We use the method of [9].
- 3.
If more than one IK solution exists, one is picked at random, and if no solution exists, the process terminates with failure.
Calculation of sub-loop sampling densities
To calculate the M-H importance ratio, we must calculate sampling density for the sampling procedure Sample-Block. Several concepts from differential geometry are required in order to derive this density .
where is the Jacobian of the function f. Here we have also introduced a positive semidefinite weighting matrix W for the purpose of weighting the relative importance of matching the prior along certain axes. In the standard case, W is an identity matrix, but it can also be useful to choose a nonuniform diagonal matrix to account for heterogeneous units (e.g., angle vs. position variables).
A remaining issue is that it is often difficult to explicitly compute the Jacobian of the IK function involved in f. In other words, with z ≡ z(y) denoting the 6 angles in the dependent chain, it is difficult to evaluate ∂ z /∂ y. So, we compute an implicit chart Jacobian by considering the implicit form of the constraints C(x B ) = 0. These vector-valued constraints state that the difference between the terminal frame of the subchain and the desired frame is zero.
holds as long as is invertible, which is true everywhere except at singular conformations. Each derivative of C in the above expression is a submatrix of the Jacobian and can be computed using standard techniques.
in which I is the identity matrix and all frame derivatives are calculated using the chain rule . These partial derivatives are calculated using standard techniques.
Beyond computing the proper sampling density, it is also important to design the algorithm to efficiently compute the M-H acceptance probability. Since clash detection takes 60 times more computation time than calculating the rest of the terms in Φ, we check collisions after determining whether a move will be accepted. Compared to the naive method, this method achieves an order of magnitude speedup.
Extension to other topologies
Although the core method applies to linear closed kinematic chains, it can be extended to handle other molecular topologies, such as free-endpoint chains and side-chains. In theory, polycyclic compounds may also be handled as well. Each new topological structure requires specialized block selection and sampling routines. For example, free-end-point chains need separate sampling subroutines for the start and end blocks. Standard MC methods are used to do so.
Side-chain deformations are important for shaping binding cavities, and SLIKMC can be adapted to generate side-chain conformations in the same graphical modeling framework. It is known that the side-chain conformation depends on the backbone dihedral angle of the corresponding residue [18]. This requires sampling side-chains after the backbone conformation is sampled. Furthermore, since the distribution of side-chain torsional angles are limited to small number of typical conformations (rotamers) for most residues [19], we sample side-chains according to experimentally-determined distributions.
Side-chain sampling
For side-chain conformation priors we use the 2010 Backbone-dependent Rotamer Library [20]. In this library, each rotameric residue is associated with a list of rotamers which representing the high probability regions for side-chain torsion angles. The probability of a rotamer conformation χ is modeled as a continuous distribution given the backbone dihedral angle pairs. The dihedral angle (φ, ψ) space of each rotameric backbone residue r is discretized into a grid and each cell [a, b] × [c, d] contains its experimentally observed probabilities P (χ | r, a ≤ φ ≤ b, c ≤ ψ ≤ d). Each distribution over χ is specified as a Gaussian mixture model. For non-rotameric residues the terminal χ angles are handled specially due to the asymmetry in their distributions.
where ϕ SC indicates steric-clashes and ϕR(r)indicates the side-chain conformation prior for residue r. Side-chain B-factors are typically not included since we want to give enough freedom to explore the conformation space, and our experiments indicate that the flexibility of the protein chain will reduce greatly when we specify B-factors as prior to both backbone and side-chain atoms.
Extending block sampling to include side-chains requires justifying the importance ratio carefully to ensure unbiased sampling. An efficient sampling procedure is as follows: first compute a closed-loop backbone subchain from the blocked Gibbs sampling step and compute its acceptance probability as usual. If accepted, sample each side chain along the block according to its backbone-dependent rotameric distribution. Because it is a Gaussian mixture, we can sample from ϕR(r)directly: pick a Gaussian from the mixture according to its weight and then sample from the Gaussian. Finally, reject the sample if the side chains collide.
Since the first term is simply the importance ratio of the backbone and ϕ SC is binary, we conclude that the block acceptance probability is either the backbone importance ratio if clash-free or zero if clashing. Hence the side-chain sampling procedure is sound.
Multiply-closed kinematic loops
It may be possible to extend SLIKMC to handle multiply-closed loops such as those that occur in polycyclic compounds. This requires special care to divide the structure into blocks that can be split into dependent and independent subchains, such that a conformation of the independent subset completely determines the dependent subset, up to some finite multiplicity. In other words, the independent subchains form a chart of the space of closed-chain conformations of the whole block. The union of all blocks must also cover all state variables.
Mixing and autocorrelation
In any MCMC method it is important to empirically examine the mixing rate of the Markov Chain. Firstly, it can potentially take many iterations to "forget" the effects of a poor initialization. For protein sampling, this is not a significant problem because we initialize the chain with the native structure in PDB, which is typically quite good.
Result and discussion
SLIKMC is implemented as an add-on to the software package LoopTK [21][22] for protein loop sampling and is available at http://www.iu.edu/~motion/slikmc/. All experiments are run on a Intel i7 2.7 GHz computer with 4 GB RAM. The library currently supports sampling with prior information from Ramachandran plots, steric clashes, and B-factors, and supports integration with the Backbone-Dependent Rotamer Library for side-chain sampling. Numerical experiments suggest that SLIKMC generates higher quality samples for large loops with lower computational cost than standard Monte Carlo techniques for open-ended chains and the RAMP loop completion package [23].
Loop sampling with prior distributions
Missing loop completion
Scalability tests on free-endpoint chains
We compare SLIKMC against a standard Metropolis-Hastings algorithm that samples backbone angles according to a Gaussian proposal distribution with 1° standard deviation. The target distribution for both methods includes steric clashes, Ramachandran plots, and B-factors. Note that standard M-H has probability zero of sampling a conformation that satisfies terminal endpoint constraints exactly, and is not applicable to closed loops. So, these tests ignore the loop closure constraint altogether.
Simultaneous backbone and side-chain sampling
We propose SLIKMC - a Markov chain Monte Carlo method for sampling closed chains according to specified probability distribution. A probabilistic graphical model (PGM) is proposed to specify the structure preferences. A novel method for sampling sub-loops is developed to generate statistically unbiased samples of probability densities restricted by loop-closure constraints and mathematical conditions necessary for unbiased sampling is derived. Simulation experiments show that SLIKMC completes large loops (> 10 residues) orders of magnitude faster than standard Monte Carlo and discrete search techniques.
SLIKMC is demonstrated to be applicable to various tasks such as conformation ensemble generation, missing structure construction. For future work we intend to integrate SLIKMC with more complex energy functions, statistical potentials, and machine-learning-based structural function predictors. Another limitation of the technique is that due to the locality of each block adjustment, large-magnitude global motions may take a huge number of iterations to sample, particularly when the motion must cross low-scoring chasms in conformation space. We intend to investigate annealing-like or random restart techniques for overcoming these difficulties, as well as different block choices that allow the algorithm to take larger steps. Finally, we are interested in extending our method to study simultaneous backbone and side-chain flexibility in protein-ligand and protein-protein binding.
This appendix presents a fundamental statement about probability densities under a transformation of variables.
for any subset U ⊆ A, where dµ is the m-volume element of M.
where X(u) is the m-volume of the parallelotope spanned by the axes of the coordinate chart f centered at u: .
Note that this can be expressed more compactly as det(A T A) where A is the matrix with v1, ..., v m as its columns. Hence, . Finally, substituting g u in the r.h.s. of (22) gives the desired result.
The authors thank Predrag Radivojac for valuable discussions that inspired us to start this project and helped clarify our understanding of protein structure and function. This research is partially supported by NSF Grant No. 1218534.
The publication costs for this article were funded by Dr. Kris Hauser.
This article has been published as part of BMC Structural Biology Volume 13 Supplement 1, 2013: Selected articles from the Computational Structural Bioinformatics Workshop 2012. The full contents of the supplement are available online at http://www.biomedcentral.com/bmcstructbiol/supplements/13/S1.
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- pbnelson: Wonderful pictures, Father. My family and I attended mass at Trinitas numerous times last fall, and your pictures bring back memories. I wish we were back there!
- Josephus Corvus: Jerome Charles said: This is no different than Jesus did… The big difference is that Jesus followed up with something like "Fro m now on avoid this sin so that someth...
- SanSan: HOW DEEP WILL THE DARKNESS BE?
- Semper Gumby: Eoin OBolguidhi r: Thanks for the movie recommenda tion. Good point about the god of the Koran, three examples: 113:2 Allah created evil 5:32 Note that killing for "cau sing...
- Fr Martin Fox: I read that report too, and it made me sick. As horrible as it is to read, there is something good about this report. Namely, it gives a very concrete image of what predatory ̶...
- Gregg the Obscure: it was with good reason that the civilized world referred to "the UNSPEAKABL E crime against natureR 21;. there isn' t good reason for perversion to be mentio...
- Semper Gumby: Thank you Fr. Z for the photos and travel writing. Please keep an eye out for scudos and scootas. (Mea culpa for that one Faddah.) acardnal: Sure, a travel bottle of ketchup will...
- SanSan: Time to really look at our parishes and young boys who are continuall y being "loo ked after̶ 1; by certain clergy. It's so sad that it has come to this. Those parishione rs...
- hwriggles4: Fr Z Good job on the contraptio n for the shower. When I was a Boy Scout, we were taught to use our resources and think. You did what works. I was also glad my dad trained my broth...
- Just Some Guy: This report was highly disturbing . But it is what people need to hear to realize the severity of our current problem. This is on tape. All the other abuse over the decades, similar...
- semperficatholic: Woah!!!!!! !!!!!!!!! What a sick and twisted, evil human being. That was such an evil laugh when he thought the boy was high. He should be kept in prison for a lot longer than his...
- Credoh: Sorry Father, http://www .personal. utulsa.edu /~marc-car lson/histo ry/coin.ht ml
- Credoh: From this web page, it appears that 4 scudi are worth roughly US$500 in AD2000 money. Which makes 15 scudi equivalent to around US$1,875. That' ;s a hefty fine alright 230; As a...
- Amerikaner: And thus the slow push we see on certain folks indicating doctrine can change over time… ;
- Gab: If God wanted a female priest He would have conferred this on the Blessed Virgin Mary. And since He didn' ;t, QED. Are there no other more pressing issues in the Church today?!!
- iamlucky13: "Lar ge numbers of our Christians are instructed by the press and do not know how to make theologica l distinctio ns because of a lack of education in theology. " It̵...
- RichR: Father, These posts remind me that there are beautiful things in this world. It also shows people that you aren't a mean old curmudgeon who sits in his home hating Vatican II ;-) You seem...
- Jerome Charles: Fr. MartinR 17;s premise is wrong. There is NO room for LGBT people in the Catholic Church. They should another church, for starters 8230; I don' t really believe that....
- Gab: Enjoying Your travelogue s, Father Z.
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- GERMANY: Pro-women's ordination group: "We want to take Mary off her pedestal"
- What's up at the southern border of these USA
- Lib liturgy positivists force people to stand after Communion
- Student 'steals' pro-life sign on camera, gets arrested, but she's the victim!
- Benedict XVI's recent essay is a subtle correction of Amoris laetitia ch. 8
- 15-18 July 2019: East Coast Priest Conference in Wheeling, WV – looks good!
- NEW BOOK from Martin Mosebach – Subversive Catholicism: Papacy, Liturgy, Church
- ASK FATHER: The TLM's Orationes Diversae and Oratio Imperata
- Historic chasuble rediviva
- MULTIPLE CMEs ARE COMING – GEOMAGNETIC STORM UNDERWAY NOW
- The shortage of priests didn't just happen by itself, it was engineered.
Let us pray…
Grant unto thy Church, we beseech Thee, O merciful God, that She, being gathered together by the Holy Ghost, may be in no wise troubled by attack from her foes. O God, who by sin art offended and by penance pacified, mercifully regard the prayers of Thy people making supplication unto Thee,and turn away the scourges of Thine anger which we deserve for our sins. Almighty and Everlasting God, in whose Hand are the power and the government of every realm: look down upon and help the Christian people that the heathen nations who trust in the fierceness of their own might may be crushed by the power of thine Arm. Through our Lord Jesus Christ, Thy Son, who liveth and reigneth with Thee in the unity of the Holy Ghost, God, world without end. R. Amen.
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subset: commoncrawl


text:
California Department of Transportation
Date: June 28, 2012
District: 10 - Stockton
Contact: Ken Paglia
Phone: (209) 948-7977
STOCKTON - Continuing the drive to rebuild California's infrastructure and spur job growth, the California Transportation Commission has allocated nearly $1 billion to 135 transportation projects statewide.
Approximately $600 million in funding was provided by Proposition 1B, a transportation bond approved by voters in 2006. The remaining allocations came from assorted state and federal transportation accounts. In total, about $13.8 billion in Proposition 1B funds have been distributed statewide.
"Proposition 1B continues to fund key transportation projects, which translates into a strengthened economy," said Caltrans Director Malcolm Dougherty. "Investing in our infrastructure will improve mobility and create a better future for Californians."
Some of the notable local projects that received funding include:
- San Joaquin County: $123,700,000 – Widen State Route 99 from four to six lanes, and improve and reconstruct various interchanges, from just north of Arch Road to just south of State Route 4 near Stockton.
- Stanislaus County: $37,100,000 – Reconstruct the interchange and construct auxiliary lanes at State Route 99/ State Route 219 (Kiernan Avenue).
- San Joaquin County: $30,994,000 – Reconstruct the interchange on State Route 99 from just south of Cottage Avenue to just north of Arch Road.
- Merced County: $1,406,000 – Construct double thrie beam median barrier from San Luis Dam Service Road to San Luis Forebay Bridge near Los Banos.
- Merced County: $11,882,000 – Realign and widen a portion of State Route 99 to six lanes and construct a new interchange to replace the Buhac Road Interchange.
Please see the attached file for more information about all the projects that received allocations.
# # # #


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A charity pirate auction to benefit Villalobos rescue will be held at the Gold Coast Pirate Festival, at Lake Casitas, Ojaj.Dog friendly too.
The dates are September 23 and 24.Come on out, it's fun!
Faire hours are: 10:00 AM to 6:00 PM both days.
Admission: Adults $14.00, Children under 12 $7.00
Seniors $12.00
Parking $3.00, Adult weekend pass $22, Children weekend pass $10.
Group rates available. Admission includes all entertainment and plays. Seating is limited on hay bales.
For more info:
Here are some cool pictures of past events.
*edited by Marinepits to add to calendar*


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WAILUKU - The county Mayor's Office is working with the state Department of Agriculture (DOA) to get the word out about an infestation of little fire ants on Maui.
According to DOA officials, the ants spread to Maui from Hawaii Island back in December. However, further investigation has shown that the ants may have been coming over on inter-island shipments to Maui for the past year.
"This is a serious matter," said Mayor Alan Arakawa. "These ants can wreak havoc on a community. Their stings can cause a lot of pain and even blind your pets if you are not careful. We need to help the Department of Agriculture to identify possible infestation sites, so that they can contain the situation. We don't want another invasive species on our island if we can help it."
Article Photos
Little fire ants are much smaller than the common tropical fire ants.
According to the DOA, the ants were traced back to hapu'u (Hawaiian tree fern) shipments at Lowe's and Home Depot on Maui.
Department officials are asking that any Maui resident who purchased hapu'u from either store over the last 12 months to check their fern and the area where it is located for ants.
The best way to do this is to apply peanut butter to a chopstick and push the stick into the fern or the ground nearby. If you see ants on the chopstick, place the chopstick in a plastic bag and put the bag in your freezer. Call the DOA, and an inspector will be sent to your residence for further investigation and, if need be, treatment to rid the area of ants.
Please note that the LFA is no more than 1/16-of-an-inch in length and should not be confused with the larger tropical fire ant that has already established itself on Maui.
The number to call the Department of Agriculture on Maui is 872-3848, or contact the Maui Invasive Species Committee at 457-6472.


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H ere is the full list of the endorsements the Camera made for 2012. Our full endorsements began on Oct. 14. Links to all of them are available online.
President of the United States:
President Barack Obama has shown cautious, steady leadership during the slow emergence from an extraordinary recession. He did so despite the most divisive, obstructionist opposition in memory. We support President Obama for a second term. Challenger Mitt Romney expresses a fundamental misunderstanding about the majority of Americans. And his positions on everything from health care to guns have so radically changed over a short span of time make him a risky choice for such an important office.
The U.S. House of Representatives:
Rep. Jared Polis is responsive to his constituents. He has shown positive leadership and intelligence in the 2nd Congressional District since 2009 and we support his continued service in Washington.
Brandon Shaffer, a Longmont military veteran, lawyer and state Senate president, is well-known as a man who can work with Republicans and Democrats alike. We endorse Shaffer for newly redrawn 4th Congressional District.
State Amendments:
No on Amendment 64.
Amendment 64 is the biggest decision facing Coloradans for the state this year. And while we support the legalization of marijuana, we urge voters to say "no" to Amendment 64. It includes putting a dedicated tax into a constitution that is riddled with tax measure problems. It includes specificity on so many issues — how to transport your plants, how to grow them behind locked doors — that it is totally problematic as a policy. Marijuana should be legal and regulated. This is not the way to do it.
Neutral on Amendment 65.
This would instruct our Congress members to support campaign finance limits, and instruct the state legislature to ratify the amendment that results. A vote for Amendment 65 will send a message to Colorado elected leaders, but we're not convinced sending messages should be enshrined in a state constitution. But we agree with the ideals of it, and we don't think it will have negative consequences.
Yes on Amendment S.
This bill would update the state personnel system, and has bipartisan support. It is reasonable that if we're going to ask the government to be more efficient, we should give it the tools to do so.
Colorado House of Representatives:
Dickey Lee Hullinghorst for House District 10.
Ellyn Hilliard for House District 11.
Mike Foote for House District 12.
Claire Levy for House District 13.
Dianne Primavera for House District 33.
Colorado Senate:
Matt Jones for State Senate District 17.
Rollie Heath for State Senate District 18.
Lee Kemp for State Senate District 23.
University of Colorado Board of Regents:
Stephen Ludwig for the at-large seat on the Board of Regents. The incumbent spearheaded efforts to make it easier for community college students to attend CU; a great solution for a tough economy and non-traditional students. He supports keeping guns off campus and favors unsubsidized tuition for undocumented high school graduates who were brought here as children.
Colorado Board of Education.
Angelika Schroeder for the Colorado Board of Education 2nd Congressional District. Schroeder has experience on the state board for four years, plus a combined 20 years of education experience before that, including eight years on the Boulder Valley school board. With so many changes going on in the schools including new ways to evaluate teachers, that experience will serve the district well.
Boulder County Board of Commissioners:
The Camera endorses Elise Jones, a Boulder Democrat, for District 1 and incumbent Deb Gardner, a Longmont Democrat, for District 2.
The Regional Transportation District 1:
Cheryl Hauger. Based on her experience and leadership on local transportation issues, the Camera endorses the former Erie Trustee. She would be an advocate for Bus Rapid Transit, and a Longmont-Denver connection, including considering rail. She was a founding member and vice chairwoman of he North Area Transportation Alliance and represented Erie on the Denver Regional Council of Governments.
Superior Town Trustees:
The Camera endorses Joe Cirelli, Elia Gourgouris and Debra Williams.
City of Boulder Issues:
Yes on 2A: Climate Action Plan Tax Extension. The tax is scheduled to expire in March, and raises about $1.8 million for energy efficiency and renewable energy programs.
Yes on 2B: Sales and Use Tax Extension. This is set to expire in 2015, so the vote will move the date back to 2035. It's a critical funding mechanism for parks and recreation.
Yes on 2C: This simply brings City Council compensation closer to reality. Members would be compensated for up to 52 meetings per year rather than four meetings per month.
Yes on 2D: This would allow the city to offer longer leases to city properties — from the Dairy to the Spice of Life Center — which would allow those organizations to get competitive loan rates to make improvements.
St. Vrain Valley School District 3A:
St. Vrain is asking voters for a $14.8 million mill levy override. It will go to early education initiatives, to keep and hire high-quality teachers and to upgrade technology. We applaud the business and community leaders in the St. Vrain Valley who see quality schools as an important engine of our local economy. Vote yes on 3A.
Longmont Ballot Question 300:
No on 300 . This measure would ban hydraulic fracturing in the city limits. The ban would be part of the city's charter. We think hodgepodge bans in Colorado are not an efficient energy strategy, especially as we attempt to reduce reliance on coal. We don't think a ban will withstand lawsuits. But the legislature and the governor's office must address fracking concerns and give local municipalities more power to address zoning, traffic, setbacks and noise. The state also needs more gas drilling and well inspectors.
— Erika Stutzman, for
the Camera editorial board


text:
Posted on Aug 22, 2014
Medication Reminders and In Home Assisted Living
Life can get pretty hectic sometimes. If you have been taking care of an elderly loved one through the summer, when life tends to be a bit more relaxing, you may find that the daily grind is making it difficult to regularly visit now that fall is approaching. Most children are back in school; summer vacation is over. If you are also working a full time job, it is understandable that attempting to balance all responsibilities can get tricky. If you are concerned about your elderly loved one and their ability to remember to take their daily medications, there are some tips to keep them on track.
Medication reminders don't have to be tremendously extravagant to be effective. Something as simple as a sticky-note on the refrigerator to help your loved one remember to take medicine with food can be very helpful. Another helpful tool for medication reminders is a weekly pill box. This pill dispenser helps to keep your loved one on track with remembering if the daily required pills were taken.
Technology can be a very useful tool when it comes to medication reminders. If your loved one is familiar with a smartphone, you can set up a calendar application to chime daily at certain times. If a smartphone is a bit complicated, a simple cell phone is capable of ringing a daily alarm as well. There are also talking alarm clock medication reminders that can be purchased online. A medicine reminder watch might also be a handy, low-key option.
If you find that you want more peace of mind when it comes to your elderly loved one taking their medications on time, but are unable to make the daily visit, in home assisted living might be the answer to your needs. A compassionate and responsible caregiver will be the daily medication reminder and will also be sure that your loved one is also eating a nutritious meal. When life gets hectic, it's nice to know that your loved one is not alone for long stretches of time. Companionship is an added bonus of in home assisted living.
If you would like to learn more about caring and dependable in home help for the elderly and the many benefits of professional in home senior care or dementia and Alzheimer's care, call Senior Helpers of Fountain Valley to speak to a senior care specialist today 714-593-1177! The compassionate senior care specialists at Senior Helpers can also guide you through the process of receiving the Veterans Administration Aid and Attendance Benefit if your elderly loved one is a veteran. In home senior care and in home assisted living allows your loved one to stay in the comforts of their own home for as long as possible while receiving the level of care they need. Senior Helpers of Fountain Valley provides a wide range of services including Alzheimer's and dementia care, personal assistance, companionship, and so much more to all areas of Orange County, Huntington Beach, Fountain Valley, Costa Mesa, Laguna Hills, and Laguna Woods, California.


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The Van Raalte Institute of Hope College and Western Theological Seminary are hosting the first half of a two-site conference scheduled in celebration of Dutch and Dutch-American contributions to North America.
The college and seminary are hosting the first part of "Colonial Clergy Conference: Dutch Traditions and American Realities" on Sunday and Monday, Sept. 27-28, at the Haworth Inn and Conference Center. The conference will continue at First Reformed Church in New Brunswick, N.J., on Saturday, Oct. 24.
The events are scheduled in conjunction with the 400th anniversary of Henry Hudson's exploration of the East Coast river that now bears his name. The English Hudson was working on behalf of the Dutch East India Company when he explored the river in 1609. His voyage ultimately led to the creation of the Dutch New Netherland colony and eventually the founding of New Amsterdam - today's New York City.
Although the conference is occasioned by Hudson's transformational voyage, the event's two locations illustrate and commemorate not only the role of the Dutch in the East in the 17th century but also the impact of the new wave of immigrants to the Midwest in the 19th, according to Dr. Jacob E. Nyenhuis, who is director of the Van Raalte Institute.
"Too often we Midwestern Dutch-Americans tend to think that the 19th-century immigration is the only one that is important for us," Nyenhuis said. "What we hope to demonstrate with this conference - as well as in other ways - is that our ancestors who settled here were connected to the earlier Dutch settlers by both national heritage and religious faith. By celebrating the colonial clergy at a conference in the Midwest, we hope to awaken a keener awareness of the ongoing traditions that link both us and the Eastern Dutch-Americans to the Netherlands."
The conference at Hope will feature presentations by scholars from the U.S. as well as abroad. They will discuss historical figures ranging from Bastiaen Krol, an early leader of the New Netherland colony, to Zeeland founder Cornelis van der Meulen. The activities will begin with a dinner on Sunday, Sept. 27, and continue with a lecture that evening as well as a series of presentations throughout the day on Monday, Sept. 28.
The topics and speakers are: "John Henry Livingston, 1746-1825," by John Coakley; "Bastiaen Krol, 1595-1645," by Willem Frijhoff; "Gideon Schaats, 1607-1694," by Firth Haring Fabend; "Rudolphus Varick, 1645-1694," by Leon van den Broeke; "Guiliam Bertholf, 1656-1725/6," by Earl Wm. Kennedy; and "Cornelis van der Meulen, 1800-1876," by Hans Krabbendam.
Sponsors of the conference are from the Netherlands and from the East and Middle West of the United States. In addition to the Van Raalte Institute and Western Theological Seminary, the sponsors include the Collegiate Church of New York; Reformed Church Center at New Brunswick Seminary; Roosevelt Study Center; and the Reformed Church Archives. A book on the conference papers is planned.
The conference is being organized by Dr. Leon van den Broeke, the Van Raalte Institute's 2009-10 NAF Visiting Research Fellow, and Russell L. Gasero, archivist of the Reformed Church in America. van den Broeke is also pastor of the Federated Protestant Congregation of St. Pancras and assistant professor of religion, law and society at the VU University of Amsterdam.
The conference at Hope is open to the general public. Registration is $20 for the entire event, with the fee waived for seminary students and retired ministers/missionaries.
More information, including a complete schedule, may be obtained online at https://hope.edu/vri/. Additional information may also be obtained by calling the conference registrar, Karen Schakel, at the Van Raalte Institute at (616) 395-7678.
More information about the October 24 conference in New Jersey may be obtained at http://www.nbts.edu/clergyconference/.
The Van Raalte Institute is housed in the Theil Research Center located at 9 E. 10th St. The institute specializes in scholarly research and writing on immigration and the contributions of the Dutch and their descendants in the United States, but is also dedicated to the study of the history of all the people who have comprised the community of Holland throughout its history.
The Haworth Inn and Conference Center is located at 225 College Ave., facing College Avenue between Ninth and 10th streets.


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The latest beta patches added a couple of interesting mounts to the game, and I know you guys like mounts! Time for a mini-preview.
- The Reins of the Grand Expedition Yak will most likely be a fairly expensive mount. The current sell price to NPC is 15 000 Gold, that makes the buying price much higher. The mount is HUGE and will apparently come with two vendors like the WotLK mammoth.
- The Reins of the Crimson Riding Crane and Reins of the Amber Scorpion are from unknown sources.
MMO-Champion Charity Livestream Marathon
Nik and Kevin have started their charity livestream marathon. They will be leveling a Pandaren Monk from 1 to max level on the beta realm of Mekkatorque while trying to raise money in the name of MMO-Champion for the Save the Children charity started by Athene (Operation Sharecraft).
Join them for their non-stop live stream where all ad revenue raised not only on this weekend but from the whole month will also be donated to the charity (please whitelist the stream). Make sure to join the live chat and be around because whenever Nik or Kevin gain a talent point a giveaway will be done for your chance to win some awesome Razer goodies and WoW TCG loot cards!
Dragon Soul Difficulty Change
Annual Pass Beta Invite Update
Blue Posts
Originally Posted by Blizzard Entertainment
The Daily Blink - Striving to Help Whenever We Can
The Daily Blink can help you with your lost items too!