text:
Lecture 27 - Modeling with Partial Differential Equations - Part 2
Dynamical Modeling Methods for Systems Biology
Course 4 of 6 in the Systems Biology and Biotechnology Specialization
An introduction to dynamical modeling techniques used in contemporary Systems Biology research. We take a case-based approach to teach contemporary mathematical modeling techniques. The course is appropriate for advanced undergraduates and beginning graduate students. Lectures provide biological background and describe the development of both classical mathematical models and more recent representations of biological processes. The course will be useful for students who plan to use experimental techniques as their approach in the laboratory and employ computational modeling as a tool to draw deeper understanding of experiments. The course should also be valuable as an introductory overview for students planning to conduct original research in modeling biological systems. This course focuses on dynamical modeling techniques used in Systems Biology research. These techniques are based on biological mechanisms, and simulations with these models generate predictions that can subsequently be tested experimentally. These testable predictions frequently provide novel insight into biological processes. The approaches taught here can be grouped into the following categories: 1) ordinary differential equation-based models, 2) partial differential equation-based models, and 3) stochastic models.
The first week on MATLAB was a great refresher since I hadn't used MATLAB in a few years
A+. Great course, easy to follow, and amazing instructor. Thank you Eric!
Modeling with Partial Differential Equations
The description goes here
Lecture 27 - Modeling with Partial Differential Equations - Part 2 17:12
Eric Sobie, PhD
[BLANK_AUDIO]
We are now onto the second lecture
on mathematical modelling with partial differential equations.
[BLANK_AUDIO].
In the second lecture on PDEs, we're
going to continue discussing the Reaction-Diffusion equation.
We've seen two examples of this already.
And we'll just sort of reiterate why is it
that this equation occurs so frequently in biological systems.
And then we're going to the rest of the lecture is
going to be to introduce some PDE examples from the literature.
How have how have PDE simulations,
and in particular, simulations of Reaction-Diffusion
systems, how have they been used to gain new insight, into biological processes?
We're going to show an example of simulations of intracellular calcium.
We're going to show the predicted effect of how
cell shape can affect signaling and then we're going to
show the study that generated predictions and also
experimental validation of activity of some kinases within cells.
Where we left off before was looking at the
one dimensional cable equation versus the epithelial reaction-diffusion equation.
We showed the cable equation that looks like this and we discussed how
this term is the diffusion term and this term is the reaction term.
This is a reaction that, that increases
or, or decreases membrane potential and membrane voltage.
And then we also showed how that was analogous
to this equation here for diffusion of bicarbonate across
the epithelium, where this is the diffusion term and
this was, this term described a reaction that consumes bicarbonate.
Now we're going to show some other biological
processes where reaction-diffusion equations also come into play.
One example of where reaction-diffusion equations come into play is when
we're thinking of changes in intracellular calcium during release.
Now if we wanted to derive equations for intracellular calcium we would use the
same sort of rules, same procedure that
we used for describing bicarbonate across the cells.
So if you could just replace bicarbonate with, with calcium
in the derivation that we had in the last lecture.
So we're not going to go through that whole derivation again,
but how did how did reaction-diffusion equations come into play here?
Well, the important thing to note is that in,
in heart cells, which is one cell type where
release of intracellular calcium is extremely important, in heart
cells, calcium is released from discrete clusters of channels.
And we can, that can be illustrated here.
We're not going to go through all of the, all
of the biological details, and all of the terminology.
But basically, this represents the cell membrane up here.
You have these discrete membrane channels within the cell membrane.
These membrane channels can let in calcium.
When calcium comes in through an open membrane channel,
so the way that we've represented this here is
that this red one is open and it's letting
calcium in, all the other membrane channels are closed.
This is, this calcium can go up and this calcium can bind
to these release channels that are part of the sarcoplasmic reticulum membrane.
So the sarcoplasmic reticulum is the endoplasmic particulum in other cells,
but in muscle we refer to this as the sarcoplasmic reticulum.
And these channels, these release channels in
the sarcoplasmic reticulum membrane are sensitive to calcium.
So when calcium comes in through this
membrane channel, those calcium ions can bind to
these release channels and these release channels can
then open and they can have calcium flow.
They can release calcium.
Calcium will flow from the inside of the sarcoplasmic reticulum into the cytosol.
And the key point here is that we're
talking about discrete clusters of, of these channels.
So if this is the only membrane channel that's open,
then you're only going to get release from these release channels here.
Whereas these other ones over here and these over
here and these over here are not going to release calcium.
Well, what that means is that when calcium comes out, it's going to diffuse.
It's going to move from left to right here or from right to left over here.
And again, we're going to have a reaction-diffusion equation, where
the reaction in this case is the release process.
And then after the calcium gets released,
it diffuses from, from one location to another.
So again, the released calcium diffuses within the cytoplasm and
the reaction, in this case, is the release of calcium.
And once the calcium gets into the,
the cytoplasm, then there will buffering reactions.
Calcium combined to, to various instances of other proteins and so those buffering
reactions are also going to be part of reaction term, in this case.
So again, release of calcium from discrete clusters of channels in heart
cells will also yield a reaction-diffusion equation describing the process.
What's another example of a reaction-diffusion
equation that's that's encountered in biological processes?
Well, other second messengers another very common one besides calcium is cyclic AMP.
Other intracellular second messengers are
also going to obey reaction-diffusion equations.
Cyclic AMP is produced by an enzyme that's illustrated
up here called adenylyl cyclase, or AC for short.
And adenylyl cyclase is located in a cell membrane.
If adenylyl cyclase were located everywhere within the cytoplasm,
then the cyclic AMP might not be able to diffuse.
But when cyclic AMP is produced at the adenylyl cyclase, it can diffuse away.
As it diffuses away, it combines to different effector molecules.
Protein kinase A is one, Epac is another effector molecule, and it
can also be degraded and the degradation process is shown here, with PDE.
For, this is not for partial differential equation in this case, this
is for phosphor-diesterase so the cyclic AMP is produced at a discreet location.
It's produced at the cell membrane by adenylyl cyclase.
It can diffuse a way and then it can bind to the different proteins or be degraded.
And so these binding and degradation processes are a reaction term.
The diffusion results from the fact that it is produced at a discrete location.
So these examples show that these sorts of processes are very common.
It's very very frequently within biology, you will encounter something
where a species is produced or generated at a particular location.
It can move away from that and then as it moves away, other things can happen to it.
Often degradation or, or binding to other, other species.
So because these processes are common,
reaction-diffusion equations are also very common.
And this, these are the reasons why reaction-diffusion
equations are encountered so frequently in describing biological processes.
Now, for the remainder of this lecture we're going to
show some examples of partial differential equation-based modeling space.
I feel like we don't have enough time in this class to really
go into PDEs with the same depth with which we went into ODEs.
And it's also true that there have been a lot more modeling studies
in Biology that have used ordinary
differential equations, compared to partial differential equations.
So we did sort of bias it in a way that was related to, to how frequently
these things are used so we're not going to have
the same amount of depth that we had previously.
But I do want to show some examples of how PDEs have been used.
We're going to go through these in a little bit of a cursory manner, however.
One example is calcium in the cytosol and
calcium in sarcoplasmic reticulum during release in heart cells.
This is actually one of the studies from my lab
that was published a few years ago in the Biophysical Journal.
And this is showing a simulation
of cytosolic calcium and sarcoplasmic reticulum calcium.
And what you can see is that these are
plotted as a function of time, which goes along
this axis here, and location, which goes along this
axis here and the concentrations are, are color coded.
The details aren't so important here.
But this and the bottom panels here, which, which
zoom in a little bit on the images that
are shown in the top, you can see simulations
from one and these are the locations that release calcium.
And we can see simulations that as the calcium
moves from one location to to the next location.
And we looked at here at slow diffusion
within sarcoplasmic reticulum and then a medium speed
of diffusion within the sarcoplasmic reticulum and fast
speed of, speed of diffusion within the sarcoplasmic reticulum.
Take all these numbers down here, which are in
units of length squared per time, are our diffusion constants.
And again, without getting into all the details the main message here is that the
calcium diffusion within the sarcoplasmic reticulum matters just
as much as calcium diffusion within the cytosol.
So in this particular example, we actually
looked at two coupled partial differential equations,
one for calcium within the cytosol, another
one for calcium within the sarcoplasmic reticulum.
And in terms of the, the patterns that, that emerged,
in terms of what we saw during the release process,
we, we found that the calcium diffusion within the sarcoplasmic
reticulum is as important as calcium diffusion within the cytosol.
A second example that I want to discuss was a study that looked at
how does the cell shape influence the signaling that is observed within a cell.
And these are some images that are shown from this paper
here by Meyers Craig, and Odde from 2006 in Current Biology.
This was a great paper where they looked at different
shapes of cells and they looked at how different shapes
of cells could could affect the the patterns that were
observed In terms of the signaling molecules that were produced.
And these images here, the, the, heat maps that are at these discrete locations
within cell, are showing relative activity of,
of the various kinases or various signalling molecules.
And the message of this cell, sorry, the message
of this particular study, this paper, was that geometry matters.
The degree of phosphorylation will be different in
thick regions, compared to thin regions of the cell.
For instance, in the thin region here you
see you get very little activation in the center.
But in the thin region here, at the very leading edge of this
polarized cell, you get very, very strong
activation of the, whatever your kinase is.
And I think that you know, biologists and biochemists are very
used to thinking that the amount of signal that you get
depends a lot on the on, on the activity of your
enzymes, depends on, on the whatever species are, are producing that signal.
So if you're talking about phosphorylation or
a particular molecule, biologists are very comfortable
with the idea that the amount of
phosphorylation you get depends on the kinase
activity, but this was a, this was an influential study and this was a
very cool study, because it illustrated that
while it's not just the, this biochemistry.
It's not just the kinase activity that matters.
It's also the geometry that matters very much.
[SOUND]
And finally, a third example that I want to discuss is a study
that predicted and then also measured
spacial gradients in, in signalling molecules.
And this was a study that actually came
out from some colleagues of mine at Mount Sinai.
The first author, Dr. Susanna Neves and the senior author on this study was
Dr. Rob A Engar, who also teaches a course on Systems Biology in Coursera.
You can see that these are some really cool
simulations they did of protein kinase-A activity and MAP-kinase activity.
We encountered MAP-kinase in some of the some of the earlier lectures.
This is mitagen-activated protein kinase activity in realistic Geometry.
So they took the neurons, they traced the geometries and then they simulated how the
activity of these would vary at different
locations within these neurons that had realistic shapes.
And in addition to doing simulations with these realistic
geometries, they also did some simulations in idealized geometries.
And these are some space-time images similar to
what we saw two slides ago in the simulations
of intercellular calcium, where you have distance along
this axis here and time along this axis here.
And these are idealized neurons with different diameters.
You can see you go from one micrometer diameter, to
1.5 micrometers, down to two and down to three micrometer diameters.
And they did simulations of how protein kinase-A activity or MAP-kinase activity
varied as a function of distance and as a function of time.
And the message in this in this paper was,
one message was, that spacial signals depend on geometry.
We saw that in the previous study, however, by Myers et al.
What was unique about this, this study by Neves, et al, was he said that spacial
signals don't only depend on Geometry, but they
depend on whatever processes are turning the signals off.
So protein kinase-A gets activated when you have when you have an increase
in cyclic AMP due to, you know, due to activation of adenylyl cyclase.
This gets shut off in part because of the phosphodiesterases.
Those are the proteins those are the enzymes that are degrading cyclic AMP.
And what was what they looked at in this study was not just the was not just how
the geometry affected these processes, but also how the,
the, regulatory networks that these processes were embedded within.
In particular, whatever the, the signals that shut off the signals were.
Whatever those, processes were, how those affected the spatial gradients.
So this was one that, that looked at both the geometry and the biochemistry.
And one other thing that was really cool about this particular study
by, by Neves et al was that they didn't just make predictions using
the mathematical model, but then they
also made measurements of these spacial gradients
that were observed in in signaling
molecules, such as protein kinase-A or MAP-kinase.
So this is showing the the prediction and
then over here, you're seeing the, the experimental data.
So the two images on the left are, are
control images and then on the right you see how
the how activation of a particular a signalling cascade will
change your, your signal as a function of, of location.
And then here you have the the prediction when you're inhibiting whatever
the, the negative feedback is, when
you're inhibiting whatever, whatever shuts it off.
But the main message here is that what was cool about this paper was that they didn't
just make the predictions using the mathematical model, then
they also went in and tested those predictions experimentally.
And we some examples of that in our, in the earlier lectures.
In particular, on, on some of the
cell cycling, the cell cycle mathematical models.
You know, the purpose of doing the mathematical
modeling is not just to build the model.
One of the main purposes is to be able to generate predictions,
that then you can, that you can then go in and test experimentally.
To summarize this lecture, what we've seen is that
reaction-diffusion equations occur repeatedly in biology, and these occur
whenever the processes that produce some species and the
processes that degrade some species are, are spatially separated.
If the, if the production and degradation processes are,
are everywhere, then you won't necessarily get a reaction-diffusion equation.
In that case, ordinary differential equations will suffice.
But if the species is being produced at
one location and then it's being degraded at
some other locations, what you're going to end
up with is a reaction-diffusion equation describing that.
So that's why these sorts of PDEs are
encountered so often when we're looking at biological processes.
Another thing we see is that modeling studies based on PDEs
can provide insight into the relative
importance of biological versus geometrical factors.
So when you have something that is described by a PDE and when it's
in particular when it's described by a
reaction-diffusion equation, that reaction part can be important.
The diffusion part can also be important and that's
why you need a mathematical model in order to
be able to to tell you, well, you know,
in which circumstance is one more important than the other.
And that's how the, the model can really help.
It can give you insight into the relevance
importance of, of the biochemistry versus the geometry.


text:
DLA Piper Global Law Firm
DLA Piper partner Genève DuBois named to the Daily Business Review's Florida Trailblazers list
DLA Piper is pleased to announce that Genève DuBois, a partner in the firm's Real Estate practice, has been named to the Daily Business Review's 2019 Florida Trailblazers list.
The list recognizes "innovators and thought leaders" who have made significant marks on the practice, policy and technological advancement of their practice areas. The publication highlighted DuBois's role in co-founding DLA Piper's China-America Legal Team, which focuses on providing tailored legal services for Chinese investors looking to conduct business in the US.
DuBois represents US and global investors in their US real estate investments. She has extensive experience in complex transactional matters, particularly in regard to investors from China and other Asia-Pacific countries.
Josh Epstein
josh.epstein@dlapiper.com
Genève DuBois
DLA Piper is a global law firm with lawyers located in more than 40 countries throughout the Americas, Europe, the Middle East, Africa and Asia Pacific, positioning us to help clients with their legal needs around the world.
© 2020 DLA Piper. DLA Piper is a global law firm operating through various separate and distinct legal entities. For further information about these entities and DLA Piper's structure, please refer to the Legal Notices page of this website. All rights reserved. Attorney advertising.
Select a local version of the site
Our site provides a full range of global and local information. Tailor your perspective of our site by selecting your location and language below.
Morocco Maroc
China 中国内地
Hong Kong SAR China 中国香港特别行政区
Austria Österreich
Denmark Danmark
Finland Finland
France France
Germany Deutschland
Netherlands Netherlands
Norway Norge
Portugal Portugal
Ukraine Україна
Argentina Argentina
Bahrain Kuwait Oman
Qatar Saudi Arabia
UAE - Abu Dhabi UAE - Dubai
Canada (English) Canada (Français)
View all locations Discover how we work

redpajama_set_name: RedPajamaCommonCrawl


text:
Read to Review
Release Day Launch & Giveaway: Forever with Me (With Me in Seattle #8) by Kristen Proby
Posted December 2, 2014 by bookstobreathe in Book Blitz/Promo, Giveaway, New Release / 0 Comments
Title: Forever with Me
Author: Kristen Proby
Series: With Me in Seattle, #8
Published by Self-Published
Genres: Contemporary Romance, Erotic Romance
More Info: Goodreads
Purchase From: Amazon US
From the New York Times and USA Today bestselling author of the With Me in Seattle Series comes the end of a saga…
Dominic Salvatore seemingly has everything a man could want. He's found a new relationship with his father and the entire Montgomery family. His vineyard, Cuppa di Vita, is a success. There's only one thing that eludes him: a certain driven, intelligent, and sexy as hell blonde named Alecia.
Alecia works tirelessly building her event planning business. It's the most important part of her life. Despite the beautiful, lavish weddings she organizes, Alecia is convinced that the idea of true love is a myth. While Dominic is a sexy, intriguing man, welcoming the handsome Italian into her bed, and her life, is a risk she's not so sure she's willing to take.
However Dominic isn't used to taking no for an answer, and it's not long before these two are burning up the sheets and discovering a connection that neither can deny. But will it be strong enough to last forever?
"I'm going to eventually make you understand how amazing you are,tesoro." – Dominic Salvatore
I am absolutely thrilled to bring you the Release Day Launch for Kristen Proby's Forever With Me! Forever With Me is an erotic contemporary romance, and is the final book in the bestselling With Me in Seattle Series!
"You know what rhymes with drunk?" Sam asks. "Sex!"
"Nuh uh," Meredith replies with a frown. "But fuck does!"
"Drunk and fuck do not rhyme," Mark says with a surprised laugh.
"It's closer than sex," she says defensively.
"Everything rhymes with sex when you get to have it with an apa," Jules says.
"Julianne," Nate warns her.
"It's true!"
"What's that like, anyway? I've always wanted to know."
"You can't have sex with my husband." Jules frowns for a second, then a smile spreads over her gorgeous face. "Well, maybe you can."
"No," Nate replies quietly, "she can't. No offense, Alecia."
"None taken." I grin at the crazy-hot man. "You're hot as fuck, though."
"He really is," Jules agrees happily. "And the apa…wow."
"Will you get one?" I ask Dominic, just as he takes a sip of wine, and he immediately chokes.
"Fuck no."
"Maybe I'll have to find someone with one," I say thoughtfully. "Just to give it a try."
"That's it." Dominic stands with me in his arms and doesn't even set me down as he begins to stalk out of the tent.
"Where are we going?" I look over his shoulder and see the others laughing and watching us leave. I wave happily and they all wave back.
They're so friendly.
"I'm going to teach you a lesson, tesoro."
"A lesson?" I giggle and bury my nose in his neck, breathing him in. "I'm kind of dizzy."
We pass by the barn. I can hear voices, heavy breathing and Meg giggling.
"I think we found Meg and Will," I whisper into Dom's ear, as he hurries past.
"Merde, I didn't need to ever hear that," Dominic grumbles, making me giggle more. He strides around the store building, where I stood a few hours ago with Jules and Natalie, sets me on my feet, and pins me against the wall.
"I dare you," he begins with fire in his bright blue eyes, "to say again that you're going to go find another man to fuck."
"Um, it was a joke, babe."
His eyes narrow and his nostrils flare, and I know I'm in big trouble.
"Are you jealous?" I ask incredulously.
"Not usually," he says. "I'm not the jealous type, but what's mine is mine, Alecia. And you're mine. What I have with you, I don't want with anyone else. You're all I fucking think about."
He's gathering my skirt in his hands until it's bunched around my waist, and he slips his finger inside the elastic of the crotch of my panties and brushes the lips of my pussy, making me gasp.
"Dom!"
"That's right." He bites my lower lip, then soothes it with his tongue and pushes his finger farther into my panties. "Me. I'm the only one who can touch you here, or anywhere. This is mine."
With Me in Seattle series
The With Me In Seattle series is a book series that focuses on a family that lives in, you guessed it, Seattle. Each book centers around a different couple, but we will continue to see the characters that we love from the first books, all the way through to the end.
Come Away with Me (With Me in Seattle, #1)
Amazon US | Amazon UK | B&N | Smashwords
Being confronted on the beach by a sexy stranger wasn't part of Natalie Conner's plans for a peaceful morning taking photos. And why on earth would he think she's taking pictures of him, anyway? Who is he? One thing's for sure, he's hot, and incredibly romantic, feeding Natalie's wounded soul.
Luke Williams just wants the world to give him a break, so seeing yet another camera aimed at his face has him ready to pounce on the beauty behind the lens. When he finds out she has no idea who he is, he's intrigued and more than a little tempted by her. Natalie has a body made for sex, a sassy mouth and Luke can't get enough of her, but he's not ready to tell her who he really his.
Natalie is a no nonsense girl who doesn't do well with lies and secrets. What will happen to this new relationship when she discovers what Luke's hiding?
Under the Mistletoe with Me (With Me in Seattle, #1.5)
Isaac and Stacy Montgomery have been married for ten years. They have a beautiful new baby girl, Isaac's construction business is thriving, and Stacy enjoys being a stay at home mom, reviewing sexy romance novels for her blog. With a very large extended family, and the many privileges they enjoy, Stacy will be the first to admit that they are blessed beyond measure.
When suspicious phone calls and text messages begin, Stacy questions Isaac's faithfulness for the first time in their marriage. She knows that a new baby brings changes into a relationship, but has the stress of parenthood sent Isaac into another woman's arms, threatening to destroy their marriage?
This With Me In Seattle novella shows us a glimpse into Jules' brother, Isaac, and his wife Stacy's lives, introduces us to some new characters, and reminds us of what it means to reconnect with the person you love the most, even if they never left in the first place.
Fight with Me (With Me in Seattle, #2)
Amazon US | Amazon UK | B&N
Jules Montgomery is too busy and content with her life to worry about a man, especially one Nate McKenna. If growing up with four brothers has taught her anything, she knows to stay away from sexy men with tattoos and motorcycles. That goes double if he's your boss. During the one incredible night they shared, he violated the no fraternization policy…among other things, and it won't happen again. Jules won't risk her career for mind-blowing sex, no matter how much her body and her damn heart keep arguing with her.
Nate McKenna could give a shit about the no fraternizing policy. He wants Jules and he'll have her. The rules could bend around them, or be damned. He's not a man to be taken lightly, and Jules Montgomery is about to find out just how he responds to being pushed aside after the best night of sex he's ever had. She can fight all she wants, but he'll have her in his bed in the end.
Play with Me (With Me in Seattle, #3)
Will Montgomery is a successful professional football player and seemingly has it all. He's not used to being told no, and certainly doesn't take no for an answer. So when he turns his charms on his sister's sexy rocker-chick friend Meg, he's not only turned down, but met with open hostility, piquing his curiosity and libido. He's determined to show her that he's not the arrogant jock she thinks he is, and to get her into his bed.
Megan McBride is not impressed with Will Montgomery, his fat contract, fancy car, or his arrogant public persona. She doesn't have time for a relationship, and if she's learned anything in life, it's that loving means losing, so she guards her heart ferociously. But she can't deny the overwhelming attraction to the sexy, tattooed athlete, and when Will starts breaking down her defenses and grabs hold of her heart, will she be able to admit her feelings for him, or will her troubled past cause her to lose the first man she's ever truly loved?
Rock with Me (With Me in Seattle, #4)
Front Man Leo Nash from the world-famous rock band, Nash, is the last person on earth Samantha Williams would trust. She's already learned about loving a celebrity the hard way and isn't signing up for another lesson.
Every time Sam gives Leo attitude, he wants to knock that chip off her fragile little shoulder. What the hell did he ever do to her, anyway? He's not used to women treating him like he's poisonous, and he isn't about to let her run away every time he gets close. He's had enough of people running away to last him a lifetime…when this one runs, he gives chase. But, catching Sam isn't as hard as he thought.
The sexual attraction between them is so thick, Sam can practically hold it in her hand. There's no way she can deny herself the promise of pleasure being with Leo would provide.
But, pleasure always comes with pain and when secrets are revealed and trust is challenged, who will run and who will chase?
Safe with Me (With Me in Seattle, #5)
Keeping others safe is what Caleb Montgomery does. He's never had a problem taking on an assignment, whether it was during his dangerous SEAL days or his most recent job of training war mercenaries. But being assigned to keep Brynna Vincent and her adorable daughters, Maddie and Josie, safe from an unknown threat has thrown Caleb off his axis. Hot for the tall brunette since she came back to town more than a year ago, being close to her day in and day out is cracking Caleb's resolve to keep his hands off her gorgeous body and his head in the mission.
Brynna is sick and tired of being afraid. All she wants is a normal, quiet life for her and her precious girls. Just as she's settling into her new home in Seattle and feeling safe again, Caleb shows up on her doorstep insisting the danger is as high as ever. But whether she needs to be sheltered from the threat in her past, or from the intense emotions she feels for the sexy, protective man sleeping in her home, remains to be seen. What will happen if Brynna and her girls fall in love with a man so broken he may not be able to protect them from the danger that threatens, much less himself?"
SAFE WITH ME is the fifth book in the With Me In Seattle series, and continues to follow this tight-knit, loving family through life's trials and tribulations with humor, passion and everlasting love.
Tied with Me (With Me in Seattle, #6)
Amazon US | Amazon UK | Kobo
A man whose lifestyle is so different from her own…
Nic Dalton's cupcake bakery is thriving. She serves both rock stars and locals alike, content with her growing business. But one adventurous night out with her best friend, Bailey, turns her life upside down. She meets a handsome stranger who makes her skin sizzle and her heart race. Their one night together is explosive and unexpected, but when he has to suddenly leave without taking her phone number, Nic resigns herself to never seeing him again.
…What will it take to trust and submit to his every desire?
Matt Montgomery is one of Seattle's finest. He works hard, loves and protects his family fiercely, and is loyal almost to a fault.
And he has a penchant for bondage.
Matt enjoys the way a woman looks wrapped up in his ropes, and makes no apologies for his preferences. When he meets Nic at a fetish festival, the small, beautiful woman catches his eye, drawing him to her. His one night with her was everything he's ever looked for in a partner, but is cut short because of a family emergency. Even before he sees her again weeks later, he knows he'll never get her out of his system.
And he'll do whatever it takes to make her his.
"Give in to this, Nic. Let me prove to you that I will be one of the best decisions you ever make." –Matt Montgomery
Breathe with Me (With Me in Seattle, #7)
Amazon US | B&N | Amazon UK | iTunes
Sometimes you meet the right person at the wrong time…
Mark Williams has loved Meredith since he was seventeen. A successful man with a strong family, he's worked hard to move on from Meredith breaking his heart all those years ago. When his path crosses with the only woman he's ever loved again years later, Mark knows there is nothing he won't do to keep her in his life. But when the going gets tough, will Meredith stick around or will he lose her again?
…But true love has a way of finding its way back.
Meredith Summers is a dancer. One of the first things she learned in following her dreams is that timing is everything. She has spent the past ten years following her dream touring with mega-stars while trying to forget the high school sweetheart she left behind. Now she's back in Seattle, running a successful dance studio with her best friend Jax and determined to move on from her gypsy past. Until the day she sees Mark Williams and time stands still. It's as if no time has passed at all when Meredith finds herself in Mark's arms again. The chemistry, the bonds and the love are as strong as ever and hearing Mark whisper breathe with me in her ear is a balm to her wounded soul. But will she grab onto this second chance at love, or is the timing all wrong for them again?
Don't miss catching up with the Montgomery and Williams clans in this latest installment of the With Me In Seattle Series from New York Times bestselling author, Kristen Proby.
"There were days that I would have exchanged a year of my life to just touch you one more time." –Mark Williams
About Kristen Proby
Kristen was born and raised in a small resort town in her beloved Montana. In her mid-twenties, she decided to stretch her wings and move to the Pacific Northwest, where she made her home for more than a dozen years.
During that time, Kristen wrote many romance novels and joined organizations such as RWA and other small writing groups. She spent countless hours in workshops, and more mornings than she can count up before the dawn, so she could write before going to work. She submitted many manuscripts to agents and editors alike, but was always told no. In the summer of 2012, the self-publishing scene was new and thriving, and Kristen had one goal: to publish just one book. It was something she longed to cross off of her bucket list.
Not only did she publish one book, she's since published close to thirty titles, many of which have hit the USA Today, New York Times and Wall Street Journal Bestsellers lists. She continues to self-publish, best known for her With Me In Seattle and Boudreaux series, and is also proud to work with William Morrow, a division of HarperCollins, with the Fusion Series.
Kristen and her husband, John, make their home in her hometown of Whitefish, Montana with their two pugs and two cats.
Website • Twitter • Facebook • Goodreads
By Kristen Proby
Release Day Launch & Giveaway: Falling for Jillian (Love Under the Big Sky #3) by Kristen Proby
Cover Reveal: Enchanting Sebastian (Big Sky Royal #1) by Kristen Proby
Release Day Blitz: Savor You (Fusion #5) by Kristen Proby
Release Day Blitz & Giveaway: Tied with Me (With Me in Seattle #6) by Kristen Proby
Cover Reveal: All It Takes (Romancing Manhattan #2) by Kristen Proby
Promo & Giveaway: My Clarity by M. Clarke
Release Day Blitz: Halo by RC Stephens
Release Day Blitz: Lines Drawn (Drawn to You #2) by Ker Dukey
Release Day Blitz & Giveaway: Worth Fighting For (Worthy #2) by Amanda Kelley
Release Day Blitz: The Hierarchy of Needs (The Portland Rebels #2) by Rebecca Grace Allen
Copyright © 2019 Books to Breathe.	Tweak Me theme by Nose Graze


Abstract: [Introduction]: Health promoting effects associated to coffee silverskin extract (CSE) largely depend on the bioaccesibility and bioavailability of chlorogenic acid (CGA) and caffeine and it is evaluated in the present study. [Methods]: CSE was in vitro gastrointestinal digested mimicking human conditions. Bioaccesibility of CSE's compounds was assayed by analysis of proteins, total phenolic compounds (TPC), CGA, caffeine and antioxidant capacity after the in vitro digestion. CGA and caffeine in vivo bioavailability was evaluated using male Wistar rats (n=32) divided into four groups (n=8). A Control group received 1 ml of sterile water; CSE group received CSE (128 mg/kg body-weight equivalent to 0.88 mg CGA/kg body-weight and 2.55 mg caffeine/kg body-weight); CGA group received 1.5 mg CGA/kg body-weight and caffeine group received 5 mg caffeine /kg body-weight. Doses were administered diluted in 1 ml of water by gavage. Animals were housed singly in metabolic cages. Urine samples were serially collected for every 1 hour up to 6 h, then every 2 hours up to 10 h and then up to 24 h. CGA and caffeine and their major metabolites, hippuric acid and paraxanthine were determined in urine by UPLC-MS/MS analysis. [Results]: Bioaccesibility of TPC, CGA and caffeine decreased due to digestion in 39%, 80% and 25%, respectively. On the contrary, the overall antioxidant capacity of CSE remained in 82% (ABTS) and 74% (ORAC) after in vitro digestion suggesting the formation of novel antioxidant during the process. Results on bioavailability indicated caffeine was highly metabolized to paraxanthine after CSE intake while free CGA wasn't bioavailable. [Conclusions, discussion and/or practical application]: Our findings seem to indicate that CSE health effects might be linked to its antioxidant character or a synergic effect of different components present in CSE including caffeine and its metabolites, but cannot be ascribed to free CGA.
Description: Póster presentado al 17th International Congress of Dietetics celebrado en Granada (España) del 7 al 10 de septiembre de 2016.


text:
Amplifier / AV Receiver | Hegel
Hegel H160 Review
Hegel H160 has won the EISA European Audiovisual Association 2015-2016 Best Amplifier Award. To know that EISA's best amplifier is awarded only once a year (EISA also has an annual Hi-End amplifier award), it is really not easy to win this award.
For the Hegel H160 integrated amplifier, to get so many professional media's excellent recommend, first of all, two conditions must be met. One is that the function must be complete, and the other is that the cost-effectiveness must be high. H160 meets both items. H160 is robust and provides efficient 150 watts × 2 channel power. Moreover, it is effortless to drive different kinds of speakers.
Hegel H160 amplifier is an integrated amplifier. In addition to traditional analog inputs (balanced and unbalanced), various digital inputs are readily available and even include DLNA/UPnP functions. H160 provides 1 RCA coaxial input and three optical inputs, which can be connected to sources such as CD turntables, Blu-ray players, game consoles, and digital set-top boxes.
It also has a type B USB input, so it's no problem to use a Mac or Windows computer as a source. In addition, Hegel H160 can support up to 24bit/192kHz sampling rate.
The most convenient is that there is an RJ45 network cable jacks on the back of H160. After connecting to the network, H160 is a network streaming player. It can directly play music files stored in NAS or computer, and users only need to download a remote control app like BubbleUPnP, and you can operate it wirelessly via a mobile phone or tablet.
If I want to play music on my phone wirelessly, can H160 do it? The answer is yes, but you must use an iPhone or iPad portable device. Hegel H160 supports Apple's AirPlay function. As long as you connect H160 to a wireless router with a network cable, you will find H160 on the Apple device's AirPlay speakers list, and then you can play the music files wirelessly.
Internal Circuit Design
Next, I will explain the internal circuit of the machine. After music file decoding and digital audio input, AKM AK4127VF (192kHz/24bit SRC) is used for the up-sampling processing in the digital conversion circuit to make the final audio signal better linearity, and keeping the digital noise away from the audio, effectively reduce noise.
Then the AKM high-end DAC chip AK4396 is used for digital conversion. Finally, the audio signal output by the DAG chip is passed through the NE5532 (low-noise dual OPA chip) and passive components to form a low-pass filter circuit. The above is the digital source part in H160.
In the pre-amplification circuit part, this machine uses JRC NJW1159 for volume control. This audio control chip feature is no voltage gain, only signal attenuation and buffer. Most audio control chips have voltage gain, and Hegel chose this module to maintain greater dominance in the design of the amplifying circuit.
The main amplifying component of the high-level amplifying circuit uses JRG NJM4556AD. This component has low noise, broadband, and high slew rate characteristics.
Power amplifier circuits have always been Hegel's strength. The designer Bent Holter developed a patented technology called "Multistage amplifier with local error correction" in the early 1990s. The error of the output signal is detected at the output of each amplifier stage, and the front-end circuit is combined with the front end of the amplifier stage to make real-time corrections. That is what Hegel later called "SoundEngine" technology.
This method can effectively solve the problems of crossover distortion so that harmonic distortion is extremely low, especially high-frequency harmonic distortion. Hegel has been applying this patented technology that they are pretty proud of since its inception, and H160 is no exception.
Hegel H160's power amplifier circuit has a low distortion rate and a sizeable current matching design. Each channel uses two pairs of Toshiba 2SA2121/2SC5949 push-pull outputs with 15-ampere current output capability. A heavyweight toroidal transformer powers the power circuit. After rectification, it uses six 10,000μF Nover audio special electrolytic capacitors for filtering.
Rich Interfaces
H160 has powerful DAC and DLNA/UPnP functions and pays attention to users using traditional input sources. In addition to RCA single-ended input, it also provides an XLR balanced input and a theater RCA input. That is, the signal does not pass through the volume control module, allowing H160 to be integrated into a multi-channel theater system at home.
Hegel H160 also provides 2 RCA outputs, one of which is with fixed volume and the other is with variable volume, meaning that the H160 can also be used as a DAC.
H160 can be connected to various sources, but I only plan to use the most straightforward configuration for the listening test. So first, I will connect the H160 to the Internet and use its DLNA/UPnP function to play music files stored in the NAS.
After the wire was connected, I was about to turn on the machine, but I couldn't find the power switch of the Hegel H160 at this time. Except for the volume and source selection knob, nothing else can be found. There are no switches beside the power socket on the back panel. It turns out that the H160's power switch is hidden on the bottom left side near the panel. You can find it by your fingers in and touching it.
There are usually two reasons for this design: aesthetics and the other because the equipment does not need to be shut down. I think the H160 is considered. H160 hides the switch underneath, maintaining the simplicity of the panel, and you do not need to reach behind the equipment when turning on/off, providing the convenience of use.
The DLNA playback function of H160 allows users to pick up the mobile phone to play remotely. If you need to use the amplifier's remote control to turn on the power, you have to press the amplifier's power switch. Therefore, it is quite reasonable to keep the H160 on. Moreover, I did not turn off the H160 for several days.
The Hegel H160 integrated amplifier is held in a low-temperature state, and there is no any overheating when listening for a long time. Therefore, it can be seen that there should be no problem without turning off the phone.
App Control Feature
To play with DLNA, you must have a remote control app. I use Bubble UPnP. It has a free version for Android, and the limitation is that the playlist can only add up to 16 songs, but it's pretty enough. After downloading and opening the BubbleUPnP app, you should see the H160 amplifier. You can select the H160 for the music playing.
When playing, I also found that the volume of the app is linked to the H160. That is to say, when you use the H160's remote control to adjust the volume, the volume of the app will follow. Conversely, if you use the app to adjust the volume, the volume number displayed on the H160 panel will also change. Therefore, the app control is really convenient.
However, Hegel H160 has one place that I think is a little inconvenient: source switching. In addition to the volume, there is only one source knob on its panel, so when switching sources, the knob must be rotated. But because there are many gears, it has to be turned many times.
So wouldn't it be enough to use the remote control? Wrong, the source switching on the H160 remote control is also up and down, so you have to switch around the input sources step by step.
During the audition, apart from playing with DLNA, I also tried the analog input, which was paired with the Japanese SPEC flagship source RMP-X3EX streaming player. In comparison, I think it sounds the most suitable to use H160's DLNA function. The H160 is originally a very thick sound amplifier. If you add a thicker source, the sound becomes less flexible, and it is not as good as the H160's DLNA.
From the things mentioned above, we can guess how thick the sound of H160 is! That's right. That is also the attraction of Hegel H160. It not only has a good sound thickness but also has a concentrated and entire sound field. The sound image is quite large. Therefore, the sound field seems to be filled with rich music rhythm, which is easy to listen to and easy to listen to.
Listen to "Bruckner's No. 8 Symphony" . It is not cramped when the volume is loud, which shows that the driving force is indeed good. Moreover, the loudspeaker is placed far away from the back wall. At this time, the H160 sound field is far-reaching, clear, and rich in layers, and it is very suitable for playing a symphony.
It is also a great pleasure to listen to rhythmic jazz with H160, such as Shirley Horn's "Yes, I know when I've had it". H160's bounce and round low-frequency performance can show a relaxed and happy, dynamic and straightforward music atmosphere, which sounds kind and sweet, without pressure.
The point is that not only does H160 sound stress-free, it also makes it easy for you to build a listening system. Perhaps its price is not cheap in terms of a single piece of equipment, but as a fully functional, versatile integrated amplifier with DAC, network streaming, and even a headphone jack, making it accommodate all the home sources is worth every penny.
H160 has made the best fusion of power and beauty. With speakers that can extend excellent high-frequency characteristics, Hegel can definitely deliver the details. If the loudspeaker's mid-low frequency is accurate enough, Hegel H160 can bring a great shock. The fine-tuning on the wire also needs to find the appropriateness, and the final result is quite gorgeous, which will definitely make you have an unforgettable listening experience.
Hegel H160 Specifications
Power output spk: 150 w/pc into 8 Ohms, 250 w/pc into 4 Ohms
Power output hp: 270 mw/pc into 64 Ohms
Analog inputs: 1 balanced (XLR), 1 unbalanced (RCA), 1 home theatre
Analog outputs: 1 fixed line level (RCA), 1 variable line level (RCA)
Digital inputs: 1 coaxial, 3 optical, 1 USB, 1 ethernet (RJ45)
Headphone output: 6.3 mm Jack (front)
Frequency response: 5Hz-100kHz
Signal-to-noise ratio: More than 100dB
Crosstalk: Less than -100dB
Distortion: 0.005% @ 50W 8 Ohms 1kHz
Intermodulation: Less than 0.01% (19kHz + 20kHz)
Damping factor: More than 1000 (main power output stage)
Dimensions/weight: 12cm x 43cm x 41cm (HxWxD)/19kg (shipping)
Dimensions/weight: 4.7″ x 16.93″ x 16.15″ (HxBxD)/42lbs (shipping)
Cambridge Audio Stream Magic 6 Review
Denon AVR-X2600H Review
Accuphase E470 Review
Cambridge Audio Azur 851E Review
Marantz PM6006 CD6006 Review


The members of the kayak.com engineering team write things that might be interesting to other software folks. We're also fishing for ideas on how to do things better. So help us out!
1. when you are doing a flight search (or hotel search), wait for the little green bar to progress all the way across. Then hit refresh. Your flights will appear!
2. Try basic mode kayak. It's kind of, um, basic, but it works with almost all browsers. Even really old ones. No AJAXy goodness, of course. Mr. Miyagi says: basic on, basic off.
could you publish or direct me to the feed for this blog? I would like to subscribe.
Could you please fix the overlapping ads on the search results page (opera 9.22 on Mac OS X here)?
Everything else works like a charm!
I can't reproduce any overlapping ads on Opera OS X. Please followup with the feedback system http://www.feedback.com/feedback/ if you have more to report.


Stockholm – Biotage AB (publ) (Biotage) has today completed the acquisition of PhyNexus, Inc. (PhyNexus), which was announced on December 4, 2018. As part of the completion, the Board of Directors of Biotage has also, pursuant to an authorization granted by the Annual General Meeting 2018, resolved on a share issue of 487,337 shares.
As previously announced, Biotage has on December 4, 2018, entered into an agreement to acquire all outstanding shares in the privately held company, PhyNexus and the purchase price amounts to approx. USD 21.4 million (corresponding to approx. SEK 191 million). Approx. USD 10.0 million (corresponding to approx. SEK 89 million) of the total purchase price consist of expected future additional purchase price payments for the years 2019 to 2023 that will be bases on future results.
The Board of Directors has today resolved to issue the consideration shares in connection with the acquisition of PhyNexus. The share issue will increase the number of shares of Biotage from 64,714,447 to 65,201,784, which will result in a dilution of 0.7 percent for existing shareholders. The newly issued shares have been subscribed by the main shareholders of PhyNexus (including the largest shareholder Doug Gjerde, representing approx. 60 percent of the shares and votes in PhyNexus). Additional shares may be issued in connection with post-closing price adjustments and earnout payments.
The information was submitted for publication, through the agency of the contact persons set out above, at 18:15 CET on January 15, 2019.
 Based on an exchange rate SEK/USD of 8.93, used throughout this press release for the conversion of USD/SEK.
Preety holds a Master's in Journalism from Ryerson University and writes professionally in a broad variety of genres. She has worked as a senior manager in public relations and communications for major telecommunication companies and is the former Deputy Director of Media Relations with the Modern Coalition.
Jennifer Smeltzer, Kansas City Market Realtor, is selected as one of America's Top 100 Real Estate Agents® for 2019.
If Web Design is Dead – Why are Small Businesses Using WordPress Over Squarespace and Wix?
CultHub has been a source of independent news in India since 2009. Our Bi-weekly newspaper and daily online content provides visitors with the latest news concerning Americans and Indians as well as coverage of world issues, technology, sports, science and entertainment.
CultHub exists to serve to audiences in the United States and English speaking people in India a comprehensive news source.


text:
Double Agent Victoire
By David Tremain
Mathilde Carré, notoriously known as La Chatte, was remarkable for all the wrong reasons. Like most spies she was temperamental, scheming and manipulative – but she was also treacherous. A dangerous mix, especially when combined with her infamous history of love affairs – on both sides. Her acts of treachery were almost unprecedented in the history of intelligence, yet her involvement in the 'Interallié affair' has only warranted a brief mention in the accounts of special operations in France during the Second World War. But what motivated her to betray more than 100 members of the Interallié network, the largest spy network in France? Was she the only guilty party, or were others equally as culpable? Using previously unpublished material from MI5 files, Double Agent Victoire explores the events that led to her betrayal, who may have 'cast the first stone', and their motivations, as well as how the lives and careers of those involved were affected. It reveals a story full of intrigue, sex, betrayal and double-dealing, involving a rich cast including members of the French Resistance, German Abwehr and British Intelligence.
Charlotte and Ellen
Castles and Strongholds of Northumberland
Letters from the Blitz
Gentlemen Rogues & Wicked Ladies
Spy Runner
Kitted Out
Secret Spitfires
Ring of Spies
The Buried Spitfires of Burma
The Indian Contingent
Buster Crabb
Tudor King in All but Name
The Solitary Spy
Gunners in Normandy


text:
Your apps know where you were last night, and they're sharing
Business // TechBurger
Jennifer Valentino-DeVries, Natasha Singer, Michael H. Keller and Aaron Krolik, New York Times
**EMBARGO: No electronic distribution, Web posting or street sales before Monday 3:01 a.m. ET Dec. 10, 2018. No exceptions for any reasons. EMBARGO set by source.** At least 75 companies receive anonymous, precise location data from apps whose users enable location services to get local news and weather or other information, The New York Times found. (The New York Times)THE NEW YORK TIMES/NYT
The millions of dots on the map trace highways, side streets and bike trails — each one following the path of an anonymous cellphone user.
One path tracks someone from a home outside Newark, New Jersey, to a nearby Planned Parenthood, remaining there for more than an hour. Another represents a person who travels with the mayor of New York during the day and returns to Long Island at night.
Yet another leaves a house in upstate New York at 7 a.m. and travels to a middle school 14 miles away, staying until late afternoon each school day. Only one person makes that trip: Lisa Magrin, a 46-year-old math teacher. Her smartphone goes with her.
An app on the device gathered her location information, which was then sold without her knowledge. It recorded her whereabouts as often as every two seconds, according to a database of more than 1 million phones in the New York area that was reviewed by The New York Times. While Magrin's identity was not disclosed in those records, The Times was able to easily connect her to that dot.
LOCATION, LOCATION, LOCATION: Your smartphone knows where you've been, puts it on a map
The app tracked her as she went to a Weight Watchers meeting and to her dermatologist's office for a minor procedure. It followed her hiking with her dog and staying at her ex-boyfriend's home, information she found disturbing.
"It's the thought of people finding out those intimate details that you don't want people to know," said Magrin, who allowed The Times to review her location data.
Dozens of companies use smartphone locations to help advertisers and even hedge funds. They say it's anonymous, but the data shows how personal it is.
Like many consumers, Magrin knew that apps could track people's movements. But as smartphones have become ubiquitous and technology more accurate, an industry of snooping on people's daily habits has spread and grown more intrusive.
At least 75 companies receive anonymous, precise location data from apps whose users enable location services to get local news and weather or other information, The Times found. Several of those businesses claim to track up to 200 million mobile devices in the United States — about half of those in use last year. The database reviewed by The Times — a sample of information gathered in 2017 and held by one company — reveals people's travels in startling detail, accurate to within a few yards and in some cases updated more than 14,000 times a day.
These companies sell, use or analyze the data to cater to advertisers, retail outlets and even hedge funds seeking insights into consumer behavior. It's a hot market, with sales of location-targeted advertising reaching an estimated $21 billion this year. IBM has gotten into the industry, with its purchase of the Weather Channel's apps. The social network Foursquare remade itself as a location marketing company. Prominent investors in location startups include Goldman Sachs and Peter Thiel, the PayPal co-founder.
Businesses say their interest is in the patterns, not the identities, that the data reveal about consumers. They note that the information apps collect is tied not to someone's name or phone number but to a unique ID. But those with access to the raw data — including employees or clients — could still identify a person without consent. They could follow someone they knew, by pinpointing a phone that regularly spent time at that person's home address. Or, working in reverse, they could attach a name to an anonymous dot, by seeing where the device spent nights and using public records to figure out who lived there.
An app on Magrin's cellphone shared her location information with other companies. The data revealed her daily habits, including hikes with her dog.NATHANIEL BROOKS/NYT
Many location companies say that when phone users enable location services, their data is fair game. But, The Times found, the explanations people see when prompted to give permission are often incomplete or misleading. An app may tell users that granting access to their location will help them get traffic information, but not mention that the data will be shared and sold. That disclosure is often buried in a vague privacy policy.
"Location information can reveal some of the most intimate details of a person's life — whether you've visited a psychiatrist, whether you went to an AA meeting, who you might date," said Sen. Ron Wyden, D-Ore., who has proposed bills to limit the collection and sale of such data, which are largely unregulated in the United States.
"It's not right to have consumers kept in the dark about how their data is sold and shared and then leave them unable to do anything about it," he added.
Mobile Surveillance Devices
After Elise Lee, a nurse in Manhattan, saw that her device had been tracked to the main operating room at the hospital where she works, she expressed concern about her privacy and that of her patients.
"It's very scary," said Lee, who allowed The Times to examine her location history in the data set it reviewed. "It feels like someone is following me, personally."
The mobile location industry began as a way to customize apps and target ads for nearby businesses, but it has morphed into a data collection and analysis machine.
Retailers look to tracking companies to tell them about their own customers and their competitors'. For a web seminar last year, Elina Greenstein, an executive at the location company GroundTruth, mapped out the path of a hypothetical consumer from home to work to show potential clients how tracking could reveal a person's preferences. For example, someone may search online for healthy recipes, but GroundTruth can see that the person often eats at fast-food restaurants.
"We look to understand who a person is, based on where they've been and where they're going, in order to influence what they're going to do next," Greenstein said.
Financial firms can use the information to make investment decisions before a company reports earnings — seeing, for example, if more people are working on a factory floor, or going to a retailer's stores.
HANG UP: Robocalls flooding your cellphone? Here's how to stop them
Health care facilities are among the more enticing but troubling areas for tracking, as Lee's reaction demonstrated. Tell All Digital, a Long Island advertising firm that is a client of a location company, says it runs ad campaigns for personal injury lawyers targeting people anonymously in emergency rooms.
"The book '1984,' we're kind of living it in a lot of ways," said Bill Kakis, a managing partner at Tell All.
Jails, schools, a military base and a nuclear power plant — even crime scenes — appeared in the data set The Times reviewed. One person, perhaps a detective, arrived at the site of a late-night homicide in Manhattan, then spent time at a nearby hospital, returning repeatedly to the local police station.
Two location firms, Fysical and SafeGraph, mapped people attending the 2017 presidential inauguration. On Fysical's map, a bright red box near the Capitol steps indicated the general location of President Donald Trump and those around him, cellphones pinging away. Fysical's chief executive said in an email that the data it used was anonymous. SafeGraph did not respond to requests for comment.
More than 1,000 popular apps contain location-sharing code from such companies, according to 2018 data from MightySignal, a mobile analysis firm. Google's Android system was found to have about 1,200 apps with such code, compared with about 200 on Apple's iOS.
The most prolific company was Reveal Mobile, based in North Carolina, which had location-gathering code in more than 500 apps, including many that provide local news. A Reveal spokesman said the popularity of its code showed that it helped app developers make ad money and consumers get free services.
To evaluate location-sharing practices, The Times tested 20 apps, most of which had been flagged by researchers and industry insiders as potentially sharing the data. Together, 17 of the apps sent exact latitude and longitude to about 70 businesses. Precise location data from one app, WeatherBug on iOS, was received by 40 companies. When contacted by The Times, some of the companies that received that data described it as "unsolicited" or "inappropriate."
WeatherBug, owned by GroundTruth, asks users' permission to collect their location and tells them the information will be used to personalize ads. GroundTruth said that it typically sent the data to ad companies it worked with, but that if they didn't want the information they could ask to stop receiving it.
LOCK IT DOWN: How to update your router's firmware and improve its security
The Times also identified more than 25 other companies that have said in marketing materials or interviews that they sell location data or services, including targeted advertising.
The spread of this information raises questions about how securely it is handled and whether it is vulnerable to hacking, said Serge Egelman, a computer security and privacy researcher affiliated with the University of California, Berkeley.
"There are really no consequences" for companies that don't protect the data, he said, "other than bad press that gets forgotten about."
A Question of Awareness
Companies that use location data say that people agree to share their information in exchange for customized services, rewards and discounts. Magrin, the teacher, noted that she liked that tracking technology let her record her jogging routes.
Brian Wong, chief executive of Kiip, a mobile ad firm that has also sold anonymous data from some of the apps it works with, says users give apps permission to use and share their data. "You are receiving these services for free because advertisers are helping monetize and pay for it," he said, adding, "You would have to be pretty oblivious if you are not aware that this is going on."
But Lee, the nurse, had a different view. "I guess that's what they have to tell themselves," she said of the companies. "But come on."
Lee had given apps on her iPhone access to her location only for certain purposes — helping her find parking spaces, sending her weather alerts — and only if they did not indicate that the information would be used for anything else, she said. Magrin had allowed about a dozen apps on her Android phone access to her whereabouts for services like traffic notifications.
But it is easy to share information without realizing it. Of the 17 apps The Times saw sending precise location data, just three on iOS and one on Android told users in a prompt during the permission process that the information could be used for advertising. Only one app, GasBuddy, which identifies nearby gas stations, indicated that data could also be shared to "analyze industry trends."
More typical was theScore, a sports app: When prompting users to grant access to their location, it said the data would help "recommend local teams and players that are relevant to you." The app passed precise coordinates to 16 advertising and location companies.
A spokesman for theScore said that the language in the prompt was intended only as a "quick introduction to certain key product features" and that the full uses of the data were described in the app's privacy policy.
The Weather Channel app, owned by an IBM subsidiary, told users that sharing their locations would let them get personalized local weather reports. IBM said the subsidiary, Weather Co., discussed other uses in its privacy policy and in a separate "privacy settings" section of the app. Information on advertising was included there, but a part of the app called "location settings" made no mention of it.
The app did not explicitly disclose that the company had also analyzed the data for hedge funds — a pilot program that was promoted on the company's website. An IBM spokesman said the pilot had ended. (IBM updated the app's privacy policy on Dec. 5, after queries from The Times, to say that it might share aggregated location data for commercial purposes such as analyzing foot traffic.)
Even industry insiders acknowledge that many people either don't read those policies or may not fully understand their opaque language. Policies for apps that funnel location information to help investment firms, for instance, have said the data is used for market analysis, or simply shared for business purposes.
"Most people don't know what's going on," said Emmett Kilduff, chief executive of Eagle Alpha, which sells data to financial firms and hedge funds. Kilduff said responsibility for complying with data-gathering regulations fell to the companies that collected it from people.
Many location companies say they voluntarily take steps to protect users' privacy, but policies vary widely.
For example, Sense360, which focuses on the restaurant industry, says it scrambles data within a 1,000-foot square around the device's approximate home location. Another company, Factual, says that it collects data from consumers at home, but that its database doesn't contain their addresses.
Some companies say they delete the location data after using it to serve ads, some use it for ads and pass it along to data aggregation companies, and others keep the information for years.
Several people in the location business said that it would be relatively simple to figure out individual identities in this kind of data, but that they didn't do it. Others suggested it would require so much effort that hackers wouldn't bother.
It "would take an enormous amount of resources," said Bill Daddi, a spokesman for Cuebiq, which analyzes anonymous location data to help retailers and others, and raised more than $27 million this year from investors including Goldman Sachs and Nasdaq Ventures. Nevertheless, Cuebiq encrypts its information, logs employee queries and sells aggregated analysis, he said.
There is no federal law limiting the collection or use of such data. Still, apps that ask for access to users' locations, prompting them for permission while leaving out important details about how the data will be used, may run afoul of federal rules on deceptive business practices, said Maneesha Mithal, a privacy official at the Federal Trade Commission.
"You can't cure a misleading just-in-time disclosure with information in a privacy policy," Mithal said.
Following the Money
Apps form the backbone of this new location data economy.
The app developers can make money by directly selling their data, or by sharing it for location-based ads, which command a premium. Location data companies pay half a cent to 2 cents per user per month, according to offer letters to app makers reviewed by The Times.
Targeted advertising is by far the most common use of the information.
Google and Facebook, which dominate the mobile ad market, also lead in location-based advertising. Both companies collect the data from their own apps. They say they don't sell it but keep it for themselves to personalize their services, sell targeted ads across the internet and track whether the ads lead to sales at brick-and-mortar stores. Google, which also receives precise location information from apps that use its ad services, said it modified that data to make it less exact.
Smaller companies compete for the rest of the market, including by selling data and analysis to financial institutions. This segment of the industry is small but growing, expected to reach about $250 million a year by 2020, according to the market research firm Opimas.
Apple and Google have a financial interest in keeping developers happy, but both have taken steps to limit location data collection. In the most recent version of Android, apps that are not in use can collect locations "a few times an hour," instead of continuously.
Apple has been stricter, for example requiring apps to justify collecting location details in pop-up messages. But Apple's instructions for writing these pop-ups do not mention advertising or data sale, only features like getting "estimated travel times."
A spokesman said the company mandates that developers use the data only to provide a service directly relevant to the app, or to serve advertising that met Apple's guidelines.
Apple recently shelved plans that industry insiders say would have significantly curtailed location collection. Last year, the company said an upcoming version of iOS would show a blue bar onscreen whenever an app not in use was gaining access to location data.
The discussion served as a "warning shot" to people in the location industry, David Shim, chief executive of the location company Placed, said at an industry event last year.
After examining maps showing the locations extracted by their apps, Lee, the nurse, and Magrin, the teacher, immediately limited what data those apps could get. Lee said she told the other operating-room nurses to do the same.
"I went through all their phones and just told them: 'You have to turn this off. You have to delete this,'" Lee said. "Nobody knew."
This article originally appeared in The New York Times.
Get more tasty tech news at TechBurger. And follow us on Twitter and Facebook.
Subscribe to the Chronicle for regular access to TechBurger stories and to be able to comment.
Jennifer Valentino-DeVries
Natasha Singer
Michael H. Keller and Aaron Krolik


The Exeter City reception and club shop will close at 4pm on Friday, September 22.
Tickets for City's trip to the Ricoh Arena on Saturday will be availabe to purchase until 3pm on Friday, however you can purchase tickets on the day at Coventry, which are priced at a higher rate.
We apologise for any inconvenience caused, the reception and shop will open as normal from Monday, September 25.