Bradley.voytek

Adeno-associated viral vectors have become a leading choice for gene therapy in the central nervous system due to their safety profile, efficient neuronal transduction, and capacity for sustained transgene expression. We previously reported that AAV2-derived capsids developed using the BRAVE (Barcoded Rational AAV Vector Evolution) approach have enhanced retrograde transport properties in the rodent brain, compared to parental AAV2. Retrograde transport enables broader coverage of connected brain regions after a single focal intraparenchymal brain injection and is therefore a powerful tool for delivery of vectors to distant sites with potentially higher specificity, transduction efficacy and safety. Because transport properties can vary among species, we further characterized a barcoded library of 25 BRAVE-derived AAV2 capsid variants, along with the parental AAV2 serotype and benchmark AAV capsids, in brains of adult cynomolgus monkeys after intraputaminal dosing. Based on RNA and DNA amplicon sequencing, single-nucleus RNA sequencing, and histological assessment, we report here capsid variants with enhanced retrograde transport and expression compared to the parental AAV2 capsid. These properties make them potentially useful for disease indications in which broader brain coverage is desirable beyond the injection site.

The prefrontal cortex regulates emotions and is influenced by serotonin. Rodents lacking the serotonin transporter (5-HTT) show increased anxiety and changes in excitatory and inhibitory cell markers in the prefrontal cortex. However, these observations are constrained by limitations in brain representation and cell segmentation, as standard immunohistochemistry is inadequate to consider volume variations in regions of interest. We utilized the deep learning network of the StarDist method in combination with novel open-source methods for automated cell counts in a wide range of prefrontal cortex subregions. We found that 5-HTT knockout rats displayed increased anxiety and diminished relative numbers of subclass excitatory VGluT2+ and activated ΔFosB+ cells in the infralimbic and prelimbic cortices and of inhibitory GAD67+ cells in the prelimbic cortex. Anxiety levels and ΔFosB cell counts were positively correlated in wild-type, but not in knockout, rats. In conclusion, we present a novel method to quantify whole brain subregions of multilabeled cells in animal models and demonstrate reduced excitatory and inhibitory neuronal marker expression in prefrontal cortex subregions of 5-HTT knockout rats.

Notice NOT-NS-19-067 from the NIH Guide for Grants and Contracts

Multiplayer party card game Cards Against Humanity is having a special Black Friday sale today ... by increasing the price of all its products by $5.

The tongue-in-cheek "sale" pokes fun at traditional Black Friday deals, which are characterized by heavily-discounted products that encourage consumers to make savings by spending money.

The Cards Against Humanity deck is normally priced at $25. For today only, buyers will be able to take part in a "once-in-a-lifetime sale," which sees the deck priced at $30. The expansions, which normally sell for $10, are currently priced at $15.

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Greetings humans! Bradley Voytek coming back with a look at the US government shutdown of 2013. Man, politics, am I right? With your side and my side fighting back and forth. The nerve of those people doing that thing.

In all seriousness, the US government shutdown has had an obvious effect on a whole lot of people, but quantifying those effects can be difficult. We at Uber were musing about how such a major financial and employment shift such as this might affect the way people move around a city. And of course, what better city to examine these effects than the very epicenter?

The first thing I wanted to do was look at a “normal” week’s worth of data for Washington, DC. Here’s a plot of all of the trips going between the different DC neighborhoods:

Briefly, neighborhoods are outlined in grey with the size of the circle in neighborhood center representing the proportion of rides going into that neighborhood. Circles with the same color are part of a related subnetwork. The weight of each line reflects the proportion of rides going between the connected neighborhoods. (For detailed methods, look at our post here.)

As can be seen, most trips move between just a few neighborhoods, however a large amount of the business day trips move between Capitol Hill and Downtown.

Here’s what a week’s worth of trips that go to Capitol Hill and Downtown look like, pre- and post- shutdown:

Note that the shutdown (the red line) occurred on Tuesday, 01 October 2013. This means that the red Monday (30 September 2013) is before the shutdown. See how much it looks like the black line Monday (23 September 2013)? I include this here to highlight just how big of an effect the shutdown had on the proportion of rides going into Capitol Hill or Downtown.

Also, see those horned spikes every workday morning and afternoon? That’s people using Uber to and from work. But as soon as the shutdown kicks in, the number of Uber work trips drops dramatically.

There’s another way to look at this, as well.

We can look at how the number of rides between neighborhoods changed as a function of the shutdown. In the graph below, blue links mean that the number of trips between those neighborhoods increased after the shutdown. Red links mean that the number of trips decreased.

Obviously this stalemate has affected a huge number of people. It’s interesting to be able to use our data to uncover some of these effects. But, for everyone’s sake, let’s hope this “interestingness” doesn’t last too much longer.