Gan et al., p. 1502 · PHOTOCHEMISTRY Using ozone below may conserve it above The accumulation of...

sciencemag.org SCIENCE1476 19 DECEMBER 2014 • VOL 346 ISSUE 6216

PHOTOCHEMISTRY

Using ozone below may conserve it above The accumulation of laughing gas

in the atmosphere isn’t a laughing

matter: Nitrous oxide (N2O) is a

powerful greenhouse gas and a

depleter of ozone. The manufac-

ture of nylon releases substantial

N2O as a byproduct during prepa-

ration of the precursor adipic

acid. Hwang and Sagadevan

now demonstrate an alternate

route to adipic acid that involves

treating cyclohexane with ozone

under concurrent ultraviolet

irradiation, generating no N2O.

RESEARCH

Thus, ironically, the application

of ozone as a chemical reagent

could ultimately help conserve its

concentration in the atmosphere.

— JSY

Science, this issue p. 1495

CANCER THERAPY

Drug resistance, up close and personal Cancer therapies that target

specific genetic mutations driving

tumor growth have shown

promising results in patients;

however, the response is often

short-lived because the tumors

acquire new mutations that

render them resistant to these

therapies. Complicating matters,

the mechanism of resistance

can vary from patient to patient.

To identify drugs most likely to

be effective against resistant

tumors, Crystal et al. established

cell lines from the tumors of indi-

vidual patients after resistance

occurred and performed a drug

screen and genetic analysis on

the cultured cells. This strategy

successfully identified drug com-

binations that halted the growth

of resistant tumor cells both in

culture and in mice. In the future,

pharmacological profiling of

patient-derived cells could be an

efficient way to direct therapeutic

choices for individual cancer

patients. — PAK


PALEOCEANOGRAPHY

A brief hiccup in deep ocean circulation During the last interglacial

period, Antarctic Bottom Water

(AABW) formation slowed mark-

edly. This densest ocean water

sinks to the bottom of the sea,

and its production helps to flush

the oceans and eventually to

recycle the carbon dioxide (CO2)

that forms from sinking organic

matter back into the atmo-

sphere. If the AABW production

rate decreases, then CO2 accu-

mulates at depth, potentially

causing a corresponding drop in

atmospheric CO2 concentration.

Hayes et al. found evidence, in

the form of a uranium spike, in

deep sea sediments that such

a slowdown in AABW forma-

tion occurred ~127,000 years

ago, which may have caused

the atmospheric CO2 minimum

observed at that time. — HJS


IMMUNE TOLERANCE

For the immune system, silence is golden For the immune system, balance

is key. Immune cells must learn

to eliminate invading pathogens

but tolerate self. A cell type

called regulatory T cells (Tregs)

help to maintain this balance,

but how they do so, particularly

in humans, is unclear. Maeda et

al. now report that Tregs “silence”

T cells with modest reactivity to

Edited by Melissa McCartney and Margaret MoerchenI N SC IENCE J O U R NA L S

CONSERVATION

Success for Europe’s large carnivores?

Despite pessimistic forecasts,

Europe’s large carnivores are making

a comeback. Chapron et al. report

that sustainable populations of

brown bear, Eurasian lynx, gray wolf,

and wolverine persist in one-third of main-

land Europe. Moreover, many individuals

and populations are surviving and increas-

ing outside protected areas set aside for

wildlife conservation. Coexistence along-

side humans has become possible, argue

the authors, because of improved public

opinion and protective legislation. — AMS


Platinum-rich edges start the growth of metal-alloy nanoparticles Gan et al., p. 1502

Education efforts lead

to an increase in European

brown bear populations.

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SCIENCE sciencemag.org 19 DECEMBER 2014 • VOL 346 ISSUE 6216 1477

self. After culture with Tregs, the

silenced T cells proliferated very

little and produced almost no

cytokines in response to antigen.

The authors then examined T

cells from healthy donors and

from people with an autoimmune

disease. Only healthy donors

harbored silenced T cells, sug-

gesting that if silencing goes awry,

autoimmunity may result. — KLM


EARTH MAGNETOSPHERE

How trans-polar arcs transpire above Auroral arcs within the polar cap

are a visual marvel, and they may

also indicate trapped energetic

plasma in Earth’s magneto-

sphere. Fear et al. combined

simultaneous observations of

both the aurora and signatures

of the trapped plasma in Earth’s

magnetotail to demonstrate one

recent instance of this phenom-

enon. Some researchers have

proposed that flux generated by

magnetic reconnection might get

trapped in the magnetotail lobe,

but the standard magnetosphere

model does not predict it. This

study confirms the idea by taking

advantage of a period when the

interplanetary magnetic field

points northward, a state not yet

well understood. — MMM


Edited by Kristen Mueller

and Jesse SmithIN OTHER JOURNALS

NETWORK BIOLOGY

Meeting the demands of a complex networkCells face intense metabolic

demands. Meeting these

demands requires genes to

interact in complex networks.

But what happens to these

networks when the participat-

ing genes acquire mutations?

To find out, Bajić et al. compu-

tationally mapped how genes

that regulate cellular metabo-

lism interact in yeast lacking

specific metabolic enzymes or

in yeast that had accumulated

neutral mutations (mutations

that did not affect their overall

fitness). Their model predicted

that deleting specific genes

would lead to alternative enzy-

matic reactions and rewired

signaling pathways, depend-

ing on the degree of network

connectivity. In the case of

neutral mutations, their model

suggested that network rewiring

would occur along with a loss

of plasticity. Experimental data

supported these predictions.

— LMZ

Genome Biol. Evol. 10.1093/gbe/evu255 (2014).

PROTEIN DESIGN

Building transmembrane zinc transporters The ability to design proteins

gives insight into the relation

between a protein’s fold and

its function and also provides

a path to custom proteins

for bioengineering applica-

tions. Impressive strides have

been made in the design of

soluble proteins, but designing

membrane proteins remains a

challenge. Joh et al. achieve a

milestone by designing a trans-

membrane Zn2+ transporter

(see the Perspective by Lupas).

The protein comprises four

helices: Two tightly interacting

pairs form a weaker interface

that facilitates the transport of

Zn2+ with concomitant reverse

transport of protons. — VV

Science, this issue p. 1520; see also p. 1455

IMAGING

Look, pathologists! No lens! Imaging entire human tissues

with a light microscope requires

stitching 500+ images together

— a digitization process largely

confined to advanced laborato-

ries. Greenbaum et al. developed

a lens-free microscope based on

low-cost holographic technol-

ogy, which enables fields

of view a hundredfold

larger than conventional

technology allows.

This tool employs a

small chip and allows

for three-dimensional

focusing through thick

tissue samples. The

team imaged human

cancer cells, abnormal

cells in Pap smears,

and sickle cells in

whole-blood smears

with sufficient resolu-

tion and contrast for

clinical diagnosis. With

its high resolution and

speedy readout, the new

platform could benefit

pathology labs world-

wide. — MLF

Sci. Transl. Med. 6, 267ra175 (2014).

ANCIENT DNA

Document DNA shows agriculture’s course

Finding a good source of ancient DNA can be tough, due

to weathering and bacterial contamination. But parch-

ment—made from livestock hides—offers an abundant,

well-preserved, and often dated source of DNA, report

Teasdale et al. The researchers worked with a 2-cm-square

piece, but have so refined their sequencing technique that it

only requires a tiny sliver of parchment; they hope eventually to

do nondestructive testing. These data, they note, can reveal the

history of agriculture over the past 700 years. — EP

Philos. Trans. R. Soc. London Ser. B, 10.1098/rstb.2013.0379(2014).

Parchment—a rich

source of ancient DNA

Aurora displays such as these over

Alaska reflect plasma processes in

Earth’s magnetosphere

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sciencemag.org SCIENCE1478-B 19 DECEMBER 2014 • VOL 346 ISSUE 6216

RESEARCH

PROTEIN EVOLUTION

Controlling the state of dynamic proteinsSmall molecules that change

the oligomeric state of proteins

by binding to a site distant from

the interface are called allo-

steric. They often act by taking

advantage of intrinsic protein

dynamics and stabilizing a

particular conformation of the

protein. Perica et al. show that

mutations can similarly act at

a distance to change protein

conformation. They identified

11 mutations in an RNA- binding

protein that determine whether

it is stable as a dimer or a tetra-

mer. Examination of ancestral

sequences showed that the

allosteric mutations are part of

a downhill adaptation to lower

environmental temperatures.

This mechanism for modulating

the oligomeric state is probably

common in evolution. — VV


CANCER EPIGENETICS

Modeling brain cancer from stem to stern Diffuse intrinsic pontine gliomas

(DIPGs) are aggressive brain

tumors primarily affecting chil-

dren. Because the tumors arise

in the brainstem, which controls

many vital functions, they

cannot be surgically excised

and are often fatal. To study

the pathogenesis of DIPGs—in

particular, the role of a histone

H3.3 mutation that occurs in

70% of cases—Funato et al.

developed a new tumor model

(see the Perspective by Becher

and Wechsler-Reya). They first

directed the differentiation of

embryonic stem cells into neural

progenitor cells. They then intro-

duced a specific combination

of genes, including the mutant

histone gene, and found that

this caused the progenitor cells

to acquire features charac-

teristic of cancer cells. During

this oncogenic transformation,

the cells reverted to a more

primitive differentiation state

and displayed altered histone

marks at several key regulatory

genes. — PAK


HUMORAL IMMUNITY

Endogenous retroviruses trigger B cells Scattered across our genome

are endogenous retroviruses

(ERVs), ancient “footprints”

of previous viral infections.

Scientists do not fully under-

stand their functions, but Zeng

et al. now report a role for ERVs

in mobilizing a particular type of

B cell–driven immune response

in mice (T cell–independent,

TID), which is usually mounted

in response to viral capids or

bacterial polysaccharides (see

the Perspective by Grasset and

Cerutti). Immunizing mice with

a model TID antigen elicited an

increase in ERV RNA and DNA

in the cytoplasm of B cells.

Innate immune receptors that

recognize cytoplasmic nucleo-

tides then triggered signaling

cascades that resulted in the

production of immunoglobulin

M. — KLM


ELECTRON TRANSFER

Big impact from a well-placed shake Since the advent of ultrashort

laser pulses, chemists have

sought to steer reaction tra-

jectories in real time by setting

particular molecular vibrations

in motion. Using this approach,

Delor et al. have demonstrated

a markedly clear-cut influence

on electron transfer prob-

abilities along the axis of a

platinum complex. The complex

comprised donor and acceptor

fragments—which respectively

give and take electrons upon

ultraviolet excitation—bridged

together by triply bonded carbon

chains linked to the metal center.

By selectively stimulating the

carbon triple-bond stretch vibra-

tion with an infrared pulse, the

authors could induce substantial

changes in the observed elec-

tron transfer pathways between

the fragments. — JSY


CATALYSIS

Dispersing catalytic gold as widely as possibleIn order to maximize the activity

of precious metals in catalysis, it

is important to place the metal on

some support with a high surface

area (such as a zeolite) and to

maintain the metal as small clus-

ters or even atoms to expose as

much metal as possible. The lat-

ter goal is more readily achieved

with oxides of reducible metals

such as cerium or titanium than

with the aluminum and silicon

oxides that make up most zeolites

and mesoporous oxides. Yang et

al. show that sodium and potas-

sium can stabilize gold along

with hydroxyl and oxo groups to

create highly active catalysts for

the water-gas shift reaction at low

temperatures, a reaction that can

be useful in applications such as

fuel cells. — PDS


NANOMATERIALS

Nanoparticle growth starts at the edgesThe high activity of precious

metals such as platinum for

reactions that occur in fuel cells

can be enhanced by alloying with

metals such as nickel and cobalt

to form shaped nanoparticles,

where platinum is concentrated

at the corner and edge sites.

Gan et al. used a combination

of high-resolution imaging and

modeling to follow the forma-

tion of octadedral nanoparticles

of these alloys with increasing

growth times. A platinum-rich

phase with an extended mor-

phology forms initially and

becomes the edges and corners

for the particles, and the alloy-

ing metals deposit to fill in the

facets. — PDS


BIOPHYSICS

Stark influence on reaction rates Enzymes accelerate chemical

processes by coaxing molecules

into just the right reactive states.

Fried et al. now elucidate the

way the enzyme ketosteroid

isomerase pushes its substrate

toward product through exertion

of a local electric field (see the

Perspective by Hildebrandt).

First the authors calibrated the

shifts in molecular vibrational

frequencies, known as Stark

shifts, that fields of varying

strength impose on a substrate

analog; then they measured

the vibrational spectrum of

that compound in the enzyme’s

active site. The experiment

uncovered an unusually strong

field that the local enzyme

structure directed to the precise

spot where the substrate would

react. — JSY


GENE EXPRESSION

Promoters tune gene expression noise Although cells in a tissue are

genetically identical and appear

the same, they often exhibit

variability in their patterns of

gene expression. Organisms

may need this to prepare for

exposure to varying environ-

mental stresses. Using the tools

of synthetic biology, Jones et

al. construct a wide range of E.

coli promoters in which the key

molecular parameters (such as

protein binding and unbinding

rates) are systematically varied

and compare the resulting

expression noise to parameter

-free model predictions. This

work demonstrates that

Edited by Melissa McCartney and Margaret MoerchenALSO IN SCIENCE JOURNALS

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expression noise is a tunable

parameter, with different gene-

regulatory architectures giving

rise to different, but predictable,

patterns of expression noise.

— BAP


PROTEIN DESIGN

Designing activity at an interface Enzymes are proteins that

are the workhorses of the

cell. Designing enzymes with

new functions that are also

manifested in living systems

could be extremely valuable in

bioengineering and synthetic

biology applications. However,

enzyme design is a challenging

task and so far has mainly been

restricted to repurposing natural

enzymes and to in vitro systems.

Song and Tezcan started with a

monomeric redox protein and

introduced mutations that cause

it to assemble into a tetramer

with catalytic zinc ions in its

interfaces. This protein assembly

displayed β-lactamase activity,

the primary mechanism of anti-

biotic resistance, and enabled

E. coli cells to survive ampicillin

treatment. — VV


CLIMATE CHANGE

Can regional climate change be predicted?Global climate models (GCMs)

provide broad-brushstroke

projections of future climate.

These projections lack the

resolution required to under-

stand and respond to regional

changes. “Downscaling”

methods use GCM results as the

starting point to model regional

climate change. Hall explains

that researchers and planners

interested in regional adapta-

tion planning should interpret

results from such downscaling

with care: Climate warming pat-

terns can often be downscaled

with confidence, but changes

in atmospheric circulation are

much harder to capture. — JFU


CANCER

Menacing exosomes spread cancerExosomes are tiny vesicles

released from cells that carry

proteins, lipids, and nucleic acids:

cargo that can affect the biology

of recipient cells. In a Perspective,

Anastasiadou and Slack highlight

recent studies that reveal how

these vesicles act as vehicles

to spread cancer. Exosomes

that are released by cancer cells

harbor oncogenic microRNAs

(miRNAs), proteins involved in

miRNA biogenesis, and miRNAs

that induce inflammatory condi-

tions that support tumor growth

and metastasis. Such cancer

exosomes cause normal cells to

form tumors in animal studies.

The findings could guide the

development of exosome-based

diagnostics and therapies for

cancer. — LDC


IMMUNOLOGY

Stopping inflammation after infectionIn response to microbes,

innate immune cells activate

the transcription factor NF-κB,

resulting in pro-inflammatory

cytokine release. Once an infec-

tion has been resolved, NF-κB

signaling must be inhibited to

prevent excessive inflamma-

tion and tissue damage. Tanaka

et al. found that this feedback

inhibition requires the chaperone

protein HSP70, which enabled

the breakdown of the NF-κB

subunit p65 in dendritic cells.

HSP70-deficient dendritic cells

produced more pro-inflammatory

cytokines than did wild-type cells,

and HSP70-deficient mice had

more sustained inflammatory

responses to bacterial infection

than did wild-type mice. — JFF

Sci. Signal. 7, ra119 (2014).

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