RESEARCH - science.sciencemag.org · Science, this issue p. 578 IMMUNOGENOMICS The development of...

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31 JULY 2020 • VOL 369 ISSUE 6503 519SCIENCE sciencemag.org

HOST AND MICROBE

This is the brain on probioticsThe gut microbiome plays an

important role in the gut-brain

axis, a system of bidirectional

communication between the

central and enteric nervous

systems. Zhang et al. analyzed

the presence and abundance

of brain peptides—the pep-

tidome—along with the gut

microbiomes of mice fed two

different species of probiotics.

Probiotic treatment altered the

abundances of many neuropep-

tides in a manner that correlated

with changes in the composition

of the gut microbiome, varied

by brain region, an d depended

on the probiotic species,

whether the probiotic was live or

heat-killed, and the duration of

treatment. —AMV

Sci. Signal. 13, eabb0443 (2020).

ORGANIC CHEMISTRY

Simple swaps of CO2The loss of carbon dioxide

(CO2) from carboxylic acids

is a common reaction in both

biochemical and synthetic

contexts, but it has generally

involved catalysis or prolonged

heating. Kong et al. now report

that certain polar solvents,

such as dimethylformamide,

promote reversible CO2 loss all

by themselves from carboxyl-

ates bridged by one carbon to

aromatic rings. With electron-

withdrawing substituents on the

ring, isotopically labeled CO2 can

be efficiently swapped in even at

room temperature. Alternatively,

reaction with aldehydes leads to

alcohol formation. —JSY

Science, this issue p. 557

PALEOBOTANY

Origins of an alpine floraThe evolution of high mountain

floras is strongly influenced by

tectonic and climatic history.

Ding et al. document the timing,

tempo, and mode by which

the world’s most species-rich

alpine flora, that of the Tibet-

Himalaya-Hengduan region, was

assembled. Alpine assemblages

in the region are older than

previously thought, with lineages

tracing their alpine ancestry to

the early Oligocene—older than

any other modern alpine system.

Alpine species diversified faster

during periods of orogeny and

intensification of the Asian

monsoon, and the Hengduan

Mountains—the most species-

rich area in this region—played

a key biogeographic role as the

location of the earliest pulse

of alpine diversification in the

Oligocene. —AMS


IMMUNOGENOMICS

The development of microgliaMicroglia are the brain’s

immune cells, and they play

important roles in health and

neurodegenerative disease.

Kracht et al. performed single-

cell analysis of human microglial

gene expression and chromatin

RESEARCHI N SC IENCE J O U R NA L S

Edited by Michael Funk

Geochemical evidence suggests a precise origin for some of the larger stones used in Stonehenge.

ARCHAEOLOGY

Source of Stonehenge’s sarsens

Despite centuries of debate, the geological origin of the

massive standing stones of Stonehenge—the sarsens—

has never been conclusively identified. Previous inference

suggested a site 30 kilometers to the north as the source.

Nash et al., using a combination of analytical techniques,

tested this assertion and discovered that 50 of the 52 sarsens

had a consistent geochemistry, thus signaling a common

source. Additional testing revealed that a location only 25

kilometers north of Stonehenge is the most probable source of

the sarsens. These findings help to clarify competing recon-

structions about how the stones were transported to the site

and lend support to hypotheses that the sarsens were erected

around the same time, roughly 2500 BCE. —MA

Sci. Adv. 10.1126/sciadv.abc0133 (2020).

Published by AAAS

plays a role in maintaining

nuclear integrity. Chromosomal

disruption and the formation of

micronuclei in a process known

as chromothripsis can lead to

pathologies, including cancer.

Using a combination of live-cell

imaging and electron tomogra-

phy in tissue culture cells, Vietri

et al. found that the nuclear

integrity surveillance system

paradoxically drives micronu-

clear catastrophe. The authors

characterized the role of the

cytosolic ESCRT-III binding pro-

tein CHMP7 and its intranuclear

partner LEMD2, which together

detect ruptures in the nuclear

envelope and then trigger

envelope repair. Ruptured micro-

nuclei, however, were unable to

control this system, which led

to the accumulation of ESCRT-

III subunits. This accumulation

drove membrane aberrations

and thereby torsional stress–

induced DNA damage. These

findings elucidate the chro-

mosome-shattering process

associated with chromothripsis

that potentially drives cancer

development. —SMH

Nat. Cell Biol.22, 856 (2020).

520 31 JULY 2020 • VOL 369 ISSUE 6503 sciencemag.org SCIENCE

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RESEARCH | IN SCIENCE JOURNALS

accessibility and compared

the results with those of other

studies of human and mice

microglial development. By

using in situ validation, these

data identify fetal microglial

subsets that appear to be

distinct from adult human

microglia, suggesting functional

differences between the devel-

oping and mature brain. —LMZ


STRUCTURAL BIOLOGY

Integrative in-cell structural biologyIn bacteria, RNA polymerases can

associate with ribosomes to form

transcription-translation units

called expressomes. Multiple

models based on structural data

of in vitro reconstitution assays

have been proposed for how the

two machineries interface with

one another. Understanding this

bacteria-specific coupling mech-

anism offers insight regarding the

central dogma of molecular biol-

ogy and might be leveraged for

antibiotic development. O’Reilly

et al. found that the NusA protein

interfaces between the two com-

plexes. The authors combined

cryo–electron tomography and

cross-linking mass spectrometry

to produce an integrative model

of the transcribing, translating

expressome of Mycoplasma

pneumoniae obtained entirely

from in-cell data. This approach

contributes to the development

of in-cell structural biology.

—SMH


BIOTECHNOLOGY

Secrets of a fast base editorCRISPR-Cas9 base editors com-

prise RNA-guided Cas proteins

fused to an enzyme that can

deaminate a DNA nucleoside.

No natural enzyme deaminates

adenine in DNA, and so a break-

through came when a natural

transfer RNA deaminase was

fused to Cas9 and evolved to give

an adenine base editor (ABE)

that works on DNA. Further

evolution provided the enzyme

ABE8e, which catalyzes deamina-

tion more than 1000 times faster

than early ABEs. Lapinaite et

al. now present a 3.2-angstrom

resolution structure of ABE8e

bound to DNA in which the target

adenine is replaced with an ana-

log designed to trap the catalytic

conformation. The structure,

together with kinetic data com-

paring ABE8e to earlier ABEs,

explains how ABE8e edits DNA

bases and could inform future

base-editor design. —VV


ULTRACOLD MATTER

Lowering the entropyAtoms loaded in an optical

lattice can convincingly mimic

the behavior of electrons in

solids. However, reaching very

low temperatures, where the

most interesting quantum

phases are expected to occur,

is tricky. Yang et al. introduced a

clever experimental technique

to reduce the entropy of their

sample. They created an array

consisting of alternating rows of

sample atoms and reservoirs.

The entropy was transferred

from the sample atoms to the

adjacent reservoirs, which were

then removed. The resulting low-

entropy system can be used as

a basis for quantum simulation

and information. —JS


ORGANIC CHEMISTRY

A switch in time saves ligandIsolating just one of two mirror-

image products, or enantiomers,

is essential in pharmaceutical

synthesis. Often distinct enantio-

meric ligands must be appended

to a catalyst to steer the reaction

one way or the other. Tu et al.

report an intriguing case in

which a single catalyst produces

either product enantiomer,

depending on reaction time.

An iridium-catalyzed allylation

of hydroxyisoquinolines yields

one product within 10 minutes

via kinetic resolution of the allyl

precursors. Over 10 more hours,

this initial product comes apart

via a catalyzed reaction with the

solvent, whereas its enantiomer

steadily builds up and stays

intact. —JSY

Nat. Chem. 10.1038/

s41557-020-0489-1 (2020).

CELL BIOLOGY

Too much of a good thing The membrane remodeling

machinery known as ESCRT-III

Edited by Caroline Ash

and Jesse SmithIN OTHER JOURNALS

Sphagnum moss, which forms

peat and is a major carbon

store, is at risk of drying out

under climate change.

A complex of RNA polymerase and

the ribosome termed the expressome,

as visualized in bacterial cells by

cryo–electron tomography

Published by AAAS

521-B 31 JULY 2020 • VOL 369 ISSUE 6503 sciencemag.org SCIENCE

RESEARCH

IMMUNOLOGY

How the thymus shaped immunologyThe function of the thymus was

discovered by Jacques Miller in

1961 and laid a foundation for

immunology and modern medi-

cine. Until that time, researchers

mistakenly believed the thymus

merely represented a remnant of

defunct lymph tissue, something

of an immune cell graveyard. In a

Review, Miller recounts the semi-

nal experiments and conceptual

thinking that led to uncovering

the critical function of the thy-

mus and provides insights that

can be learned from those early

days. How knowledge of thymus

function subsequently spawned

the field of T cell biology and the

impact it has had on immune cell

interactions, vaccination, cancer

immunotherapy, and the micro-

biome are also discussed. —PNK


CORONAVIRUS

How does COVID-19 develop?Coronavirus disease 2019

(COVID-19) is a heterogeneous

disease, with patients experienc-

ing diverse symptoms ranging

from none to fatal respiratory

distress. Severe acute respira-

tory syndrome coronavirus 2

(SARS-CoV-2), which causes

COVID-19, infects numerous cell

types, which is determined by

the cellular receptor, or recep-

tors, it binds. In a Perspective,

Matheson and Lehner discuss

how receptor binding deter-

mines the pattern of COVID-19

disease symptoms, the unan-

swered questions about the

biology of infection, and whether

infection can be prevented to

attenuate severe disease. —GKA


STRUCTURAL BIOLOGY

Revealing family differencesIn response to low blood glucose

concentrations, both the gluca-

gon receptor (GCGR)—a family B

G protein–coupled receptor

(GPCR)—and the b2

adrenergic

receptor (b2AR)—a family A

GPCR—are activated and act

through the cyclic adenosine

monophosphate signaling

pathway to increase glucose

production. The kinetics of the

response is different for the two

receptors. Based on structural

and spectroscopic data, Hilger et

al. show that the conformation

of transmembrane helix 6 in the

activated state is a key differen-

tiator (see the Perspective by

Lebon). In b2AR, the helix moves

toward its active conforma-

tion when an agonist binds, but

in GCGR, both agonist and G

protein binding are required. This

likely explains why activation of

its partner G protein is slower for

GCGR than for b2AR. —VV

Science, this issue p. 523;

see also p. 507

BIOCHEMISTRY

Dephosphorylating RNA moleculesTransfer RNA (tRNA) and mes-

senger RNA molecules often

acquire a terminal 2′,3′-cyclic

phosphate group when pro-

cessed in the cell. These cyclic

phosphates provide attachment

points for tRNA ligases and must

be removed to recycle tRNAs

from stalled ribosomes. Pinto

et al. identified an enzyme from

human tissue culture cells that

can do the job. Biochemical

characterization and analysis

of a crystal structure reveal

ANGEL2 as a 2′,3′-cyclic phos-

phatase with functions for RNA

processing and modification.

—BAP


NEUROGENOMICS

Effects of allele-specific open chromatinGenetic variants in noncoding

regions of the genome may

underlie the development of

disease. However, we are just

beginning to tease apart the

function of such variants associ-

ated with neuropsychiatric

disease. Using five types of neu-

ral progenitor cells derived from

20 human induced pluripotent

stem cell lines, Zhang et al.

looked at allele-specific open

chromatin (ASoC) variants.

Many ASoC variants overlapped

with genomic elements, such

as transcription factor bind-

ing sites, and loci identified in

genome-wide association stud-

ies for neurological traits. From

the experimental and computa-

tional analyses, they identified

single-nucleotide polymor-

phisms and illuminate how

one schizophrenia-associated

variant affects neurodevelop-

ment. —LMZ


NEURODEVELOPMENT

Neocortex in the fetal brainAlong the path of human

evolution, gene duplication and

divergence produced a protein,

ARHGAP11B, that is found in

humans but not nonhuman

primates or other mammals.

Heide et al. analyzed the effects

of ARHGAP11B gene expression,

under control of its own human-

specific promoter, in the fetal

marmoset (see the Perspective

by Dehay and Kennedy). In the

early weeks of fetal growth, the

gene drove greater elabora-

tion of neural progenitors and

neocortex than is evident in

the normal fetal marmoset.

ARHGAP11B expression may be

one cause of the more robust

neocortex that characterizes the

human brain. —PJH


see also p. 506

MOLECULAR DIFFUSION

Reactions give solvents a kickDuring a chemical reaction, the

reorganization of solvent mol-

ecules not directly in contact

with reactants and products

is normally viewed as a simple

diffusion response. Wang et al.

studied molecular diffusion in

six common reactions—includ-

ing the copper-catalyzed click

reaction and the Diels-Alder

reaction—with pulsed-field

gradient nuclear magnetic reso-

nance. They observed a boost in

mobility relative to Brownian dif-

fusion that was stronger for the

catalyzed reactions that were

studied. The mobilities for the

click reaction were verified with

a microfluidic gradient method.

They argue that energy release

produces transient translational

motion of reacting centers that

mechanically perturbs solvent

molecules. —PDS


NANOMATERIALS

Graphene nanoribbons made on oxidesAtomically precise nanogra-

phenes and nanoribbons have

been synthesized on metal

surfaces that catalyze cyclode-

hydrogenation of precursors.

However, for use in devices,

these structures usually must

be transferred to insulating

or semiconducting surfaces.

Kolmer et al. synthesized precise

graphene nanoribbons on the

surface of rutile titanium dioxide

(TiO2) that assisted the cyclode-

hydrofluorination of specifically

designed precursor molecules

through a series of thermally

triggered transformations.

Scanning tunneling microscopy

and spectroscopy confirmed the

formation of well-defined zigzag

ends of the nanoribbons as well

as their weak interaction with

the substrate. —PDS


Edited by Michael FunkALSO IN SCIENCE JOURNALS

Published by AAAS

31 JULY 2020 • VOL 369 ISSUE 6503 521-CSCIENCE sciencemag.org

RESEARCH

MATERIALS SCIENCE

Deformable semiconductorsSemiconductors are usually

brittle and do not deform easily.

Wei et al. found that bulk single

crystals of indium selenide

instead have excellent flexibility

(see the Perspective by Han).

The deformability comes from

the compliant intralayer bonding

between indium and selenium.

The authors used these observa-

tions along with a previously

discovered silver sulfide to

determine a deformability factor

for materials that may help find

other deformable semiconduc-

tors. —BG


see also p. 509

AIR POLLUTION

Cleaner skiesParticulate air pollution in the

contiguous United States has

decreased considerably over

recent decades, but where

exactly has that progress been

made? Colmer et al. analyzed 36

years of data and found that the

spatial distribution of fine par-

ticulate matter concentrations

has remained largely unchanged

over that interval (see the

Perspective by Ma). Although,

fine particulate pollution levels

have dropped overall, those

areas that were most and least

polluted in 1981 remain so today.

We may have made important

strides in pollution control, but

we have been less success-

ful in addressing disparities of

exposure between communities.

—HJS


see also p. 503

CORONAVIRUS

Epidemic in Northern CaliforniaGenome sequencing of severe

acute respiratory syndrome

coronavirus 2 (SARS-CoV-2)

outbreaks is valuable for tracing

the sources and perhaps for

drawing lessons about prevent-

ing future outbreaks. Genomic

analysis by Deng et al. revealed

that Northern California

experienced a complex series

of introductions of the virus,

deriving not only from state-

to-state transmission but also

from international travel by air

and ship. The study highlights

the importance of being able to

rapidly test and trace contacts

of positive cases to enable swift

control. —CA


SOLAR PHYSICS

Predicting large solar flaresThe sudden release of magnetic

energy on the Sun drives power-

ful solar flares, which are difficult

to predict. Kusano et al. derived

physics-based thresholds for the

onset of large solar flares and

show how they can be predicted

from routine solar observations

(see the Perspective by Veronig).

They tested their method using

observations of the Sun from

2008 to 2019. In most cases,

the method correctly identifies

which regions will produce large

flares within the next 20 hours,

although there are some false

positives and false negatives.

The method also provides the

exact location where each flare

will begin and limits on how

powerful it will be. Accurate

predictions of solar flares could

improve forecasts of space

weather conditions around

Earth. —KTS


see also p. 504

CARDIOMYOPATHY

Lovastatin for cardiolaminopathyMutations in the gene LMNA,

which encodes nuclear enve-

lope proteins, can cause dilated

cardiomyopathy associated

with arrhythmia and sudden

cardiac death. To understand

the mechanisms contribut-

ing to this disease, Sayed et al.

studied induced pluripotent

stem cell–derived endothelial

cells (iPSC-ECs) from a family

harboring an LMNA mutation.

They found down-regulation of

a protein involved in mechano-

transduction, which caused

endothelial dysfunction.

Lovastatin could induce this

protein in iPSC-ECs, improving

cardiomyocyte function in cocul-

ture and clinical endothelial cell

function in two patients treated

with the drug. This study demon-

strates a wor kflow for identifying

and validating potential drug

treatments for patients with

cardiolaminopathy. —CC

Sci. Transl. Med. 12, eaax9276 (2020).

IMMUNODEFICIENCY

A human immune system sans MAIT cellsMucosal-associated invariant T

(MAIT) cells represent ~5% of

circulating human T cells, reside

in high frequency in mucosal

tissues, and provide enhanced

immunity against bacterial and

viral infections. Howson et al. set out to determine the genetic

basis of immunodeficiency in a

patient with persistent tattoo-

associated human papilloma

virus–positive warts. The gene

MR1 encodes a major histocom-

patibility complex–like molecule

that presents bacteria-derived

riboflavin metabolites to MAIT

cells. Whole-exome sequencing

led the researchers to identify

a rare point mutation in both

copies of the MR1 gene. By solv-

ing the structure of the mutant

MR1 protein, they demonstrated

that the mutation disrupted the

ligand-binding domain of MR1.

Consistent with this finding, the

patient lacked circulating MAIT

cells. —AB

Sci. Immunol. 5, eabc9492 (2020).

Published by AAAS

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