SCIENCE science.org 8 APRIL 2022 • VOL 376 ISSUE 6589 150-B
RESEARCHIMMUNOGENOMICS
Analyzing immune system
gene expression
Diseases involving the immune
system are heritable, but it is
unknown how genetic variation
contributes to different diseases.
To identify how implicated
loci affect gene expression in
immune cells from individuals
from different populations, two
groups performed single-cell
RNA sequencing of immune cells,
with each study investigating
hundreds of individuals and more
than 1 million immune cells (see
the Perspective by Sumida and
Hafler). These studies examined
both proximal (cis) and distal
(trans) genetic variants affecting
gene expression in 14 different
immune cell types. Perez et al.
studied healthy individuals of
both European and Asian descent,
as well as individuals diagnosed
with systemic lupus erythema-
tosus. Yazar et al. performed a
population-based study inves-
tigating how segregating alleles
contribute to variation in immune
function. Integrating these data
with autoimmune disease cohorts
identifies causal effects for
more than 160 loci. Both studies
observed how gene expression
patterns are cell-type and context
specific and can explain observed
variation in immune cell func-
tion among individuals. Both
studies also identified causal links
between genome-wide analyses
and expression quantitative trait
loci, identifying potential mecha-
nisms underlying autoimmune
diseases. —LMZ
Science, abf1970, abf3041,
this issue p. 153, p. 154;
see also abq0426, p. 134
PROTEIN ENGINEERING
Increasing potency
but not toxicity
Cancer immunotherapy takes
advantage of natural immune
responses. In one approach,
T cells are engineered to be
activated in response to a
Edited by Michael FunkALSO IN SCIENCE JOURNALS
tumor-specific antigen. A chal-
lenge is that increasing the affinity
of a T cell receptor (TCR) for
the tumor-specific antigen to
increase cancer cell killing can
lead to off-target toxicities. Zhao
et al. took advantage of the fact
that an extended bond lifetime
characteristic of so-called catch
bonds is associated with agonist
potency. The authors screened
for TCR mutants that acquired
catch bonds by selecting those
that showed high activation
paired with low antigen-binding
affinity. They engineered a tumor
antigen–specific TCR that had
killing potency at least equal to a
previously described high-affinity
TCR but without the associated
adverse cross-reactivity. —VV
Science, abl5282, this issue p. 155NANOMATERIALS
Diversifying nanoparticles
Multielement nanoparticles
are attractive for a variety of
applications in catalysis, energy,
and other fields. A more diverse
range and larger number of
elements can be mixed together
because of high-entropy
mixing states accessed by a
number of recently developed
techniques. Yao et al. review
these techniques along with
characterization methods,
high-throughput screening,
and data-driven discovery for
targeted applications. The wide
range of different elements that
can be mixed together presents
a large number of opportunities
and challenges. —BG
Science, abn3103, this issue p. 151CANCER GENOMICS
Noncoding mutations
decoded
Numerous large-scale efforts
have been undertaken to catalog
and understand the biology of
cancer-associated mutations
in regions that directly code for
proteins. Much of the genome,
however, consists of noncod-
ing regions that do not directlyencode specific proteins, but
instead perform other func-
tions such as regulating protein
expression. These genome
regions can also play key roles
in cancer. Dietlein et al. devel-
oped a computational approach
to systematically detect
cancer-associated mutations in
noncoding regions of different
cancer types and directly exam-
ined the biological function of one
such region involved in breast
cancer. Using this genome-wide
approach, researchers should be
able to comprehensively examine
the contributions of noncoding
regions to cancer development.
—Y N
Science, abg5601, this issue p. 152STRUCTURAL BIOLOGY
How JAKs are activated
Janus kinases (JAKs) are
essential to the many biological
outcomes of cytokine signaling.
They bind to cytokine receptors
and are activated when cytokine
binding leads to receptor dimer-
ization. Dimerization leads to
activation of signal transducer
and activator of transcription
(STAT) transcription factors,
which translocate to the nucleus
and initiate the transcription
of cytokine-responsive genes.
Mutations in JAKs and STATs
lead to immunodeficiency and
myeloproliferative disorders.
Glassman et al. report the struc-
ture of a full-length JAK bound
to an engineered construct that
displays a dimer of the intra-
cellular domains of a cytokine
receptor (see the Perspective by
Levine and Hubbard). The struc-
ture provides insight into how
cytokine receptor dimerization
drives JAK activation and how
a range of disease mutations
affect function. —VV
Science, abn8933, this issue p. 163;
see also abo7788, p. 139PARTICLE PHYSICS
Weighing the W boson
W bosons mediate the
weak interaction, one of thefundamental forces in physics.
Because the Standard Model
(SM) of particle physics places
tight constraints on the mass
of the W boson, measuring the
mass puts the SM to the test.
The Collider Detector at Fermilab
(CDF) Collaboration now reports
a precise measurement of the W
boson mass extracted from data
taken at the Tevatron particle
accelerator (see the Perspective
by Campagnari and Mulders).
Surprisingly, the researchers
found that the mass of the boson
was significantly higher than the
SM predicts, with a discrepancy
of 7 standard deviations. —JS
Science, abk1781, this issue p. 170;
see also abm0101, p. 136BIOMATERIALS
Key aspects of bone
mineralization
Bone is a hierarchical material
consisting of organic fibers,
mainly in the form of collagen,
which are mineralized with
inorganic crystals, primar-
ily hydroxyapatite. It is this
structure that gives bone its
remarkable combination of
strength and toughness. Ping et
al. examined the deposition of
minerals on both the outside and
inside of the fibers over time (see
the Perspective by Nudelman
and Kröger). They found that
large contractile forces occur
within the collagen during intrafi-
brillar mineralization regardless
of the mineral type, thus giving
bone its unusual combination
of mechanical properties. This
feature is analogous to the
reinforcement of concrete using
prestressed steel rods. —MSL
Science, abm2664, this issue p. 188;
see also abo1264, p. 137RESPIRATORY DISEASE
Characterizing
cardiopulmonary disease
Bronchopulmonary dysplasia
(BPD) and BPD-associated pul-
monary hypertension (BPD-PH)