Nature Reviews Drug Discovery,
Journal Year:
2023,
Volume and Issue:
22(6), P. 496 - 520
Published: April 28, 2023
Single-cell
technologies,
particularly
single-cell
RNA
sequencing
(scRNA-seq)
methods,
together
with
associated
computational
tools
and
the
growing
availability
of
public
data
resources,
are
transforming
drug
discovery
development.
New
opportunities
emerging
in
target
identification
owing
to
improved
disease
understanding
through
cell
subtyping,
highly
multiplexed
functional
genomics
screens
incorporating
scRNA-seq
enhancing
credentialling
prioritization.
ScRNA-seq
is
also
aiding
selection
relevant
preclinical
models
providing
new
insights
into
mechanisms
action.
In
clinical
development,
can
inform
decision-making
via
biomarker
for
patient
stratification
more
precise
monitoring
response
progression.
Here,
we
illustrate
how
methods
being
applied
key
steps
discuss
ongoing
challenges
their
implementation
pharmaceutical
industry.
There
have
been
significant
recent
advances
development
remarkable
Ferran
colleagues
primarily
pipeline,
from
decision-making.
Ongoing
potential
future
directions
discussed.
Cell,
Journal Year:
2021,
Volume and Issue:
184(13), P. 3573 - 3587.e29
Published: May 31, 2021
The
simultaneous
measurement
of
multiple
modalities
represents
an
exciting
frontier
for
single-cell
genomics
and
necessitates
computational
methods
that
can
define
cellular
states
based
on
multimodal
data.
Here,
we
introduce
"weighted-nearest
neighbor"
analysis,
unsupervised
framework
to
learn
the
relative
utility
each
data
type
in
cell,
enabling
integrative
analysis
modalities.
We
apply
our
procedure
a
CITE-seq
dataset
211,000
human
peripheral
blood
mononuclear
cells
(PBMCs)
with
panels
extending
228
antibodies
construct
reference
atlas
circulating
immune
system.
Multimodal
substantially
improves
ability
resolve
cell
states,
allowing
us
identify
validate
previously
unreported
lymphoid
subpopulations.
Moreover,
demonstrate
how
leverage
this
rapidly
map
new
datasets
interpret
responses
vaccination
coronavirus
disease
2019
(COVID-19).
Our
approach
broadly
applicable
strategy
analyze
look
beyond
transcriptome
toward
unified
definition
identity.
Nature,
Journal Year:
2021,
Volume and Issue:
598(7879), P. 111 - 119
Published: Oct. 6, 2021
Abstract
The
primary
motor
cortex
(M1)
is
essential
for
voluntary
fine-motor
control
and
functionally
conserved
across
mammals
1
.
Here,
using
high-throughput
transcriptomic
epigenomic
profiling
of
more
than
450,000
single
nuclei
in
humans,
marmoset
monkeys
mice,
we
demonstrate
a
broadly
cellular
makeup
this
region,
with
similarities
that
mirror
evolutionary
distance
are
consistent
between
the
transcriptome
epigenome.
core
molecular
identities
neuronal
non-neuronal
cell
types
allow
us
to
generate
cross-species
consensus
classification
types,
infer
properties
species.
Despite
overall
conservation,
however,
many
species-dependent
specializations
apparent,
including
differences
cell-type
proportions,
gene
expression,
DNA
methylation
chromatin
state.
Few
marker
genes
species,
revealing
short
list
candidate
regulatory
mechanisms
responsible
features
homologous
such
as
GABAergic
chandelier
cells.
This
allows
use
patch–seq
(a
combination
whole-cell
patch-clamp
recordings,
RNA
sequencing
morphological
characterization)
identify
corticospinal
Betz
cells
from
layer
5
non-human
primates
characterize
their
highly
specialized
physiology
anatomy.
These
findings
highlight
robust
underpinnings
diversity
M1
mammals,
point
pathways
functional
identity
species-specific
adaptations.
Genome biology,
Journal Year:
2020,
Volume and Issue:
21(1)
Published: May 11, 2020
Abstract
Technological
advances
have
enabled
the
profiling
of
multiple
molecular
layers
at
single-cell
resolution,
assaying
cells
from
samples
or
conditions.
Consequently,
there
is
a
growing
need
for
computational
strategies
to
analyze
data
complex
experimental
designs
that
include
modalities
and
groups
samples.
We
present
Multi-Omics
Factor
Analysis
v2
(MOFA+),
statistical
framework
comprehensive
scalable
integration
multi-modal
data.
MOFA+
reconstructs
low-dimensional
representation
using
computationally
efficient
variational
inference
supports
flexible
sparsity
constraints,
allowing
jointly
model
variation
across
sample
modalities.
Nature,
Journal Year:
2021,
Volume and Issue:
598(7879), P. 86 - 102
Published: Oct. 6, 2021
Here
we
report
the
generation
of
a
multimodal
cell
census
and
atlas
mammalian
primary
motor
cortex
as
initial
product
BRAIN
Initiative
Cell
Census
Network
(BICCN).
This
was
achieved
by
coordinated
large-scale
analyses
single-cell
transcriptomes,
chromatin
accessibility,
DNA
methylomes,
spatially
resolved
morphological
electrophysiological
properties
cellular
resolution
input-output
mapping,
integrated
through
cross-modal
computational
analysis.
Our
results
advance
collective
knowledge
understanding
brain
cell-type
organization
