Table Of Contents Page, PNAS Volume 121, Number 34
Special Feature
From Basic Mechanisms and Cellular Machineries to AI Solutions in Protein Folding
Two years on from the initial release of AlphaFold, we have seen its widespread adoption
as a structure prediction tool. Here, we discuss some of the latest work based on
AlphaFold, with a particular focus on its use within the structural biology ...
How did specific useful protein sequences arise from simpler molecules at the origin
of life? This seemingly needle-in-a-haystack problem has remarkably close resemblance
to the old Protein Folding Problem, for which the solution is now known from ...
Mutations in protein active sites can dramatically improve function. The active site,
however, is densely packed and extremely sensitive to mutations. Therefore, some mutations
may only be tolerated in combination with others in a phenomenon known as ...
The process of protein phase separation into liquid condensates has been implicated
in the formation of membraneless organelles (MLOs), which selectively concentrate
biomolecules to perform essential cellular functions. Although the importance of this
...
The enzyme UDP-glucose: glycoprotein glucosyltransferase (UGGT) is the gatekeeper
of protein folding within the endoplasmic reticulum (ER). One-third of the human proteome
traverses the ER where folding and maturation are facilitated by a complex protein
...
Amyloid formation by α-synuclein (αSyn) occurs in Parkinson’s disease, multiple system
atrophy, and dementia with Lewy bodies. Deciphering the residues that regulate αSyn
amyloid fibril formation will not only provide mechanistic insight but may also ...
Mechanical energy, specifically in the form of ultrasound, can induce pressure variations
and temperature fluctuations when applied to an aqueous media. These conditions can
both positively and negatively affect protein complexes, consequently altering ...
Kinetic stability is thought to be an attribute of proteins that require a long lifetime,
such as the transporter of thyroxine and holo retinol-binding protein or transthyretin
(TTR) functioning in the bloodstream, cerebrospinal fluid, and vitreous humor. ...
This Week in PNAS
Opinion
QnAs
Retrospective
Commentaries
Perspective
Successful implementation of the Kunming-Montreal Global Biodiversity Framework requires
identifying a process for measuring and valuing changes in biodiversity that build
on the recognition that economics and valuation must play a key role in “halting ...
Letters
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On the roles of function and selection in evolving systems
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Changes in holopelagic Sargassum spp. biomass composition across an unusual year
Brief Report
Desired fertility measures are routinely collected and used by researchers and policy
makers, but their self-reported nature raises the possibility of reporting bias. In
this paper, we test for the presence of such bias by comparing responses to direct
...
Physical Sciences
Applied Mathematics
In the age of information explosion, the exponential growth of digital data far exceeds
the capacity of current mainstream storage media. DNA is emerging as a promising alternative
due to its higher storage density, longer retention time, and lower power ...
Applied Physical Sciences
Electron transport in complex fluids, biology, and soft matter is a valuable characteristic
in processes ranging from redox reactions to electrochemical energy storage. These
processes often employ conductor–insulator composites in which electron ...
Electrical triggering of a metal–insulator transition (MIT) often results in the formation
of characteristic spatial patterns such as a metallic filament percolating through
an insulating matrix or an insulating barrier splitting a conducting matrix. When
...
Biophysics and Computational Biology
When biological populations expand into new territory, the evolutionary outcomes can
be strongly influenced by genetic drift, the random fluctuations in allele frequencies.
Meanwhile, spatial variability in the environment can also significantly influence
...
RAS GTPases associate with the biological membrane where they function as molecular
switches to regulate cell growth. Recent studies indicate that RAS proteins oligomerize
on membranes, and disrupting these assemblies represents an alternative therapeutic
...
RNA’s diversity of structures and functions impacts all life forms since primordia.
We use calorimetric force spectroscopy to investigate RNA folding landscapes in previously
unexplored low-temperature conditions. We find that Watson–Crick RNA hairpins, ...
Schizophrenia phenotypes are suggestive of impaired cortical plasticity in the disease,
but the mechanisms of these deficits are unknown. Genomic association studies have
implicated a large number of genes that regulate neuromodulation and plasticity, ...
Chemistry
Self-healing covalent adaptable networks (CANs) are not only of fundamental interest
but also of practical importance for achieving carbon neutrality and sustainable development.
However, there is a trade-off between the mobility and cross-linking ...
Clean production of hydrogen peroxide (H2O2) with water, oxygen, and renewable energy is considered an important green synthesis
route, offering a valuable substitute for the traditional anthraquinone method. Currently,
renewable energy–driven production ...
The fusion of hydrogenases and photosynthetic reaction centers (RCs) has proven to
be a promising strategy for the production of sustainable biofuels. Type I (iron-sulfur-containing)
RCs, acting as photosensitizers, are capable of promoting electrons to a ...
Earth, Atmospheric, and Planetary Sciences
Triton and Pluto are believed to share a common origin, both forming initially in
the Kuiper Belt but Triton being later captured by Neptune. Both objects display similar
sizes, densities, and atmospheric and surface ice composition, with the presence of
...
Global warming during the Last Glacial Termination was interrupted by millennial-scale
cool intervals such as the Younger Dryas and the Antarctic Cold Reversal (ACR). Although
these events are well characterized at high latitudes, their impacts at low ...
This study analyzes H2O and HDO vertical profiles in the Venus mesosphere using Venus Express/Solar Occultation
in the InfraRed data. The findings show increasing H2O and HDO volume mixing ratios with altitude, with the D/H ratio rising significantly
from ...
Engineering
The human neck is a unique mechanical structure, highly flexible but fatigue prone.
The rising prevalence of neck pain and chronic injuries has been attributed to increasing
exposure to fatigue loading in activities such as prolonged sedentary work and ...
Fluorescence guidance is routinely used in surgery to enhance perfusion contrast in
multiple types of diseases. Pressure-enhanced sensing of tissue oxygenation (PRESTO)
via fluorescence is a technique extensively analyzed here, that uses an FDA-approved
...
Physics
Recent advances in single-cell sequencing technology have revolutionized our ability
to acquire whole transcriptome data. However, uncovering the underlying transcriptional
drivers and nonequilibrium driving forces of cell function directly from these ...
Sustainability Science
Ecosystem restoration is inherently a complex activity with inevitable tradeoffs in
environmental and societal outcomes. These tradeoffs can potentially be large when
policies and practices are focused on single outcomes versus joint achievement of
...
Social Sciences
Economic Sciences
Despite ethical and historical arguments for removing race from clinical algorithms,
the consequences of removal remain unclear. Here, we highlight a largely undiscussed
consideration in this debate: varying data quality of input features across race ...
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Political Sciences
Ethics standards reference the need for special consideration of vulnerable populations,
such as pregnant women, incarcerated individuals, and minors. The concept of vulnerability
is poorly conceptualized in the medical sciences where it originated, and ...
Psychological and Cognitive Sciences
The social and behavioral sciences have been increasingly using automated text analysis
to measure psychological constructs in text. We explore whether GPT, the large-language
model (LLM) underlying the AI chatbot ChatGPT, can be used as a tool for ...
Across 11 experimental studies (n = 12,257), we show that female victims of sexual assault are blamed more and seen
as less morally virtuous if their assault follows voluntary sexual intimacy, a factor
we term “adjacent consent”. Moreover, we illuminate a ...
The language network of the human brain has core components in the inferior frontal
cortex and superior/middle temporal cortex, with left-hemisphere dominance in most
people. Functional specialization and interconnectivity of these neocortical regions
is ...
Social Sciences
As health and health care systems continue to face massive challenges from local to
global well-being, understanding the processes that lead to improvement or deterioration
in human health has embraced a broad range of forces from genes to national ...
Sustainability Science
Ecosystem restoration is inherently a complex activity with inevitable tradeoffs in
environmental and societal outcomes. These tradeoffs can potentially be large when
policies and practices are focused on single outcomes versus joint achievement of
...
Using global data for around 180 countries and territories and 170 food/feed types
primarily derived from FAOSTAT, we have systematically analyzed the changes in greenhouse
gas (GHG) emission intensity (GHGi) (kg CO2eq per kg protein production) over the ...
Biological Sciences
Agricultural Sciences
Using global data for around 180 countries and territories and 170 food/feed types
primarily derived from FAOSTAT, we have systematically analyzed the changes in greenhouse
gas (GHG) emission intensity (GHGi) (kg CO2eq per kg protein production) over the ...
Discovering and engineering herbicide-resistant genes is a crucial challenge in crop
breeding. This study focuses on the 4-hydroxyphenylpyruvate dioxygenase Inhibitor
Sensitive 1-Like (HSL) protein, prevalent in higher plants and exhibiting weak catalytic
...
Biochemistry
In the age of information explosion, the exponential growth of digital data far exceeds
the capacity of current mainstream storage media. DNA is emerging as a promising alternative
due to its higher storage density, longer retention time, and lower power ...
RAS GTPases associate with the biological membrane where they function as molecular
switches to regulate cell growth. Recent studies indicate that RAS proteins oligomerize
on membranes, and disrupting these assemblies represents an alternative therapeutic
...
The fusion of hydrogenases and photosynthetic reaction centers (RCs) has proven to
be a promising strategy for the production of sustainable biofuels. Type I (iron-sulfur-containing)
RCs, acting as photosensitizers, are capable of promoting electrons to a ...
Cysteine palmitoylation or S-palmitoylation catalyzed by the ZDHHC family of acyltransferases regulates the biological
function of numerous mammalian proteins as well as viral proteins. However, understanding
of the role of S-palmitoylation in antiviral ...
Myo-inositol-1-phosphate synthase (MIPS) catalyzes the NAD+-dependent isomerization of glucose-6-phosphate (G6P) into inositol-1-phosphate (IMP),
controlling the rate-limiting step of the inositol pathway. Previous structural studies
focused on the ...
Ubiquitination status of proliferating cell nuclear antigen (PCNA) is crucial for
regulating DNA lesion bypass. After the resolution of fork stalling, PCNA is subsequently
deubiquitinated, but the underlying mechanism remains undefined. We found that the
...
Transcription of eukaryotic protein-coding genes generates immature mRNAs that are
subjected to a series of processing events, including capping, splicing, cleavage,
and polyadenylation (CPA), and chemical modifications of bases. Alternative ...
Biophysics and Computational Biology
Recent advances in single-cell sequencing technology have revolutionized our ability
to acquire whole transcriptome data. However, uncovering the underlying transcriptional
drivers and nonequilibrium driving forces of cell function directly from these ...
RNA’s diversity of structures and functions impacts all life forms since primordia.
We use calorimetric force spectroscopy to investigate RNA folding landscapes in previously
unexplored low-temperature conditions. We find that Watson–Crick RNA hairpins, ...
Protein folding in the cell often begins during translation. Many proteins fold more
efficiently cotranslationally than when refolding from a denatured state. Changing
the vectorial synthesis of the polypeptide chain through circular permutation could
...
Cell Biology
Most mammalian cells have molecular circadian clocks that generate widespread rhythms
in transcript and protein abundance. While circadian clocks are robust to fluctuations
in the cellular environment, little is known about the mechanisms by which the ...
Integrin activation resulting in enhanced adhesion to the extracellular matrix plays
a key role in fundamental cellular processes. Although integrin activation has been
extensively studied in circulating cells such as leukocytes and platelets, much less
...
The first steps of vision take place in the ciliary outer segment compartment of photoreceptor
cells. The protein composition of outer segments is uniquely suited to perform this
function. The most abundant among these proteins is the visual pigment, ...
Vesicular transport relies on multimeric trafficking complexes to capture cargo and
drive vesicle budding and fusion. Faithful assembly of the trafficking complexes is
essential to their functions but remains largely unexplored. Assembly of AP2 adaptor,
a ...
TORC1 (target of rapamycin complex 1) is a highly conserved protein kinase that plays
a central role in regulating cell growth. Given the role of mammalian TORC1 (mTORC1)
in metabolism and disease, understanding mTORC1 downstream signaling and feedback
...
Ecology
Extending and safeguarding tropical forest ecosystems is critical for combating climate
change and biodiversity loss. One of its constituents, lianas, is spreading and increasing
in abundance on a global scale. This is particularly concerning as lianas ...
Vascular plants are diverse and a major component of terrestrial ecosystems, yet their
geographic distributions remain incomplete. Here, I present a global database of vascular
plant distributions by integrating species distribution models calibrated to ...
Evolutionary rescue, whereby adaptive evolutionary change rescues populations from
extinction, is theorized to enable imperiled animal populations to persist under increasing
anthropogenic change. Despite a large body of evidence in theoretical and ...
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Evolution fails to rescue a population in an increasingly variable environment
Global migrations of diverse animal species often converge along the same routes,
bringing together seasonal assemblages of animals that may compete, prey on each other,
and share information or pathogens. These interspecific interactions, when energetic
...
Evolution
When biological populations expand into new territory, the evolutionary outcomes can
be strongly influenced by genetic drift, the random fluctuations in allele frequencies.
Meanwhile, spatial variability in the environment can also significantly influence
...
Beluga whales play a critical role in the subsistence economies and cultural heritage
of Indigenous communities across the Arctic, yet the effects of Indigenous hunting
on beluga whales remain unknown. Here, we integrate paleogenomics, genetic simulations,...
Genetics
The language network of the human brain has core components in the inferior frontal
cortex and superior/middle temporal cortex, with left-hemisphere dominance in most
people. Functional specialization and interconnectivity of these neocortical regions
is ...
Polyomaviruses are small, circular dsDNA viruses that can cause cancer. Alternative
splicing of polyomavirus early transcripts generates large and small tumor antigens
(LT, ST) that play essential roles in viral replication and tumorigenesis. Some ...
Homologous recombination (HR) is essential for the maintenance of genome stability.
During HR, Replication Protein A (RPA) rapidly coats the 3′-tailed single-strand DNA
(ssDNA) generated by end resection. Then, the ssDNA-bound RPA must be timely replaced
...
Immunology and Inflammation
To broadly measure the spectrum of cellular self-antigens for natural killer T cells
(NKT), we developed a sensitive lipidomics system to analyze lipids trapped between
CD1d and NKT T cell receptors (TCRs). We captured diverse antigen complexes formed
in ...
Alloreactive memory T cells have been implicated as central drivers of transplant
rejection. Perplexingly, innate cytokines, such as IL-6, IL-1β, and IL-12, are also
associated with rejection of organ transplants. However, the pathways of innate immune
...
Medical Sciences
Fluorescence guidance is routinely used in surgery to enhance perfusion contrast in
multiple types of diseases. Pressure-enhanced sensing of tissue oxygenation (PRESTO)
via fluorescence is a technique extensively analyzed here, that uses an FDA-approved
...
Significant racial disparities exist between Black and White patients with uterine
serous carcinoma (USC). While the reasons for these disparities are unclear, several
studies have demonstrated significantly different rates of driver mutations between
...
In acute promyelocytic leukemia (APL), the promyelocytic leukemia-retinoic acid receptor
alpha (PML/RARα) fusion protein destroys PML nuclear bodies (NBs), leading to the
formation of microspeckles. However, our understanding, largely learned from ...
Insig-1 and Insig-2 are endoplasmic reticulum (ER) proteins that inhibit lipid synthesis
by blocking transport of sterol regulatory element-binding proteins (SREBP-1 and SREBP-2)
from ER to Golgi. In the Golgi, SREBPs are processed proteolytically to ...
Microbiology
Microsporidia are intracellular eukaryotic pathogens that pose a substantial threat
to immunocompromised hosts. The way these pathogens manipulate host cells during infection
remains poorly understood. Using a proximity biotinylation strategy we ...
The removal of mis-incorporated nucleotides by proofreading activity ensures DNA replication
fidelity. Whereas the ε-exonuclease DnaQ is a well-established proofreader in the
model organism Escherichia coli, it has been shown that proofreading in a ...
The ZIKA virus (ZIKV) evades the host immune response by degrading STAT2 through its
NS5 protein, thereby inhibiting type I interferon (IFN)-mediated antiviral immunity.
However, the molecular mechanism underlying this process has remained elusive. In
...
Most bacteria are surrounded by a cell wall that contains peptidoglycan (PG), a large
polymer composed of glycan strands held together by short peptide cross-links. There
are two major types of cross-links, termed 4-3 and 3-3 based on the amino acids ...
Neuroscience
Schizophrenia phenotypes are suggestive of impaired cortical plasticity in the disease,
but the mechanisms of these deficits are unknown. Genomic association studies have
implicated a large number of genes that regulate neuromodulation and plasticity, ...
The primary motor cortex does not uniquely or directly produce alpha motoneurone (α-MN)
drive to muscles during voluntary movement. Rather, α-MN drive emerges from the synthesis
and competition among excitatory and inhibitory inputs from multiple ...
Evidence accumulates that the cerebellum’s role in the brain is not restricted to
motor functions. Rather, cerebellar activity seems to be crucial for a variety of
tasks that rely on precise event timing and prediction. Due to its complex structure
and ...
Mutations in the PSEN genes are the major cause of familial Alzheimer’s disease, and presenilin (PS) is
the catalytic subunit of γ-secretase, which cleaves type I transmembrane proteins,
including the amyloid precursor protein (APP) to release Aβ ...
Survival in animals relies on navigating environments aligned with physiological needs.
In Drosophila melanogaster, antennal ionotropic receptors (IRs) sensing humidity changes govern hygrotaxis behavior.
This study sheds light on the crucial role of IR8a ...
Astrotactin 2 (ASTN2) is a transmembrane neuronal protein highly expressed in the
cerebellum that functions in receptor trafficking and modulates cerebellar Purkinje
cell (PC) synaptic activity. Individuals with ASTN2 mutations exhibit neurodevelopmental ...
Pharmacology
Over half of spinal cord injury (SCI) patients develop opioid-resistant chronic neuropathic
pain. Safer alternatives to opioids for treatment of neuropathic pain are gabapentinoids
(e.g., pregabalin and gabapentin). Clinically, gabapentinoids appear to ...
Lysosomal degradation pathways coordinate the clearance of superfluous and damaged
cellular components. Compromised lysosomal degradation is a hallmark of many degenerative
diseases, including lysosomal storage diseases (LSDs), which are caused by loss-of-...
Physiology
Skeletal muscle atrophy is a morbidity and mortality risk factor that happens with
disuse, chronic disease, and aging. The tissue remodeling that happens during recovery
from atrophy or injury involves changes in different cell types such as muscle fibers,...
Plant Biology
Low phosphate (Pi) availability decreases photosynthesis, with phosphate limitation
of photosynthesis occurring particularly during grain filling of cereal crops; however,
effective genetic solutions remain to be established. We previously discovered that
...
Correction
Cover image: Pictured is an artistic illustration of a folded protein on a computer chip. A collection of articles in the From Basic Mechanisms and Cellular Machineries to AI Solutions in Protein Folding Special Feature highlights recent advances in the use of deep learning models and AI algorithms to understand and predict protein structures and folding patterns. Together, the articles explore the physico-chemical rules that govern protein folding, the biological machinery of protein quality control, and the origins of neurodegenerative pathologies associated with protein misfolding. See the Introduction to the Special Feature, e2411135121. Image credit: Art by Sarina Bromberg (Three Arrows Cooperative Society, Putnam Valley, NY), with concept by Charles D. Kocher and Ken A. Dill (Stony Brook University, Stony Brook, NY).
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