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The most popular reactions used by medicinal chemists are often incompatible with nanoscale ultrahigh-throughput experimentation (ultraHTE). Now, ultraHTE-amenable reaction conditions are developed through miniaturization of four of the most important drug discovery transformations, and their generality and scalability are tested on a range of natural products and drug candidates.

Base editor technology combined with a fluorescent reporter of DNA methyltransferase activity enable in situ mutational scanning of DNMT3A, revealing a requirement of DNA binding by the PWWP histone reader ___domain for full activity.

Cenozoic landscape evolution of southwestern North America remains debated. Here, the authors reconstruct landscape using 4-D numerical models, which can explain extensional collapse and superficial geological record for the Basin and Range Province

The majority of discrete structures obtained by self-assembly possess high symmetry, and thus low complexity: all subunits relate to their neighbours in a similar manner. Now, the spontaneous formation of complex low-symmetry assemblies produced from a single building block has been demonstrated using a systems chemistry approach. The single building block oligomerizes to form specific homomeric cyclic macromolecules that adopt a folded conformation.

Robust molecular junctions demand highly reproducible switching between two or more well-defined conductance states upon control. Here, Gerhardet al. show the utility of elastic deformation of tripodal spirobifluorene derivatives in the junction of a scanning tunnelling microscope to achieve this goal.

The extent and mechanisms by which developmental process may constraint natural variation are poorly understood. Here, Fritz et al. show that beak shape in songbirds is strongly constrained by developmental mechanics shared by several bird species.

Nanopore sensors have shown tremendous potential for biomolecule sensing, though the diffusion-controlled capture can limit the speed of analysis. Here, the authors report a dielectrophoretic method to concentrate DNA near the tip of a nanopore, reducing the limit of detection by three orders of magnitude.

Phosphorescent materials made of purely organic components are typically less efficient than their organometallic counterparts. Here, the authors report a strategy to improve the phosphorescence efficiency of metal-free materials by reducing radiationless transitions by covalently linking into a polymer matrix.

Thermal diagenesis is generally seen as detrimental to the preservation of organic biosignatures. Using synchrotron-based XANES data, Alleon et al.find preservation of the molecular signatures of organic microfossils from the 1.88 Ga Gunflint cherts.

Host–guest chemistry in hollow coordination cages can be exploited for a range of applications, but is often limited by inner cavity dimensions. Here, Schmitt and co-workers fabricate supramolecular keplerates that possess ultra-large cross-sectional diameters and are composed of multiple sub-cages.

A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.

The heterogeneity of androgen receptor (AR) gene alterations across metastases in prostate cancer remains unresolved. Here, the authors characterise AR genomic complexity across spatially separated lethal metastases from 10 prostate cancer patients and investigate how AR alterations evolve.

A robust, cost-effective technique based on whole-exome sequencing data can be used to characterize immune infiltrates, relate the extent of these infiltrates to somatic changes in tumours, and enables prediction of tumour responses to immune checkpoint inhibition therapy.

UvrD is a model helicase from the non-hexameric Superfamily 1. Here, the authors use optical tweezers to measure directly the stepwise translocation of UvrD along a DNA hairpin, and propose a mechanism in which UvrD moves one base pair at a time, but sequesters the nascent single strands, releasing them after a variable number of ATP hydrolysis cycles.

Retinal prostheses are being developed to fight severe retinal diseases where wider visual field and higher visual acuity are desired. Here Ferlauto et al. design a foldable and wide-field epiretinal prosthesis that can meet the performance and safety requirements and show a long lifetime of 2 years.

How soft tissues respond to mechanical load is essential to their biological function. Here, the authors discover that – contrary to predictions of poroelasticity – fluid mobility in collagenous tissues induces drastic volume decrease with tensile loading and pronounced chemo-mechanical coupling.

Artificial spin ice formed of nanomagnets arranged on a lattice mimics frustrated magnetism seen in condensed matter. By controlling magnetic interactions, theoretically predicted phase transitions are now observed in artificial kagome-lattice spin ice.

The development of high-performance implantable soft electronics as diagnostic platforms is key to realizing improved health monitoring. Here, the authors design wireless, battery-free, implantable bioelectronics that interface with the osseosurface for chronic musculoskeletal system monitoring.

Phage and robotics-assisted near-continuous evolution enables phage-assisted continuous evolution in high throughput, allowing for improved exploration of sequence space and insight into how variables affect evolution outcomes.

Nonlinear optical parametric polaritons are observed in a WS₂ monolayer microcavity, opening the way for all-optical valley polariton nonlinear devices.

Dick et al. show that in youth, post-traumatic stress related to Hurricane Irma was predicted by self-reported direct and media exposure. Furthermore, neural responses in brain regions associated with anxiety conferred particular vulnerability to media exposure.

An anomalous upturn of the critical field at low temperature observed in disordered superconductors has long puzzled researchers. A joint experimental and theoretical study suggests that the origin of the anomaly lies in the physics of vortex glasses.

An image-inspired deep-learning model is developed to generate realistic de novo protein structures and scaffolds around functional sites, which helps the search for new structures and functions in protein engineering.

Huang et al. explore using aqueous humor to identify biomarkers associated with geographic atrophy (GA) secondary to age-related macular degeneration (AMD) through an affinity-based proteomics approach. They find 82 significantly altered proteins in GA, such as SMOC2 and IL-6.

A substantial proportion of patients with cardiometabolic conditions appear to have normal BMI. Conversely, not all obese individuals exhibit these disorders. Here, we show that a metabolic BMI score derived from lipidomic models, allows quantify metabolic dysregulation in obesity independently of BMI.

Control of HIV and SIV infection is largely thought to be achieved through direct lysis of target cells. Here, using mathematical modelling of viral load data from rhesus macaques, the authors propose that virus control is best explained by the combination of cytolytic and non-cytolytic effects.

Large classes of metal clusters are expected to have dipole-allowed electronic transitions in the near-infrared, but precise experimental characterization of such low-lying states is lacking. Here, the authors probe cationic cobalt clusters of 4 to 15 atoms using IR photofragmentation spectroscopy with krypton as a messenger atom to show that low-lying electronic excited states are responsible for the size-dependent radiative decay of these highly excited clusters.

The rich magnetic phase behaviour of MnSi reflects the complexity of the physics underlying itinerant ferromagnetism. Here the authors present evidence that MnSi is strongly influenced by Hund’s coupling effects, suggesting a broader class of materials may fall into the class of Hund metals.

Repetition codes running many cycles of quantum error correction achieve exponential suppression of errors with increasing numbers of qubits.

Advanced fabrication techniques enable a wide range of quantum devices, such as the realization of a topological qubit. Here, the authors introduce an on-chip fabrication technique based on shadow walls to implement topological qubits in an InSb nanowire without fabrication steps such as lithography and etching.

Bulk RNA sequencing of organs and plasma proteomics at different ages across the mouse lifespan is integrated with data from the Tabula Muris Senis, a transcriptomic atlas of ageing mouse tissues, to describe organ-specific changes in gene expression during ageing.

Does the spatial tuning of grid cells in the medial entorhinal cortex (MEC) require spatially tuned inhibition? Buetfering and colleagues recorded optogenetically identified parvalbumin (PV) interneurons in the mouse MEC during foraging and found that they were broadly tuned. Moreover, the authors found that stimulating PV cells suppressed firing in grid and head-direction cells but did not alter the spatial tuning of these cells.

By amplifying a soliton in a multistage cascade, few-femtosecond extreme-ultraviolet free-electron laser pulses are achieved.

Warming ocean water plays a significant role in accelerating Arctic sea ice melt. Here the authors present detailed observations of warm water of Pacific origin entering and diving beneath the Arctic ocean surface, and explore the dynamical processes governing its evolution.

Human induced pluripotent stem cell (iPSC) cells have been used to model disease in specific cell types. Here, the authors develop an automated long-term culturing platform of human iPSC neurons, astrocytes, and microglia and use it to model some cellular aspects of Alzheimer’s disease.

Scalable trajectory inference for multi-omic single cell datasets is challenging in terms of capturing non-tree complex topologies. Here the authors present a method, VIA, that scales to millions of cells across multiple omic modalities using lazy-teleporting random walks.

The authors show that, unlike the consolidation and refinement of excitatory connections observed during sensory map formation, a dramatic broadening of patterned activation domains, connectivity, and tuning occurs in interneurons in the olfactory bulb. This developmental expansion is sensitive to activity manipulations and may reveal general principles of interneuron network development.

Current understanding of Long COVID is limited, in part, due to lack of evidence from population-representative studies. Here, the authors analyse data from ten UK population-based studies and electronic health records, and find wide variation in the frequency of Long COVID between studies but some consistent risk factors.

Spins are transmitted over a distance of 5 μm through a piece of antiferromagnetic graphene. This shows that graphene can be a platform to explore the fundamental physics of spin transport in antiferromagnets for application in spintronics.

Switching of antiferromagnetic domains by the propagation of ___domain walls is demonstrated using electrical current-induced torques.

Targeted protein degradation of cell-surface glycoproteins suppresses cancer in mice.

Current experimental monoclonal antibodies (mAbs) for Ebola virus (EBOV) post-exposure immunotherapy are ineffective against Sudan (SUDV) or Marburg virus (MARV). Here, authors develop cocktails of mAbs that protect nonhuman primates against EBOV, SUDV, and MARV infection when given four days post infection.

Cross-talk between innate immune cells helps to enhance the antitumor T cell response during checkpoint blockade therapy.

Gold nanoparticles that passively deliver CRISPR machinery to blood repopulating cells have been developed and are shown to be capable of precise editing of multiple genetic loci of therapeutic interest without cytotoxicity or reduced fitness.

While solar-to-fuel conversion offers a promising technology to produce energy, device components can limit light absorption and reduce performances. Here, authors show copper thiocyanate to assist hole transport in photoelectrodes and enable a 4.55% solar-to-hydrogen efficiency in tandem devices.