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Structural studies show how the PfRCR complex of Plasmodium falciparum forms a bridge between erythrocyte and parasite membranes, and how PfCyRPA-binding antibodies neutralize invasion through a steric mechanism, opening the way to new approaches in rational vaccine design.

As Nature Aging celebrates its fifth anniversary, the journal asks some of the researchers who contributed to the journal early on to reflect on the past and the future of aging and age-related disease research, the impact of the field on human health now and in the future, and what challenges need to be addressed to ensure sustained progress.

A comprehensive benchmarking of 19 histopathology foundation models finds that a vision-language foundation model outperforms vision-only models.

Nonlinear light-matter coupling has applications in quantum technologies, for instance in quantum-non-demolition measurements, but its strength is typically limited. Here the authors demonstrate near-ultrastrong nonlinear light-matter coupling in a superconducting circuit with two transmons and a quarton coupler.

How changes in brain blood vessels lead to a chronic reduction in blood flow and, consequently, to vascular dementia is poorly understood. Here, the authors show that venous endothelial dysfunction driven by EPAS1 promotes abnormal vascular remodeling and contributes to cognitive decline.

We asked a group of academic innovators, entrepreneurs, investors and start-up mentors to provide advice to aspiring entrepreneurs through the critical stages of their journey — from ideation and research through piloting, scale-up and eventual exit strategies. Their insights offer practical guidance for navigating the unique challenges of building chemical technology companies.

Respiratory complex I is pivotal for cellular energy conversion. Here, the authors present the structure of complex I from the α-proteobacterium Paracoccus denitrificans, revealing the elements that stabilise the closed state and completing P. denitrificans complex I as a unified platform for combining structure, function and genetics in mechanistic studies.

IgE mediates allergic hypersensitivity and it is found tightly associated with its cellular receptor FcɛRI. Now crystal structure and binding studies reveal that the Cɛ2 domain from IgE Fc, which does not contact the receptor, contributes nevertheless to the high affinity by rendering the Cɛ3 domain more ordered, and thus minimizing the entropy gain upon receptor dissociation.

Rab3GAP, a guanine nucleotide exchange factor for Rab18, regulates membrane trafficking and lipid droplet metabolism. The authors elucidated its molecular structure, mapped its potential substrate binding interface, and uncovered that disease-associated mutations likely impair Rab18 binding.

Hu et al. discovered that the truncated form of human epidermal growth factor receptor 2 (HER2), called p95HER2, drives tumor progression and resistance to the antibody–drug conjugate trastuzumab deruxtecan in HER2⁺ breast cancer. Blocking p95HER2 restores antitumor immunity.

The biomechanical mechanisms enabling the invasive growth of brain tumors remain opaque. Here, Junqueira Alves et al. reveal that the guidance receptor Plexin-B2 controls membrane tension, facilitating confined migration of brain tumor cells.

RH5, which is part of the trimeric RCR-complex essential for invasion, is a vaccine candidate for malaria. Here, Williams et al. show that monoclonal antibodies targeting each of the three proteins in the RCR-complex can work together to more effectively block the invasion of red blood cells by Plasmodium falciparum and design a combination vaccine candidate.

Studies of cell heterogeneity in white matter in primates have been limited to date. Here the authors describe a marmoset brain cell atlas that bridges rodent and human data, revealing strong gray-white matter glial segregation.

An approach to design proteins that can capture amyloidogenic protein regions present in, for example, tau and Aβ42 has now been developed. These designer proteins can inhibit the formation of pathogenic amyloid fibrils and protect cells from toxic species.

HIV-1 vaccine design aims to induce broadly neutralizing antibodies such as IOMA, the only described antibody in its class. Here, the authors present the isolation, characterisation and structure of three additional antibodies within the IOMA class

Gli and Hedgehog genes compound knockout fish exhibited a combination of actinopterygian fish and stem-tetrapod pectoral girdle characteristics, suggesting the evolutionary origin of terrestrial girdles as a tuning of a deeply conserved developmental program.

Amaryllidaceae alkaloids, such as the Alzheimer’s medication galantamine, are currently extracted from low-yielding daffodils. Here, authors pair biosensor-assisted screening with machine learning-guided protein design to rapidly engineer an improved Amaryllidaceae enzyme in a microbial host.

Deep learning methods have been used to design proteins that can neutralize the effects of three-finger toxins found in snake venom, which could lead to the development of safer and more accessible antivenom treatments.

A large, open dataset containing parallel recordings from six visual cortical and two thalamic areas of the mouse brain is presented, from which the relative timing of activity in response to visual stimuli and behaviour is used to construct a hierarchy scheme that corresponds to anatomical connectivity data.

The cytoplasmic DNA sensor cGAS detects DNA in ruptured micronuclei and activates an innate immune response.

Protonation of periplasmic protein carboxylic groups creates a Donnan equilibrium in the bacterial periplasmic space at low pH, leading to accumulation of Cl⁻ and unfolding and aggregation of periplasmic proteins, which can be rescued by chaperones.

Malaria cases are predominant during the rainy seasons in many endemic regions owing to the life cycle of the mosquito vector. How Plasmodium falciparum adapts in humans during the intervening dry season, without causing malaria symptoms or killing the host, offers new insights into its persistence in humans.

How does DNA encode shape? Here, via in toto light sheet microscopy and optogenetic control of cellular forces, the authors show that spatially patterned mechanical feedback loops establish the cytoskeletal patterns driving axis elongation tissue flow in Drosophila.

Using cryo-EM, Chung et al. investigate conformational states of mammalian respiratory complex I to reveal an ubiquinone-10 molecule occupying the full length of the Q-binding channel. Molecular dynamics simulations suggest how the charge states of key residues influence the substrate binding pose.

A meta-analysis of genome-wide association studies of type 2 diabetes (T2D) identifies more than 600 T2D-associated loci; integrating physiological trait and single-cell chromatin accessibility data at these loci sheds light on heterogeneity within the T2D phenotype.

Electrospray ionization loses most ions upon transfer into high vacuum in a mass spectrometer. Here, the authors present a nanopore ion source that emits ions directly into vacuum from aqueous solutions, achieving an ion transmission efficiency of over 90%.

This study identifies three conserved shadow enhancers (T3, C, I) regulating notochord expression of Brachyury across vertebrates using genomic data, transgenic assays, and enhancer knockouts, which are critical for vertebrate notochord development.

The authors use computational protein design to stabilize the active conformation of cGAS, generating constitutively active cGAS variants that could potentiate prophylactic and therapeutic effects.

Gaps in geographic coverage of species abundance data, especially in the tropics, make determining species’ responses to climate change difficult. Modelling a dataset on global waterbird abundance shows abundance declines in the tropics and increases at higher latitudes when temperatures increase.

Prew et al. uncovered a structural basis for human VLCAD deficiency that arises from point mutations within the enzyme’s membrane-binding region, which was shown to fold as a putative α-helical hairpin. Helix-breaking mutations selectively disrupt membrane interaction and thus homeostatic function.

Molecular systems with coincident cyclic and superhelical symmetry axes have considerable advantages for materials design as they can be lengthened or shortened by changing the length of the monomers. Now a systematic approach to generate modular repeat protein oligomers with combined symmetry that can be extended by repeat propagation has been developed.

High-resolution imaging has traditionally required thin sectioning, a process that disrupts long-range connectivity in the case of brains: here, intact mouse brains and human brain samples have been made fully transparent and macromolecule permeable using a new method termed CLARITY, which allows for intact-tissue imaging as well as repeated antibody labelling and in situ hybridization of non-sectioned tissue.

The respiratory complex I (NADH:ubiquinone oxidoreductase) is a large redox-driven proton pump that initiates respiration in mitochondria. Here, the authors present the 3.0 Å cryo-EM structure of complex I from mouse heart mitochondria with the ubiquinone-analogue inhibitor piericidin A bound in the active site and with kinetic measurements and MD simulations they further show that this inhibitor acts competitively against the native ubiquinone-10 substrate.

Cancer biomarkers are often continuous measurements, which poses challenges for their prediction using classification-based deep learning. Here, the authors develop a regression-based deep learning method to predict continuous biomarkers - such as the homologous repair deficiency score - from cancer histopathology images.

It is still unclear why HIV-1 vaccines targeting MPER induce antibodies that fail to bind HIV. Here, the authors show that antibodies targeting membrane-proximal linear epitopes of virion spike proteins must generate relevant antibody paratopes and approach angles to ligate their quarry in a topologically restricted site.

Cryo-EM analyses of mitochondrial complex I (NADH:ubiquinone oxidoreductase) isolated from mouse heart allow comparisons between the active and deactive states and provide new mechanistic insights into this important complex.

Macrocyclic peptides are promising scaffolds for chemical tools and potential therapeutics, but their synthesis is currently difficult. Here, the authors report the characterization of Ulm16, a peptide cyclase of the penicillin-binding protein (PBP)-type class of thioesterases, that catalyzes head-to-tail macrolactamization of nonribosmal peptides of 4–6 amino acids in length.

This work introduces lightweight, leaf-like photoelectrochemical devices for unassisted water splitting and syngas production, which could be used in the fabrication of floating systems for solar fuel production.

The pro-apoptotic BAX protein is a monomer under homeostatic conditions and, in response to stress, transforms into oligomers that induce apoptosis. Here, the authors characterize structural features of BAX that individually stabilize the monomer while collectively contributing to oligomerization.

A survey of SARS-CoV-2 RBD antibodies identifies those with activity against diverse SARS-CoV-2 variants and SARS-related coronaviruses, highlighting epitopes and features to prioritize in antibody and vaccine development.

UDP-glucuronic acid is a component of the extracellular matrix. Here, the authors report biallelic variants in the gene encoding UDP-Glucose 6-Dehydrogenase (UGDH) in individuals affected by developmental epileptic encephalopathies that impair UGDH stability, oligomerization, or enzymatic activity in vitro.