The Human Cell Atlas from a cell census to a unified foundation model.

With the convergence in exciting advances in molecular and spatial profiling methods and new computational approaches leveraging artificial intelligence and machine learning (AI/ML), the construction of cell atlases is progressing from data collection to atlas integration and beyond. Here, we explore five ways in which cell atlases, including the Human Cell Atlas, are already revealing valuable biological insights, and how they are poised to provide even greater benefits in the coming years. In particular, we discuss cell atlases as censuses of cells; as 3D maps of cells in the body, across modalities and scales; as maps connecting genotype causes to phenotype effects; as 4D maps of development; and, ultimately, as foundation models of biology unifying all these aspects and helping to transform medicine.

Identification of an Alternating-Access Dynamics Mutant of EmrE with Impaired Transport.

Proteins that perform active transport must alternate the access of a binding site, first to one side of a membrane and then to the other, resulting in the transport of bound substrates across the membrane. To better understand this process, we sought to identify mutants of the small multidrug resistance transporter EmrE with reduced rates of alternating access. We performed extensive scanning mutagenesis by changing every amino acid residue to Val, Ala, or Gly, and then screening the drug resistance phenotypes of the resulting mutants.

Structures of an apo and a binary complex of an evolved archeal B family DNA polymerase capable of synthesising highly cy-dye labelled DNA.

Thermophilic DNA polymerases of the polB family are of great importance in biotechnological applications including high-fidelity PCR. Of particular interest is the relative promiscuity of engineered versions of the exo- form of polymerases from the Thermo- and Pyrococcales families towards non-canonical substrates, which enables key advances in Next-generation sequencing. Despite this there is a paucity of structural information to guide further engineering of this group of polymerases.

A structural model for maturation of the hepatitis B virus core.

Hepatitis B virus, a widespread and serious human pathogen, replicates by reverse transcription of an RNA intermediate. The virus consists of an inner nucleocapsid or core, surrounded by a lipid envelope containing virally encoded surface proteins. Using electron cryomicroscopy, we compare the structures of the bacterially expressed RNA-containing core particle and the mature DNA-containing core particle extracted from virions.

Partitioning of the serotonin transporter into lipid microdomains modulates transport of serotonin.

The serotonin transporter (SERT) is an integral membrane protein responsible for the clearance of serotonin from the synaptic cleft following the release of the neurotransmitter. SERT plays a prominent role in the regulation of serotoninergic neurotransmission and is a molecular target for multiple antidepressants as well as substances of abuse. Here we show that SERT associates with lipid rafts in both heterologous expression systems and rat brain and that the inclusion of the transporter into lipid microdomains is critical for serotonin uptake activity.