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Peptide secondary metabolites have a diverse range of functions. Here the authors present a method to design and screen a large library of modified peptides in E. coli against a target of interest.

A CRISPR–Cas9 screen combined with heparan sulfate (HS)-binding reagents identifies genes involved in HS biosynthesis and assembly and reveals the unexpected role of histone demethylase KDM2B in regulating HS presentation on the cell surface.

Simultaneous profiling of the genome, methylome, epigenome and transcriptome using single-molecule chromatin fiber sequencing and multiplexed arrays isoform sequencing identifies the genetic and molecular basis of an undiagnosed Mendelian disease case with an X;13-balanced translocation.

Prime editing of large DNA sequences is achieved with two pegRNAs and site-specific recombinases.

A microfluidic assay that quantifies cell migration and proliferation can prospectively categorize patients with glioblastoma according to progression-free survival.

Cultivation of a cellulolytic consortium reveals successional community dynamics and the presence of multidomain glycoside hydrolases assembled into stable complexes distinct from cellulosomes, which are produced by a potential pioneer population.

The authors identify a molecular switch that regulates the balance between neurotoxic and neuroprotective astrocyte populations, with potential application in the treatment of glaucoma and other optic neuropathies.

A microglial state, featuring lipid droplets and secretion of neurotoxic factors, is shown to be most prominent in people with Alzheimer’s disease who have the APOE4 genotype.

Polθ has been recently identified as a therapeutic target in cancer but specific inhibitors are currently unavailable. Here, the authors identify small molecule inhibitors of Polθ’s polymerase activity which elicit BRCA1/2 synthetic lethality, enhance the effect of PARP inhibitors and target PARP inhibitor resistance caused by 53BP1/Shieldin pathway defects.

Individual animals are cultivated in custom microfabricated multiwell substrates. This protocol describes how to design, produce, and image the plates, as well as analyze the resulting behavioral data.

The actin-based molecular motors, myosins, have also been linked to transcription, but their precise role has remained elusive. Here the authors show RNA polymerase II (RNAPII) is lost from chromatin upon myosin perturbation and that myosin acts as a molecular anchor to maintain RNAPII spatial organisation.

The conversion of methane to oxygenated molecules is a very challenging reaction that often requires the use of a coreductant or stoichiometric conditions. Here, the authors report the use of gold supported on ZSM-5 as a promising catalyst for this process in combination with oxygen in the absence of coreductants.

Transcriptomic analysis often doesn’t differentiate between newly synthesized and stabilized mRNAs. Using rapid 4-thiouracil incorporation, Painter et al. here define genome-wide active transcription throughout Plasmodium blood-stage developmental stages and identify associated regulatory DNA sequence motifs.

Combinatorial CRISPR screens can be utilized to identify genetic interactions and functional redundancies of multiple genes. Here, the authors benchmark ten digenic CRISPR technologies and identify novel Cas9 tracrRNA combinations that show superior performance.

In a mouse model of progeria, an adenine base editor delivered with adeno-associated virus corrects the pathogenic mutation in LMNA, rescues vascular pathology and markedly extends the lifespan of the mice.

Human neural progenitor cells with familial Alzheimer's disease mutations are differentiated in a 3D Matrigel matrix, leading to the extracellular aggregation of amyloid-β peptides and accumulation of hyperphosphorylated and aggregated tau protein.

While membrane contact sites between intracellular organelles are abundant, little is known about the contacts between membranes that delimit extracellular junctions within cells, such as intracellular parasites. Here authors demonstrate the segregation of a lipid transporter from a solute transporter in the malarial host-parasite interface.

3D printing agarose hydrogels embedded with Bacillus subtilis spores produce custom-shaped materials that are resistant to environmental stresses, while the bacteria maintain the ability to germinate on the surface and respond to stimuli.

Current methods for acquiring dissemination kinetics of rare circulating tumor cells (CTCs) that form metastases have several limitations. Here, the authors show an approach for measuring endogenous CTC kinetics by continuously exchanging CTC-containing blood between un-anesthetized, tumor-bearing mice and healthy, tumor-free counterparts.

The kinetics of prion aggregation are now dissected in mice, revealing slower PrP^Sc replication in vivo than in vitro and the contribution of aggregate fragmentation.

Biofilm formation in Bacillus subtilis requires expression of matrix production genes, which are upregulated by transcriptional activator RemA. Here, the authors show that RemA forms octameric rings with the potential to form a 16-meric superstructure, suggesting that the protein can wrap DNA through a LytTR-related domain.

Skeletal muscles are impressive as they can achieve reversible, macroscopic, anisotropic motion in soft materials. Here the authors show a bottom-up design of macroscopic hydrogel tubes containing supramolecular nanofibers that can undergo anisotropic actuation by thermal stimuli.

Public antibody clonotypes that recognize SARS-CoV-2 spike protein are important for protection against COVID-19. Here, the authors characterize sequence motifs in the heavy chain complementarity-determining region (CDR) H3s of two public clonotypes and their association with light chain identity.

Understanding the pathology and immunological response to SARS CoV2 infection in specific patient groups is essential for informing the scientific and clinical handling of infections within these patient populations. Here the authors characterise the adaptive immune response to SARS-CoV2 infection in people living with HIV.

Activity profiles generated from quantitative high-throughput screening improve drug candidate prediction.

The SOX2 pioneer transcription factor performs critical roles in pluripotency and self-renewal of embryonic stem cells. Here the authors show that SOX2’s two nuclear localization signal sequences form a contiguous binding interface on the nuclear import receptor importin-α3, and provide a structural basis for the preference of SOX2 binding to IMPα3.

Production of aromatic monoterpene molecules in hop flowers is affected by genetic, environmental, and processing factors. Here, the authors engineer brewer’s yeast for the production of linalool and geraniol, and show pilot-scale beer produced by engineered strains reconstitutes some qualities of hop flavor.

Biochemical analysis, and imaging using a copper-sensitive fluorescent sensor, demonstrate that copper regulates cAMP-mediated lipolysis by inhibiting the activity of the cAMP-degrading phosphodiesterase PDE3B.

We demonstrate a novel and efficient bioprocess for production of the cephalosporin intermediates, 7-aminocephalosporank acid (7-ACA) or 7-amino deacetoxycephalosporanic acid (7-ADCA). The Streptomyces clavuligerus expandase gene or the Cephalosporium acremonium expandase-hydroxylase gene, with and without the acetyltransferase gene, were expressed in a penicillin production strain of Penicillium chrysogenum. Growth of these transformants in media containing adipic acid as the side chain precursor resulted in efficient production of cephalosporins having an adipyl side chain, proving that adipyl-6-APA is a substrate for either enzyme in vivo. Strains expressing expandase produced adipyl-7-ADCA, whereas strains expressing expandase-hydroxylase produced both adipyl-7-ADCA and adipyl-7-ADAC (aminodeace-tylcephalosporanic acid). Strains expressing expandase-hydroxylase and acetyltransferase produced adipyl-7-ADCA, adipyl-7-ADAC and adipyl-7-ACA. The adipyl side chain of these cephalosporins was easily removed with a Pseudomonas-derived amidase to yield the cephalosporin intermediates.

A novel drug, ribocil, is shown to mimic the binding of a natural ligand to a bacterial riboflavin riboswitch (a non-coding stretch of messenger RNA whose structure is affected by a ligand—usually one related to the function of the protein encoded by the messenger RNA) to cause inhibition of bacterial growth; the ability to target an RNA structural element with a synthetic small molecule may expand our view of the target space susceptible to therapeutic intervention.

SF3B1 mutations confer sensitivity to poly (ADP-ribose) polymerase inhibitors (PARPi). Mechanistically, this is independent of homologous recombination repair and instead relies on a defective replication stress response due to a reduction of the cyclin-dependent kinase 2 interacting protein (CINP). PARPi treatment of SF3B1 mutant (SF3B1^MUT) tumors leads to replication stress induced by increased fork origin firing and culminates in cell cycle stalling.

Microsporidia are obligate intracellular parasitic fungi that can cause opportunistic infections in humans. Here, Antao et al. investigate the intracellular life cycle of human-infecting Encephalitozoon intestinalis using serial block-face scanning electron microscopy to characterize parasite organelle development and host-cell mitochondrial remodeling.

The type III secretion system is a needle-like molecular machine under tight regulatory control. Here the authors construct a synthetic type III secretion system gene cluster by deconstructing and rebuilding the wild-typeSalmonellapathogenicity island 1.

A study of SARS-CoV-2 variants examining their transmission, infectivity, and potential resistance to therapies provides insights into the biology of the Delta variant and its role in the global pandemic.

Data-independent acquisition-mass spectrometry (MS) typically requires many preparatory MS runs to produce experiment-specific spectral libraries. Here, the authors show that empirical correction of in silico predicted spectral libraries enables efficient generation of high-quality experiment-specific libraries.

It is highly desirable, yet challenging to build actuators in a dry environment that can undergo autonomous oscillation. Here, Kumar et al.achieve this goal in a soft actuator based on the use of a nematic liquid crystal film doped by ortho-fluoroazobenzene that is responsive to sunlight.

Despite methodological improvements, it remains extremely difficult to routinely establish cell lines from human primary tumours. Here, the authors develop a culture medium that allows efficient cell line establishment and use this to generate 25 ovarian cancer cell lines.

Myo-Inositol phosphates (InsPs) and pyrophosphates (PP-InsPs) are important second messengers but their analysis remains challenging. Here, the authors develop a capillary electrophoresis-mass spectrometry method for the identification and quantitation of InsP and PP-InsP isomers in cells and tissues.

Detailed atomic models of axonemes from algal flagella and human respiratory cilia, which are hair-like protrusions from cells that enable motility and clear mucus from human airways, could provide insights into how they function.

Printed organic and inorganic electronics continue to be of large interest for several applications. Here, the authors propose laser printing as a facile process for fabricating printed electronics with minimum feature sizes below 1 µm and demonstrate functional diodes, memristors, and physically unclonable functions.

The authors present a workflow integrating metabolic perturbations with protein structural analysis to identify drug off-targets, demonstrating how combining machine learning methods with mechanistic analyses can benefit off-target identification.

A suite of tools and resources for Vibrio natriegens introduces the bacterium as a faster-growing alternative to E. coli for molecular biology and biotechnology applications.

Temperature shapes the adaptation and composition of microbiomes, but whether their enzymes drive the thermal response remains unknown. Using an analysis of seven enzyme classes from worldwide marine microbiome data, this study shows that enzyme thermal properties explain microbial thermal plasticity and they are both finely tuned by the thermal variability of the environment.

The development of direct-acting antivirals to combat COVID-19 remains an important goal. Here the authors design covalent inhibitors that target the papain-like protease from SARS-CoV-2. The most promising inhibitor blocks viral replication in mammalian cells.

Eukaryotic trans-regulatory mechanisms are exploited to synthesize a stringent tetracycline-repressible circuit and a heat-inducible circuit for negative/positive metabolic controls using the GAL system in Saccharomyces cerevisiae.

By using in vivo ultrafast TA spectroscopy, extraction of electrons directly from photoexcited PSI and PSII in cyanobacterial cells using exogenous electron mediators is demonstrated.