Global freshwater scarcity and degradation demand reconceptualizing wastewater as a resource within circular economy transitions. This review utilizes the resource-stack model and treatment-train design space to evaluate wastewater valorization, assessing recovery of water, energy, nutrients, carbon, and trace elements. It examines barriers, inefficiencies, costs, regulatory gaps, and societal resistance and highlights that aligning innovation with policy and governance can transform wastewater systems into infrastructures supporting water security and climate resilience.

Cellular immunotherapies encompass a broad and rapidly developing group of treatments comprising expanded and/or genetically engineered immune cells, which use the specific properties of human immune cells to counteract human immune-mediated disease. Initially approved for cancers of the B cell lineage, a growing arsenal of cellular immunotherapies are being applied to autoimmune diseases, including chimeric antigen receptor (CAR) T cells, chimeric autoantibody receptor T cells, regulatory T cells and CAR-engineered innate immune cells. These approaches represent a major shift in the way scientists and physicians pursue the treatment of human disease compared to standard immunosuppressive therapies. Here, we review the clinical progress of engineered cellular immunotherapies for autoimmunity. We focus on how antigenic target, engineered cell type, CAR design and treatment regimens affect the therapeutic efficacy and safety of these treatments and how these emerging clinical data can inform future directions in the field. Engineered cellular immunotherapy shows great potential for treating autoimmune diseases. Payne and colleagues review emerging clinical data of the most recently developed technologies.

Klebsiella pneumoniae intestinal colonization contributes to infectious and non-infectious diseases. Recent studies have uncovered the complex interplay between the gut microbiota and K. pneumoniae colonization, highlighting its role in disease development and progression and illustrating the potential of microbiome-based therapies. Yang et al. summarize that Klebsiella pneumoniae affects infectious and non-infectious disease via gut colonization; commensals provide colonization resistance, but K. pneumoniae adapts via multiple mechanisms.

Chemical inducers of proximity (CIPs) stabilize biomolecular interactions, often causing an emergent rewiring of cellular biochemistry. While the discovery of heterobifunctional CIPs is expedited by rational design strategies, molecular glues have relied predominantly on serendipity. We hypothesized that preexisting ligands could be systematically decorated with chemical modifications to discover compounds that recruit proteins to a composite protein–ligand interface. Using sulfur(VI) fluoride exchange-based high-throughput chemistry (HTC) to install 3,163 structurally diverse building blocks onto ENL (eleven-nineteen leukemia) and BRD4 (bromodomain-containing protein 4) ligands, we screened each analog for degrader activity. This revealed dHTC1, an ENL degrader that recruits CRL4CRBN complex through an extended interface of protein–protein contacts and only engages CRBN after pre-forming the ENL:dHTC1 complex. We also identified dHTC3, a molecular glue that selectively dimerizes BRD4 bromodomain 1 to SCFFBXO3, an E3 ligase not previously accessible for chemical rewiring. Altogether, this study introduces HTC as a facile tool to discover new CIPs and new effectors for proximity pharmacology. Molecular glue degraders have consistently been discovered retrospectively, despite their increasing importance. Herein, a high-throughput approach is described that modifies existing ligands into molecular glue degraders.

Deep learning has successfully been applied to design cis-regulatory elements (CREs) for a few species, but a broadly applicable platform for generating functional promoters for thousands of prokaryotes remains lacking. In this study, we introduce a language model for prokaryotic CREs, referred to as PromoGen2, to design CREs without prior experimental data. PromoGen2 was pretrained on CREs derived from 17 000 prokaryotic genomes. It achieved the highest zero-shot prediction correlation of promoter strength across species, improving the average Spearman correlation from 0.27 to 0.50 compared to the best baseline, while reducing the number of parameters by 103. Artificial CREs designed with PromoGen2 demonstrated a 100% success rate in E. coli, Bacillus subtilis, Bacillus licheniformis, and Agrobacterium tumefaciens. Based on PromoGen2, we developed the Promoter-Factory framework to design promoters from unannotated genomes. Experimental validation showed that most of the promoters designed for Jejubacter sp. L23, a newly isolated halophilic bacterium with no available CREs, were active and capable of driving lycopene overproduction. Additionally, we introduced PromoGen2-proka, a taxonomy-aware model for CRE design based on prokaryotic genera. Experimental validation confirmed its reliable success rate. The combined use of PromoGen2-proka and Promoter-Factory offers a broadly applicable tool for designing CREs for prokaryotes, fulfilling the needs of synthetic biology and microbiology research.

Therapeutic modalities to programmably increase protein production are in critical need to address diseases caused by deficient gene expression via haploinsufficiency. Restoring physiological protein levels by increasing translation of their cognate messenger RNA would be an advantageous approach to correct gene expression but has not been evaluated in an in vivo disease model. Here, we investigated whether a translational activator could improve phenotype in a Dravet syndrome mouse model, a severe developmental and epileptic encephalopathy caused by SCN1a haploinsufficiency, by increasing translation of the SCN1a mRNA. We identify and engineer human proteins capable of increasing mRNA translation using the CRISPR–Cas-inspired RNA-targeting system (CIRTS) platform to enable programmable, guide RNA-directed translational activation with entirely engineered human proteins. We identify a compact (601 amino acid) CIRTS translational activator (CIRTS-4GT3) that can drive targeted, sustained translation increases up to 100% from three endogenous transcripts relevant to epilepsy and neurodevelopmental disorders. AAV-delivery of CIRTS-4GT3 targeting SCN1a mRNA to a Dravet syndrome mouse model led to increased SCN1a translation and improved survivability and seizure threshold—key phenotypic indicators of Dravet syndrome. This work validates a strategy to address SCN1a haploinsufficiency and emphasizes the preclinical potential of targeted translational activation to address neurological haploinsufficiency.

Agmatine, a natural polyamine generated from arginine by arginine decarboxylase (ADC), has attracted increasing attention because of its pleiotropic beneficial effects on neuroprotection, lifestyle-related diseases, and gut-brain axis-mediated pathways. Although mammals appear to possess only limited capacity to synthesize endogenous agmatine, accumulating evidence suggests that agmatine derived from diet and the gut microbiota contributes to systemic levels of this polyamine. Previous studies have revealed that Aspergillus oryzae, the filamentous fungus foundational to traditional Japanese cuisine and indispensable for starch saccharification in sake, miso, soy sauce, mirin, and other fermented foods, produces high levels of agmatine specifically under solid-state cultivation. Subsequent studies identified a novel pyruvoyl-dependent ADC (Ao-ADC1) responsible for this unique agmatine production. This mini-review summarizes current knowledge on solid-state cultivation-specific agmatine production by A. oryzae, with a particular focus on the discovery and biochemical characteristics of Ao-ADC1. These findings challenge the commonly accepted notion that ascomycetes lack ADC. Understanding the molecular rationale and physiological significance of this unique agmatine biosynthetic pathway provides a foundation for rational strategies to enhance agmatine production in A. oryzae and for the development of agmatine-enriched fermented foods and nutraceuticals. Furthermore, integrating this fungal pathway with emerging insights into microbe-host interactions may further illuminate how fermentation-derived agmatine contributes to human health through gut-brain axis mediated mechanisms.

Dihydroxyacetone phosphate (DHAP), glycerol-3-phosphate (Gro3P) and reduced/oxidized nicotinamide adenine dinucleotide (NADH/NAD⁺) are key metabolites of the Gro3P shuttle, which transfers reducing equivalents between the cytosol and mitochondria. Targeted activation of Gro3P biosynthesis has recently emerged as a promising strategy to alleviate reductive stress. However, because Gro3P constitutes the backbone of triglycerides, its accumulation can promote extensive lipogenesis. Here we show that a genetically encoded tool based on a di-domain glycerol-3-phosphate dehydrogenase from the alga Chlamydomonas reinhardtii (CrGPDH) effectively operates both the alternative Gro3P shunt, which regenerates NAD⁺ while converting DHAP to Gro3P, and the glycerol shunt, which converts Gro3P to glycerol and inorganic phosphate, across transformed and primary mammalian cell cultures as well as mouse liver. CrGPDH expression supported proliferation of cancer cells under respiratory chain inhibition or hypoxia, as well as patient-derived fibroblasts with mitochondrial dysfunction. Moreover, CrGPDH decreased triglyceride levels in kidney cancer cell lines and reversed ethanol-induced triglyceride accumulation in mouse liver. Thus, CrGPDH represents a promising xenotopic tool to alleviate redox imbalance and associated impaired lipogenesis in conditions ranging from primary mitochondrial diseases to steatosis. The authors present a genetically encoded tool based on a bifunctional enzyme that can regenerate NAD+ while executing an engineered glycerol shunt. The tool successfully restored redox imbalance and modulated lipid metabolism in vitro and in a mouse hepatic steatosis model.

Achieving neutral nitrogen (N) budgets is critical for soil health and sustainable agriculture. Thus, 31 studies were conducted for soybeans (Glycine max L.) throughout the United States, determining N inputs, biological N2 fixation via δ15N natural abundance method, and N outputs, seed N removal. On average, 53% of the N demand was met through N2 fixation, while the requirement of 62% indicates a significant shortfall for achieving neutral N budgets.

Temperature stress is a fundamental challenge for all organisms. While two-component systems (TCSs) are known to transduce environmental signals in microbes, their role in thermal sensing remains underexplored. Here, we unveil a novel thermosensitive TCS, DhqSR, in the thermophile Thermus thermophilus HB27. We demonstrate that the histidine kinase DhqS perceives thermal cues and autophosphorylates at His327. Its cognate response regulator, DhqR, is activated through a unique tyrosine-phosphorylation mechanism: phosphorylation at a unique Tyr84 residue, rather than the canonical aspartate. This atypical DhqSR system orchestrates cellular thermoadaptation by directly regulating a key enzyme in the shikimate pathway, type II 3-dehydroquinate dehydratase (DHQase). Our findings reveal a novel molecular mechanism of temperature sensing and adaptation, providing a new paradigm for microbial environmental adaptation and offering a unique toolbox for engineering thermotolerance.