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1. Disruptive lysosomal-metabolic signaling and neurodevelopmental deficits that precede Purkinje cell loss in a mouse model of Niemann-Pick Type-C disease

   https://doi.org/10.1038/s41598-023-32971-0  

   Kim, Sarah; Ochoa, Kathleen; Melli, Sierra E.; Yousufzai, Fawad A.; Barrera, Zerian D.; Williams, Aela A.; McIntyre, Gianna; Delgado, Esteban; Bolish, James N.; Macleod, Collin M.; et al (April 2023, Scientific Reports)

   Abstract Purkinje cell (PC) loss occurs at an early age in patients and animal models of Niemann-Pick Type C (NPC), a lysosomal storage disease caused by mutations in theNpc1orNpc2genes. Although degeneration of PCs occurs early in NPC, little is known about how NPC1 deficiency affects the postnatal development of PCs. Using theNpc1^nmf164mouse model, we found that NPC1 deficiency significantly affected the postnatal development of PC dendrites and synapses. The developing dendrites of Npc1^nmf164PCs were significantly deficient in mitochondria and lysosomes. Furthermore, anabolic (mTORC1) and catabolic (TFEB) signaling pathways were not only perturbed but simultaneously activated in NPC1-deficient PCs, suggesting a loss of metabolic balance. We also found that mice with conditional heterozygous deletion of the Phosphatase and Tensin Homolog Deleted on Chromosome 10 gene (Pten-cHet), an inhibitor of mTORC1, showed similar early dendritic alterations in PCs to those found inNpc1-deficient mice. However, in contrast toNpc1^nmf164mice,Pten-cHet mice exhibited the overactivation of the mTORC1 pathway but with a strong inhibition of TFEB signaling, along with no dendritic mitochondrial reductions by the end of their postnatal development. Our data suggest that disruption of the lysosomal-metabolic signaling in PCs causes dendritic and synaptic developmental deficits that precede and promote their early degeneration in NPC. 

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2. Impact of Oxygen and Sulfur Heteroatom Core Substitution on Catalyst Properties of Phenoxazines and Their Performance in Organocatalyzed Atom Transfer Radical Polymerization (O‐ATRP)

   https://doi.org/10.1002/chem.202501179  

   Lathrop, Jessica L; Portela, Brandon S; Paton, Robert S; Miyake, Garret M (July 2025, Chemistry – A European Journal)

   Abstract Phenoxazines are a successful class of organic photoredox catalysts (PCs) with tunable redox and photophysical properties. Originally, we aimed to realize more reducing phenoxazine PCs through heteroatom core substituted (HetCS) derivatives, while maintaining an efficiently oxidizing PC^·+. However, core modification with thioether or ether functionality to a PC that exhibits photoinduced intramolecular charge transfer (CT) negligibly alters the singlet excited state reduction potential (E_S1°*), while yielding a less oxidizing PC^·+(E_1/2) (E_1/2 = 0.50–0.64 V vs. SCE) compared to the noncore modified PC1(0.68 V vs. SCE). Photophysical characterization of HetCS PCs revealed that increasing electron density on the core of a CT exhibiting PC stabilizes the emissive state and PC^·+, resulting in a relatively unchangedE_S1°* compared to PC1. In contrast, modifying the core of a PC that does not exhibit CT yields a highly reducingE_S1°* (PC3= −2.48 V vs. SCE) compared to its CT equivalent (PC1d= −1.68 V vs. SCE). The impact of PC property on photocatalytic ability was evaluated through organocatalyzed atom transfer radical polymerization (O‐ATRP). HetCS PCs were able to yield poly(methyl methacrylate) with low dispersity and moderate targeted molecular weight as evaluated by initiator efficiency (I*) in DMAc (Ð= 1.20–1.26;I*= 47–57%). Ultimately, this work provides insight into how phenoxazine PC properties are altered through structural modification, which can inform future PC design. 

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3. Nodule‐specific Cu ⁺ ‐chaperone NCC1 is required for symbiotic nitrogen fixation in Medicago truncatula root nodules

   https://doi.org/10.1111/nph.19360  

   Navarro‐Gómez, Cristina; León‐Mediavilla, Javier; Küpper, Hendrik; Rodríguez‐Simón, Mario; Paganelli‐López, Alba; Wen, Jiangqi; Burén, Stefan; Mysore, Kirankumar S.; Bokhari, Syed Nadeem; Imperial, Juan; et al (January 2024, New Phytologist)

   Summary Cu⁺‐chaperones are a diverse group of proteins that allocate Cu⁺ions to specific copper proteins, creating different copper pools targeted to specific physiological processes.Symbiotic nitrogen fixation carried out in legume root nodules indirectly requires relatively large amounts of copper, for example for energy delivery via respiration, for which targeted copper deliver systems would be required.MtNCC1 is a nodule‐specific Cu⁺‐chaperone encoded in theMedicago truncatulagenome, with a N‐terminus Atx1‐like domain that can bind Cu⁺with picomolar affinities. MtNCC1 is able to interact with nodule‐specific Cu⁺‐importer MtCOPT1.MtNCC1is expressed primarily from the late infection zone to the early fixation zone and is located in the cytosol, associated with plasma and symbiosome membranes, and within nuclei. Consistent with its key role in nitrogen fixation,ncc1mutants have a severe reduction in nitrogenase activity and a 50% reduction in copper‐dependent cytochromecoxidase activity.A subset of the copper proteome is also affected in thencc1mutant nodules. Many of these proteins can be pulled down when using a Cu⁺‐loaded N‐terminal MtNCC1 moiety as a bait, indicating a role in nodule copper homeostasis and in copper‐dependent physiological processes. Overall, these data suggest a pleiotropic role of MtNCC1 in copper delivery for symbiotic nitrogen fixation. 

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4. Diverse Subpopulations of Reactive Astrocytes Following Chronic Toxoplasma Infection

   https://doi.org/10.1002/glia.70053  

   Figueroa, Zoe A; Martin, Jose L; Ulu, Arzu; Agnew‐Svoboda, William; Ubina, Teresa; Riccomagno, Martin M; Fiacco, Todd A; Wilson, Emma H (October 2025, Glia)

   ABSTRACT Astrocytes provide physical and metabolic support for neurons, regulate the blood–brain barrier, and react to injury, infection, and disease. When astrocytes become reactive, maintenance of the inflammatory state and its functional implications throughout chronic neuroinflammation are all poorly understood. Several models of acute inflammation have revealed astrocyte subpopulations that go beyond a two‐activation state model, instead encompassing distinct functional subsets. However, how reactive astrocyte (RA) subsets evolve over time during chronic inflammatory disease or infection has been difficult to address. Here we use a prolific human pathogen,Toxoplasma gondii, that causes lifelong infection in the brain alongside aLcn2CreERT2reporter mouse line to examine reactive astrocyte subsets during chronic neuroinflammation. Single‐cell RNA sequencing revealed diverse astrocyte populations including transcriptionally uniqueLcn2CreERT2+ RAs which change over the course of infection in a subset‐dependent manner. In addition to an immune‐regulatingLcn2CreERT2+ astrocyte population enriched with gene transcripts encoding chemokines CCL5, CXCL9, CXCL10, and receptors CCR7 and IL7R, a specific subset ofLcn2CreERT2+ astrocytes highly expressedtransthyretin(Ttr), a secreted carrier protein involved in glycolytic enzyme activation and potential vasculature regulation and angiogenesis. These findings provide novel information about the evolution and diversity of reactive astrocyte subtypes and functional signatures at different stages of infection, revealing an undocumented role for transthyretin‐expressing astrocytes in immune regulation at the central nervous system (CNS) vasculature. 

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5. Early life exposure to broccoli sprouts confers stronger protection against enterocolitis development in an immunological mouse model of inflammatory bowel disease

   https://doi.org/10.1128/msystems.00688-23  

   Holcomb, Lola; Holman, Johanna M; Hurd, Molly; Lavoie, Brigitte; Colucci, Louisa; Hunt, Benjamin; Hunt, Timothy; Kinney, Marissa; Pathak, Jahnavi; Mawe, Gary M; et al (December 2023, mSystems)

   Chu, Hiutung (Ed.)

   ABSTRACT Crohn’s disease (CD) is a presentation of inflammatory bowel disease (IBD) that manifests in childhood and adolescence and involves chronic and severe enterocolitis, immune and gut microbial dysregulation, and other complications. Diet and gut-microbiota-produced metabolites are sources of anti-inflammatories that could ameliorate symptoms. However, questions remain on how IBD influences biogeographic patterns of microbial location and function in the gut, how early life transitional gut communities are affected by IBD and diet interventions, and how disruption to biogeography alters disease mediation by diet components or microbial metabolites. Many studies on diet and IBD use a chemically induced ulcerative colitis model, despite the availability of an immune-modulated CD model. Interleukin-10-knockout (IL-10-KO) mice on a C57BL/6 background, beginning at age 4 or 7 weeks, were fed a control diet or one containing 10% (wt/wt) raw broccoli sprouts, which was high in the sprout-sourced anti-inflammatory sulforaphane. Diets began 7 days prior to, and for 2 weeks after inoculation withHelicobacter hepaticus,which triggers Crohn’s-like symptoms in these immune-impaired mice. The broccoli sprout diet increased sulforaphane in plasma; decreased weight stagnation, fecal blood, and diarrhea associated; and increased microbiota richness in the gut, especially in younger mice. Sprout diets resulted in some anatomically specific bacteria in younger mice and reduced the prevalence and abundance of pathobiont bacteria which trigger inflammation in the IL-10-KO mouse, for example,Escherichia coliandHelicobacter. Overall, the IL-10-KO mouse model is responsive to a raw broccoli sprout diet and represents an opportunity for more diet-host-microbiome research. IMPORTANCETo our knowledge, IL-10-KO mice have not previously been used to investigate the interactions of host, microbiota, and broccoli, broccoli sprouts, or broccoli bioactives in resolving symptoms of CD. We showed that a diet containing 10% raw broccoli sprouts increased the plasma concentration of the anti-inflammatory compound sulforaphane and protected mice to varying degrees against disease symptoms, including weight loss or stagnation, fecal blood, and diarrhea. Younger mice responded more strongly to the diet, further reducing symptoms, as well as increased gut bacterial richness, increased bacterial community similarity to each other, and more location-specific communities than older mice on the diet intervention. Crohn’s disease disrupts the lives of patients and requires people to alter dietary and lifestyle habits to manage symptoms. The current medical treatment is expensive with significant side effects, and a dietary intervention represents an affordable, accessible, and simple strategy to reduce the burden of symptoms. 

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