Biology subjects

Zhang, N.

Publications and source records attributed to Zhang, N..

At least 127 records · Page 7Linked to original sources

bioRxiv2024

TRAMP assembly alters the conformation and RNA binding of Mtr4 and Trf4-Air2

The TRAMP complex contains two enzymatic activities essential for RNA processing upstream of the nuclear exosome. Within TRAMP, RNA is 3 polyadenylated by a sub-complex of Trf4/5 and Air1/2 and unwound 3 to 5 by Mtr4, a DExH helicase. The molecular mechanisms of TRAMP assembly and RNA shuffling between the two TRAMP catalytic sites are poorly understood. Here, we report solution hydrogen-deuterium exchange data with thermodynamic and functional assays to uncover these mechanisms for yeast TRAMP with Trf4 and Air2 homologs. We show that TRAMP assembly constrains RNA-recognition motifs that are peripheral to catalytic sites. These include the Mtr4 Arch and Air2 zinc knuckles 1, 2, and 3. While the Air2 Arch-interacting motif likely constrains the Mtr4 Arch via transient interactions, these do not fully account for the importance of the Mtr4 Arch in TRAMP assembly. We further show that tRNA binding by single active-site subunits, Mtr4 and Trf4-Air2, differs from the double active-site TRAMP. TRAMP has reduced tRNA binding on the Mtr4 Fist and RecA2 domains, offset by increased tRNA binding on Air2 zinc knuckles 2 and 3. Competition between these RNA-binding sites may drive tRNA transfer between TRAMP subunits. We identify dynamic changes upon TRAMP assembly and RNA-recognition motifs that transfer RNA between TRAMP catalytic sites.

biochemistry↗

bioRxiv2024

SSRI antidepressant citalopram reverses the Warburg effect to inhibit hepatocellular carcinoma by directly targeting GLUT1

Although there is growing appreciation for effective repurposing of selective serotonin reuptake inhibitors (SSRIs) for cancer therapy, particularly hepatocellular carcinoma (HCC), efforts are hampered by limited knowledge of their molecular targets and mechanism of action. Global inverse gene-expression profiling method, drug affinity responsive target stability assay, and in silico molecular docking analysis was performed to identify the targets of SSRIs. Murine subcutaneous, orthotopic models, and patient-derived xenograft were employed to explore the therapeutic effects and underlying mechanisms of SSRIs in HCC. The clinical relevance of SSRI use was verified with real world data. SSRIs exhibit significant anti-HCC effects independent of their known target serotonin reuptake transporter. The glucose transporter 1 (GLUT1) is identified as a new target of SSRIs. Citalopram binds to and antagonizes GLUT1, resulting in reduced glycolytic flux and ATP generation. Mutant GLUT1 in the binding site E380 of citalopram compromises the inhibitory effects of citalopram on the Warburg effect and tumor growth. In preclinical models, citalopram dampens the growth kinetics of GLUT1high liver tumors and displays a synergistic effect with anti-PD-1 therapy. Retrospective analysis of health records found that SSRIs use is associated with a lower risk of metastasis among HCC patients. Our study reveals an unprecedented role of SSRIs in cancer metabolism, and establishes a rationale for repurposing SSRIs as potential anticancer drugs for HCC.

cancer biology↗

bioRxiv2024

Interspecies interaction reshapes the fitness landscape of evolved genotypes

Microbial interaction and their evolution is vital for shaping the structure and function of microbial communities. However, the mechanisms governing the directionality and stability of the evolution of interactions within microbial communities remain poorly understood. Here, we used a syntrophic two-species biofilm consortium composed of Bacillus velezensis SQR9 and Pseudomonas stutzeri XL272 that promotes plant growth through their metabolic interactions and investigated how the interactions within the consortium change over evolutionary timescale to characterize the phenotypic and genetic diversification. The focal species B. velezensis SQR9 rapidly diversified into diverse colony morphotypes, both in the presence and absence of its interactor, P. stutzeri XL272, with variable frequencies. These morphotypes displayed phenotypic differentiation among biofilm formation, planktonic growth, and spore formation. The evolved P. stutzeri altered the fitness landscape of B. velezensis morphotypes, allowing the weaker rough morphotype to outcompete the biofilm-enhanced slimy morphotype. Whole genome re-sequencing correlated these phenotypic changes with mutations in specific genes encoding regulators of B. velezensis, including ywcC, comA, comP, degS, degQ and spo0F. The coevolutionary partner, P. stutzeri increased its exopolysaccharide production that could be explained by a frame shift mutation in cpsA gene encoding capsular polysaccharide (CPS) biosynthesis protein. Compared with the mono-evolution, co-evolved B. velezensis populations showed greater mutation accumulation in intergenic regions, which led to greater genetic parallelism. Furthermore, the dissimilarity between mono-evolved and co-evolved populations increased over time. Our study reveals intricate genetic diversification and fitness differentiation within a biofilm consortium, shaped by both abiotic conditions and biotic interactions.

microbiology↗

bioRxiv2024

Intraperitoneal activation of myeloid cells clears ascites and reveals IL27-dependent regression of metastatic ovarian cancer

Patients with metastatic ovarian cancer (OvCa) have a 5-year survival rate of less than 30% due to persisting dissemination of chemoresistant cells in the peritoneal fluid and the immunosuppressive microenvironment in the peritoneal cavity. Here, we report that intraperitoneal administration of {beta}-glucan and IFN{gamma} (BI) induced robust tumor regression in clinically relevant models of metastatic OvCa. BI induced tumor regression by controlling fluid tumor burden and activating localized antitumor immunity. {beta}-glucan alone cleared ascites and eliminated fluid tumor cells by inducing intraperitoneal clotting in the fluid and Dectin-1-Syk-dependent NETosis in the omentum. In omentum tumors, BI expanded a novel subset of immunostimulatory IL27+ macrophages and neutralizing IL27 impaired BI efficacy in vivo. Moreover, BI directly induced IL27 secretion in macrophages where single agent treatment did not. Finally, BI extended mouse survival in a chemoresistant model and significantly improved chemotherapy response in a chemo-sensitive model. In summary, we propose a new therapeutic strategy for the treatment of metastatic OvCa.

immunology↗

bioRxiv2024

Bridging the Gap: biofilm-mediated establishment of Bacillus velezensis on Trichoderma guizhouense mycelia

Bacterial-fungal interactions (BFIs) are important in ecosystem dynamics, especially within the soil rhizosphere. The bacterium Bacillus velezensis SQR9 and the fungus Trichoderma guizhouense NJAU 4742 have garnered considerable attention due to their roles in promoting plant growth and protecting their host against pathogens. In this study, we utilized these two model microorganisms to investigate BFI. We firstly demonstrate that while co-inoculation of B. velezensis and T. guizhouense could promote tomato growth, these two microorganisms display mutual antagonism on agar solidified medium. To resolve this contradiction, we developed an inoculation method, that allows B. velezensis colonization of T. guizhouense hyphae and performed a transcriptome analysis. During colonization of the fungal hyphae, B. velezensis SQR9 upregulates expression of biofilm related genes (e.g. eps, tasA, and bslA) that is distinct from free-living cells. This result suggested an intricate association between extracellular matrix expression and hyphae colonization. In accordance, deletion epsD, tasA, or both epsD and tasA genes of B. velezensis diminished colonization of the T. guizhouense hyphae. The insights from our study demonstrate that soil BFIs are more complex than we understood, potentially involving both competition and cooperation. These intricate biofilm-mediated BFI dynamics might contribute to the remarkable diversity observed within soil microbiota, providing a fresh perspective for further exploration of BFIs in the plant rhizosphere.

microbiology↗

bioRxiv2024

PP2C phosphatase Pic14 negatively regulates tomato Pto/Prf-triggered immunity by inhibiting MAPK activation

Type 2C protein phosphatases (PP2Cs) are emerging as important regulators of plant immune responses, although little is known about how they might impact nucleotide-binding, leucine-rich repeat (NLR)-triggered immunity (NTI). We discovered that expression of the PP2C-immunity associated candidate 14 gene (Pic14) is induced upon activation of the Pto/Prf-mediated NTI response in tomato. Pto/Prf recognize the effector AvrPto translocated into plant cells by the pathogen Pseudomonas syringae pv. tomato (Pst) and activate a MAPK cascade and other responses which together confer resistance to bacterial speck disease. Pic14 encodes a PP2C with an N-terminal kinase-interacting motif (KIM) and a C-terminal phosphatase domain. Upon inoculation with Pst-AvrPto, Pto/Prf-expressing tomato plants with loss-of-function mutations in Pic14 developed less speck disease, specifically in older leaves, compared to wild-type plants. Transient expression of Pic14 in leaves of Nicotiana benthamiana and tomato inhibited cell death typically induced by Pto/Prf and the MAPK cascade members M3K and Mkk2. The cell death-suppressing activity of Pic14 was dependent on the KIM and the catalytic phosphatase domain. Pic14 inhibited M3K- and Mkk2-mediated activation of immunity-associated MAPKs and Pic14 was shown to be an active phosphatase that physically interacts with and dephosphorylates Mkk2 in a KIM-dependent manner. Together, our results reveal Pic14 as an important negative regulator of Pto/Prf-triggered immunity by interacting with and dephosphorylating Mkk2. SIGNIFICANCE STATEMENTPlant intracellular immune receptors, typically nucleotide-binding, leucine-rich repeat proteins (NLRs) such as the tomato Prf protein activate NLR-triggered immunity (NTI) in response to specific pathogen virulence proteins. This paper reveals how a protein phosphatase interacts with and dephosphorylates a key signaling component acting downstream of Pto/Prf, likely to moderate negative effects of NTI on growth or other plant processes.

plant biology↗

bioRxiv2024

Exploring memory-related network via dorsal hippocampus suppression

Memory is a complex brain process that requires coordinated activities in a large-scale brain network. However, the relationship between coordinated brain network activities and memory-related behavior is not well understood. In this study, we investigated this issue by suppressing the activity in the dorsal hippocampus (dHP) using chemogenetics and measuring the corresponding changes in brain-wide resting-state functional connectivity (RSFC) and memory behavior in awake rats. We identified an extended brain network contributing to the performance in a spatial-memory related task. Our results were cross-validated using two different chemogenetic actuators, clozapine (CLZ) and clozapine-N-oxide (CNO). This study provides a brain network interpretation of memory performance, indicating that memory is associated with coordinated brain-wide neural activities. Significance StatementSuccessful memory processes require coordinated activity in a large-scale brain network, extending beyond a few key, well-known brain regions like the hippocampus. However, the specific brain regions involved and how they orchestrate their activity that is pertinent to memory processing remain unclear. Our study, using a chemogenetics-rsfMRI- behavior approach in awake rats, elucidates a comprehensive framework of the extended memory-associated network. This knowledge offers a broader interpretation of memory processes, enhancing our understanding of the neural mechanisms behind memory function, particularly from a network perspective.

neuroscience↗

bioRxiv2024

Temperature-Dependent Fold-Switching Mechanism of the Circadian Clock Protein KaiB

The oscillator of the cyanobacterial circadian clock relies on the ability of the KaiB protein to switch reversibly between a stable ground-state fold (gsKaiB) and an unstable fold-switched fold (fsKaiB). Rare fold-switching events by KaiB provide a critical delay in the negative feedback loop of this post-translational oscillator. In this study, we experimentally and computationally investigate the temperature dependence of fold switching and its mechanism. We demonstrate that the stability of gsKaiB increases with temperature compared to fsKaiB and that the Q10 value for the gsKaiB [->] fsKaiB transition is nearly three times smaller than that for the reverse transition. Simulations and native-state hydrogen-deuterium exchange NMR experiments suggest that fold switching can involve both subglobally and near-globally unfolded intermediates. The simulations predict that the transition state for fold switching coincides with isomerization of conserved prolines in the most rapidly exchanging region, and we confirm experimentally that proline isomerization is a rate-limiting step for fold switching. We explore the implications of our results for temperature compensation, a hallmark of circadian clocks, through a kinetic model.

biochemistry↗

bioRxiv2024

Sequential deactivation across the thalamus-hippocampus-mPFC pathway during loss of consciousness

How consciousness is lost in states such as sleep or anesthesia remains a mystery. To gain insight into this phenomenon, we conducted concurrent recordings of electrophysiology signals in the anterior cingulate cortex and whole-brain functional magnetic resonance imaging (fMRI) in rats exposed to graded propofol, undergoing the transition from consciousness to unconsciousness. Our results reveal that upon the loss of consciousness (LOC), as indicated by the loss of righting reflex, there is a sharp increase in low-frequency power of the electrophysiological signal. Additionally, simultaneously measured fMRI signals exhibit a cascade of deactivation across a pathway including the hippocampus, thalamus, and medial prefrontal cortex (mPFC) surrounding the moment of LOC, followed by a broader increase in brain activity across the cortex during sustained unconsciousness. Furthermore, sliding window analysis demonstrates a temporary increase in synchrony of fMRI signals across the hippocampus-thalamus-mPFC pathway preceding LOC. These data suggest that LOC might be triggered by sequential activities in the hippocampus, thalamus and mPFC, while wide-spread activity increases in other cortical regions commonly observed during anesthesia-induced unconsciousness might be a consequence, rather than a cause of LOC. Taken together, our study identifies a cascade of neural events unfolding as the brain transitions into unconsciousness, offering critical insight into the systems-level neural mechanisms underpinning LOC.

neuroscience↗

bioRxiv2024

SlSAURs, targeted by SlSTOP1, inhibit SlPP2C.Ds to modulate H+-ATPase and tomato root elongation under aluminum stress

Aluminum (Al) stress, a prevalent constraint in acid soils, is known to inhibit plant growth by inhibiting root elongation through restricted cell expansion. The molecular mechanisms of Al-induced root inhibition, however, are not fully understood. This study aimed to elucidate the role of SlSAUR (Small auxin up-regulated RNA) proteins, which were downstream of the key Al stress-responsive transcription factor SlSTOP1 and its enhancer SlSZP1, in modulating root elongation under Al stress in tomato (Solanum lycopersicum). Our findings demonstrated that tomato lines with SlSAURs knockout exhibited shorter root lengths when subjected to Al stress. Further investigation into the underlying mechanisms revealed that SlSAURs interact with D-clade type 2C protein phosphatases, specifically SlPP2C.Ds. This interaction was pivotal as it suppresses the phosphatase activity, leading to the derepression of SlPP2C.Ds inhibitory effect on H+-ATPase. Consequently, this promoted cell expansion and root elongation under Al stress conditions. Our research significantly contributes to the current understanding of the molecular mechanisms by which Al ions modulate root elongation. The discovery of the SlSAUR-SlPP2C.D interaction and its impact on H+-ATPase activity provides a novel perspective on the adaptive strategies employed by plants to cope with Al toxicity. This knowledge may pave the way for the development of tomato cultivars with enhanced Al stress tolerance, thereby improving crop productivity in acid soils.

plant biology↗

bioRxiv2024

pH-Controlled chemoselective rapid azo-coupling reaction (CRACR) enables global profiling of serotonylation proteome in cancer cells

Serotonylation has been identified as a novel protein post-translational modification for decades, where an isopeptide bond is formed between the glutamine residue and serotonin through transamination. Transglutaminase 2 (also known as TGM2 or TGase2) was proven to act as the main "writer" enzyme for this PTM and a number of key regulatory proteins (including small GTPases, fibronectin, fibrinogen, serotonin transporter, and histone H3) have been characterized as the substrates of serotonylation. However, due to the lack of pan-specific antibodies for serotonylated glutamine, the precise enrichment and proteomic profiling of serotonylation still remain challenging. In our previous research, we developed an aryldiazonium probe to specifically label protein serotonylation in a bioorthogonal manner, which depended on a pH-controlled chemoselective rapid azo-coupling reaction (CRACR). Here, we report the application of a photoactive aryldiazonium-biotin probe for the global profiling of serotonylation proteome in cancer cells. Thus, over 1,000 serotonylated proteins were identified from HCT 116 cells, many of which are highly related to carcinogenesis. Moreover, a number of modification sites of these serotonylated proteins were determined, attributed to the successful application of our chemical proteomic approach. Overall, these findings provided new insights into the significant association between cellular protein serotonylation and cancer development, further suggesting that to target TGM2-mediated monoaminylation may serve as a promising strategy for cancer therapeutics. TOC O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/593574v2_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@67e538org.highwire.dtl.DTLVardef@f9f722org.highwire.dtl.DTLVardef@cfe5fdorg.highwire.dtl.DTLVardef@104674f_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

Chemical proteomic profiling of protein dopaminylation in colorectal cancer cells

Histone dopaminylation is a newly identified epigenetic mark that plays a role in the regulation of gene transcription, where an isopeptide bond is formed between the fifth amino acid residue of H3 (i.e., glutamine) and dopamine. In our previous studies, we discovered that the dynamics of this post-translational modification (including installation, removal, and replacement) were regulated by a single enzyme, transglutaminase 2 (TGM2), through reversible transamination. Recently, we developed a chemical probe to specifically label and enrich histone dopaminylation via bioorthogonal chemistry. Given this powerful tool, we found that histone H3 glutamine 5 dopaminylation (H3Q5dop) was highly enriched in colorectal tumors, which could be attributed to the high expression level of TGM2 in colon cancer cells. Due to the enzyme promiscuity of TGM2, non-histone proteins have also been identified as targets of dopaminylation on glutamine residues, however, the dopaminylated proteome in cancer cells still remains elusive. Here, we utilized our chemical probe to enrich dopaminylated proteins from colorectal cancer cells in a bioorthogonal manner and performed the chemical proteomics analysis. Therefore, 425 dopaminylated proteins were identified, many of which are involved in nucleic acid metabolism and transcription pathways. More importantly, a number of modification sites of these dopaminylated proteins were identified, attributed to the successful application of our chemical probe. Overall, these findings shed light on the significant association between cellular protein dopaminylation and cancer development, further suggesting that to block the installation of protein dopaminylation may become a promising anti-cancer strategy. TOC O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/591460v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1a3e9dorg.highwire.dtl.DTLVardef@104ecddorg.highwire.dtl.DTLVardef@5ab948org.highwire.dtl.DTLVardef@3a5d8b_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

Microbiota from young mice counteracts susceptibility to age-related gout through modulating butyric acid levels in aged mice

Gout is a prevalent form of inflammatory arthritis that occurs due to high levels of uric acid in the blood leading to the formation of urate crystals in and around the joints, particularly affecting the elderly. Recent research has provided evidence of distinct differences in the gut microbiota of patients with gout and hyperuricemia when compared to healthy individuals. However, the link between gut microbiota and age-related gout remained underexplored. Our study found that gut microbiota plays a crucial role in determining susceptibility to age-related gout. Specifically, we observed that age-related gut microbiota regulated the activation of the NLRP3 inflammasome pathway and modulated uric acid metabolism. More scrutiny highlighted the positive impact of "younger" microbiota on the gut microbiota structure of old or aged mice, enhancing butanoate metabolism and butyric acid content. Experimentation with butyrate supplementation indicated that butyric acid exerts a dual effect, inhibiting inflammation in acute gout and reducing serum uric acid levels. These insights emphasize the potential of gut microbiome rejuvenation in mitigating senile gout, unraveling the intricate dynamics between microbiota, aging, and gout. It potentially serves as a therapeutic target for senile gout-related conditions.

microbiology↗

bioRxiv2024

Spatiotemporal transcriptomic profiling reveals the dynamic immunological landscape of alveolar echinococcosis

Alveolar echinococcosis (AE) is caused by the invasive growth of the metacestodes of Echinococcus multilocularis (E. multilocularis). The early diagnosis, management, and treatment of AE remains challenging. Herein, we integrated bulk RNA-seq, scRNA-seq, and ST technologies to reveal the immune characteristics both spatially and chronologically in E. multilocularis infected mouse liver. An unprecedented high-resolution spatial atlas of the E. multilocularis infection foci was obtained, revealing the pivotal role of neutrophils, Spp1+ monocyte-derived macrophages (MoMFs), and fibroblasts in AE progression. We observed continuous recruitment of neutrophils and macrophages into the infected tissues, indicating prolonged immune stimulation by the growing metacestodes. However, their spatial distribution patterns and functions changed during the infection cause. At the early infection stage, Il1bhi neutrophils aggregated in the lesion displayed the highest pattern-recognition receptor activity and may kill the metacestodes through NETosis, but their death in the infection foci might also trigger immune suppression. Meanwhile, Spp1+ MoMFs attached to the protoscoleces to clear the infection. At the late infection stage, the neutrophils failed to infiltrate into the lesion although their continuous recruitment into the infected liver. Even though the Spp1+ MoMFs enclosing the microcysts of E. multilocularis may retain their pathogen-killing ability, they may also promote fibrosis and angiogenesis through interaction with fibroblasts. The pro- and anti-inflammatory phenotype balance of these immune cells may be associated with the transition of parasite control strategy from "active killing" to "negative segregation" by the host. Our findings identify key molecular traits involved in AE development, which may benefit the treatment of echinococcosis.

immunology↗

bioRxiv2024

DeepSS2GO: protein function prediction from secondary structure

Predicting protein function is crucial for understanding biological life processes, preventing diseases, and developing new drug targets. In recent years, methods based on sequence, structure, and biological networks for protein function annotation have been extensively researched. Although obtaining a protein in three-dimensional structure through experimental or computational methods enhances the accuracy of function prediction, the sheer volume of proteins sequenced by high-throughput technologies presents a significant challenge. To address this issue, we introduce a deep neural network model DeepSS2GO (Secondary Structure to Gene Ontology). It is a predictor incorporating secondary structure features along with primary sequence and homology information. The algorithm expertly combines the speed of sequence-based information with the accuracy of structure-based features, while streamlining the redundant data in primary sequences and bypassing the timeconsuming challenges of tertiary structure analysis. The results show that the prediction performance surpasses state-ofthe-art algorithms. It has the ability to predict key functions by effectively utilizing secondary structure information, rather than broadly predicting general Gene Ontology terms. Additionally, DeepSS2GO predicts five times faster than advanced algorithms, making it highly applicable to massive sequencing data. The source code and trained models are available at https://github.com/orca233/DeepSS2GO.

bioinformatics↗

bioRxiv2024

Bioorthogonal labeling and enrichment of histone monoaminylation reveal its accumulation and regulatory function in cancer cell chromatin

Histone monoaminylation (i.e., serotonylation and dopaminylation) is an emerging category of epigenetic mark occurring on the fifth glutamine (Q5) residue of H3 N-terminal tail, which plays significant roles in gene transcription. Current analysis of histone monoaminylation is mainly based on site-specific antibodies and mass spectrometry, which either lacks high resolution or is time-consuming. In this study, we report the development of chemical probes for bioorthogonal labeling and enrichment of histone serotonylation and dopaminylation. These probes were successfully applied for the monoaminylation analysis of in vitro biochemical assays, cells, and tissue samples. The enrichment of monoaminylated histones by the probes further confirmed the crosstalk between H3Q5 monoaminylation and H3K4 methylation. Finally, combining the ex vivo and in vitro analyses based on the developed probes, we have shown that both histone serotonylation and dopaminylation are highly enriched in tumor tissues that overexpress transglutaminase 2 (TGM2) and regulate the three-dimensional architecture of cellular chromatin. TOC O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=154 SRC="FIGDIR/small/586010v3_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@1bee3f7org.highwire.dtl.DTLVardef@1687013org.highwire.dtl.DTLVardef@1960bd0org.highwire.dtl.DTLVardef@1e19a04_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

Cytokine expression patterns predict suppression of vulnerable neural circuits in a mouse model of Alzheimer's disease

Alzheimers disease is a neurodegenerative disorder characterized by progressive amyloid plaque accumulation, tau tangle formation, neuroimmune dysregulation, synapse and neuron loss, and changes in neural circuit activation that lead to cognitive decline and dementia. Early molecular and cellular disease-instigating events occur 20 or more years prior to presentation of symptoms, making them difficult to study, and for many years amyloid-{beta}, the aggregating peptide seeding amyloid plaques, was thought to be the toxic factor responsible for cognitive deficit. However, strategies targeting amyloid-{beta} aggregation and deposition have largely failed to produce safe and effective therapies, and amyloid plaque levels poorly correlate with cognitive outcomes. However, a role still exists for amyloid-{beta} in the variation in an individuals immune response to early, soluble forms of aggregates, and the downstream consequences of this immune response for aberrant cellular behaviors and creation of a detrimental tissue environment that harms neuron health and causes changes in neural circuit activation. Here, we perform functional magnetic resonance imaging of awake, unanesthetized Alzheimers disease mice to map changes in functional connectivity over the course of disease progression, in comparison to wild-type littermates. In these same individual animals, we spatiotemporally profile the immune milieu by measuring cytokines, chemokines, and growth factors across various brain regions and over the course of disease progression from pre-pathology through established cognitive deficit. We identify specific signatures of immune activation predicting hyperactivity followed by suppression of intra- and then inter-regional functional connectivity in multiple disease-relevant brain regions, following the pattern of spread of amyloid pathology.

neuroscience↗

bioRxiv2024

Targeted protein degradation of the CPSF complex by benzoxaboroles through sumoylation

Benzoxaboroles (BoBs) feature a boron-heterocyclic core and are an important innovation in the development of drugs against a range of pathogens and other pathologies. A broad spectrum of pharmacology is associated with chemically diverse BoB derivatives and includes multiple modes-of-action (MoA) and targets. However, a consensus MoA for BoBs targeting evolutionarily diverse protozoan pathogens has emerged with the identification of CPSF3/CPSF73 in the CPSF complex in both apicomplexan and kinetoplastida parasites. Here we establish a functional connection between protein sumoylation and the boron-heterocyclic scaffold shared by all BoBs using comprehensive genetic screens in Trypanosoma brucei. There is a rapid temporal and spatial shift in global protein sumoylation following BoB exposure and members of the CPSF complex are specifically destabilised in a SUMO and proteosome-dependent manner. Finally, we find rapid decrease in bulk mRNA levels, consistent with the role of CPSF3 in mRNA maturation. We propose that a combination of direct inhibition coupled with targeted degradation of CPSF3 underpins the specificity of BoBs against trypanosomatids.

cell biology↗