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Inhibitor-based modulation of huntingtin aggregation mechanisms mitigates fibril-induced cellular stress
Abstract Huntington’s disease (HD) is a neurodegenerative disorder in which mutated fragments of the huntingtin protein (Htt) undergo misfolding and aggregation. Since aggregated proteins can cause cellular stress and cytotoxicity, there is an interest in the development of small molecule aggregation inhibitors as potential modulators of HD pathogenesis. Here, we study how a polyphenol modulates the aggregation mechanism of huntingtin exon 1 (HttEx1) even at sub-stoichiometric ratios. Sub-stoichiometric amounts of curcumin impacted the primary and/or secondary nucleation events, extending the pre-aggregation lag phase. Remarkably, the disrupted aggregation process changed both the aggregate structure and its cell metabolic properties. When administered to neuronal cells, the ‘break-through’ protein aggregates induced significantly reduced cellular stress compared to aggregates formed in absence of inhibitors. Structural analysis by electron microscopy, small angle X-ray scattering (SAXS), and solid-state NMR spectroscopy identified changes in the fibril structures, probing the flanking domains in the fuzzy coat and the fibril core. We propose that changes in the latter relate to the presence or absence of polyglutamine (polyQ) β-hairpin structures. Our findings highlight multifaceted consequences of small molecule inhibitors that modulate the protein misfolding landscape, with potential implications for treatment strategies in HD and other amyloid disorders.
MGAT1-Guided complex N-Glycans on CD73 regulate immune evasion in triple-negative breast cancer
Abstract Despite the widespread application of immunotherapy, treating immune-cold tumors remains a significant challenge in cancer therapy. Using multiomic spatial analyses and experimental validation, we identify MGAT1, a glycosyltransferase, as a pivotal factor governing tumor immune response. Overexpression of MGAT1 leads to immune evasion due to aberrant elevation of CD73 membrane translocation, which suppresses CD8+ T cell function, especially in immune-cold triple-negative breast cancer (TNBC). Mechanistically, addition of N-acetylglucosamine to CD73 by MGAT1 enables the CD73 dimerization necessary for CD73 loading onto VAMP3, ensuring membrane fusion. We further show that THBS1 is an upstream etiological factor orchestrating the MGAT1-CD73-VAMP3-adenosine axis in suppressing CD8+ T cell antitumor activity. Spatial transcriptomic profiling reveals spatially resolved features of interacting malignant and immune cells pertaining to expression levels of MGAT1 and CD73. In preclinical models of TNBC, W-GTF01, an inhibitor specifically blocked the MGAT1-catalyzed CD73 glycosylation, sensitizing refractory tumors to anti-PD-L1 therapy via restoring capacity to elicit a CD8+ IFNγ-producing T cell response. Collectively, our findings uncover a strategy for targeting the immunosuppressive molecule CD73 by inhibiting MGAT1.
Shared pathway-specific network mechanisms of dopamine and deep brain stimulation for the treatment of Parkinson’s disease
Abstract Deep brain stimulation is a brain circuit intervention that can modulate distinct neural pathways for the alleviation of neurological symptoms in patients with brain disorders. In Parkinson’s disease, subthalamic deep brain stimulation clinically mimics the effect of dopaminergic drug treatment, but the shared pathway mechanisms on cortex – basal ganglia networks are unknown. To address this critical knowledge gap, we combined fully invasive neural multisite recordings in patients undergoing deep brain stimulation surgery with normative MRI-based whole-brain connectomics. Our findings demonstrate that dopamine and stimulation exert distinct mesoscale effects through modulation of local neural population activity. In contrast, at the macroscale, stimulation mimics dopamine in its suppression of excessive interregional network synchrony associated with indirect and hyperdirect cortex – basal ganglia pathways. Our results provide a better understanding of the circuit mechanisms of dopamine and deep brain stimulation, laying the foundation for advanced closed-loop neurostimulation therapies.
Disrupting bile acid metabolism by suppressing Fxr causes hepatocellular carcinoma induced by YAP activation
Prevention and control of avian influenza virus: Recent advances in diagnostic technologies and surveillance strategies
The role of land use in terrestrial support of boreal lake food webs
Abstract There is growing awareness of the importance of cross-boundary energy and nutrient transfers between adjacent ecosystems. Lake ecosystems receive inputs of terrestrial organic matter that microbes can make available to higher level consumers. However, how environmental drivers influence this terrestrial support of benthic and pelagic consumers at multiple trophic levels remains underexplored. Using hydrogen stable isotopes as a tracer of terrestrial organic matter, we find large variation in terrestrial support of aquatic consumers (i.e., consumer allochthony) among 35 boreal lakes. Of 19 different aquatic organisms, benthic consumers show the highest allochthony. Consumer allochthony decreases along an environmental gradient from forested to agricultural catchments, likely due to shifts in the origin and nature of lake organic matter. Our results demonstrate how cross-ecosystem transfer of organic matter can influence community dynamics in recipient ecosystems, with anthropogenic management of donor terrestrial ecosystems affecting the structure and function of food webs in recipient aquatic ecosystems.
Author Correction: Tuning Li occupancy and local structures for advanced Co-free Ni-rich positive electrodes
Global increases of salt intrusion in estuaries under future environmental conditions
Stretchable composites with high oxide loading
Electrochemical upcycling of uranyl from radioactive organic wastewater with a self-standing covalent-organic framework electrode
Dispersion hardening using amorphous nanoparticles deployed via additive manufacturing
Positive rhizosphere priming accelerates carbon release from permafrost soils
Abstract Thawing permafrost soils are predicted to release substantial amounts of carbon by 2100. In addition to this, warming-induced active-layer deepening and increased rooting depth may result in further carbon losses from previously-frozen soil by stimulating microbial communities through fresh carbon inputs inducing positive rhizosphere priming. While models based on temperate data predict significant permafrost carbon loss through rhizosphere priming, data from permafrost soils are lacking. Here, we provide direct evidence of live plant-induced positive rhizosphere priming in permafrost and active-layer soils across diverse soil types from Arctic and Subarctic Canada. By 13CO2 labelling plants in a controlled environment, we show that root activity increases carbon loss from previously frozen soils by 31%. This rhizosphere priming effect persists longer in permafrost than in active-layer soils, suggesting greater vulnerability of permafrost carbon. These findings underscore the urgency of incorporating plant–soil–microbe interactions into models predicting greenhouse gas emissions from thawing permafrost.
Tunable magnons of an antiferromagnetic Mott insulator via interfacial metal-insulator transitions
Distinct metabolome and flux responses in the retinal pigment epithelium to cytokines associated with age-related macular degeneration: comparison of ARPE-19 cells and eyecups
Assessment of air pollution and mortality in Portugal using AirQ+ and the effects of COVID-19 on their relationship
Electrically induced hemodynamic enhancement via sock-integrated electrodes is more comfortable and efficient at 1 hz as compared to 36 hz
Abstract This study evaluated the hemodynamic effects, discomfort, and energy efficiency of low-intensity neuromuscular electrical stimulation (LI-NMES) of the calf delivered via sock-integrated transverse textile electrodes (TTE) at different frequencies and plateau times. Fifteen healthy participants underwent NMES stimulation through 3 × 3 cm TTE with ten combinations of frequency (1–36 Hz) and plateau times (0.5–7 s). NMES was increased until plantar flexion occurred, at which point ultrasound-measurements were made of popliteal peak venous velocity (PVV), time-averaged mean velocity (TAMV), average duration of blood flow pulse (ADBP) and ejection volume (EV). Discomfort (NRS, 0–10), current amplitude, and energy consumption were recorded. Median values were analyzed with significance set at p < 0.05. Both 1 Hz and 36 Hz C-LI-NMES significantly improved PVV and TAMV (p ≤ 0.008). EV increased significantly for plateau times of 1.5, 5.0, and 7.0 s (p < 0.05). Compared to 36 Hz, 1 Hz showed significantly lower discomfort (NRS: 0.4 vs. 1.6) and energy consumption (0.4 vs. 31.3 mJ, both p ≤ 0.01) but required higher current amplitude (33.2 vs. 23.3 mA, p < 0.01) to reach plantar flexion. The study concludes that both 1 Hz and 36 Hz frequency improve venous hemodynamics, but 1 Hz stimulation minimizes discomfort and energy use while maintaining effectiveness. Trial registration: Retrospectively registered with Clinical Trials, trial ID: NCT06082297.
Unraveling the effects of serial intravitreal Aflibercept injections on the ocular surface of patients with glaucoma and retinal comorbidity
Abstract To evaluate ocular surface and eyelid modifications occurring in glaucomatous patients diagnosed with glaucoma therapy-related ocular surface disease (GT-OSD) and retinal comorbidities who previously underwent serial Intravitreal injections (IVIs) of aflibercept. Thirty-two eyes of 32 patients with a diagnosis of GT-OSD and concomitant retinal diseases were enrolled in a two-center retrospective observational study. The main outcome measures were: Noninvasive tear film break-up time (NIBUT), Tear meniscus height (TMH), Bulbar redness score (BRS), fluorescein Tear film Break Up Time (TBUT), Corneal Fluorescence Staining (CFS), Schirmer test I (ST), and inferior eyelid Meibomian Glands (MGs) dropout. Differences between treated and fellow eye (TE, FE), were considered. The median number of IVIs (aflibercept) in TE was 4 (interquartile range (IQR) 3-6.50). Mean BRS was significantly lower (p = 0.011) and median TBUT higher (p = 0.037) in TE compared to FE. Despite CFS and NIBUT did not significantly differ between eyes, their median values showed a marginal tendency for better results in TE compared to FE. Serial IVIs of aflibercept positively affected some features of the GT-OSD, reducing conjunctival hyperemia and improving the tear film stability. These preliminary results could open to new strategies for ocular surface management in glaucoma, whether confirmed in larger prospective studies.