-
ACS Nano Jun 2024Parkinson's disease (PD) is an increasingly prevalent and currently incurable neurodegenerative disorder linked to the accumulation of α-synuclein (αS) protein...
Parkinson's disease (PD) is an increasingly prevalent and currently incurable neurodegenerative disorder linked to the accumulation of α-synuclein (αS) protein aggregates in the nervous system. While αS binding to membranes in its monomeric state is correlated to its physiological role, αS oligomerization and subsequent aberrant interactions with lipid bilayers have emerged as key steps in PD-associated neurotoxicity. However, little is known of the mechanisms that govern the interactions of oligomeric αS (OαS) with lipid membranes and the factors that modulate such interactions. This is in large part due to experimental challenges underlying studies of OαS-membrane interactions due to their dynamic and transient nature. Here, we address this challenge by using a suite of microfluidics-based assays that enable in-solution quantification of OαS-membrane interactions. We find that OαS bind more strongly to highly curved, rather than flat, lipid membranes. By comparing the membrane-binding properties of OαS and monomeric αS (MαS), we further demonstrate that OαS bind to membranes with up to 150-fold higher affinity than their monomeric counterparts. Moreover, OαS compete with and displace bound MαS from the membrane surface, suggesting that disruption to the functional binding of MαS to membranes may provide an additional toxicity mechanism in PD. These findings present a binding mechanism of oligomers to model membranes, which can potentially be targeted to inhibit the progression of PD.
PubMed: 38916260
DOI: 10.1021/acsnano.3c10889 -
BioRxiv : the Preprint Server For... Jun 2024Certain areas of the brain involved in episodic memory and behavior, such as the hippocampus, express high levels of insulin receptors and glucose transporter-4 (GLUT4)...
Certain areas of the brain involved in episodic memory and behavior, such as the hippocampus, express high levels of insulin receptors and glucose transporter-4 (GLUT4) and are responsive to insulin. Insulin and neuronal glucose metabolism improve cognitive functions and regulate mood in humans. Insulin-dependent GLUT4 trafficking has been extensively studied in muscle and adipose tissue, but little work has demonstrated either how it is controlled in insulin-responsive brain regions or its mechanistic connection to cognitive functions. In this study, we demonstrate that inhibition of WNK (With-No-lysine (K)) kinases improves learning and memory in mice. Neuronal inhibition of WNK enhances in vivo hippocampal glucose uptake. Inhibition of WNK enhances insulin signaling output and insulin-dependent GLUT4 trafficking to the plasma membrane in mice primary neuronal cultures and hippocampal slices. Therefore, we propose that the extent of neuronal WNK kinase activity has an important influence on learning, memory and anxiety-related behaviors, in part, by modulation of neuronal insulin signaling.
PubMed: 38915673
DOI: 10.1101/2024.06.09.598125 -
Cell-inspired, massive electromodulation of friction via transmembrane fields across lipid bilayers.Nature Materials Jun 2024Transient electric fields across cell bilayer membranes can lead to electroporation and cell fusion, effects crucial to cell viability whose biological implications have...
Transient electric fields across cell bilayer membranes can lead to electroporation and cell fusion, effects crucial to cell viability whose biological implications have been extensively studied. However, little is known about these behaviours in a materials context. Here we find that transmembrane electric fields can lead to a massive, reversible modulation of the sliding friction between surfaces coated with lipid-bilayer membranes-a 200-fold variation, up to two orders of magnitude greater than that achieved to date. Atomistic simulations reveal that the transverse fields, resembling those at cell membranes, lead to fully reversible electroporation of the confined bilayers and the formation of inter-bilayer bridges analogous to the stalks preceding intermembrane fusion. These increase the interfacial dissipation through reduced hydration at the slip plane, forcing it to revert in part from the low-dissipation, hydrated lipid-headgroup plane to the intra-bilayer, high-dissipation acyl tail interface. Our results demonstrate that lipid bilayers under transmembrane electric fields can have striking materials modification properties.
PubMed: 38914644
DOI: 10.1038/s41563-024-01926-9 -
JCI Insight May 2024Immune therapy is the new frontier of cancer treatment. Therapeutic radiation is a known inducer of immune response and can be limited by immunosuppressive mediators...
Immune therapy is the new frontier of cancer treatment. Therapeutic radiation is a known inducer of immune response and can be limited by immunosuppressive mediators including cyclooxygenase-2 (COX2) that is highly expressed in aggressive triple negative breast cancer (TNBC). A clinical cohort of TNBC tumors revealed poor radiation therapeutic efficacy in tumors expressing high COX2. Herein, we show that radiation combined with adjuvant NSAID (indomethacin) treatment provides a powerful combination to reduce both primary tumor growth and lung metastasis in aggressive 4T1 TNBC tumors, which occurs in part through increased antitumor immune response. Spatial immunological changes including augmented lymphoid infiltration into the tumor epithelium and locally increased cGAS/STING1 and type I IFN gene expression were observed in radiation-indomethacin-treated 4T1 tumors. Thus, radiation and adjuvant NSAID treatment shifts "immune desert phenotypes" toward antitumor M1/TH1 immune mediators in these immunologically challenging tumors. Importantly, radiation-indomethacin combination treatment improved local control of the primary lesion, reduced metastatic burden, and increased median survival when compared with radiation treatment alone. These results show that clinically available NSAIDs can improve radiation therapeutic efficacy through increased antitumor immune response and augmented local generation of cGAS/STING1 and type I IFNs.
Topics: Animals; Membrane Proteins; Mice; Female; Signal Transduction; T-Lymphocytes, Cytotoxic; Triple Negative Breast Neoplasms; Indomethacin; Cell Line, Tumor; Humans; Lung Neoplasms; Cyclooxygenase Inhibitors; Nucleotidyltransferases; Interferon Type I; Cyclooxygenase 2; Lymphocytes, Tumor-Infiltrating; Mice, Inbred BALB C
PubMed: 38912586
DOI: 10.1172/jci.insight.165356 -
Industrial & Engineering Chemistry... May 2024The basic principles of a steady-state mass transfer model and the resistance-in-series film model are assessed with the aid of a series of experiments in a gas-liquid...
The basic principles of a steady-state mass transfer model and the resistance-in-series film model are assessed with the aid of a series of experiments in a gas-liquid contact membrane mini-module (3 M Liqui-Cel MM-1.7 × 5.5) using an aqueous solution of diethanolamine (DEA) of 0.25 M (mol/L) for biogas upgrading. Experimental data show that CO removal may exceed 67% and reach 100% in combination with the highest possible recovery of CH when employing biogas flow rates in the range of 2.8 × 10 - 3.6 × 10 m/s and solvent flow rates within 0.47 × 10 - 0.58 × 10 m/s. For the experimental data set, a correlation has been developed, effectively interpolating CO removal with the gas and liquid flow rates. The wetting values calculated are concentrated close to each other for the same liquid flow rate without considerably depending on the gas flow rate, especially when applying the Hikita-Yun (reaction rate-shell-side correlation) compared with the Hikita-Costello pair. Furthermore, the calculated wetting diminishes with increasing liquid flow rate, a result that is consistent with previous modeling attempts and relevant literature indications. The assumption of enhanced mass transfer in the liquid-filled part of the membrane pores due to the reaction is scrutinized, leading to objectionable computational wetting values. It is shown that for a concentration of DEA equal to 0.25 M the Hatta numbers and the enhancement factors are not equal in the whole reaction path; thus, the choice of the shell-side correlation has an appreciable impact on the overall analysis, especially for the determination of the wetting values.
PubMed: 38911336
DOI: 10.1021/acs.iecr.4c00525 -
RSC Medicinal Chemistry Jun 2024Synthetic cannabinoid receptor agonists (SCRAs) comprise the second largest class of new psychoactive substances (NPS), and typically α-amino acid moieties are...
Synthetic cannabinoid receptor agonists (SCRAs) comprise the second largest class of new psychoactive substances (NPS), and typically α-amino acid moieties are incorporated as part of their design. Limited investigation has been performed into elucidating structure-activity relationships around commonly used α-amino acid-derived head groups, mainly with valine and -leucine-derived compounds previously described. As such, proactive synthesis, characterisation and pharmacological evaluation were performed to explore structure-activity relationships of 15 α-amino acid derivatives, with both the natural isomers and their enantiomers at CB and CB investigated using a fluorescence-based membrane potential assay. This library was based around the detected SCRAs MPP-5F-PICA, MMB-5F-PICA, and MDMB-5F-PICA, with the latter showing significant receptor activation at CB (pEC = 8.34 ± 0.05 M; = 108 ± 3%) and CB (pEC = 8.13 ± 0.07 M; = 99 ± 2%). Most valine and leucine derivatives were potent and efficacious SCRAs, while smaller derivatives generally showed reduced activity at CB and CB, and larger derivatives also showed reduced activity. SAR trends observed were rationalised induced fit docking. Overall, while natural enantiomers showed equipotent or greater activity than the unnatural isomers in most cases, this was not universal. As such, a number of these compounds should be monitored as emerging NPS, and various substituents described herein.
PubMed: 38911147
DOI: 10.1039/d3md00758h -
Biochimica Et Biophysica Acta.... Jun 2024The natural transformation system of the thermophilic bacterium Thermus thermophilus comprises at least 16 competence proteins. Recently we found that the outer membrane...
The natural transformation system of the thermophilic bacterium Thermus thermophilus comprises at least 16 competence proteins. Recently we found that the outer membrane (OM) competence protein PilW interacts with the secretin channel, which guides type IV pili (T4P) and potential DNA transporter pseudopili through the OM. Here we have used biochemical techniques to study the interactions of cytoplasmic, inner membrane (IM) and OM components of the DNA transporter in T. thermophilus. We report that PilW is part of a heteropolymeric complex comprising of the cytoplasmic PilM protein, IM proteins PilN, PilO, PilC and the secretin PilQ. Co-purification studies revealed that PilO directly interacts with PilW. In vitro affinity co-purification studies using His-tagged PilC led to the detection of PilC-, PilW-, PilN- and PilO-containing complexes. PilO was identified as direct interaction partner of the polytopic IM protein PilC. PilC was also found to directly interact with the cytoplasmic T4P disassembly ATPase PilT1 thereby triggering PilT1 ATPase activity. This, together with the detection of heteropolymeric PilC complexes which contain PilT1 and the pilins PilA2, PilA4 and PilA5 is in line with the hypothesis that PilC connects the depolymerization ATPase to the base of the pili possibly allowing energy transduction for disassembly of the pilins.
PubMed: 38909880
DOI: 10.1016/j.bbamem.2024.184363 -
Cryobiology Jun 2024Cryopreservation of goat spermatozoa is challenging due to several factors, including one of the most essential, i.e., oxidative stress. It is particularly essential in...
Cryopreservation of goat spermatozoa is challenging due to several factors, including one of the most essential, i.e., oxidative stress. It is particularly essential in goat semen due to its scanty ejaculate volume and high sperm concentration. This leaves a narrow sperm-to-seminal plasma ratio owing to marginal antioxidant support; moreover, semen extension further dilutes the antioxidant level, leading to an imbalance of oxidant-antioxidant equilibrium. The present study aimed to evaluate the effect of quercetin on curtailing oxidative stress and its reflection on the post-thaw survivability and membrane integrity of goat spermatozoa. For this study, six bucks were selected. Six ejaculates from each buck totaling 36 ejaculates were collected, which were then split into five parts; furthermore, each part was added with a semen extender having a particular concentration of additive. Group C without quercetin and T containing Vit E at 3 mmol/mL were considered the control and positive control respectively, whereas T, T, and T contain 10, 20, and 30 μmol/mL of Quercetin respectively. The final sperm concentration of each group was kept at 200×10 spermatozoa/mL. All groups were subjected to equilibration at 4 °C for 4 hours, then filled in French mini (0.25 mL) straws, followed by sealing and cryopreservation. Samples after 72 hours of cryopreservation were subjected to evaluation of plasma membrane integrity and viability through staining, acrosomal integrity, and mitochondrial membrane activity through flowcytometry. Evaluation of sperm kinematics as well as the oxidant-antioxidant status of sperm (ROS and nitric oxide) and seminal plasma (SOD, CAT, GPx, FRAP, and lipid peroxidation through MDA estimation) were also carried out. Quercetin, when supplemented at 20 μmol/mL in buck semen extender, significantly (p<0.01) improved cryopreserved sperm functions in terms of plasma membrane integrity, viability, acrosomal integrity, mitochondrial membrane activity, and sperm kinematics of buck semen. Similarly, Quercetin supplementation at 20 μmol/mL significantly reduced reactive oxygen and nitrogen species (RONS) in sperm and improved the antioxidant status of seminal plasma, which was indicated by reduced oxidative damage and improved the antioxidant status of buck semen. In conclusion, Quercetin at 20 μmol/mL reduced oxidative stress, improved semen antioxidant status, and improved sperm membrane integrity and kinematics.
PubMed: 38909672
DOI: 10.1016/j.cryobiol.2024.104931 -
Seminars in Nuclear Medicine Jun 2024The aim of this overview was to consolidate existing evidence syntheses and provide a comprehensive overview of the evidence for F-prostate specific membrane antigen... (Review)
Review
Diagnostic Accuracy of F-Prostate Specific Membrane Antigen (PSMA) PET/CT Radiotracers in Staging and Restaging of Patients With High-Risk Prostate Cancer or Biochemical Recurrence: An Overview of Reviews.
The aim of this overview was to consolidate existing evidence syntheses and provide a comprehensive overview of the evidence for F-prostate specific membrane antigen (PSMA) PET/CT in the staging of high-risk prostate cancer and restaging after biochemical recurrence. An overview of reviews was performed and reported in line with the preferred reporting items for overview of reviews (PRIOR) statement and synthesis without meta-analysis (SWiM) reporting guidelines. A comprehensive database and grey literature search were conducted up to July 18, 2023. Systematic reviews were assessed using the risk of bias in systematic reviews (ROBIS) tool. The certainty of the evidence was assessed using grading of recommendations, assessment, development and evaluations (GRADE). 11 systematic reviews were identified; 10 were at high or unclear risk of bias. Evidence reported on a per-patient, per-lymph node, and per-lesion basis for sensitivity, specificity and overall accuracy was identified. There was a lack of data on dose, adverse events and evidence directly comparing F-PSMA PET/CT to other imaging modalities. Evidence with moderate to very low certainty indicated high sensitivity, specificity and accuracy of F-PSMA PET/CT in patients with high-risk prostate cancer and biochemical recurrence. There was considerably lower certainty evidence and greater variability in effect estimates for outcomes for the combined intermediate/high-risk cohort. While evidence gaps remain for some outcomes, and most systematic reviews were at high or unclear risk of bias, the current evidence base is broadly supportive of F-PSMA PET/CT imaging in the staging and restaging of patients with high-risk prostate cancer and biochemical recurrence.
PubMed: 38906759
DOI: 10.1053/j.semnuclmed.2024.05.003 -
Journal of Neurointerventional Surgery Jun 2024Mechanical thrombectomy (MT) is part of the standard of care for stroke treatment, and improving its efficacy is one of the main objectives of clinical investigation. Of...
BACKGROUND
Mechanical thrombectomy (MT) is part of the standard of care for stroke treatment, and improving its efficacy is one of the main objectives of clinical investigation. Of importance is placement of the distal end of balloon-guided catheters (BGC). We aim to determine if this influences outcomes.
METHODS
We analyzed data from the ASSIST Registry, an international, multicenter prospective study of 1492 patients. We divided patients treated with BGC according to the placement of the BGC: low cervical (LCG (the lower 2/3 of cervical internal carotid artery (ICA)) or high cervical (HCG (upper 1/3 of cervical ICA, petro-lacerum or higher)). We analyzed characteristics and outcomes overall and stratified on the primary MT technique: Stent-Retriever only (SR Classic), Combined use of aspiration catheter and SR (Combined), and Direct Aspiration (ADAPT).
RESULTS
Our study included 704 subjects -323 in the low cervical and 381 in the high cervical groups. Statistical differences were seen in the proportion of females and tandem lesions (both higher for LCG). Placing the BGC in the high cervical segment is associated with better recanalization rates (expanded treatment in cerebral infarction (eTICI) score of 2c-3) at the end of the procedure (P<0.0001) and shorter procedures (P=0.0005). After stratifying on the three primary techniques (SR Classic, Combined, and ADAPT), placing the BGC in the high segment is associated with a better first-pass effect (FPE), less distal emboli, and better clinical outcomes in the SR Classic technique.
CONCLUSIONS
Placing the distal end of the BGC at the high cervical segment or higher is associated with better recanalization.
PubMed: 38906685
DOI: 10.1136/jnis-2024-021650