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Boosting CAR T-cell efficacy by blocking proteasomal degradation of membrane antigens
Abstract Chimeric antigen receptor (CAR) T cells exhibit high response rates in B-cell malignancies, but most patients eventually relapse. A key mechanism of treatment failure is the loss or downregulation of tumor antigen expression, yet strategies to modulate cell surface levels of CAR T-cell targets remain largely unexplored. Here, we identify B-cell maturation antigen (BCMA), a central CAR T-cell target in multiple myeloma (MM), as a highly short-lived protein that undergoes K48-linked polyubiquitylation at the plasma membrane, leading to its p97-dependent degradation via the ubiquitin-proteasome system (UPS). This previously unprecedented mechanism of plasma membrane protein regulation enables significant enhancement of BCMA expression via proteasome inhibitors (PIs). The clinically approved PI carfilzomib (CFZ) significantly enhances the efficacy of BCMA-directed CAR T cells against both PI-sensitive and -refractory MM cells in vitro and in vivo. Notably, CFZ treatment of 10 patients with BMCA CAR T-cell therapy relapse, under the CFZ after BCMA CAR T-cell (CarCAR) protocol, resulted in increased BCMA expression in all patients. However, clinical responses were observed only in those with residual and/or expanding CAR T cells, suggesting restored CAR T-cell function. These findings provide a rationale for the use of CFZ treatment in relapsed or refractory MM after BCMA CAR T-cell therapy, advocate for future trials combining CFZ with BCMA CAR T cells, and provide a framework for exploring UPS-dependent degradation of other immunotherapy antigens.
The complex role of nutrients in cancer spread
Spinal cord stimulation therapy for gait impairment in Parkinson’s disease: a double-blinded, randomised feasibility trial with an open extension
Mechanistic insights into the lipotropic and atheroprotective effects of rosuvastatin-loaded glycerosomes in dyslipidemic rats
Abstract Dyslipidemia is a major risk factor for the development of NAFLD, atherosclerosis and cardiovascular diseases. Rosuvastatin (ROS) is a lipid-lowering drug that protects against the development of NAFLD and atherosclerosis. However, the mechanism of this protection remains obscure. Therefore, the current study aims to explore the mechanism by which ROS-loaded glycerosomes (ROS-GLY) protect against NAFLD and atherosclerosis. Hence, for this purpose, hepatic lncRNA-H19/miR-130a/PPAR-γ and aortic PPAR-γ/LXRα/ABCA1 signaling pathways were assessed. In addition, these target pathways were predicted using molecular docking analysis. Thirty-five male Sprague Dawley rats were separated into control, dyslipidemic (poloxamer 407 (P 407)), P 407+ROS-GLY, P 407+NC, and P 407+ROS-GLY+NC groups. ROS-GLY improved lipid profile, hepatic MDA, SOD, catalase and total antioxidant capacity (TAC) in compared to P 407 group. In the dyslipidemic group, ROS-GLY downregulated hepatic lncRNA-H19 expression which leads to an upregulate of the miR-130a level and subsequent reduction of the PPAR-γ level. Consequently, the hepatic expression level of lipogenic genes such as, ACC-1, FASN and SCD-1 was significantly downregulated in the ROS-GLY group than the dyslipidemic one. Aortic PPAR-γ/LXRα/ABCA1 signaling pathway was significantly upregulated in the ROS-GLY group compared to the dyslipidemic group. Furthermore, ROS-GLY modulated IL-6 and IL-10 immunoprotein expression in hepatic and aortic tissues. Interestingly, ROS showed a substantial binding affinity with PPAR-γ, LXR-α, and FASN, according to a molecular docking study. The current study indicated that ROS-GLY protected against the progression of NAFLD and atherosclerosis in dyslipidemic rats via modulation of lipid profile, oxidative stress, pro-/anti-inflammatory cytokines, hepatic lncRNA-H19/miR-130a/PPAR-γ, and aortic PPAR-γ/LXRα/ABCA1 signaling pathways.
Limit of atomic-resolution-tomography reconstruction of amorphous nanoparticles
Expression of CD38+CD8+ T cells in hepatitis B-related acute-on-chronic liver failure and its prognostic value
A new method for predicting the shear strength of loess based on moisture content and large and medium pore volume
Synthesis and characterization of g-C3N5/CuS/AgNPs nanocomposite as a Z-scheme photocatalyst for efficient methyl parathion degradation
Abstract Water pollutants constitute a significant environmental concern today. Organophosphorus compounds, notably parathion, represent a critical category of water pollutants. Their extensive usage poses substantial risks to human health and the environment, necessitating their removal from water sources. This study focuses on the photocatalytic degradation of parathion, utilizing a g-C 3 N 5 /CuS/AgNPs nanocomposite synthesized through a combination of hydrothermal and ultrasonic methods. The nanocomposite was characterized using microscopic and spectroscopic techniques and demonstrated the capacity to degrade approximately 94.90% of parathion in the presence of visible light within one hour at pH 6. Parameters such as pH, initial pollutant concentration, and photocatalyst concentration were optimized. The study’s findings highlight that • O 2 − and • OH play a predominant role in the degradation process of this contaminant.
Advancing regulatory variant effect prediction with AlphaGenome
Abstract Deep learning models that predict functional genomic measurements from DNA sequences are powerful tools for deciphering the genetic regulatory code. Existing methods involve a trade-off between input sequence length and prediction resolution, thereby limiting their modality scope and performance 1–5 . We present AlphaGenome, a unified DNA sequence model, which takes as input 1 Mb of DNA sequence and predicts thousands of functional genomic tracks up to single-base-pair resolution across diverse modalities. The modalities include gene expression, transcription initiation, chromatin accessibility, histone modifications, transcription factor binding, chromatin contact maps, splice site usage and splice junction coordinates and strength. Trained on human and mouse genomes, AlphaGenome matches or exceeds the strongest available external models in 25 of 26 evaluations of variant effect prediction. The ability of AlphaGenome to simultaneously score variant effects across all modalities accurately recapitulates the mechanisms of clinically relevant variants near the TAL1 oncogene 6 . To facilitate broader use, we provide tools for making genome track and variant effect predictions from sequence.
A meta learning framework for few shot personalized gait cycle generation and reconstruction
Altered histone modifications in Aedes aegypti midguts following Rift Valley fever virus exposure
Abstract When arthropod-borne viruses (arboviruses) are delivered to vector mosquitoes in infectious bloodmeals, viral components interact with host proteins to hijack cells and initiate replication. The extent to which arbovirus infection alters mosquito host transcriptional regulatory processes is currently unknown. We hypothesized that histone modifications would be altered in mosquitoes exposed to Rift Valley fever virus (RVFV MP12). H3K27ac and H3K9me3 marks were interrogated using CUT&RUN in a mosquito species that has a predicted dissemination barrier, Aedes aegypti . Global H3K27ac peaks showed progressive depletion over time compared to bloodfed controls. Gene set enrichment analysis revealed that immune response transcripts were enriched at 1 and 3 days post-feeding (dpf). For virus-exposed samples, the highest proportion of DEGs proximal to histone marks occurred with depletion of repressive H3K9me3 peaks at 3 dpf. Associated DEGs included transcription factors, secondary messengers and processes affecting cell polarization. Analysis of midguts after a non-infectious bloodmeal versus sugar-fed controls revealed global changes to H3K27ac and H3K9me3 marks, as well. Differential H3K27ac marks were proximal to one quarter of all DEGs at 1 dpf, consistent with an important role of H3K27ac in bloodmeal digestion. Together, these results demonstrate that H3K27ac and H3K9me3 patterns are altered upon virus exposure in a complex interplay that could be due to viral manipulation or host defense.
The effect of non-pharmaceutical interventions on influenza throughout the COVID-19 pandemic: an 8-year interrupted time series study
How to eat well and within Earth’s limits
Sinus membrane thickness and its correlation with anatomical parameters using cone beam computed tomography: a cross-sectional study
The public health burden of nervous system tumors in Anambra State, Nigeria necessitates strategic resource allocation
Wideband circularly polarized leaky wave rectenna
Abstract This paper presents a circular polarized rectenna based on a leaky wave antenna (LWA). Integrating circular polarization with leaky wave radiation greatly improves energy harvesting by minimizing polarization losses and extending the spatial range of captured RF signals. The LWA exhibits rapid frequency-dependent beam scanning, which is efficient by enabling harvesting RF power at different directions based on the received power direction. The proposed rectenna consists of LWA array integrated with a rectifier circuit and is designed to harvest RF power at the 5G midrange band. The implemented LWA has wide beam scanning angle from − 21 to 29 o with a high gain value of 9.8 dBi at 5.3 GHz. A Rectifier circuit correlated with a matching circuit is implemented. The designed matching circuit is based on a wideband compression network to compress the variation ratio of the input impedance. The results of the matched rectifier circuit show that the implemented circuit can operate from 4.1 to 5.5 GHz with effective impedance matching and stable wideband performance. The rectifier circuit is designed using an SMS7630 Schottky diode with a low turn-on voltage. The LWA is fabricated, its parameters are measured, and compared with simulated results. Then the LWA is used in the receiving mode, integrated with the rectifier circuit, and measured. The proposed rectenna obtained a maximum measured DC output voltage of 1.2 V with conversion efficiency of 53.8% at 4.2 GHz with received power of 0 dBm.
Viral RNA blocks circularization to evade host codon usage control
Anticipation of periodic events influences cell motility in amoeba proteus
Abstract All migrating cells (both single-cell organisms and as part of multicellular organisms) sense environmental conditions and respond to physical and molecular cues by changing the direction and speed of cellular movement. Adaptive behaviors enable motile cells to thrive in dynamic environments. A study with slime mold suggested an ability to anticipate dry and cold periods. However, experimental evidence for anticipation in other single-cell organisms is lacking. Here, we investigated whether Amoeba proteus can anticipate unfavourable periodic stimuli. Amoeba proteus react to blue light (405 nm) by reducing their streaming speed in response to each stimulation. As expected, after four periodic blue light stimulations A. proteus presented spontaneous in-phase reduction in streaming speed at the time point when the next stimulation would have occurred. Our results corroborate the claim that single cells are able to anticipate periodic environmental cues and change their behaviour in anticipation of these cues. These findings may have implications for the interpretation of cellular processes in vitro and in vivo even in complex multicellular systems.