Miracle-dz/UniFAR-FTUs huggingface dataset:
An RNA Damage Response Network Mediates the Lethality of 5-FU in Clinically Relevant Tumor Types

5-fluorouracil (5-FU) is a successful and broadly used anti-cancer therapeutic. A major mechanism of action of 5-FU is thought to be through thymidylate synthase (TYMS) inhibition resulting in dTTP depletion and activation of the DNA damage response. This suggests that 5-FU should synergize with other DNA damaging agents. However, we found that combinations of 5-FU and oxaliplatin or irinotecan failed to display any evidence of synergy in clinical trials, and resulted in sub-additive killing in a panel of colorectal cancer (CRC) cell lines. In seeking to understand this antagonism, we unexpectedly found that an RNA damage response during ribosome biogenesis dominates the drug’s efficacy in tumor types for which 5-FU shows clinical benefit. 5-FU has an inherent bias for RNA incorporation, and blocking this greatly reduced drug-induced lethality, indicating that accumulation of damaged RNA is more deleterious than the lack of new RNA synthesis. Using 5-FU metabolites that specifically incorporate into either RNA or DNA revealed that CRC cell lines and patient-derived colorectal cancer organoids are inherently more sensitive to RNA damage. This difference held true in cell lines from other tissues in which 5-FU has shown clinical utility, whereas cell lines from tumor tissues that lack clinical 5-FU responsiveness typically showed greater sensitivity to the drug’s DNA damage effects. Analysis of changes in the phosphoproteome and ubiquitinome shows RNA damage triggers the selective ubiquitination of multiple ribosomal proteins leading to autophagy-dependent rRNA catabolism and proteasome-dependent degradation of ubiquitinated ribosome proteins. Further, RNA damage response to 5-FU is selectively enhanced by compounds that promote ribosome biogenesis, such as KDM2A inhibitors. These results demonstrate the presence of a strong RNA damage response linked to apoptotic cell death, with clear utility of combinatorially targeting this response in cancer therapy.
A Ray of Light Against Age Related Neurodegeneration

Mitochondrial function declines with age and many pathological processes of neurodegenerative diseases stem from this dysfunction when mitochondria fail to produce the necessary energy required. Photobiomodulation (PBM), long-wavelength light therapy, has been shown to rescue mitochondrial function in animal models and improve human health, but clinical uptake is limited due to uncertainty around efficacy and the mechanisms responsible. Through combined theoretical Monte Carlo light modelling and practical 31P Magnetisation Transfer Magnetic Resonance Spectroscopy (MT-MRS) we quantify the effects of 670 nm PBM treatment on healthy aging brains. 31P MT-MRS revealed a significant increase in the rate of ATP flux after PBM in a sample of older adults. Light modelling shows 1% absorption in grey matter and confirms absorption peaks at 670 and 820 nm. Our study provides evidence of PBM therapeutic efficacy and strengthens confidence in PBM as an acceptable healthcare technology to improve mitochondrial function and human health.
Unlocking the Secrets of the Primate Visual Cortex: A CNN-Based Approach Traces the Origins of Major Organizational Principles to Retinal Sampling

Primate visual cortex exhibits key organizational principles: Cortical magnification, eccentricity-dependent receptive field size and spatial frequency tuning as well as radial bias. We provide compelling evidence that these principles arise from the interplay of the non-uniform distribution of retinal ganglion cells (RGCs), and a quasi-uniform convergence rate from the retina to the cortex. We show that convolutional neural networks (CNNs) outfitted with a retinal sampling layer, which resamples images according to retinal ganglion cell density, develop these organizational principles. Surprisingly, our results indicate that radial bias is spatial-frequency dependent and only manifests for high spatial frequencies. For low spatial frequencies, the bias shifts towards orthogonal orientations. These findings introduce a novel hypothesis about the origin of radial bias. Quasi-uniform convergence limits the range of spatial frequencies (in retinal space) that can be resolved, while retinal sampling determines the spatial frequency content throughout the retina.
Protein homeostasis from diffusion-dependent control of protein synthesis and degradation

It has been proposed that the concentration of proteins in the cytoplasm maximizes the speed of important biochemical reactions. Here we have used the Xenopus extract system, which can be diluted or concentrated to yield a range of cytoplasmic protein concentrations, to test the effect of cytoplasmic concentration on mRNA translation and protein degradation. We found that protein synthesis rates are maximal in ∼1x cytoplasm, whereas protein degradation continues to rise to an optimal concentration of ∼1.8x. This can be attributed to the greater sensitivity of translation to cytoplasmic viscosity, perhaps because it involves unusually large macromolecular complexes like polyribosomes. The different concentration optima sets up a negative feedback homeostatic system, where increasing the cytoplasmic protein concentration above the 1x physiological level increases the viscosity of the cytoplasm, which selectively inhibits translation and drives the system back toward the 1x set point.
Aging-associated Decline in Vascular Smooth Muscle Cell Mechanosensation is Mediated by Piezo1 Channel

Aging of the vasculature is associated with detrimental changes in vascular smooth muscle cell (VSMC) mechanosensitivity to extrinsic forces in their surrounding microenvironment. However, how chronological aging alters VSMCs’ ability to sense and adapt to mechanical perturbations remains unexplored. Here, we show defective VSMC mechanosensation in aging measured with ultrasound tweezers-based micromechanical system, force instantaneous frequency spectrum and transcriptome analyses. The mechanobiological study reveals that aged VSMCs adapt a relatively inert solid-like state with altered actin cytoskeletal integrity, resulting in an impairment in their mechanosensitivity and dynamic mechanoresponse to mechanical perturbations. The aging-associated decline in mechanosensation behaviors is mediated by hyperactivity of Piezo1-dependent calcium signaling. Inhibition of Piezo1 alleviates vascular aging and partially restores the loss in dynamic contractile properties in aged cells. Altogether, our study reveals the novel signaling pathway underlying aging-associated aberrant mechanosensation in VSMC and identifies Piezo1 as a potential therapeutic mechanobiological target to alleviate vascular aging.
Interplay between fecundity, sexual and growth selection on the spring phenology of European beech (Fagus sylvatica L.)

Background Plant phenological traits such as the timing of budburst or flowering can evolve on ecological timescales through response to fecundity and viability selection. However, interference with sexual selection may arise from assortative mating. This study aims to investigate how these three components of selection on spring phenology may combine in European beech populations in contrasting environments (high versus low altitude). Methods we monitored the timing of budburst (TBB) in 339 adult beech trees and estimated their fecundity using spatially explicit mating models. Fecundity selection was infered by regressing fecundities on TBB, while sexual selection was inferred by regressing fecundities on mating opportunities (i.e., TBB mismatch). The correlation between mates for flowering time (i.e., assortative mating) was estimated based on paternity analyses. Morever, TBB and growth were surveyed in 3261 seedlings from 40 families grown planted in a common garden, and viability selection was inferred by regressing growth on TBB. Results Overall, directional fecundity selection on female fitness favored trees with earlier TBB. Sexual selection acted only on male fitness through assortative mating favoring trees with mean TBB value (stabilizing selection). In the common garden, early budburst was associated with higher seedling growth. The respective intensities of directional and stabilizing selection varied with the environment: at low altitude, directional selection for earlier phenology was modulated by strong assortative mating and by an interaction effect between TBB an size on female fecundity, whereas at high altitude, directional selection for earlier phenology was reinforced by selection through male fecundity. Discussion This study showed that selection through female fecundity and seedlings growth predominantly selected for earlier TBB, while sexual selection on male fitness through assortative mating modulated this trend. This interplay between fecundity and sexual selection calls for an integrative approach to predict the evolution of spring phenology under a changing climate.
Chimeric Antigen Receptor Macrophages Target and Resorb Amyloid Plaques in a Mouse Model of Alzheimer’s Disease

Substantial evidence suggests a role for immunotherapy in treating Alzheimer’s disease (AD). Several monoclonal antibodies targeting aggregated forms of beta amyloid (Aβ), have been shown to reduce amyloid plaques and in some cases, mitigate cognitive decline in early-stage AD patients. We sought to determine if genetically engineered macrophages could improve the targeting and degradation of amyloid plaques. Chimeric antigen receptor macrophages (CAR-Ms), which show promise as a cancer treatment, are an appealing strategy to enhance target recognition and phagocytosis of amyloid plaques in AD. We genetically engineered macrophages to express a CAR containing the anti-amyloid antibody aducanumab as the external domain and the Fc receptor signaling domain internally. CAR-Ms recognize and degrade Aβ in vitro and on APP/PS1 brain slices ex vivo; however, when injected intrahippocampally, these first-generation CAR-Ms have limited persistence and fail to reduce plaque load. We overcame this limitation by creating CAR-Ms that secrete M-CSF and self-maintain without exogenous cytokines. These CAR-Ms have greater survival in the brain niche, and significantly reduce plaque load locally in vivo. These proof-of-principle studies demonstrate that CAR-Ms, previously only applied to cancer, may be utilized to target and degrade unwanted materials, such as amyloid plaques in the brains of AD mice. Amyloid targeting CAR Macrophages engineered to secrete M-CSF promote their own local survival and expansion while resorbing amyloid plaques in the brains of Alzheimer’s disease APP/PS1 mice, resulting in significant local clearance of amyloid plaques of all sizes.
B RAIN 2GAN: F EATURE - DISENTANGLED NEURAL CODING OF VISUAL PERCEPTION IN THE PRIMATE BRAIN

A challenging goal of neural coding is to characterize the neural representations underlying visual perception. To this end, we analyzed the relationship between multi-unit activity of macaque visual cortex and latent representations of state-of-the-art deep generative models, including feature-disentangled representations of generative adversarial networks (i.e., w -latents of StyleGAN) and language-contrastive representations of latent diffusion networks (i.e., CLIP-latents of Stable Diffusion). A mass univariate neural encoding analysis of the latent representations showed that feature-disentangled representations explain increasingly more variance than the alternative representations over the ventral stream. Subsequently, a multivariate neural decoding analysis of the feature-disentangled representations resulted in state-of-the-art spatiotemporal reconstructions of visual perception. Taken together, our results not only highlight the important role of feature-disentanglement in shaping high-level neural representations underlying visual perception but also serve as an important benchmark for the future of neural coding.
Generalised Kalman–Yakubovich–Popov lemma with its application in finite frequency positive realness control for two-dimensional continuous-discrete systems in the Roesser model form

This study is concerned with the problem of generalised Kalman–Yakubovich–Popov (GKYP) lemma and its application to two-dimensional (2D) continuous-discrete systems described by Roesser model. On the basis of the feature of states in the system, a rectangular finite frequency range is characterised by a linear matrix inequality and then combined with 𝒮-procedure, the GKYP lemma is developed for 2D continuous-discrete systems in Roesser model. As special cases of this lemma, 2D continuous-discrete case finite frequency bounded realness and positive realness are investigated as well. Furthermore, the finite frequency 2D positive realness control problem via state-feedback controllers are considered based on the developed lemma. Finally, numerical examples are given to illustrate the effectiveness of the proposed method.
Optimization of irrigation and evaluation of consumptive water use efficiency for rabi pigeonpea {Cajanus cajan (L) Millsp}

Irrigated pigeonpea is a cash crop growing in rabi season in the South Gujarat to overcome the water logging problem occurred during kharif Season. Ascending irrigation levels progressively increased the grain yield without altering the harvest index but the significant increase occurred upto 0.30 IW/CPE ratio. The percentage increase in grain yield over control was 128.45 and 135.88 under 0.30 and 0.60 IW/CPE ratio, respectively. The consumptive use (CU) of water increased with increasing irrigation levels, reaching as high as 323.50 mm under 0.60 IW/CPE ratio. Water use efficiency (WUE), on the other hand decreased with ascending irrigation regimes but more sharply beyond 0.30 IW/CPE ratio.
Revisiting Aire and tissue-restricted antigens at single-cell resolution

The thymus is a highly specialized organ that plays an indispensable role in the establishment of self-tolerance, a process characterized by the “education” of developing T-cells. To provide competent T-cells tolerant to self-antigens, medullary thymic epithelial cells (mTECs) orchestrate negative selection by ectopically expressing a wide range of genes, including various tissue-restricted antigens (TRAs). Notably, recent advancements in the high-throughput single-cell analysis have revealed remarkable heterogeneity in mTECs, giving us important clues for dissecting the mechanisms underlying TRA expression. We overview how recent single-cell studies have furthered our understanding of mTECs, with a focus on the role of Aire in inducing mTEC heterogeneity to encompass TRAs.
Time-dependent upwelling in the tropical lower stratosphere estimated from the zonal-mean momentum budget

Dynamical variability in the extratropical stratosphere occurs on a broad range of timescales, from daily to seasonal. Extratropical wave transience is correlated with variations in the mean meridional (Brewer‐Dobson) circulation that links the Tropics and the extratropics. In this study, the variability of observed temperature and calculated vertical velocity in the tropical lower stratosphere is examined to isolate the imprint of forcing by extratropical waves. The influence of the waves is quantified by estimating zonal-mean tropical upwelling from the zonal-mean momentum balance on a daily basis; a large fraction of the variance of tropical upwelling occurs at periods of 10‐40 days, forced by transient waves. In addition, significant coherence is found between calculated upwelling and observed temperatures in the tropical lower stratosphere on weekly to seasonal timescales. This relationship is quantitatively consistent with simple thermodynamic balance, and suggests that the large annual cycle of temperature near the tropical tropopause is mainly a result of the relatively long radiative timescales in that region. The results indicate that EP flux divergence due to extratropical waves is a major determinant of zonal-mean temperatures in the tropical lower stratosphere.
Naproxen chemoprevention induces proliferation of cytotoxic lymphocytes in Lynch Syndrome colorectal mucosa

Background Recent clinical trial data from Lynch Syndrome (LS) carriers demonstrated that naproxen administered for 6-months is a safe primary chemoprevention that promotes activation of different resident immune cell types without increasing lymphoid cellularity. While intriguing, the precise immune cell types enriched by naproxen remained unanswered. Here, we have utilized cutting-edge technology to elucidate the immune cell types activated by naproxen in mucosal tissue of LS patients. Methods Normal colorectal mucosa samples (pre- and post-treatment) from a subset of patients enrolled in the randomized and placebo-controlled ‘Naproxen Study’ were obtained and subjected to a tissue microarray for image mass cytometry (IMC) analysis. IMC data was processed using tissue segmentation and functional markers to ascertain cell type abundance. Computational outputs were then used to quantitatively compare immune cell abundance in pre- and post-naproxen specimens. Results Using data-driven exploration, unsupervised clustering identified four populations of immune cell types with statistically significant changes between treatment and control groups. These four populations collectively describe a unique cell population of proliferating lymphocytes within mucosal samples from LS patients exposed to naproxen. Conclusions Our findings show that daily exposure of naproxen promotes T-cell proliferation in the colonic mucosa, which paves way for developing combination of immunoprevention strategies including naproxen for LS patients.
Edwardsiella piscicida infection reshapes the intestinal microbiome and metabolome of big-belly seahorses: mechanistic insights of synergistic actions of virulence factors

Uncovering the mechanism underlying the pathogenesis of Edwardsiella piscicida-induced enteritis is essential for global aquaculture. In the present study, we identified E. piscicida as a lethal pathogen of the big-belly seahorse (Hippocampus abdominalis) and revealed its pathogenic pattern and characteristics by updating our established bacterial enteritis model and evaluation system. Conjoint analysis of metagenomic and metabolomic data showed that 15 core virulence factors could mutually coordinate the remodeling of intestinal microorganisms and host metabolism and induce enteritis in the big-belly seahorse. Specifically, the Flagella, Type IV pili, and Lap could significantly increase the activities of the representative functional pathways of both flagella assembly and bacterial chemotaxis in the intestinal microbiota (P < 0.01) to promote pathogen motility, adherence, and invasion. Legiobactin, IraAB, and Hpt could increase ABC transporter activity (P < 0.01) to compete for host nutrition and promote self-replication. Capsule1, HP-NAP, and FarAB could help the pathogen to avoid phagocytosis. Upon entering epithelial cells and phagocytes, Bsa T3SS and Dot/Icm could significantly increase bacterial secretion system activity (P < 0.01) to promote the intracellular survival and replication of the pathogen and the subsequent invasion of the neighboring tissues. Finally, LPS3 could significantly increase lipopolysaccharide biosynthesis (P < 0.01) to release toxins and kill the host. Throughout the pathogenic process, BopD, PhoP, and BfmRS significantly activated the two-component system (P < 0.01) to coordinate with other VFs to promote deep invasion. In addition, the levels of seven key metabolic biomarkers, Taurine, L-Proline, Uridine, L-Glutamate, Glutathione, Xanthosine, and L-Malic acid, significantly decreased (P < 0.01), and they can be used for characterizing E. piscicida infection. Overall, the present study systematically revealed how a combination of virulence factors mediate E. piscicida-induced enteritis in fish for the first time, providing a theoretical reference for preventing and controlling this disease in the aquaculture of seahorses and other fishes.
Characteristics of tobacco use among secondary school students: a cross-sectional study in a school in Valencia, Spain

Introduction Cigarette smoking is a significant public health problem, and it is essential to work actively with young people to limit the incorporation of this addiction. This study aimed to identify characteristics associated with tobacco use in adolescents in a real setting. Methods Epidemiologic, cross-sectional study including secondary school students aged 12–17 years in the 1st, 2nd, and 3rd grades of “Joan Fuster High School” in the city of Sueca, Valencia (Spain). An anonymous, self-administered questionnaire was used to collect data on demographics, cigarette smoking history, alcohol consumption, nicotine dependence, and exposure to parental cigarette smoking. Results The final sample of individuals surveyed included 306 students (50.6% females) with a median age of 13 years. The prevalence of cigarette smoking was 11.8% (13.5% in females and 9.9% in males). The mean age of cigarette smoking onset was 12.7 ± 1.6 years. Ninety-three students (30.4%) were repeaters, and 114 (37.3%) reported alcohol consumption. Significant factors associated with tobacco use were being a repeater (odds ratio [OR] 4.19, 95% confidence interval [CI] 1.75–10.55, p = 0.002), alcohol consumption (OR 4.06, 95% CI 1.75–10.15, p = 0.002) and parental cigarette smoking (OR 3.76, 95% CI 1.52–10.74, p = 0.007). Discussion An operational profile of features associated with tobacco consumption was identified in the presence of parental cigarette smoking, alcohol consumption, and poor academic performance. Consideration of these factors could be useful in the operational design of cigarette smoking cessation interventions for young people in a context where there is a great need for better prevention and control of cigarette smoking.
Clinical, imaging features and outcomes of patients with anti-GFAP antibodies: a retrospective study

Objective To evaluate and compare the clinical features, imaging, overlapping antibodies, and prognosis of pediatric and adult patients with anti-GFAP antibodies. Methods This study included 59 patients with anti-GFAP antibodies (28 females and 31 males) who were admitted between December 2019 and September 2022. Results Out of 59 patients, 18 were children (under 18 years old), and 31 were adults. The overall cohort’s median age at onset was 32 years old, 7 for children, and 42 for adults. There were 23 (41.1%) patients with prodromic infection, 1 (1.7%) patient with a tumor, 29 (53.7%) patients with other non-neurological autoimmune diseases, and 17 (22.8%) patients with hyponatremia. Fourteen (23.7%) patients had multiple neural autoantibodies, with the AQP4 antibody being the most common. Encephalitis (30.5%) was the most common phenotypic syndrome. Common clinical symptoms included fever (59.3%), headache (47.5%), nausea and vomiting (35.6%), limb weakness (35.6%), and disturbance of consciousness (33.9%). Brain MRI lesions were primarily located in the cortex/subcortex (37.3%), brainstem (27.1%), thalamus (23.7%), and basal ganglia (22.0%). Spinal cord MRI lesions often involved the cervical and thoracic spinal cord. There was no statistically significant difference in the MRI lesion site between children and adults. Out of 58 patients, 47 (81.0%) had a monophasic course, and 4 died. The last follow-up showed that 41/58 (80.7%) patients had an improved functional outcome (mRS <3), and children were more likely than adults to have no residual disability symptoms (p = 0.001). Conclusion There was no statistically significant difference in clinical symptoms and imaging findings between children and adult patients with anti-GFAP antibodies; Patients with anti-GFAP antibodies may present with normal MRI findings or delayed MRI abnormalities, and patients with overlapping antibodies were common. Most patients had monophasic courses, and those with overlapping antibodies were more likely to relapse. Children were more likely than adults to have no disability. Finally, we hypothesize that the presence of anti-GFAP antibodies is a non-specific witness of inflammation.