RESUMEN

Autoimmune diseases, among the most common disorders of young adults, are mediated by genetic and environmental factors. Although CD4+FOXP3+ regulatory T cells (Tregs) play a central role in preventing autoimmunity, the molecular mechanism underlying their dysfunction is unknown. Here, we performed comprehensive transcriptomic and epigenomic profiling of Tregs in the autoimmune disease multiple sclerosis (MS) to identify critical transcriptional programs regulating human autoimmunity. We found that up-regulation of a primate-specific short isoform of PR domain zinc finger protein 1 (PRDM1-S) induces expression of serum and glucocorticoid-regulated kinase 1 (SGK1) independent from the evolutionarily conserved long PRDM1, which led to destabilization of forkhead box P3 (FOXP3) and Treg dysfunction. This aberrant PRDM1-S/SGK1 axis is shared among other autoimmune diseases. Furthermore, the chromatin landscape profiling in Tregs from individuals with MS revealed enriched activating protein-1 (AP-1)/interferon regulatory factor (IRF) transcription factor binding as candidate upstream regulators of PRDM1-S expression and Treg dysfunction. Our study uncovers a mechanistic model where the evolutionary emergence of PRDM1-S and epigenetic priming of AP-1/IRF may be key drivers of dysfunctional Tregs in autoimmune diseases.

Asunto(s)

RESUMEN

PURPOSE: Although rapid cognitive decline (RCD) is an important unfavorable prognostic factor, not much is known about it, especially in amyloid-negative individuals. The purpose of this study was to investigate risk factors for RCD in amyloid-negative individuals. PATIENTS AND METHODS: We retrospectively enrolled 741 individuals who were either cognitively unimpaired or had early-stage cognitive ability loss and who underwent 18F-florbetaben (FBB) (n = 402) or 18F-flutemetamol (FMM) (n = 339) PET/CT. Based on visual and semiquantitative (SUV ratio [SUVR]-based) analysis, the following amyloid-negative groups were established: visual-negative FBB (n = 232), visual-negative FMM (n = 161), SUVR-negative FBB (n = 104), and SUVR-negative FMM (n = 101). Univariable and multivariable logistic regression analyses were performed for RCD using 5 SUVRs, 5 cortical thicknesses, and 5 neuropsychological domains and clinico-demographic factors. RESULTS: In the amyloid-negative groups, a decline in language function was commonly identified as a significant risk factor for RCD (P = 0.0044 in the visual-negative FBB group, P = 0.0487 in the visual-negative FMM group, P = 0.0031 in the SUVR-negative FBB group, and P = 0.0030 in the SUVR-negative FMM group). In addition, declines in frontal/executive function, frontal SUVR, and parietal SUVR; a longer duration of education; and mild cognitive decline in the amyloid-negative groups were also significant risk factors for RCD. CONCLUSIONS: Even in amyloid-negative individuals without cognitive impairment or with early-stage cognitive ability loss, those with decreased language and frontal/executive functions on neuropsychological testing are at risk of progression to RCD.

RESUMEN

Probabilistic topic modelling has become essential in many types of single-cell data analysis. Based on probabilistic topic assignments in each cell, we identify the latent representation of cellular states. A dictionary matrix, consisting of topic-specific gene frequency vectors, provides interpretable bases to be compared with known cell type-specific marker genes and other pathway annotations. However, fitting a topic model on a large number of cells would require heavy computational resources-specialized computing units, computing time and memory. Here, we present a scalable approximation method customized for single-cell RNA-seq data analysis, termed ASAP, short for Annotating a Single-cell data matrix by Approximate Pseudobulk estimation. Our approach is more accurate than existing methods but requires orders of magnitude less computing time, leaving much lower memory consumption. We also show that our approach is widely applicable for atlas-scale data analysis; our method seamlessly integrates single-cell and bulk data in joint analysis, not requiring additional preprocessing or feature selection steps.

Asunto(s)

RESUMEN

Efficient data processing is heavily reliant on prioritizing specific stimuli and categorizing incoming information. Within human biological systems, dorsal root ganglions (particularly nociceptors situated in the skin) perform a pivotal role in detecting external stimuli. These neurons send warnings to our brain, priming it to anticipate potential harm and prevent injury. In this study, we explore the potential of using a ferroelectric memristor device structured as a metal-ferroelectric-insulator-semiconductor as an artificial nociceptor. The aim of this device is to electrically receive external damage and interpret signals of danger. The TiN/HfAlOx (HAO)/HfSiOx (HSO)/n+ Si configuration of this device replicates the key functions of a biological nociceptor. The emulation includes crucial aspects, such as threshold reactivity, relaxation, no adaptation, and sensitization phenomena known as "allodynia" and "hyperalgesia." Moreover, we propose establishing a connection between nociceptors and synapses by training the Hebbian learning rule. This involves exposing the device to injurious stimuli and using this experience to enhance its responsiveness, replicating synaptic plasticity.

Asunto(s)

RESUMEN

As genomic selection emerges as a promising breeding method for both plants and animals, numerous methods have been introduced and applied to various real and simulated data sets. Research suggests that no single method is universally better than others; rather, performance is highly dependent on the characteristics of the data and the nature of the prediction task. This implies that each method has its strengths and weaknesses. In this study, we exploit this notion and propose a different approach. Rather than comparing multiple methods to determine the best one for a particular study, we advocate combining multiple methods to achieve better performance than each method in isolation. In pursuit of this goal, we introduce and develop a computational method of the stacked generalization within ensemble methods. In this method, the meta-model merges predictions from multiple base models to achieve improved performance. We applied this method to plant and animal data and compared its performance with currently available methods using standard performance metrics. We found that the proposed method yielded a lower or comparable mean squared error in predicting phenotypes compared to the current methods. In addition, the proposed method showed greater resistance to overfitting compared to the current methods. Further analysis included statistical hypothesis testing, which showed that the proposed method outperformed or matched the current methods. In summary, the proposed stacked generalization integrates currently available methods to achieve stable and better performance. In this context, our study provides general recommendations for effective practices in genomic selection.

RESUMEN

This study investigated a novel radioimmunotherapy strategy for targeting tumor angiogenesis. We developed a radiopharmaceutical complex by labeling an anti-adenosine triphosphate synthase (ATPS) monoclonal antibody (mAb) with the radioisotope 177Lu using DOTA as a chelating agent. 177Lu-DOTA-ATPS mAb demonstrated high labeling efficiency (99.0%) and stability in serum. MKN-45 cancer cells exhibited the highest cellular uptake, which could be specifically blocked by unlabeled ATPS mAb. In mice, 177Lu-DOTA-ATPS mAb accumulated significantly in tumors, with a tumor uptake of 16.0 ± 1.5%ID/g on day 7. 177Lu-DOTA-ATPS mAb treatment significantly reduced the viability of MKN-45 cells in a dose-dependent manner. In a xenograft tumor model, this radioimmunotherapy strategy led to substantial tumor growth inhibition (82.8%). Furthermore, combining 177Lu-DOTA-ATPS mAb with sunitinib, an anti-angiogenic drug, enhanced the therapeutic efficacy of sunitinib in the mouse model. Our study successfully developed 177Lu-DOTA-ATPS mAb, a radioimmunotherapy agent targeting tumor blood vessels. This approach demonstrates significant promise for inhibiting tumor growth, both as a single therapy and in combination with other anti-cancer drugs.

RESUMEN

Triptolide is a natural compound in herbal remedies with anti-inflammatory and anti-proliferative properties. We studied its effects on critical signaling processes within the cell, including Notch1 and STAT3 signaling. Our research showed that triptolide reduces cancer cell proliferation by decreasing the expression of downstream targets of these signals. The levels of each signal-related protein and mRNA were analyzed using Western blot and qPCR methods. Interestingly, inhibiting one signal with a single inhibitor alone did not significantly reduce cancer cell proliferation. Instead, MTT assays showed that the simultaneous inhibition of Notch1 and STAT3 signaling reduced cell proliferation. The effect of triptolide was similar to a combination treatment with inhibitors for both signals. When we conducted a study on the impact of triptolide on zebrafish larvae, we found that it inhibited muscle development and interfered with muscle cell proliferation, as evidenced by differences in the staining of myosin heavy chain and F-actin proteins in confocal fluorescence microscopy. Additionally, we noticed that inhibiting a single type of signaling did not lead to any significant muscle defects. This implies that triptolide obstructs multiple signals simultaneously, including Notch1 and STAT3, during muscle development. Chemotherapy is commonly used to treat cancer, but it may cause muscle loss due to drug-related adverse reactions or other complex mechanisms. Our study suggests that anticancer agents like triptolide, inhibiting essential signaling pathways including Notch1 and STAT3 signaling, may cause muscle atrophy through anti-proliferative activity.

Asunto(s)

RESUMEN

Weeds pose multifaceted challenges in rice cultivation, leading to substantial economic losses through reduced yield and poor grain quality. Harnessing the natural genetic diversity in germplasm collections becomes crucial for identifying novel herbicide resistance loci in crops. A comprehensive analysis was conducted on 475 rice accessions from the KRICE depository, assessing their response to TFT (tefuryltrione) and probing the underlying HIS1 (HPPD INHIBITOR SENSITIVE 1) genotypic variations. The HIS1 gene, responsible for detoxifying benzobicyclon (BBC) and imparting broad-spectrum herbicide resistance, holds significant promise in rice breeding. This study explores the genetic landscape of HIS1 within Korean rice collection (KRICE), aiming to unveil genetic variations, haplotype diversity, and evolutionary relationships across diverse rice ecotypes. The indica ecotype showed the highest nucleotide diversity, while the wild and temperate japonica groups exhibited low diversity, hinting at selective sweeps and possible population expansion. Negative Tajima's D values in temperate japonica and wild groups indicate an excess of low-frequency mutations, potentially resulting from selective sweeps. In contrast, with positive Tajima's D values, admixture, indica, and aus groups suggest balancing selection. Furthermore, haplotype analysis uncovered 42 distinct haplotypes within KRICE, with four shared haplotypes between cultivated and wild accessions, four specific to cultivated accessions, and 34 specific to wild types. Phenotypic assessments of these haplotypes revealed that three haplotypes, viz., Hap_1 (predominant in japonica), Hap_2 (predominant in indica), and Hap_3 (specific to indica), displayed significant differences from aus-specific Hap_4 and indica-specific Hap_5. This study offers insights into genetic diversity, selective pressures, and ecotype-specific responses, ultimately paving the way for developing HPPD-inhibiting herbicide-resistant rice cultivars.

Asunto(s)

RESUMEN

The key genes BADH2, GBSS1, GBSS2, and HIS1 regulate the fragrance, starch synthesis, and herbicide resistance in rice. Although the molecular functions of four genes have been investigated in the Oryza sativa species, little is known regarding their evolutionary history in the Oryza genus. Here, we studied the evolution of four focal genes in 10 Oryza species using phylogenetic and syntenic approaches. The HIS1 family underwent several times of tandem duplication events in the Oryza species, resulting in copy number variation ranging from 2 to 7. At most one copy of BADH2, GBSS1, and GBSS2 orthologs were identified in each Oryza species, and gene loss events of BADH2 and GBSS2 were identified in three Oryza species. Gene transfer analysis proposed that the functional roles of GBSS1 and GBSS2 were developed in the Asian and African regions, respectively, and most allelic variations of BADH2 in japonica rice emerged after the divergence between the Asian and African rice groups. These results provide clues to determine the origin and evolution of the key genes in rice breeding as well as valuable information for molecular breeders and scientists to develop efficient strategies to simultaneously improve grain quality and yield potential in rice.

Asunto(s)

RESUMEN

PURPOSE: We aimed to develop deep learning (DL)-based attenuation correction models for Tl-201 myocardial perfusion SPECT (MPS) images and evaluate their clinical feasibility. PATIENTS AND METHODS: We conducted a retrospective study of patients with suspected or known coronary artery disease. We proposed a DL-based image-to-image translation technique to transform non-attenuation-corrected images into CT-based attenuation-corrected (CT AC ) images. The model was trained using a modified U-Net with structural similarity index (SSIM) loss and mean squared error (MSE) loss and compared with other models. Segment-wise analysis using a polar map and visual assessment for the generated attenuation-corrected (GEN AC ) images were also performed to evaluate clinical feasibility. RESULTS: This study comprised 657 men and 328 women (age, 65 ± 11 years). Among the various models, the modified U-Net achieved the highest performance with an average mean absolute error of 0.003, an SSIM of 0.990, and a peak signal-to-noise ratio of 33.658. The performance of the model was not different between the stress and rest datasets. In the segment-wise analysis, the myocardial perfusion of the inferior wall was significantly higher in GEN AC images than in the non-attenuation-corrected images in both the rest and stress test sets ( P < 0.05). In the visual assessment of patients with diaphragmatic attenuation, scores of 4 (similar to CT AC images) or 5 (indistinguishable from CT AC images) were assigned to most GEN AC images (65/68). CONCLUSIONS: Our clinically feasible DL-based attenuation correction models can replace the CT-based method in Tl-201 MPS, and it would be useful in case SPECT/CT is unavailable for MPS.

Asunto(s)

RESUMEN

Molecular quantitative trait loci (QTLs) allow us to understand the biology captured in genome-wide association studies (GWASs). The placenta regulates fetal development and shows sex differences in DNA methylation. We therefore hypothesized that placental methylation QTL (mQTL) explain variation in genetic risk for childhood onset traits, and that effects differ by sex. We analyzed 411 term placentas from two studies and found 49,252 methylation (CpG) sites with mQTL and 2,489 CpG sites with sex-dependent mQTL. All mQTL were enriched in regions that typically affect gene expression in prenatal tissues. All mQTL were also enriched in GWAS results for growth- and immune-related traits, but male- and female-specific mQTL were more enriched than cross-sex mQTL. mQTL colocalized with trait loci at 777 CpG sites, with 216 (28%) specific to males or females. Overall, mQTL specific to male and female placenta capture otherwise overlooked variation in childhood traits.

RESUMEN

Gamma-tocopherol methyltransferase (γ-TMT), a key gene in the vitamin E biosynthesis pathway, significantly influences the accumulation of tocochromanols, thereby determining rice nutritional quality. In our study, we analyzed the γ-TMT gene in 475 Korean rice accessions, uncovering 177 genetic variants, including 138 SNPs and 39 InDels. Notably, two functional SNPs, tmt-E2-28,895,665-G/A and tmt-E4-28,896,689-A/G, were identified, causing substitutions from valine to isoleucine and arginine to glycine, respectively, across 93 accessions. A positive Tajima's D value in the indica group suggests a signature of balancing selection. Haplotype analysis revealed 27 haplotypes, with two shared between cultivated and wild accessions, seven specific to cultivated accessions, and 18 unique to wild types. Further, profiling of vitamin E isomers in 240 accessions and their association with haplotypes revealed that Hap_2, distinguished by an SNP in the 3' UTR (tmt-3UTR-28,897,360-T/A) exhibited significantly lower α-tocopherol (AT), α-tocotrienol (AT3), total tocopherol, and total tocotrienol, but higher γ-tocopherol (GT) in the japonica group. Additionally, in the indica group, Hap_2 showed significantly higher AT, AT3, and total tocopherol, along with lower GT and γ-tocotrienol, compared to Hap_19, Hap_20, and Hap_21. Overall, this study highlights the genetic landscape of γ-TMT and provides a valuable genetic resource for haplotype-based breeding programs aimed at enhancing nutritional profiles.

RESUMEN

This study presents findings indicating that the ferroelectric tunnel junction (FTJ) or resistive random-access memory (RRAM) in one cell can be intentionally selected depending on the application. The HfAlO film annealed at 700 °C shows stable FTJ characteristics and can be converted into RRAM by forming a conductive filament inside the same cell, that is, the process of intentionally forming a conductive filament is the result of defect generation and redistribution, and applying compliance current prior to a hard breakdown event of the dielectric film enables subsequent RRAM operation. The converted RRAM demonstrated good memory performance. Through current-voltage fitting, it was confirmed that the two resistance states of the FTJ and RRAM had different transport mechanisms. In the RRAM, the 1/f noise power of the high-resistance state (HRS) was about ten times higher than that of the low-resistance state (LRS). This is because the noise components increase due to the additional current paths in the HRS. The 1/f noise power according to resistance states in the FTJ was exactly the opposite result from the case of the RRAM. This is because the noise component due to the Poole-Frenkel emission is added to the noise component due to the tunneling current in the LRS. In addition, we confirmed the potentiation and depression characteristics of the two devices and further evaluated the accuracy of pattern recognition through a simulation by considering a dataset from the Modified National Institute of Standards and Technology.

RESUMEN

OBJECTIVE: Fungal balls (FB) are the main form of non-invasive fungal rhinosinusitis found in immunocompetent hosts. Bacterial coinfection affects clinical symptoms. We investigated the sinonasal microbiome and inflammatory profiles in FB and chronic rhinosinusitis (CRS) patients. METHODS: Thirty-three participants were prospectively recruited. Nasal swab samples and sinonasal tissues were collected from controls, and FB and CRS patients. DNA extraction and microbiome analysis using V3-V4 region 16S rRNA sequencing were performed. Inflammatory cytokine levels in the sinonasal tissues, blood eosinophil counts, and serum total IgE were measured. RESULTS: No significant differences were observed in species richness or evenness measures. The phylogenetic tree demonstrated that the FB samples were different from the controls. The sinus bacteria composition differed among the groups. At the phylum level, Firmicutes in FB were significantly depleted compared with those in CRS, while Proteobacteria were more enriched in FB than that in controls and CRS. At the genus level, in FB, Staphylococcus and Corynebacterium were significantly decreased compared to those in the controls. The prevalence of Haemophilus was the highest in FB. Blood eosinophil counts and IL-5 and periostin levels in the sinonasal tissue of the FB group were significantly lower than those in the CRS group. CONCLUSIONS: FB patients had different microbiome compositions and fewer type 2 inflammatory profiles than CRS patients did. However, whether these findings cause FB or result from bacterial and/or fungal infection remains unclear. Further studies are needed to reveal how these differences occur and affect the development of FB and clinical symptoms.

Asunto(s)

RESUMEN

Near-infrared organic light-emitting diodes (NIR OLEDs) have significant potential for wearable phototherapeutic applications because of the unique properties of the OLEDs, including their free-form electronics and the excellent biomedical effects of NIR emission. In spite of their tremendous promise, given that the majority of NIR OLEDs in previous research have relied on the utilization of an intrinsically brittle indium tin oxide (ITO) electrode, their practicality in the field of wearable electronics is inherently constrained. Here, we report wearable and wavelength-tunable NIR OLEDs that employ a high-performance NIR emitter and an innovative architecture by replacing the ITO with a silver (Ag) electrode. The NIR OLEDs permit wavelength tuning of emissions from 700 to 800 nm and afford stable operation even under repeated bending conditions. The NIR OLEDs provide a lowered device temperature of 37.5 °C even during continuous operation under several emission intensities. In vitro experiments were performed with freshly fabricated NIR OLEDs. The outcomes were evaluated against experimental results performed using the same procedure utilizing blue, green, and red OLEDs. When exposed to NIR light irradiation, the promoting effect of cell proliferation surpassed the proliferative responses observed under the influence of visible light irradiation. The proliferation effect of human hair follicle dermal papilla cells is clearly related to the irradiation wavelength and time, thus underscoring the potential of wavelength-tunable NIR OLEDs for efficacious phototherapy. This work will open novel avenues for wearable NIR OLEDs in the field of biomedical application.

RESUMEN

This study presents a preliminary exploration of thermally oxidized TaOx-based memristors and their potential as artificial synapses. Unlike the 10-min annealed devices, which display instability due to current overshoots, the 5-min annealed device exhibits stable resistive switching, retention, and endurance characteristics. Moreover, our memristor showcases synaptic behaviors encompassing potentiation, depression, spike-timing-dependent plasticity, and excitatory postsynaptic currents. This synaptic emulation holds tremendous promise for applications in neuromorphic computing, offering the opportunity to replicate the adaptive learning principles observed in biological synapses. In addition, we evaluate the device's suitability for pattern recognition within a neural network using the modified National Institute of Standards and Technology dataset. Our assessment reveals that the Pt/TaOx/Ta memristor with an oxidized insulator achieves outstanding potential manifested by an accuracy of 93.25% for the identical pulse scheme and an impressive accuracy of 95.42% for the incremental pulse scheme.

RESUMEN

We investigate a synaptic device with short-term memory characteristics using IGZO/SnOx as the switching layer. The thickness and components of each layer are analyzed by using x-ray photoelectron spectroscopy and transmission electron microscopy. The memristor exhibits analog resistive switching and a volatile feature with current decay over time. Moreover, through ten cycles of potentiation and depression, we demonstrate stable conductance modulation, leading to high-accuracy Modified National Institute of Standards and Technology pattern recognition. We effectively emulate the learning system of a biological synapse, including paired-pulse facilitation, spiking-amplitude-dependent plasticity, and spiking-rate-dependent plasticity (SRDP) by pulse trains. Ultimately, 4-bit reservoir computing divided into 16 states is incarnated using a pulse stream considering short-term memory plasticity and decay properties.

RESUMEN

In the domains of wearable electronics, robotics, and the Internet of Things, there is a demand for devices with low power consumption and the capability of multiplex sensing, memory, and learning. Triboelectric nanogenerators (TENGs) offer remarkable versatility in this regard, particularly when integrated with synaptic transistors that mimic biological synapses. However, conventional TENGs, generating only two spikes per cycle, have limitations when used in synaptic devices requiring repetitive high-frequency gating signals to perform various synaptic plasticity functions. Herein, a multi-layered micropatterned TENG (M-TENG) consisting of a polydimethylsiloxane (PDMS) film and a composite film that includes 1H,1H,2H,2H-perfluorooctyltrichlorosilane/BaTiO3 /PDMS are proposed. The M-TENG generates multiple spikes from a single touch by utilizing separate triboelectric charges at the multiple friction layers, along with a contact/separation delay achieved by distinct spacers between layers. This configuration allows the maximum triboelectric output charge of M-TENG to reach up to 7.52 nC, compared to 3.69 nC for a single-layered TENG. Furthermore, by integrating M-TENGs with an organic electrochemical transistor, the spike number multiplication property of M-TENGs is leveraged to demonstrate an artificial synaptic device with low energy consumption. As a proof-of-concept application, a robotic hand is operated through continuous memory training under repeated stimulations, successfully emulating long-term plasticity.

RESUMEN

Genetic variants associated with complex traits are primarily noncoding, and their effects on gene-regulatory activity remain largely uncharacterized. To address this, we profile epigenomic variation of histone mark H3K27ac across 387 brain, heart, muscle and lung samples from Genotype-Tissue Expression (GTEx). We annotate 282 k active regulatory elements (AREs) with tissue-specific activity patterns. We identify 2,436 sex-biased AREs and 5,397 genetically influenced AREs associated with 130 k genetic variants (haQTLs) across tissues. We integrate genetic and epigenomic variation to provide mechanistic insights for disease-associated loci from 55 genome-wide association studies (GWAS), by revealing candidate tissues of action, driver SNPs and impacted AREs. Lastly, we build ARE-gene linking scores based on genetics (gLink scores) and demonstrate their unique ability to prioritize SNP-ARE-gene circuits. Overall, our epigenomic datasets, computational integration and mechanistic predictions provide valuable resources and important insights for understanding the molecular basis of human diseases/traits such as schizophrenia.

Asunto(s)