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Alternative splicing (AS) plays crucial roles in regulating various biological processes in plants. However, the genetic mechanisms underlying AS and its role in controlling important agronomic traits in rice (Oryza sativa) remain poorly understood. In this study, we explored AS in rice leaves and panicles using the rice minicore collection. Our analysis revealed a high level of transcript isoform diversity, with approximately one fifth of potential isoforms acting as major transcripts in both tissues. Regarding the genetic mechanism of AS, we found that the splicing of 833 genes in the leaf and 1,230 genes in the panicle was affected by cis-genetic variation. Twenty-one percent of these AS events could only be explained by large structural variations. Approximately 77.5% of genes with significant splicing quantitative trait loci (sGenes) exhibited tissue-specific regulation, and AS can cause 26.9% (leaf) and 23.6% (panicle) of sGenes to have altered, lost or gained functional domains. Additionally, through splicing-phenotype association analysis, we identified phosphate-starvation induced RING-type E3 ligase (OsPIE1; LOC_Os01g72480), whose splicing ratio was significantly associated with plant height. In summary, this study provides an understanding of AS in rice and its contribution to the regulation of important agronomic traits.
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Detailed knowledge of the genetic variations in diverse crop populations forms the basis for genetic crop improvement and gene functional studies. In the present study, we analyzed a large rice population with a total of 10 548 accessions to construct a rice super-population variation map (RSPVM), consisting of 54 378 986 single nucleotide polymorphisms, 11 119 947 insertion/deletion mutations and 184 736 presence/absence variations. Assessment of variation detection efficiency for different population sizes revealed a sharp increase of all types of variation as the population size increased and a gradual saturation of that after the population size reached 10 000. Variant frequency analysis indicated that â¼90% of the obtained variants were rare, and would therefore likely be difficult to detect in a relatively small population. Among the rare variants, only 2.7% were predicted to be deleterious. Population structure, genetic diversity and gene functional polymorphism of this large population were evaluated based on different subsets of RSPVM, demonstrating the great potential of RSPVM for use in downstream applications. Our study provides both a rich genetic basis for understanding natural rice variations and a powerful tool for exploiting great potential of rare variants in future rice research, including population genetics and functional genomics.
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Variación Genética , Oryza , Genética de Población , Genómica , Oryza/genética , Polimorfismo de Nucleótido SimpleRESUMEN
Rice (Oryza sativa) is a significant crop worldwide with a genome shaped by various evolutionary factors. Rice centromeres are crucial for chromosome segregation, and contain some unreported genes. Due to the diverse and complex centromere region, a comprehensive understanding of rice centromere structure and function at the population level is needed. We constructed a high-quality centromere map based on the rice super pan-genome consisting of a 251-accession panel comprising both cultivated and wild species of Asian and African rice. We showed that rice centromeres have diverse satellite repeat CentO, which vary across chromosomes and subpopulations, reflecting their distinct evolutionary patterns. We also revealed that long terminal repeats (LTRs), especially young Gypsy-type LTRs, are abundant in the peripheral CentO-enriched regions and drive rice centromere expansion and evolution. Furthermore, high-quality genome assembly and complete telomere-to-telomere (T2T) reference genome enable us to obtain more centromeric genome information despite mapping and cloning of centromere genes being challenging. We investigated the association between structural variations and gene expression in the rice centromere. A centromere gene, OsMAB, which positively regulates rice tiller number, was further confirmed by expression quantitative trait loci, haplotype analysis and clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein 9 methods. By revealing the new insights into the evolutionary patterns and biological roles of rice centromeres, our finding will facilitate future research on centromere biology and crop improvement.
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ADN Satélite , Oryza , ADN Satélite/metabolismo , Oryza/genética , Oryza/metabolismo , Secuencia de Bases , Centrómero/genética , Genoma de Planta/genéticaRESUMEN
Continuously increasing global temperatures present great challenges to food security. Grain size, one of the critical components determining grain yield in rice (Oryza sativa L.), is a prime target for genetic breeding. Thus, there is an immediate need for genetic improvement in rice to maintain grain yield under heat stress. However, quantitative trait loci (QTLs) endowing heat stress tolerance and grain size in rice are extremely rare. Here, we identified a novel negative regulator with pleiotropic effects, Thermo-Tolerance and grain Length 1 (TTL1), from the super pan-genomic and transcriptomic data. Loss-of-function mutations in TTL1 enhanced heat tolerance, and caused an increase in grain size by coordinating cell expansion and proliferation. TTL1 was shown to function as a transcriptional regulator and localized to the nucleus and cell membrane. Furthermore, haplotype analysis showed that hapL and hapS of TTL1 were obviously correlated with variations of thermotolerance and grain size in a core collection of cultivars. Genome evolution analysis of available rice germplasms suggested that TTL1 was selected during domestication of the indica and japonica rice subspecies, but still had much breeding potential for increasing grain length and thermotolerance. These findings provide insights into TTL1 as a novel potential target for the development of high-yield and thermotolerant rice varieties.
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Oryza , Termotolerancia , Oryza/genética , Termotolerancia/genética , Fenotipo , Fitomejoramiento , Grano Comestible/genéticaRESUMEN
This study identified literatures from the Web of Science Core Collection on the application of artificial intelligence in wastewater treatment from 2011 to 2022, through bibliometrics, to summarize achievements and capture the scientific and technological progress. The number of papers published is on the rise, and especially, the number of papers issued after 2018 has increased sharply, with China contributing the most in this regard, followed by the US, Iran and India. The University of Tehran has the largest number of papers, WATER is the most published journal, and Nasr M has the largest number of articles. Collaborative network has been developed mainly through cooperation between European countries, China and the US. Remote sensing in developing countries needs to be further integrated with water quality monitoring programs. It is worth noting that artificial neural network is a research hotspot in recent years. Through keyword clustering analysis, 'machine learning' and 'deep learning' are hot keywords that have emerged since 2019. The use of neural networks for predicting the effectiveness of treatment of difficult to degrade wastewater is a future research trend. The rapid advancement of deep learning provides the opportunity to build automated pipeline defect detection systems through image recognition.
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Inteligencia Artificial , Purificación del Agua , Bibliometría , Publicaciones , ChinaRESUMEN
BACKGROUND: Schizophrenia (SZ) and obsessive-compulsive disorder (OCD) share many demographic characteristics and severity of clinical symptoms, genetic risk factors, pathophysiological underpinnings, and brain structure and function. However, the differences in the spontaneous brain activity patterns between the two diseases remain unclear. Here this study aimed to compare the features of intrinsic brain activity in treatment-naive participants with SZ and OCD and to explore the relationship between spontaneous brain activity and the severity of symptoms. METHODS: In this study, 22 treatment-naive participants with SZ, 27 treatment-naive participants with OCD, and sixty healthy controls (HC) underwent a resting-state functional magnetic resonance imaging (fMRI) scan. The amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo) and degree of centrality (DC) were performed to examine the intrinsic brain activity of participants. Additionally, the relationships among spontaneous brain activity, the severity of symptoms, and the duration of illness were explored in SZ and OCD groups. RESULTS: Compared with SZ group and HC group, participants with OCD had significantly higher ALFF in the right angular gyrus and the left middle frontal gyrus/precentral gyrus and significantly lower ALFF in the left superior temporal gyrus/insula/rolandic operculum and the left postcentral gyrus, while there was no significant difference in ALFF between SZ group and HC group. Compared with HC group, lower ALFF in the right supramarginal gyrus/inferior parietal lobule and lower DC in the right lingual gyrus/calcarine fissure and surrounding cortex of the two patient groups, higher ReHo in OCD group and lower ReHo in SZ group in the right angular gyrus/middle occipital gyrus brain region were documented in the present study. DC in SZ group was significantly higher than that in HC group in the right inferior parietal lobule/angular gyrus, while there were no significant DC differences between OCD group and HC group. In addition, ALFF in the left postcentral gyrus were positively correlated with positive subscale score (r = 0.588, P = 0.013) and general psychopathology subscale score (r = 0.488, P = 0.047) respectively on the Positive and Negative Syndrome Scale (PANSS) in SZ group. ALFF in the left superior temporal gyrus/insula/rolandic operculum of participants with OCD were positively correlated with compulsion subscale score (r = 0.463, P = 0.030) on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). The longer the illness duration in SZ group, the smaller the ALFF of the left superior temporal gyrus/insula/rolandic operculum (Rho = 0.-492, P = 0.020). The longer the illness duration in OCD group, the higher the ALFF of the right supramarginal gyrus/inferior parietal lobule (Rho = 0.392, P = 0.043) and the left postcentral gyrus (Rho = 0.385, P = 0.048), and the lower the DC of the right inferior parietal lobule/angular gyrus (Rho = - 0.518, P = 0.006). CONCLUSION: SZ and OCD show some similarities in spontaneous brain activity in parietal and occipital lobes, but exhibit different patterns of spontaneous brain activity in frontal, temporal, parietal, occipital, and insula brain regions, which might imply different underlying neurobiological mechanisms in the two diseases. Compared with OCD, SZ implicates more significant abnormalities in the functional connections among brain regions.
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Trastorno Obsesivo Compulsivo , Esquizofrenia , Encéfalo/diagnóstico por imagen , Mapeo Encefálico , Humanos , Imagen por Resonancia Magnética , Trastorno Obsesivo Compulsivo/diagnóstico por imagen , Esquizofrenia/diagnóstico por imagenRESUMEN
Although thousands of long noncoding RNAs (lncRNAs) have been annotated, only a limited number of them have been functionally characterized. Here, we identified an oncogenic lncRNA, named lnc-UCID (lncRNA up-regulating CDK6 by interacting with DHX9). Lnc-UCID was up-regulated in hepatocellular carcinoma (HCC), and a higher lnc-UCID level was correlated with shorter recurrence-free survival of HCC patients. Both gain-of-function and loss-of function studies revealed that lnc-UCID enhanced cyclin-dependent kinase 6 (CDK6) expression and thereby promoted G1/S transition and cell proliferation. Studies from mouse xenograft models revealed that tumors derived from lnc-UCID-silenced HCC cells had a much smaller size than those from control cells, and intratumoral injection of lnc-UCID small interfering RNA suppressed xenograft growth. Mechanistically, the 850-1030-nt domain of lnc-UCID interacted physically with DEAH (Asp-Glu-Ala-His) box helicase 9 (DHX9), an RNA helicase. On the other hand, DHX9 post-transcriptionally suppressed CDK6 expression by binding to the 3'-untranslated region (3'UTR) of CDK6 mRNA. Further investigation disclosed that lnc-UCID enhanced CDK6 expression by competitively binding to DHX9 and sequestering DHX9 from CDK6-3'UTR. In an attempt to explore the mechanisms responsible for lnc-UCID up-regulation in HCC, we found that the lnc-UCID gene was frequently amplified in HCC. Furthermore, miR-148a, whose down-regulation was associated with an increase of lnc-UCID in HCC, could bind lnc-UCID and inhibit its expression. Conclusion: Up-regulation of lnc-UCID, which may result from amplification of its gene locus and down-regulation of miR-148a, can promote HCC growth by preventing the interaction of DHX9 with CDK6 and subsequently enhancing CDK6 expression. These findings provide insights into the biological functions of lncRNAs, the regulatory network of cell cycle control, and the mechanisms of HCC development, which may be exploited for anticancer therapy.
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Carcinoma Hepatocelular/metabolismo , Quinasa 6 Dependiente de la Ciclina/metabolismo , ARN Helicasas DEAD-box/metabolismo , Neoplasias Hepáticas/metabolismo , MicroARNs/metabolismo , Proteínas de Neoplasias/metabolismo , Animales , Carcinoma Hepatocelular/etiología , Ciclo Celular , Células HEK293 , Células Hep G2 , Humanos , Neoplasias Hepáticas/etiología , Ratones , ARN Largo no Codificante/metabolismoRESUMEN
The somatic embryogenesis (SE) process of plants is regulated by exogenous hormones. During the SE, different genes sensitively respond to hormone signals through complex regulatory networks to exhibit plant totipotency. When cultured in indole-3-butyric acid (IBA) concentration gradient medium supplemented with 0 mg dm-3, 0.025 mg dm-3, and 0.05 mg dm-3 IBA, the callus differentiation rate first increased then decreased in cotton. To characterize the molecular basis of IBA-induced regulating SE, transcriptome analysis was conducted on embryogenic redifferentiation. Upon the examination of the IBA's embryogenic inductive effect, it was revealed that pathways related to plant hormone signal transduction and alcohol degradation were significantly enriched in the embryogenic responsive stage (5 days). The photosynthesis, alcohol metabolism and cell cycle pathways were specifically regulated in the pre-embryonic initial period (20 days). Upon the effect of the IBA dose, in the embryogenic responsive stage (5 days), the metabolism of xenobiotics by the cytochrome P450 pathway and secondary metabolism pathways of steroid, flavonoid, and anthocyanin biosynthesis were significantly enriched. The phenylpropanoid, brassinosteroid, and anthocyanin biosynthesis pathways were specifically associated in the pre-embryonic initial period (20 days). At different developmental stages of embryogenic induction, photosynthesis, flavonoid biosynthesis, phenylpropanoid biosynthesis, mitogen-activated protein kinase (MAPK) signaling, xenobiotics metabolism by cytochrome P450, and brassinosteroid biosynthesis pathways were enriched at low a IBA concentration. Meanwhile, at high IBA concentration, the carbon metabolism, alcohol degradation, circadian rhythm and biosynthesis of amino acids pathways were significantly enriched. The results reveal that complex regulating pathways participate in the process of IBA-induced redifferentiation in cotton somatic embryogenesis. In addition, collections of potential essential signaling and regulatory genes responsible for dose IBA-induced efficient embryogenic redifferentiation were identified. Quantitative real-time PCR (qRT-PCR) was performed on the candidate genes with different expression patterns, and the results are basically consistent with the RNA-seq data. The results suggest that the complicated and concerted IBA-induced mechanisms involving multiple cellular pathways are responsible for dose-dependent plant growth regulator-induced SE. This report represents a systematic study and provides new insight into molecular signaling and regulatory basis underlying the process of dose IBA-induced embryogenic redifferentiation during SE.
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Diferenciación Celular/genética , Perfilación de la Expresión Génica , Regulación de la Expresión Génica de las Plantas , Gossypium/embriología , Gossypium/genética , Indoles/farmacología , Empalme Alternativo/genética , Diferenciación Celular/efectos de los fármacos , Cromosomas de las Plantas/genética , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Regulación de la Expresión Génica de las Plantas/efectos de los fármacos , Gossypium/efectos de los fármacos , Cinetina/farmacología , Redes y Vías Metabólicas/efectos de los fármacos , Redes y Vías Metabólicas/genética , Anotación de Secuencia Molecular , Reproducibilidad de los Resultados , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genéticaRESUMEN
Plant regeneration via somatic embryogenesis (SE) is a key step during genetic engineering. In the current study, integrated widely targeted metabolomics and RNA sequencing were performed to investigate the dynamic metabolic and transcriptional profiling of cotton SE. Our data revealed that a total of 581 metabolites were present in nonembryogenic staged calli (NEC), primary embryogenic calli (PEC), and initiation staged globular embryos (GE). Of the differentially accumulated metabolites (DAMs), nucleotides, and lipids were specifically accumulated during embryogenic differentiation, whereas flavones and hydroxycinnamoyl derivatives were accumulated during somatic embryo development. Additionally, metabolites related to purine metabolism were significantly enriched in PEC vs. NEC, whereas in GE vs. PEC, DAMs were remarkably associated with flavonoid biosynthesis. An association analysis of the metabolome and transcriptome data indicated that purine metabolism and flavonoid biosynthesis were co-mapped based on the Kyoto encyclopedia of genes and genomes (KEGG) database. Moreover, purine metabolism-related genes associated with signal recognition, transcription, stress, and lipid binding were significantly upregulated. Moreover, several classic somatic embryogenesis (SE) genes were highly correlated with their corresponding metabolites that were involved in purine metabolism and flavonoid biosynthesis. The current study identified a series of potential metabolites and corresponding genes responsible for SE transdifferentiation, which provides a valuable foundation for a deeper understanding of the regulatory mechanisms underlying cell totipotency at the molecular and biochemical levels.
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Flavonoides/metabolismo , Gossypium/metabolismo , Purinas/metabolismo , Transdiferenciación Celular , Regulación de la Expresión Génica de las Plantas/genética , Gossypium/genética , Metaboloma/genética , Metaboloma/fisiología , Transcriptoma/genéticaRESUMEN
AIMS: To prospectively study the surgical outcomes of unilateral anterior temporal lobectomy (ATL) in patients with intractable bilateral temporal lobe epilepsy (TLE) as well as two-staged contralateral hippocampal stimulation in patients after failed unilateral ATL. METHODS: Eighteen carefully selected patients with bilateral TLE underwent unilateral ATL. Five cases with failed ATL underwent two-staged contralateral hippocampal stimulation. Seizure control and changes in intelligence quotient (IQ), memory quotient, and quality of life (QOL) were analyzed 2-5 years after treatment. RESULTS: In the patients with unilateral ATL, the percentages seizure free were 55.6% (10/18), 50.0% (9/18), and 44.4% (4/9) at the 1-, 2-, and 5-year follow-up visits, respectively. There were significant difference in seizure control between the patients with unilateral ATL and the 12 cases in the medication group. Significant differences were also found in changes in the patients' QOL and full-scale IQ at the 2-year follow-up between the surgical and medication groups. Five patients who underwent contralateral hippocampal stimulation after failed unilateral ATL experienced 80-100% seizure reductions, and 80% were seizure free 1 year after hippocampal stimulation. CONCLUSION: Unilateral ATL provides good seizure control and does not cause serious memory or IQ injury in carefully selected patients with true bilateral TLE. Contralateral hippocampal stimulation is a useful approach for patients who experience unilateral ATL failure.
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Lobectomía Temporal Anterior/métodos , Epilepsia del Lóbulo Temporal/cirugía , Hipocampo/cirugía , Lóbulo Temporal/cirugía , Adolescente , Adulto , Niño , Epilepsia del Lóbulo Temporal/diagnóstico por imagen , Femenino , Estudios de Seguimiento , Hipocampo/diagnóstico por imagen , Humanos , Masculino , Estudios Prospectivos , Lóbulo Temporal/diagnóstico por imagen , Insuficiencia del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: The first prospective trial for resective surgery combined with corpus callosotomy (CCT) was performed to investigate the outcomes of the combined surgery in children with Lennox-Gastaut syndrome (LGS) without focal lesion on brain MRI. METHODS: This study enrolled 68 children with LGS and without focal lesion on brain MRI, of which 25 received medicine (medicine group) and 43 underwent surgery (surgery group), including 20 with exclusively resective surgery (exclusively resection subgroup) and 23 with resective surgery combined with CCT (combined CCT subgroup). All patients were followed for 3-5 years. RESULTS: Significant differences in seizure control were observed between the medicine group and the exclusively resection subgroup and combined CCT subgroup at the 1-year, 3-year, and 5-year follow-ups. There was a trend that the children with resection combined with CCT had better seizure control than those with exclusively resection at the three follow-ups, but this could not be verified by the statistical method used. Furthermore, significant differences were not observed in seizure control between children with different MRI findings, age at surgery, or pathology in the surgery group. The percentage of long-term seizure-free did not remain as high as the percentage of early stage seizure-free at 1-year follow-up. However, the children with combined CCT surgery demonstrated more postoperative improvement than the children with resective surgery alone based on the mean QOL score (10.78 vs. 5.75, p = 0.0152) and full-scale IQ (7.91 vs. 4.55, p = 0.0446). CONCLUSIONS: Resective surgery combined with CCT can provide favorable seizure control and obvious improvements in QOL and IQ in children with LGS. This combined approach can be performed in carefully selected LGS children without focal lesions and can localize the epileptogenic zone following a comprehensive preoperative evaluation.
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Cuerpo Calloso/cirugía , Síndrome de Lennox-Gastaut/cirugía , Psicocirugía/efectos adversos , Adolescente , Niño , Cuerpo Calloso/diagnóstico por imagen , Femenino , Humanos , Síndrome de Lennox-Gastaut/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Complicaciones Posoperatorias , Psicocirugía/métodosRESUMEN
OBJECTIVE: To explore the effects of different doses of 5-HT2A/2CR agonist or 5-HT2AR antagonist on genioglossus discharge in chronic intermittent hypoxia rats. METHODS: Thirty adult male Sprague-Dawley rats, each 180-200 g, were randomly divided into the normoxia group (group A, n=5) and the chronic intermittent hypoxia group (CIH group, n=25) by the random number table. The rats in the CIH group were fed in the intermittent hypoxia animal chambers, while the normoxia control group was placed in the normoxia animal chambers for 8 h per day for 4 consecutive weeks. After 28 days, 5 min×3 times of stimulation with acute intermittent hypoxia (AIH) were given and the genioglossus muscle activity were then recorded and compared before and after intravenous injection of saline (group B, n=5), the 5-HT2A/2CR agonist 30 µg/3 µl (group C, n=5) or 50 µg/5 µl group (group D, n=5), 5-HT2AR antagonist 10 µg/1 µl (group E, n=5) or 70 µg/7 µl (group F, n=5). RESULTS: The average peak amplitude in 60 min of genioglossus muscle activity in the CIH saline control group (group B) was significantly higher than that in the normoxia group (group A), while the genioglossus discharge in the 2 groups were (42.29 ± 1.78) µV, (25.38 ± 0.89) µV respectively (P<0.01). The 5-HT2A/2CR agonist (30 µg/3 µl or 50 µg/5 µl) caused the amplitude of genioglossus muscle activity firstly to increase and then to decrease, with the peak changes showing statistical difference (P<0.05). 10 µg/1 µl 5-HT2AR antagonist did not influence genioglossus muscle activity (P>0.05), however, after intravenous injection of 70 µg/7 µl 5-HT2AR antagonist, the amplitude of genioglossus discharge firstly decreased and then gradually returned to baseline level, the difference being statistically significant, P<0.01. CONCLUSION: Our results indicate that CIH strengthens the genioglossus discharge in CIH rats. The 5-HT2A/2CR agonist can strengthen the genioglossus discharge but the 5-HT2AR antagonists can weaken the effect, both of which have dose-related effects.
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Hipoxia , Animales , Ligandos , Masculino , Músculo Esquelético , Ratas , Ratas Sprague-Dawley , Agonistas del Receptor de Serotonina 5-HT2 , LenguaRESUMEN
3D SHINKEI neurography is a new sequence for imaging the peripheral nerves. The study aims at assessing traumatic brachial plexus injury using this sequence. Fifty-eight patients with suspected trauma induced brachial plexus injury underwent MR neurography (MRN) imaging in 3D SHINKEI sequence at 3 T. Surgery and intraoperative somatosensory evoked potentials or clinical follow-up results were used as the reference standard. MRN, surgery and electromyography (EMG) findings were recorded at four levels of the brachial plexus-roots, trunks, cords and branches. Fifty-eight patients had pre- or postganglionic injury. The C5-C6 nerve postganglionic segment was the most common (average 42%) among the postganglionic injuries detected by 3D SHINKEI MRN. The diagnostic accuracy (83.75%) and the specificity (90.30%) of MRN higher than that of EMG (p < 0.001). There was no significant difference in the diagnostic sensitivity of MRN compared with EMG (p > 0.05). Eighteen patients with brachial plexus injury underwent surgical exploration after MRN examination and the correlation between MRN and surgery was 66.7%. Due to the high diagnostic accuracy and specificity, 3D SHINKEI MRN can comprehensively display the traumatic brachial plexus injury. This sequence has great potential in the accurate diagnosis of traumatic brachial plexus injury.
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Neuropatías del Plexo Braquial , Plexo Braquial , Humanos , Neuropatías del Plexo Braquial/diagnóstico por imagen , Neuropatías del Plexo Braquial/cirugía , Imagen por Resonancia Magnética/métodos , Plexo Braquial/lesiones , Nervios Periféricos , Estudios ProspectivosRESUMEN
BACKGROUND: The renal sympathetic nervous system modulates systemic blood pressure, cardiac performance, and renal function. Pathological increases in renal sympathetic nerve activity contribute to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). We investigated the effects of renal sympathetic denervation performed at early or late stages of HFpEF progression. METHODS AND RESULTS: Male ZSF1 obese rats were subjected to radiofrequency renal denervation (RF-RDN) or sham procedure at either 8 weeks or 20 weeks of age and assessed for cardiovascular function, exercise capacity, and cardiorenal fibrosis. Renal norepinephrine and renal nerve tyrosine hydroxylase staining were performed to quantify denervation following RF-RDN. In addition, renal injury, oxidative stress, inflammation, and profibrotic biomarkers were evaluated to determine pathways associated with RDN. RF-RDN significantly reduced renal norepinephrine and tyrosine hydroxylase content in both study cohorts. RF-RDN therapy performed at 8 weeks of age attenuated cardiac dysfunction, reduced cardiorenal fibrosis, and improved endothelial-dependent vascular reactivity. These improvements were associated with reductions in renal injury markers, expression of renal NLR family pyrin domain containing 3/interleukin 1ß, and expression of profibrotic mediators. RF-RDN failed to exert beneficial effects when administered in the 20-week-old HFpEF cohort. CONCLUSIONS: Our data demonstrate that early RF-RDN therapy protects against HFpEF disease progression in part due to the attenuation of renal fibrosis and inflammation. In contrast, the renoprotective and left ventricular functional improvements were lost when RF-RDN was performed in later HFpEF progression. These results suggest that RDN may be a viable treatment option for HFpEF during the early stages of this systemic inflammatory disease.
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Insuficiencia Cardíaca , Humanos , Masculino , Ratas , Animales , Insuficiencia Cardíaca/metabolismo , Volumen Sistólico , Tirosina 3-Monooxigenasa/metabolismo , Riñón/metabolismo , Simpatectomía/métodos , Inflamación/metabolismo , Norepinefrina , Fibrosis , DesnervaciónRESUMEN
BACKGROUND AND PURPOSE: Sodium glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a potent therapy for heart failure with preserved ejection fraction (HFpEF). Hydrogen sulphide (H2S), a well-studied cardioprotective agent, could be beneficial in HFpEF. SGLT2i monotherapy and combination therapy involving an SGLT2i and H2S donor in two preclinical models of cardiometabolic HFpEF was investigated. EXPERIMENTAL APPROACH: Nine-week-old C57BL/6N mice received L-NAME and a 60% high fat diet for five weeks. Mice were then randomized to either control, SGLT2i monotherapy or SGLT2i and H2S donor, SG1002, for five additional weeks. Ten-week-old ZSF1 obese rats were randomized to control, SGLT2i or SGLT2i and SG1002 for 8 weeks. SG1002 monotherapy was investigated in additional animals. Cardiac function (echocardiography and haemodynamics), exercise capacity, glucose handling and multiorgan pathology were monitored during experimental protocols. KEY RESULTS: SGLT2i treatment improved E/e' ratio and treadmill exercise in both models. Combination therapy afforded increases in cardiovascular sulphur bioavailability that coincided with improved left end-diastolic function (E/e' ratio), exercise capacity, metabolic state, cardiorenal fibrosis, and hepatic steatosis. Follow-up studies with SG1002 monotherapy revealed improvements in diastolic function, exercise capacity and multiorgan histopathology. CONCLUSIONS AND IMPLICATIONS: SGLT2i monotherapy remediated pathological complications exhibited by two well-established HFpEF models. Adjunctive H2S therapy resulted in further improvements of cardiometabolic perturbations beyond SGLT2i monotherapy. Follow-up SG1002 monotherapy studies inferred an improved phenotype with combination therapy beyond either monotherapy. These data demonstrate the differing effects of SGLT2i and H2S therapy while also revealing the superior efficacy of the combination therapy in cardiometabolic HFpEF.
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Transposable elements (TEs) are ubiquitous genomic components and hard to study due to being highly repetitive. Here we assembled 232 chromosome-level genomes based on long-read sequencing data. Coupling the 232 genomes with 15 existing assemblies, we developed a pan-TE map comprising both cultivated and wild Asian rice. We detected 177 084 high-quality TE variations and inferred their derived state using outgroups. We found TEs were one source of phenotypic variation during rice domestication and differentiation. We identified 1246 genes whose expression variation was associated with TEs but not single-nucleotide polymorphisms (SNPs), such as OsRbohB, and validated OsRbohB's relative expression activity using a dual-Luciferase (LUC) reporter assays system. Our pan-TE map allowed us to detect multiple novel loci associated with agronomic traits. Collectively, our findings highlight the contributions of TEs to domestication, differentiation and agronomic traits in rice, and there is massive potential for gene cloning and molecular breeding by the high-quality Asian pan-TE map we generated.
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For sessile plants, gene expression plays a pivotal role in responding to salinity stress by activating or suppressing specific genes. However, our knowledge of genetic variations governing gene expression in response to salt stress remains limited in natural germplasm. Through transcriptome analysis of the Global Mini-Core Rice Collection consisting of a panel of 202 accessions, we identified 22 345 and 27 610 expression quantitative trait loci associated with the expression of 7787 and 9361 eGenes under normal and salt-stress conditions, respectively, leveraging the super pan-genome map. Notably, combined with genome-wide association studies, we swiftly pinpointed the potential candidate gene STG5-a major salt-tolerant locus known as qSTS5. Intriguingly, STG5 is required for maintaining Na+/K+ homeostasis by directly regulating the transcription of multiple members of the OsHKT gene family. Our study sheds light on how genetic variants influence the dynamic changes in gene expression responding to salinity stress and provides a valuable resource for the mining of salt-tolerant genes in the future.
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PURPOSE: Outcomes for patients undergoing chemoradiation for cervical cancer are dependent on adherence to radiation therapy (RT). In other diseases, quality of life (QoL) is associated with treatment adherence, but the association between QoL and RT adherence for patients with cervical cancer remains unclear. METHODS AND MATERIALS: This prospective study included patients undergoing RT for cervical cancer from 2017 to 2021 at an urban safety net hospital. The Functional Assessment of Cancer Therapy-Cervical Cancer Version 4 was used to assess QoL based on 5 subscales (physical, functional, social and emotional, and cervical-cancer specific). The survey was administered at radiation consult, then weekly during RT and at follow-up. Patient information was abstracted from the medical record. Radiation nonadherence was defined as missing ≥2 days of external beam RT. The Functional Assessment of Cancer Therapy-Cervical Cancer Version 4 total and subscale scores were compared between adherent and nonadherent patients. Multivariable logistic regression was performed to control for confounding variables. RESULTS: Ninety-three patients were enrolled, completing 522 surveys. Median age at diagnosis was 46 years (interquartile range, 40-51); 76% of patients were Hispanic, and 12% were Black. Only 30% of patients were nonadherent with RT. A psychiatric comorbidity (P = .012) and symptomatic presentation (P = .027) were associated with decreased adherence. Baseline total QoL was higher in treatment-adherent than in nonadherent patients (median, 124.86; range, 48-160; 108.9, 46-150; P = .01). Higher baseline functional and physical subscale scores were associated with adherence (P < .05). Change from baseline to lowest score during treatment in the emotional subscale was also associated with patient adherence (P < .05). In multivariable analysis, higher baseline physical score, baseline total score, and change in emotional subscale score were associated with adherence (P < .05). CONCLUSIONS: Poor QoL during chemoradiation for cervical cancer is associated with missed treatments. Physician assessment of a patient's well-being while they are undergoing RT is of utmost importance to improve adherence to treatment.