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1.
Life Sci Alliance ; 7(12)2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-39384430

RESUMEN

Actin is a critical component of the eukaryotic cytoskeleton. In animals, actins undergo unique N-terminal processing by dedicated enzymes resulting in mature acidic and acetylated forms. The final step, N-terminal acetylation, is catalyzed by NAA80 in humans. N-terminal acetylation of actin is crucial for maintaining normal cytoskeletal dynamics and cell motility in human cell lines. However, the physiological impact of actin N-terminal acetylation remains to be fully understood. We developed a zebrafish naa80 knockout model and demonstrated that Naa80 acetylates both muscle and non-muscle actins in vivo. Assays with purified Naa80 revealed a preference for acetylating actin N-termini. Zebrafish lacking actin N-terminal acetylation exhibited normal development, morphology, and behavior. In contrast, humans with pathogenic actin variants can present with hypotonia and hearing impairment. Whereas zebrafish lacking naa80 showed no obvious muscle defects or abnormalities, we observed abnormal inner ear development, small otoliths, and impaired response to sound. In conclusion, we have established that zebrafish Naa80 N-terminally acetylates actins in vitro and in vivo, and that actin N-terminal acetylation is essential for normal hearing.


Asunto(s)
Actinas , Proteínas de Pez Cebra , Pez Cebra , Animales , Humanos , Acetilación , Acetiltransferasas/metabolismo , Acetiltransferasas/genética , Actinas/metabolismo , Audición/fisiología , Pez Cebra/metabolismo , Proteínas de Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética
2.
Acta Neurochir (Wien) ; 166(1): 349, 2024 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-39180559

RESUMEN

BACKGROUND: Ventriculoperitoneal (VP) shunts are commonly used for managing hydrocephalus, with mechanical dysfunction being the most common cause of complications that require revision. A VP shunt placed using a real-time three-dimensional (3D) robotic C-arm navigation system may have better outcomes and fewer complications. METHODS: In this technical note, we introduced the workflow of the use of the real-time 3D robotic C-arm navigation system for ventriculoperitoneal shunting. CONCLUSION: The real-time 3D robotic C-arm can provide a more precise approach to the target. Furthermore, this technique may lower the risk of complications and increase the success rate of shunt placements.


Asunto(s)
Hidrocefalia , Imagenología Tridimensional , Procedimientos Quirúrgicos Robotizados , Derivación Ventriculoperitoneal , Derivación Ventriculoperitoneal/métodos , Derivación Ventriculoperitoneal/instrumentación , Humanos , Hidrocefalia/cirugía , Procedimientos Quirúrgicos Robotizados/métodos , Procedimientos Quirúrgicos Robotizados/instrumentación , Imagenología Tridimensional/métodos , Cirugía Asistida por Computador/métodos
3.
Adv Sci (Weinh) ; : e2401216, 2024 Aug 29.
Artículo en Inglés | MEDLINE | ID: mdl-39206928

RESUMEN

Head-direction (HD) cells are a fundamental component in the hippocampal-entorhinal circuit for spatial navigation and help maintain an internal sense of direction to anchor the orientation in space. A classical HD cell robustly increases its firing rate when the head is oriented toward a specific direction, with each cell tuned to only one direction. Although unidirectional HD cells are reported broadly across multiple brain regions, computation modelling has predicted the existence of multiple equilibrium states of HD network, which has yet to be proven. In this study, a novel HD variant of bipolar HD cells in the medial entorhinal cortex (MEC) are identified that exhibit stable double-peaked directional tuning properties. The bipolar patterns remain stable in the darkness and across environments of distinct geometric shapes. Moreover, bipolar HD cells co-rotate coherently with unipolar HD cells to anchor the external visual cue. The discovery reveals a new spatial cell type of bipolar HD cells, whose unique activity patterns may comprise a potential building block for a sophisticated local neural circuit configuration for the internal representation of direction. These findings may contribute to the understanding of how the brain processes spatial information by shedding light on the role of bipolar HD cells in this process.

4.
Nat Commun ; 15(1): 7239, 2024 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-39174524

RESUMEN

Developmental and epileptic encephalopathies (DEEs) feature altered brain development, developmental delay and seizures, with seizures exacerbating developmental delay. Here we identify a cohort with biallelic variants in DENND5A, encoding a membrane trafficking protein, and develop animal models with phenotypes like the human syndrome. We demonstrate that DENND5A interacts with Pals1/MUPP1, components of the Crumbs apical polarity complex required for symmetrical division of neural progenitor cells. Human induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division with an inherent propensity to differentiate into neurons. These phenotypes result from misalignment of the mitotic spindle in apical neural progenitors. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state, ultimately shortening the period of neurogenesis. This study provides a mechanism for DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families.


Asunto(s)
División Celular , Células Madre Pluripotentes Inducidas , Células-Madre Neurales , Animales , Femenino , Humanos , Masculino , Ratones , Polaridad Celular , Modelos Animales de Enfermedad , Factores de Intercambio de Guanina Nucleótido/metabolismo , Factores de Intercambio de Guanina Nucleótido/genética , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/citología , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Células-Madre Neurales/metabolismo , Células-Madre Neurales/citología , Neurogénesis/genética
5.
Huan Jing Ke Xue ; 45(7): 4014-4022, 2024 Jul 08.
Artículo en Chino | MEDLINE | ID: mdl-39022949

RESUMEN

The influences of landscape pattern on water quality are dependent on spatial-temporal scales. However, the effects of landscape composition, landscape configuration, and landscape slope metrics on seasonal water quality at different spatial scales remain unclear. Based on the total nitrogen, total phosphorus, nitrate-N, and ammonium-N data from 26 sampling sites in the Qingshan Lake watershed, this study coupled landscape pattern analysis, redundancy analysis, and partial redundancy analysis to quantify the spatiotemporal scale effects of landscape pattern on riverine nitrogen (N) and phosphorus (P) concentrations. The results showed that: ① The explanatory ability of landscape pattern at the sub-watershed scale on riverine N and P concentrations was 6.8%-8.4% higher than that at the buffer scale, and this effect was more obvious in the dry season. ② At the sub-watershed scale, the percentage of forestland and the interspersion and juxtaposition degree of residential land had a greater influence on riverine N and P concentrations. At the buffer scale, the slope of farmland and residential land and the aggregation degree of forestland patches were the key factors affecting riverine N and P concentrations. ③ The contribution rate of landscape configuration to riverine N and P concentration variations (20.1%-36.5%) was the highest. The sensitivity of the effect of landscape configuration on riverine N and P concentrations to seasonal changes was the highest, and the effect of landscape slope on riverine N and P concentrations had the highest sensitivity to spatial scale changes. Therefore, landscape pattern-regulated non-point source pollution should be considered from a multi-scale perspective. These results can provide scientific basis for the formulation of landscape pattern optimization measures aiming at non-point source pollution control.

6.
Nat Commun ; 15(1): 5613, 2024 Jul 04.
Artículo en Inglés | MEDLINE | ID: mdl-38965236

RESUMEN

Advancements in CRISPR technology, particularly the development of base editors, revolutionize genetic variant research. When combined with model organisms like zebrafish, base editors significantly accelerate and refine in vivo analysis of genetic variations. However, base editors are restricted by protospacer adjacent motif (PAM) sequences and specific editing windows, hindering their applicability to a broad spectrum of genetic variants. Additionally, base editors can introduce unintended mutations and often exhibit reduced efficiency in living organisms compared to cultured cell lines. Here, we engineer a suite of adenine base editors (ABEs) called ABE-Ultramax (Umax), demonstrating high editing efficiency and low rates of insertions and deletions (indels) in zebrafish. The ABE-Umax suite of editors includes ABEs with shifted, narrowed, or broadened editing windows, reduced bystander mutation frequency, and highly flexible PAM sequence requirements. These advancements have the potential to address previous challenges in disease modeling and advance gene therapy applications.


Asunto(s)
Adenina , Sistemas CRISPR-Cas , Edición Génica , Mutación INDEL , Pez Cebra , Pez Cebra/genética , Animales , Edición Génica/métodos , Adenina/metabolismo , ARN Guía de Sistemas CRISPR-Cas/genética , ARN Guía de Sistemas CRISPR-Cas/metabolismo , Animales Modificados Genéticamente , Alelos
7.
Proc Natl Acad Sci U S A ; 121(25): e2321614121, 2024 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-38857401

RESUMEN

The medial prefrontal cortex (mPFC) is a key brain structure for higher cognitive functions such as decision-making and goal-directed behavior, many of which require awareness of spatial variables including one's current position within the surrounding environment. Although previous studies have reported spatially tuned activities in mPFC during memory-related trajectory, the spatial tuning of mPFC network during freely foraging behavior remains elusive. Here, we reveal geometric border or border-proximal representations from the neural activity of mPFC ensembles during naturally exploring behavior, with both allocentric and egocentric boundary responses. Unlike most of classical border cells in the medial entorhinal cortex (MEC) discharging along a single wall, a large majority of border cells in mPFC fire particularly along four walls. mPFC border cells generate new firing fields to external insert, and remain stable under darkness, across distinct shapes, and in novel environments. In contrast to hippocampal theta entrainment during spatial working memory tasks, mPFC border cells rarely exhibited theta rhythmicity during spontaneous locomotion behavior. These findings reveal spatially modulated activity in mPFC, supporting local computation for cognitive functions involving spatial context and contributing to a broad spatial tuning property of cortical circuits.


Asunto(s)
Corteza Prefrontal , Ritmo Teta , Corteza Prefrontal/fisiología , Corteza Prefrontal/citología , Animales , Ritmo Teta/fisiología , Masculino , Ratones , Corteza Entorrinal/fisiología , Neuronas/fisiología , Hipocampo/fisiología , Memoria Espacial/fisiología , Ratones Endogámicos C57BL , Memoria a Corto Plazo/fisiología
8.
Nucleic Acids Res ; 52(6): 2808-2820, 2024 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-38426933

RESUMEN

Chemical modifications in RNAs play crucial roles in diversifying their structures and regulating numerous biochemical processes. Since the 1990s, several hydrophobic prenyl-modifications have been discovered in various RNAs. Prenyl groups serve as precursors for terpenes and many other biological molecules. The processes of prenylation in different macromolecules have been extensively studied. We introduce here a novel chemical biology toolkit that not only labels i6A, a prenyl-modified RNA residue, by leveraging the unique reactivity of the prenyl group, but also provides a general strategy to incorporate fluorescence functionalities into RNAs for molecular tracking purposes. Our findings revealed that iodine-mediated cyclization reactions of the prenyl group occur rapidly, transforming i6A from a hydrogen-bond acceptor to a donor. Based on this reactivity, we developed an Iodine-Mediated Cyclization and Reverse Transcription (IMCRT) tRNA-seq method, which can profile all nine endogenous tRNAs containing i6A residues in Saccharomyces cerevisiae with single-base resolution. Furthermore, under stress conditions, we observed a decline in i6A levels in budding yeast, accompanied by significant decrease of mutation rate at A37 position. Thus, the IMCRT tRNA-seq method not only permits semi-quantification of i6A levels in tRNAs but also holds potential for transcriptome-wide detection and analysis of various RNA species containing i6A modifications.


Asunto(s)
Isopenteniladenosina , Procesamiento Postranscripcional del ARN , ARN de Transferencia , Yodo , Neopreno , ARN de Transferencia/metabolismo , Saccharomyces cerevisiae , Análisis de Secuencia de ARN
9.
Clin Epigenetics ; 16(1): 42, 2024 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-38491513

RESUMEN

BACKGROUND: Congenital heart disease (CHD) is a prevalent congenital cardiac malformation, which lacks effective early biological diagnosis and intervention. MicroRNAs, as epigenetic regulators of cardiac development, provide potential biomarkers for the diagnosis and treatment of CHD. However, the mechanisms underlying miRNAs-mediated regulation of cardiac development and CHD malformation remain to be further elucidated. This study aimed to explore the function of microRNA-20b-5p (miR-20b-5p) in cardiac development and CHD pathogenesis. METHODS AND RESULTS: miRNA expression profiling identified that miR-20b-5p was significantly downregulated during a 12-day cardiac differentiation of human embryonic stem cells (hESCs), whereas it was markedly upregulated in plasma samples of atrial septal defect (ASD) patients. Our results further revealed that miR-20b-5p suppressed hESCs-derived cardiac differentiation by targeting tet methylcytosine dioxygenase 2 (TET2) and 5-hydroxymethylcytosine, leading to a reduction in key cardiac transcription factors including GATA4, NKX2.5, TBX5, MYH6 and cTnT. Additionally, knockdown of TET2 significantly inhibited cardiac differentiation, which could be partially restored by miR-20b-5p inhibition. CONCLUSIONS: Collectively, this study provides compelling evidence that miR-20b-5p functions as an inhibitory regulator in hESCs-derived cardiac differentiation by targeting TET2, highlighting its potential as a biomarker for ASD.


Asunto(s)
Dioxigenasas , MicroARNs , Humanos , Diferenciación Celular , Dioxigenasas/genética , ADN/metabolismo , Metilación de ADN , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , MicroARNs/genética , MicroARNs/metabolismo
10.
medRxiv ; 2024 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-38352438

RESUMEN

Developmental and epileptic encephalopathies (DEEs) are a heterogenous group of epilepsies in which altered brain development leads to developmental delay and seizures, with the epileptic activity further negatively impacting neurodevelopment. Identifying the underlying cause of DEEs is essential for progress toward precision therapies. Here we describe a group of individuals with biallelic variants in DENND5A and determine that variant type is correlated with disease severity. We demonstrate that DENND5A interacts with MUPP1 and PALS1, components of the Crumbs apical polarity complex, which is required for both neural progenitor cell identity and the ability of these stem cells to divide symmetrically. Induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division during neural induction and have an inherent propensity to differentiate into neurons, and transgenic DENND5A mice, with phenotypes like the human syndrome, have an increased number of neurons in the adult subventricular zone. Disruption of symmetric cell division following loss of DENND5A results from misalignment of the mitotic spindle in apical neural progenitors. A subset of DENND5A is localized to centrosomes, which define the spindle poles during mitosis. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state and ultimately shortening the period of neurogenesis. This study provides a mechanism behind DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families.

11.
Front Chem ; 12: 1330378, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38312345

RESUMEN

The telomeric DNA, a distal region of eukaryotic chromosome containing guanine-rich repetitive sequence of (TTAGGG)n, has been shown to adopt higher-order structures, specifically G-quadruplexes (G4s). Previous studies have demonstrated the implication of G4 in tumor inhibition through chromosome maintenance and manipulation of oncogene expression featuring their G-rich promoter regions. Besides higher order structures, several regulatory roles are attributed to DNA epigenetic markers. In this work, we investigated how the structural dynamics of a G-quadruplex, formed by the telomeric sequence, is affected by inosine, a prevalent modified nucleotide. We used the standard (TTAGGG)n telomere repeats with guanosine mutated to inosine at each G position. Sequences (GGG)4, (IGG)4, (GIG)4, (GGI)4, (IGI)4, (IIG)4, (GII)4, and (III)4, bridged by TTA linker, are studied using biophysical experiments and molecular modeling. The effects of metal cations in quadruplex folding were explored in both Na+ and K+ containing buffers using CD and UV-melting studies. Our results show that antiparallel quadruplex topology forms with the native sequence (GGG)4 and the terminal modified DNAs (IGG)4 and (GGI)4 in both Na+ and K+ containing buffers. Specifically, quadruplex hybrid was observed for (GGG)4 in K+ buffer. Among the other modified sequences, (GIG)4, (IGI)4 and (GII)4 show parallel features, while (IIG)4 and (III)4 show no detectable conformation in the presence of either Na+ or K+. Our studies indicate that terminal lesions (IGG)4 and (GGI)4 may induce certain unknown conformations. The folding dynamics become undetectable in the presence of more than one inosine substitution except (IGI)4 in both buffer ions. In addition, both UV melting and CD melting studies implied that in most cases the K+ cation confers more thermodynamic stability compared to Na+. Collectively, our conformational studies revealed the diverse structural polymorphisms of G4 with position dependent G-to-I mutations in different ion conditions.

12.
ACS Chem Biol ; 19(2): 348-356, 2024 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-38252964

RESUMEN

A-to-I editing catalyzed by adenosine deaminase acting on RNAs impacts numerous physiological and biochemical processes that are essential for cellular functions and is a big contributor to the infectivity of certain RNA viruses. The outcome of this deamination leads to changes in the eukaryotic transcriptome functionally resembling A-G transitions since inosine preferentially pairs with cytosine. Moreover, hyper-editing or multiple A to G transitions in clusters were detected in measles virus. Inosine modifications either directly on viral RNA or on cellular RNA can have antiviral or pro-viral repercussions. While many of the significant roles of inosine in cellular RNAs are well understood, the effects of hyper-editing of A to I on viral polymerase activity during RNA replication remain elusive. Moreover, biological strategies such as molecular cloning and RNA-seq for transcriptomic interrogation rely on RT-polymerase chain reaction with little to no emphasis placed on the first step, reverse transcription, which may reshape the sequencing results when hypermodification is present. In this study, we systematically explore the influence of inosine modification, varying the number and position of inosines, on decoding outcomes using three different reverse transcriptases (RTs) followed by standard Sanger sequencing. We find that inosine alone or in clusters can differentially affect the RT activity. To gain structural insights into the accommodation of inosine in the polymerase site of HIV-1 reverse transcriptase (HIV-1-RT) and how this structural context affects the base pairing rules for inosine, we performed molecular dynamics simulations of the HIV-1-RT. The simulations highlight the importance of the protein-nucleotide interaction as a critical factor in deciphering the base pairing behavior of inosine clusters. This effort sets the groundwork for decrypting the physiological significance of inosine and linking the fidelity of reverse transcriptase and the possible diverse transcription outcomes of cellular RNAs and/or viral RNAs where hyper-edited inosines are present in the transcripts.


Asunto(s)
ARN Viral , Transcripción Reversa , Emparejamiento Base , ARN Viral/genética , Inosina/análisis , Inosina/química , Inosina/genética , Adenosina Desaminasa/genética
13.
Heliyon ; 10(1): e23184, 2024 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-38163209

RESUMEN

Papillary renal cell carcinoma (PRCC) is a highly heterogeneous cancer, and PRCC patients with advanced/metastatic subgroup showed obviously shorter survival compared to other kinds of renal cell carcinomas. However, the molecular mechanism and prognostic predictors of PRCC remain unclear and are worth deep studying. The aim of this study is to identify novel molecular classification and construct a reliable prognostic model for PRCC. The expression data were retrieved from TCGA, GEO, GTEx and TARGET databases. CRISPR data was obtained from Depmap database. The key genes were selected by the intersection of CRISPR-Cas9 screening genes, differentially expressed genes, and genes with prognostic capacity in PRCC. The molecular classification was identified based on the key genes. Drug sensitivity, tumor microenvironment, somatic mutation, and survival were compared among the novel classification. A prognostic model utilizing multiple machine learning algorithms based on the key genes was developed and tested by independent external validation set. Our study identified three clusters (C1, C2 and C3) in PRCC based on 41 key genes. C2 had obviously higher expression of the key genes and lower survival than C1 and C3. Significant differences in drug sensitivity, tumor microenvironment, and mutation landscape have been observed among the three clusters. By utilizing 21 combinations of 9 machine learning algorithms, 9 out of 41 genes were chosen to construct a robust prognostic signature, which exhibited good prognostic ability. SERPINH1 was identified as a critical gene for its strong prognostic ability in PRCC by univariate and multiple Cox regression analyses. Quantitative real-time PCR and Western blot demonstrated that SERPINH1 mRNA and protein were highly expressed in PRCC cells compared with normal human renal cells. This study exhibited a new molecular classification and prognostic signature for PRCC, which may provide a potential biomarker and therapy target for PRCC patients.

14.
Brain ; 147(4): 1436-1456, 2024 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-37951597

RESUMEN

The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Using exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with myristic acid alkyne (YnMyr) chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), aged 1-50 years, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%) and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%) and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%) and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each) as well as hypertrophy of the clava (24%) were common neuroimaging findings. Acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localization and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-myristoylation was similarly affected in acbd6-deficient zebrafish and X. tropicalis models, including Fus, Marcks and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders.


Asunto(s)
Discapacidad Intelectual , Microcefalia , Trastornos del Movimiento , Malformaciones del Sistema Nervioso , Trastornos del Neurodesarrollo , Animales , Femenino , Humanos , Masculino , Transportadoras de Casetes de Unión a ATP , Discapacidad Intelectual/genética , Trastornos del Movimiento/genética , Malformaciones del Sistema Nervioso/genética , Trastornos del Neurodesarrollo/genética , Temblor , Pez Cebra , Lactante , Preescolar , Niño , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad
15.
Small ; 20(1): e2304463, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37649191

RESUMEN

The high activity of water molecules results in a series of awful parasitic reaction, which seriously impede the development of aqueous zinc batteries. Herein, a new gel electrolyte with multiple molecular anchors is designed by employing natural biomaterials from chitosan and chlorophyll derivative. The gel electrolyte firmly anchors water molecules by ternary hydrogen bonding to reduce the activity of water molecules and inhibit hydrogen evolution reaction. Meanwhile, the multipolar charged functional groups realize the gradient induction and redistribution of Zn2+ , which drives oriented Zn (002) plane deposition of Zn2+ and then achieves uniform Zn deposition and dendrite-free anode. As a result, it endows the Zn||Zn cell with over 1700 h stripping/plating processes and a high efficiency of 99.4% for the Zn||Cu cell. In addition, the Zn||V2 O5 full cells also exhibit capacity retention of 81.7% after 600 cycles at 0.5 A g-1 and excellent long-term stability over 1600 cycles at 2 A g-1 , and the flexible pouch cells can provide stable power for light-emitting diodes even after repeated bending. The gel electrolyte strategy provides a reference for reversible zinc anode and flexible wearable devices.

17.
BMC Nurs ; 22(1): 457, 2023 Dec 04.
Artículo en Inglés | MEDLINE | ID: mdl-38049804

RESUMEN

BACKGROUND: Coronary heart disease (CHD) is a cardiovascular disease with high mortality. At present, percutaneous coronary intervention (PCI) is considered as the main effective treatment for CHD due to less trauma, shorter course of treatment, and better curative effect. However, PCI alone is not a permanent cure, so cardiac rehabilitation (CR) is needed for a supplement. Nowadays, the evaluation of the nursing-sensitive quality of CR after PCI focuses on the outcomes of patients, lacks a complete evaluation indicator system, and is prone to problems such as nursing management imbalance. OBJECTIVE: A scientific, sensitive, comprehensive and practical nursing-sensitive quality indicator system based on the structure-process-outcome model was constructed to provide a reference for evaluating nursing-sensitive quality of CR after PCI. METHODS: Firstly, through literature analysis and semi-structured interview, the indicator system was collected, screened and determined. Then, the framework of the indicator system was established, and the draft of nursing-sensitive quality indicator system of CR after PCI was formed. Subsequently, the nursing-sensitive quality indicator system of CR after PCI was initially established using Delphi method. Finally, the specific weight was determined by analytic hierarchy process (AHP), and the nursing-sensitive quality indicator system of CR after PCI was established and perfected. RESULTS: Two rounds of expert consultations were separately given 15 questionnaires, and all these questionnaires were returned, with a questionnaire response rate of 100%. Such result indicated that experts were highly motivated. Besides, the authoritative coefficients for two rounds of expert consultations were 0.865 and 0.888, and the coordination coefficients were 0.491 and 0.522, respectively. Hence, the experts' authority and coordination were high and the results were reliable. After the second round of expert consultation, the nursing-sensitive quality indicator system of CR after PCI was established, eventually. This system consisted of 3 first-level indicators (structural indicator, process indicator and outcome indicator), 11 s-level indicators and 29 third-level indicators. CONCLUSION: A relatively complete and reliable nursing-sensitive quality indicator system of CR after PCI has been established in this study. Such system is scientific and reliable and can provide a reference for the evaluation of clinical teaching quality of CR after PCI.

18.
Genome Med ; 15(1): 102, 2023 Nov 29.
Artículo en Inglés | MEDLINE | ID: mdl-38031187

RESUMEN

BACKGROUND: Biallelic variants in OGDHL, encoding part of the α-ketoglutarate dehydrogenase complex, have been associated with highly heterogeneous neurological and neurodevelopmental disorders. However, the validity of this association remains to be confirmed. A second OGDHL patient cohort was recruited to carefully assess the gene-disease relationship. METHODS: Using an unbiased genotype-first approach, we screened large, multiethnic aggregated sequencing datasets worldwide for biallelic OGDHL variants. We used CRISPR/Cas9 to generate zebrafish knockouts of ogdhl, ogdh paralogs, and dhtkd1 to investigate functional relationships and impact during development. Functional complementation with patient variant transcripts was conducted to systematically assess protein functionality as a readout for pathogenicity. RESULTS: A cohort of 14 individuals from 12 unrelated families exhibited highly variable clinical phenotypes, with the majority of them presenting at least one additional variant, potentially accounting for a blended phenotype and complicating phenotypic understanding. We also uncovered extreme clinical heterogeneity and high allele frequencies, occasionally incompatible with a fully penetrant recessive disorder. Human cDNA of previously described and new variants were tested in an ogdhl zebrafish knockout model, adding functional evidence for variant reclassification. We disclosed evidence of hypomorphic alleles as well as a loss-of-function variant without deleterious effects in zebrafish variant testing also showing discordant familial segregation, challenging the relationship of OGDHL as a conventional Mendelian gene. Going further, we uncovered evidence for a complex compensatory relationship among OGDH, OGDHL, and DHTKD1 isoenzymes that are associated with neurodevelopmental disorders and exhibit complex transcriptional compensation patterns with partial functional redundancy. CONCLUSIONS: Based on the results of genetic, clinical, and functional studies, we formed three hypotheses in which to frame observations: biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all. Our study further highlights the continuing challenges of assessing the validity of reported disease-gene associations and effects of variants identified in these genes. This is particularly more complicated in making genetic diagnoses based on identification of variants in genes presenting a highly heterogenous phenotype such as "OGDHL-related disorders".


Asunto(s)
Proteínas , Pez Cebra , Animales , Humanos , Frecuencia de los Genes , Complejo Cetoglutarato Deshidrogenasa/genética , Complejo Cetoglutarato Deshidrogenasa/metabolismo , Fenotipo , Proteínas/genética , Pez Cebra/genética
19.
Nucleic Acids Res ; 51(20): 11291-11297, 2023 11 10.
Artículo en Inglés | MEDLINE | ID: mdl-37811879

RESUMEN

There are >170 naturally occurring RNA chemical modifications, with both known and unknown biological functions. Analytical methods for detecting chemical modifications and for analyzing their effects are relatively limited and have had difficulty keeping pace with the demand for RNA chemical biology and biochemistry research. Some modifications can affect the ability of RNA to hybridize with its complementary sequence or change the selectivity of base pairing. Here, we investigate the use of affinity-based DNA nanoswitches to resolve energetic differences in hybridization. We found that a single m3C modification can sufficiently destabilize hybridization to abolish a detection signal, while an s4U modification can selectively hybridize with G over A. These results establish proof of concept for using DNA nanoswitches to detect certain RNA modifications and analyzing their effects in base pairing stability and specificity.


Asunto(s)
ADN , ARN , Emparejamiento Base , Secuencia de Bases , ADN/química , Hibridación de Ácido Nucleico , ARN/química
20.
Clin Biomech (Bristol, Avon) ; 110: 106115, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37797369

RESUMEN

BACKGROUND: Various strain studies of the supraspinatus have been done in isolation. Given that rotator cuff muscles function as a group, it may be physiologically representative to measure strain behaviour with the glenohumeral joint intact. Here, we explored a novel method in measuring simultaneous strain behaviour of the rotator cuff tendons and investigated the effect of full-thickness anterior tear of the supraspinatus on the infraspinatus and subscapularis tendons. METHODS: Nine cadaveric shoulders were evaluated on a customized rig. Using linear differential variable transducers to measure strain, each shoulder was subjected to up to 60° of elevation in the coronal, scapular, and sagittal planes. We also assessed 30° of external rotation and up to 60° of internal rotation of the humerus. Full-thickness anterior tear of the supraspinatus was then made before re-assessing strain patterns in the scapular plane. FINDINGS: Strain measurements of the intact tendons revealed a significant strain gradient between the articular and bursal sides of the supraspinatus during increasing degrees of elevation in the coronal and scapular planes. Full thickness anterior tear of the supraspinatus is localised to the tendon and does not affect the surrounding cuff musculature, with a potential shielding effect of the infraspinatus during early glenohumeral abduction. INTERPRETATION: Significant strain gradient exists between the articular and bursal sides of the supraspinatus during abduction but not during forward flexion in an intact glenohumeral joint. Rehabilitation exercises for anterior supraspinatus tears can be appropriately targeted on the remaining intact rotator cuff musculature.


Asunto(s)
Laceraciones , Lesiones del Manguito de los Rotadores , Articulación del Hombro , Humanos , Manguito de los Rotadores , Hombro , Tendones , Rotura , Rango del Movimiento Articular/fisiología , Cadáver , Fenómenos Biomecánicos
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