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1.
Nature ; 623(7987): 580-587, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37938769

RESUMEN

Microsatellite repeat expansions within genes contribute to a number of neurological diseases1,2. The accumulation of toxic proteins and RNA molecules with repetitive sequences, and/or sequestration of RNA-binding proteins by RNA molecules containing expanded repeats are thought to be important contributors to disease aetiology3-9. Here we reveal that the adenosine in CAG repeat RNA can be methylated to N1-methyladenosine (m1A) by TRMT61A, and that m1A can be demethylated by ALKBH3. We also observed that the m1A/adenosine ratio in CAG repeat RNA increases with repeat length, which is attributed to diminished expression of ALKBH3 elicited by the repeat RNA. Additionally, TDP-43 binds directly and strongly with m1A in RNA, which stimulates the cytoplasmic mis-localization and formation of gel-like aggregates of TDP-43, resembling the observations made for the protein in neurological diseases. Moreover, m1A in CAG repeat RNA contributes to CAG repeat expansion-induced neurodegeneration in Caenorhabditis elegans and Drosophila. In sum, our study offers a new paradigm of the mechanism through which nucleotide repeat expansion contributes to neurological diseases and reveals a novel pathological function of m1A in RNA. These findings may provide an important mechanistic basis for therapeutic intervention in neurodegenerative diseases emanating from CAG repeat expansion.


Asunto(s)
Adenosina , Caenorhabditis elegans , Proteínas de Unión al ADN , Drosophila melanogaster , Enfermedades Neurodegenerativas , ARN , Expansión de Repetición de Trinucleótido , Animales , Humanos , Adenosina/análogos & derivados , Adenosina/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Unión al ADN/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , ARN/química , ARN/genética , ARN/metabolismo , Expansión de Repetición de Trinucleótido/genética , Citoplasma/metabolismo , Modelos Animales de Enfermedad
2.
Nature ; 597(7878): 666-671, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34588666

RESUMEN

The use of non-fullerene acceptors (NFAs) in organic solar cells has led to power conversion efficiencies as high as 18%1. However, organic solar cells are still less efficient than inorganic solar cells, which typically have power conversion efficiencies of more than 20%2. A key reason for this difference is that organic solar cells have low open-circuit voltages relative to their optical bandgaps3, owing to non-radiative recombination4. For organic solar cells to compete with inorganic solar cells in terms of efficiency, non-radiative loss pathways must be identified and suppressed. Here we show that in most organic solar cells that use NFAs, the majority of charge recombination under open-circuit conditions proceeds via the formation of non-emissive NFA triplet excitons; in the benchmark PM6:Y6 blend5, this fraction reaches 90%, reducing the open-circuit voltage by 60 mV. We prevent recombination via this non-radiative channel by engineering substantial hybridization between the NFA triplet excitons and the spin-triplet charge-transfer excitons. Modelling suggests that the rate of back charge transfer from spin-triplet charge-transfer excitons to molecular triplet excitons may be reduced by an order of magnitude, enabling re-dissociation of the spin-triplet charge-transfer exciton. We demonstrate NFA systems in which the formation of triplet excitons is suppressed. This work thus provides a design pathway for organic solar cells with power conversion efficiencies of 20% or more.

3.
Proc Natl Acad Sci U S A ; 121(28): e2405473121, 2024 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-38950361

RESUMEN

Cycling cells replicate their DNA during the S phase through a defined temporal program known as replication timing. Mutation frequencies, epigenetic chromatin states, and transcriptional activities are different for genomic regions that are replicated early and late in the S phase. Here, we found from ChIP-Seq analysis that DNA polymerase (Pol) κ is enriched in early-replicating genomic regions in HEK293T cells. In addition, by feeding cells with N 2-heptynyl-2'-deoxyguanosine followed by click chemistry-based enrichment and high-throughput sequencing, we observed elevated Pol κ activities in genomic regions that are replicated early in the S phase. On the basis of the established functions of Pol κ in accurate and efficient nucleotide insertion opposite endogenously induced N 2-modified dG lesions, our work suggests that active engagement of Pol κ may contribute to diminished mutation rates observed in early-replicating regions of the human genome, including cancer genomes. Together, our work expands the functions of Pol κ and offered a plausible mechanism underlying replication timing-dependent mutation accrual in the human genome.


Asunto(s)
Replicación del ADN , ADN Polimerasa Dirigida por ADN , Fase S , Humanos , ADN Polimerasa Dirigida por ADN/metabolismo , ADN Polimerasa Dirigida por ADN/genética , Células HEK293 , Genoma Humano , Momento de Replicación del ADN
4.
Proc Natl Acad Sci U S A ; 121(7): e2322375121, 2024 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-38315835

RESUMEN

Protein S-acyl transferases (PATs) catalyze S-acylation, a reversible post-translational modification critical for membrane association, trafficking, and stability of substrate proteins. Many plant proteins are potentially S-acylated but few have corresponding PATs identified. By using genomic editing, confocal imaging, pharmacological, genetic, and biochemical assays, we demonstrate that three Arabidopsis class C PATs positively regulate BR signaling through S-acylation of BRASSINOSTEROID-SIGNALING KINASE1 (BSK1). PAT19, PAT20, and PAT22 associate with the plasma membrane (PM) and the trans-Golgi network/early endosome (TGN/EE). Functional loss of all three genes results in a plethora of defects, indicative of reduced BR signaling and rescued by enhanced BR signaling. PAT19, PAT20, and PAT22 interact with BSK1 and are critical for the S-acylation of BSK1, and for BR signaling. The PM abundance of BSK1 was reduced by functional loss of PAT19, PAT20, and PAT22 whereas abolished by its S-acylation-deficient point mutations, suggesting a key role of S-acylation in its PM targeting. Finally, an active BR analog induces vacuolar trafficking and degradation of PAT19, PAT20, or PAT22, suggesting that the S-acylation of BSK1 by the three PATs serves as a negative feedback module in BR signaling.


Asunto(s)
Proteínas de Arabidopsis , Arabidopsis , Proteínas Serina-Treonina Quinasas , Acilación , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Brasinoesteroides/metabolismo , Regulación de la Expresión Génica de las Plantas , Transducción de Señal , Transferasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo
6.
Nucleic Acids Res ; 51(16): 8434-8446, 2023 09 08.
Artículo en Inglés | MEDLINE | ID: mdl-37427784

RESUMEN

High-order chromatin organization plays an important role in biological processes and disease development. Previous studies revealed a widespread occurrence of guanine quadruplex (G4) structures in the human genome, with enrichment in gene regulatory regions, especially in promoters. However, it remains unclear whether G4 structures contribute to RNA polymerase II (RNAPII)-mediated long-range DNA interactions and transcription activity. In this study, we conducted an intuitive overlapping analysis of previously published RNAPII ChIA-PET (chromatin interaction analysis with paired-end tag) and BG4 ChIP-seq (chromatin immunoprecipitation followed by sequencing using a G4 structure-specific antibody) data. We observed a strong positive correlation between RNAPII-linked DNA loops and G4 structures in chromatin. Additionally, our RNAPII HiChIP-seq (in situ Hi-C followed by ChIP-seq) results showed that treatment of HepG2 cells with pyridostatin (PDS), a small-molecule G4-binding ligand, could diminish RNAPII-linked long-range DNA contacts, with more pronounced diminutions being observed for those contacts involving G4 structure loci. RNA sequencing data revealed that PDS treatment modulates the expression of not only genes with G4 structures in their promoters, but also those with promoters being connected with distal G4s through RNAPII-linked long-range DNA interactions. Together, our data substantiate the function of DNA G4s in RNAPII-associated DNA looping and transcription regulation.


Asunto(s)
Cromatina , G-Cuádruplex , Humanos , Cromatina/genética , ARN Polimerasa II/genética , ARN Polimerasa II/metabolismo , Cromosomas/metabolismo , ADN/genética
7.
Proc Natl Acad Sci U S A ; 119(38): e2119630119, 2022 09 20.
Artículo en Inglés | MEDLINE | ID: mdl-36095216

RESUMEN

Trigeminal neuralgia (TN) is a unique pain disorder characterized by intense paroxysmal facial pain within areas innervated by the trigeminal nerve. Although most cases of TN are sporadic, familial clusters of TN suggest that genetic factors may contribute to this disorder. Whole-exome sequencing in patients with TN reporting positive family history demonstrated a spectrum of variants of ion channels including TRP channels. Here, we used patch-clamp analysis and Ca2+ and Na+ imaging to assess a rare variant in the TRPM7 channel, p.Ala931Thr, within transmembrane domain 3, identified in a man suffering from unilateral TN. We showed that A931T produced an abnormal inward current carried by Na+ and insensitive to the pore blocker Gd3+. Hypothesizing that replacement of the hydrophobic alanine at position 931 with the more polar threonine destabilizes a hydrophobic ring, near the voltage sensor domain, we performed alanine substitutions of F971 and W972 and obtained results suggesting a role of A931-W972 hydrophobic interaction in S3-S4 hydrophobic cleft stability. Finally, we transfected trigeminal ganglion neurons with A931T channels and observed that expression of this TRPM7 variant lowers current threshold and resting membrane potential, and increases evoked firing activity in TG neurons. Our results support the notion that the TRPM7-A931T mutation located in the S3 segment at the interface with the transmembrane region S4, generates an omega current that carries Na+ influx in physiological conditions. A931T produces hyperexcitability and a sustained Na+ influx in trigeminal ganglion neurons that may underlie pain in this kindred with trigeminal neuralgia.


Asunto(s)
Proteínas Serina-Treonina Quinasas , Canales Catiónicos TRPM , Ganglio del Trigémino , Neuralgia del Trigémino , Alanina/genética , Humanos , Masculino , Mutación , Neuronas/fisiología , Proteínas Serina-Treonina Quinasas/genética , Canales Catiónicos TRPM/genética , Canales Catiónicos TRPM/metabolismo , Ganglio del Trigémino/fisiopatología , Neuralgia del Trigémino/genética
8.
Nano Lett ; 24(20): 6192-6200, 2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38666542

RESUMEN

Creating artificial synapses that can interact with biological neural systems is critical for developing advanced intelligent systems. However, there are still many difficulties, including device morphology and fluid selection. Based on Micro-Electro-Mechanical System technologies, we utilized two immiscible electrolytes to form a liquid/liquid interface at the tip of a funnel nanochannel, effectively enabling a wafer-level fabrication, interactions between multiple information carriers, and electron-to-chemical signal transitions. The distinctive ionic transport properties successfully achieved a hysteresis in ionic transport, resulting in adjustable multistage conductance gradient and synaptic functions. Notably, the device is similar to biological systems in terms of structure and signal carriers, especially for the low operating voltage (200 mV), which matches the biological neural potential (∼110 mV). This work lays the foundation for realizing the function of iontronics neuromorphic computing at ultralow operating voltages and in-memory computing, which can break the limits of information barriers for brain-machine interfaces.


Asunto(s)
Nanotecnología , Sinapsis , Sinapsis/fisiología , Nanotecnología/instrumentación , Electrólitos/química , Nanoestructuras/química , Neuronas/fisiología , Conductividad Eléctrica
9.
J Am Chem Soc ; 146(14): 9871-9879, 2024 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-38547318

RESUMEN

Carbenes, recognized as potent intermediates, enable unique chemical transformations, and organoborons are pivotal in diverse chemical applications. As a hybrid of carbene and the boryl group, α-boryl carbenes are promising intermediates for the construction of organoborons; unfortunately, such carbenes are hard to access and have low structural diversity with their asymmetric transformations largely uncharted. In this research, we utilized boryl cyclopropenes as precursors for the swift synthesis of α-boryl metal carbenes, a powerful category of intermediates for chiral organoboron synthesis. These α-boryl carbenes undergo a series of highly enantioselective transfer reactions, including B-H and Si-H insertion, cyclopropanation, and cyclopropanation/Cope rearrangement, catalyzed by a singular chiral copper complex. This approach opens paths to previously unattainable but easily transformable chiral organoborons, expanding both carbene and organoboron chemistry.

10.
Anal Chem ; 96(11): 4673-4681, 2024 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-38451931

RESUMEN

Perfluorooctanesulfonic acid potassium salt (PFOS) residues in ecosystems over long periods are of increasing concern and require a selective and stable optical probe for monitoring. Herein, two functional groups (-F and -NH2) with opposite electronic modulation ability were introduced into Fe/Zn-BDC (denoted as Fe/Zn-BDC-F4 and Fe/Zn-BDC-NH2, respectively) to tailor the coordination environment of the Fe metal center, further regulating the nanozyme activity efficiently. Notably, the peroxidase-like activity is related to the coordination environment of the nanozymes and obeys the following order Fe/Zn-BDC-F4 > Fe/Zn-BDC > Fe/Zn-BDC-NH2. Based on the excellent peroxidase-like activity of Fe/Zn-BDC-F4 and the characteristics of being rich in F atoms, a rapid, selective, and visible colorimetric method was developed for detecting PFOS with a detection limit of 100 nM. The detection mechanism was attributed to various interaction forces between Fe/Zn-BDC-F4 and PFOS, including electrostatic interactions, Fe-S interactions, Fe-F bonds, and halogen bonds. This work not only offers new insights into the atomic-scale rational design of highly active nanozymes but also presents a novel approach to detecting PFOS in environmental samples.


Asunto(s)
Ecosistema , Potasio , Colorimetría , Peroxidasas , Zinc
11.
Anal Chem ; 96(8): 3553-3560, 2024 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-38362858

RESUMEN

Lead halide perovskite nanocrystals with excellent photophysical properties are promising electrochemiluminescence (ECL) candidates, but their poor stability greatly restricts ECL applications. Herein, hydrogen-bonded cocrystal-encapsulated CsPbBr3 perovskite nanocrystals (PeNCs@NHS-M) were synthesized by using PeNCs as nuclei for inducing the crystallization of melamine (M) and N-hydroxysuccinimide (NHS). The as-synthesized composite exhibits multiplicative ECL efficiencies (up to 24-fold that of PeNCs) without exogenous coreactants and with excellent stability in the aqueous phase. The enhanced stability can be attributed to the well-designed heterostructure of the PeNCs@NHS-M composite, which benefits from both moiety passivation and protection of the peripheral cocrystal matrix. Moreover, the heterostructure with covalent linkage facilitates charge transfer between PeNCs and NHS-M cocrystals, realizing effective ECL emission. Meanwhile, the NHS and M components act as coreactants for PeNCs, shortening the electron-transport distance and resulting in a significant increase in the ECL signal. Furthermore, by taking advantage of the specific binding effect between NHS-M and uranyl (UO22+), an ECL system with both a low detection limit (1 nM) and high selectivity for monitoring UO22+ in mining wastewater is established. The presence of UO22+ disrupted the charge-transfer effect within PeNCs@NHS-M, weakening the ECL signals. This work provides an efficient design strategy for obtaining stable and efficient ECLs from perovskite nanocrystals, offering a new perspective for the discovery and application of perovskite-based ECL systems.

12.
Anal Chem ; 96(12): 5037-5045, 2024 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-38477697

RESUMEN

Uranium poses severe health risks due to its radioactivity and chemical toxicity if released into the environment. Therefore, there is an urgent demand to develop sensing materials in situ monitoring of uranium with high sensitivity and stability. In this work, a fluorescent Eu3+-TFPB-Bpy is synthesized by grafting Eu3+ cation onto TFPB-Bpy covalent organic framework (COF) synthesized through Schiff base condensation of monomers 1,3,5-tris(4-formylphenyl)benzene (TFPB) and 5,5'-diamino-2,2'-bipyridine (Bpy). The fluorescence of Eu3+-TFPB-Bpy is enhanced compared with that of TFPB-Bpy, which is originated from the intramolecular rotations of building blocks limited by the bipyridine units of TFPB-Bpy coordinated with Eu3+. More significantly, Eu3+-TFPB-Bpy is a highly efficient probe for sensing UO22+ in aqueous solution with the luminescence intensity efficiently amplified by complexation of UO22+ with Eu3+. The turn-on sensing capability was derived from the resonance energy transfer occurring from UO22+ to the Eu3+-TFPB-Bpy. The developed probe displayed desirable linear range from 5 nM to 5 µM with good selectivity and rapid response time (2 s) for UO22+ in mining wastewater. This strategy provides a vivid illustration for designing luminescence lanthanide COF hybrid materials with applications in environmental monitoring.

13.
Anal Chem ; 2024 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-38330425

RESUMEN

Uranyl ions (UO22+) are recognized as important indicators for monitoring sudden nuclear accidents. However, the interferences coexisting in the complicated environmental matrices impart serious constraints on the reliability of current on-site monitoring methods. Herein, a novel ratiometric method for the highly sensitive and selective detection of UO22+ is reported based on a [Eu(diaminoterephthalic acid)] (Eu-DATP) metal-organic framework. Benefiting from the unique chemical structure of Eu-DATP, energy transfer from DATP to UO22+ was enabled, resulting in the up-regulated fluorescence of UO22+ and the simultaneous down-regulated fluorescence of Eu3+. The limit of detection reached as low as 2.7 nM, which was almost 2 orders of magnitude below the restricted limit in drinking water set by the United States Environmental Protection Agency (130 nM). The Eu-DATP probe showed excellent specificity to UO22+ over numerous interfering species, as the intrinsic emissions of UO22+ were triggered. This unprecedentedly high selectivity is especially beneficial for monitoring UO22+ in complicated environmental matrices with no need for tedious sample pretreatment, such as filtration and digestion. Then, by facilely equipping a Eu-DATP-based sampler on a drone, remotely controlled sampling and on-site analysis in real water samples were realized. The concentrations of UO22+ were determined to be from 16.5 to 23.5 nM in the river water of the Guangzhou downtown area, which was consistent with the results determined by the gold-standard inductively coupled plasma mass spectrometry. This study presents a reliable and convenient method for the on-site analysis of UO22+.

14.
BMC Plant Biol ; 24(1): 519, 2024 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-38851682

RESUMEN

Rice seeds of different varieties exhibited distinct metabolic profiles in our study. We analyzed the metabolites in seeds of six rice varieties (CH, HM, NX, YX, HY, and MX) using non-targeted GC-MS. Our findings revealed that amino acids, sugars, and organic acids were predominant in all varieties, with significant differences observed in CH compared to the others. Specifically phenylalanine and glycine content differed notably in NX and YX, respectively. Additionally, 1,5-anhydroglucitol content in NX, and glutamate, aspartate, and lactulose in NX, YX, HM, HY, and MX were up-regulated. Due to the biological functions of these amino acids and sugars, these indicated that compared to CH, rice of NX were more conducive to metabolism of carbohydrate and fat, and healthy growth maintenance in the human body, but mightThese variations suggest that NX rice may be more beneficial for carbohydrate and fat metabolism and overall health maintenance compared to CH. However, it may not be suitable for diabetic patients. YX rice may not be an ideal glycine supplement, rice ofwhile HM, HY, and MX rice could serve as potential lactulose sources. Furthermore, NX and YX rice exhibited higher levels of main storage proteins compared to CH. This study offers valuable insights into the metabolic differences among various rice varieties.


Asunto(s)
Cromatografía de Gases y Espectrometría de Masas , Metabolómica , Oryza , Semillas , Oryza/metabolismo , Semillas/metabolismo , Semillas/química , Metabolómica/métodos , Aminoácidos/metabolismo , Aminoácidos/análisis , Metaboloma
15.
Small ; 20(25): e2310672, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38229539

RESUMEN

At present, poor stability and carrier transfer efficiency are the main problems that limit the development of perovskite-based photoelectric technologies. In this work, hydrogen-bonded cocrystal-coated perovskite composite (PeNCs@NHS-M) is easily obtained by inducing rapid crystallization of melamine (M) and N-hydroxysuccinimide (NHS) with PeNCs as the nuclei. The outer NHS-M cocrystal passivates the undercoordinated lead atoms by forming covalent bonds, thereby greatly reducing the trap density while maintaining good structure stability for perovskite nanocrystals. Moreover, benefiting from the interfacial covalent band linkage and long-range ordered structures of cocrystals, the charge transfer efficiency is effectively enhanced and PeNCs@NHS-M displays superior photoelectric performance. Based on the excellent photoelectric performance and abundant active sites of PeNCs@NHS-M, photocatalytic reduction of uranium is realized. PeNCs@NHS-M exhibits U(VI) reduction removal capability of up to 810.1 mg g-1 in the presence of light. The strategy of cocrystals trapping perovskite nanocrystals provides a simple synthesis method for composites and opens up a new idea for simultaneously improving the stability and photovoltaic performance of perovskite.

16.
Plant Cell Environ ; 47(7): 2396-2409, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38516697

RESUMEN

Stomatal movement is critical for water transpiration, gas exchange, and responses to biotic stresses. Abscisic acid (ABA) induces stomatal closure to prevent water loss during drought. We report that Arabidopsis CIPK8 negatively regulates ABA-mediated stomatal closure and drought tolerance. CIPK8 is highly enriched in guard cells and transcriptionally induced by ABA. Functional loss of CIPK8 results in hypersensitive stomatal closure to ABA and enhanced drought tolerance. Guard cell-specific downregulation of CIPK8 mimics the phenotype of cipk8 whereas guard cell-specific expression of a constitutive active CIPK8 (CIPK8CA) has an opposite effect, suggesting a cell autonomous activity of CIPK8. CIPK8 physically interacts with CBL1 and CBL9. Functional loss of CBL1 and CBL9 mimics ABA-hypersensitive stomatal closure of cipk8 whereas abolishes the effect of CIPK8CA, indicating that CIPK8 and CBL1/CBL9 form a genetic module in ABA-responsive stomatal movement. SlCIPK7, the functional homolog of CIPK8 in tomato (Solanum lycopersicum), plays a similar role in ABA-responsive stomatal movement. Genomic editing of SlCIPK7 results in more drought-tolerant tomato, making it a good candidate for germplasm improvement.


Asunto(s)
Ácido Abscísico , Proteínas de Arabidopsis , Arabidopsis , Sequías , Regulación de la Expresión Génica de las Plantas , Estomas de Plantas , Solanum lycopersicum , Ácido Abscísico/metabolismo , Ácido Abscísico/farmacología , Estomas de Plantas/fisiología , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Arabidopsis/fisiología , Arabidopsis/genética , Solanum lycopersicum/fisiología , Solanum lycopersicum/genética , Solanum lycopersicum/metabolismo , Proteínas de Unión al Calcio/metabolismo , Proteínas de Unión al Calcio/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Plantas Modificadas Genéticamente , Resistencia a la Sequía
17.
Opt Express ; 32(8): 13450-13466, 2024 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-38859315

RESUMEN

We highlight what we believe to be a novel optical set-up which enables the confinement of cold atoms in a finite set of sub-wavelength bottle traps. This involves two counter-propagating vortex beams with the same winding number ℓ = ±1 and the same circular polarization ($\sigma =\mp 1)$. Strong focusing generates significant longitudinal field components which become responsible for an on-axis standing wave enabling the axial confinement of far blue-detuned atoms. The off-axis radial confinement is provided by the optical potential due to the transverse components of the light. The trap characteristics are illustrated using experimentally accessible parameters and are tunable by changing the power, focusing and ellipticity of the light. Atoms trapped in such a set-up are useful for applications, including quantum simulation and quantum information processing.

18.
Artículo en Inglés | MEDLINE | ID: mdl-39013564

RESUMEN

BACKGROUND: The causative genes for over 60% of inherited peripheral neuropathy (IPN) remain unidentified. This study endeavours to enhance the genetic diagnostic rate in IPN cases by conducting screenings focused on non-coding repeat expansions. METHODS: We gathered data from 2424 unrelated Japanese patients diagnosed with IPN, among whom 1555 cases with unidentified genetic causes, as determined through comprehensive prescreening analyses, were selected for the study. Screening for CGG non-coding repeat expansions in LRP12, GIPC1 and RILPL1 genes was conducted using PCR and long-read sequencing technologies. RESULTS: We identified CGG repeat expansions in LRP12 from 44 cases, establishing it as the fourth most common aetiology in Japanese IPN. Most cases (29/37) exhibited distal limb weakness, without ptosis, ophthalmoplegia, facial muscle weakness or bulbar palsy. Neurogenic changes were frequently observed in both needle electromyography (97%) and skeletal muscle tissue (100%). In nerve conduction studies, 28 cases primarily showed impairment in motor nerves without concurrent involvement of sensory nerves, consistent with the phenotype of hereditary motor neuropathy. In seven cases, both motor and sensory nerves were affected, resembling the Charcot-Marie-Tooth (CMT) phenotype. Importantly, the mean CGG repeat number detected in the present patients was significantly shorter than that of patients with LRP12-oculopharyngodistal myopathy (p<0.0001). Additionally, GIPC1 and RILPL1 repeat expansions were absent in our IPN cases. CONCLUSION: We initially elucidate LRP12 repeat expansions as a prevalent cause of CMT, highlighting the necessity for an adapted screening strategy in clinical practice, particularly when addressing patients with IPN.

19.
Am J Nephrol ; 55(3): 345-360, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38330925

RESUMEN

INTRODUCTION: The aim of this study was to explore the renoprotective effects of Klotho on podocyte injury mediated by complement activation and autoantibodies in idiopathic membranous nephropathy (IMN). METHODS: Rat passive Heymann nephritis (PHN) was induced as an IMN model. Urine protein levels, serum biochemistry, kidney histology, and podocyte marker levels were assessed. In vitro, sublytic podocyte injury was induced by C5b-9. The expression of Klotho, transient receptor potential channel 6 (TRPC6), and cathepsin L (CatL); its substrate synaptopodin; and the intracellular Ca2+ concentration were detected via immunofluorescence. RhoA/ROCK pathway activity was measured by an activity quantitative detection kit, and the protein expression of phosphorylated-LIMK1 (p-LIMK1) and p-cofilin in podocytes was detected via Western blotting. Klotho knockdown and overexpression were performed to evaluate its role in regulating the TRPC6/CatL pathway. RESULTS: PHN rats exhibited proteinuria, podocyte foot process effacement, decreased Klotho and Synaptopodin levels, and increased TRPC6 and CatL expression. The RhoA/ROCK pathway was activated by the increased phosphorylation of LIMK1 and cofilin. Similar changes were observed in C5b-9-injured podocytes. Klotho knockdown exacerbated podocyte injury, while Klotho overexpression partially ameliorated podocyte injury. CONCLUSION: Klotho may protect against podocyte injury in IMN patients by inhibiting the TRPC6/CatL pathway. Klotho is a potential target for reducing proteinuria in IMN patients.


Asunto(s)
Citoesqueleto de Actina , Catepsina L , Glomerulonefritis Membranosa , Glucuronidasa , Proteínas Klotho , Podocitos , Transducción de Señal , Canal Catiónico TRPC6 , Podocitos/metabolismo , Podocitos/patología , Glomerulonefritis Membranosa/metabolismo , Glomerulonefritis Membranosa/patología , Animales , Glucuronidasa/metabolismo , Ratas , Canal Catiónico TRPC6/metabolismo , Masculino , Citoesqueleto de Actina/metabolismo , Catepsina L/metabolismo , Proteína de Unión al GTP rhoA/metabolismo , Humanos , Modelos Animales de Enfermedad , Proteínas de Microfilamentos/metabolismo , Proteinuria/metabolismo , Ratas Sprague-Dawley , Quinasas Asociadas a rho/metabolismo , Canales Catiónicos TRPC/metabolismo , Complejo de Ataque a Membrana del Sistema Complemento/metabolismo
20.
Mol Psychiatry ; 28(1): 423-433, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-35668159

RESUMEN

The long-term physical and mental sequelae of COVID-19 are a growing public health concern, yet there is considerable uncertainty about their prevalence, persistence and predictors. We conducted a comprehensive, up-to-date meta-analysis of survivors' health consequences and sequelae for COVID-19. PubMed, Embase and the Cochrane Library were searched through Sep 30th, 2021. Observational studies that reported the prevalence of sequelae of COVID-19 were included. Two reviewers independently undertook the data extraction and quality assessment. Of the 36,625 records identified, a total of 151 studies were included involving 1,285,407 participants from thirty-two countries. At least one sequelae symptom occurred in 50.1% (95% CI 45.4-54.8) of COVID-19 survivors for up to 12 months after infection. The most common investigation findings included abnormalities on lung CT (56.9%, 95% CI 46.2-67.3) and abnormal pulmonary function tests (45.6%, 95% CI 36.3-55.0), followed by generalized symptoms, such as fatigue (28.7%, 95% CI 21.0-37.0), psychiatric symptoms (19.7%, 95% CI 16.1-23.6) mainly depression (18.3%, 95% CI 13.3-23.8) and PTSD (17.9%, 95% CI 11.6-25.3), and neurological symptoms (18.7%, 95% CI 16.2-21.4), such as cognitive deficits (19.7%, 95% CI 8.8-33.4) and memory impairment (17.5%, 95% CI 8.1-29.6). Subgroup analysis showed that participants with a higher risk of long-term sequelae were older, mostly male, living in a high-income country, with more severe status at acute infection. Individuals with severe infection suffered more from PTSD, sleep disturbance, cognitive deficits, concentration impairment, and gustatory dysfunction. Survivors with mild infection had high burden of anxiety and memory impairment after recovery. Our findings suggest that after recovery from acute COVID-19, half of survivors still have a high burden of either physical or mental sequelae up to at least 12 months. It is important to provide urgent and appropriate prevention and intervention management to preclude persistent or emerging long-term sequelae and to promote the physical and psychiatric wellbeing of COVID-19 survivors.


Asunto(s)
COVID-19 , Femenino , Humanos , Masculino , Ansiedad , COVID-19/complicaciones , COVID-19/epidemiología , COVID-19/psicología , Pandemias , Síndrome Post Agudo de COVID-19/patología , Pulmón/patología , Factores de Riesgo
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