ABSTRACT
High Mountain Asia (HMA) has experienced a spatial imbalance in water resources in recent decades, partly because of a dipolar pattern of precipitation changes known as South Drying-North Wetting1. These changes can be influenced by both human activities and internal climate variability2,3. Although climate projections indicate a future widespread wetting trend over HMA1,4, the timing and mechanism of the transition from a dipolar to a monopolar pattern remain unknown. Here we demonstrate that the observed dipolar precipitation change in HMA during summer is primarily driven by westerly- and monsoon-associated precipitation patterns. The weakening of the Asian westerly jet, caused by the uneven emission of anthropogenic aerosols, favoured a dipolar precipitation trend from 1951 to 2020. Moreover, the phase transition of the Interdecadal Pacific Oscillation induces an out-of-phase precipitation change between the core region of the South Asian monsoon and southeastern HMA. Under medium- or high-emission scenarios, corresponding to a global warming of 0.6-1.1 °C compared with the present, the dipolar pattern is projected to shift to a monopolar wetting trend in the 2040s. This shift in precipitation patterns is mainly attributed to the intensified jet stream resulting from reduced emissions of anthropogenic aerosols. These findings underscore the importance of considering the impact of aerosol emission reduction in future social planning by policymakers.
Subject(s)
Air , Altitude , Climate , Rain , Aerosols/analysis , Asia , Global Warming , Seasons , Air/analysis , Air/standards , Human Activities , Pacific OceanABSTRACT
Pyroelectricity describes the generation of electricity by temporal temperature change in polar materials1-3. When free-standing pyroelectric materials approach the 2D crystalline limit, how pyroelectricity behaves remained largely unknown. Here, using three model pyroelectric materials whose bonding characters along the out-of-plane direction vary from van der Waals (In2Se3), quasi-van der Waals (CsBiNb2O7) to ionic/covalent (ZnO), we experimentally show the dimensionality effect on pyroelectricity and the relation between lattice dynamics and pyroelectricity. We find that, for all three materials, when the thickness of free-standing sheets becomes small, their pyroelectric coefficients increase rapidly. We show that the material with chemical bonds along the out-of-plane direction exhibits the greatest dimensionality effect. Experimental observations evidence the possible influence of changed phonon dynamics in crystals with reduced thickness on their pyroelectricity. Our findings should stimulate fundamental study on pyroelectricity in ultra-thin materials and inspire technological development for potential pyroelectric applications in thermal imaging and energy harvesting.
ABSTRACT
Intracellular decay of N6 -methyladenine (m6A)-containing RNA potentially induces aberrant N6 -methyl-2'-adenine (6mdA) misincorporation into DNA. Biophysically, misincorporated 6mdA may destabilize the DNA duplex in a manner similar to bona fide methylated 6mdA DNA, thereby affecting DNA replication and transcription. Utilizing heavy stable isotope labeling and ultrasensitive UHPLC-MS/MS assay, we demonstrate that intracellular m6A-RNA decay does not generate free 6mdA species, nor lead to any misincorporated DNA 6mdA in most mammalian cell lines tested, unveiling the existence of a sanitation mechanism that prevents 6mdA misincorporation. Depletion of deaminase ADAL increases the levels of free 6mdA species, concomitant with the presence of DNA-misincorporated 6mdA resulting from intracellular RNA m6A decay, suggesting that ADAL catabolizes 6mdAMP in vivo. Furthermore, we show that the overexpression of adenylate kinase 1 (AK1) promotes 6mdA misincorporation, while AK1 knockdown diminishes 6mdA incorporation, in ADAL-deficient cells. We conclude that ADAL together with other factors (such as MTH1) contributes to 2'-deoxynucleotide pool sanitation in most cells but compromised sanitation (e.g., in NIH3T3 cells) and increased AK1 expression may facilitate aberrant 6mdA incorporation. This sanitation mechanism may provide a framework for the maintenance of the epigenetic 6mdA landscape.
Subject(s)
Sanitation , Tandem Mass Spectrometry , Animals , Mice , NIH 3T3 Cells , DNA , Adenylate Kinase/genetics , RNA , MammalsABSTRACT
With advanced technologies to map RNA modifications, our understanding of them has been revolutionized, and they are seen to be far more widespread and important than previously thought. Current next-generation sequencing (NGS)-based modification profiling methods are blind to RNA modifications and thus require selective chemical treatment or antibody immunoprecipitation methods for particular modification types. They also face the problem of short read length, isoform ambiguities, biases and artifacts. Direct RNA sequencing (DRS) technologies, commercialized by Oxford Nanopore Technologies (ONT), enable the direct interrogation of any given modification present in individual transcripts and promise to address the limitations of previous NGS-based methods. Here, we present the first ONT-based database of quantitative RNA modification profiles, DirectRMDB, which includes 16 types of modification and a total of 904,712 modification sites in 25 species identified from 39 independent studies. In addition to standard functions adopted by existing databases, such as gene annotations and post-transcriptional association analysis, we provide a fresh view of RNA modifications, which enables exploration of the epitranscriptome in an isoform-specific manner. The DirectRMDB database is freely available at: http://www.rnamd.org/directRMDB/.
Subject(s)
High-Throughput Nucleotide Sequencing , RNA Processing, Post-Transcriptional , Sequence Analysis, RNA , High-Throughput Nucleotide Sequencing/methods , Molecular Sequence Annotation , Protein Isoforms , RNA/genetics , Sequence Analysis, RNA/methods , Databases, Nucleic AcidABSTRACT
Hexanucleotide G4C2 repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Dipeptide repeat proteins (DPRs) generated by translation of repeat-containing RNAs show toxic effects in vivo as well as in vitro and are key targets for therapeutic intervention. We generated human antibodies that bind DPRs with high affinity and specificity. Anti-GA antibodies engaged extra- and intra-cellular poly-GA and reduced aggregate formation in a poly-GA overexpressing human cell line. However, antibody treatment in human neuronal cultures synthesizing exogenous poly-GA resulted in the formation of large extracellular immune complexes and did not affect accumulation of intracellular poly-GA aggregates. Treatment with antibodies was also shown to directly alter the morphological and biochemical properties of poly-GA and to shift poly-GA/antibody complexes to more rapidly sedimenting ones. These alterations were not observed with poly-GP and have important implications for accurate measurement of poly-GA levels including the need to evaluate all centrifugation fractions and disrupt the interaction between treatment antibodies and poly-GA by denaturation. Targeting poly-GA and poly-GP in two mouse models expressing G4C2 repeats by systemic antibody delivery for up to 16 mo was well-tolerated and led to measurable brain penetration of antibodies. Long-term treatment with anti-GA antibodies produced improvement in an open-field movement test in aged C9orf72450 mice. However, chronic administration of anti-GA antibodies in AAV-(G4C2)149 mice was associated with increased levels of poly-GA detected by immunoassay and did not significantly reduce poly-GA aggregates or alleviate disease progression in this model.
Subject(s)
Genes, Regulator , Poly A , Animals , Humans , Mice , Antigen-Antibody Complex , C9orf72 Protein/genetics , Dipeptides , Disease Models, AnimalABSTRACT
Forkhead box protein 1 (FOXP1) serves as a tumour promoter or suppressor depending on different cancers, but its effect in oesophageal squamous cell carcinoma has not been fully elucidated. This study investigated the role of FOXP1 in oesophageal squamous cell carcinoma through bioinformatics analysis and experimental verification. We determined through public databases that FOXP1 expresses low in oesophageal squamous cell carcinoma compared with normal tissues, while high expression of FOXP1 indicates a better prognosis. We identified potential target genes regulated by FOXP1, and explored the potential biological processes and signalling pathways involved in FOXP1 in oesophageal squamous cell carcinoma through GO and KEGG enrichment, gene co-expression analysis, and protein interaction network construction. We also analysed the correlation between FOXP1 and tumour immune infiltration levels. We further validated the inhibitory effect of FOXP1 on the proliferation of oesophageal squamous cell carcinoma cells through CCK-8, colony formation and subcutaneous tumour formation assays. This study revealed the anticarcinogenic effect of FOXP1 in oesophageal squamous cell carcinoma, which may serve as a novel biological target for the treatment of tumour.
Subject(s)
Cell Proliferation , Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Forkhead Transcription Factors , Gene Expression Regulation, Neoplastic , Repressor Proteins , Humans , Forkhead Transcription Factors/metabolism , Forkhead Transcription Factors/genetics , Esophageal Squamous Cell Carcinoma/genetics , Esophageal Squamous Cell Carcinoma/pathology , Esophageal Squamous Cell Carcinoma/metabolism , Esophageal Neoplasms/genetics , Esophageal Neoplasms/metabolism , Esophageal Neoplasms/pathology , Cell Line, Tumor , Animals , Repressor Proteins/metabolism , Repressor Proteins/genetics , Computational Biology/methods , Mice , Prognosis , Protein Interaction Maps/genetics , Signal Transduction , Gene Regulatory Networks , Mice, NudeABSTRACT
Glycidic esters represent pivotal constituents in synthetic chemistry, offering enhanced versatility for tailoring toward a diverse array of molecular targets in comparison with simple epoxides. While considerable progress has been made in the asymmetric synthesis of trans- and trisubstituted glycidic esters, achieving enantioselective preparation of cis-glycidic esters has remained a long-standing challenge. Here, we demonstrate a selectivity-predictable modular platform for the asymmetric synthesis of cis-glycidic esters via a novel dinuclear (salen)titanium(III)-catalyzed radical-type kinetic resolution (KR) approach. This radical KR protocol operates under mild conditions and demonstrates a wide substrate scope, facilitating the synthesis of alkyl- and aryl-substituted cis-glycidic esters with high levels of regioselectivity and enantioselectivity, along with hydroxy ester byproducts representing synthetically valuable motifs as well. This study presents a unique exploration of radical-type KR applied to epoxides, effectively overcoming the steric challenges inherent in conventional nucleophilic-type methodologies typically employed in epoxide chemistry.
ABSTRACT
Because of their innate chemical stability, the ubiquitous perfluoroalkyl and polyfluoroalkyl substances (PFASs) have been dubbed "forever chemicals" and have attracted considerable attention. However, their stability under environmental conditions has not been widely verified. Herein, perfluorooctanoic acid (PFOA), a widely used and detected PFAS, was found to be spontaneously degraded in aqueous microdroplets under room temperature and atmospheric pressure conditions. This unexpected fast degradation occurred via a unique multicycle redox reaction of PFOA with interfacial reactive species on the droplet surface. Similar degradation was observed for other PFASs. This study extends the current understanding of the environmental fate and chemistry of PFASs and provides insight into aid in the development of effective methods for removing PFASs.
ABSTRACT
There is a lack of evidence from cohort studies on the causal association of long-term exposure to ambient fine particulate matter (PM2.5) and its chemical components with the risk of nasopharyngeal carcinoma (NPC) recurrence. Based on a 10-year prospective cohort of 1184 newly diagnosed NPC patients, we comprehensively evaluated the potential causal links of ambient PM2.5 and its chemical components including black carbon (BC), organic matter (OM), sulfate (SO4 2-), nitrate (NO3 -), and ammonium (NH4 +) with the recurrence risk of NPC using a marginal structural Cox model adjusted with inverse probability weighting. We observed 291 NPC patients experiencing recurrence during the 10-year follow-up and estimated a 33% increased risk of NPC recurrence (hazard ratio [HR]: 1.33, 95% confidence interval [CI]: 1.02-1.74) following each interquartile range (IQR) increase in PM2.5 exposure. Each IQR increment in BC, NH4 +, OM, NO3 -, and SO4 2- was associated with HRs of 1.36 (95%CI: 1.13-1.65), 1.35 (95%CI: 1.07-1.70), 1.33 (95%CI: 1.11-1.59), 1.32 (95%CI: 1.06-1.64), 1.31 (95%CI: 1.08-1.57). The elderly, patients with no family history of cancer, no smoking history, no drinking history, and those with severe conditions may exhibit a greater likelihood of NPC recurrence following exposure to PM2.5 and its chemical components. Additionally, the effect estimates of the five components are greater among patients who were exposed to high concentration than in the full cohort of patients. Our study provides solid evidence for a potential relationship between long-term exposure to PM2.5 and its components and the risk of NPC recurrence.
ABSTRACT
Nanoplastics have attracted much attention due to their potential hazards. However, analysis of nanoplastics remains challenging. In this study, ionic liquid-assisted cloud-point extraction (IL-assisted CPE) was developed to enrich nanoplastics in the aqueous environment and further coupled with electromagnetic heating pyrolysis mass spectrometry. The use of trace ILs improves the extraction efficiency of CPE for nanoplastics. The effects of ILs (types, contents), nanoplastic properties (type, size), and environmental factors (aging time, humic acid content) were systematically investigated to evaluate the applicability. The limits of detection of poly(methyl methacrylate) (PMMA) and polystyrene (PS) were determined to be 1.78 and 2.67 µg/L, respectively. Real environmental samples including lake water, rainwater, and influent and effluent from wastewater treatment plant were analyzed with good accuracy (79.58-116.87%) and satisfactory precision (RSD ≤ 11.99%). A possible mechanism for ILs being absorbed into the ordered surfactant micellar and generating larger micelles to synergically enclose hydrophobic nanoplastics was proposed. This work provides a simple and efficient approach to the extraction and analysis of nanoplastics in aqueous environments.
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BACKGROUND AND AIMS: Liver fibrosis is a chronic disease characterized by different etiological agents; dysregulated interactions between hepatocytes and HSCs contribute to this disease. ß-arrestin 1 (ARRB1) plays an important role in liver fibrosis; however, the effect of ARRB1 on the crosstalk between hepatocytes and HSCs in liver fibrosis is unknown. The aim of this study is to investigate how ARRB1 modulates hepatocyte and HSC activation during liver fibrosis. APPROACH AND RESULTS: Normal and fibrotic human liver and serum samples were obtained. CCl 4 -induced liver fibrosis and methionine-choline deficiency-induced NASH models were constructed. Primary hepatocytes and HSCs were isolated, and human hepatic LO2 and stellate LX2 cells were used. Small extracellular vesicles (EVs) were purified, and key proteins were identified. ARRB1 was up-regulated in hepatocytes and associated with autophagic blockage in liver fibrosis. ARRB1 increased the release of hepatocyte-derived small EVs by inhibiting multivesicular body lysosomal degradation and activating Rab27A, thereby activating HSCs. Proteomic analyses showed that mannan-binding lectin serine protease 1 (MASP1) was enriched in hepatocyte-derived small EVs and activated HSCs via p38 mitogen-activated protein kinase (MAPK)/activating transcription factor 2 (ATF2) signaling. ARRB1 up-regulated MASP1 expression in hepatocytes. MASP1 promoted liver fibrosis in mice. Clinically, MASP1 expression was increased in the serum and liver tissue of patients with liver fibrosis. CONCLUSIONS: ARRB1 up-regulates the release of hepatocyte-derived MASP1-enriched small EVs by regulating the autophagic-lysosomal/multivesicular body pathway and Rab27A. Hepatocyte-derived MASP1 activates HSCs to promote liver fibrogenesis through p38 MAPK/ATF2 signaling. Thus, MASP1 is a pivotal therapeutic target in liver fibrosis.
Subject(s)
Extracellular Vesicles , Hepatic Stellate Cells , Humans , Mice , Animals , Hepatic Stellate Cells/metabolism , Proteomics , Hepatocytes/metabolism , Liver Cirrhosis/metabolism , Liver/pathology , Extracellular Vesicles/metabolism , Mannose-Binding Protein-Associated Serine Proteases/adverse effects , Mannose-Binding Protein-Associated Serine Proteases/metabolismABSTRACT
Intercropping is a widely recognised technique that contributes to agricultural sustainability. While intercropping leguminous green manure offers advantages for soil health and tea plants growth, the impact on the accumulation of theanine and soil nitrogen cycle are largely unknown. The levels of theanine, epigallocatechin gallate and soluble sugar in tea leaves increased by 52.87% and 40.98%, 22.80% and 6.17%, 22.22% and 29.04% in intercropping with soybean-Chinese milk vetch rotation and soybean alone, respectively. Additionally, intercropping significantly increased soil amino acidnitrogen content, enhanced extracellular enzyme activities, particularly ß-glucosidase and N-acetyl-glucosaminidase, as well as soil multifunctionality. Metagenomics analysis revealed that intercropping positively influenced the relative abundances of several potentially beneficial microorganisms, including Burkholderia, Mycolicibacterium and Paraburkholderia. Intercropping resulted in lower expression levels of nitrification genes, reducing soil mineral nitrogen loss and N2 O emissions. The expression of nrfA/H significantly increased in intercropping with soybean-Chinese milk vetch rotation. Structural equation model analysis demonstrated that the accumulation of theanine in tea leaves was directly influenced by the number of intercropping leguminous green manure species, soil ammonium nitrogen and amino acid nitrogen. In summary, the intercropping strategy, particularly intercropping with soybean-Chinese milk vetch rotation, could be a novel way for theanine accumulation.
Subject(s)
Camellia sinensis , Fabaceae , Glutamates , Fabaceae/metabolism , Manure , Legumins , Soil/chemistry , Camellia sinensis/metabolism , Glycine max , Tea , Nitrogen/metabolismABSTRACT
The spectral emission of laser-induced plasma in water has a broadband continuum containing ultraviolet light, which can be used as a novel light source for the degradation of organic compounds. We studied the degradation process of the organic dye Rhodamine B (RhB) using plasma light source excited by the "Laser + Fe" mode. Spectral analysis and reaction kinetics modelling were used to study the degradation mechanism. The degradation process using this light source could be divided into two stages. The initial stage was mainly photocatalytic degradation, where ultraviolet light broke the chemical bond of RhB, and then RhB was degraded by the strong oxidising ability of ·OH. As the iron and hydrogen ion concentrations increased, the synergistic effect of photocatalysis and the Fenton reaction further enhanced the degradation rate in the later stage. The plasma excited by the "Laser + Fe" mode achieved photodegradation by effectively enhancing the ultraviolet wavelength ratio of the emission spectrum and triggered the Fenton reaction to achieve rapid organic matter degradation. Our findings indicate that the participation of the Fenton reaction can increase the degradation rate by approximately 10 times. Besides, the impact of pH on degradation efficiency demonstrates that both acidic and alkaline environments have better degradation effects than neutral conditions; this is because acidic environments can enhance the Fenton reaction, while alkaline environments can provide more ·OH.
ABSTRACT
Topological edge state, a unique mode for manipulating electromagnetic waves (EMs), has been extensively studied in both fundamental and applied physics. Up to now, the work on topological edge states has focused on manipulating linearly polarized waves. Here, we realize chirality-dependent topological edge states in one-dimensional photonic crystals (1DPCs) to manipulate circularly polarized waves. By introducing the magneto-electric coupling term (chirality), the degeneracy Dirac point (DP) is opened in PCs with symmetric unit cells. The topological properties of the upper and lower bands are different in the cases of left circularly polarized (LCP) and right circularly polarized (RCP) waves by calculating the Zak phase. Moreover, mapping explicitly 1D Maxwell's equations to the Dirac equation, we demonstrate that the introduction of chirality can lead to different topological properties of bandgaps for RCP and LCP waves. Based on this chirality-dependent topology, we can further realize chirality-dependent topological edge states in photonic heterostructures composed of two kinds of PCs. Finally, we propose a realistic structure for the chirality-dependent topological edge states by placing metallic helixes in host media. Our work provides a method for manipulating topological edge states for circularly polarized waves, which has a broad range of potential applications in designing optical devices including polarizers, filters, and sensors with robustness against disorder.
ABSTRACT
Interactions between oxygen molecules play an important role in atmospheric chemistry and hypersonic flow chemistry in atmospheric entries. Recently, high-quality ab initio potential energy surface (PES) of the quintet O4 was reported by Paukku etâ al. [J. Chem. Phys. 147, 034301 (2017)]. 10543 configurations were sampled and calculated at the level of MS-CASPT2/maug-cc-pVTZ with scaled external correlation. The PES was fitted to a many-body (MB) form with the many-body part described by the permutationally invariant polynomial approach (MB-PIP). In this work, the PIP-Neural Network (PIP-NN) and MB-PIP-NN methods were used to refit the PES based on the same data by Paukku etâ al. Three PESs were compared. It was found that the performances differ significantly in the O+O3 region as well as in the long-range region. Therefore, additional 1300â points were sampled, and the efficient compressed-state multistate pair-density functional theory (CMS-PDFT) was used to calculate the electronic structure of these 1300â points and 10543â points by Paukku etâ al. Then, a completely new quintet PES was fitted using the MB-PIP-NN method. Based on this PES, the quasi-classical trajectory (QCT) approach was used to reveal all possible reaction channels for hyperthermal O2-O2 collisions.
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Antimony sulfide (Sb2S3) has been recognized as a catalytic material for splitting water by solar energy because of its suitable narrow band gap, high absorption coefficient, and abundance of elements. However, many deep-level defects in Sb2S3 result in a significant recombination of photoexcited electron-hole pairs, weakening its photoelectrochemical performance. Here, by using a simple hydrothermal and spin-coating method, we fabricated a step-scheme heterojunction of Sb2S3/α-Fe2O3 to improve the photoelectrochemical performance of pure Sb2S3. Our Sb2S3/α-Fe2O3 photoanode has a photocurrent density of 1.18 mA/cm2 at 1.23 V vs reversible hydrogen electrode, 1.39 times higher than that of Sb2S3 (0.84 mA/cm2). In addition, our heterojunction has a lower onset potential, a higher absorbance intensity, a higher incident photon-to-current conversion efficiency, a higher applied bias photon-to-current efficiency, and a lower charge transfer resistance compared to pure Sb2S3. Based on ultraviolet photoelectron spectroscopy, we constructed a step-scheme band structure of Sb2S3/α-Fe2O3 to explain its photoelectrochemical enhancement. This work offers a promising strategy to optimize the performance of Sb2S3 photoelectrodes for solar-driven photoelectrochemical water splitting.
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AIM: Malnutrition is prevalent in hepatocellular carcinoma (HCC) patients, linked to poor outcomes, necessitating early intervention. This study aimed to investigate malnutrition in HCC patients, assess Nutrition Risk Screening 2002 (NRS-2002) and Patient-Generated Subjective Global Assessment (PG-SGA) vs. Global Leadership Initiative on Malnutrition (GLIM) criteria, and identify independent risk factors. METHOD: A cross-sectional retrospective study was conducted on 207 patients with HCC. Nutritional screening/assessment results and blood samples were collected within 72 h of admission. This study assessed the prevalence of malnutrition using the NRS-2002 and PG-SGA and retrospectively using the GLIM criteria. The performance of the screening tools was evaluated using kappa (K) values. Logistic regression analyses were performed to determine whether laboratory parameters were associated with malnutrition as identified by the GLIM criteria. RESULTS: Of the participants, 30.4% were at risk of malnutrition according to NRS-2002. The agreement between the NRS-2002 and GLIM criteria was substantial. The GLIM criteria and PG-SGA diagnosed malnutrition in 43 and 54.6% of the participants, respectively. Age, anemia, and ascites correlated with malnutrition in regression. CONCLUSION: The GLIM criteria, along with NRS-2002 and PG-SGA, aid in diagnosing malnutrition in HCC patients. Recognizing risk factors improves accuracy, enabling timely interventions for better outcomes.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Malnutrition , Humans , Nutritional Status , Carcinoma, Hepatocellular/complications , Carcinoma, Hepatocellular/epidemiology , Prevalence , Retrospective Studies , Cross-Sectional Studies , Leadership , Nutrition Assessment , Liver Neoplasms/complications , Liver Neoplasms/epidemiology , Malnutrition/diagnosis , Malnutrition/epidemiology , Malnutrition/etiology , Risk FactorsABSTRACT
Elucidating the mechanism of effect of phosphate (PO43-) uptake on the growth of algal cells helps understand the frequent outbreaks of algal blooms caused by eutrophication. In this study, we develop a comprehensive mathematical model that incorporates two stages of PO43- uptake and accounts for transport time delay. The model parameter values are determined by fitting experimental data of Prorocentrum donghaiense and the model is validated using experimental data of Karenia mikimotoi. The numerical results demonstrate that the model successfully captures the general characteristics of algal growth and PO43- uptake under PO43- sufficient conditions. Significantly, the experimental and mathematical findings suggest that the time delay associated with the transfer of PO43- from the surface-adsorbed PO43- (Ps) pool to the intracellular PO43- (Pi) pool may serve as a physiologically plausible mechanism leading to oscillations of algal cell quota. These results have important implications for resource managers, enabling them to predict and deepen their understanding of harmful algal blooms.
Subject(s)
Dinoflagellida , Phosphates , Harmful Algal Bloom , Kinetics , Models, TheoreticalABSTRACT
Mutations in the human kinesin family member 5A (KIF5A) gene were recently identified as a genetic cause of amyotrophic lateral sclerosis (ALS). Several KIF5A ALS variants cause exon 27 skipping and are predicted to produce motor proteins with an altered C-terminal tail (referred to as ΔExon27). However, the underlying pathogenic mechanism is still unknown. Here, we confirm the expression of KIF5A mutant proteins in patient iPSC-derived motor neurons. We perform a comprehensive analysis of ΔExon27 at the single-molecule, cellular, and organism levels. Our results show that ΔExon27 is prone to form cytoplasmic aggregates and is neurotoxic. The mutation relieves motor autoinhibition and increases motor self-association, leading to drastically enhanced processivity on microtubules. Finally, ectopic expression of ΔExon27 in Drosophila melanogaster causes wing defects, motor impairment, paralysis, and premature death. Our results suggest gain-of-function as an underlying disease mechanism in KIF5A-associated ALS.
Subject(s)
Amyotrophic Lateral Sclerosis , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/metabolism , Animals , DNA, Antisense/genetics , Drosophila melanogaster , Gain of Function Mutation , Humans , Kinesins/genetics , Motor Neurons/metabolism , Mutation , Transcription Factor 7-Like 2 Protein/metabolismABSTRACT
OBJECTIVES: To predict the probability of occult lymph node metastasis (OLNM) in the central cervical by analyzing the dual-energy computed tomography (DECT) parameters derived from papillary thyroid carcinoma (PTC). METHODS: Data were retrospectively collected from patients with pathologically confirmed PTC who underwent arterial and venous phases of enhanced DECT with concurrent central neck lymph node dissection (CLND). Three clinical features, three shape-related features, and twenty-six DECT-derived parameters were measured. The univariate and multivariate analyses were applied to select the relevant parameters and develop the nomogram. RESULTS: A total 140 cases with negative diagnosis of cervical central lymph node metastases by preoperative evaluation were included, among which 88 patients with metastasis (OLNM +) and 52 patients without metastasis (OLNM -) were finally confirmed by pathology. (1) Anteroposterior/transverse diameter ratio (A/T) derived from the PTC focus had significant difference between the OLNM + and OLNM - groups (p < 0.05). (2) In the arterial phase, iodine concentration (ICarterial), normalized iodine concentration (NICarterial), effective atomic number (Zeff-arterial), electron density (EDarterial), and slope of energy curve (karterial) from PTC focus showed significant difference (all p < 0.05) between the two groups. In the venous phase, only the CT value under the 40 keV (HU40keVvenous) had differences (p < 0.05). (3) The nomogram was produced to predict the probability of OLNM, and the AUC, sensitivity, and specificity in the training and test cohort were 0.830, 75.0%, 76.9%, and 0.829, 65.9%, 84.6%, respectively. CONCLUSIONS: DECT parameters combined with shape-related feature derived from PTC might be used as predictors of OLNM in the central neck. CLINICAL RELEVANCE STATEMENT: Preoperative imaging evaluation combining shape-related features and dual-energy CT parameters could serve as a reference to discern occult lymph node metastasis in central neck during the surgically planning of papillary thyroid carcinoma. KEY POINTS: ⢠Papillary thyroid carcinoma (PTC) patients may have occult lymph node metastasis (OLNM) in the central neck, which is extremely difficult to find by preoperative imaging examination. ⢠Dual-energy CT quantitative evaluation has higher accuracy than conventional CT and can predicting OLNM in the central neck of PTC. ⢠Dual-energy CT quantitative parameters and morphology of PTC can serve as a useful tool in predicting OLNM in the central neck, and as a guide for personalized treatment.