A liver immune rheostat regulates CD8 T cell immunity in chronic HBV infection.

Chronic hepatitis B virus (HBV) infection affects 300 million patients worldwide1,2, in whom virus-specific CD8 T cells by still ill-defined mechanisms lose their function and cannot eliminate HBV-infected hepatocytes3-7. Here we demonstrate that a liver immune rheostat renders virus-specific CD8 T cells refractory to activation and leads to their loss of effector functions. In preclinical models of persistent infection with hepatotropic viruses such as HBV, dysfunctional virus-specific CXCR6+ CD8 T cells accumulated in the liver and, as a characteristic hallmark, showed enhanced transcriptional activity of cAMP-responsive element modulator (CREM) distinct from T cell exhaustion. In patients with chronic hepatitis B, circulating and intrahepatic HBV-specific CXCR6+ CD8 T cells with enhanced CREM expression and transcriptional activity were detected at a frequency of 12-22% of HBV-specific CD8 T cells. Knocking out the inhibitory CREM/ICER isoform in T cells, however, failed to rescue T cell immunity. This indicates that CREM activity was a consequence, rather than the cause, of loss in T cell function, further supported by the observation of enhanced phosphorylation of protein kinase A (PKA) which is upstream of CREM. Indeed, we found that enhanced cAMP-PKA-signalling from increased T cell adenylyl cyclase activity augmented CREM activity and curbed T cell activation and effector function in persistent hepatic infection. Mechanistically, CD8 T cells recognizing their antigen on hepatocytes established close and extensive contact with liver sinusoidal endothelial cells, thereby enhancing adenylyl cyclase-cAMP-PKA signalling in T cells. In these hepatic CD8 T cells, which recognize their antigen on hepatocytes, phosphorylation of key signalling kinases of the T cell receptor signalling pathway was impaired, which rendered them refractory to activation. Thus, close contact with liver sinusoidal endothelial cells curbs the activation and effector function of HBV-specific CD8 T cells that target hepatocytes expressing viral antigens by means of the adenylyl cyclase-cAMP-PKA axis in an immune rheostat-like fashion.

Differential spatial working memory-related functional network reconfiguration in young and older adults.

Functional brain networks have preserved architectures in rest and task; nevertheless, previous work consistently demonstrated task-related brain functional reorganization. Efficient rest-to-task functional network reconfiguration is associated with better cognition in young adults. However, aging and cognitive load effects, as well as contributions of intra- and internetwork reconfiguration, remain unclear. We assessed age-related and load-dependent effects on global and network-specific functional reconfiguration between rest and a spatial working memory (SWM) task in young and older adults, then investigated associations between functional reconfiguration and SWM across loads and age groups. Overall, global and network-level functional reconfiguration between rest and task increased with age and load. Importantly, more efficient functional reconfiguration associated with better performance across age groups. However, older adults relied more on internetwork reconfiguration of higher cognitive and task-relevant networks. These reflect the consistent importance of efficient network updating despite recruitment of additional functional networks to offset reduction in neural resources and a change in brain functional topology in older adults. Our findings generalize the association between efficient functional reconfiguration and cognition to aging and demonstrate distinct brain functional reconfiguration patterns associated with SWM in aging, highlighting the importance of combining rest and task measures to study aging cognition.

Brain networks identified by functional connectivity (FC) have preserved architectures from rest to task and across task demands. Higher similarity, implying more efficient network reconfiguration, was associated with better cognition and task performance in young adults. To examine how it may be influenced by aging, we compared whole-brain and network-level FC similarities between resting-state and spatial working memory fMRI in young and older adults. At whole-brain level and higher order cognitive networks, older adults evidenced less efficient network reconfiguration from rest to task than young adults. Importantly, more efficient reconfiguration was associated with better accuracy. This relationship relied more on internetwork connections in older adults. Despite reduced neural resources compared to young, maintaining efficient network updating still contributes to better cognition at older age.

Proton spot dose estimation based on positron activity distributions with neural network.

BACKGROUND: Positron emission tomography (PET) has been investigated for its ability to reconstruct proton-induced positron activity distributions in proton therapy. This technique holds potential for range verification in clinical practice. Recently, deep learning-based dose estimation from positron activity distributions shows promise for in vivo proton dose monitoring and guided proton therapy. PURPOSE: This study evaluates the effectiveness of three classical neural network models, recurrent neural network (RNN), U-Net, and Transformer, for proton dose estimating. It also investigates the characteristics of these models, providing valuable insights for selecting the appropriate model in clinical practice. METHODS: Proton dose calculations for spot beams were simulated using Geant4. Computed tomography (CT) images from four head cases were utilized, with three for training neural networks and the remaining one for testing. The neural networks were trained with one-dimensional (1D) positron activity distributions as inputs and generated 1D dose distributions as outputs. The impact of the number of training samples on the networks was examined, and their dose prediction performance in both homogeneous brain and heterogeneous nasopharynx sites was evaluated. Additionally, the effect of positron activity distribution uncertainty on dose prediction performance was investigated. To quantitatively evaluate the models, mean relative error (MRE) and absolute range error (ARE) were used as evaluation metrics. RESULTS: The U-Net exhibited a notable advantage in range verification with a smaller number of training samples, achieving approximately 75% of AREs below 0.5 mm using only 500 training samples. The networks performed better in the homogeneous brain site compared to the heterogeneous nasopharyngeal site. In the homogeneous brain site, all networks exhibited small AREs, with approximately 90% of the AREs below 0.5 mm. The Transformer exhibited the best overall dose distribution prediction, with approximately 92% of MREs below 3%. In the heterogeneous nasopharyngeal site, all networks demonstrated acceptable AREs, with approximately 88% of AREs below 3 mm. The Transformer maintained the best overall dose distribution prediction, with approximately 85% of MREs below 5%. The performance of all three networks in dose prediction declined as the uncertainty of positron activity distribution increased, and the Transformer consistently outperformed the other networks in all cases. CONCLUSIONS: Both the U-Net and the Transformer have certain advantages in the proton dose estimation task. The U-Net proves well suited for range verification with a small training sample size, while the Transformer outperforms others at dose-guided proton therapy.

Exhaustive clinical examination of etiology and initial response to first-line treatment in 577 children with infantile epileptic spasm syndrome children: A 5-year retrospective observational study.

OBJECTIVE: Employing whole-exome sequencing (WES) technology to investigate the etiology of infantile epileptic spasm syndrome (IESS), and determining whether different etiologies exhibit phenotypic variations, while elucidating the potential associated factors, might improve short-term responses to first-line treatment. METHODS: We retrospectively evaluated patients with IESS admitted for treatment between January 2018 and June 2023. Clinical phenotypic differences among etiological classifications and clinical manifestations were analyzed. Variable selection using the best subset method was performed, followed by logistic regression analysis to identify the factors influencing treatment response. RESULTS: A total of 577 patients were included; 412 completed trio-WES. Magnetic resonance imaging abnormalities were detected in 387 patients (67.1%). Patients with etiology as structural abnormalities were likelier to have non-spasms at the initial seizure onset. A total of 532 patients completed the first-line treatment; 273 patients received it for the first time at our hospital (initial response rates: 30.1% and 42.1%, respectively). The response group had a lower proportion of early-onset seizures (≤3 months) than the no-response group (11.3% vs. 23.7%, p < 0.01 and 11.3% vs. 21.5%, p = 0.03, respectively). Logistic regression analysis indicated that earlier initiation of first-line treatment was associated with a higher likelihood of an initial response. However, the etiological classification did not have a significant impact on the initial response. INTERPRETATION: IESS patients with structural abnormalities are more likely to present with non-spasm seizures at initial onset. Early initiation of first-line treatment is crucial; however, initial responses may be less favorable when seizures occur in early infancy.

Biventricular function after Ebstein anomaly repair from a single-center echocardiography study.

OBJECTIVE: We aimed to examine biventricular remodeling and function after Ebstein anomaly (EbA) surgical correction using echocardiographic techniques, particularly, the relations between the biventricular changes and the EbA types. METHODS: From April 2015 to August 2022, 110 patients with EbA were included in this retrospective study based on the Carpentier classification. Echocardiography assessments during the preoperative, early, and mid-term postoperative periods were performed. RESULTS: The 54 patients with types A and B EbA were included in group 1, whereas the 56 patients with types C and D were in group 2. Seventy-eight patients underwent surgical correction of EbA. The median age at operation was 8.8 years. During the mid-term follow-up, only 9.1% of the patients had moderate or severe tricuspid regurgitation. Right ventricular (RV) systolic function worsened in group 2 at discharge (fractional area change: 27.6 ± 11.2 vs. 35.4 ± 11.5 [baseline], P < 0.05; global longitudinal strain: -10.8 ± 4.4 vs. -17.9 ± 4.7 [baseline], P = 0.0001). RV function slowly recovered at a mean of 12 months of follow-up. Regarding left ventricular (LV) and RV systolic function, no statistical difference was found between before and after surgery in group 1. CONCLUSION: A high success rate of surgical correction of EbA, with an encouraging durability of the valve, was noted. Biventricular systolic function was maintained fairly in most patients with types A and B postoperatively. A late increase in RV systolic function after an initial reduction and unchanged LV systolic function were observed in the patients with types C and D postoperatively.

Design, synthesis and biological evaluation of 1-aryldonepezil analogues as anti-Alzheimer's disease agents.

Aim: To design and synthesize a novel series of 1-aryldonepezil analogues. Materials & methods: The 1-aryldonepezil analogues were synthesized through palladium/PCy3-catalyzed Suzuki reaction and were evaluated for cholinesterase inhibitory activities and neuroprotective effects. In silico docking of the most effective compound was conducted. Results: The 4-tert-butylphenyl analogue exhibited good inhibitory potency against acetylcholinesterase and butyrylcholinesterase and had a favorable neuroprotective effect on H2O2-induced SH-SY5Y cell injury. Conclusion: The 4-tert-butylphenyl derivative is a promising lead compound for anti-Alzheimer's disease drug development.

[Box: see text].

Single-Cell Spatial Transcriptomics Unveils Platelet-Fueled Cycling Macrophages for Kidney Fibrosis.

With the increasing incidence of kidney diseases, there is an urgent need to develop therapeutic strategies to combat post-injury fibrosis. Immune cells, including platelets, play a pivotal role in this repair process, primarily through their released cytokines. However, the specific role of platelets in kidney injury and subsequent repair remains underexplored. Here, the detrimental role of platelets in renal recovery following ischemia/reperfusion injury and its contribution to acute kidney injury  to chronic kidney disease transition is aimed to investigated. In this study, it is shown that depleting platelets accelerates injury resolution and significantly reduces fibrosis. Employing advanced single-cell and spatial transcriptomic techniques, macrophages as the primary mediators modulated by platelet signals is identified. A novel subset of macrophages, termed "cycling M2", which exhibit an M2 phenotype combined with enhanced proliferative activity is uncovered. This subset emerges in the injured kidney during the resolution phase and is modulated by platelet-derived thrombospondin 1 (THBS1) signaling, acquiring profibrotic characteristics. Conversely, targeted inhibition of THBS1 markedly downregulates the cycling M2 macrophage, thereby mitigating fibrotic progression. Overall, this findings highlight the adverse role of platelet THBS1-boosted cycling M2 macrophages in renal injury repair and suggest platelet THBS1 as a promising therapeutic target for alleviating inflammation and kidney fibrosis.

Rethinking therapeutic strategies of dual-target drugs: An update on pharmacological small-molecule compounds in cancer.

Oncogenes and tumor suppressors are well-known to orchestrate several signaling cascades, regulate extracellular and intracellular stimuli, and ultimately control the fate of cancer cells. Accumulating evidence has recently revealed that perturbation of these key modulators by mutations or abnormal protein expressions are closely associated with drug resistance in cancer therapy; however, the inherent drug resistance or compensatory mechanism remains to be clarified for targeted drug discovery. Thus, dual-target drug development has been widely reported to be a promising therapeutic strategy for improving drug efficiency or overcoming resistance mechanisms. In this review, we provide an overview of the therapeutic strategies of dual-target drugs, especially focusing on pharmacological small-molecule compounds in cancer, including small molecules targeting mutation resistance, compensatory mechanisms, synthetic lethality, synergistic effects, and other new emerging strategies. Together, these therapeutic strategies of dual-target drugs would shed light on discovering more novel candidate small-molecule drugs for the future cancer treatment.

[Clinical and genetic analysis of a child with West syndrome due to a de novo variant of NEXMIF gene].

OBJECTIVE: To investigate the clinical features and genetic variant of a child with West syndrome due to a variant of NEXMIF gene. METHODS: A child who was admitted to the First Medical Center of Chinese PLA General Hospital in March 2021 was selected as the study subject. Clinical data of the patient was collected. The child and his parents were subjected to whole exome sequencing. Candidate variant was verified by Sanger sequencing and pathogenicity analysis. RESULTS: The child, a 4-month-old boy, had presented with spastic seizures with no obvious cause. Abnormal EEG, severe hypsarrhythmia, and multiple spastic seizures were discovered. Cranial MRI revealed widening of the extracerebral space at the top of the frontal lobe. Physical examination revealed that the child could not hold his head up, and could not respond to sounds or follow objects with his eyes. He also has microcephaly, with height < 1 s. The child was diagnosed with West syndrome at a local hospital, and was given prednisone orally for 3 months, with seizures under control. Topiramate tablets were taken orally for maintenance treatment, and he has been seizure-free for 7 months. DNA sequencing revealed that he has harbored a de novo nonsense variant of c.982_c.983delTT (p.L328Dfs*23) in the NEXMIF gene. CONCLUSION: For children with West syndrome with severe developmental delay or even regression as the first symptoms, uncontrollable seizures and abnormal facial appearance, mutations of the NEXMIF gene should be suspected, and genetic testing can facilitate early diagnosis and treatment.

Lacticaseibacillus paracasei PS23 increases ghrelin levels and modulates microbiota composition: a post-hoc analysis of a randomized controlled study.

Muscle damage can occur due to excessive, high-intensity, or inappropriate exercise. It is crucial for athletes and sports enthusiasts to have access to ways that expedite their recovery and alleviate discomfort. Our previous clinical trial demonstrated the anti-inflammatory and muscle damage-ameliorating properties of Lacticaseibacillus paracasei PS23 (PS23), prompting us to further explore the role of this probiotic in muscle damage recovery. This post-hoc analysis of a randomized controlled study investigated potential mediators between the intake of PS23 and the prevention of strength loss after muscle damage. We recruited 105 students from a sports university who had participated in the previously published clinical trial. These participants were randomly allocated to three groups, receiving capsuled live PS23 (L-PS23), heat-treated PS23 (HT-PS23), or a placebo over a period of six weeks. Baseline and endpoint measurements were taken for the levels of circulating ghrelin and other blood markers, stress, mood, quality of life, and the fecal microbiota. A significant increase in ghrelin levels was recorded in the L-PS23 group compared to the other groups. Additionally, both L-PS23 and HT-PS23 interventions led to positive shifts in the gut microbiota composition, particularly in elevated Lacticaseibacillus, Blautia, and Lactobacillus populations. The abundance of these bacteria was positively correlated with exercise performance and inversely correlated with inflammatory markers. In conclusion, dietary supplementation with PS23 may enhance exercise performance and influence muscle damage by increasing ghrelin levels and modulating the gut microbiota composition. Further clarification of the possible mechanisms and clinical implications is required.

A rare case of an endobronchial mass due to Neurospora intermedia.

The ascomycete filamentous fungus Neurospora intermedia is commonly used in the food industry and considered nonpathogenic to humans. This study characterizes four N. intermedia isolates recovered from three patients. The first patient had a mediastinal germ cell tumor with multiple metastases. N. intermedia was recovered from his endotracheal aspirate and from the endobronchial mass obtained by bronchoscopic forceps biopsy. Histopathology of the biopsy tissue revealed necrotic tissue mixed with septate fungal hyphae with right-angle branching. An endobronchial mass caused by N. intermedia was thus diagnosed. Another two N. intermedia isolates were recovered from the endotracheal aspirates of two critically ill patients. In vitro, N. intermedia grows rapidly and forms orange, conidiating colonies composed of septate hyphae. Two isolates from the first patient belong to mating type a; the other two isolates belong to mating type A. Coculture of isolates of opposite mating types yielded dark ascomata containing ascospores, supporting that N. intermedia is a heterothallic fungus. N. intermedia isolates cross-reacted with the Aspergillus galactomannan antigen assay and were susceptible to amphotericin B and voriconazole. In conclusion, this report describes the first human infection (endobronchial mass) caused by N. intermedia, highlighting its potential to invade the human respiratory tract.

In-beam PET monitoring of proton therapy: a method for filtering prompt radiation events.

Objective. In-beam positron emission tomography (PET) is a promising technology for real-time monitoring of proton therapy. Random coincidences between prompt radiation events and positron annihilation photon pairs can deteriorate imaging quality during beam-on operation. This study aimed to improve the PET image quality by filtering out the prompt radiation events.Approach. We investigated a prompt radiation event filtering method based on the accelerator radio frequency phase and assessed its performance using various prompt gamma energy thresholds. An in-beam PET prototype was used to acquire the data when the 70 MeV proton beam irradiated a water phantom and a mouse. The signal-to-background ratio (SBR) indicator was utilized to evaluate the quality of the PET reconstruction image.Main results. The selection of the prompt gamma energy threshold will affect the quality of the reconstructed image. Using the optimal energy threshold of 580 keV can obtain a SBR of 1.6 times for the water phantom radiation experiment and 2.0 times for the mouse radiation experiment compared to those without background removal, respectively.Significance. Our results show that using this optimal threshold can reduce the prompt radiation events, enhancing the SBR of the reconstructed image. This advancement contributes to more accurate real-time range verification in subsequent steps.

Clinical Presentations and Intense FDG-avidity in Pulmonary Angiomatoid Fibrous Histiocytoma with Potential Diagnostic Pitfalls: A Case Report and Literature Review.

INTRODUCTION: Angiomatoid fibrous histiocytoma (AFH) is a borderline tumor usually affecting the the children or young adults. 18F-Fluorodexoyglucose (FDG) positron emission tomography/computed tomography (PET/CT) investigations of pulmonary AFH are rare, and there are currently no reports of intense FDG uptake in AFH. CASE REPORT: We report an AFH that occurred in the lung of a 57-year-old woman. She presented with paroxysmal cough and occasional bloodshot sputum. 18FFDG PET/CT revealed a right parahilar nodule with intense FDG-avidity, middle lobe atelectasis, and several bilateral axillary lymph nodes with mild hypermetabolic activity. This patient underwent a right middle lobe lobectomy via video-assisted thoracoscopy. Histopathologically, the diagnosis was pulmonary AFH. She had an uneventful postoperative course, and the bilateral axillary lymph nodes regressed during postoperative follow-up. CONCLUSIONS: The clinical presentation and image findings of patients with primary pulmonary AFH may be potential diagnosis pitfalls. The diagnosis of lymph nodes or distant metastases should be approached with caution. To avoid misdiagnosis, biopsy with histological examination and immunohistochemichal staining should be performed as early as possible.

Synchronous papillary and follicular thyroid carcinomas: the first retrospective cohort study and literature review.

Background: Papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) contribute to more than 95% of thyroid malignancies. However, synchronous PTC and FTC are less common; it is most commonly discovered incidentally as synchronous malignancies during operation, which adds difficulties to intraoperative decision-making and postoperative treatment. Therefore, we analyzed the clinicopathological characteristics and prognosis of patients with PTC and FTC in our center. Methods: We conducted a search of single PTC, single FTC, and synchronous PTC/FTC patients who received initial surgery treatment at Fudan University Shanghai Cancer Center from 2006 to 2018 and collected paraffin-embedded samples of synchronous patients. Clinicopathological characteristics were collected from the electronic medical record system. Follow-up was performed through telephone contact or medical records. Exome sequencing was performed by ThyroLead panel. Results: Total of 42 synchronous PTC/FTC patients, 244 single FTC patients, and 2,959 single PTC patients were included. It showed a similarity between the clinicopathological features of synchronous thyroid cancer patients and single PTC patients, with a greater proportion of females, higher probabilities of lymph node metastasis, and higher rate of concurrence of Hashimoto's disease. The disease-free survival (DFS) curve indicated a worse prognosis of the synchronous group and single PTC group compared to the single FTC group, who had a propensity for neck lymph node recurrence; however, logistic multivariate regression analysis did not find any factor related to recurrence in the synchronous group. After re-checking pathology, DNA extraction, and quality control, genetic alteration information of 62 samples including primary tumors and metastatic lymph nodes from 35 synchronous cancer patients was displayed. In total, 81 mutations and 1 fusion gene were identified, including mutations related to outcomes and targeted therapy. Besides, some rare mutations in thyroid cancer were found in these patients. Conclusions: To conclude, synchronous PTC/FTC tend to be incidentally discovered during or after operation, behaving more like single PTC. The prognosis of synchronous patients is worse than that of single FTC patients and supplemental cervical lymph node dissection, total thyroidectomy, and postoperative radioiodine therapy should be taken into consideration after diagnosis. The next-generation sequencing (NGS) showed a unique molecular feature of synchronous patients with some rare mutations.

Klebsiella pneumoniae alters zebrafish circadian rhythm via inflammatory pathways and is dependent on light cues.

Klebsiella pneumoniae is an opportunistic pathogen causing severe infections. The circadian rhythm is the internal rhythm mechanism of an organism and plays an important role in coping with changes in the 24-h circadian rhythm. Disruption of the circadian rhythm can lead to immune, behavioral, mental, and other related disorders. Whether K. pneumoniae can disrupt the circadian rhythm after infection remains unclear. Here, we examined the effects of K. pneumoniae NTUH-K2044 infection on biological rhythm and inflammation in zebrafish using behavioral assays, quantitative real-time reverse transcription PCR, neutrophil and macrophage transgenic fish, and drug treatment. The results showed that K. pneumoniae infection decreased the motor activity of zebrafish and reduced the circadian rhythm amplitude, phase, and period. The expression of core circadian rhythm-associated genes increased under light-dark conditions, whereas they were downregulated under continuous darkness. Analysis of Klebsiella pneumoniae-mediated inflammation using Tg(mpx:EGFP) and Tg(mpeg:EGFP) transgenic zebrafish, expressing fluorescent neutrophils and macrophages, respectively, showed increased induction of inflammatory cells, upregulated expression of inflammatory factor genes, and stronger inflammatory responses under light-dark conditions. These effects were reversed by the anti-inflammatory drug G6PDi-1, and the expression of clock genes following K. pneumoniae treatment was disrupted. We determined the relationship among K. pneumoniae, inflammation, and the circadian rhythm, providing a theoretical reference for studying circadian rhythm disorders caused by inflammation.

A multi-view graph contrastive learning framework for deciphering spatially resolved transcriptomics data.

Spatially resolved transcriptomics data are being used in a revolutionary way to decipher the spatial pattern of gene expression and the spatial architecture of cell types. Much work has been done to exploit the genomic spatial architectures of cells. Such work is based on the common assumption that gene expression profiles of spatially adjacent spots are more similar than those of more distant spots. However, related work might not consider the nonlocal spatial co-expression dependency, which can better characterize the tissue architectures. Therefore, we propose MuCoST, a Multi-view graph Contrastive learning framework for deciphering complex Spatially resolved Transcriptomic architectures with dual scale structural dependency. To achieve this, we employ spot dependency augmentation by fusing gene expression correlation and spatial location proximity, thereby enabling MuCoST to model both nonlocal spatial co-expression dependency and spatially adjacent dependency. We benchmark MuCoST on four datasets, and we compare it with other state-of-the-art spatial domain identification methods. We demonstrate that MuCoST achieves the highest accuracy on spatial domain identification from various datasets. In particular, MuCoST accurately deciphers subtle biological textures and elaborates the variation of spatially functional patterns.

Expanding the clinical phenotype and genetic spectrum of GEMIN5 disorders: Early-infantile developmental and epileptic encephalopathies.

BACKGROUND: Several biallelic truncating and missense variants of the gem nuclear organelle-associated protein 5 (GEMIN5) gene have been reported to cause neurodevelopmental disorders characterized by cerebellar atrophy, intellectual disability, and motor dysfunction. However, the association between biallelic GEMIN5 variants and early-infantile developmental and epileptic encephalopathies (EIDEEs) has not been reported. PURPOSE: This study aimed to expand the phenotypic spectrum of GEMIN5 and explore the correlations between epilepsy and molecular sub-regional locations. METHODS: We performed whole-exome sequencing in two patients with EIDEE with unexplained etiologies. The damaging effects of variants were predicted using multiple in silico tools and modeling. All reported patients with GEMIN5 pathogenic variants and detailed neurological phenotypes were analyzed to evaluate the genotype-phenotype relationship. RESULTS: Novel biallelic GEMIN5 variants were identified in two unrelated female patients with EIDEE, including a frameshift variant (Hg19, chr5:154284147-154284148delCT: NM_015465: c.2551_c.2552delCT: p.(Leu851fs*30)), a nonsense mutation (Hg19, chr5:154299603-154299603delTinsAGA: NM_015465: c.1523delTinsAGA: p.(Leu508*)), and two missense variants (Hg19, chr5:154282663T > A: NM_015465: c.2705T > A: p.(Leu902Gln) and Hg19, chr5:154281002C > G: NM_015465: c.2911C > G: p.(Gln971Glu)), which were inherited from asymptomatic parents and predicted to be damaging or probably damaging using in silico tools. Except p.Leu508*, all these mutations are located in tetratricopeptide repeat (TPR) domain. Our two female patients presented with seizures less than 1 month after birth, followed by clusters of spasms. Brain magnetic resonance imaging suggests dysgenesis of the corpus callosum and cerebellar hypoplasia. Video electroencephalogram showed suppression-bursts. Through a literature review, we found 5 published papers reporting 48 patients with biallelic variants in GEMIN5. Eight of 48 patients have epilepsy, and 5 patients started before 1 year old, which reminds us of the relevance between GEMIN5 variants and EIDEE. Further analysis of the 49 GEMIN5 variants in those 50 patients demonstrated that variants in TPR-like domain or RBS domain were more likely to be associated with epilepsy. CONCLUSIONS: We found novel biallelic variants of GEMIN5 in two individuals with EIDEE and expanded the clinical phenotypes of GEMIN5 variants. It is suggested that the GEMIN5 gene should be added to the EIDEE gene panel to aid in the clinical diagnosis of EIDEE and to help determine patient prognosis.

Rapid Access to Tigliane, Ingenane, and Rhamnofolane Diterpenes from a Lathyrane Precursor via Biomimetic Skeleton Transformation Strategy.

Bioinspired skeleton transformation of a tricyclic lathyrane-type Euphorbia diterpene was conducted to efficiently construct a tetracyclic tigliane diterpene on a gram scale via a key aldol condensation. The tigliane diterpene was then respectively converted into naturally rare ingenane and rhamnofolane diterpenes through a semipinacol rearrangement and a visible-light-promoted regioselective cyclopropane ring-opening reaction. This work provides a concise strategy for high-efficiency access to diverse polycyclic Euphorbia diterpene skeletons from abundant lathyrane-type natural products and paves the way for biological activity investigation of naturally rare molecules.

Potassium affects the association between dietary intake of vitamin C and NAFLD among adults in the United States.

INTRODUCTION: Although the association between nonalcoholic fatty liver disease (NAFLD) and vitamin C has been well studied, the effects of dietary potassium intake on this relationship are still unclear. Thus, this study aimed to determine the effects of dietary potassium intake on the association between vitamin C and NAFLD. METHODS: We performed a cross-sectional learn about with 9443 contributors the usage of 2007-2018 NHANES data. Multiple logistic regression evaluation has been utilized to check out the affiliation of dietary vitamin C intake with NAFLD and advanced hepatic fibrosis (AHF). Subsequently, we plotted a smoothed match curve to visualize the association. Especially, the analysis of AHF was conducted among the NAFLD population. In addition, stratified evaluation used to be developed primarily based on demographic variables to verify the steadiness of the results. Effect amendment by way of dietary potassium intake used to be assessed via interplay checks between vitamin C and NAFLD in the multivariable linear regression. RESULTS: In this cross-sectional study, we found that vitamin C was negatively related to NAFLD and AHF. The relationship between vitamin C and NAFLD was different in the low, middle and high potassium intake groups. Furthermore, potassium intake significantly modified the negative relationship between vitamin C and NAFLD in most of the models. CONCLUSION: Our research showed that potassium and vitamin C have an interactive effect in reducing NAFLD, which may have great importance for clinical medication.