Allele-specific RNA N 6-methyladenosine modifications reveal functional genetic variants in human tissues.

An intricate network of cis- and trans-elements acts on RNA N 6-methyladenosine (m6A), which in turn may affect gene expression and, ultimately, human health. A complete understanding of this network requires new approaches to accurately measure the subtle m6A differences arising from genetic variants, many of which have been associated with common diseases. To address this gap, we developed a method to accurately and sensitively detect transcriptome-wide allele-specific m6A (ASm6A) from MeRIP-seq data and applied it to uncover 12,056 high-confidence ASm6A modifications from 25 human tissues. We also identified 1184 putative functional variants for ASm6A regulation, a subset of which we experimentally validated. Importantly, we found that many of these ASm6A-associated genetic variants were enriched for common disease-associated and complex trait-associated risk loci, and verified that two disease risk variants can change m6A modification status. Together, this work provides a tool to detangle the dynamic network of RNA modifications at the allelic level and highlights the interplay of m6A and genetics in human health and disease.

Heterozygous variants in USP25 cause genetic generalized epilepsy.

USP25 encodes ubiquitin-specific proteases 25, a key member of deubiquitinating enzyme family and is involved in neural fate determination. Although abnormal expression in Down's syndrome was reported previously, the specific role of USP25 in human diseases has not been defined. In this study, we performed trio-based whole exome sequencing in a cohort of 319 cases (families) with generalized epilepsy of unknown etiology. Five heterozygous USP25 variants including two de novo and three co-segregated variants were determined in eight individuals affected by generalized seizures and/or febrile seizures from five unrelated families. The frequency of USP25 variants showed a significantly high aggregation in this cohort compared to the East Asian population and all populations in the gnomAD database. The mean onset ages of febrile and afebrile seizures were 10 months (infancy) and 11.8 years (juvenile), respectively. The patients achieved seizure freedom except one had occasional nocturnal seizures at the last follow-up. Two patients exhibited intellectual disability. Usp25 was ubiquitously expressed in mouse brain with two peaks on embryonic days (E14‒E16) and postnatal day 21, respectively. Similarly, USP25 expressed in fetus/early childhood stage with a second peak at approximately 12‒20 years old in human brain, consistent with the seizure onset age at infancy and juvenile in the patients. To investigate the functional impact of USP25 deficiency in vivo, we established Usp25 knock-out mice, which showed increased seizure susceptibility compared to wild-type mice in pentylenetetrazol-induced seizure test. To explore the impact of USP25 variants, we employed multiple functional detections. In HEK293T cells, the severe phenotype associated variant (p.Gln889Ter) led to a significant reduction of mRNA and protein expressions but formed a stable truncated dimers with increment of deubiquitinating enzyme activities and abnormal cellular aggregations, indicating a gain-of-function effect. The p.Gln889Ter and p.Leu1045del increased neuronal excitability in mice brain, with a higher firing ability in p.Gln889Ter. These functional impairments align with the severity of the observed phenotypes, suggesting a genotype-phenotype correlation. Hence, a moderate association between USP25 and epilepsy was noted, indicating USP25 is potentially a predisposing gene for epilepsy. Our results from Usp25 null mice and the patient-derived variants indicated that USP25 would play epileptogenic role via loss-of-function or gain-of-function effects. The truncated variant p.Gln889Ter would have profoundly different effect on epilepsy. Together, our results underscore the significance of USP25 heterozygous variants in epilepsy, thereby highlighting the critical role of USP25 in the brain.

Rational Design of High-Performance Electrodes Based on Ferric Oxide Nanosheets Deposited on Reduced Graphene Oxide for Advanced Hybrid Supercapacitors.

The core strategy for constructing ultra-high-performance hybrid supercapacitors is the design of reasonable and effective electrode materials. Herein, a facile solvothermal-calcination strategy is developed to deposit the phosphate-functionalized Fe2O3 (P-Fe2O3) nanosheets on the reduced graphene oxide (rGO) framework. Benefiting from the superior conductivity of rGO and the high conductivity and fast charge storage dynamics of phosphate ions, the synthesized P-Fe2O3/rGO anode exhibits remarkable electrochemical performance with a high capacitance of 586.6 F g-1 at 1 A g-1 and only 4.0% capacitance loss within 10 000 cycles. In addition, the FeMoO4/Fe2O3/rGO nanosheets are fabricated by utilizing Fe2O3/rGO as the precursor. The introduction of molybdates successfully constructs open ion channels between rGO layers and provides abundant active sites, enabling the excellent electrochemical features of FeMoO4/Fe2O3/rGO cathode with a splendid capacity of 475.4 C g-1 at 1 A g-1. By matching P-Fe2O3/rGO with FeMoO4/Fe2O3/rGO, the constructed hybrid supercapacitor presents an admirable energy density of 82.0 Wh kg-1 and an extremely long working life of 95.0% after 20 000 cycles. Furthermore, the continuous operation of the red light-emitting diode for up to 30 min demonstrates the excellent energy storage properties of FeMoO4/Fe2O3/rGO//P-Fe2O3/rGO, which provides multiple possibilities for the follow-up energy storage applications of the iron-based composites.

Optimal exposure of mycophenolic acid for induction therapy of childhood lupus nephritis patients: an observational cohort study.

OBJECTIVES: Mycophenolic acid (MPA) is recommended for lupus nephritis (LN) treatment, but with large inter-individual variability in pharmacokinetics (PK). The aim of this study is to reveal the relationship between MPA exposure and disease response and adverse drug reactions in pediatric LN patients. METHOD: This was a population-based observational cohort study. A total of 86 pediatric LN patients treated with mycophenolate mofetil (MMF) for induction therapy were enrolled. The area-under the concentration-time curve (AUC) was calculated using MPA concentrations according to a limited sampling strategy. Receiver operating characteristic analysis was performed to assess the MPA-AUC threshold values. The cumulative incidence of renal remission and inactive systemic lupus erythematosus (SLE) over time was evaluated by Kaplan-Meier's analysis. RESULTS: MPA-AUC was identified as an independent factor associated with renal remission and lupus activity at 6 and 12 months after MMF treatment, and the improved renal remission rates were correlated with higher MPA-AUC, with thresholds of 29.81 and 30.63 µg·h·mL-1 at 6 months and 12 months, respectively. Furthermore, the thresholds for maintaining the hypoactive state of LN were 30.96 and 31.19 µg·h·mL-1at 6 months and 12 months, respectively. Patients reaching target thresholds for MPA-AUC achieved renal response or stable disease earlier. In addition, the MPA-AUC threshold for decreasing MMF-related adverse reactions was 50.80 µg·h·mL-1. CONCLUSION: The initial and long-term treatments of pediatric LN patients with MMF should be individualized according to the MPA-AUC, and the recommended MPA exposure is 31.19-50.80 µg·h·mL-1.

Computer holography using deep neural network with Fourier basis.

The use of a deep neural network is a promising technique for rapid hologram generation, where a suitable training dataset is vital for the reconstruct quality as well as the generalization of the model. In this Letter, we propose a deep neural network for phase hologram generation with a physics-informed training strategy based on Fourier basis functions, leading to orthonormal representations of the spatial signals. The spatial frequency characteristics of the reconstructed diffraction fields can be regulated by recombining the Fourier basis functions in the frequency domain. Numerical and optical results demonstrate that the proposed method can effectively improve the generalization of the model with high-quality reconstructions.

Efficacy and safety of multi-target therapy in children with lupus nephritis.

BACKGROUND: To analyze the efficacy and safety of multi-target therapy in children with lupus nephritis (LN). METHODS: In our retrospective study from January 2009 to December 2021, the multi-target therapy of glucocorticoids, MMF and tacrolimus was adopted as induction therapy or re-induction therapy for 36 LN children who had combined proliferative and membranous LN or for who were ineffective to combination therapy of glucocorticoids with IV-CYC or MMF for at least 6 months. The clinical and pathological data were collected and analyzed. RESULTS: The levels of 24-h urinary protein, anti-dsDNA antibody and SLE disease activity index were decreased, while the levels of albumin and complement 3 were increased after multi-target therapy. More than 90% of LN children achieved partial or complete remission within 6 months. In terms of adverse effects, there was no significant difference between the level of eGFR before and after multi-target therapy. During the follow-up period, four children had infection, two children had hyperuricemia, and one child had liver dysfunction. All of them improved after symptomatic therapy. CONCLUSIONS: Multi-target therapy could be an effective treatment option with minimal adverse effects for LN children who are refractory to initial first-line induction therapies or had combined proliferative and membranous LN. IMPACT: The multi-target therapy of glucocorticoids, mycophenolate mofetil and tacrolimus was adopted in 36 children with lupus nephritis. Multi-target therapy could be an effective treatment option for lupus nephritis children who are refractory to initial first-line induction therapies or had combined proliferative and membranous lupus nephritis. Adverse effects of multi-target therapy were infrequent and minimal that can be improved by symptomatic therapy.

Clinicopathologic features in childhood-onset lupus nephritis with antineutrophil cytoplasmic antibody positivity--a multi-center retrospective study.

BACKGROUND: Positive antineutrophil cytoplasmic antibody (ANCA) serology in adult-onset lupus nephritis (LN) is associated with more active disease and distinct renal pathology, but data with respect to childhood-onset LN remain scarce. Here, we aimed to determine the impact of positive ANCA serology on clinical and histopathologic features and renal outcomes in children with LN from multiple centers. METHODS: Clinical and histopathologic data of 61 ANCA-positive and 330 ANCA-negative LN children (1

Incidence of relapse and frequently relapsing/steroid-dependent nephrotic syndrome in Chinese children with steroid-sensitive nephrotic syndrome: A cohort study.

AIM: This study aimed to investigate the incidence of relapse and FR/SDNS in Chinese children with SSNS and to develop clinical prediction models for relapse and FR/SDNS. METHODS: This retrospective cohort study involved 339 newly onset SSNS patients between 2006 and 2016. The incidence of relapse and FR/SDNS were estimated using the Kaplan-Meier method. Prediction models were constructed based on Cox proportional-hazards regression. RESULTS: The median follow-up time was 8.7 years. The cumulative incidence of relapse at 1-, 2-, and 5-year was 51.0%, 62.5%, and 66.6%. The cumulative incidence of FR/SDNS at 1-, 2-, and 5-year was 18.4%, 29.0%, and 32.9%. The final prediction model for first relapse included four variables (serum albumin, triglycerides, IgM, and time to first remission). The model's discriminative ability was low (Harrell's C index = 0.62). The final prediction model for FR/SDNS included four variables (serum albumin, lipoprotein(a), time to first remission, and time to first relapse). The discrimination and calibration of the prediction model for FR/SDNS were acceptable (Harrell's C index = 0.73, Brier score at 1- and 2-year were 0.11 and 0.17). CONCLUSION: The first relapse and FR/SDNS mainly occurred in the first 2 years after initial SSNS onset. The prediction model for relapse developed using common clinical parameters performed poorly, while the prediction model for FR/SDNS might be useful.

Misdiagnosed Branchio-Oto-Renal syndrome presenting as proteinuria and renal insufficiency with insidious signs since early childhood: a report of three cases.

BACKGROUND: Branchio-oto-renal (BOR) syndrome is an inherited multi-systemic disorder. Auricular and branchial signs are highly suggestive of BOR syndrome but often develop insidiously, leading to a remarkable misdiagnosis rate. Unlike severe morphological abnormalities of kidneys, knowledge of glomerular involvement in BOR syndrome were limited. CASE PRESENTATION: Three cases, aged 8 ~ 9 years, visited pediatric nephrology department mainly for proteinuria and renal insufficiency, with 24-h proteinuria of 23.8 ~ 68.9 mg/kg and estimated glomerular filtration rate of 8.9 ~ 36.0 mL/min/1.73m2. Moderate-to-severe albuminuria was detected in case 1, while mixed proteinuria was detected in case 2 and 3. Insidious auricular and branchial fistulas were noticed, all developing since early childhood but being neglected previously. EYA1 variants were confirmed by genetic testing in all cases. Delay in diagnosis was 8 ~ 9 years since extra-renal appearances, and 0 ~ 6 years since renal abnormalities. In case 1, therapy of glucocorticoid and immunosuppressive agents to accompanying immune-complex mediated glomerulonephritis was unsatisfying. CONCLUSIONS: BOR syndrome is a rare cause of proteinuria and abnormal kidney function and easily missed, thus requiring more awareness. Careful medical history taking and physical examination are essential to early diagnosis. Massive proteinuria was occasionally seen in BOR syndrome, which might be related to immune complex deposits. A novel pathogenic variant (NM_000503.6 (EYA1): c.1171delT p.Ser391fs*9) was firstly reported.

Model-Based Predictive Control and Reinforcement Learning for Planning Vehicle-Parking Trajectories for Vertical Parking Spaces.

This paper proposes a vehicle-parking trajectory planning method that addresses the issues of a long trajectory planning time and difficult training convergence during automatic parking. The process involves two stages: finding a parking space and parking planning. The first stage uses model predictive control (MPC) for trajectory tracking from the initial position of the vehicle to the starting point of the parking operation. The second stage employs the proximal policy optimization (PPO) algorithm to transform the parking behavior into a reinforcement learning process. A four-dimensional reward function is set to evaluate the strategy based on a formal reward, guiding the adjustment of neural network parameters and reducing the exploration of invalid actions. Finally, a simulation environment is built for the parking scene, and a network framework is designed. The proposed method is compared with the deep deterministic policy gradient and double-delay deep deterministic policy gradient algorithms in the same scene. Results confirm that the MPC controller accurately performs trajectory-tracking control with minimal steering wheel angle changes and smooth, continuous movement. The PPO-based reinforcement learning method achieves shorter learning times, totaling only 30% and 37.5% of the deep deterministic policy gradient (DDPG) and twin-delayed deep deterministic policy gradient (TD3), and the number of iterations to reach convergence for the PPO algorithm with the introduction of the four-dimensional evaluation metrics is 75% and 68% shorter compared to the DDPG and TD3 algorithms, respectively. This study demonstrates the effectiveness of the proposed method in addressing a slow convergence and long training times in parking trajectory planning, improving parking timeliness.

Speckle-free compact holographic near-eye display using camera-in-the-loop optimization with phase constraint.

We present a compact holographic near-eye display system with high-quality speckle-free optical reconstructions using camera-in-the-loop (CITL) optimization with phase constraint strategy. The CITL optimization with phase constraint is used to iteratively synthesize the computer-generated holograms (CGHs) based on the in-system optical feedback. The phase constraint embedded into the whole CGH optimization process can effectively smooth the phase profile of reconstructed wave field, which helps to suppress the speckle noise caused by the phase singularities in CGH reconstruction. Numerical and optical experiments have been performed to demonstrate that the proposed method can provide speckle-free optical reconstructions with excellent image fidelity for holographic near-eye display in a compact setup.

Application of adrenocorticotropic hormone in recurrent focal segmental glomerulosclerosis post-transplantation: A case report and literature review.

BACKGROUND: The recurrence rate of focal segmental glomerulosclerosis (FSGS) post-renal transplantation is as high as 30%-50%. However, the pathogenesis is unclear. At present, there is no unified standard for the treatment of recurrent FSGS post-transplantation. Its treatment is full of risks and challenges. METHODS: We report a child with recurrent FSGS with massive proteinuria 6~9 g/m2 /day and resistance to plasma exchange (PE) and rituximab (RTX). On the basis of receiving anti-rejection therapy of prednisone, tacrolimus, and mycophenolate mofetil (MMF), we treated the child with adrenocorticotropic hormone (ACTH), and reviewed the literature on the application of ACTH in the recurrence of FSGS post-transplantation. RESULTS: After 1 year of treatment with ACTH, the patient's urinary protein decreased and fluctuated between 0.6 and 1.1 g/m2 /day. The albumin (ALB) and cholesterol (CHOL) returned to the normal range. The patient achieved complete remission after 19 months of ACTH treatment and maintained until now. There was no obvious adverse reaction. Literature review showed that up to February 2021, a total of 8 studies showed the use of ACTH in kidney transplant patients, and all the patients in the study achieved remission. CONCLUSIONS: ACTH is a potential option for treating recurrent FSGS post-transplantation with fewer side effects and relatively safe for patients. However, further evaluation is needed to better adapt to different populations.

A perspective on the diagnosis of cracked tooth: imaging modalities evolve to AI-based analysis.

Despite numerous clinical trials and pre-clinical developments, the diagnosis of cracked tooth, especially in the early stages, remains a challenge. Cracked tooth syndrome is often accompanied by dramatic painful responses from occlusion and temperature stimulation, which has become one of the leading causes for tooth loss in adults. Current clinical diagnostical approaches for cracked tooth have been widely investigated based on X-rays, optical light, ultrasound wave, etc. Advances in artificial intelligence (AI) development have unlocked the possibility of detecting the crack in a more intellectual and automotive way. This may lead to the possibility of further enhancement of the diagnostic accuracy for cracked tooth disease. In this review, various medical imaging technologies for diagnosing cracked tooth are overviewed. In particular, the imaging modality, effect and the advantages of each diagnostic technique are discussed. What's more, AI-based crack detection and classification methods, especially the convolutional neural network (CNN)-based algorithms, including image classification (AlexNet), object detection (YOLO, Faster-RCNN), semantic segmentation (U-Net, Segnet) are comprehensively reviewed. Finally, the future perspectives and challenges in the diagnosis of the cracked tooth are lighted.

Dyslipidemia may be a risk factor for progression in children with IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is often chronically progressive and commonly accompanied by dyslipidemia. However, the intrinsic relationship between dyslipidemia and IgAN remains to be elucidated. This study aimed to investigate the impact of different types of dyslipidemia on clinical and pathological characteristics in children with IgAN. METHODS: In our retrospective cohort study from January 2006 to January 2021, 276 children with IgAN were ultimately included in the baseline analysis, and 169 were included in the follow-up analysis. The clinical and pathological features of different types of dyslipidemia and their effect on kidney prognosis were analyzed. RESULTS: Children in the dyslipidemia group had more severe clinical characteristics (higher blood urea nitrogen, serum uric acid, and 24-h proteinuria; higher proportion of hypertension; and lower serum albumin and estimated glomerular filtration rate) and pathological changes (higher proportion of Lee grades IV-V and E1, S1, and C2 in MEST-C). Furthermore, the clinical and pathological characteristics were worse in the mixed hyperlipidemia group. Multivariate logistic analysis showed that hypertension, steroid treatment, lower serum albumin, severe proteinuria, and segmental glomerulosclerosis were independent risk factors for dyslipidemia in children with IgAN. The Kaplan-Meier analysis revealed that the probability of kidney survival in children with dyslipidemia was lower than that in those without dyslipidemia, with a median follow-up of 5.9 years. CONCLUSIONS: Children with IgAN and dyslipidemia, especially mixed hyperlipidemia, are prone to more severe clinical and pathological changes. Our study provides further insight into dyslipidemia as a potential risk factor in children with IgAN. A higher resolution version of the Graphical abstract is available as Supplementary information.

Classification and rising medication therapy in stiff skin syndrome: A case report and literature review.

Stiff skin syndrome (SSS) is a rare disorder characterized by skin induration and limited joint mobility in the absence of visceral, musculoskeletal, vascular, or immunologic abnormalities. Distinctive subsets of SSS could be distinguished by various manifestation and mechanism, which accounts for the high heterogeneity in SSS cases. Although rehabilitation training remains the mainstay of management, rising medications has drawn awareness in recent years, owing to the potential efficacy. Nevertheless, experience was limited, especially in widespread SSS. We report on a 5-year-old girl with widespread SSS, whose lesion stopped progressing after combination therapy by mycophenolic acid (MPA) and losartan (LST) in addition to rehabilitation exercise. Despite limited experience, a combined therapy of MPA and LST seems to be effective in retarding progression of widespread SSS.

Optimized Fresnel phase hologram for ringing artifacts removal in lensless holographic projection.

Ringing artifacts are the main noise sources in holographic projection when the quadratic phase is introduced to suppress speckle noise. In this study, the mechanisms of ringing artifacts on reconstructed images are theoretically analyzed, which illustrates the ringing artifacts are related to the bandwidth properties of the reconstructed wave field. Based on the frequency analysis, a band-limited iterative algorithm is proposed to optimize the phase hologram in the Fresnel domain. The proposed method can effectively suppress the ringing artifacts as well as the speckle noise of the Fresnel hologram by optimizing the phase distribution with bandwidth constraint. Numerical simulations and optical experiments have been performed to validate the proposed method for providing quality reconstructions in lensless holographic projection.

Phase hologram optimization with bandwidth constraint strategy for speckle-free optical reconstruction.

An iterative method with bandwidth constraint strategy is proposed to design phase holograms for high-quality speckle-free optical reconstruction. The bandwidth properties of the reconstructed field are analyzed theoretically based on the sampling theory, which helps in properly allocating the sampling resources for efficiently describing the speckles and artifacts in the reconstructed field. Iterative calculation with bandwidth constraint strategy of the reconstructed field and quadratic initial phase can optimize the phase hologram without stagnation problem, which provides effective controls of the reconstructed intensity fluctuations and helps to suppress the speckles and artifacts. Numerical and optical experiments have been performed to validate the proposed method can achieve excellent image fidelity.

[Clinicopathological features of children with lupus nephritis with positive antineutrophil cytoplasmic antibody].

OBJECTIVE: To study the clinicopathological features of children with lupus nephritis (LN) with positive anti-neutrophil cytoplasmic antibody (ANCA). METHODS: A retrospective analysis was performed for the children who were diagnosed with LN in the First Affiliated Hospital of Sun Yat-sen University from January 2003 to December 2019. According to the results of serum ANCA, they were divided into two groups: ANCA-positive group (n=59) and ANCAnegative group (n=454). The two groups were compared in terms of clinical manifestations, histopathological features, remission rate, and prognosis. RESULTS: Compared with the ANCA-negative group, the ANCA-positive group had a significant reduction in leukocytes and a significant increase in erythrocyte sedimentation rate (P < 0.05). There were no significant differences between the two groups in serum creatinine, urine protein, and urine red blood cell count (P > 0.05). A total of 308 children underwent kidney biopsy. The results on light microscopy showed that compared with the ANCAnegative group, the ANCA-positive group had a significantly higher proportion of children with cellular fibrous crescents (P < 0.05) and a significantly lower proportion of children with immune complex deposition (P < 0.05). There were no significant differences between the two groups in the remission rate and survival rate (P > 0.05). CONCLUSIONS: Children with ANCA-positive LN tend to have more severe renal pathological injury, which is not exactly parallel with clinical manifestations, suggesting that timely renal biopsy is of great importance.

Non-iterative phase hologram generation with optimized phase modulation.

A non-iterative algorithm is proposed to generate phase holograms with optimized phase modulation. A quadratic initial phase with continuous distributed spectrum is utilized to iteratively optimize the phase modulation in the reconstruction plane, which can be used as an optimized phase distribution for arbitrary target images. The phase hologram can be calculated directly according to the modulated wave field distribution in the reconstruction plane. Fast generation of the phase holograms can be achieved by this non-iterative implementation, and the avoidance of the random phase modulation helps to suppress the speckle noise. Numerical and optical experiments have demonstrated that the proposed method can efficiently generate phase holograms with quality reconstructions.

Early diagnosis and successful treatment of cytomegalovirus peritonitis in children with primary nephrotic syndrome: case series and literature review.

Cytomegalovirus (CMV) is a major pathogen in immunocompromised population and CMV infections in immunocompromised patients cause substantial morbidity and mortality. The common clinical manifestations of CMV infection are pneumonia, hepatitis, colitis and so on, while CMV peritonitis without gut perforation is rare. Reviewing the literature, CMV peritonitis in patients with nephrotic syndrome (NS) had not been reported. Only four cases of CMV peritonitis without gut perforation were reported in adults with other diseases. Two cases were diagnosed by reverse-transcription polymerase chain reaction (RT-PCR) of ascites while the other two cases by histopathological examination of peritoneal tissue. We report four cases of primary nephrotic syndrome complicated with CMV peritonitis. Four cases all diagnosed by RT-PCR of ascites (659-455 000 copies/mL). We mainly discusses the diagnosis and treatment of CMV peritonitis without gut perforation.