Effective Manipulation of a Colossal Second-Order Transverse Response in an Electric-Field-Tunable Graphene Moiré System.

The second-order nonlinear transport illuminates a frequency-doubling response emerging in quantum materials with a broken inversion symmetry. The two principal driving mechanisms, the Berry curvature dipole and the skew scattering, reflect various information including ground-state symmetries, band dispersions, and topology of electronic wave functions. However, effective manipulation of them in a single system has been lacking, hindering the pursuit of strong responses. Here, we report on the effective manipulation of the two mechanisms in a single graphene moiré superlattice, AB-BA stacked twisted double bilayer graphene. Most saliently, by virtue of the high tunability of moiré band structures and scattering rates, a record-high second-order transverse conductivity ∼ 510 µm S V-1 is observed, which is orders of magnitude higher than any reported values in the literature. Our findings establish the potential of electrically tunable graphene moiré systems for nonlinear transport manipulations and applications.

Cardiac function evaluation in children with spinal muscular atrophy: A case-control study.

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by degeneration of lower motor neurons, resulting in progressive muscle weakness and atrophy. However, little is known regarding the cardiac function of children with SMA. METHODS: We recruited SMA patients younger than 18 years of age from January 1, 2022, to April 1, 2022, in the First Affiliated Hospital of Sun Yat-sen University. All patients underwent a comprehensive cardiac evaluation before treatment, including history taking, physical examination, blood tests of cardiac biomarkers, assessment of echocardiography and electrocardiogram. Age/gender-matched healthy volunteers were recruited as controls. RESULTS: A total of 36 SMA patients (26 with SMA type 2 and 10 with SMA type 3) and 40 controls were enrolled in the study. No patient was clinically diagnosed with heart failure. Blood tests showed elevated values of creatine kinase isoenzyme M and isoenzyme B (CK-MB) mass and high-sensitivity cardiac troponin T (hs-cTnT) in spinal muscular atrophy (SMA) patients. Regarding echocardiographic parameters, SMA children were detected with lower global left and right ventricular longitudinal strain, abnormal diastolic filling velocities of trans-mitral and trans-tricuspid flow. The results revealed no clinical heart dysfunction in SMA patients, but subclinical ventricular dysfunction was seen in SMA children including the diastolic function and myocardial performance. Some patients presented with elevated heart rate and abnormal echogenicity of aortic valve or wall. Among these SMA patients, seven patients (19.4%) had scoliosis. The Cobb's angles showed a significant negative correlation with LVEDd/BSA, but no correlation with other parameters, suggesting that mild scoliosis did not lead to significant cardiac dysfunction. CONCLUSIONS: Our findings warrant increased attention to the cardiac status and highlight the need to investigate cardiac interventions in SMA children.

Causal links between sedentary behavior, physical activity, and psychiatric disorders: a Mendelian randomization study.

BACKGROUND: Studies suggest a correlation between excessive sedentary behavior, insufficient physical activity, and an elevated likelihood of experiencing psychiatric disorder. Nonetheless, the precise influence of sedentary behavior and physical activity on psychiatric disorder remains uncertain. Hence, the objective of this research was to investigate the possible causal relationship between sedentary behavior, physical activity, and the susceptibility to psychiatric disorder (depression, schizophrenia and bipolar disorder), utilizing a two-sample Mendelian randomization (MR) approach. METHODS: Potential genetic instruments related to sedentary leisure behaviors were identified from the UK Biobank database, specifically a summary-level genome-wide association study (GWAS) involving 422,218 individuals of European descent. The UK Biobank database also provided the GWAS data for physical activity. Primary analysis was performed using inverse variance weighting (IVW) to assess the causal relationship between sedentary behavior, physical activity, and the risk of psychiatric disorder (depression, schizophrenia and bipolar disorder). Sensitivity analysis was conducted using Cochran's Q test, the MR-Egger intercept test, the MR-pleiotropy RESidual sum and outlier test, leave-one-out analysis, and funnel plot analysis. RESULTS: According to the IVW analysis, there was a significant association between genetically predicted leisure television watching and an increased risk of depression (odds ratio [OR] = 1.027, 95% confidence interval [CI]: 1.001-1.053; P = 0.04). The IVW analysis also indicated that there was a decreased risk of depression associated with fraction accelerations of > 425 milligravities, as measured by accelerometers (OR = 0.951, 95%CI: 0.914-0.989; P = 0.013). The other MR methods obtained consistent but non-significant results in the same direction. However, there was no evidence of a causal association between genetic liability for moderate-to-vigorous physical activity, accelerometer-assessed physical activity, computer use, or driving and the risk of depression. Furthermore, IVW analysis has also found that driving has a slight effect in reducing the risk of schizophrenia (OR = 0.092, 95%CI: 0.010-0.827; P = 0.033), while leisure television viewing has a significant protective effect against the onset of bipolar disorder (OR = 0.719, 95%CI: 0.567-0.912; P = 0.006). CONCLUSION: The study provides compelling evidence of a link between depression, bipolar disorder, and excessive TV watching. Furthermore, it suggests that higher accelerometer-assessed fraction accelerations of > 425 milligravities can serve as a genetic protective factor against depression. To mitigate the risk of developing depression, it is advisable to reduce sedentary activities, particularly television watching, and prioritize engaging in vigorous physical exercise.

Giant Second-Order Nonlinear Hall Effect in Twisted Bilayer Graphene.

In the second-order response regime, the Hall voltage can be nonzero without time-reversal symmetry breaking but inversion symmetry breaking. Multiple mechanisms contribute to the nonlinear Hall effect. The disorder-related contributions can enter the NLHE in the leading role, but experimental investigations are scarce, especially the exploration of the contributions from different disorder sources. Here, we report a giant nonlinear response in twisted bilayer graphene, dominated by disorder-induced skew scattering. The magnitude and direction of the second-order nonlinearity can be effectively tuned by the gate voltage. A peak value of the second-order Hall conductivity reaching 8.76 µm SV^{-1} is observed close to the full filling of the moiré band, four order larger than the intrinsic contribution detected in WTe_{2}. The scaling shows that the giant second-order nonlinear Hall effect in twisted bilayer graphene stems from the collaboration of the static (impurities) and dynamic (phonons) disorders. It is mainly determined by the impurity skew scattering at 1.7 K. The phonon skew scattering, however, has a much larger coupling coefficient, and becomes comparable to the impurity contribution as the temperature rises. Our observations provide a comprehensive experimental understanding of the disorder-related mechanisms in the nonlinear Hall effect.

The topological key lncRNA H2k2 from the ceRNA network promotes mesangial cell proliferation in diabetic nephropathy via the miR-449a/b/Trim11/Mek signaling pathway.

Evidence has shown that long noncoding RNAs (lncRNAs) in the competing endogenous RNA (ceRNA) network are involved in various diseases. However, there is a lack of studies of the ceRNA network in diabetic nephropathy (DN). In this study, we investigated the effect of lncRNAs on mesangial cell (MC) proliferation in DN-related ceRNA networks. Differences in lncRNA and mRNA expression between DN and normal mouse kidney tissues were detected with RNA-seq, and DN-related lncRNA/mRNA/microRNA (miRNA) ceRNA networks were constructed by R3.4.3. Computational analysis was performed, and expression and interactions between the topological RNAs were detected by bioinformatics methods, real-time quantitative PCR (qPCR), and luciferase assay. Cell proliferation ability was measured by 5-ethynyl-2'-deoxyuridine (EdU) in MCs cultured under high- or low-glucose conditions. Moreover, the effect of the topological key lncRNA histocompatibility 2 K region locus 2 (H2k2) H2k2 on MC proliferation via the miRNA (miR)-449a/b/triplet motif 11 (Trim11)/Mek signaling pathway was examined by EdU, flow cytometry analysis, and Western blot. In total, 153 lncRNAs, 428 mRNAs, and 2242 interactions were included in the constructed DN-related ceRNA network. There were 15 RNAs in the top 5% of degree and betweenness. The expression of lncRNA H2k2 and mRNA Trim11 in MCs was increased in DN, which is consistent with the results of RNA-seq and real-time qPCR invivo and in vitro. miR-449a and miR-449b, which were down-regulated in MCs cultured with high glucose, were selected for further analysis. The results of real-time qPCR and luciferase assay revealed the lncRNA H2k2-miR-449a/b-Trim11 interaction in MCs. In addition, the data showed that H2k2 regulates MC proliferation via the miR-449ab/Trim11/Mek signaling pathway. Taken together, these results provide new insight into the association between the topological key lncRNA H2k2 in the DN-related ceRNA network and the miR-449a/b/Trim11/Mek signaling pathway during MC proliferation in DN.-Chen, W., Peng, R., Sun, Y., Liu, H., Zhang, L., Peng, H., Zhang, Z. The topological key lncRNA H2k2 from the ceRNA network promotes mesangial cell proliferation in diabetic nephropathy via the miR-449a/b/Trim11/Mek signaling pathway.

Whole transcriptome analysis of diabetic nephropathy in the db/db mouse model of type 2 diabetes.

Whole-transcriptome analysis using RNA sequencing (RNA-seq) affords broader insights about gene expression regulatory networks in diabetic nephropathy (DN). To better explore the molecular basis of DN, kidney tissue from db/db DN model mice and control mice were submitted to RNA-seq analysis. Thousands of long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs) were found to be significantly differentially expressed in the DN group relative to the control group. To research the regulatory mechanism of these lncRNAs and mRNAs, the integrated co-expression networks were constructed for 322 mRNAs and 27 lncRNAs that revealed significantly correlated expression patterns in DN. The potential roles of these co-expressed mRNAs were classified by Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses. The co-expression networks involved 27 lncRNAs interacting with 38 key mRNAs related to metabolic processes, including ND4/4L, Ndufa2/5, Ndufb4/7, Ndufs3, Uqcrc1, Aco2, Alad, Alas1, Alpl, Atp5j2, Coq5, Coq6, Cth, and CytB, all of which are highly related to encoding subunits of the mitochondrial complexes. Thus, mitochondrial dysfunction could result in renal function decline in DN. Seven dysregulated lncRNAs and nine dysregulated mRNAs in the DN model were confirmed by quantitative real-time polymerase chain reaction. The lncRNA-mRNA co-expression network provides novel evidence to support the contention that metabolic changes are associated with metabolic reprogramming in the kidneys, and that these changes play a critical role during the progression of DN.

The Long Noncoding RNA 150Rik Promotes Mesangial Cell Proliferation via miR-451/IGF1R/p38 MAPK Signaling in Diabetic Nephropathy.

BACKGROUND/AIMS: Diabetic nephropathy (DN) as the primary cause of end-stage kidney disease is a common complication of diabetes. However, the initiating molecular events triggering DN are unknown. Recently, long noncoding RNAs (lncRNAs) have been shown to play important roles in DN. METHODS: The expression level of lncRNA 1500026H17Rik (150Rik for short) was measured by qRT-PCR (quantitative real-time PCR). Cell proliferation ability was detected by 5-Ethynyl-2'-deoxyuridine (EdU). The relationship between 150Rik and microRNA 451 (miR-451) was examined by luciferase assay and RNA immunoprecipitation (RIP) assay. Finally, the effect of 150Rik on cell proliferation through the miR-451/insulin-like growth factor 1 receptor (IGF1R)/mitogen-activated protein kinases (p38MAPK) pathway was detected by EdU, flow cytometry analysis, western blot. RESULTS: We found that 150Rik, an evolutionarily conserved lncRNA, was significantly upregulated in renal tissue of db/db DN mice and in mesangial cells (MCs) cultured under a high glucose condition. Further, overexpression or knockdown of 150Rik was found to regulate cell proliferation in MCs. Moreover, 150Rik was found to interact with miR-451 in both a direct and argonaute-2 (Ago2)-dependent manner. Results also revealed that overexpression of 150Rik inhibited cell proliferation through the miR-451/IGF1R/p38MAPK pathway in MCs under the high glucose condition, while knockdown of 150Rik increased cell proliferation via the miR-451/IGF1R/p38MAPK pathway. CONCLUSION: Taken together, these results provide new insight into the association between 150Rik and the miR-451/IGF1R/p38MAPK signaling pathway during DN progression.

Morphological and phylogenetic analysis of Nosema sp. HR (Microsporidia, Nosematidae): a new microsporidian pathogen of Histia rhodope Cramer (Lepidoptera, Zygaenidae).

A new microsporidium was isolated from Histia rhodope Cramer (Lepidoptera, Zygaenidae), a pest of Bischofia javanica BL. in China. The morphology and molecular systematic of this novel microsporidian isolate had been described in this study. The spores were long oval and measured 3.1 × 1.9 µm on fresh smears. Ultrastructure of the spores was characteristic for the genus Nosema: 14-15 polar filament coils, posterior vacuole, and a diplokaryon. The sequenced rRNA gene of this isolate is 4309 bp long. The organization of the rRNA gene is 5'-LSU rRNA-ITS-SSU rRNA-IGS-5S-3', which is similar to that of other Nosema species (such as Nosema bombycis). Phylogenetic analysis based on LSU rRNA gene and SSU rRNA gene both revealed that this novel micorsporidian which isolated from H. rhodope had close relationship to the genus Nosema. Additionally, this isolate can also cause systemic infection of Bombyx mori. So, we should pay attention not only to N. bombycis, but also to other microsporidian (such as Nosema sp. HR) in sericulture in the future.

Association of dietary inflammatory index with obesity among children and adolescents in the United States NHANES cohort: a population-based study.

BACKGROUND: Childhood obesity has become a huge challenge to childhood health, and there is a lack of understanding about the relationship between dietary inflammatory index (DII) and childhood obesity. The main objective of this study was to analyze the potential link between DII and obesity among children and adolescents residing in the United States. METHODS: A cross-sectional analysis was performed using data obtained from the National Health and Nutrition Examination Survey between 2009 and 2018. In total, 12,454 participants were included in the analysis. DII was calculated based on dietary data from the first day of the 24-hour dietary recall. Logistic regression was used to analyze the association between DII and obesity, as well as central obesity defined by the waist-to-height ratio of 0.5 or higher or waist circumference ≥ 90th percentile for age and sex. RESULTS: The mean dietary inflammation index was 2.05 (SE = 0.02), with higher levels in children than in adolescents (P = 0.01). According to our findings, the prevalence of central obesity was higher among adolescents (38.0%) than among children (31.4%). The adolescents in the third quartile of DII have a higher risk of overweight/obesity (OR = 1.46, 95% CI: 1.24-1.71) after adjusting for age, sex, and race. This positive association remained significant even after physical activity was added to the model. Concerning central obesity, the adolescents in the highest quartile of DII have a higher risk, independent of demographic characteristics and physical activity. However, no significant association was observed among children. CONCLUSIONS: The dietary inflammation index was positively associated with overweight/obesity and central obesity among adolescents in the United States after adjusting for confounding factors. These findings highlight the importance of promoting anti-inflammatory diets in adolescents to prevent obesity and its associated complications.

Heterodimensional Kondo superlattices with strong anisotropy.

Localized magnetic moments in non-magnetic materials, by interacting with the itinerary electrons, can profoundly change the metallic properties, developing various correlated phenomena such as the Kondo effect, heavy fermion, and unconventional superconductivity. In most Kondo systems, the localized moments are introduced through magnetic impurities. However, the intrinsic magnetic properties of materials can also be modulated by the dimensionality. Here, we report the observation of Kondo effect in a heterodimensional superlattice VS2-VS, in which arrays of the one-dimensional (1D) VS chains are encapsulated by two-dimensional VS2 layers. In such a heterodimensional Kondo superlattice, we observe the typical Kondo effect but with intriguing anisotropic field dependence. This unique anisotropy is determined to originate from the magnetic anisotropy which has the root in the unique 1D chains in the structure, as corroborated by the first-principles calculation. Our results open up a novel avenue of studying exotic correlated physics in heterodimensional materials.

Local Gate Enhanced Correlated Phases in Twisted Monolayer-Bilayer Graphene.

Manipulating the flat band degeneracy and thus getting the correlated insulating phases has been an ideal thread for realizing the exotic quantum phenomenon in the moiré system. To achieve this goal, the delicately tuned twist angle and a substantial displacement field (D) are rigorously requested. Here, we report our scanning tunneling microscope (STM) work on reaching these correlated insulating states in twisted monolayer-bilayer graphene through a decorated tip. It acts as a local top gate, leading to an enhanced local D, and enables us to fully lift the 8-fold degeneracy of the flat bands. With the aid of this technique, we further expand the correlated insulating states into a more tolerant twist angle that is down to 0.92°. Moreover, the correlated insulating phases in the hole-doping regime are realized. Our tip decoration method allows us to integrate the STM study with the high displacement field for the correlated phases in the twisted moiré systems.

A cingulate-hippocampal circuit mediates early depressive-like behavior in the mouse model of Alzheimer disease.

Depressive symptoms usually precede the cognitive decline in Alzheimer disease (AD) and worsen the clinical outcome. However, the neural circuitry mediating early emotional dysfunction, especially depressive symptoms in AD, remains elusive. Anterior cingulate cortex (ACC) is closely related to depression and vulnerable in AD. By quantitative whole-brain mapping and electrophysiological recording, we found that the decreased axonal calcium activity in neurons of ACC and the glutamatergic projection from ACC to the ventral hippocampal CA1 (vCA1) is significantly impaired in 3-month-old 5×FAD mice, which exhibit depressive-like phenotype before cognition defects in early stage. The activation of ACC-vCA1 circuit by chemogenetic manipulation efficiently ameliorated the early depressive-like behaviors in 5×FAD mice. We further identified the upregulated neuregulin-1 (Nrg1) in ACC impaired the excitatory synaptic transmission from the ACC to vCA1 in AD. Our work reveals the role of ACC-vCA1 circuit in regulating AD associated depression symptom in a mouse model of AD.

[Effect of carcinoma-associated fibroblasts on cancer occurrence and development].

Tumor microenvironment has been confirmed to play an important role in the occurrence, invasion and metastasis of many kinds of tumors. Carcinoma-associated fibroblasts (CAFs) are the primary type of host cells in the tumor microenvironment. CAFs have an assignable role in tumor development. CAFs create a suitable "soil" for tumor origination, secrete a large amount of growth factors promoting tumor growth and angiogenic factors promoting tumor angiogenesis. In addition, CAFs attract a large number of inflammatory cytokines, and secrete a great quantity of soluble products promoting tumor cell invasion and metastasis. Therefore, CAFs may become new targets for targeted cancer therapy, and provide new ideas for the clinical cancer comprehensive treatment.

How self-leadership promotes job crafting: Based on the perspective of self-determination theory.

According to self-determination theory, the present study develops a moderated mediation model to investigate how and when self-leadership promotes employees' job crafting, emphasizing the mediating effect of autonomous motivation and the moderating effect of leader empowering behavior. We analyze and test the hypotheses based on 269 valid three-wave data from employees. The findings show that self-leadership has a significantly positive impact on job crafting, and a positive indirect effect on job crafting via autonomous motivation. Furthermore, leader empowering behavior not only enhances the positive impact of self-leadership on autonomous motivation, but also positively moderates the mediating effect of autonomous motivation in the relationship between self-leadership and job crafting. Practically, our study provides insights into how to promote job crafting. We also propose limitations and directions for future research.

NIRF, a novel ubiquitin ligase, interacts with hepatitis B virus core protein and promotes its degradation.

Hepatitis B virus (HBV) core protein (HBc) is a major component of viral nucleocapsid and a multifunctional protein involved in viral maturation and release. It is unstable and present in cells at low level because of K96 lysine residue, which is a ubiquitin acceptor site. Np95/ICBP90-like RING finger protein (NIRF) has auto-ubiquitination activity which is the hallmark of a ubiquitin ligase. In the present study, ubiquitin ligase, NIRF, binds to HBc and leads to the proteasome-mediated degradation of HBc in vivo. NIRF down-regulates HBc protein level, resulting in the decrease of the amount of HBV particles in supernatant of HepG2.2.15 cells. However knockdown of NIRF significantly increases endogenous HBc protein level, leading to HBV release. The results reveal that NIRF interacts with HBc and promotes the degradation of HBc in vivo. The pathway of NIRF-mediated ubiquitin-proteasome affects the release of HBV particles by controlling the amounts of HBc. It indicates that NIRF may participate in the maturation of HBV.

Superconducting quantum interference effect in NbSe2/NbSe2van der Waals junctions.

Layered materials with exotic properties, such as superconducting, ferromagnetic, and so on, have attracted broad interest. The advances in van der Waals (vdW) stacking technology have enabled the fabrication of numerous types of junction structures. The dangling-bond-free interface provides an ideal platform to generate and probe various physics phenomena. Typical progress is the realization of vdW Josephson junctions with high supercurrent transparency constructed of two NbSe2layers. Here we report the observation of periodic oscillations of the voltage drop across a NbSe2/NbSe2vdW junctions under an in-plane magnetic field. The voltage-drop oscillations come from the interface and the magnitude of the oscillations has a non-monotonic temperature dependence which increases first with increasing temperature. These features make the oscillations different from the modulation of the critical current of a Josephson junction by the magnetic field and the Little-Parks effect. The oscillations are determined to be generated by the quantum interference effect between two superconducting junctions formed between the two NbSe2layers. Our results thus provide a unique way to make an in-plane superconducting quantum interference device that can survive under a high magnetic field utilizing the Ising-paring nature of the NbSe2.

Clinical Characteristics of Hospitalized Pediatric Patients With Hypertensive Crisis-A Retrospective, Single-Center Study in China.

Background: A hypertensive crisis is a medical emergency that causes acute damage to multiple organs. However, the etiology, clinical features, and prognosis of hypertensive crisis in Chinese children remain relatively unknown. The purpose of this study was to analyze the clinical characteristics of pediatric hypertensive crisis patients from a single center in China. Methods: We analyzed data from 70 children with hypertensive crisis between January, 2000, and January, 2022. The patients were divided into two groups: those diagnosed with a hypertensive emergency (n = 46) and those diagnosed with hypertensive urgency (n = 24). Baseline etiologies and risk factors were compared between the two groups. The following data were collected and analyzed: age, sex, weight, height, family history of hypertension, blood pressure, clinical manifestations of hypertensive crisis, underlying causes, biochemical indicators, and antihypertensive drugs. Results: The major symptoms of hypertensive crisis were headache (n = 31, 44.29%), followed by visual symptoms (n = 15, 21.43%), and dizziness (n = 13, 18.57%). Further analysis showed that the incidence of convulsions was significantly higher in patients with hypertensive emergency than those with hypertensive urgency (χ2 = 5.38, p = 0.02). The leading underlying causes were renal disease (n = 34, 48.57%), followed by vascular disease (n = 11, 15.71%), essential hypertension (n = 9, 12.86%), oncological disease (n = 9, 12.86%), central nervous system disease (n = 3, 4.29%), endocrine and metabolic diseases (n = 2, 2.86%), and other (one case with lead poisoning, one case with histiocytosis). End-organ damage occurred in 46 patients with hypertensive crisis, including retinal damage (n = 20, 43.48%), brain damage (n = 19, 41.30%), heart damage (n = 15, 32.61%), and renal damage (n = 3, 6.52%). Hypertensive crisis was most common among children aged 7-12 years. Among children aged 13-18 years, hypertensive urgency was more common than hypertensive emergency. The incidence of dyslipidemia, elevated serum creatinine, and elevated uric acid did not differ significantly between the two groups. Most patients with hypertensive crisis need combined antihypertensive therapy (n = 60, 85.71%). There were no cases of mortality. Conclusions: Hypertensive crisis is caused by secondary diseases, especially renal disease and vascular disease, in the majority of pediatric patients. Combination therapy with antihypertensive agents and treatment of secondary etiology results in a good prognosis.

Personalized optimal nutrition lifestyle for self obesity management using metaalgorithms.

Precision medicine applies machine learning methods to estimate the personalized optimal treatment decision based on individual information, such as genetic data and medical history. The main purpose of self obesity management is to develop a personalized optimal life plan that is easy to implement and adhere to, thereby reducing the incidence of obesity and obesity-related diseases. The methodology comprises three components. First, we apply catboost, random forest and lasso covariance test to evaluate the importance of individual features in forecasting body mass index. Second, we apply metaalgorithms to estimate the personalized optimal decision on alcohol, vegetable, high caloric food and daily water intake respectively for each individual. Third, we propose new metaalgorithms named SX and SXwint learners to compute the personalized optimal decision and compare their performances with other prevailing metalearners. We find that people who receive individualized optimal treatment options not only have lower obesity levels than others, but also have lower obesity levels than those who receive 'one-for-all' treatment options. In conclusion, all metaalgorithms are effective at estimating the personalized optimal decision, where SXwint learner shows the best performance on daily water intake.

Haploinsufficiency of A20 in a Chinese child caused by loss-of-function mutations in TNFAIP3: A case report and review of the literature.

Case Presentation: A 3-year-and-6-month-old child was reported to have recurrent high fever with generalized lymph node enlargement and significant elevation of inflammatory markers such as C-reactive protein and procalcitonin in tests. Later, whole exome sequencing determined that the child's disease was haploinsufficiency of A20 (HA20). Results: After immunosuppressive therapy, the child's symptoms improved significantly, and the inflammatory markers dropped to the normal range. Conclusion: Because of the characteristics of HA20, this disease is often underdiagnosed and misdiagnosed in clinical practice. By reporting this case of HA20 in a child, we hope to increase the awareness of this disease in the clinic.

Duchenne Muscular Dystrophy With Low Acidic α-Glucosidase Activity: Two Case Reports and Literature Review.

Background: Pompe disease is usually considered in children with elevated creatine kinase (CK) levels and decreased acidic α-glucosidase (GAA) enzyme activity. However, there are exceptions, such as GAA pseudo deficiency alleles, which result in lower GAA enzyme activity but do not cause Pompe disease. Here, we report two cases presenting with high CK levels and low GAA activity who were ultimately diagnosed with Duchenne muscular dystrophy (DMD). Case Presentation: Case 1 patient was a 2-month-old boy who presented with an extremely high serum CK level (5,480∼11,880 U/L) and low GAA activity (2.72 nmol/1 h/mg). The whole-exome sequencing did not find the pathogenic GAA gene mutation, however, there was a DMD gene hemizygous variation (c. 7657C > T, p. Arg2553Ter) inherited from his mother, which was verified by the first-generation sequencing. Further genetic analysis of GAA identified two homozygous pseudo deficiency alleles (c.1726G > A, p. Gly576Ser and c.2065G > A, p. Glu689Lys), which were believed to induce the patient's low GAA activity. Therefore, the boy was diagnosed with DMD, although he had extremely low GAA activity. Case 2 patient was also a 2-month-old boy presenting with a significant increase in CK level (12,408∼24,828 U/L). His blood GAA activity (colorimetric method) was 9.02 nmol/1 h/mg. Similarly, his whole-exome sequencing did not find the pathogenic mutation of the GAA gene, but a DMD gene hemizygous variation (c.5571del, p. Lys1857AsnfsTer8), hence he was diagnosed with DMD as well. Regarding GAA activity, the case 2 patient was not as low as the case 1 patient, mainly because his two GAA pseudo deficiency alleles were heterozygous. Conclusion: Pompe disease is usually screened in infants with high CK levels. We should be aware that pseudo deficiency alleles can cause low GAA activities but not Pompe disease. Genetic tests would be helpful to distinguish cases with GAA pseudo deficiency alleles from patients with some muscular disorder diseases such as DMD.