Structural basis for activity regulation of MLL family methyltransferases.

The mixed lineage leukaemia (MLL) family of proteins (including MLL1-MLL4, SET1A and SET1B) specifically methylate histone 3 Lys4, and have pivotal roles in the transcriptional regulation of genes involved in haematopoiesis and development. The methyltransferase activity of MLL1, by itself severely compromised, is stimulated by the three conserved factors WDR5, RBBP5 and ASH2L, which are shared by all MLL family complexes. However, the molecular mechanism of how these factors regulate the activity of MLL proteins still remains poorly understood. Here we show that a minimized human RBBP5-ASH2L heterodimer is the structural unit that interacts with and activates all MLL family histone methyltransferases. Our structural, biochemical and computational analyses reveal a two-step activation mechanism of MLL family proteins. These findings provide unprecedented insights into the common theme and functional plasticity in complex assembly and activity regulation of MLL family methyltransferases, and also suggest a universal regulation mechanism for most histone methyltransferases.

[Clinical and gene mutation features of cystic fibrosis: an analysis of 8 cases]. / 8ä¾‹å›Šæ€§çº¤ç»´åŒ–æ‚£å„¿ä¸´åºŠåŠåŸºå› çªå˜åˆ†æž.

OBJECTIVES: To study the clinical features and gene mutation sites of children with cystic fibrosis (CF), in order to improve the understanding of CF to reduce misdiagnosis and missed diagnosis. METHODS: A retrospective analysis was performed on the medical records of 8 children with CF who were diagnosed in Hebei Children's Hospital from 2018 to 2021. RESULTS: Among the 8 children with CF, there were 5 boys and 3 girls, with an age of 3-48 months (median 8 months) at diagnosis, and the age of onset ranged from 0 to 24 months (median 2.5 months). Clinical manifestations included recurrent respiratory infection in 7 children, sinusitis in 3 children, bronchiectasis in 4 children, diarrhea in 8 children, fatty diarrhea in 3 children, suspected pancreatic insufficiency in 6 children, pancreatic cystic fibrosis in 1 child, malnutrition in 5 children, and pseudo-Bartter syndrome in 4 children. The most common respiratory pathogens were Pseudomonas aeruginosa (4 children). A total of 16 mutation sites were identified by high-throughput sequencing, multiplex ligation-dependent probe amplification, and Sanger sequencing, including 5 frameshift mutations, 4 nonsense mutations, 4 missense mutations, 2 exon deletions, and 1 splice mutation. CFTR mutations were found in all 8 children. p.G970D was the most common mutation (3 children), and F508del mutation was observed in one child. Four novel mutations were noted: deletion exon15, c.3796_3797dupGA(p.I1267Kfs*12), c.2328dupA(p.V777Sfs*2), and c.2950G>A(p.D984N). CONCLUSIONS: p.G970D is the most common mutation type in children with CF. CF should be considered for children who have recurrent respiratory infection or test positive for Pseudomonas aeruginosa, with or without digestive manifestations or pseudo-Bartter syndrome.

[Epidemiological features of severe acute respiratory syndrome coronavirus 2 infection in children in Shijiazhuang, China: an analysis of 133 cases].

OBJECTIVE: To study the epidemiological features of children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Shijiazhuang, China. METHODS: Based on the information officially announced on the official website of the Health Commission of Hebei Province, epidemiological data were collected from 133 children, aged 0-18 years, who were diagnosed with SARS-CoV-2 infection in Shijiazhuang from January 2 to January 30, 2021. A statistical analysis was performed for general status, regional distribution, presence or absence of clusters, and results of SARS-CoV-2 nucleic acid tests. RESULTS: Among the 133 children with SARS-CoV-2 infection, there were 65 boys and 68 girls, with a male/female ratio of 0.96:1. The youngest age of onset was 3 months and 7 days, and the mean age of onset was (9±5) years. Of all the 133 children, 90(67.7%) were the first confirmed case of SARS-CoV-2 infection among their family members. Of all the children, 108(81.2%) came from the Gaocheng District in Shijiazhuang, among whom 38(28.6%) were from Xiaoguozhuang Village where the first patient with a confirmed diagnosis lived. SARS-CoV-2 nucleic acid test at week 2 after the outbreak showed positive results in 88 children (66.2%), and only 5 children had clinical symptoms before positive SARS-CoV-2 results were obtained. Of all the 133 children, 19(14.3%) were found positive in the first SARS-CoV-2 nucleic acid test after the outbreak, and 70(52.6%) had positive results for ≥4 times. There were 98 school students with infection, among whom 74(75.5%) were the first confirmed case in their family, and among 35 non-school students, 16(45.7%) were the first confirmed case in their family (P < 0.05). CONCLUSIONS: Among the children confirmed with SARS-CoV-2 infection in Shijiazhuang, there is a high proportion of children who are the first confirmed case in their family, and the children are mainly distributed in the rural areas of Gaocheng. Most of these children are students, so the prevention and control of cluster infection in schools should be taken seriously. There are often no symptoms before SARS-CoV-2 nucleic acid test, with a low positive rate of the first nucleic acid test, which increases the difficulty of early discovery of the epidemic.

[Efficacy of early treatment via fiber bronchoscope in children with Mycoplasma pneumoniae pneumonia complicated by airway mucus obstruction].

OBJECTIVE: To study the efficacy of early treatment via fiber bronchoscope in children with Mycoplasma pneumoniae pneumonia (MPP) complicated by airway mucus obstruction. METHODS: According to the time from admission to the treatment via fiber bronchoscope, the children with MPP who were found to have airway mucus obstruction under a fiber bronchoscope were randomly divided into early intervention group (≤3 days; n=40) and late intervention group (>3 days; n=56). The two groups were compared in terms of clinical data and imaging recovery.The children were followed for 1-3 months. RESULTS: Of the 96 children, 38 were found to have the formation of plastic bronchial tree, among whom 10 were in the early intervention group and 28 were in the late intervention group (P=0.01). Compared with the late intervention group, the early intervention group had a shorter duration of fever, length of hospital stay, and time to the recovery of white blood cell count and C-reactive protein (P<0.05), as well as a higher atelectasis resolution rate (P<0.05). Compared with the late intervention group, the early intervention group had a higher percentage of children with a ≥ 60% absorbed area of pulmonary consolidation at discharge. After 3 months of follow-up, the early intervention group had a higher percentage of children with a ≥ 90% absorbed area of pulmonary consolidation than the late intervention group (80% vs 55%; P=0.01), and the early intervention group had a lower incidence rate of atelectasis than the late intervention group (P<0.05). CONCLUSIONS: Early treatment via fiber bronchoscope can shorten the course of the disease and reduce complications and sequelae in MPP children with airway mucus obstruction.

Correlation analysis of serum thyroglobulin, thyroid-stimulating hormone levels, and thyroid-cancer risk in thyroid nodule surgery.

BACKGROUND: Thyroglobulin (Tg) is one of the markers of thyroid cancer, and its concentration may be elevated in patients with malignant thyroid tumors. Thyroid-stimulating hormone (TSH) is secreted by the pituitary gland, which has a significant impact on thyroid gland function. Excessively high or low TSH levels may be associated with an increased risk of thyroid cancer. Thus, in-depth studies on the association of serum Tg and TSH levels with thyroid cancer risk in patients with thyroid nodules are warranted. This can help determine whether Tg and TSH levels can predict the degree of malignancy of thyroid nodules, which can in turn guide doctors in making accurate diagnoses and treatment decisions. Furthermore, such studies can provide more accurate diagnostic methods for thyroid nodules and help patients become aware of the presence of thyroid cancer as early as possible, thereby improving the success rate of treatment and prognosis. AIM: To investigate the association of serum Tg and TSH levels with the risk of thyroid cancer in patients undergoing thyroid nodule surgery. METHODS: The clinical data and laboratory examination results of 130 patients who underwent thyroid nodule surgery were retrospectively analyzed. Furthermore, their preoperative serum Tg and TSH levels were recorded. Histopathological examination conducted during follow-up revealed the presence of thyroid cancer. Correlation analysis were used to analyze the association of Tg and TSH levels with the risk of thyroid cancer. RESULTS: Of the 130 patients, 60 were diagnosed with thyroid cancer. Statistical analysis revealed a significant positive correlation between serum Tg levels and the risk of thyroid cancer (P < 0.05). This suggests that high serum Tg levels are associated with an increased risk of thyroid cancer. However, no significant correlation was observed between serum TSH levels and the risk of thyroid cancer (P > 0.05). CONCLUSION: In patients who underwent thyroid nodule surgery, serum Tg levels exhibited a significant correlation with the risk of thyroid cancer but serum TSH levels did not. These findings suggest that serum Tg can serve as an important biomarker for assessing the risk of thyroid cancer in these patients.

[Risk factors for infection with extended-spectrum beta-lactamase-producing strains in children].

OBJECTIVE: To study the risk factors for infection with extended-spectrum beta-lactamase (ESBL) producing strains in children. METHODS: The clinical data of 242 pediatric in-patients with lower respiratory tract infections from February 2009 to January 2011 were retrospectively analyzed. The risk factors of ESBL-producing strain infections were investigated using univariate analysis and multivariate logistic regression analysis. RESULTS: Univariate analysis showed that six factors were related with ESBL-producing strain infections: repeated sucking of phlegm (OR: 2.279, P<0.01), tracheal intubation(OR: 3.101, P<0.01), administration of the third generation cephalosporin for more than three days (OR: 3.628, P<0.01), admission to the pediatric intensive care unit (PICU) (OR: 2.378, P<0.01), indwelling of nasogastric tube (OR: 2.460, P<0.01), prophylactic use of antibiotics (OR: 1.747, P<0.05). Multivariate logistic regression showed that the application of the third-generation cephalosporin for more than three days (OR: 5.672, P<0.01), repeated sucking of phlegm (OR: 3.917, P<0.01), tracheal intubation (OR: 3.717, P<0.01), indwelling of nasogastric tube (OR: 2.961, P<0.01), and admission to PICU (OR: 3.237, P<0.01) were the independent risk factors for the infections. CONCLUSIONS: The infections of ESBL-producing strains are caused by many factors, among which the application of the third-generation cephalosporin for more than three days, invasive operations, and admission to PICU are the independent risk factors.

Structural insights into NDH-1 mediated cyclic electron transfer.

NDH-1 is a key component of the cyclic-electron-transfer around photosystem I (PSI CET) pathway, an important antioxidant mechanism for efficient photosynthesis. Here, we report a 3.2-Å-resolution cryo-EM structure of the ferredoxin (Fd)-NDH-1L complex from the cyanobacterium Thermosynechococcus elongatus. The structure reveals three ß-carotene and fifteen lipid molecules in the membrane arm of NDH-1L. Regulatory oxygenic photosynthesis-specific (OPS) subunits NdhV, NdhS and NdhO are close to the Fd-binding site whilst NdhL is adjacent to the plastoquinone (PQ) cavity, and they play different roles in PSI CET under high-light stress. NdhV assists in the binding of Fd to NDH-1L and accelerates PSI CET in response to short-term high-light exposure. In contrast, prolonged high-light irradiation switches on the expression and assembly of the NDH-1MS complex, which likely contains no NdhO to further accelerate PSI CET and reduce ROS production. We propose that this hierarchical mechanism is necessary for the survival of cyanobacteria in an aerobic environment.

Morphometry of the Hand Knob Region and Motor Function Change in Eloquent Area Glioma Patients.

PURPOSE: The hand knob area is the cortical representation of motor hand function. The current study aimed to investigate the effects of eloquent area gliomas on the morphometry of the hand motor cortex and preoperative hand motor function. METHODS: A retrospective study of 320 glioma patients was conducted. Seventy-eight patients with gliomas involving motor functional area were finally enrolled. Using axial T2-weight magnetic resonance images, the width and height of the hand knob were measured in both hemispheres, and differences were compared between the affected and unaffected hemispheres. Receiver operating characteristic (ROC) curve and logistic regression analysis were used to estimate the degree of correlation between distance measurements and motor impairment. RESULTS: The width and height of the hand knob in the affected and unaffected hemispheres were significantly different (p < 0.0001). The width, height and distance from the tumor to hand knob were reduced in the functionally impaired group compared to the unimpaired group (p = 0.0003, p < 0.0001, p = 0.0005, respectively). The three parameters were significantly correlated and remained significant in ROC and logistic regression analysis. The optimal cut-off value of width, height and distance for identifying preoperative hand muscle strength were 5.73 mm, 5.80 mm and 5.92 mm, respectively. CONCLUSION: The morphometry of the hand knob is often changed by the infiltration or extrusion of the tumors that were located in or near the hand knob. The width, height of hand knob and the distance from tumor to hand knob could serve as anatomic biomarkers related to preoperative neurological motor deficits.

The Electrochemical Performance of Silicon Nanoparticles in Concentrated Electrolyte.

Silicon is a promising material for anodes in energy-storage devices. However, excessive growth of a solid-electrolyte interphase (SEI) caused by the severe volume change during the (de)lithiation processes leads to dramatic capacity fading. Here, we report a super-concentrated electrolyte composed of lithium bis(fluorosulfonyl)imide (LiFSI) and propylene carbonate (PC) with a molar ratio of 1:2 to improve the cycling performance of silicon nanoparticles (SiNPs). The SiNP electrode shows a remarkably improved cycling performance with an initial delithiation capacity of approximately 3000 mAh g-1 and a capacity of approximately 2000 mAh g-1 after 100 cycles, exhibiting about 6.8 times higher capacity than the cells with dilute electrolyte LiFSI-(PC)8 . Raman spectra reveal that most of the PC solvent and FSI anions are complexed by Li+ to form a specific solution structure like a fluid polymeric network. The reduction of FSI anions starts to play an important role owing to the increased concentration of contact ion pairs (CIPs) or aggregates (AGGs), which contribute to the formation of a more mechanically robust and chemically stable complex SEI layer. The complex SEI layer can effectively suppress the morphology evolution of silicon particles and self-limit the excessive growth, which mitigates the crack propagation of the silicon electrode and the deterioration of the kinetics. This study will provide a new direction for screening cycling-stable electrolytes for silicon-based electrodes.

The Tetrahymena telomerase p75-p45-p19 subcomplex is a unique CST complex.

Tetrahymena telomerase holoenzyme subunits p75, p45 and p19 form a subcomplex (7-4-1) peripheral to the catalytic core. We report structures of p45 and p19 and reveal them as the Stn1 and Ten1 subunits of the CST complex, which stimulates telomerase complementary-strand synthesis. 7-4-1 binds telomeric single-stranded DNA, and mutant p19 overexpression causes telomere 3'-overhang elongation. We propose that telomerase-tethered Tetrahymena CST coordinates telomere G-strand and C-strand synthesis.