Endurance training improves oxygen uptake/demand mismatch, metabolic flexibility and recovery in patients with sickle cell disease.

Patients with sickle cell disease (SCD) display lower slope coefficients of the oxygen uptake (V_O2) vs. work rate (W) relationship (delineating an O2 uptake/demand mismatch) and a poor metabolic flexibility. Because endurance training (ET) increases the microvascular network and oxidative enzymes activity including one involved in lipid oxidation, ET might improve the slope coefficient of the V_O2 vs. W curve and the metabolic flexibility of SCD patients. ET may also contribute to improve patient post-exercise cardiopulmonary and metabolic recovery. Fifteen patients with SCD performed a submaximal incremental test on a cycle ergometer before (SIT1) and after (SIT2) 8 weeks of ET. Minute ventilation, ventilation rate (VR), heart rate (HR), V_O2, CO2 production, respiratory exchange ratio, carbohydrate/lipid utilization and partitioning (including %Lipidox) and blood lactate concentration ([lactate]b) were measured during and after SIT1 and SIT2. At baseline, the slope coefficient of the V_O2 vs. W curve positively correlated with total hemoglobin, mean corpuscular hemoglobin and percentage of HbF. After training, the slope coefficient of the V_O2 vs. W curve was significantly higher and the [lactate]b increase was delayed. If patients' energy metabolism apparently relied largely on carbohydrate sources during SIT1, %Lipidox tended to increase at low exercise intensities during SIT2, supporting a training-induced improvement of metabolic flexibility in patients with SCD. Post-exercise recovery of VR, V_E/V_CO2, HR and [lactate]b was faster after training. We concluded that ET in patients with SCD i) ameliorated the oxygen uptake/demand mismatch, ii) blunted the metabolic inflexibility, and iii) improved post-exercise cardiopulmonary and metabolic responses.

Concepts of Lactate Metabolic Clearance Rate and Lactate Clamp for Metabolic Inquiry: A Mini-Review.

Lactate is known to play a central role in the link between glycolytic and mitochondrial oxidative metabolism, as well as to serve as a primary gluconeogenic precursor. Blood lactate concentration is sensitive to the metabolic state of tissues and organs as lactate rates of appearance and disposal/disappearance in the circulation rise and fall in response to physical exercise and other metabolic disturbances. The highest lactate flux rates have been measured during moderate intensity exercise in endurance-trained individuals who exhibit muscular and metabolic adaptations lending to superior oxidative capacity. In contrast, a diminished ability to utilize lactate is associated with poor metabolic fitness. Given these widespread implications in exercise performance and health, we discuss the concept of lactate metabolic clearance rate, which increases at the onset of exercise and, unlike flux rates, reaches a peak just below the power output associated with the maximal lactate steady state. The metabolic clearance rate is determined by both disposal rate and blood concentration, two parameters that are mutually interdependent and thus difficult to parse during steady state exercise studies. We review the evolution of the in vivo lactate clamp methodology to control blood lactate concentration and discuss its application in the investigation of whole-body lactate disposal capacities. In conclusion, we assert that the lactate clamp is a useful research methodology for examining lactate flux, in particular the factors that drive metabolic clearance rate.

[Research on the establishment of standard limits for perfluorooctanoic acid and perfluorooctane sulfonate in the "Standards for Drinking Water Quality（GB5749-2022）"in China].

Perfluorinated compounds, especially Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), are widely detected in water environments in China. Considering the potential health risks of drinking water exposure routes, PFOA and PFOS have been added to the water quality reference index of the newly issued "Standards for Drinking Water Quality (GB5749-2022)", with limit values of 40 and 80 ng/L, respectively. This study analyzed and discussed the relevant technical contents for determining the limits of the hygiene standard, including the environmental existence level and exposure status of PFOA and PFOS, health effects, derivation of safety reference values, and determination of hygiene standard limits. It also proposed prospects for the future direction of formulating drinking water standards.

[Research on the determination of the limit value of perchlorate in the "Standards for Drinking Water Quality（GB5749-2022）" in China].

Perchlorate is an environmental pollutant that has been a focus of attention in recent years. It has been detected in many environmental water bodies and drinking water in China, with a high level of presence in some areas of the Yangtze River Basin. The human body may ingest perchlorate through exposure pathways such as drinking water and food, and its main health effect is to affect the thyroid's absorption of iodine. The "Standards for Drinking Water Quality" (GB5749-2022) includes perchlorate as an expanded indicator of water quality, with a limit value of 0.07 mg/L. This article analyzes the technical content related to the determination of hygiene standard limits for perchlorate in drinking water, including the environmental presence level and exposure status of perchlorate, main health effects, derivation of safety reference values, and determination of hygiene standard limits.

[Effect of CKIP-1 on hepatocyte apoptosis in nonalcoholic fatty liver disease].

Objective: To explore the effect and underlying mechanism of casein kinase 2 interacting protein-1 (CKIP-1) on hepatocyte apoptosis in nonalcoholic fatty liver disease (NAFLD). Methods: Experimental study. An NAFLD cell model was established by inducing human hepatoma cell line, HepG2 cells, with oleic acid (OA). Flag-CKIP-1 expression vector and shRNA-CKIP-1 were transfected into HepG2 cells. Flow cytometry was used to detect the effect of CKIP-1 on the activity and apoptosis of NAFLD hepatocytes. The levels of apoptosis-related proteins were detected by Western blot. CKIP-1 knockout mice in C57BL/6 back-ground were fed with either standard or high-fat diet for 8 weeks. Apoptosis-related signal proteins in NAFLD hepatocytes were detected by immunohistochemistry. Results: After CKIP-1 was transfected into HepG2 cells, the degree of OA induced cell liposis was significantly reduced (P<0.05). Annexin V-FITC/PI flow cytometry showed that CKIP-1 reduced the apoptosis of steatotic hepatocytes. Overexpression of CKIP-1 could significantly inhibit the expression of caspase-3 and caspase-9 and increase the expression of Bcl-2/Bax (P<0.05). Knockdown of CKIP-1 could increase the expression of caspase-3 and caspase-9 (P<0.05). CKIP-1 knockout could further increase the expression of caspase-3 and caspase-9 in NAFLD mice (P<0.01,P<0.05), and further decrease the expression of Bcl-2/Bax (P<0.05). Conclusion: CKIP-1 inhibited the apoptosis of steatotic hepatocytes by up-regulating the expression of apoptosis inhibitor gene, Bcl-2/Bax, and affecting the proteases, caspase-3 and caspase-9.

[Digitalized analysis of the gingival and bone morphology in the maxillary anterior teeth in patient with posterior dental implant].

Objective: To explore and analyze the correlation between labial gingival morphology and alveolar bone morphology of maxillary anterior teeth in patients with posterior dental implant, so as to provide reference basis for restoration design and esthetic reconstruction of anterior teeth. Methods: Sixty-four patients [24 males, 40 females (25.6±3.3) years old] who planned to receive posterior dental implant restoration were recruited randomly with the inclusion and exclusion criteria in Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University from May 2020 to May 2021. According to the visibility of periodontal probe through gingival margin, the subjects were divided into thin and thick gingival biotypes, including 29 cases of thin biotype and 35 cases of thick biotype. The 3Shape software was used to perform oral scanning, and cone beam CT (CBCT) was taken for each patient. Geomagic and Mimics software were used to measure and record the labial crown width and length, gingival papilla height, gingival angle, bone papilla height and bone margin angle of maxillary anterior teeth. Results: The crown width length ratios of maxillary central incisors, lateral incisors and canines were 0.85±0.08, 0.80±0.08 and 0.86±0.09 (F=10.71, P<0.01). The height of gingival papilla between maxillary central incisors, between central incisors and lateral incisors, between lateral incisors and canines were (3.93±0.86), (3.47±0.84) and (3.38±0.91) mm respectively (F=7.44, P<0.01), and the height of corresponding bone papilla were (3.44±0.88), (3.12±0.75) and (2.72±0.63) mm respectively (F=14.26, P<0.01). The gingival margin angles of maxillary central incisors, lateral incisors and canines were 88.3°±7.7°, 84.7°±8.9° and 81.2°±6.6° (F=13.15, P<0.01), and the bone margin angles were 103.2°±13.1°, 99.5°±11.2° and 110.6°±13.0° (F=13.25, P<0.01). The crown width length ratio (0.81±0.08), gingival margin angle (82.2°±7.4°) and bone margin angle (99.4°±12.9°) of thin gingival subjects were significantly lower than those of thick gingival subjects (0.85±0.09, 86.5°±8.6°, 108.5°±11.4°) (t=-2.79, 3.63, 5.20, P<0.01). The height of gingival papilla [(3.93±0.81) mm] and bone papilla [(3.43±0.80) mm] in thin gingival subjects were significantly lower than those in thick gingival subjects [(3.34±0.84) and (2.85±0.71) mm, respectively] (t=-4.89, -5.36, P<0.01). The height of labial gingival papilla of upper anterior teeth was positively correlated with that of bone papilla in all patients (r=0.66, P<0.01); the ratio of crown width to length of upper anterior teeth was positively correlated with the angle of bone margin (r=0.42, P<0.01); the height of anterior gingival papilla was negatively correlated with the angle of bone margin (r=-0.58, P<0.01), and the height of bone papilla was negatively correlated with the angle of bone margin (r=-0.82, P<0.01). Conclusions: The crown shape, gingival shape and alveolar bone shape of maxillary anterior teeth were different in different tooth positions. Patients with different periodontal phenotypes had different crown width length ratio, gingival papilla height, bone papilla height, gingival margin angle, and bone margin angle.

[Digital analysis of the correlation between gingival thickness and alveolar bone thickness in the maxillary anterior teeth region].

Objective: To measure the labial gingival thickness and bone lamella thickness in the maxillary anterior area using digital method, and to analyze the correlation between the two, so as to provide a reference for esthetic restoration and implantation treatment of the upper anterior area. Methods: Fifty-seven patients [23 males, 34 females, (25.8±4.5) years old] who planned to receive posterior dental implant restoration were recruited randomly with the inclusion and exclusion criteria in Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University from May 2020 to October 2020. The 3Shape software was used to perform oral scanning, and cone beam CT (CBCT) was taken for each patient. The image data was fitted and registered by the 3Shape software. The gingival thickness at 2 mm below the gingival margin, bone thickness and gingival thickness at 2 and, 4 mm below the crest of the labial alveolar crest in maxillary central incisors, lateral incisors and canines, were measured. Results: The gingival thickness at 2 mm below the gingival margin of maxillary central incisors, lateral incisors and canines was (1.42±0.21), (1.19±0.17) and (1.23±0.20) mm respectively (F=12.47, P<0.001). The gingival thickness at 2 mm below gingival margin and 4 mm below crest of residual ridge in the male patients were (1.31±0.21) and (0.67±0.22) mm, and those in the female patients were (1.26±0.22) and (0.58±0.19) mm respectively, and there were statistically significant differences in the gingival thickness between the "2 mm below gingival margin" group and the "4 mm below crest of residual ridge" group (t=2.01 and 3.97, P<0.05). There was a positive correlation between gingival thickness and alveolar bone thickness at 2 mm and 4 mm below the crest of residual ridge in maxillary anterior region, and the correlation coefficients (r) were 0.387 and 0.344 respectively (P<0.05). Conclusions: Gingival thickness of maxillary anterior area is related to the tooth position and gender. The gingival thickness of men is greater than that of women.The gingival thickness at 2 and 4 mm below the crest of the alveolar crest is positively correlated with the thickness of the alveolar bone.

Recurrence and mortality rates with different treatment approaches of Merkel cell carcinoma: a systematic review and meta-analysis.

BACKGROUND: Comprehensive treatment recommendations for Merkel cell carcinoma are complex. We aimed to systematically review the published data on recurrence and mortality rates associated with various treatment approaches for Merkel cell carcinoma. METHODS: Search of MEDLINE, Embase, Web of Science, and Scopus from inception to August 2015. Studies were included that reported comparative survival and recurrence data for two or more treatment modalities. Two reviewers independently reviewed and abstracted recurrence and mortality rates. Event rates for individual treatment arms in each study were pooled and meta-analyzed across studies using a random-effects model. RESULTS: Fifty-two retrospective studies met inclusion criteria, revealing a total of 1,804 patients with primary Merkel cell carcinoma with data available for analyses. The recurrence rate was higher for surgery alone (55.0%) versus a combination of surgery and radiotherapy (39.0%) (odds ratio, 2.089; 95% CI, 1.374-3.177; P < 0.001). Combination therapy including surgery, radiotherapy, and chemotherapy had a higher mortality rate (44.6%) than did combined surgery and radiotherapy (23.2%) (odds ratio, 2.688; 95% CI, 1.196-6.037; P = 0.02). CONCLUSIONS: The treatment of Merkel cell carcinoma with surgery plus adjuvant radiotherapy may produce lower recurrence rates.

[Chronic kidney disease after adrenalectomy in a patient with primary aldosteronism].

We report one case of estimated glomerular filtration rate (eGFR) decline after taking unilateral adrenalectomy due to aldosterone adenoma. A 60-year-old male with 23-year history of hypertension was reported to the endocrinologist due to hypokalemia (serum potassium 3.01 mmol/L). Urine microalbumin/creatinine (ALB/CR) was 70.15 mg/g, serum creatinine was 82 µmol/L and eGFR was 89.79 mL/(min·1.73 m2). Random serum aldosterone was 172.2-203.5 ng/L, and random plasma rennin activity was 0-0.17 µg/(L·h). His captopril challenge test suggested that his aldosterone le-vels were suppressed by 8% (< 30%) and the adrenal enhanced computed tomography scan revealed a left adrenal tumor. The patient was diagnosed with primary hyperaldosteronism (PA), aldosterone adenoma and underwent left laparoscopic adrenalectomy. Histological examination confirmed adrenal cortical adenoma. One week after the operation, his serum creatinine was increased to 127 µmol/L compared with preoperative level; eGFR was 32.34 mL/(min·1.73 m2). His systolic blood pressure (SBP) was 110 mmHg and diastolic blood pressure (DBP) was 60 mmHg (hypotensive drugs discontinued), and serum potassium level was 5.22 mmol/L. At the end of the 2-year follow up, the serum creatinine of this patient remained at 109-158 µmol/L and eGFR fluctuated from 63.28-40.12 mL/(min·1.73 m2). PA is one of the most common causes of secondary hypertension. Several studies have reported renal function deterioration of PA patients after unilateral adrenalectomy, like the patient in this article. Age, preoperative plasma aldosterone concentration, albuminuria and preoperative potassium level might be significant predictors of a decrease in the eGFR. Growing evidence suggests that aldosterone could contribute to structural kidney damage, arterial injury and hemodynamic disorder. At the same time, patients with PA exhibit glomerular hyperfiltration and glomerular vascular hypertension, leading to the misinterpretation of renal function in PA patients as subtle kidney damage may be masked by the glomerular hyperfiltration before treatment. After a unilateral adrenalectomy, glomerular hyperfiltration by aldosterone excess is resolved and renal damage can be unmasked. In conclusion, kidney function deterioration after adrenalectomy can be detected in some patients with PA. Thus, accurate evaluation of kidney function in patients with PA may be essential, especially for those with preoperative risk factors for postoperative renal impairment. After unilateral adrenalectomy, close monitoring of renal function and adequate management are required for PA patients.

Delayed Rebound of Glycemia During Recovery Following Short-Duration High-Intensity Exercise: Are There Lactate and Glucose Metabolism Interactions?

Lactate constitutes the primary gluconeogenic precursor in healthy humans at rest and during low-intensity exercise. Data on the interactions between lactate and glucose metabolisms during recovery after short-duration high-intensity exercise are sparse. The aim of the present study was to describe blood glucose ([glucose]b) and lactate ([lactate]b) concentration curves during recovery following short-duration high-intensity exercise. Fifteen healthy Cameroonian subjects took part in the study and performed successively (i) an incremental exercise to exhaustion to determine maximal work rate (Pmax) and (ii) a 2-min 110% Pmax exercise after which blood lactate and glucose concentrations were measured during the 80-min passive recovery. In response to the 2-min 110% Pmax exercise, [glucose]b remained stable (from 4.93 ± 1.13 to 4.65 ± 0.74 mmol.L-1, NS) while [lactate]b increased (from 1.35 ± 0.36 to 7.87 ± 1.66 mmol.L-1, p < 0.0001). During recovery, blood lactate concentrations displayed the classic biphasic curve while blood glucose concentrations displayed a singular shape including a delayed and transitory rebound of glycemia. This rebound began at 27.7 ± 6.2 min and peaked at 6.78 ± 0.53 mmol.L-1 at 56.3 ± 9.7 min into recovery. The area under the curve (AUC) of [lactate]b during the rebound of glycemia was positively correlated with the peak value of glycemia and the AUC of [glucose]b during the rebound. In conclusion, the delayed rebound of glycemia observed in the present study was associated with lactate availability during this period.

"This Life is Normal for Me": A Study of Everyday Life Experiences and Coping Strategies of Live-in Carers in Taiwan.

Recruiting migrant live-in carers has become the main strategy to address the rapid increase in the number of older persons with intensive care needs in many parts of the developed world. This is also the case in northern Taiwan, where this study took place. Thirteen live-in carers from Indonesia and the Philippines were interviewed in the fall of 2019. In this article, we discuss their two main coping strategies: a) "accepting destiny", which refers to carers accepting their life and viewing their role as a live-in carer as a job that allowed them to meet their parents' expectations of financial support; and b) "connecting to significant others", which is the most important way carers found motivation to keep going. However, despite their coping strategies, working as a live-in carer was experienced as a challenging and precarious lifestyle. In the conclusion, we discuss how professional social workers in collaboration with decision-makers and non-governmental organizations in Taiwan could contribute to fostering a system that would support live-in carers in ways that allow them, and the older persons they care for, to thrive.

Skeletal Muscle Hyperemia: A Potential Bridge Between Post-exercise Hypotension and Glucose Regulation.

For both healthy individuals and patients with type 2 diabetes (T2D), the hemodynamic response to regular physical activity is important for regulating blood glucose, protecting vascular function, and reducing the risk of cardiovascular disease. In addition to these benefits of regular physical activity, evidence suggests even a single bout of dynamic exercise promotes increased insulin-mediated glucose uptake and insulin sensitivity during the acute recovery period. Importantly, post-exercise hypotension (PEH), which is defined as a sustained reduction in arterial pressure following a single bout of exercise, appears to be blunted in those with T2D compared to their non-diabetic counterparts. In this short review, we describe research that suggests the sustained post-exercise vasodilation often observed in PEH may sub-serve glycemic regulation following exercise in both healthy individuals and those with T2D. Furthermore, we discuss the interplay of enhanced perfusion, both macrovascular and microvascular, and glucose flux following exercise. Finally, we propose future research directions to enhance our understanding of the relationship between post-exercise hemodynamics and glucose regulation in healthy individuals and in those with T2D.

[Study on constructing the U-shaped response relationship of urinary iodine level and thyroid nodule prevalence based on piecewise function quantile regression method].

Objective: To establish an asymmetric U-shaped response relationship between urinary iodine level and thyroid nodule prevalence. Methods: Taking "Iodine" "Urine Iodine" "Thyroid" and "Thyroid Nodule" as Chinese keywords, and "Urine Iodine" "Goiter" and "Thyroid Nodule" as English keywords, literatures about urine iodine level and thyroid nodule prevalence were searched in China Biology Medicine disc, China National Knowledge Internet, Wanfang Data, PubMed and Springer databases from January 2000 to December 2019 respectively. The language of literatures was restricted in Chinese and English. There were 46 articles (24 domestic and 22 foreign) included in the study. The quantile regression method and Sigmoid function model were used to fit the dose-response relationship between different levels of urinary iodine and thyroid nodule prevalence to estimate the prevalence of thyroid nodule in Chinese residents. Results: The fitted dose-response curves between different levels of urine iodine, ranging from low level to appropriate level and then to high level, and thyroid nodule prevalence had a good performance on the simulation of the asymmetric U-shaped relationship between urine iodine level and thyroid nodule prevalence. The median level of urinary iodine at the cut-off point of the piecewise function was 198 µg/L. Based on the weighted calculation of the total sample size included in the literature, the prevalence of thyroid nodules (95%CI) in Chinese residents was 23.0% (17.3%-30.7%). Conclusion: The asymmetric U-shaped response relationship between urinary iodine level and thyroid nodule prevalence based on piecewise function has good feasibility and fitting effect.

Analysis of clinical features and imaging signs of COVID-19 with the assistance of artificial intelligence.

OBJECTIVE: To explore the CT imaging features/signs of patients with different clinical types of Coronavirus Disease 2019 (COVID-19) via the application of artificial intelligence (AI), thus improving the understanding of COVID-19. PANTIENTS AND METHODS: Clinical data and chest CT imaging features of 58 patients confirmed with COVID-19 in the Fifth Medical Center of PLA General Hospital were retrospectively analyzed. According to the Guidelines on Novel Coronavirus-Infected Pneumonia Diagnosis and Treatment (Provisional 6th Edition), COVID-19 patients were divided into mild type (7), common type (34), severe type (7) and critical type (10 patients). The CT imaging features of the patients with different clinical types of COVID-19 types were analyzed, and the volume percentage of pneumonia lesions with respect to the lung lobes (where the lesion was located) and to the whole lung was calculated with the use of AI software. SPSS 21.0 software was used for statistical analysis. RESULTS: Common clinical manifestations of COVID-19 patients: fever was found in 47 patients (81.0%), cough in 31 (53.4%) and weakness in 10 (17.2%). Laboratory examinations: normal or decreased white blood cell (WBC) counts were observed in 52 patients (89.7%), decreased lymphocyte counts (LCs) in 14 (24.1%) and increased C-reactive protein (CRP) levels in 18 (31.0%). CT imaging features: there were 48 patients (94.1%) with lesions distributed in both lungs and 46 patients (90.2%) had lesions most visible in the lower lungs; the primary manifestations in patients with common type COVID-19 were ground-glass opacities (GGOs) (23/34, 67.6%) or mixed type (17/34, 50.0%), with lesions mainly distributed in the periphery of the lungs (28/34, 82.4%); the primary manifestations of patients with severe/critical type COVID-19 were consolidations (13/17, 76.5%) or mixed type (14/17, 82.4%), with lesions distributed in both the peripheral and central areas of lungs (14/17,82.4%); other common signs, including pleural parallel signs, halo signs, vascular thickening signs, crazy-paving signs and air bronchogram signs, were visible in patients with different clinical types, and pleural effusion was found in 5 patients with severe/critical COVID-19. AI software was used to calculate the volume percentages of pneumonia lesions with respect to the lung lobes (where the lesion was located) and to the whole lung. There were significant differences in the volume percentages of pneumonia lesions for the superior lobe of the left lung, the inferior lobe of the left lung, the superior lobe of the right lung, the inferior lobe of the right lung and the whole lung among patients with different clinical types (p<0.05). The area under the ROC curve (AUC) of the volume percentage of pneumonia lesions for the whole lung for the diagnosis of severe/critical type COVID-19 was 0.740, with sensitivity and specificity of 91.2% and 58.8%, respectively. CONCLUSIONS: The clinical and CT imaging features of COVID-19 patients were characteristic to a certain degree; thus, the clinical course and severity of COVID-19 could be evaluated with a combination of an analysis of clinical features and CT imaging features and assistant diagnosis by AI software.

Potassium channels act as chemosensors for solute transporters.

Potassium channels form physical complexes with solute transporters in vivo, yet little is known about their range of possible signaling modalities and the underlying mechanisms. The KCNQ2/3 potassium channel, which generates neuronal M-current, is voltage-gated and its activity is also stimulated by binding of various small molecules. KCNQ2/3 forms reciprocally regulating complexes with sodium-coupled myo-inositol transporters (SMITs) in mammalian neurons. Here, we report that the neurotransmitter γ-aminobutyric acid (GABA) and other small molecules directly regulate myo-inositol transport in rat dorsal root ganglia, and by human SMIT1-KCNQ2/3 complexes in vitro, by inducing a distinct KCNQ2/3 pore conformation. Reciprocally, SMIT1 tunes KCNQ2/3 sensing of GABA and related metabolites. Ion permeation and mutagenesis studies suggest that SMIT1 and GABA similarly alter KCNQ2/3 pore conformation but via different KCNQ subunits and molecular mechanisms. KCNQ channels therefore act as chemosensors to enable co-assembled myo-inositol transporters to respond to diverse stimuli including neurotransmitters, metabolites and drugs.

Discovery of Selective Inhibitors of Endoplasmic Reticulum Aminopeptidase 1.

ERAP1 is an endoplasmic reticulum-resident zinc aminopeptidase that plays an important role in the immune system by trimming peptides for loading onto major histocompatibility complex proteins. Here, we report discovery of the first inhibitors selective for ERAP1 over its paralogues ERAP2 and IRAP. Compound 1 (N-(N-(2-(1H-indol-3-yl)ethyl)carbamimidoyl)-2,5-difluorobenzenesulfonamide) and compound 2 (1-(1-(4-acetylpiperazine-1-carbonyl)cyclohexyl)-3-(p-tolyl)urea) are competitive inhibitors of ERAP1 aminopeptidase activity. Compound 3 (4-methoxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid) allosterically activates ERAP1's hydrolysis of fluorogenic and chromogenic amino acid substrates but competitively inhibits its activity toward a nonamer peptide representative of physiological substrates. Compounds 2 and 3 inhibit antigen presentation in a cellular assay. Compound 3 displays higher potency for an ERAP1 variant associated with increased risk of autoimmune disease. These inhibitors provide mechanistic insights into the determinants of specificity for ERAP1, ERAP2, and IRAP and offer a new therapeutic approach of specifically inhibiting ERAP1 activity in vivo.

[Clinical and molecular characteristics of GATA2 related pediatric primary myelodysplastic syndrome].

Objective: To clarify the prevalence, clinical features and molecular characteristics of germline GATA2 mutations in pediatric primary myelodysplastic syndromes (MDS) . Methods: Next-generation sequencing technology was used to detect mutations in GATA2 and other myeloid malignancy genes in 129 children with primary MDS from Jan. 2007 to Jan. 2018. The relationship between genotypes and phenotypes was analyzed. Results: Germline GATA2 mutations accounted for 8.5% (11/129) of all primary MDS cases, and 14.0% (11/50) of MDS with excess blasts (MDS-EB) and acute myeloid leukaemia with myelodysplasia-related changes (AML-MRC) . Compared with GATA2 wild-type patients, GATA2 mutated patients were older at diagnosis[8 (1-16) years old vs 6 years old (range: 1 month old-18 years old) , P=0.035]and higher risk of monosomy 7 (72.7%vs 5.2%, P<0.001) and classified into MDS-EB and AML-MRC compared with refractory cytopenia of childhood (RCC) (63.6%vs 36.4%, P=0.111) . The multivariate analysis showed SETBP1 mutation (P=0.041, OR=9.003, 95%CI 1.098-73.787) and isolated monosomy 7 (P=0.002, OR=24.835, 95%CI 3.305-186.620) were significantly associated with germline mutated GATA2. Overall survival (OS) and outcomes of hematopoietic stem cell transplantation (HSCT) were not influenced by GATA2 mutational status. Conclusions: Our data identify germline GATA2 mutations have a high prevalence in older pediatric patients with monosomy 7, and high risk of progression into advanced MDS subtypes. GATA2 mutation status does not affect OS in pediatric primary MDS.

Producing multi-coloured bunches through beam-induced ionization injection in plasma wakefield accelerator.

This paper discusses the properties of electron beams formed in plasma wakefield accelerators through ionization injection. In particular, the potential for generating a beam composed of co-located multi-colour beamlets is demonstrated in the case where the ionization is initiated by the evolving charge field of the drive beam itself. The physics of the processes of ionization and injection are explored through OSIRIS simulations. Experimental evidence showing similar features are presented from the data obtained in the E217 experiment at the FACET facility of the SLAC National Laboratory. This article is part of the Theo Murphy meeting issue 'Directions in particle beam-driven plasma wakefield acceleration'.

Betatron radiation and emittance growth in plasma wakefield accelerators.

Beam-driven plasma wakefield acceleration (PWFA) has demonstrated significant progress during the past two decades of research. The new Facility for Advanced Accelerator Experimental Tests (FACET) II, currently under construction, will provide 10 GeV electron beams with unprecedented parameters for the next generation of PWFA experiments. In the context of the FACET II facility, we present simulation results on expected betatron radiation and its potential application to diagnose emittance preservation and hosing instability in the upcoming PWFA experiments. This article is part of the Theo Murphy meeting issue 'Directions in particle beam-driven plasma wakefield acceleration'.