Encephalitozoon hellem infection after haploidentical allogeneic hematopoietic stem cell transplantation in children: a case report

BackgroundEncephalitozoon hellem (E. hellem) infection is a zoonotic disease, rarely observed in individuals, causing various clinical manifestations including diarrhea, keratoconjunctivitis, cystitis, etc. E. hellem infection after hematopoietic stem-cell transplantation (HSCT) is a rare, serious complication.Case presentationHerein, we present a case of E. hellem infection developing during HLA-haploidentical HSCT in a 9-year-old boy who suffered from aplastic anemia. On 15 days after HSCT, the patient developed recurrent and prolonged fever, diarrhea and hematuria. It is challenging to differentiate whether the symptoms mentioned in this case are caused by graft-versus-host disease (GVHD) or a specific infection. Based on the result of metagenomic next-generation sequencing (mNGS) and clinical observation, the patient was diagnosed as E. hellem infection, and received albendazole and decreased the immunosuppressive treatment. Finally, he had recovered.ConclusionWe should pay attention to the uncommon disease caused by the E. hellem infection after HSCT, especially in cases with immune reconstitution unrecovered. Among those rare infection, mNGS can be performed for better understanding the source of infection and targeted therapy, which can benefit the patients

Scour protection of submarine pipelines using rubber plates underneath the pipes

YesThis paper presents the results from laboratory experiments to investigate the protection of scour around submarine pipelines under unidirectional flow using a rubber plate placed underneath the pipes. The pressure difference on the two sides of the pipeline is the driving force to initiate the movement of sediment particles and can be obtained by force balance analysis. Experiments covering a wide range of incoming flow velocity, pipe diameter and plate length show that there exists a critical pressure difference over which the movement of sediment and, thus, scour takes place. Analysis of the experimental results demonstrates that this critical pressure difference is related to the pressure difference of the axial points between upstream and downstream of the pipe, which can be easily determined. This critical pressure difference is used to develop an empirical formula for estimating the critical length of the rubber plate, over which the sediment movement and scour will not take place. Good agreement between the experiments and calculated critical plate length using the proposed formula is obtained.National High-Tech Research and Development program of China (863 Program, Grant No.2008AA09Z309), National Nature Science Fund of China (Grant No.50879084, 51279071 and 51279189), the Open Funding from the State Key Laboratory of Hydraulics and Mountain River Engineering, Sichuan University (SKLH-OF-1306

Fishing for small molecules to treat diabetes, from a beta cell perspective

Maintenance of glucose homeostasis necessitates a precise control of insulin secretion. Pancreatic β cells sense fluctuation of blood glucose and secret insulin in response. However, functional β cell mass is decreased in diabetes. Here, to recover functional β cell mass, we use zebrafish as a model to perform in vivo drug discovery. In paper I, to discover drugs that could expand β cell mass through proliferation, we performed an in vivo screen in zebrafish based on a luminescence ubiquitination-based cell cycle indicator (LUCCI), identified a small molecule called HG-9-91-01, an inhibitor of salt-inducible kinases (SIKs), as a mitogen of mouse and human β cells. Mechanistic studies found HG-9-91-01 induced a transient upregulation of ATF6-dependent unfolded protein response (UPR), which together with other downstream effectors including CRTC1, CRTC2, mTOR and IRE1 led to a mitogenic response in β cells. In paper II, to discover drugs that could increase β cell mass from other origins, we performed in vivo screening in zebrafish for stimulators that convert glucagon-expressing ⍺ cells, somatostatin-expressing ẟ cells, and elastase-expressing acinar cells to β cells. 4 hits were identified in the screens and shown to promote β cell regeneration as well as reduce glucose in zebrafish with β cell ablation. However, only one hit called A-674563 induced a modest increase in reprogramming of ⍺ cells to β cells in lineage tracing experiments, whereas the other hits failed to promote reprogramming. Spontaneous conversion of ⍺- or ẟ- cells to β cells was rare, and no conversion of acinar cells to β cells was observed during β cell regeneration. Together, reprogramming of other pancreatic cells to β cells is rare and difficult to stimulate by small molecules in zebrafish. In paper III, a small molecule called Adjudin, identified in paper II, was discovered to promote β cell function in zebrafish. In translational studies using in vitro cultured mouse islets, we found that Adjudin promoted functional maturation of isolated islets from postnatal day 0 (P0) mice, as they gained capability of glucose responsive insulin secretion; Adjudin also improved recovery of islets from a type 2 diabetic mouse model. Moreover, Adjudin stimulated hepatic glucose uptake, an effect we further found largely independent of insulin in zebrafish and validated in primary human hepatocyte (PHH) formed spheroids with insulin resistance. Next, we examined Adjudin in a type 2 diabetic mouse model (db/db mice), observed improved glucose homeostasis in the mice that received Adjudin treatment. Together, Adjudin may serve as a potential therapeutic drug for diabetes. To summarize, using in vivo drug screening in zebrafish, we identified small molecules that could either expand β cell mass or promote β cell function, such findings may pave the way for future research and development of a novel treatment for diabetes

Trend Analysis and Prediction of Cardiovascular Disease Mortality in China from 2009 to 2021

Background With the prevalence of unhealthy lifestyles and the accelerated trend of population aging, the mortality rate of cardiovascular diseases remains high in China. A timely understanding of the current and future trends of cardiovascular disease mortality in China, as well as exploring potential influencing factors and solutions, can provide a reference for formulating cardiovascular disease prevention and control measures. Objective To analyze the trend of cardiovascular disease mortality in China from 2009 to 2021 and predict the future trends from 2022 to 2030. Methods Cardiovascular disease mortality data were selected and analyzed based on gender, urban-rural areas, regions, and age groups from the "China Death Surveillance Data Set (2009-2021) " published by the Chinese Center for Disease Control and Prevention. The Joinpoint regression model was used to calculate the annual percentage change (APC) and average annual percentage change (AAPC) to analyze the changing trends. Additionally, a GM (1, 1) model was established using R (4.3.1) software to predict the crude mortality rate of cardiovascular diseases in China from 2022 to 2030. Results From 2009 to 2021, the crude mortality rate of cardiovascular diseases in China increased from 235.83/100 000 in 2009 to 353.31/100 000 in 2021, with the AAPC of 3.3% (95%CI=2.8% to 3.8%, P<0.001). The age-standardized mortality rate decreased from 281.82/100 000 in 2009 to 221.24/100 000 in 2021, with the AAPC of -1.9% (95%CI=-2.6% to -1.2%, P<0.001). During this period, the standardized mortality rate for cardiovascular diseases in China showed a decreasing trend across different genders (AAPC for males=-2.0%, AAPC for females=-2.1%; P<0.05), urban and rural areas (AAPC for urban=-1.3%, AAPC for rural=-2.4%; P<0.05), and regions (AAPC for eastern region=-2.1%, AAPC for central region=-2.2%, AAPC for western region=-1.0%; P<0.05). Notably, the mortality rate decline was greater in females than males, in rural areas than urban areas, and the central region than the eastern and western regions. The results of the GM (1, 1) model showed that the crude mortality rate of cardiovascular diseases in China will continue to rise to 461.57/100 000 from 2022 to 2030. Conclusion From 2009 to 2021, the overall crude mortality rate of cardiovascular disease in China has shown a continuous upward trend, while the overall standardized mortality rate has shown a downward trend. The burden of cardiovascular disease mortality in China still faces severe challenges. The GM (1, 1) model predicts a continuous increase in the crude mortality rate of cardiovascular diseases in China from 2022 to 2030. Therefore, it is necessary to formulate and implement scientifically effective measures for the prevention and control of cardiovascular diseases, with a focus on male, elderly and rural residents

Factors influencing the horizontal inter-well interference in tight gas reservoirs

With the continuous shortening of horizontal well clusters and the increase in the single-stage fracturing scale, the inter-well interference phenomenon has increased. Moderate inter-well interference can improve single-well production, but excessive inter-well interference will reduce gas well production and slow production recovery. This paper analyzes the causes of inter-well interference from well patterns and spacing, single-stage fracturing scale and engineering. Taking three infill horizontal wells in the Sulige East II area gas field as examples, the effects of inter-well interference on productivity are analyzed by field data, which has certain guiding significance for optimizing fracturing design

A Study on the Influence of Mining Depth on the Stress Distribution Characteristics of Stope Surrounding Rock

The occurrence of severe mine pressure in stope is of high risk, and the mining depth is the main control factor which affecting the occurrence of mine pressure in stope. In order to study the influence law of mining depth on stope strata behavior, taking 11318E fully mechanized working face in Xieqiao Coal Mine of Huainan Mining Group as the engineering background, the stress distribution and evolution characteristics of stope surrounding rock under mining depth were studied by similar material simulation. And the evolution laws of mechanical characteristics of stope surrounding rock under different mining depths of 600 m and 1200 m were simulated. It is concluded that with the increase of mining depth, the damage range of surrounding rock on the mining field increases significantly. The initial collapse of the immediate roof above the working face is not affected by the mining depth. The periodic weighting caving step decreases with the increase of mining depth, and the height of two zones above the working face increases with the increase of mining depth. The stress transfer and evolution characteristics of the strata above the stope were revealed. The increase of front caving angle indicates that the pressure on the support of the working face is greater, indicating that the support of the working face should be strengthened with the increase of mining depth. The research results have a guiding role in the control of surrounding rock and disaster prevention of deep mine stope

Genome-wide CRISPR screen identifies ESPL1 limits the response of gastric cancer cells to apatinib

Abstract Apatinib was the first anti-angiogenic agent approved for treatment of metastatic gastric cancer (GC). However, the emergence of resistance was inevitable. Thus investigating new and valuable off-target effect of apatinib directly against cancer cells is of great significance. Here, we identified extra spindle pole bodies-like 1 (ESPL1) was responsible for apatinib resistance in GC cells through CRISPR genome-wide gain-of-function screening. Loss of function studies further showed that ESPL1 inhibition suppressed cell proliferation, migration and promoted apoptosis in vitro, and accordingly ESPL1 knockdown sensitized GC cells to apatinib. In addition, we found ESPL1 interacted with mouse double minute 2 (MDM2), a E3 ubiquitin protein ligase, and the combination of MDM2 siRNA with apatinib synergistically ameliorated the resistance induced by ESPL1 overexpression. In summary, our study indicated that ESPL1 played a critical role in apatinib resistance in GC cells. Inhibition of MDM2 could rescue the sensitivity of GC cells to apatinib and reverse ESPL1-mediated resistance