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Introduction: Despite rasburicase's proven efficiency in Caucasians, Japanese, and Koreans, studies evaluating the safety and effectiveness of rasburicase in Chinese pediatric patients with non-Hodgkin's lymphoma (NHL) and acute leukemia (AL) in particular are lacking. Objective: The aim was to evaluate the safety and effectiveness of rasburicase in Chinese pediatric patients with NHL and AL. Methods: In this phase IV, open-label, non-randomized, single-arm, multi-center, interventional study (NCT04349306), children newly diagnosed with NHL or AL who received 0.20 mg/kg/day of rasburicase were included. The primary objective was to assess the safety of rasburicase by the incidence of adverse events (AEs). The secondary objective was to determine the effectiveness of rasburicase in the control of hyperuricemia. Results: Out of 50 patients, 25 reported a total of 76 treatment-emergent adverse events (TEAEs), including eight TEAEs of grade ≥ 3 in 12 patients. A drug-related serious AE was reported in one patient, and there was no incidence of death. The response rate in the intent-to-treat population was 100.0% (95% confidence interval 82.4–100.0) in patients (n = 19) with baseline uric acid level of > 8.0 mg/dL. Similarly, the response rate was 86.2% (n = 25) among 29 patients (60.4%) with baseline uric acid levels of ≤ 8.0 mg/dL. The maximum mean percentage decrease of plasma uric acid level in the overall patients was 96.9%. Conclusion: Rasburicase was well tolerated and effective in controlling hyperuricemia in Chinese pediatric patients with NHL and AL. [ABSTRACT FROM AUTHOR]

Land systems are those that most closely interact with human beings in terms of natural resources. The relationship between the simulation of their dynamic evolution and their microscopic and macroscopic elements is complex and nonlinear. In this study, we aimed to design a scientific model that could unify the macroscopic statistical distribution with microscopic individual movements, in order to simplify the model structure and definition of transformation rules. Taking Yucheng District, City, China, as a study site, we constructed an artificial neural network cellular automata (ANN-CA) model that uses neural network algorithms to predict the land area required to restrict the number of cellular automat (CA) space simulations. First, we took the raster data of the current land-use map of Yucheng District for the years 2001 and 2009, and the effect coefficients of slope, the river system, and other elements were used as initial data for the ANN-CA model. We then analyzed the superimposed land-use evolution law from 2001 to 2009. Next, within the error limits of the results for the 2017 neural network area prediction and the space center of gravity for each land type, we predicted the land-use changes for 2017 and determined the final land type for all grid units based on the set evolution rules and land conversion threshold. Finally, the land-use prediction simulation map for 2017 and actual land-use conditions were verified for quantitative and spatial accuracy. The results reveal that the model simulated the land-use changes for Yucheng District relatively accurately. It was also found that selecting the appropriate thresholds and random variable parameters improved the model's simulation accuracy and that the land use in the study area exhibits a clear urbanization trend. [ABSTRACT FROM AUTHOR]

An arc array synthetic aperture radar (AA-SAR) is a new type of omnidirectional observation and imaging system. Based on linear array 3D imaging, this paper introduces a keystone algorithm combined with the arc array SAR 2D imaging method and proposes a modified 3D imaging algorithm based on keystone transformation. The first step is to discuss the target azimuth angle, retain the far-field approximation method of the first-order term, analyze the influence of the forward motion of the platform on the along-track position, and realize the two-dimensional focusing of the target slant range–azimuth direction. The second step is to redefine a new azimuth angle variable in the slant-range along-track imaging and use the keystone-based processing algorithm in the range frequency domain to eliminate the coupling term generated by the array angle and the slant-range time. The corrected data are used to perform along-track pulse compression to obtain the focused image of the target and realize the three-dimensional imaging of the target. Finally, in this article, the spatial resolution of the AA-SAR system in the forward-looking state is analyzed in detail, and the change in the spatial resolution of the system and the effectiveness of the algorithm are verified through simulation. [ABSTRACT FROM AUTHOR]

Background: Whole-exome sequencing (WES) is an effective method in the prenatal setting for identification of the underlying genetic etiology of fetal ultrasound abnormalities. To investigate the diagnostic value of WES in fetuses with ultrasound abnormalities that resulted in fetal demise or pregnancy termination. Methods: 61 deceased fetuses with ultrasound abnormalities and normal copy number variation Sequencing were retrospectively collected. Proband-only or trio-WES were performed on the products of conception. Result: Collectively, 28 cases were positive with 39 variants (10 pathogenic, 22 likely pathogenic and 7 variants of uncertain significance) of 18 genes, and the overall diagnostic rate was 45.9% (28/61), of which 39.2% (11/28) were de novo variants. In addition, 21 variants in 11 genes among the positive cases had not been previously reported. The diagnostic yield for definitive findings for trio analysis was 55.9% (19/34) compared to 33.3% (9/27) for singletons. The most common ultrasound abnormalities were skeletal system abnormalities 39.2% (11/28), followed by multiple system abnormalities (17.9%, 5/28) and genitourinary abnormalities (17.9%, 5/28). Conclusion: Our results support the use of WES to identify genetic etiologies of ultrasound abnormalities and improve understanding of pathogenic variants. The identification of disease-related variants provided information for subsequent genetic counseling of recurrence risk and management of subsequent pregnancies. [ABSTRACT FROM AUTHOR]

This study aimed to compare the screening performance of genome-wide cfDNA testing for chromosomal abnormalities between two periods where additional findings were reported and not reported. Data were obtained from consecutive pregnant women with a singleton pregnancy at ≥10 weeks who requested cfDNA testing during 2015–2019. The performance of screening of the cfDNA test was determined by calculating the concordance rate, detection rate, and false-positive rate. Data from 3981 women were included. The no-result rates were similar between the two reporting periods (2.04% vs. 2.08%). Concordance rates for trisomy 21 and 18 were 100% and 100%, respectively. There were two cases tested high risk for trisomy 13, with a concordance rate of 0%. In total, 12 cases were high risk for any sex chromosome aneuploidy with an overall concordance of 75%, and 15 cases tested high risk for any rare autosomal trisomy, with a 13.3% concordance rate. The detection rates for trisomy 21 and 18 were 100% and 100%, respectively. For any SCA, the detection rate was 90%. For the two reporting periods, the combined false-positive rates were 0.93% and 0.17%, which were significantly different (p = 0.002). Restricting the reporting of additional findings from genome-wide cfDNA analysis has reduced the false-positive rate but without a reduction in the no-result rate. [ABSTRACT FROM AUTHOR]

Extreme climate events have exerted strong effects on permafrost environments over the past few decades. The occurrence of extreme warming events during the cold season can alter the hydrothermal dynamics of the active layer. Here, we used meteorological and observational soil hydrothermal data to investigate variations in extreme warming events and their impacts on the hydrothermal regimes of the active layer in three permafrost regions in China. The results indicated that the eight analyzed extreme warming indices showed statistically significant increasing trends with differing rates from 1962 to 2019. Prominent differences existed in the mean values and linear trend magnitudes not only among the three permafrost regions but also among the eight indices. Most recorded high-intensity extreme warming events occurred primarily in the past 15 years (2005–2019). The occurrence times of extreme events and the active layer freeze–thaw process codetermined the influential extents of the extreme events on the active layer hydrothermal conditions at the Tanggula permafrost Monitoring Site. Events that occurred from March to April could cause soil temperature to increase with a greater magnitude than that induced by events occurring from October to November. Different event types could also lead to distinct differences in their corresponding influential extents. [ABSTRACT FROM AUTHOR]

Background: Balanced reciprocal translocation is one of the most common chromosomal abnormalities in humans that may lead to infertility, recurrent pregnancy loss, or having children with physical or mental abnormalities. Karyotyping and FISH are traditional detection approaches with a low resolution. Bionano optical genome mapping (OGM) developed in recent years can be used to analyze chromosomal abnormalities at a higher resolution, providing the possibility of more in‐depth analyses of balanced chromosome translocations. Methods: To evaluate the feasibility of OGM to detect chromosome balanced translocations, 10 genetic outpatients were collected and detected simultaneously by karyotype analysis, FISH, CNV‐seq, and Bionano OGM in this study. Results: The results showed that the karyotypes of the patients were detected by karyotype analysis, FISH, and Bionano OGM, but one patient with karyotype t(Y,19) was not correctly detected by OGM. There were not find any chromosome abnormality by CNV‐seq. More importantly, OGM allowed the location of the mutation to the gene level, which is important for aiding diagnoses, compared to karyotype analysis, and FISH. Conclusions: This study shows that OGM can be a high adjunctive diagnostic method for detecting balanced chromosome translocations, but the accuracy and precision of OGM detecting mutations need to be gradually improved in telomere and centromere regions. [ABSTRACT FROM AUTHOR]

Maple syrup urine disease (MSUD) is a rare autosomal recessive disorder that affects the degradation of branched chain amino acids (BCAAs). Only a few cases of MSUD have been documented in Mainland China. In this report, 8 patients (4 females and 4 males) with MSUD from 8 unrelated Chinese Han families were diagnosed at the age of 6 days to 4 months. All the coding regions and exon/intron boundaries of BCKDHA, BCDKHB, DBT and DLD genes were analyzed by targeted NGS in the 8 MSUD pedigrees. Targeted NGS revealed 2 pedigrees with MSUD Ia, 5 pedigrees with Ib, 1 pedigree with MSUD II. Totally, 13 variants were detected, including 2 variants (p.Ala216Val and p.Gly281Arg) in BCKDHA gene, 10 variants (p.Gly95Ala, p.Ser171Pro, p.Phe175Leu, p.Arg183Trp, p.Lys222Thr, p.Arg285Ter, p.Arg111Ter, p.S184Pfs*46, p.Arg170Cys, p.I160Ffs*25) in BCKDHB gene, 1 variant (p.Arg431Ter) in DBT gene. In addition, 4 previously unidentified variants (p.Gly281Arg in BCKDHA gene, p.Ser171Pro, p.Gly95Ala and p.Lys222Thr in BCKDHB gene) were identified. NGS plus Sanger sequencing detection is effective and accurate for gene diagnosis. Computational structural modeling indicated that these novel variations probably affect structural stability and considered as likely pathogenic variants. [ABSTRACT FROM AUTHOR]

Maple syrup urine disease (MSUD) is a rare autosomal recessive disorder that affects the degradation of branched chain amino acids (BCAAs). Only a few cases of MSUD have been documented in Mainland China. In this report, 8 patients (4 females and 4 males) with MSUD from 8 unrelated Chinese Han families were diagnosed at the age of 6 days to 4 months. All the coding regions and exon/intron boundaries of BCKDHA, BCDKHB, DBT and DLD genes were analyzed by targeted NGS in the 8 MSUD pedigrees. Targeted NGS revealed 2 pedigrees with MSUD Ia, 5 pedigrees with Ib, 1 pedigree with MSUD II. Totally, 13 variants were detected, including 2 variants (p.Ala216Val and p.Gly281Arg) in BCKDHA gene, 10 variants (p.Gly95Ala, p.Ser171Pro, p.Phe175Leu, p.Arg183Trp, p.Lys222Thr, p.Arg285Ter, p.Arg111Ter, p.S184Pfs*46, p.Arg170Cys, p.I160Ffs*25) in BCKDHB gene, 1 variant (p.Arg431Ter) in DBT gene. In addition, 4 previously unidentified variants (p.Gly281Arg in BCKDHA gene, p.Ser171Pro, p.Gly95Ala and p.Lys222Thr in BCKDHB gene) were identified. NGS plus Sanger sequencing detection is effective and accurate for gene diagnosis. Computational structural modeling indicated that these novel variations probably affect structural stability and considered as likely pathogenic variants. [ABSTRACT FROM AUTHOR]

Objective. Cancer-derived exosomes can facilitate drug resistance in cervical cancer. However, the mechanisms remain elusive. Herein, we observed the roles of exosomal miR-651 in cisplatin resistance of cervical cancer. Methods. Circulating miR-651 was detected in cervical cancer and healthy individuals. The diagnostic efficacy was determined. When transfected with miR-651 mimics, cisplatin resistance, apoptosis, and proliferation were assessed. The cancer-derived exosomes were separated and identified. We observed the uptake of PKH67-labeled exosomes by HeLa/S cells. After coculture with exosomes secreted by HeLa/S or HeLa/DDP cells, malignant behaviors were examined in HeLa/S cells. The interactions between ATG3 and miR-651 were validated by dual luciferase report. Biological behaviors were investigated for HeLa/S cells cocultured with exosomes secreted by miR-651 mimic-transfected HeLa/DDP cells. Results. Downregulated circulating miR-651 was found in cancer subjects than healthy individuals. It possessed high sensitivity and accuracy in diagnosing cervical cancer (AUC = 0.9050). Lower miR-651 expression was confirmed in HeLa/DDP than HeLa/S cells. Forced miR-651 lessened cisplatin resistance and proliferation and elevated apoptosis in HeLa cells. ATG3 was a direct target of miR-651. The exosomes isolated from HeLa cells were rich in CD63, CD9, and CD81 proteins, thereby identifying the isolated exosomes. Exosomes secreted by HeLa/DDP cells can be absorbed by HeLa/S cells. When being cocultured with exosomes secreted by HeLa/DDP cells, malignant behaviors of HeLa/S cells were enhanced, which were ameliorated by miR-651 mimic exosomes. Conclusion. Our findings showed that cancer-derived exosomal miR-651 restrained cisplatin resistance and directly targeted ATG3, indicating that exosomal miR-651 could be a therapeutic agent. [ABSTRACT FROM AUTHOR]

Summary: The treatment of choice for patients with severe aplastic anaemia (SAA) includes immunosuppressive therapy (IST) with anti‐thymocyte globulin (ATG) and ciclosporin A. However, the optimal dose for rabbit ATG has yet to be established. We herein report the first prospective, randomized, multicentre study comparing two doses of rabbit ATG in patients with SAA. Patients with SAA who required initial IST in Japan (n = 89), China (n = 85) and Korea (n = 48) were enrolled between May 2012 and October 2017. A 1:1 block randomization was employed for two doses of rabbit ATG. In total, 222 patients were randomized, with 112 patients receiving 2·5 mg/kg and 110 receiving 3·5 mg/kg of rabbit ATG for 5 days. The primary endpoint was the haematological response at day 180. After 6 months, no significant difference in response rates was observed between the 2·5 and 3·5 mg/kg groups (49% vs. 48%, P = 0·894). Overall survival at 3 years was similar between the two groups [85% (95% confidence interval [CI], 76%−91%) vs. 91% (95% CI, 82%−96%); P = 0·107]. The current study revealed no significant differences in the efficacy and safety between the 2·5 and 3·5 mg/kg doses of rabbit ATG in patients with SAA. Trial registration: UMIN000011134. [ABSTRACT FROM AUTHOR]

Graft-derived-cell-free DNA (Gcf-DNA) in plasma is a promising biomarker to monitor graft-rejection after liver transplantation (LTx). However, current methods of measuring Gcf-DNA have several limitations including high cost, long turnaround-time and the need to request donor's genetic information. In this study, eleven patients diagnosed with different inborn errors of metabolism (IEMs) who required living-related LTx were enrolled in order to establish a potentially useful noninvasive method to monitor graft damage. Circulating cell-free DNA (cfDNA) was extracted from plasma specimens serially collected at specific time points (day 0, day 1, day 7, day 14, day 30, day 60) after LTx. The distribution of Gcf-DNA fragment sizes was measured using sequencing read lengths and quantified by using Y-chromosome capture methodology in seven sex-mismatched recipients. In the analysis of fragment size distribution, we observed Gcf-DNA exhibited smaller fragment sizes than the recipient-cfDNA. Based on this phenomenon, two fragment sizes (105-145 bp, 160-170 bp) of the cfDNA pool were extracted to enrich Gcf-DNA. Accordingly, the ratio of short fragments to long fragments (S/L-Frag) in cfDNA was calculated. A high S/L-Frag ratio pointed towards an early trend of graft injury when compared to two routine liver function enzymes (ALT and AST) and Gcf-DNA, and it significantly correlated with ALT (P < 0.0001) and AST (P < 0.0001) during full-blown rejection. In conclusion, we established the Gcf-DNA size profile in patients who have undergone living-related LTx and established a potential biomarker to monitor graft function after LTx. [ABSTRACT FROM AUTHOR]

Abstract Stable isotopic tracing has proven to be a useful tool for assessing surface water source dynamics and hydrological connectivity in permafrost regions. This study has investigated the contribution of precipitation to water within the active layer at three long-term observation sites, including Fenghuoshan (FHS), Hoh Xil (KKXL) and Wudaoliang (WDL), by using isotopic tracer technique and two-component mixing model. The results showed that precipitation was the predominant source for water within the active layer, permafrost and ground ice near permafrost table at the three sites. Precipitation in August was the predominant source for water within the active layer at FHS, and precipitation in September was the main source at KKXL and WDL. The variation of isotopic values at different levels indicated that the water sources within the active layer could vary as the depth increases. The evaporation fractionation of water within the active layer at WDL was noticeable at depths of 0–50 cm, and the evaporation intensity decrease gradually from late June to late September. The relationship of isotopic tracing values between precipitation and water within the active layer at depths of 0–50 cm becomes more significant as the amount of the recently-occurring precipitation increases. Moreover, the relatively higher d-excess in precipitation indicates that local recycled moisture has greater contribution to precipitation. The differences of d-excess in most water within the active layer, permafrost and ground ice near permafrost table revealed that there were isotopic fractionation when precipitation supplying to above-mentioned three water bodies. The precipitation event amounted to 8.1 mm at KKXL can exert 49% ± 7.1% and 30.8% ± 3.6% contribution to water within the active layer at depths of 0–10 cm and 10–20 cm, respectively. While the long-period contribution cannot be identified because of the impact of evaporation. The results would provide new insights into the contribution of precipitation to water within the active layer on the QTP, which is also helpful to improve process-based hydrological models in the permafrost regions. Graphical abstract Unlabelled Image Highlights • Precipitation is the predominant source for water within the active layer. • Obvious evaporation fractionation sign for water within the active layer exists at depths of 0–50 cm. • The contribution ratio of single precipitation event to water within the active layer can be identified. [ABSTRACT FROM AUTHOR]

Objectives: Prior studies reported incidence of hypoactive and hyperactive subtypes of postoperative delirium, but did not consider cognitive symptoms of delirium which are highlighted in the DSM‐5 criteria for delirium. This study aims to address this gap in the literature by classifying cases of delirium according to their constellation of cognitive and motoric symptoms of delirium using a statistical technique called Latent Class Analysis (LCA). Methods: Data were from five independent study cohorts (N = 1968) of patients who underwent elective spine, knee/hip, or elective gastrointestinal and thoracic procedures, between 2001 and 2017. Assessments of delirium symptoms were conducted using the long form of the Confusion Assessment Method (CAM) pre‐ and post‐surgery. Latent class analyses of CAM data from the first 2 days after surgery were conducted to determine subtypes of delirium based on patterns of cognitive and motoric symptoms of delirium. We also determined perioperative patient characteristics associated with each latent class of delirium and assessed whether the length of delirium for each of the patterns of delirium symptoms identified by the latent class analysis. Results: The latent class model from postoperative day 1 revealed three distinct patterns of delirium symptoms. One pattern of symptoms, denoted as the Hyperalert class, included patients whose predominant symptoms were being hyperalert or overly sensitive to environmental stimuli and having a low level of motor activity. Another pattern of symptoms, denoted as the Hypoalert class, included patients whose predominant symptom was being hypoalert (lethargic or drowsy). A third pattern of symptoms, denoted as the Cognitive Changes class, included patients who experienced new onset of disorganized thinking, memory impairment, and disorientation. Among 352 patients who met CAM criteria for delirium on postoperative day 1, 34% had symptoms that fit within the Hyperalert latent class, 39% had symptoms that fit within the Hypoalert latent class, and 27% had symptoms that fit within the Cognitive Changes latent class. Similar findings were found when latent class analysis was applied to those who met CAM criteria for delirium on postoperative day 2. Multinomial regression analyses revealed that ASA class, surgery type, and preoperative cognitive status as measured by the Telephone Interview for Cognitive Status (TICS) scores were associated with class membership. Length of delirium differed between the latent classes with the Cognitive Changes latent class having a longer duration compared to the other two classes. Conclusions: Older elective surgery patients who did not have acute events or illnesses or a diagnosis of dementia prior to surgery displayed varying symptoms of delirium after surgery. Compared to prior studies that described hypoactive and hyperactive subtypes of delirium, we identified a novel subtype of delirium that reflects cognitive symptoms of delirium. The three subtypes of delirium reveal distinct patterns of delirium symptoms which provide insight into varying risks and care needs of patients with delirium, indicating the necessity of future research on reducing risk for cognitive symptoms of delirium. Key Points: Although hypoactive and hyperactive motoric subtypes of postoperative delirium have been identified in literature, prior studies have not considered cognitive symptoms of delirium which are highlighted by the DSM‐5 criteria for delirium.Among elective surgery patients who did not have a diagnosis of dementia, and were not experiencing acute illnesses, events, or changes in mental status at hospital admission, we found that more than 40% of patients experienced cognitive symptoms of delirium using the long‐form of the Confusion Assessment Method that comprehensively assesses cognitive and motoric symptoms of delirium and its range of symptoms.Latent class analysis revealed three patterns of symptoms: patients in the first latent class predominantly displayed a hyperalert level of consciousness; patients in the second latent class predominantly displayed a hypoalert level of consciousness; and patients in the third latent class predominately displayed acute onset of disorganized thinking, disorientation, and memory impairment.Compared to those in the Hypoalert latent class, those in the Hyperalert latent class were more likely to have general surgery and have lower preoperative mental status scores, and those in the acute onset of cognitive symptoms latent class (Cognitive Changes) were more likely to have lower preoperative mental status scores. [ABSTRACT FROM AUTHOR]

The synthesis and structure determination of atomically precise alloy nanoclusters have attracted much attention in recent research. Herein, we report a new alloy nanocluster Au 24- x Ag x (TBBM) 20 ( x ∼ 1) synthesized via a ligand-exchange-induced size/structure transformation method. Its X-ray structure is obtained successfully and the dopant Ag is found to occupy three special positions in the kernel, rather than equivalently over all the kernel sites. This selective occupancy is interesting and DFT calculation results suggest that the relative oxidation state (rationalized as difference in the charge) of the Ag when doped into the cluster is likely determining the most favorable doping positions. This work provides a new strategy for controlled synthesis of new Au-Ag nanoclusters and also reveals a new scenario for the doping position of Ag atoms in Au-Ag bimetal nanoclusters. [ABSTRACT FROM AUTHOR]

Precipitation in different types has great influence not only on water resources and distribution of annual precipitation in cold regions, but also on the thermal regimes of frozen ground. The long-term variations of the ratios of snow, rain and sleet to precipitation were analyzed in this study. The 44 meteorological stations were selected, which are located on the Qinghai-Tibet Plateau (QTP) including permafrost and seasonal frozen ground regions. The results indicate that the monthly snow/precipitation ratio in permafrost regions is far higher than that in seasonal frozen ground regions, but the monthly rain/precipitation ratio in permafrost regions is lower than that in seasonal frozen ground regions, and the monthly variation of sleet/precipitation ratio is indistinctive. The annual ratios of snow and sleet to precipitation show decreasing trends in both regions, and annual rain/precipitation ratio shows an increasing tendency. The dropping magnitude of annual snow/precipitation ratio in seasonal frozen ground regions is larger than that in permafrost regions. The maximum and minimum annual snow/precipitation ratios in both regions occur in winter and summer, respectively, and the second is in spring, instead, the maximum and minimum annual rain/precipitation ratios appear in summer and winter, respectively. The spatial features of the ratios of snow and rain to precipitation are largely opposite, that is, the low snow/precipitation ratio stations are usually associated with the high rain/precipitation ratio, and prominent seasonal diversities of three ratios can be found from their spatial patterns. In addition, the decreasing (increasing) tendency of snow (rain)/precipitation ratio in spring and autumn is more significant than that in winter and summer, and these stations of snow/precipitation ratio with downward trends are mainly located at the edge of the QTP. The ratios of snow and sleet to precipitation will gradually decrease (increase), and the rain/precipitation ratio will increase (decrease) with the air temperature (altitude) rises, respectively, while there are significant seasonal discrepancies. Moreover, the altitude zone showing remarkable variations of the ratios of snow and rain to precipitation ranges from 3000 to 4000 m a.s.l, especially in spring and summer. [ABSTRACT FROM AUTHOR]

• The warming magnitudes of air temperature were summarized in the QTP and Mongolian on seasonal and annual scales. • The spatio-temporal changes of air freezing and thawing indices were characterized in the QTP and Mongolia. • The changes of air freezing and thawing indices could imply that the difference of warming characteristics in the QTP and Mongolia. • The changes of air freezing and thawing indices indicate that climate warming have great influence on the permafrost. The majority of the Qinghai-Tibet Plateau (QTP) and Mongolia are underlain by permafrost. We have examined trends in air temperature and associated freezing/thawing index by using a non-parametric statistical method for the QTP and Mongolia from 1961 to 2011. The annual air temperature and associated freezing/thawing index exhibit similar patterns, suggesting similar warming trend in the two regions. The annual warming trends of air temperature are 0.33 °C/decade and 0.37 °C/decade in the QTP and Mongolia, respectively. The freezing index show significantly decreasing trends with −56.7 °C·days/decade and −57.5 °C·days/decade, while the thawing index present obvious increasing trends of 68.2 °C·days/decade and 68.3 °C·days/decade in the QTP and Mongolia, respectively. We find that the variations of air temperature and freezing/thawing index exhibit prominent spatial heterogeneity, and the warming trends is attributed to different seasonal warming. The warming trends in the QTP are dominated by winter warming, it is coincide with previous studies. Contrary to the QTP, autumn warming mainly accounts for the warming trends in the Mongolia. In addition, a winter cooling trend is observed in the Mongolia during the last two decades. These findings will be helpful to better understand the spatial heterogeneity of permafrost changes. [ABSTRACT FROM AUTHOR]

To investigate the reliability of global gridded precipitation datasets with horizontal resolution of 0.5° × 0.5° in arid Xinjiang, central Asia, the monthly precipitation datasets released by the Climatic Research Unit (CRU TS, version 3.21), the University of Delaware (Terrestrial Precipitation: 1900–2010 Gridded Monthly Time Series, version 3.01), the Global Precipitation Climatology Centre (GPCC Full Data Reanalysis Product, version 6) and the National Oceanic and Atmospheric Administration (NOAA's Precipitation Reconstruction over Land) during 1979–2010 were selected. A precipitation dataset released by the National Meteorological Information Center, China Meteorological Administration is applied as the observation series. The result indicates that changes in seasonal and annual precipitation can be simulated by the four gridded datasets in most regions of Xinjiang, but there are seasonal and regional discrepancies in the correlation coefficients ( R ), mean bias error (MBE) and root-mean-square error (RMSE). Generally speaking, the gridded datasets can be more effective in simulating precipitation in low-lying basins, that is, the elevation is less than 1500 m (mainly desert and scattered oasis), while RMSE in mountainous areas is much larger than that in low-lying areas. In Altay, Tianshan and Kunlun Mountains, the precipitation simulated by the gridded datasets is less than that of observation series. The accuracy of gridded precipitation datasets generally decreases with elevation. On a seasonal basis, the errors of gridded precipitation datasets in summer months are generally higher than those in other seasons, and RMSE usually shows low values during wintertime. Among the four gridded precipitation datasets, RMSE of CRU is slightly larger than other three datasets in most areas of Xinjiang. The wetting trend magnitude in this study area from 1979 to 2010 is generally underrated by all the gridded datasets, indicating that the long-term precipitation trend using gridded datasets should be treated with caution. [ABSTRACT FROM AUTHOR]

Acute leukemia characterized by chromosomal rearrangements requires additional molecular disruptions to develop into full-blown malignancy, yet the cooperative mechanisms remain elusive. Using whole-genome sequencing of a pair of monozygotic twins discordant for MLL (also called KMT2A) gene-rearranged leukemia, we identified a transforming MLL-NRIP3 fusion gene and biallelic mutations in SETD2 (encoding a histone H3K36 methyltransferase). Moreover, loss-of-function point mutations in SETD2 were recurrent (6.2%) in 241 patients with acute leukemia and were associated with multiple major chromosomal aberrations. We observed a global loss of H3K36 trimethylation (H3K36me3) in leukemic blasts with mutations in SETD2. In the presence of a genetic lesion, downregulation of SETD2 contributed to both initiation and progression during leukemia development by promoting the self-renewal potential of leukemia stem cells. Therefore, our study provides compelling evidence for SETD2 as a new tumor suppressor. Disruption of the SETD2-H3K36me3 pathway is a distinct epigenetic mechanism for leukemia development. [ABSTRACT FROM AUTHOR]

The original article can be found online at https://doi.org/10.1038/s41598-021-98357-2. Correction to: I Scientific Reports i https://doi.org/10.1038/s41598-021-98357-2, published online 23 September 2021 The original version of this Article contained an error in the order of the author names, which was incorrectly given as Xiaohua Fang, Xiaofan Zhu, Yin Feng, Ying Bai, Xuechao Zhao, Xiangdong Kong & Ning Liu. [Extracted from the article]

Chimeric antigen receptor‐natural killer (CAR‐NK) cell therapy is emerging as a promising cancer treatment, with notable safety and source diversity benefits over CAR‐T cells. This study focused on optimizing CAR constructs for NK cells to maximize their therapeutic potential. We designed seven CD19 CAR constructs and expressed them in NK cells using a retroviral system, assessing their tumour‐killing efficacy and persistence. Results showed all constructs enhanced tumour‐killing and prolonged survival in tumour‐bearing mice. In particular, CAR1 (CD8 TMD‐CD3ζ SD)‐NK cells showed superior efficacy in treating tumour‐bearing animals and exhibited enhanced persistence when combined with OX40 co‐stimulatory domain. Of note, CAR1‐NK cells were most effective at lower effector‐to‐target ratios, while CAR4 (CD8 TMD‐OX40 CD‐ FcεRIγ SD) compromised NK cell expansion ability. Superior survival rates were noted in mice treated with CAR1‐, CAR2 (CD8 TMD‐ FcεRIγ SD)‐, CAR3 (CD8 TMD‐OX40 CD‐ CD3ζ SD)‐ and CAR4‐NK cells over those treated with CAR5 (CD28 TMD‐ FcεRIγ SD)‐, CAR6 (CD8 TMD‐4‐1BB CD‐CD3ζ 1‐ITAM SD)‐ and CAR7 (CD8 TMD‐OX40 CD‐CD3ζ 1‐ITAM SD)‐NK cells, with CAR5‐NK cells showing the weakest anti‐tumour activity. Increased expression of exhaustion markers, especially in CAR7‐NK cells, suggests that combining CAR‐NK cells with immune checkpoint inhibitors might improve anti‐tumour outcomes. These findings provide crucial insights for developing CAR‐NK cell products for clinical applications. [ABSTRACT FROM AUTHOR]

To evaluate the performance of noninvasive prenatal screening (NIPS) in the detection of common aneuploidies in a population-based study, a total of 86,262 single pregnancies referred for NIPS were prospectively recruited. Among 86,193 pregnancies with reportable results, follow-up was successfully conducted in 1160 fetuses reported with a high-risk result by NIPS and 82,511 cases (95.7%) with a low-risk result. The screen-positive rate (SPR) of common aneuploidies and sex chromosome abnormalities (SCAs) provided by NIPS were 0.7% (586/83,671) and 0.6% (505/83,671), respectively. The positive predictive values (PPVs) for Trisomy 21, Trisomy 18, Trisomy 13 and SCAs were calculated as 89.7%, 84.0%, 52.6% and 38.0%, respectively. In addition, less rare chromosomal abnormalities, including copy number variants (CNVs), were detected, compared with those reported by NIPS with higher read-depth. Among these rare abnormalities, only 23.2% (13/56) were confirmed by prenatal diagnosis. In total, four common trisomy cases were found to be false negative, resulting in a rate of 0.48/10,000 (4/83,671). In summary, this study conducted in an underdeveloped region with limited support for the new technology development and lack of cost-effective prenatal testing demonstrates the importance of implementing routine aneuploidy screening in the public sector for providing early detection and precise prognostic information. [ABSTRACT FROM AUTHOR]

Trisomy 7 is the most frequently observed type of rare autosomal trisomies in genome-wide non-invasive prenatal screening (NIPS). Currently, the clinical significance of trisomy 7 NIPS-positive results is still unknown. We reviewed two independent cohorts from two laboratories where similar NIPS metrics were applied. A total of 70,441 singleton cases who underwent genome-wide NIPS were analyzed, among which 39 pregnancies were positive for trisomy 7, yielding a screen-positive rate of 0.055% (39/70,441). There were 28 cases with invasive testing results available; the positive predictive value (PPV) was 3.6% (1/28). We then searched the published NIPS studies to generate a large cohort of 437,873 pregnancies and identified 247 cases (0.056%) that were screened positive for trisomy 7. The overall PPV was 3.4% (4/118) in the combined data. The presence of uniparental disomy 7 was not detected in the NIPS trisomy 7-positive pregnancies with normal fetal karyotype. Among the 85 cases with pregnancy outcome available in combined data, 88.2% were normal live births, 14.1% had intrauterine growth restriction, preterm birth or low birth weight, 3.5% presented with ultrasound abnormality, and no fetal loss was observed. Our data provide valuable information for counseling and management of trisomy 7-positive NIPS pregnancies. [ABSTRACT FROM AUTHOR]

Relict permafrost presents an ideal opportunity to understand the impacts of climatic warming on the ground thermal regime since it is characterized by a mean annual ground temperature close to 0 ∘ C and relatively thin permafrost. The long-term and continuous observations of permafrost thermal state and climate background are of great importance to reveal the links between the energy balance on hourly to annual timescales, to evaluate the variations in permafrost thermal state over multiannual periods and to validate the remote sensing dataset. We present 11 years of meteorological and soil data from the Mahan Mountain relict permafrost site of northeastern Qinghai–Tibet Plateau. The meteorological data comprise air and land surface temperature, relative humidity, wind speed and direction, shortwave and longwave downwards and upwards radiation, water vapor pressure, and precipitation on a half-hour timescale. The active layer data include daily soil temperature and soil volumetric water content at five different depths. The permafrost data consist of the ground temperature at 20 different depths up to 28.4 m. The high-quality and long-term datasets are expected to serve as accurate forcing data in land surface models and evaluate remote-sensing products for a broader geoscientific community. The datasets are available from the National Tibetan Plateau/Third Pole Environment Data Center (10.11888/Cryos.tpdc.271838, Wu and Xie, 2021). [ABSTRACT FROM AUTHOR]

• The article included 48 unrelated Chinese mucopolysaccharidosis (MPS) patients. • We identified 11 novel gene variants among 69 gene variants. • Targeted next-generation sequencing applied for the gene testing of MPS disorder. • Genotype-phenotype relationship in MPS patients had been explored. • There variants were associated with impaired protein structure and function. Mucopolysaccharidosis (MPS) refers to a group of lysosomal storage disorders for which seven types and 11 subtypes are currently recognized. Targeted next-generation sequencing (NGS) offers an important method of disease typing, diagnosis, prenatal diagnosis, and treatment. Gene variations in 48 Chinese MPS patients were evaluated using NGS, and the pathogenicity of the DNA alterations was evaluated using PolyPhen2, SIFT, and Mutation Taster. The effect of amino acid substitution on protein structure was also assessed. Four pedigrees with MPS I (8.3%), 28 with MPS II (58.3%), two with MPS IIIA (4.2%), two with MPS IIIB (4.2%), six with MPS IVA (12.5%), one with MPS IVB (2.1%), and five with MPS VI (10.4%) were identified. Of the 69 variations identified, 11 were novel variants (three in IDUA , five in IDS , and three in GALNS), all of which were predicted to be disease-causing except for one, and were associated with impaired protein structure and function. Targeted NGS technology is effective for the gene-based testing of MPS disorders, which show high allelic heterogeneity. MPS II was the predominant form in Chinese. Our study expands the existing variation spectrum of MPS, which is important for disease management and genetic counseling. [ABSTRACT FROM AUTHOR]

Relict permafrost presents an ideal opportunity to understand the impacts of climatic warming on the ground thermal regime since it is characterized by mean annual ground temperature close to 0 °C and relatively thin permafrost. The long-term and continuous observations of permafrost thermal state and climate background are of great importance to reveal the links between the energy balance on hourly to annual timescales, to evaluate the variations of permafrost thermal state over multi-annual periods and to validate the remote sensing dataset. Until now there are few data available in relict permafrost regions although those data are important to understand the impacts of climate changes on permafrost especially in the boundary regions between permafrost and seasonally frozen ground regions. In this study, we present 11 years of meteorological and soil data in a relict permafrost site of the Mahan Mountain on the northeast of the Qinghai-Tibet Plateau. The meteorological data are comprised of air and ground surface temperature, relative humidity, wind speed and direction, shortwave and longwave downward and upward radiation, water vapor pressure, and precipitation on half-an-hour timescale. The active layer data include daily soil temperature and soil moisture at five different depths. The permafrost data consist of ground temperature at twenty different depths up to 28.4 m. The high-quality and long-term datasets are expected to serve as accurate forcing data in land surface models and evaluate remote-sensing products for a broader geoscientific community. The datasets are available from the National Tibetan Plateau/Third Pole Environment Data Center (https://doi.org/10.11888/Cryos.tpdc.271838, Wu and Xie, 2021). [ABSTRACT FROM AUTHOR]

Myelodysplastic syndrome (MDS) is a rare clonal hematopoietic disorder in children. The risk stratification system and treatment strategy for adults are unfit for children. The role of hypomethylating agents (HMAs) in higher-risk childhood MDS has not been identified. This study aimed to investigate the outcomes of hematopoietic stem cell transplantation (HSCT) in children with higher-risk MDS at one single center. A retrospective study was conducted in children with higher-risk MDS undergoing HSCT between September 2019 and March 2023 at Blood Diseases Hospital CAMS. The clinical characteristics and transplantation information were reviewed and analyzed. A total of 27 patients were analyzed, including 11 with MDS with excess blasts (MDS-EB), 14 with MDS-EB in transformation (MDS-EBt) or acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), and 2 with therapy-related MDS/AML (t-MDS/AML). Eight patients harbored monosomy 7. Before transplantation, induction therapy was administered to 25 patients, and 19 of them achieved bone marrow blasts <5% before HSCT. The stem cell source was unmanipulated-related bone marrow or peripheral blood stem cells for nineteen patients and unrelated cord blood for eight. All patients received decitabine-containing and Bu/Cy-based myeloablative conditioning; 26 patients achieved initial engraftment. The cumulative incidences of grade II–IV and grade III–IV acute graft-versus-host disease (GvHD) at 100 days were 65.4% and 42.3%, respectively. The incidence of cGvHD was 38.5%. The median follow-up was 26 (range 4–49) months after transplantation. By the end of follow-up, two patients died of complications and two died of disease progression. The probability of 3-year overall survival (OS) was 84.8% (95%CI, 71.1 to 98.5%). In summary, decitabine-containing myeloablative conditioning resulted in excellent outcomes for children with higher-risk MDS undergoing allogeneic HSCT. [ABSTRACT FROM AUTHOR]

The freezing index (FI) is one of the most important indicators that shows the variation of permafrost. However, the relationship between climate change and the thermal conditions of permafrost is not understood well. This study analyzed the variation of FI based on 5-cm soil temperature derived from 74 meteorological stations from 1977 to 2016 on the Qinghai-Tibet Plateau (QTP). Furthermore, the factors affecting the FI variation and its relationship with permafrost degradation were also discussed. The results showed that FI was much smaller in the interior than other areas of the QTP, and it increased at a rate of 53.0 °C d/10a during the 40 years. FI in the main body of the QTP was relatively stable than surrounding areas; it was more stable in the northern part than in the southern part. On average, the FI variation coefficient was larger than 10%, indicating the large fluctuation of FI during the 40 years. FI decreased with the increasing altitude; it was more sensitive to the altitude in the south of 33° N than in the north. The variation of FI was closely related to the maximum freezing depth (MFD) and the active layer thickness (ALT). It was observed that MFD decreased and ALT increased by approximately 1.4 cm and 1.6 cm, respectively, with each 10.0 °C d increase in FI. The results exhibited the thermal condition variation of the permafrost in QTP and revealed a degrading trend of the permafrost. [ABSTRACT FROM AUTHOR]

Due to the difficult degradation and high cost of polyester polyols (PPs), their further development in controlled-release fertilizers (CRFs) has been limited. It was of great significance to partially substitute PPs with soybean oil polyols (SOPs) in the preparation of CRFs, which can adjust the proportion of substitution to balance the nutrient release period and membrane degradability. And it is possible to adjust the nitrogen release curve and prepare coated urea with different release days without changing the coating thickness. In this study, a two-factor five-level interaction experiment was designed with different SOP addition ratios (70%, 60%, 50%, 40%, and 30%) and mass ratios of polyols to PAPI (1:1.2; 1:1; 1.2:1; 1.4:1; and 1.6:1). In 25 groups of soybean-oil-modified polyester polyurethane-coated urea (SMPCU) treatments, with the increase in SOP, the thermal decomposition performance of the coated urea was improved, and the residual ash contents of the coating material was reduced. The coating surface was made smoother and denser with a reasonable ratio of polyols to PAPI, preventing the release of non-film-forming substances. When the proportion of soybean oil was 60% and the ratio of polyols to PAPI was 1.2:1, the N release days of the prepared SMPCU reached 137 days. Compared to soybean-oil polyol-coated urea (SOPCU) and polyester polyol-coated urea (PPCU), the nitrogen release days increased by 73.42% (79 days) and 234.15% (41 days), respectively. The ratio of polyols to polyaryl polymethylene isocyanate (PAPI) was explored, as well as the effect of polyol composition on coatings, and prepared SMPCUs with different nitrogen release days. According to the growth needs of crops and soil environmental characteristics, adjusting the proportion of coating materials, prolonging or shortening the nitrogen fertilizer release time, meets the nutritional needs of crops under different planting systems and provides conditions for farmers to plant different crops. [ABSTRACT FROM AUTHOR]

Background: Acute myeloid leukaemia (AML) is characterised by the malignant accumulation of myeloid progenitors with a high recurrence rate after chemotherapy. Blasts (leukaemia cells) exhibit a complete myeloid differentiation hierarchy hiding a wide range of temporal information from initial to mature clones, including genesis, phenotypic transformation, and cell fate decisions, which might contribute to relapse in AML patients. Methods: Based on the landscape of AML surface antigens generated by mass cytometry (CyTOF), we combined manifold analysis and principal curve-based trajectory inference algorithm to align myelocytes on a single-linear evolution axis by considering their phenotype continuum that correlated with differentiation order. Backtracking the trajectory from mature clusters located automatically at the terminal, we recurred the molecular dynamics during AML progression and confirmed the evolution stage of single cells. We also designed a 'dispersive antigens in neighbouring clusters exhibition (DANCE)' feature selection method to simplify and unify trajectories, which enabled the exploration and comparison of relapse-related traits among 43 paediatric AML bone marrow specimens. Results: The feasibility of the proposed trajectory analysis method was verified with public datasets. After aligning single cells on the pseudotime axis, primitive clones were recognized precisely from AML blasts, and the expression of the inner molecules before and after drug stimulation was accurately plotted on the trajectory. Applying DANCE to 43 clinical samples with different responses for chemotherapy, we selected 12 antigens as a general panel for myeloblast differentiation performance, and obtain trajectories to those patients. For the trajectories with unified molecular dynamics, CD11c overexpression in the primitive stage indicated a good chemotherapy outcome. Moreover, a later initial peak of stemness heterogeneity tended to be associated with a higher risk of relapse compared with complete remission. Conclusions: In this study, pseudotime was generated as a new single-cell feature. Minute differences in temporal traits among samples could be exhibited on a trajectory, thus providing a new strategy for predicting AML relapse and monitoring drug responses over time scale. [ABSTRACT FROM AUTHOR]

Background: Individuals diagnosed with Fanconi anemia (FA), an uncommon disorder characterized by chromosomal instability affecting the FA signaling pathway, exhibit heightened vulnerability to the onset of myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). Methods: Herein, we employed diverse bioinformatics and statistical analyses to investigate the potential associations between the expression/mutation patterns of FA pathway genes and MDS/AML. Results: The study included 4295 samples, comprising 3235 AML and 1024 MDS from our and nine other online cohorts. We investigated the distinct proportion of race, age, French-American-British, and gender factors. Compared to the FA wild-type group, we observed a decrease in the expression of FNACD2, FANCI, and RAD51C in the FA mutation group. The FA mutation group exhibited a more favorable clinical overall survival prognosis. We developed a random forest classifier and a decision tree based on FA gene expression for cytogenetic risk assessment. Furthermore, we created an FA-related Nomogram to predict survival rates in AML patients. Conclusions: This investigation facilitates a deeper understanding of the functional links between FA and MDS/AML. [ABSTRACT FROM AUTHOR]

Purpose: This study investigated the clinical and antimicrobial characteristics of Acinetobacter spp. bloodstream infection (BSI) in hematological patients. Risk factors for 30-day mortality and carbapenem-resistant Acinetobacter spp. (CRA) BSI acquisition were also identified. Methods: We reviewed forty hematological patients with Acinetobacter spp. BSI in a large Chinese blood disease hospital between 2013 and 2022. The remaining CRA isolates were subjected to whole-genome sequencing. Results: The 30-day mortality rate was high at 35%. Hematological patients with Acinetobacter spp. BSI often presented with severe conditions and co-infections at multiple sites. All strains were colistin-susceptible and 40.0% were CR. Multivariate analysis identified several risk factors associated with CRA BSI acquisition, including previous exposure to carbapenems within 30 days and CRA colonization. Very severe aplastic anaemia, tetracycline-resistant Acinetobacter spp. BSI, and unresolved neutropenia after infection were closely associated with 30-day mortality. Non-survivors often presented with higher median PCT and CRP levels and severe complications, such as intracranial infection, cardiac dysfunction, respiratory failure, and severe sepsis or septic shock. Our study also identified inappropriate empirical antibiotic therapy as an independent predictor of 30-day mortality (OR: 11.234, 95% CI: 1.261–20.086, P = 0.030). This study was the first to report A. oleivorans as a human pathogen, and to identify its unique oxacillinase, OXA-325. Conclusion: An environment-originated non-pathogenic species can become pathogenic when the body's immunity is compromised. Our results also highlighted the importance of improving neutropenia after infection, treating severe organ dysfunction, and administering appropriate empirical antibiotic therapy to reduce mortality in this patient population. [ABSTRACT FROM AUTHOR]

Summary: Due to the infrequency of essential thrombocythemia (ET) in children, little is known about its pathophysiological mechanism. To learn about the clinical and molecular features of Chinese children with ET, we retrospectively analysed 40 children with ET in a single center from 2015–2021. More than half of the children (51.3%, 20/39) were asymptomatic at diagnosis. Nearly half of the children (48.7%, 19/39) had microvascular symptoms, including headache, dizziness, stomachache, and paresthesia. Only two cases experienced vascular events. The proportion of children with typical "driver gene mutations" (i.e., JAK2 p.V617F, CALR exon 9, or MPL exon 10 mutation) was low (12.5%, 5/40). The equivalent ratio of children carried atypical driver gene mutations; however, 30 (75%) patients did not harbour driver gene mutations. Children carrying JAK2 p.V617F had lower platelet count (938 × 109/L vs. 1654 × 109/L, p = 0.031) compared to those without driver gene mutations. Cases harbouring typical driver mutations had higher median WBC counts than those without driver gene mutations (15.14 × 109/L vs. 8.01 × 109/L, p = 0.015). Compared to those without driver gene mutations, cases carrying typical and atypical driver gene mutations were both younger (median ages were 12, 6, and 7 years old, respectively; p = 0.023). The most prevalent non‐driver gene mutations and those mutations with prognostic significance in adult counterparts were less common in children with ET compared to adults with ET. [ABSTRACT FROM AUTHOR]

Climate changes significantly impact the hydrological cycle. Precipitation is one of the most important atmospheric inputs to the terrestrial hydrologic system, and its variability considerably influences environmental and socioeconomic development. Atmospheric warming intensifies the hydrological cycle, increasing both atmospheric water vapor concentration and global precipitation. The relationship between heavy precipitation and temperature has been extensively investigated in literature. However, the relationship in different percentile ranges has not been thoroughly analyzed. Moreover, a percentile-based regression provides a simple but effective framework for investigation into other factors (precipitation type) affecting this relationship. Herein, a comprehensive investigation is presented on the temperature dependence of daily precipitation in various percentile ranges over the Qinghai–Tibet Plateau. The results show that 1) most stations exhibit a peaklike scaling structure, while the northeast part and south margin of the plateau exhibit monotonic positive and negative scaling structures, respectively. The scaling structure is associated with the precipitation type, and 2) the positive and negative scaling rates exhibit similar spatial patterns, with stronger (weaker) sensitivity in the south (north) part of the plateau. The overall increase rate of daily precipitation with temperature is scaled by Clausius–Clapeyron relationship. 3) The higher percentile of daily precipitation shows a larger positive scaling rate than the lower percentile. 4) The peak-point temperature is closely related to the local temperature, and the regional peak-point temperature is roughly around 10°C. Significance Statement: This study aims to better understand the relationship between precipitation and surface air temperature in various percentile ranges over the Qinghai–Tibet Plateau. This is important because percentile-based regression not only accurately describes the response of precipitation to warming temperature but also provides a simple but effective framework for investigating other factors (precipitation type) that may be affecting this relationship. Furthermore, the sensitivity and peak-point temperature are evaluated and compared among different regions and percentile ranges; this study also attempts to outline their influencing factors. To our knowledge, this study is the first integration of percentile-based analysis of the dependence of daily precipitation on surface air temperature. [ABSTRACT FROM AUTHOR]

The Qinghai–Tibet Plateau is an area known to be sensitive to global climate change, and the problems caused by permafrost degradation in the context of climate warming potentially have far-reaching effects on regional hydrogeological processes, ecosystem functions, and engineering safety. Soil thermal conductivity (STC) is a key input parameter for temperature and surface energy simulations of the permafrost active layer. Therefore, understanding the spatial distribution patterns and variation characteristics of STC is important for accurate simulation and future predictions of permafrost on the Qinghai–Tibet Plateau. However, no systematic research has been conducted on this topic. In this study, based on a dataset of 2972 STC measurements, we simulated the spatial distribution patterns and spatiotemporal variation of STC in the shallow layer (5 cm) of the Qinghai–Tibet Plateau and the permafrost area using a machine learning model. The monthly analysis results showed that the STC was high from May to August and low from January to April and from September to December. In addition, the mean STC in the permafrost region of the Qinghai–Tibet Plateau was higher during the thawing period than during the freezing period, while the STC in the eastern and southeastern regions is generally higher than that in the western and northwestern regions. From 2005 to 2018, the difference between the STC in the permafrost region during the thawing and freezing periods gradually decreased, with a slight difference in the western hinterland region and a large difference in the eastern region. In areas with specific landforms such as basins and mountainous areas, the changes in the STC during the thawing and freezing periods were different or even opposite. The STC of alpine meadow was found to be most sensitive to the changes during the thawing and freezing periods within the permafrost zone, while the STC for bare land, alpine desert, and alpine swamp meadow decreased overall between 2005 and 2018. The results of this study provide important baseline data for the subsequent analysis and simulation of the permafrost on the Qinghai–Tibet Plateau. [ABSTRACT FROM AUTHOR]

The Arctic amplification (AA) has exacerbated permafrost degradation, posing a serious threat to infrastructure security and other areas. Therefore, it is crucial to accurately assess the current status and future changes of permafrost, and reliable soil thermal conductivity (STC) is an important prerequisite for permafrost prediction. However, few methods and products are available for regional-scale STC simulations in permafrost of the Arctic, which lead to greater uncertainty in the simulation of land surface temperatures. This study conducted a preliminary STC simulation based on the XGBoost method. The results show that the average STC during the freezing period is between 0.71∼0.73 W·m−1K−1, and around 0.67 W·m−1K−1 during the thawing period; The variation of STC between the thawing and freezing period ranged from −0.34–0.23 W·m−1K−1, with an average value of −0.02 W·m−1K−1; The areas where STC of the thawing period is smaller than that of the freezing period are mainly concentrated in the marginal areas near the sea on the continental side of North America and in the typical areas of plains, lowlands, and plateaus on the continental side of Eurasia. The areas with large STC during the thawing period are concentrated in mountainous areas. [ABSTRACT FROM AUTHOR]

Fanconi anemia (FA) is a rare autosomal recessive, X-linked or autosomal dominant disease. Few large-scale FA investigations of rare disease cohorts have been conducted in China. We enrolled 148 patients diagnosed with FA according to evidence from the clinical phenotype, family history, and a set of laboratory tests. Next, the clinical manifestations and correlation between the genotype and phenotype of FA pediatric cases were investigated. The most common FA subtype in our cohort was FA-A (51.4 %), followed by FA-D2 and FA-P. Finger (26 %) and skin (25 %) deformities were the most common malformations. Based on family history, blood system diseases (51 %) had the highest incidence rate, followed by digestive system tumours. A set of new or prognosis-related mutation sites was identified. For example, c.2941 T > G was a new most common missense mutation site for FANCA. FANCP gene mutation sites were mainly concentrated in exons 12/14/15. The mutations of FANCI/FANCD2 were mainly located at the α helix and β corners of the protein complex. FA-A/D1 patients with splicing or deletion mutations showed more severe disease than those with missense mutations. Chromosome 1/3/7/8 abnormalities were closely linked to the progression of FA to leukemia. Our study investigated the clinical features and genotype/phenotype correlation of 148 Chinese pediatric FA patients, providing new insight into FA. [ABSTRACT FROM AUTHOR]

This study assessed the relapse characteristics and prognosis of 145 children newly diagnosed with T-cell acute lymphoblastic leukemia (T-ALL). The overall complete response (CR) rate was 91.7% (133/145), and the overall recurrence rate was 31.6% (42/133). The recurrence rate in the intermediate-risk (IR) group and high-risk (HR) group was 15.4% and 47.1%, respectively (p < 0.001). Patients with young age, early T-cell precursor ALL, central nervous system (CNS) involvement, TCRγ gene rearrangement, karyotypic abnormalities, or absence of TCRβ gene rearrangement (p < 0.05) tended to relapse. All recurrences occurred within 36 months after diagnosis. The HR group recurred earlier than the IR group (p= 0.026). The 3-year overall survival (OS) rate was significantly lower in the HR group than in the IR group (p < 0.001). All relapsed children died within 12 months after recurrence. Early intervention may benefit children with a high risk of recurrence. [ABSTRACT FROM AUTHOR]

Background: Fetal skeletal dysplasia (SD) is a common congenital disability comprising a complex group of skeletal disorders with substantial clinical and genetic heterogeneity. Many of these defects are detected prenatally using ultrasound (US). However, the diagnostic accuracy of the US is limited.Methods: We recruited 55 unrelated fetuses with US-detected skeletal anomalies and performed sequential tests using copy number variation sequencing, targeted skeletal gene panel sequencing, or whole exome sequencing. The detected variants were validated using Sanger sequencing or multiplex ligation-dependent probe amplification. We conducted breakpoint analysis and structural modeling of variants possibly involved in fetal SD.Results: A definitive diagnosis was achieved in 81.82% of affected fetuses (45/55). We identified chromosomal abnormalities in seven cases and 36 variants, of which 18 were novel pathogenic or likely pathogenic in 11 genes in 38 cases. De novo variants were identified in 27 cases (71.05%, 27/38), and one gonosomal mosaicism variant was found in the mother of one fetus. Our case examples demonstrated the high heterogeneity of fetal SDs and the rare fetal SD-associated challenges.Conclusions: Careful clinical evaluation of fetuses with SD can guide appropriate molecular testing. Our study extends the SD-associated pathogenic variant spectrum and provides useful genetic counselling guidance and an accurate prenatal diagnosis strategy. [ABSTRACT FROM AUTHOR]

This letter published in the Annals of Hematology discusses a rare and risky condition called B-cell lineage acute lymphoblastic leukemia (B-ALL) with Loeffler's endocarditis. The letter presents a case study of a 6-year-old male with B-ALL and Loeffler's endocarditis, detailing his symptoms, diagnosis, and treatment. The patient was initially treated with methylprednisolone, which successfully reduced leukocyte and eosinophil counts and alleviated heart failure symptoms. After standard chemotherapy was omitted due to potential complications, the patient received two cycles of blinatumomab, a bispecific T cell engager, which resulted in remission without rebounded eosinophils or heart failure. The letter concludes by highlighting the rarity of this condition and the importance of effectively combining intensity-reduced chemotherapy with blinatumomab. [Extracted from the article]

PROteolysis TArgeting Chimeras (PROTACs) degrade target proteins via the ubiquitin-proteasome system, providing novel insights into drug development for hematologic malignancies. PROTACs outperform conventional therapeutics and currently available small molecule inhibitors in terms of efficacy, tissue-and cell-selectivity, and side effect profile. Most importantly, PROTACs are a powerful tool for addressing "undruggable" oncogenic proteins. Despite their numerous benefits, PROTACs as therapeutics face many challenges not only in the design and synthesis but also in the evaluation of anticancer effects and clinical application. In this article, we focus on PROTACs that have demonstrated preclinical efficacy and clinical potential in the treatment of various hematologic malignancies in the last 5 years. We start with a brief overview of the functioning mechanism and major breakthroughs in this field. To provide a balanced perspective on PROTACs, we discuss the pros and cons of exploiting PROTACs for therapeutic purposes. Following that, we brainstorm ideas to optimize PROTACs for clinical application. More PROTACs will enter clinical trials soon, benefiting patients with hematologic malignancies. [ABSTRACT FROM AUTHOR]

The increase in temperatures and changing precipitation patterns resulting from climate change are accelerating the occurrence and development of landslides in cold regions, especially in permafrost environments. Although the boundary regions between permafrost and seasonally frozen ground are very sensitive to climate warming, slope failures and their kinematics remain barely characterized or understood in these regions. Here, we apply multisource remote sensing and field investigation to study the activity and kinematics of two adjacent landslides (hereafter referred to as "twin landslides") along the Datong River in the Qilian Mountains of the Qinghai-Tibet Plateau. After failure, there is no obvious change in the area corresponding to the twin landslides. Based on InSAR measurements derived from ALOS PALSAR-1 and -2, we observe significant downslope movements of up to 15 mm/day within the twin landslides and up to 5 mm/day in their surrounding slopes. We show that the downslope movements exhibit distinct seasonality; during the late thaw and early freeze season, a mean velocity of about 4 mm/day is observed, while during the late freeze and early thaw season the downslope velocity is nearly inactive. The pronounced seasonality of downslope movements during both pre- and post-failure stages suggest that the occurrence and development of the twin landslide are strongly influenced by freeze–thaw processes. Based on meteorological data, we infer that the occurrence of twin landslides are related to extensive precipitation and warm winters. Based on risk assessment, InSAR measurements, and field investigation, we infer that new slope failure or collapse may occur in the near future, which will probably block the Datong River and cause catastrophic disasters. Our study provides new insight into the failure mechanisms of slopes at the boundaries of permafrost and seasonally frozen ground. [ABSTRACT FROM AUTHOR]

Background: Fanconi anemia (FA) is a rare disease of bone marrow failure. FA patients are prone to develop myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, the molecular clonal evolution of the progression from FA to MDS/AML remains elusive. Methods: Herein, we performed a comprehensive genomic analysis using an FA patient (P1001) sample that transformed to MDS and subsequently AML, together with other three FA patient samples at the MDS stage. Results: Our finding showed the existence of polyclonal pattern in these cases at MDS stage. The clonal evolution analysis of FA case (P1001) showed the mutations of UBASH3A, SF3B1, RUNX1 and ASXL1 gradually appeared at the later stage of MDS, while the IDH2 alteration become the dominant clone at the leukemia stage. Moreover, single-cell sequencing analyses further demonstrated a polyclonal pattern was present at either MDS or AML stages, whereas IDH2 mutated cell clones appeared only at the leukemia stage. Conclusions: We thus propose a clonal evolution model from FA to MDS and AML for this patient. The results of our study on the clonal evolution and mutated genes of the progression of FA to AML are conducive to understanding the progression of the disease that still perplexes us. [ABSTRACT FROM AUTHOR]

Summary: To create a personal prognostic model and modify the risk stratification of paediatric acute myeloid leukaemia, we downloaded the clinical data of 597 patients from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database as a training set and included 189 patients from our centre as a validation set. In the training set, age at diagnosis, ‐7/del(7q) or ‐5/del(5q), core binding factor fusion genes, FMS‐like tyrosine kinase 3‐internal tandem duplication (FLT3‐ITD)/nucleophosmin 1 (NPM1) status, Wilms tumour 1 (WT1) mutation, biallelic CCAAT enhancer binding protein alpha (CEBPA) mutation were strongly correlated with overall survival and included to construct the model. The prognostic model demonstrated excellent discriminative ability with the Harrell's concordance index of 0.68, 3‐ and 5‐year area under the receiver operating characteristic curve of 0.71 and 0.72 respectively. The model was validated in the validation set and outperformed existing prognostic systems. Additionally, patients were stratified into three risk groups (low, intermediate and high risk) with significantly distinct prognosis, and the model successfully identified candidates for haematopoietic stem cell transplantation. The newly developed prognostic model showed robust ability and utility in survival prediction and risk stratification, which could be helpful in modifying treatment selection in clinical routine. [ABSTRACT FROM AUTHOR]

Isolating seasonal deformation from Interferometric Synthetic Aperture Radar (InSAR) time‐series is critical to quantitative understanding the freeze‐thaw processes in permafrost regions. Physics‐ or statistics‐based approaches have been developed to extract seasonal deformation, yet both constraining their evolution in time domain, and thus impeded the quantification of their amplitude variability especially over large scales. By applying Independent Component Analysis (ICA) on Sentinel‐1 InSAR measurements during 2015–2019 on the central Qinghai‐Tibet Plateau, we reveal that the averaged seasonal deformation is increasing with a linear trend of around 0.17 cm/year. The growing seasonal amplitude is attributed to an 8 cm increase of the Equivalent Water Thickness in the active layer. The results demonstrate the capability of ICA‐based decomposition on isolating freeze‐thaw‐related deformation from other components. The large‐scale spatial distribution of varied seasonal deformation can provide new insight into quantifying the water mass balance in vast permafrost regions. Plain Language Summary: Permafrost is ground that remains at or below 0°C for at least 2 years. The variations of water content in the seasonally thawed layer underlain by permafrost have strong impacts on the water storage balance, the ecosystems and the infrastructure stability in cold regions. Their inter‐annual variations can be reflected by ground deformation, but are hard to quantify over large scales. Here, we apply a satellite remote sensing technique to measure ground deformation during 2015–2019 on the central Qinghai‐Tibet Plateau. Using a multivariate statistical method, called independent component analysis, we successfully extract the ground deformation related to the inter‐annual soil water variations. We infer the total water content increase in our study area and corroborate it with independent remote sensing products and in‐situ measurements. This study demonstrates the potential of remote sensing measurements in characterizing the subsurface soil water variations in cold regions with permafrost. Key Points: Interferometric Synthetic Aperture Radar and independent component Analysis capture varied seasonal deformation in a large permafrost regionIncreasing amplitude of seasonal deformation is observed on the central Qinghai‐Tibet Plateau between 2015 and 2019Increase of equivalent water thickness in active layer may correspond to intensified hydrologic cycle [ABSTRACT FROM AUTHOR]

The thermal dynamics was important for permafrost change processes under climate change. However, little studies were focused on the soil thermal dynamics with long-term observed data in the permafrost region on the Qinghai-Tibetan Plateau (QTP). From 2005 to 2017, we have monitored thermal dynamic of active layer overlying permafrost in the Kunlun Pass (CN06 site) region of the QTP. Results demonstrated that the number of thaw days is lower than the number of freeze days, and the start dates of thawing and freezing were delayed over this period. Moreover, air and soil temperature were all fastest warming in summer at different depths, then in autumn, except in spring and winter which has a cooling trend at some depths. Accordingly, the mean annual soil temperatures exhibited an evident warming trend at different depths. In addition, thawing degree-days (TDD) for air and soil temperature (at 10 cm) showed an increasing trend, whereas the respective freezing degree-days (FDD) had a decreasing trend. The mean freezing and thawing n factor were 1.43 and 0.50 from 2005 to 2017, and the surface offset of the study site ranged from 2.65 to 3.42 °C, which was lower than those in the subarctic and Arctic regions. Meanwhile, there was a linear relationship between the TDDs and active layer thickness, and a power function relationship between the TDDa and active layer thickness. The active layer thickness exhibited a significant increase with the rate of 2.4 cm/year from 2005 to 2017. These results can be used to understand the thermal dynamics response to climate change and indicate related changes and differences in permafrost in different permafrost regions. [ABSTRACT FROM AUTHOR]

Atmospheric water vapor plays a key role in the water cycle, especially on the Tibetan Plateau, where precipitation is an invaluable contributor to water resources. To better understand which water vapor source areas influence precipitation on the northeastern Tibetan Plateau (NETP), we applied the flexible particle dispersion method (FLEXPART) to simulate water vapor trajectories and water vapor source contribution related to precipitation events during the snow season from 1979 to 2017 on the NETP. The results show that continental water vapor source areas contributed 92.33% of the water vapor to precipitation events on the NETP, which was obviously greater than the water vapor contribution from oceanic areas. One key continental water vapor source area, the Tibetan Plateau without the study area, contributed 66.13% of the water vapor to the precipitation, and central Asia supplied 8.69%, ranking second. Comparing the distributions of the water vapor contributions to extensive and regional precipitation events revealed that the only difference between extensive and regional precipitation events is in the magnitudes of the water vapor contributions, and the spatial distributions of the water vapor contributions are extremely similar. Central and southern China obviously supplied more water vapor to extensive precipitation events than to regional precipitation events. These results help us better understand the recent drastic precipitation changes on the NETP. Significance Statement: We sought to understand how water vapor influences precipitation over the northeastern Tibetan Plateau and which water vapor source areas play a key role in the water vapor supply. Therefore, we applied a numerical model to investigate the relationship between water vapor and precipitation from 1979 to 2017 during the snow season. Continental water vapor source areas contributed considerably more water vapor than oceanic water vapor source areas. The most important continental water vapor contributor was the Tibetan Plateau without the northeastern Tibetan Plateau area, and the second highest contributor was central Asia. Future work should focus on how water vapor impacts the precipitation changes in this wetter and warming area. [ABSTRACT FROM AUTHOR]

Background: The ubiquitin–proteasome system plays important roles in maintaining the self-renewal and differentiation of stem and progenitor cells through highly ordered degradation of cellular proteins. Fbxw11, an E3 ligase, participates in many important biological processes by targeting a broad range of proteins. However, its roles in hematopoietic stem/progenitor cells (HSPCs) have not been established. Methods: In this study, the effects of Fbxw11 on HSPCs were studied in vitro and in vivo by an overexpression strategy. Real-time PCR was performed to detect the expression of Fbxw11 in hematopoietic subpopulations. Colony-forming assays were performed to evaluate the in vitro function of Fbxw11 on HSPCs. Hoechst 33342 and Ki67 staining was performed to determine the cell-cycle distribution of HSPCs. Competitive transplantation experiments were used to evaluate the effect of Fbxw11 on the reconstitution potential of HSPCs. Single-cell RNA sequencing (scRNA-seq) was employed to reveal the transcriptomic alterations in HSPCs. Results: The expression of Fbxw11 was higher in Lin−c-Kit+Sca-1+ (LSK) cells and myeloid progenitors than in lymphoid progenitors. Fbxw11 played negative roles in colony-forming and quiescence maintenance of HSPCs in vitro. Furthermore, serial competitive transplantation experiments revealed that Fbxw11 impaired the repopulation capacity of HSPCs. The proportion of granulocytes (Gr-1+CD11b+) in the differentiated mature cells was significantly higher than that in the control group, T cells and B cells were lower. Moreover, scRNA-seq revealed seven cell clusters in HSPCs. In addition, Fbxw11 downregulated the expression of Cebpa, Myc and Arid5b, which are significant regulators of HSPC activity, in most cell clusters. Conclusion: Our data demonstrate that Fbxw11 plays a negative role in the maintenance of HSPCs in vitro and repopulation capacity in vivo. Our data also provide valuable transcriptome references for HSPCs in homeostasis. [ABSTRACT FROM AUTHOR]

Actual evapotranspiration (ETa) is important since it is an important link to water, energy, and carbon cycles. Approximately 96% of the Qinghai-Tibet Plateau (QTP) is underlain by frozen ground, however, the ground observations of ETa are particularly sparse–which is especially true in the permafrost regions–leading to great challenge for the accurate estimation of ETa. Due to the impacts of freeze-thaw cycles and permafrost degradation on the regional ET process, it is therefore urgent and important to find a reasonable approach for ETa estimation in the regions. The complementary relationship (CR) approach is a potential method since it needs only routine meteorological variables to estimate ETa. The CR approach, including the modified advection-aridity model by Kahler (K2006), polynomial generalized complementary function by Brutsaert (B2015) and its improved versions by Szilagyi (S2017) and Crago (C2018), and sigmoid generalized complementary function by Han (H2018) in the present study, were assessed against in situ measured ETa at four observation sites in the frozen ground regions. The results indicate that five CR-based models are generally capable of simulating variations in ETa, whether default and calibrated parameter values are employed during the warm season compared with those of the cold season. On a daily basis, the C2018 model performed better than other CR-based models, as indicated by the highest Nash-Sutcliffe efficiency (NSE) and lowest root mean square error (RMSE) values at each site. On a monthly basis, no model uniformly performed best in a specific month. On an annual basis, CR-based models estimating ETa with biases ranging from −94.2 to 28.3 mm year−1, and the H2018 model overall performed best with the smallest bias within 15 mm year−1. Parameter sensitivity analysis demonstrated the relatively small influence of each parameter varying within regular fluctuation magnitude on the accuracy of the corresponding model. [ABSTRACT FROM AUTHOR]