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Acute kidney injury (AKI) is a heterogeneous syndrome prevalent among hospitalized patients. Personalized risk estimation and risk factor identification may allow effective intervention and improved outcomes.To develop and validate personalized AKI risk estimation models using electronic health records (EHRs), examine whether personalized models were beneficial in comparison with global and subgroup models, and assess the heterogeneity of risk factors and their outcomes in different subpopulations.This diagnostic study analyzed EHR data from 1 tertiary care hospital and used machine learning and logistic regression to develop and validate global, subgroup, and personalized risk estimation models. Transfer learning was implemented to enhance the personalized model. Predictor outcomes across subpopulations were analyzed, and metaregression was used to explore predictor interactions. Adults who were hospitalized for 2 or more days from November 1, 2007, to December 31, 2016, were included in the analysis. Patients with moderate or severe kidney dysfunction at admission were excluded. Data were analyzed between August 28, 2019, and May 8, 2022.Clinical and laboratory variables in the EHR.The main outcome was AKI of any severity, and AKI was defined using the Kidney Disease: Improving Global Outcomes serum creatinine criteria. Performance of the models was measured with area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve, and calibration.The study cohort comprised 76 957 inpatient encounters. Patients had a mean (SD) age of 55.5 (17.4) years and included 42 159 men (54.8%). The personalized model with transfer learning outperformed the global model for AKI estimation in terms of AUROC among general inpatients (0.78 [95% CI, 0.77-0.79] vs 0.76 [95% CI, 0.75-0.76]; P .001) and across the high-risk subgroups (0.79 [95% CI, 0.78-0.80] vs 0.75 [95% CI, 0.74-0.77]; P .001) and low-risk subgroups (0.74 [95% CI, 0.73-0.75] vs 0.71 [95% CI, 0.70-0.72]; P .001). The AUROC improvement reached 0.13 for the high-risk subgroups, such as those undergoing liver transplant and cardiac surgery. Moreover, the personalized model with transfer learning performed better than or comparably with the best published models in well-studied AKI subgroups. Predictor outcomes varied significantly between patients, and interaction analysis uncovered modifiers of the predictor outcomes.Results of this study demonstrated that a personalized modeling with transfer learning is an improved AKI risk estimation approach that can be used across diverse patient subgroups. Risk factor heterogeneity and interactions at the individual level highlighted the need for agile, personalized care.

Histone acetyltransferases (HATs) catalyze the transfer of an acetyl group from acetyl-CoA to lysine residues of histones and play a central role in transcriptional regulation in diverse biological processes. Dysregulation of HAT activity can lead to human diseases including developmental disorders and cancer. Through genome-wide CRISPR-Cas9 screens, we identified several HATs of the MYST family as fitness genes for acute myeloid leukemia (AML). Here we investigate the essentiality of lysine acetyltransferase KAT7 in AMLs driven by the MLL-X gene fusions. We found that KAT7 loss leads to a rapid and complete loss of both H3K14ac and H4K12ac marks, in association with reduced proliferation, increased apoptosis, and differentiation of AML cells. Acetyltransferase activity of KAT7 is essential for the proliferation of these cells. Mechanistically, our data propose that acetylated histones provide a platform for the recruitment of MLL-fusion-associated adaptor proteins such as BRD4 and AF4 to gene promoters. Upon KAT7 loss, these factors together with RNA polymerase II rapidly dissociate from several MLL-fusion target genes that are essential for AML cell proliferation, including MEIS1, PBX3, and SENP6. Our findings reveal that KAT7 is a plausible therapeutic target for this poor prognosis AML subtype.

Funder: United Arab Emirates University (UAEU); doi: https://doi.org/10.13039/501100006013, Microbial communities are composed of cells of varying metabolic capacity, and regularly include auxotrophs that lack essential metabolic pathways. Through analysis of auxotrophs for amino acid biosynthesis pathways in microbiome data derived from >12,000 natural microbial communities obtained as part of the Earth Microbiome Project (EMP), and study of auxotrophic-prototrophic interactions in self-establishing metabolically cooperating yeast communities (SeMeCos), we reveal a metabolically imprinted mechanism that links the presence of auxotrophs to an increase in metabolic interactions and gains in antimicrobial drug tolerance. As a consequence of the metabolic adaptations necessary to uptake specific metabolites, auxotrophs obtain altered metabolic flux distributions, export more metabolites and, in this way, enrich community environments in metabolites. Moreover, increased efflux activities reduce intracellular drug concentrations, allowing cells to grow in the presence of drug levels above minimal inhibitory concentrations. For example, we show that the antifungal action of azoles is greatly diminished in yeast cells that uptake metabolites from a metabolically enriched environment. Our results hence provide a mechanism that explains why cells are more robust to drug exposure when they interact metabolically.

Metabolism is fundamentally intertwined with the ageing process. We here report that a key determinant of cellular lifespan is not only nutrient supply and intracellular metabolism, but also metabolite exchange interactions that occur between cells. Studying chronological ageing in yeast, we observed that metabolites exported by young, exponentially growing, cells are re- imported during the stationary phase when cells age chronologically, indicating the existence of cross-generational metabolic interactions. We then used self-establishing metabolically cooperating communities (SeMeCos) to boost cell-cell metabolic interactions and observed a significant lifespan extension. A search for the underlying mechanisms, coupling SeMeCos, metabolic profiling, proteomics and genome-scale metabolic modelling, attributed a specific role to methionine consumer cells. These cells were enriched over time, adopted glycolytic metabolism and increased export of protective metabolites. Glycerol, in particular, accumulated in the communal metabolic environment and extended the lifespan of all cells in the community in a paracrine fashion. Our results hence establish metabolite exchange interactions as a determinant of the ageing process and show that metabolically cooperating cells shape their metabolic environment to achieve lifespan extension.

Claudin-2 promotes breast cancer liver metastasis by enabling seeding and early cancer cell survival. We now demonstrate that Claudin-2 is functionally required for colorectal cancer liver metastasis and that Claudin-2 expression in primary colorectal cancers is associated with poor overall and liver metastasis-free survival. We have examined the role of Claudin-2, and other claudin family members, as potential prognostic biomarkers of the desmoplastic and replacement histopathological growth pattern associated with colorectal cancer liver metastases. Immunohistochemical analysis revealed higher Claudin-2 levels in replacement type metastases when compared to those with desmoplastic features. In contrast, Claudin-8 was highly expressed in desmoplastic colorectal cancer liver metastases. Similar observations were made following immunohistochemical staining of patient-derived xenografts (PDXs) that we have established, which faithfully retain the histopathology of desmoplastic or replacement type colorectal cancer liver metastases. We provide evidence that Claudin-2 status in patient-derived extracellular vesicles may serve as a relevant prognostic biomarker to predict whether colorectal cancer patients have developed replacement type liver metastases. Such a biomarker will be a valuable tool in designing optimal treatment strategies to better manage patients with colorectal cancer liver metastases., Tabariès et al. describe that claudin 2 is a promoter of colorectal cancer liver metastasis. Furthermore, high Claudin-2 expression is associated with shorter time to liver-specific recurrence and is a biomarker of replacement type CRC liver metastases.

原发性胸腺透明细胞癌罕见，本文回顾性分析1例胸腺原发性透明细胞癌临床病理学资料并复习总结相关文献。镜下观察肿瘤细胞分叶状排列，具有明显的玻璃样变间质，肿瘤细胞胞质大多呈透明样，核异型性不明显，核仁小而清晰。荧光原位杂交结果显示EWSR1基因断裂。排除具有透明细胞改变的纵隔原发或转移性肿瘤后，最终病理诊断为胸腺透明细胞癌玻璃样变亚型。胸腺透明细胞癌玻璃样变亚型是第5版WHO胸部肿瘤分类新提出的亚型，其特点是伴有明显玻璃样变间质并具有EWSR1基因易位。大部分胸腺原发性透明细胞癌预后差，患者多在术后2年内发生转移或死亡。胸腺透明细胞癌玻璃样变亚型预后尚无单独数据报道，但细胞形态学温和，推测预后可能较好。.

Eukaryotic cells can survive the loss of their mitochondrial genome, but consequently suffer from severe growth defects. Since the discovery of this phenotype in the 1940s, ‘petite yeast’ remained instrumental for studying mitochondrial function and physiology. However, the molecular cause of the slow-growth defect remained an open question. Here, we used adaptive laboratory evolution, and identified recurrent mutations within the ATP synthase gene ATP3 that restore the growth rate of petite Saccharomyces cerevisiae cells. Then, we use a combination of molecular genetics, and -omics approaches to pinpoint the metabolic limitations overcome by fast growing petites. Changes in ATP metabolism, mitochondrial morphology or retrograde signalling were detected in petites, but did not explain the growth recovery in evolved petites. Instead, we found that the synthesis of glutamate, glutamine, leucine and arginine is growth limiting in petites. The evolution of fast growth did overcome these amino acid deficiencies, by alleviating a defect in mitochondrial iron metabolism and by restoring a previously overlooked defect in the mitochondrial TCA cycle, caused by aconitase inhibition. Our results hence explain the slow growth of mitochondrial genome-deficient cells with a partial auxotrophy in four amino acids that results from distorted iron metabolism and an inhibited TCA cycle.

Direct in vivo reprogramming of cardiac fibroblasts into myocytes is an attractive therapeutic intervention in resolving myogenic deterioration. Current transgene-dependent approaches can restore cardiac function, but dependence on retroviral delivery and persistent retention of transgenic sequences are significant therapeutic hurdles. Chemical reprogramming has been established as a legitimate method to generate functional cell types, including those of the cardiac lineage. Here, we have extended this approach to generate progenitor cells that can differentiate into endothelial cells and cardiomyocytes using a single inhibitor protocol. Depletion of terminally differentiated cells and enrichment for proliferative cells result in a second expandable progenitor population that can robustly give rise to myofibroblasts and smooth muscle. Deployment of a genome-wide knockout screen with clustered regularly interspaced short palindromic repeats-guide RNA library to identify novel mediators that regulate the reprogramming revealed the involvement of DNA methyltransferase 1-associated protein 1 (Dmap1). Loss of Dmap1 reduced promoter methylation, increased the expression of Nkx2-5, and enhanced the retention of self-renewal, although further differentiation is inhibited because of the sustained expression of Cdh1. Our results hence establish Dmap1 as a modulator of cardiac reprogramming and myocytic induction. Stem Cells 2019;37:958–972

Accurate quantification of the proteome remains challenging for large sample series and longitudinal experiments. We report a data-independent acquisition method, Scanning SWATH, that accelerates mass spectrometric (MS) duty cycles, yielding quantitative proteomes in combination with short gradients and high-flow (800 µl min-1) chromatography. Exploiting a continuous movement of the precursor isolation window to assign precursor masses to tandem mass spectrometry (MS/MS) fragment traces, Scanning SWATH increases precursor identifications by ~70% compared to conventional data-independent acquisition (DIA) methods on 0.5-5-min chromatographic gradients. We demonstrate the application of ultra-fast proteomics in drug mode-of-action screening and plasma proteomics. Scanning SWATH proteomes capture the mode of action of fungistatic azoles and statins. Moreover, we confirm 43 and identify 11 new plasma proteome biomarkers of COVID-19 severity, advancing patient classification and biomarker discovery. Thus, our results demonstrate a substantial acceleration and increased depth in fast proteomic experiments that facilitate proteomic drug screens and clinical studies.

To investigate the prevalence ofA total of 235 pregnant women receiving prenatal diagnosis at the First People's Hospital of Yuhang District during the period between February 2018 through December 2019 were recruited as the observation group, and 235 age-matched, non-pregnant healthy women at the same hospital during the same period served as the control group. The subjects'medical records were captured from the hospital management information system. Blood samples were collected from the observation and control groups and detected for the presence of IgG antibodies againstThe subjects in the observation group had a mean age of 26.5 ± 4.3 years (range, 23 to 31 years), and gestational ages of 10 to 27 weeks, and the subjects in the control group had a mean age of 26.1 ± 5.7 years (range, 20 to 30 years). The seroprevalence rates of IgG antibodies againstThe seroprevalence rates of

肺玻璃样变肉芽肿是一种罕见的肺部良性疾病，其临床症状无特异性，影像学上可出现恶性肿瘤征象，部分患者氟代脱氧葡萄糖（FDG）-PET/CT可观察到高代谢活动，易误诊为肺癌，确诊主要靠病理学检查。现报道1例肺玻璃样变肉芽肿，探讨其临床病理特点、诊断及鉴别诊断。患者为53岁女性，体检发现右肺结节入院，临床诊断为肺占位。行胸腔镜下右上肺叶楔形切除术。镜下见一界限尚清的玻璃样变结节，结节由束状或不规则排列的玻璃样变胶原纤维构成，伴有浆细胞、淋巴细胞浸润，有淋巴滤泡形成。刚果红染色阴性。肺玻璃样变肉芽肿的治疗主要靠手术切除，大部分预后良好。.

Histone acetyltransferases (HATs) catalyze the transfer of an acetyl group from acetyl-CoA to lysine residues of histones and play a central role in transcriptional regulation in diverse biological processes. Dysregulation of HAT activity can lead to human diseases including developmental disorders and cancer. Through genome-wide CRISPR-Cas9 screens, we identified several HATs of the MYST family as fitness genes for acute myeloid leukaemia (AML). Here we investigate the essentiality of lysine acetyltransferase KAT7 in AMLs driven by the MLL-X gene fusions. We found that KAT7 loss leads to a rapid and complete loss of both H3K14ac and H4K12ac marks, in association with reduced proliferation, increased apoptosis and differentiation of AML cells. Acetyltransferase activity of KAT7 is essential for the proliferation of these cells. Mechanistically, our data propose that acetylated histones provide a platform for the recruitment of MLL-fusion-associated adaptor proteins such as BRD4 and AF4 to gene promoters. Upon KAT7 loss, these factors together with RNA polymerase II rapidly dissociate from several MLL-fusion target genes that are essential for AML cell proliferation, including MEIS1, PBX3 and SENP6. Our findings reveal that KAT7 is a plausible therapeutic target for this poor prognosis AML subtype.

Summary The genetic basis of naive pluripotency maintenance and loss is a central question in embryonic stem cell biology. Here, we deploy CRISPR-knockout-based screens in mouse embryonic stem cells to interrogate this question through a genome-wide, non-biased approach using the Rex1GFP reporter as a phenotypic readout. This highly sensitive and efficient method identified genes in diverse biological processes and pathways. We uncovered a key role for negative regulators of mTORC1 in maintenance and exit from naive pluripotency and provided an integrated account of how mTORC1 activity influences naive pluripotency through Gsk3. Our study therefore reinforces Gsk3 as the central node and provides a comprehensive, data-rich resource that will improve our understanding of mechanisms regulating pluripotency and stimulate avenues for further mechanistic studies., Graphical Abstract, Highlights • Genome-wide CRISPR screening identifies naive pluripotency regulators in mouse ESCs • mTORC1-negative regulators from two axes show opposing phenotypes • Gator1 is required for proper self-renewal and differentiation via Gsk3 regulation • Tsc2 loss causes Akt-dependent, mTORC1-dependent Gsk3 suppression, Li et al. conducted genome-wide CRISPR screens in mouse ESCs to identify genes affecting maintenance of and exit from naive pluripotency using a Rex1GFP reporter. They show that loss of two mTORC1-negative regulators, Tsc1/2 and Gator1, can cause opposing phenotypes through differential regulation of Gsk3 activity.

To understand and master the infection status of key parasitic diseases in Baise City from 2006 to 2015, so as to provide evidence for the development and adjustment of the control strategy for parasitic diseases.The relevant information of the final evaluation of the key parasitic diseases in 12 counties (cities and districts) of Baise City from 2006 to 2015 was collected, and analyzed.During the period of 2006-2015, a total of 20 654 person-times were investigated for parasitic diseases in Baise City and 1 147 persons were infected, with an average infection rate of 5.55%. In 2006, the infection rate was the highest (28.67%, 362/1 254), while the lowest was in 2013 (2.08%, 44/2 113). The infection rate ofThe infection rate of parasitic diseases presents a decline trend overall in Baise City from 2006 to 2013, however it rebounded in 2014 and 2015. The next step is to strengthen the prevention and control of parasitic diseases by promoting health education, regular insect repellent, and fecundity management.

We evaluated the methods of direct plate count (DPC) on Modified Oxford agar and most probable number (MPN) using Fung-Yu tubes for the detection of natural contamination by Listeria spp. by examining 100 retail samples of raw meat (beef, lamb, pork; and turkey). Listeria monocytogenes was isolated from 10 samples. Other Listeria spp. ( L. innocua , L. murrayi , and L. welshimeri ) were isolated from 27 samples. Despite the fact that very low numbers of Listeria were found on these products, the MPN method was significantly more sensitive than the DPC method. The isolation efficiencies of the MPN and DPC methods were 31 and 17%, respectively. Quantitation of indigenous Listeria showed that many meat samples contaminated with ≤ 4 colony-forming units (CFU) per g tested negative by the DPC method but positive by the MPN method.

Diabetic Kidney Disease (DKD) is a critical and morbid complication of diabetes and the leading cause of chronic kidney disease in the developed world. Electronic medical records (EMRs) hold promise for supporting clinical decision-making with its nationwide adoption as well as rich information characterizing patients' health care experience. However, few retrospective studies have fully utilized the EMR data to model DKD risk. This study examines the effectiveness of an unbiased data driven approach in identifying potential DKD patients in 6 months prior to onset by utilizing EMR on a broader spectrum. Meanwhile, we evaluate how different levels of data granularity of Medications and Diagnoses observations would affect prediction performance and knowledge discovery. The experimental results suggest that different data granularity may not necessarily influence the prediction accuracy, but it would dramatically change the internal structure of the predictive models.

OBJECTIVES To analyze clinical efficacy between fiberoptic ductoscopy plus ultrasound-guided minimally invasive irrigation and lesion resection in treating plasma cell mastitis (PCM), aiming to provide clinical evidence for treating PCM. MATERIALS AND METHODS 119 patients undergoing fiberoptic ductoscopy plus ultrasound-guided minimally invasive surgery in Ningxia People's Hospital were allocated into the breast duct irrigation group, and 95 counterparts receiving lesion resection in the Affiliated Hospital of Ningxia Medical University into the control group. Clinico-pathological characteristics and therapeutic effect were compared between two groups. RESULTS The cure rate in the breast duct irrigation group was 98.31% (117/119), significantly higher than 90.53% in the control group (p < 0.05). In the breast duct irrigation group, overall treatment time was 20.13 days, significantly longer than 15.15 days in the control group (p < 0.05). During postoperative follow-up, no recurrence was observed, significantly lower compared with 48.8% (42/86) in the control group. The degree of satisfaction in the breast duct irrigation group was 95.79% (114/119), significantly higher compared with 74.74% (71/95) in the control group. CONCLUSIONS Fiberoptic ductoscopy plus with ultrasound-guided minimally invasive drainage is a novel and effective treatment of PCM with high cure rate, low recurrence rate, slight pain, and effectively maintains breast integrity.

Phosphatidylinositide 3 kinases (PI3Ks) and their downstream mediators AKT and mammalian target of rapamycin (mTOR) constitute the core components of the PI3K/AKT/mTOR signalling cascade, regulating cell proliferation, survival and metabolism. Although these functions are well-defined in the context of tumorigenesis, recent studies – in particular those using pluripotent stem cells – have highlighted the importance of this pathway to development and cellular differentiation. Here, we review the recent in vitro and in vivo evidence for the role PI3K/AKT/mTOR signalling plays in the control of pluripotency and differentiation, with a particular focus on the molecular mechanisms underlying these functions.

Rab coupling protein (RCP)-induced tumor cell migration has been implicated in tumor pathophysiology and patient outcomes. In the present study, we demonstrate that RCP stabilizes β1 integrin leading to increased β1 integrin levels and activation of a signaling cascade culminating in Slug induction, epithelial-to-mesenchymal transition and increased invasion. Ectopic expression of RCP induced Slug expression. Silencing β1 integrin efficiently inhibited RCP-induced Slug expression and subsequent cancer cell invasion. Conversely, ectopic expression of β1 integrin was sufficient to induce Slug expression. Pharmacological inhibition of integrin linked kinase (ILK), EGFR and NF-κB, as well as transfection of a dominant-negative mutant of Ras (RasN17), significantly inhibited RCP-induced Slug expression and cancer cell invasion. Strikingly, ectopic expression of RCP was sufficient to enhance metastasis of ovarian cancer cells to the lung. Collectively, we demonstrate a mechanism by which RCP promotes cancer cell aggressiveness through sequential β1 integrin stabilization, activation of an ILK/EGFR/Ras/NF-κB signaling cascade and subsequent Slug expression.

Forward genetic screens are a powerful and unbiased approach for uncovering the genetic basis behind a specific phenotype. Genome-wide mutagenesis followed by phenotypic screening represents the ultimate manifestation of this method, directly linking biological phenomena to its corresponding genetic cause. Whilst this has been successful in lower organisms, deployment of genome-wide screens in mammalian systems has been hampered by both limitations of scale and inefficient bi-allelic mutagenesis. CRISPR-Cas9 technology has now largely resolved these issues, whereby delivery of genome-scale gRNA libraries in the presence of gRNA-guided Cas9 endonuclease enables the generation of mutant cell libraries; the perfect platform for performing phenotypic screens. Although the tools are now available for virtually any molecular biology laboratory to conduct such screens, many researchers are daunted by the sheer complexity and scale at which such experiments are performed. This Review will address these concerns, presenting a contextual and practical guide to deploying CRISPR-KO screens in mammalian systems. We will discuss key considerations required in all aspects of screening from initiation to conclusion, which will enable researchers to conduct screens of their own, maximising the potential of this powerful technology.

Both single and multicellular organisms depend on anti-stress mechanisms that enable them to deal with sudden changes in the environment, including exposure to heat and oxidants. Central to the stress response are dynamic changes in metabolism, such as the transition from the glycolysis to the pentose phosphate pathway—a conserved first-line response to oxidative insults1,2. Here we report a second metabolic adaptation that protects microbial cells in stress situations. The role of the yeast polyamine transporter Tpo1p3–5 in maintaining oxidant resistance is unknown6. However, a proteomic time-course experiment suggests a link to lysine metabolism. We reveal a connection between polyamine and lysine metabolism during stress situations, in the form of a promiscuous enzymatic reaction in which the first enzyme of the polyamine pathway, Spe1p, decarboxylates lysine and forms an alternative polyamine, cadaverine. The reaction proceeds in the presence of extracellular lysine, which is taken up by cells to reach concentrations up to one hundred times higher than those required for growth. Such extensive harvest is not observed for the other amino acids, is dependent on the polyamine pathway and triggers a reprogramming of redox metabolism. As a result, NADPH—which would otherwise be required for lysine biosynthesis—is channelled into glutathione metabolism, leading to a large increase in glutathione concentrations, lower levels of reactive oxygen species and increased oxidant tolerance. Our results show that nutrient uptake occurs not only to enable cell growth, but when the nutrient availability is favourable it also enables cells to reconfigure their metabolism to preventatively mount stress protection. The harvest of large quantities of lysine by yeast and other microbes triggers a reprogramming of redox metabolism, in which NADPH is channelled into glutathione metabolism to reduce levels of reactive oxygen species and increase tolerance to oxidative stress.

To analyze clinical efficacy between fiberoptic ductoscopy plus ultrasound-guided minimally invasive irrigation and lesion resection in treating plasma cell mastitis (PCM), aiming to provide clinical evidence for treating PCM.119 patients undergoing fiberoptic ductoscopy plus ultrasound-guided minimally invasive surgery in Ningxia People's Hospital were allocated into the breast duct irrigation group, and 95 counterparts receiving lesion resection in the Affiliated Hospital of Ningxia Medical University into the control group. Clinico-pathological characteristics and therapeutic effect were compared between two groups.The cure rate in the breast duct irrigation group was 98.31% (117/119), significantly higher than 90.53% in the control group (p0.05). In the breast duct irrigation group, overall treatment time was 20.13 days, significantly longer than 15.15 days in the control group (p0.05). During postoperative follow-up, no recurrence was observed, significantly lower compared with 48.8% (42/86) in the control group. The degree of satisfaction in the breast duct irrigation group was 95.79% (114/119), significantly higher compared with 74.74% (71/95) in the control group.Fiberoptic ductoscopy plus with ultrasound-guided minimally invasive drainage is a novel and effective treatment of PCM with high cure rate, low recurrence rate, slight pain, and effectively maintains breast integrity.

Siberian larch (Larix sibirica) trees were studied in a drought-stressed, lowe-levation Taiga forest in the Altay Mountains for their potential to be used for reconstructing precipitation. A climate/growth analysis provided evidence that the tree-ring widths were strongly determined by the climatic conditions from May to July, positively by precipitation and negatively by temperature. Nevertheless, the resulting regional tree-ring chronology of Siberian larch offers only a limited possibility to perform reliable reconstructions of precipitation as only 30.8% of the total variation of the actual April–July precipitation was explainable. Drought events reflected by the chronology were compared with historical records and other tree-ring derived climate reconstructions, showing some common events of climate extremes over much of Central Asia. This new Siberian larch chronology and an earlier maximum latewood density (MXD) chronology from the neighboring region reveal that the local climate is mainly characterized by cold/wet and warm/dry situations over the past 251 years. This study demonstrates that the use of both tree-ring width and MXD data may increase information of past climate variability in the Altay mountain region.

The isothermal section of the Dy-Mn-As ternary system at 773 K has been investigated by using x-ray diffraction, scanning electron microscopy and energy dispersive spectroscopy. This isothermal section consists of 12 single-phase regions, 21 two-phase regions and 10 three-phase regions. The highest solid solubility of Dy in MnAs is about 0.65 at.%Dy, and that of Mn in DyAs is less than 0.79 at.%Mn. The maximum solubility of As in DyMn2 is less than 0.33 at.%As. No ternary compound was found to exist in this section at 773 K.

Following the publication of this article the authors noted that images were inadvertently duplicated in Fig. 1b. The corrected Fig. 1 can be found in the associated Correction. The conclusions of this paper are not affected. The authors sincerely apologize for this error. This error has not been corrected in the HTML or PDF of the original Article.

A flash flood forecasting model including a state-of-the-art data assimilation method was developed to provide a precise water stage forecast for flood emergency response. The model integrates a flash flood routing model (FFRM) coupled with an ensemble Kalman filter (EnKF) and an artificial neural network (ANN) submodel. In the model, the ANN forecasts river water stages at gauge stations first. Then, these are used as the initial and boundary conditions of the FFRM. The water stages, simulated from the FFRM, are then corrected by the EnKF for lead time. The model was applied to the Tanshui River watershed in northern Taiwan during past typhoons. The model forecasts almost covered the data observed during a typhoon period to within 95% confidence intervals. Compared with the use of FFRM without EnKF, the forecast water stages from the EnKF improved the accuracy at the conjunctions between upstream and downstream channels and the steep slope location.

The PI3K-AKT-mTOR pathway is frequently hyper-activated in breast cancer and several inhibitors targeting the PI3K pathway, including AKT (Capivasertib; AZD5363) and PI3Kβ/δ (AZD8186), are currently in clinical development (phase I/II) targeting tumours with mutational activation of the pathway including those with loss of PTEN. A better understanding of the mechanisms of resistance/sensitization to Capivasertib and AZD8186 in PTEN-null breast cancer is critical to fully exploit the anti-tumour activity of these compounds and to develop combination strategies for more effective therapy. Here we performed genome-wide CRISPR-Cas9 knockout screens to identify genes that when targeted promote resistance (gRNA enrichment) or sensitivity (gRNA depletion) to Capivasertib and AZD8186 in three PTEN-null breast cancer cell lines. Our screens identified five genes (NPRL2, DEPDC5, DDIT4, HNRNPD and ZC3H4) whose inactivation promoted resistance to Capivasertib; two resistance genes (PIK3R2 and INPPL1) for AZD8186 and three resistance genes (TSC2, TSC1 and FIBP) for both compounds across all three cell lines. While this result strongly suggests that mTOR pathway reactivation is the major resistance mechanism, we also identified novel resistance genes such as FIBP. Our screens also identified a number of genes that when inactivated sensitize cells to Capivasertib and AZD8186 treatment. Eighteen of these sensitizers have inhibitors in clinical development and we have performed a combination screen to identify compounds that give the best synergy with Capivasertib/AZD8186. The most striking combination effect was detected with the Mcl-1 inhibitor, AZD5991. Mechanistic work is ongoing and our data suggest that Capivasertib/AZD8186 prime cells for apoptosis by a previously undescribed mechanism and combined inhibition with AZD5991 drives a rapid apoptotic response. Importantly, the combination with AZD5991 remains effective in breast cancer cells with acquired resistance to Capivasertib/AZD8186. These combinations showed synergistic tumour suppressive effect in a PTEN-null TNBC breast cancer xenograft model (AZD5991 + AZD8186/Capivasertib) and activity in a patient-derived xenograft model (AZD5991 + Capivasertib). Overall, our CRISPR screening data provide new insights into the genes and pathways that drive resistance to inhibitors of the PI3K pathway in PTEN-null breast cancer and have identified novel synergistic combinations to maximize therapeutic response. Citation Format: Shanade Dunn, Jason Yu, Albert Gris-Oliver, James Pilling, Philip Hopcroft, Urs Yelland, Natalie Cureton, Anna Staniszewsla, Yan Zi Au, Swee Hoe Ong, Beverley Isherwood, Violeta Serra, Simon Barry, Barry R. Davies, James T. Lynch, Kosuke Yusa. Genome-wide CRISPR screens identify combination strategies for Capivasertib (AZD5363; AKT) and AZD8186 (PI3Kβ/δ) in PTEN-null breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 321.

The CCAAT/enhancer-binding protein β gene (C/EBPβ) is one of the key regulating factors of lipid metabolic balance in the liver. To better understand how C/EBPβ affects lipid accumulation in the Landes goose liver, its DNA was cloned. The goose C/EBPβ DNA sequence (2,075 bp) contains a 984-bp open reading frame and part of the 5'-flanking region, and shares 96.66 and 62.07% similarity with the chicken and human sequences at the amino acid level, respectively. Tissue expression profiling showed that the relative expression level was high in the liver and adipose tissue. To understand the effect of betaine on C/EBPβ in goose liver, the relative expression levels of C/EBPβ were detected under different treatments. Compared with the control group, C/EBPβ expression increased in the high-carbohydrate group (P0.01) and decreased in the betaine treatment group (P0.05). Using bisulfite sequencing PCR, the gene methylation status was analyzed among the different treatment groups. None of the 54 CpG sites in the promoter region or the 28 CpG sites in the structural domain of the coding region showed any significantly different methylation patterns among the groups. Taken together, the results showed that betaine decreased the goose C/EBPβ gene expression, but did not directly regulate its methylation. The data may form the basis for further investigation of the mechanisms of the effect of C/EBPβ on the regulation of lipometabolism in the goose liver and the effect of betaine on lipid metabolic genes at the molecular level.

Human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) provide an unlimited source for the generation of human hepatocytes, owing to their indefinite self-renewal and pluripotent properties. Both hESC-/iPSC-derived hepatocytes hold great promise in treating liver diseases as potential candidates for cell replacement therapies or as an in vitro platform to conduct new drug trials. It has been previously demonstrated that the initiation of hESC differentiation in monolayer cultures increases the generation of definitive endoderm (DE) and subsequently of hepatocyte differentiation. However, monolayer culture may hinder the maturation of hESC-derived hepatocytes, since such two-dimensional (2D) conditions do not accurately reflect the complex nature of three-dimensional (3D) hepatocyte specification in vivo. Here, we report the sequential application of 2D and 3D culture systems to differentiate hESCs to hepatocytes. Human ESCs were initially differentiated in a monolayer culture to DE cells, which were then inoculated into Algimatrix scaffolds. Treatments of hESC-DE cells with a ROCK inhibitor before and after inoculation dramatically enhanced their survival and the formation of spheroids, which are distinct from HepG2 carcinoma cells. In comparison with monolayer culture alone, sequential 2D and 3D cultures significantly improved hepatocyte differentiation and function. Our results demonstrate that hESC-DE cells can be incorporated into Algimatrix 3D culture systems to enhance hepatocyte differentiation and function.

This study presents the design, implementation and driving control of a switched-reluctance motor (SRM)-driven cooling fan. First, after exploring the motor structural features, a 70-W three-phase SRM with six of four teeth is designed, manufactured and estimated its key parameters. Secondly, a Miller converter and an asymmetric bridge converter are constructed with their switching and commutation shift schemes being properly designed. Thorough experimental evaluations are conducted for the SRM-driven fan powered by different converters. It shows that proper commutation shift can enhance the driving performance of SRM drive, particularly for the one powered using Miller converter. Further comparative performance assessment is also made between the developed SRM-driven fan and an available brushless DC motor fan with the same fan blade, the results confirm the application potential possessed by SRM. Finally, a front-end flyback switch-mode rectifier (SMR) is developed and used to establish well-regulated DC-link voltage for the SRM converter from mains with satisfactory line-drawn power quality.