Excessive ER-phagy mediated by FAM134B contributes to trophoblast cell mitochondrial dysfunction in preeclampsia.

Autophagy dysregulation and Ca 2+-induced mitochondrial dysfunction in trophoblast cells are proposed to contribute to preeclampsia (PE) development. FAM134B is identified as a receptor associated with endoplasmic reticulum autophagy (ER-phagy). In this study, the placentas of normal pregnant women and PE patients are collected and analyzed by immunohistochemistry, quantitative real-time PCR, and western blot analysis. The effects of ER-phagy are investigated in HTR8/SVneo cells. Significantly increased levels of FAM134B, inositol-1,4,5-triphosphate receptor type 1 (IP3R), calnexin, cleaved caspase 3 and cytochrome C are detected in the PE placenta and sodium nitroprusside (SNP)-treated HTR-8/SVneo cells. Overexpression of FAM134B in HTR-8/SVneo cells results in increased apoptosis, impaired invasion capacity, and diminished mitochondrial function, while an autophagy inhibitor improves mitochondrial performance. Excessive ER-phagy is also associated with an increased concentration of gamma linolenic acid. Our findings suggest that FAM134B contributes to trophoblast apoptosis by mediating ER-mitochondria Ca 2+ transfer through mitochondria-associated endoplasmic reticulum membranes (MAMs) and subsequent mitochondrial function, further enhancing our understanding of PE etiology.

The metabolic role of the CD73/adenosine signaling pathway in HTR-8/SVneo cells: A Double-Edged Sword?

The ecto-5'-nucleotidase (CD73)/adenosine signaling pathway has been reported to regulate tumor epithelial-mesenchymal transition (EMT), migration and proliferation. However, little is known about the metabolic mechanisms underlying its role in trophoblast proliferation and migration. In this study, we aimed to investigate the metabolic role of the CD73/adenosine signaling pathway on the proliferation and migration of trophoblast. We found that CD73 levels were upregulated in preeclamptic placentas compared with the placentas of normotensive pregnant women. EMT and migration of HTR-8/SVneo cells were enhanced when treated with a CD73 inhibitor (100 µM) in vitro. Conversely, excessive adenosine (25 or 50 µM) suppressed trophoblast cell EMT, migration and proliferation. RNA-seq, metabolomics and seahorse findings showed that adenosine treatment resulted in increased expression of PDK1, suppression of aerobic respiration, glycolysis and amino acids synthesis, as well as increased utilization of short-chain fatty acids (SCFAs). Furthermore, the 13C-adenosine isotope tracking experiment demonstrated that adenosine served as a carbon source for the tricarboxylic acid (TCA) cycle. Our results reveal the role of adenosine in regulating trophoblast energy metabolism is like a double-edged sword - either inhibiting aerobic respiration or supplementing carbon sources into metabolic flux. CD73/adenosine signaling regulated trophoblast EMT, migration, and proliferation by modulating energy metabolism. This study indicates that CD73/adenosine signaling potentially plays a role in the occurrence of placenta-derived diseases, including preeclampsia.

Predicting willingness to donate blood based on machine learning: two blood donor recruitments during COVID-19 outbreaks.

Machine learning methods are a novel way to predict and rank donors' willingness to donate blood and to achieve precision recruitment, which can improve the recruitment efficiency and meet the challenge of blood shortage. We collected information about experienced blood donors via short message service (SMS) recruitment and developed 7 machine learning-based recruitment models using PyCharm-Python Environment and 13 features which were described as a method for ranking and predicting donors' intentions to donate blood with a floating number between 0 and 1. Performance of the prediction models was assessed by the Area under the receiver operating characteristic curve (AUC), accuracy, precision, recall, and F1 score in the full dataset, and by the accuracy in the four sub-datasets. The developed models were applied to prospective validations of recruiting experienced blood donors during two COVID-19 pandemics, while the routine method was used as a control. Overall, a total of 95,476 recruitments via SMS and their donation results were enrolled in our modelling study. The strongest predictor features for the donation of experienced donors were blood donation interval, age, and donation frequency. Among the seven baseline models, the eXtreme Gradient Boosting (XGBoost) and Support vector machine models (SVM) achieved the best performance: mean (95%CI) with the highest AUC: 0.809 (0.806-0.811), accuracy: 0.815 (0.812-0.818), precision: 0.840 (0.835-0.845), and F1 score of XGBoost: 0.843 (0.840-0.845) and recall of SVM: 0.991 (0.988-0.994). The hit rate of the XGBoost model alone and the combined XGBoost and SVM models were 1.25 and 1.80 times higher than that of the conventional method as a control in 2 recruitments respectively, and the hit rate of the high willingness to donate group was 1.96 times higher than that of the low willingness to donate group. Our results suggested that the machine learning models could predict and determine the experienced donors with a strong willingness to donate blood by a ranking score based on personalized donation data and demographical details, significantly improve the recruitment rate of blood donors and help blood agencies to maintain the blood supply in emergencies.

A Ctnnb1 enhancer regulates neocortical neurogenesis by controlling the abundance of intermediate progenitors.

ß-catenin-dependent canonical Wnt signaling plays a plethora of roles in neocortex (Ncx) development, but its function in regulating the abundance of intermediate progenitors (IPs) is elusive. Here we identified neCtnnb1, an evolutionarily conserved cis-regulatory element with typical enhancer features in developing Ncx. neCtnnb1 locates 55 kilobase upstream of and spatially close to the promoter of Ctnnb1, the gene encoding ß-catenin. CRISPR/Cas9-mediated activation or interference of the neCtnnb1 locus enhanced or inhibited transcription of Ctnnb1. neCtnnb1 drove transcription predominantly in the subventricular zone of developing Ncx. Knock-out of neCtnnb1 in mice resulted in compromised expression of Ctnnb1 and the Wnt reporter in developing Ncx. Importantly, knock-out of neCtnnb1 lead to reduced production and transit-amplification of IPs, which subsequently generated fewer upper-layer Ncx projection neurons (PNs). In contrast, enhancing the canonical Wnt signaling by stabilizing ß-catenin in neCtnnb1-active cells promoted the production of IPs and upper-layer Ncx PNs. ASH2L was identified as the key trans-acting factor that associates with neCtnnb1 and Ctnnb1's promoter to maintain Ctnnb1's transcription in both mouse and human Ncx progenitors. These findings advance understanding of transcriptional regulation of Ctnnb1, and provide insights into mechanisms underlying Ncx expansion during development.

Rodents on a high-fat diet born to mothers with gestational diabetes exhibit sex-specific lipidomic changes in reproductive organs.

Maternal gestatonal diabetes mellitus (GDM) and offspring high-fat diet (HFD) have been shown to have sex-specific detrimental effects on the health of the offspring. Maternal GDM combined with an offspring HFD alters the lipidomic profiles of offspring reproductive organs with sex hormones and increases insulin signaling, resulting in offspring obesity and diabetes. The pre-pregnancy maternal GDM mice model is established by feeding maternal C57BL/6 mice and their offspring are fed with either a HFD or a low-fat diet (LFD). Testis, ovary and liver are collected from offspring at 20 weeks of age. The lipidomic profiles of the testis and ovary are characterized using gas chromatography-mass spectrometry. Male offspring following a HFD have elevated body weight. In reproductive organs and hormones, male offspring from GDM mothers have decreased testes weights and testosterone levels, while female offspring from GDM mothers show increased ovary weights and estrogen levels. Maternal GDM aggravates the effects of an offspring HFD in male offspring on the AKT pathway, while increasing the risk of developing inflammation when expose to a HFD in female offspring liver. Testes are prone to the effect of maternal GDM, whereas ovarian metabolite profiles are upregulated in maternal GDM and downregulated in offspring following an HFD. Maternal GDM and an offspring HFD have different metabolic effects on offspring reproductive organs, and PUFAs may protect against detrimental outcomes in the offspring, such as obesity and diabetes.

Clinical Characteristics and Outcome Analysis for HLA Loss Patients Following Partially Mismatched Related Donor Transplantation Using HLA Chimerism for Loss of Heterozygosity Analysis by Next-Generation Sequencing.

Genomic loss of mismatched human leukocyte antigen (HLA loss) is one of the most vital immune escape mechanisms of leukemic cells after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the methods currently used for HLA loss analysis have some shortcomings. Limited literature has been published, especially in lymphoid malignancies. This study aims to evaluate the incidences, risk factors of HLA loss, and clinical outcomes of HLA loss patients. In all, 160 patients undergoing partially mismatched related donor (MMRD) transplantation from 18 centers in China were selected for HLA loss analysis with the next-generation sequencing (NGS)-based method, which was validated by HLA-KMR. Variables of the prognostic risk factors for HLA loss or HLA loss-related relapse were identified with the logistic regression or the Fine and Gray regression model. An HLA loss detection system, HLA-CLN [HLA chimerism for loss of heterozygosity (LOH) analysis by NGS], was successfully developed. Forty (25.0%) patients with HLA loss were reported, including 27 with myeloid and 13 with lymphoid malignancies. Surprisingly, 6 of those 40 patients did not relapse. The 2-year cumulative incidences of HLA loss (22.7% vs 22.0%, P = 0.731) and HLA loss-related relapse (18.4% vs 20.0%, P = 0.616) were similar between patients with myeloid and lymphoid malignancies. The number of HLA mismatches (5/10 vs <5/10) was significantly associated with HLA loss in the whole cohort [odds ratio (OR): 3.15, P = 0.021] and patients with myeloid malignancies (OR: 3.94, P = 0.021). A higher refined-disease risk index (OR: 6.91, P = 0.033) and donor-recipient ABO incompatibility (OR: 4.58, P = 0.057) contributed to HLA loss in lymphoid malignancies. To sum up, HLA-CLN could overcome the limitations of HLA-KMR and achieve a better HLA coverage for more patients. The clinical characteristics and outcomes were similar in patients with HLA loss between myeloid and lymphoid malignancies. In addition, the results suggested that a patient with HLA loss might not always relapse.

Novel truncating variant of MN1 penultimate exon identified in a Chinese patient with newly recognized MN1 C-terminal truncation syndrome: Case report and literature review.

MN1 C-terminal truncation (MCTT) syndrome is a newly recognized neurodevelopmental disorder due to heterozygous gain-of-function C-terminal truncating mutations clustering in the last or penultimate exon of MN1 gene (MIM: 156100). Up to date, only 25 affected patients have been reported. Here, we report a 2-year-old Chinese girl with MCTT syndrome. The girl presented with the characteristic features of the syndrome, including global developmental delay (GDD), facial dysmorphism and hearing impairment. Notably, the patient did not have other frequently observed symptoms such as hypotonia, cranial or brain abnormalities, indicating variability of the phenotype of patients with MN1 C-terminal truncating mutations. Trio whole-exome sequencing revealed a novel de novo heterozygous nonsense variant in the extreme 3' region of penultimate exon of MN1 (NM_002430.3: c.3743G > A, p.Trp1248*). This rare truncating variant was classified as pathogenic due to its predicted gain-of-function effect, given that the gain-of-function MN1 truncating variants producing C-terminally truncated proteins have been confirmed to cause the recognizable syndrome. Additionally, a systematic review of previously reported MN1 variants including C-terminal truncating variants and N-terminal truncating variants shows that different location of MN1 truncating variants causes two distinct clinical subtypes. To our knowledge, this is the first reported case of MCTT syndrome caused by a novel MN1 C-terminal truncating variant in a Chinese population, which enriched the mutation spectrum of MN1 gene and further supporting the association of the novel MCTT syndrome with MN1 C-terminal truncating variants.

A Universal Positioning System for Coupling Characterization of SEM and AFM.

Hyphenated techniques, providing comprehensive information in various aspects such as constituent, structure, functional group, and morphology, play an important role in scientific research. Nowadays, coupling characterization of the same position in microscale is in great need in the field of nanomaterial research and exploration. In this article, a new hyphenated technique was developed to facilitate the coupling characterization of atomic force microscope (AFM) and scanning electron microscope (SEM) by designing a universal positioning system. The system consisted of a specimen holder with coordinate grids and a software for converting the coordinate values of the same point to fit SEM, specimen holder, and AFM system. In working condition, the coordinates of the labeled points and target position were firstly extracted from the SEM operation software, then converted into the numerical values adapted to the specimen holder itself, and finally transformed into the coordinates matching the AFM system. The experimental result showed that a retrieving rate of 96% was achieved for a spherical target with a diameter of 1 µm in a 30 µm × 30 µm square. The hyphenated technique is a universal, accurate, efficient, and financially feasible method in microanalysis field and has great application potential.

Preventive and Therapeutic Effects of a Novel JAK Inhibitor SHR0302 in Acute Graft-Versus-Host Disease.

Acute graft-versus-host disease (aGVHD) is one of the most common complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Janus kinase (JAK) inhibitors are considered as reliable and promising agents for patients with aGVHD. The prophylactic and therapeutic effects of SHR0302, a novel JAK inhibitor, were evaluated in aGVHD mouse models. The overall survival (OS), progression-free survival (PFS), bodyweight of mice, GVHD scores were observed and recorded. The bone marrow and spleen samples of diseased model mice or peripheral blood of patients were analyzed. SHR0302 could prevent and reverse aGVHD in mouse models with preserving graft-versus-tumor effect. Functionally, SHR0302 improved the OS and PFS, restored bodyweight, reduced GVHD scores, and reduced immune cells infiltrated in target tissues. SHR0302 treatment also enhanced the hematopoietic reconstruction compared to the control group. Mechanistically, our results suggested that SHR0302 could inhibit the activation of T cells and modulate the differentiation of helper T (Th) cells by reducing Th1 and increasing regulatory T (Treg) cells. In addition, SHR0302 decreased the expression of chemokine receptor CXCR3 on donor T cells and the secretion of cytokines or chemokines including interleukin (IL)-6, interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), CXCL10, etc. thereby destroying the IFN-γ/CXCR3/CXCL10 axis which promotes the progression of GVHD. Besides, SHR0302 decreased the phosphorylation of JAK and its downstream STATs, AKT and ERK1/2, which ultimately regulated the activation, proliferation, and differentiation of lymphocytes. Experiments on primary cells from aGVHD patients also confirmed the results. In summary, our results indicated that JAK inhibitor SHR0302 might be used as a novel agent for patients with aGVHD.

Abnormal neocortex arealization and Sotos-like syndrome-associated behavior in Setd2 mutant mice.

Proper formation of area identities of the cerebral cortex is crucial for cognitive functions and social behaviors of the brain. It remains largely unknown whether epigenetic mechanisms, including histone methylation, regulate cortical arealization. Here, we removed SETD2, the methyltransferase for histone 3 lysine-36 trimethylation (H3K36me3), in the developing dorsal forebrain in mice and showed that Setd2 is required for proper cortical arealization and the formation of cortico-thalamo-cortical circuits. Moreover, Setd2 conditional knockout mice exhibit defects in social interaction, motor learning, and spatial memory, reminiscent of patients with the Sotos-like syndrome bearing SETD2 mutations. SETD2 maintains the expression of clustered protocadherin (cPcdh) genes in an H3K36me3 methyltransferase-dependent manner. Aberrant cortical arealization was recapitulated in cPcdh heterozygous mice. Together, our study emphasizes epigenetic mechanisms underlying cortical arealization and pathogenesis of the Sotos-like syndrome.

An epigenetic circuit controls neurogenic programs during neocortex development.

The production and expansion of intermediate progenitors (IPs) are essential for neocortical neurogenesis during development and over evolution. Here, we have characterized an epigenetic circuit that precisely controls neurogenic programs, particularly properties of IPs, during neocortical development. The circuit comprises a long non-coding RNA (LncBAR) and the BAF (SWI/SNF) chromatin-remodeling complex, which transcriptionally maintains the expression of Zbtb20. LncBAR knockout neocortex contains more deep-layer but fewer upper-layer projection neurons. Intriguingly, loss of LncBAR promotes IP production, but paradoxically prolongs the duration of the cell cycle of IPs during mid-later neocortical neurogenesis. Moreover, in LncBAR knockout mice, depletion of the neural progenitor pool at embryonic stage results in fewer adult neural progenitor cells in the subventricular zone of lateral ventricles, leading to a failure in adult neurogenesis to replenish the olfactory bulb. LncBAR binds to BRG1, the core enzymatic component of the BAF chromatin-remodeling complex. LncBAR depletion enhances association of BRG1 with the genomic locus of, and suppresses the expression of, Zbtb20, a transcription factor gene known to regulate both embryonic and adult neurogenesis. ZBTB20 overexpression in LncBAR-knockout neural precursors reverses compromised cell cycle progressions of IPs.

Transcriptome Analysis Identifies SenZfp536, a Sense LncRNA that Suppresses Self-renewal of Cortical Neural Progenitors.

Long non-coding RNAs (lncRNAs) regulate transcription to control development and homeostasis in a variety of tissues and organs. However, their roles in the development of the cerebral cortex have not been well elucidated. Here, a bioinformatics pipeline was applied to delineate the dynamic expression and potential cis-regulating effects of mouse lncRNAs using transcriptome data from 8 embryonic time points and sub-regions of the developing cerebral cortex. We further characterized a sense lncRNA, SenZfp536, which is transcribed downstream of and partially overlaps with the protein-coding gene Zfp536. Both SenZfp536 and Zfp536 were predominantly expressed in the proliferative zone of the developing cortex. Zfp536 was cis-regulated by SenZfp536, which facilitates looping between the promoter of Zfp536 and the genomic region that transcribes SenZfp536. Surprisingly, knocking down or activating the expression of SenZfp536 increased or compromised the proliferation of cortical neural progenitor cells (NPCs), respectively. Finally, overexpressing Zfp536 in cortical NPCs reversed the enhanced proliferation of cortical NPCs caused by SenZfp536 knockdown. The study deepens our understanding of how lncRNAs regulate the propagation of cortical NPCs through cis-regulatory mechanisms.

Skin disease is more recalcitrant than muscle disease: A long-term prospective study of 184 children with juvenile dermatomyositis.

BACKGROUND: Persistent skin manifestations, especially calcinoses, contribute to morbidity in children with juvenile dermatomyositis. OBJECTIVE: To compare the course of skin and muscle involvement and document frequency of calcinosis in juvenile dermatomyositis. METHODS: Prospective cohort study of 184 untreated children with juvenile dermatomyositis (July 1971 to May 2019) at a single children's hospital. RESULTS: Disease Activity Scores (DASs) were persistently higher for skin versus muscle at all points; clinical inactivity (DAS ≤2) occurred earlier for muscle than skin. Among vascular features for DAS for skin, eyelid margin capillary dilatation was most frequent (54.3%) and persisted longest. Intravenous methylprednisolone reduced DAS for skin more than oral prednisone at 12 months (P = .04). Overall, 16.8% of patients (n = 31) had calcifications, with 4.9% at enrollment. Despite therapy, 25.0% of calcifications recurred and 22.6% failed to resolve; of the latter, 71.4% (n = 5) were present at enrollment. Children with persistent calcifications had longer duration of untreated disease than those whose calcifications resolved (mean 12.5 months) (P < .001). Hydroxychloroquine did not improve DAS for skin (P = .89). LIMITATIONS: DAS does not quantify nailfold capillary dropout. CONCLUSIONS: In juvenile dermatomyositis, skin disease presents with greater activity and is more recalcitrant to therapies than muscle disease. Early and aggressive treatment can limit the severity and persistence of calcifications identified later in the disease course.

Metformin administration during pregnancy attenuated the long-term maternal metabolic and cognitive impairments in a mouse model of gestational diabetes.

BACKGROUND: Gestational diabetes mellitus (GDM) is a metabolic disease that can have long-term adverse effects on the cognitive function of mothers. In our study, we explored the changes in metabolic health and cognitive function in mice of middle- and old- age after exposure to GDM, and whether metformin therapy during pregnancy provided long-term benefits. RESULTS: Mice with GDM demonstrated significant cognitive impairment in old age, which was associated with insulin resistance. Gestational metformin therapy was shown to increase insulin sensitivity and improve cognition. The ovarian aging rate was also accelerated in mice exposed to GDM during pregnancy, which may be related to fatty acid metabolism in the ovaries. CONCLUSION: Treatment with metformin during pregnancy was shown to improve fatty acid metabolism in ovarian tissues. METHOD: During pregnancy, mice were fed with a high-fat diet (GDM group) or a low-fat diet (Control group), and a third group received metformin while receiving a high-fat diet (Treatment group). At 12 months old, the mice completed an oral glucose tolerance test, insulin tolerance test, Morris water maze test, female sex hormones were measured, and metabolite profiles of tissue from the ovaries, hypothalamus, and pituitary glands were analysed using gas chromatography-mass spectrometry.

Metabolic analysis of adipose tissues in a rodent model of pre-pregnancy maternal obesity combined with offsprings on high-carbohydrate diet.

Maternal obesity is associated with adverse effects on the health of offsprings. Consumption of a high-carbohydrate (HC) diet has been found to promote abnormal fatty acid metabolism in adipose tissue. Therefore, we hypothesised that maternal obesity combined with an offspring HC diet would alter the fatty acid metabolism of adipose tissue and subsequently contribute to offspring obesity. Leprdb/+ mice were used to model pre-pregnancy maternal obesity and the C57BL/6 wildtype were used as a control group. Offspring were fed either HC diet or a normal-carbohydrate (NC) diet after weaning. Brown adipose tissue (BAT) and white adipose tissue (WAT) were collected from offspring at 20 weeks of age and their fatty acid metabolome was characterized using gas chromatography-mass spectrometry. We found that HC diet increased the body weight of offspring (males increased by 14.70% and females increased by 1.05%) compared to control mothers. However, maternal obesity alone caused a 7.9% body weight increase in female offspring. Maternal obesity combined with an offspring HC diet resulted in dynamic alterations of the fatty acid profiles of adipose tissue in male offspring. Under the impact of a HC diet, the fatty acid metabolome was solely elevated in female WAT, whereas, the fatty acid metabolites in BAT showed a similar trend in the male and female offsprings. 6,9-octadecadienoic acid and 12,15-cis-octadecatrienoic acid were significantly affected in female WAT, in response to offspring consumption of a HC diet. Our study demonstrated that maternal obesity and offspring HC diet have different metabolic effects on adipose tissue in male and female offsprings.

Oral Ganglioside Supplement Improves Growth and Development in Patients with Ganglioside GM3 Synthase Deficiency.

Ganglioside GM3 synthase is a key enzyme involved in the biosynthesis of gangliosides. GM3 synthase deficiency (GM3D) causes an absence of GM3 and all downstream biosynthetic derivatives. The affected individuals manifest with severe irritability, intractable seizures, and profound intellectual disability. The current study is to assess the effects of an oral ganglioside supplement to patients with GM3D, particularly on their growth and development during early childhood. A total of 13 young children, 11 of them under 40 months old, received oral ganglioside supplement through a dairy product enriched in gangliosides, for an average of 34 months. Clinical improvements were observed in most children soon after the supplement was initiated. Significantly improved growth and development were documented in these subjects as average percentiles for weight, height, and occipitofrontal circumference increased in 1-2 months. Three children with initial microcephaly demonstrated significant catch-up head growth and became normocephalic. We also illustrated brief improvements in developmental and cognitive scores, particularly in communication and socialization domains through Vineland-II. However, all improvements seemed transient and gradually phased out after 12 months of supplementation. Gangliosides GM1 and GM3, although measureable in plasma during the study, were not significantly changed with ganglioside supplementation for up to 30 months. We speculate that the downstream metabolism of ganglioside biosynthesis is fairly active and the potential need for gangliosides in the human body is likely substantial. As we search for new effective therapies for GM3D, approaches to reestablish endogenous ganglioside supplies in the affected individuals should be considered.

Roles of the bone marrow niche in hematopoiesis, leukemogenesis, and chemotherapy resistance in acute myeloid leukemia.

OBJECTIVES: To summarize the effects of the bone marrow niche on hematopoiesis and leukemogenesis and discuss the chemotherapy resistance that can arise from interactions between the niche and leukemia stem cells. METHODS: We review the major roles of the bone marrow niche in cell proliferation, adhesion and drug resistance. The signaling pathways and major molecular participants in the niche are discussed. We also address potential niche-targeting strategies for the treatment of acute myeloid leukemia (AML). RESULTS: The bone marrow niche supports normal hematopoiesis and affects acute myeloid leukemia (AML) initiation, progression and chemotherapy resistance. DISCUSSION: AML is a group of heterogeneous malignant diseases characterized by the excessive proliferation of hematopoietic stem and/or progenitor cells. Even with intensive chemotherapy regimens and stem cell transplantation, the overall survival rate for AML is poor. The bone marrow niches of malignant cells are remodeled into a leukemia-permissive environment, and these reformed niches protect AML cells from chemotherapy-induced cell death. Inhibiting the cellular and molecular interactions between the niche and leukemia cells is a promising direction for targeted therapies for AML treatment. CONCLUSIONS: Interactions between leukemia cells and the bone marrow niche influence hematopoiesis, leukemogenesis, and chemotherapy resistance in AML and require ongoing study. Understanding the mechanisms that underlie these interactions will help identify rational niche-targeting therapies to improve treatment outcomes in AML patients.

Development and Validation of a Nausea Severity Scale for Assessment of Nausea in Children with Abdominal Pain-Related Functional Gastrointestinal Disorders.

The objective of this study was to develop a pediatric measure of chronic nausea severity, the Nausea Severity Scale (NSS), and evaluate its reliability and validity in youth with abdominal pain-related functional gastrointestinal disorders (AP-FGID). Pediatric patients (aged 11⁻17 years-old, n = 236) presenting to an outpatient clinic for evaluation of abdominal pain completed the NSS, Children's Somatization Inventory (CSI), Functional Disability Inventory (FDI), Abdominal Pain Index (API), Patient-Report Outcomes Measurement Information System (PROMIS), Anxiety and Depression Scales and the Pediatric Rome III Questionnaire for FGIDs. The NSS demonstrated good concurrent, discriminant, and construct validity, as well as good internal consistency. One-third (34%) of AP-FGID patients reported experiencing nausea "most" or "every day" in the previous two weeks. The severity of nausea was higher in females than males and correlated significantly with the severity of somatic symptoms, functional disability, anxiety, and depression. The NSS is a valid and reliable measure of nausea in children with AP-FGID.

Mechanisms of Long Non-Coding RNAs in the Assembly and Plasticity of Neural Circuitry.

The mechanisms underlying development processes and functional dynamics of neural circuits are far from understood. Long non-coding RNAs (lncRNAs) have emerged as essential players in defining identities of neural cells, and in modulating neural activities. In this review, we summarized latest advances concerning roles and mechanisms of lncRNAs in assembly, maintenance and plasticity of neural circuitry, as well as lncRNAs' implications in neurological disorders. We also discussed technical advances and challenges in studying functions and mechanisms of lncRNAs in neural circuitry. Finally, we proposed that lncRNA studies would advance our understanding on how neural circuits develop and function in physiology and disease conditions.

Otoprotective effects of mouse nerve growth factor in DBA/2J mice with early-onset progressive hearing loss.

As it displays progressive hair-cell loss and degeneration of spiral ganglion neurons (SGNs) characterized by early-onset progressive hearing loss (ePHL), DBA/2J is an inbred mouse strain widely used in hearing research. Mouse nerve growth factor (mNGF), as a common exogenous nerve growth factor (NGF), has been studied extensively for its ability to promote neuronal survival and growth. To determine whether mNGF can ameliorate progressive hearing loss (PHL) in DBA/2J mice, saline or mNGF was given to DBA/2J mice of either sex by daily intramuscular injection from the 1st to the 9th week after birth. At 5, 7, and 9 weeks of age, in comparison with vehicle groups, mNGF groups experienced decreased auditory-evoked brainstem response (ABR) thresholds and increased distortion product otoacoustic emission (DPOAE) amplitudes, the prevention of hair cell loss, and the inhibition of apoptosis of SGNs. Downregulation of Bak/Bax and Caspase genes and proteins in cochleae of mice receiving the mNGF treatment was detected by real-time PCR, Western blot, and immunohistochemistry. This suggests that the Bak-dependent mitochondrial apoptosis pathway may be involved in the otoprotective mechanism of mNGF in progressive hearing loss of DBA/2J mice. Our results demonstrate that mNGF can act as an otoprotectant in the DBA/2J mice for the early intervention of PHL and, thus, could become of great value in clinical applications. © 2017 Wiley Periodicals, Inc.