Miracle-dz/UniFAR-FTUs huggingface dataset:
FVIII expression by its native promoter sustains long-term correction avoiding immune response in hemophilic mice.

Here we describe a successful gene therapy approach for hemophilia A (HA), using the natural F8 promoter (pF8) to direct gene replacement to factor VIII (FVIII)-secreting cells. The promoter sequence and the regulatory elements involved in the modulation of F8 expression are still poorly characterized and biased by the historical assumption that FVIII expression is mainly in hepatocytes. Bioinformatic analyses have highlighted an underestimated complexity in gene expression at this locus, suggesting an activation of pF8 in more cell types than those previously expected. C57Bl/6 mice injected with a lentiviral vector expressing green fluorescent protein (GFP) under the pF8 (lentiviral vector [LV].pF8.GFP) confirm the predominant GFP expression in liver sinusoidal endothelial cells, with a few positive cells detectable also in hematopoietic organs. Therapeutic gene delivery (LV.pF8.FVIII) in hemophilic C57/Bl6 and 129-Bl6 mice successfully corrected the bleeding phenotype, rescuing up to 25% FVIII activity, using a codon-optimized FVIII, with sustained activity for the duration of the experiment (1 year) without inhibitor formation. Of note, LV.pF8. FVIII delivery in FVIII-immunized HA mice resulted in the complete reversion of the inhibitor titer with the recovery of therapeutic FVIII activity. Depletion of regulatory T cells (Tregs) in LV-treated mice allowed the formation of anti-FVIII antibodies, indicating a role for Tregs in immune tolerance induction. The significant blood loss reduction observed in all LV.pF8. FVIII-treated mice 1 year after injection confirmed the achievement of a long-term phenotypic correction. Altogether, our results highlight the potency of pF8-driven transgene expression to correct the bleeding phenotype in HA, as well as potentially in other diseases in which an endothelial-specific expression is required.
Phosphatidylinositol 4,5‐bisphosphate controls Rab7 and PLEKHM1 membrane cycling during autophagosome–lysosome fusion

The small GTPase Rab7 is a key organizer of receptor sorting and lysosomal degradation by recruiting of a variety of effectors depending on its GDP/GTP‐bound state. However, molecular mechanisms that trigger Rab7 inactivation remain elusive. Here we find that, among the endosomal pools, Rab7‐positive compartments possess the highest level of PI4P, which is primarily produced by PI4K2A kinase. Acute conversion of this endosomal PI4P to PI(4,5)P2 causes Rab7 dissociation from late endosomes and releases a regulator of autophagosome–lysosome fusion, PLEKHM1, from the membrane. Rab7 effectors Vps35 and RILP are not affected by acute PI(4,5)P2 production. Deletion of PI4K2A greatly reduces PIP5Kγ‐mediated PI(4,5)P2 production in Rab7‐positive endosomes leading to impaired Rab7 inactivation and increased number of LC3‐positive structures with defective autophagosome–lysosome fusion. These results reveal a late endosomal PI4P‐PI(4,5)P2‐dependent regulatory loop that impacts autophagosome flux by affecting Rab7 cycling and PLEKHM1 association.
Prognostic significance of tumour-infiltrating lymphocytes for oestrogen receptor-negative breast cancer without lymph node metastasis

Tumour-infiltrating lymphocytes (TILs) are regarded as significant prognostic markers in patients with breast cancer. However, the prognostic utility of TIL expression based on the intrinsic subtypes has just been identified. The present study investigated the relationship between TIL grades and prognosis in 294 Japanese paitents with breast cancer stratified based on the intrinsic subtypes and clinicopathological characteristics. Stromal TIL status was evaluated using haematoxylin and eosin staining, and TIL grades were categorised into low (<10%), intermediate (≥10 and ≤40%) and high (>40%) groups. The relationship between TIL expression and the intrinsic subtypes, clinicopathological characteristics and patient prognosis was analyzed. It was revealed that high TIL expression was correlated with negative oestrogen receptor (ER) expression and high histological grade (P<0.001). Among the ER-negative patients, the relapse-free survival (RFS) rate of the high-grade TIL group was significantly higher than that of the low-grade TIL group (P=0.04). Among the ER-negative patients without lymph node metastasis, RFS and cancer-specific survival (CSS) rates of patients with high-grade TILs were significantly higher than the RFS and CSS rates of patients with low-grade TILs (P=0.01). However, among ER-positive patients, RFS was significantly higher in the low-grade TIL group than in the high-grade TIL group (P=0.02). In conclusion, TIL expression correlated with ER status and tumour proliferation. High TIL expression was a poor prognostic marker in ER-positive patients but was a good prognostic marker in ER-negative patients. Therefore, the biological association between TILs and primary breast tumours may differ between ER-positive and ER-negative breast cancer.
MicroRNA-26b acts as an antioncogene and prognostic factor in cervical cancer

Cervical cancer is the second most frequent malignant neoplasm in women all over the world. MicroRNA-26b (miR-26b) has been reported to be downregulated and play a great role in many malignancies, nevertheless, there are scarce studies on cervical cancer. The purpose of the present study was to detect how miR-26b is involved in cervical carcinoma. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was utilized to detect the expression levels of miR-26b and Jagged1 (JAG1) mRNA. Transwell assay was applied to calculate the cell migration and invasion capacity. Luciferase reporter assay was employed to determine JAG1 as a target of miR-26b. The results revealed that miR-26b is downregulated in cervical cancer tissues and cells compared with paracancerous tissues and normal cervical epithelial cells. The low expression of miR-26b in cervical cancer demonstrated that miR-26b inhibits cell migration and invasion, as measured by Transwell assay. JAG1 was verified to be a target of miR-26b and have a negative correlation with miR-26b, as detected by luciferase reporter assay. In addition, miR-26b was found to suppress cell migration and invasion via mediating JAG1 expression, which impact is partially reversed by JAG1. In conclusion, miR-26b suppresses cell migration and invasion of cervical cancer through directly targeting JAG1. It is suggested that miR-26b/JAG1 axis may present a new target for the treatment of cervical cancer.
Combination of phospholipase Cε knockdown with GANT61 sensitizes castration-resistant prostate cancer cells to enzalutamide by suppressing the androgen receptor signaling pathway

Castration-resistant prostate cancer (CRPC) is a major challenge in the treatment of prostate cancer (PCa). Phospholipase Cε (PLCε), an oncogene, has been found to be involved in the carcinogenesis, tumor proliferation and migration of several types of cancer. The effects, however, of PLCε on CRPC remains unclear. In the present study, the expression of PLCε and glioma-associated homolog (Gli)-1/Gli-2 in benign prostatic hyperplasia (BPH), PCa and CRPC tissues and cells was investigated, and the correlations between PLCε and Gli-1/Gli-2 in CRPC tissues and cell lines were further explored. In addition, the effect of PLCε on cell proliferation and invasion was assessed in CRPC cell lines, and the sensitivity of EN-R and 22RV1 cells to enzalutamide following the downregulation of PLCε expression was determined using lentivirus-mediated shPLCε and/or treatment with specific Gli inhibitor GANT61. It was found that the PLCε expression was excessively upregulated in the majority of CRPC tissues, and PLCε positivity was linked to poor progression-free survival (PFS) and overall survival (OS) in patients with PCa. Furthermore, PLCε knockdown significantly suppressed CRPC cell proliferation and invasion. Of note, it was found that PLCε knockdown increased the sensitivity of CRPC cells to enzalutamide in vitro by suppressing androgen receptor (AR) activities via the non-canonical Hedgehog/Gli-2 and p-STAT3 signaling pathways. PLCε knockdown was shown to increase the sensitivity of CRPC cell xenografts to enzalutamide in vivo. Finally, the combination of PLCε knockdown with GANT61 significantly sensitized CRPC cells to enzalutamide. Collectively, the results of the present study suggest that PLCε is a potential therapeutic target for CRPC.
Journal of Experimental Psychology: General Overestimating the Valuations and Preferences of Others

2205186 or http://dx.doi.org/10.2139/ssrn.2205186 Sloman, S. A. (1996). The Probative value of simultaneous contradictory belief: Reply to Gigerenzer and Regier (1996). Psychological Bulletin, 119, 27–30. http://dx.doi.org/10.1037/0033-2909.119. 1.27 Slovic, P. (1995). The construction of preference. American Psychologist, 50, 364–371. http://dx.doi.org/10.1037/0003-066X.50. 5.364 Thaler, R. (1980). Toward a positive theory of consumer choice. Journal of Economic Behavior & Organization, 1, 39–60. http://dx.doi.org/10 . 1016/0167-2681(80)90051-7 Tversky, A. , & Kahneman, D. (1973). Availability: A heuristic for judging frequency and probability. Cognitive Psychology, 5, 207–232. http://dx . doi.org/10.1016/0010-0285(73)90033-9 Tversky, A. , & Kahneman, D. (1981). The framing of decisions and the psychology of choice. Science, 211, 453–458. http://dx.doi.org/10.1126/
Efficient and Robust Skeleton-Based Quality Assessment and Abnormality Detection in Human Action Performance

Elderly people can be provided with safer and more independent living by the early detection of abnormalities in their performing actions and the frequent assessment of the quality of their motion. Low-cost depth sensing is one of the emerging technologies that can be used for unobtrusive and inexpensive motion abnormality detection and quality assessment. In this study, we develop and evaluate vision-based methods to detect and assess neuromusculoskeletal disorders manifested in common daily activities using three-dimensional skeletal data provided by the SDK of a depth camera (e.g., MS Kinect and Asus Xtion PRO). The proposed methods are based on extracting medically -justified features to compose a simple descriptor. Thereafter, a probabilistic normalcy model is trained on normal motion patterns. For abnormality detection, a test sequence is classified as either normal or abnormal based on its likelihood, which is calculated from the trained normalcy model. For motion quality assessment, a linear regression model is built using the proposed descriptor in order to quantitatively assess the motion quality. The proposed methods were evaluated on four common daily actions—sit to stand, stand to sit, flat walk, and gait on stairs—from two datasets, a publicly released dataset and our dataset that was collected in a clinic from 32 patients suffering from different neuromusculoskeletal disorders and 11 healthy individuals. Experimental results demonstrate promising results, which is a step toward having convenient in-home automatic health care services.
Parent-Adolescent Sexual Communication and Adolescent Sexual Behavior: A Meta-Analysis Review

Parent-adolescent sexual communication is a crucial subject in terms of knowledge transferring for an adolescent to spare from the dangers of sexual behavior. This is due to the notable role of parents in conveying sexual information and exerting a significant influence on adolescent sexual behaviors, values, and beliefs as to the risks. Numerous studies have demonstrated a positive correlation between parent-adolescent sexual communication and adolescent sexual behavior, i.e. delaying sexual debut, reducing sexual activities, increasing contraception and the use of condoms, and reducing the number of sexual partners. Nevertheless, there are still inconsistencies in the empirical literature. Other studies, for instance, have come up with an insignificant or even negative correlation. A sense of shame, inaccurate knowledge, and low self-efficacy can inhibit parent-adolescent sexual communication. This study aimed to synthesize literature and integratively scrutinize the correlation between parent-adolescent sexual communication and adolescent sexual behavior through the use of meta-analysis method. There were 28 studies used in the meta-analysis. The artifacts used for correction was error sampling (bare-bones meta-analysis). The findings showed a positive correlation between parent-adolescent sexual communication and adolescent sexual behavior at 0.0186, with a confidence level of 95%.
Current Status of Simultaneous Liver‐Kidney Transplantation in the United States

On August 10, 2017, a formal policy was enacted in the United States that defined listing criteria for simultaneous liver‐kidney transplantation and priority for patients who received a liver transplantation (LT) and subsequently developed significant kidney disease after LT. This article reviews and summarizes the rationale for such policies, the policies themselves, and the potential impact on LT candidates.
Inflammatory cytokine-induced expression of MASTL is involved in hepatocarcinogenesis by regulating cell cycle progression

Microtubule associated serine/threonine kinase-like (MASTL) is the functional mammalian ortholog of Greatwall kinase (Gwl), which was originally discovered in Drosophila. Gwl is an essential kinase for accurate chromosome condensation and mitotic progression, and inhibits protein phosphatase 2A (PP2A), which subsequently dephosphorylates the substrates of cyclin B1-cyclin-dependent kinase 1, leading to mitotic exit. Previous studies have indicated that MASTL has a critical function in the regulation of mitosis in HeLa and U2OS cell lines, though there is currently limited evidence for the involvement of MASTL in hepatocarcinogenesis. The results of the present study revealed that MASTL was inducible by the proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α), which promoted the proliferation and mitotic entry of human liver cancer cells. It was also determined that MASTL was significantly overexpressed in cancerous liver tissues compared with non-tumor liver tissues. Mechanistically, stimulation by IL-6 and TNF-α induced the trimethylation of histone H3 lysine 4 (H3K4Me3) at the MASTL promoter to facilitate chromatin accessibility. Additionally, H3K4Me3 was associated with the activation of nuclear factor-κB, which subsequently upregulated MASTL expression. These findings suggested that MASTL may have pivotal functions in the development of hepatocarcinoma, and that it may be a potential target for treatment.
A Multiclass Multiple Instance Learning Method with Exact Likelihood

We study a multiclass multiple instance learning (MIL) problem where the labels only suggest whether any instance of a class exists or does not exist in a training sample or example. No further information, e.g., the number of instances of each class, relative locations or orders of all instances in a training sample, is exploited. Such a weak supervision learning problem can be exactly solved by maximizing the model likelihood fitting given observations, and finds applications to tasks like multiple object detection and localization for image understanding. We discuss its relationship to the classic classification problem, the traditional MIL, and connectionist temporal classification (CTC). We use image recognition as the example task to develop our method, although it is applicable to data with higher or lower dimensions without much modification. Experimental results show that our method can be used to learn all convolutional neural networks for solving real-world multiple object detection and localization tasks with weak annotations, e.g., transcribing house number sequences from the Google street view imagery dataset.
Attention-Based Structural-Plasticity

Catastrophic forgetting/interference is a critical problem for lifelong learning machines, which impedes the agents from maintaining their previously learned knowledge while learning new tasks. Neural networks, in particular, suffer plenty from the catastrophic forgetting phenomenon. Recently there has been several efforts towards overcoming catastrophic forgetting in neural networks. Here, we propose a biologically inspired method toward overcoming catastrophic forgetting. Specifically, we define an attention-based selective plasticity of synapses based on the cholinergic neuromodulatory system in the brain. We define synaptic importance parameters in addition to synaptic weights and then use Hebbian learning in parallel with backpropagation algorithm to learn synaptic importances in an online and seamless manner. We test our proposed method on benchmark tasks including the Permuted MNIST and the Split MNIST problems and show competitive performance compared to the state-of-the-art methods.
Response Surface Analysis of Genomic Prediction Accuracy Values Using Quality Control Covariates in Soybean

An important and broadly used tool for selection purposes and to increase yield and genetic gain in plant breeding programs is genomic prediction (GP). Genomic prediction is a technique where molecular marker information and phenotypic data are used to predict the phenotype (eg, yield) of individuals for which only marker data are available. Higher prediction accuracy can be achieved not only by using efficient models but also by using quality molecular marker and phenotypic data. The steps of a typical quality control (QC) of marker data include the elimination of markers with certain level of minor allele frequency (MAF) and missing marker values and the imputation of missing marker values. In this article, we evaluated how the prediction accuracy is influenced by the combination of 12 MAF values, 27 different percentages of missing marker values, and 2 imputation techniques (IT; naïve and Random Forest (RF)). We constructed a response surface of prediction accuracy values for the two ITs as a function of MAF and percentage of missing marker values using soybean data from the University of Nebraska–Lincoln Soybean Breeding Program. We found that both the genetic architecture of the trait and the IT affect the prediction accuracy implying that we have to be careful how we perform QC on the marker data. For the corresponding combinations MAF-percentage of missing values we observed that implementing the RF imputation increased the number of markers by 2 to 5 times than the simple naïve imputation method that is based on the mean allele dosage of the non-missing values at each loci. We conclude that there is not a unique strategy (combination of the QCs and imputation method) that outperforms the results of the others for all traits.
Effect of Diabetes during Pregnancy to Fetal Tooth Germ Growth and Development

Diabetes mellitus is a chronic metabolic disease characterized by hyperglicemia caused by pancreatic insulin production deficiency or ineffectiveness insulin produced. The objective was to determine the effect of fetal tooth germ growth and development disturbance due to diabetic during pregnancy. Five pregnant rats were induced by diabetes using 40 mg/kg b.w streptozotocin intraperitonealy and five pregnant normal rats as a control group. Pregnant rats with blood glucose level ≥ 200 mg/dl considered as diabetes. Blood glucose level was measured before, after induction, and just after birth. One rat offspring sample taken from each pregnant rats using simple random sampling and euthanized on 1 day postnatal. Rat offspring right maxilla taken to observe tooth germ growth and development. Paraffin-embedded tissue cut 4μm in thickness and stained using Haematoxylin-Eosin, Mallory’s Trichrome and insulin-like growth factor 1 (IGF-1) Immunohistochemistry staining. Rat offspring who born from diabetic pregnant showed lower body weight which is statistically significant difference and histologically seen delayed of enamel matrix formation, tooth development stages, and also reduced in tooth size compared to control group. Therefore, seems different of IGF-1 expression in inner enamel epithelium tooth germ between two groups. Rat offspring who born from diabetic pregnant had tooth germ growth and development disturbance. Experimental article (J Int Dent Med Res 2019; 12(4): 1328-1334)
Aging, Melatonin, and the Pro- and Anti-Inflammatory Networks

Aging and various age-related diseases are associated with reductions in melatonin secretion, proinflammatory changes in the immune system, a deteriorating circadian system, and reductions in sirtuin-1 (SIRT1) activity. In non-tumor cells, several effects of melatonin are abolished by inhibiting SIRT1, indicating mediation by SIRT1. Melatonin is, in addition to its circadian and antioxidant roles, an immune stimulatory agent. However, it can act as either a pro- or anti-inflammatory regulator in a context-dependent way. Melatonin can stimulate the release of proinflammatory cytokines and other mediators, but also, under different conditions, it can suppress inflammation-promoting processes such as NO release, activation of cyclooxygenase-2, inflammasome NLRP3, gasdermin D, toll-like receptor-4 and mTOR signaling, and cytokine release by SASP (senescence-associated secretory phenotype), and amyloid-β toxicity. It also activates processes in an anti-inflammatory network, in which SIRT1 activation, upregulation of Nrf2 and downregulation of NF-κB, and release of the anti-inflammatory cytokines IL-4 and IL-10 are involved. A perhaps crucial action may be the promotion of macrophage or microglia polarization in favor of the anti-inflammatory phenotype M2. In addition, many factors of the pro- and anti-inflammatory networks are subject to regulation by microRNAs that either target mRNAs of the respective factors or upregulate them by targeting mRNAs of their inhibitor proteins.
Anti-obesity effect in high-fat-diet-induced obese C57BL/6 mice: Study of a novel extract from mulberry (Morus alba) leaves fermented with Cordyceps militaris

The therapeutic effects of mulberry (Morus alba) leaves on lipid metabolism, including lipogenesis, lipolysis and hyperlipidemia are widely known, although their fermented products are yet to be applied. To investigate the therapeutic effects of a novel extract of mulberry leaves fermented with Cordyceps militaris (EMfC) on lipid metabolism, the lipid profile of serum, lipid accumulation, lipolytic activity and lipogenesis regulation were measured in high fat diet (HFD)-induced obese C57BL/6 mice treated with EMfC for 12 weeks. Briefly, the concentrations of low-density lipoprotein, triglyceride, total cholesterol and glucose significantly decreased in the serum of the HFD+EMfC treated group when compared with the HFD+Vehicle treated group, while the levels of high-density lipoprotein increased in the HFD+EMfC group. The amount of abdominal fat and the size of adipocytes were significantly lower in the HFD+EMfC treated group when compared with the HFD+Vehicle treated group. The weight and number of lipid droplets of liver tissue exhibited a similar decrease. Furthermore, the mRNA levels of peroxisome proliferator-activated receptor-γ for adipogenesis as well as adipocyte protein 2 and Fas cell surface death receptor for lipogenesis reduced following EMfC treatment for 12 weeks. Phosphorylation of perilipin and hormone-sensitive lipase, and in the adipose triglyceride lipase expression showed a significant increase in the HFD+EMfC treated group. These results indicated that EMfC may prevent fat accumulation in the HFD-induced obese C57BL/6 mice through the inhibition of lipogenesis and by stimulating lipolysis. Thus, the results provide evidence for the potential use of EMfC as an anti-obesity complex in the treatment of obesity.