Miracle-dz/UniFAR-FTUs huggingface dataset:
PMEPA1/TMEPAI Is a Unique Tumorigenic Activator of AKT Promoting Proteasomal Degradation of PHLPP1 in Triple-Negative Breast Cancer Cells

Simple Summary TMEPAI/PMEPA1 is known to be highly expressed in various types of cancer, including triple-negative breast cancer (TNBC). Here, we found that TMEPAI-knockout (KO) in TNBC cells showed less tumorigenic abilities and upregulated PHLPP1, which dephosphorylates AKT at Ser473. Additionally, PHLPP1 depletion in TMEPAI-KO cells partially but significantly recovered AKT Ser473 phosphorylation, as well as in vitro and in vivo tumorigenic activities. Moreover, we demonstrated that TMEPAI PPxY (PY) motifs are essential for binding to NEDD4-2, an E3 ubiquitin ligase, and the complex formation of PHLPP1 with NEDD4-2, which leads to the polyubiquitination and proteasomal degradation of PHLPP1. These findings indicate that the PY motifs of TMEPAI induce the degradation of PHLPP1 and maintain AKT Ser473 phosphorylation at high levels to enhance the tumorigenic potentiality of TNBC. Therefore, the putative oncogenic role of TMEPAI may lead to developing TMEPAI based targeted therapy and/or diagnosis of TNBC in future. Abstract Transmembrane prostate androgen-induced protein (TMEPAI), also known as PMEPA1, is highly expressed in many types of cancer and promotes oncogenic abilities. However, the mechanisms whereby TMEPAI facilitates tumorigenesis are not fully understood. We previously established TMEPAI-knockout (KO) cells from human triple-negative breast cancer (TNBC) cell lines and found that TMEPAI-KO cells showed reduced tumorigenic abilities. Here, we report that TMEPAI-KO cells upregulated the expression of pleckstrin homology (PH) domain and leucine-rich repeat protein phosphatase 1 (PHLPP1) and suppressed AKT Ser473 phosphorylation, which was consistent with TCGA dataset analysis. Additionally, the knockdown (KD) of PHLPP1 in TMEPAI-KO cells partially but significantly rescued AKT Ser473 phosphorylation, as well as in vitro and in vivo tumorigenic activities, thus showing that TMEPAI functions as an oncogenic protein through the regulation of PHLPP1 subsequent to AKT activation. Furthermore, we demonstrated that TMEPAI PPxY (PY) motifs are essential for binding to NEDD4-2, an E3 ubiquitin ligase, and PHLPP1-downregulatory ability. Moreover, TMEPAI enhanced the complex formation of PHLPP1 with NEDD4-2 and PHLPP1 polyubiquitination, which leads to its proteasomal degradation. These findings indicate that the PY motifs of TMEPAI suppress the amount of PHLPP1 and maintain AKT Ser473 phosphorylation at high levels to enhance the tumorigenic potentiality of TNBC.
Identifying Common Pathogenic Features in Deep Endometriotic Nodules and Uterine Adenomyosis

Increasing imaging data point to a link between deep endometriotic nodules (DENs) and uterine adenomyosis (AD). The study aimed to investigate this link at the histological level and detect potential features shared by the two diseases. We collected formalin-fixed paraffin-embedded tissue (endometrium and lesions) from women with DENs of the rectovaginal septum (n = 13), AD (n = 14), and control subjects (n = 14). Immunohistochemical analyses of CD41 and CD68 were conducted to explore the roles of platelets and macrophages, respectively. Picrosirius red staining was carried out to gather evidence of fibrosis. Vascular endothelial growth factor (VEGF) was assessed, and total numbers of CD31-positive vessels were calculated to investigate the mechanism governing angiogenesis. Double immunohistochemistry for CD31 and alpha smooth muscle actin (αSMA) was performed to discern stable vessels. Platelet aggregation was significantly decreased in both types of lesions compared to their corresponding eutopic endometrium and healthy controls. Macrophage numbers were higher in both lesions than in their corresponding endometrium and healthy subjects. Significantly higher rates of collagen accumulation were detected in DENs and AD lesions compared to their corresponding eutopic and healthy endometrium. VEGF expression was downregulated in the stromal compartment of AD lesions compared to the healthy endometrium. The total number of vessels per area was significantly higher in DENs and AD lesions than in the healthy endometrium. Rates of αSMA-surrounded vessels were decreased in DENs and AD lesions compared to their corresponding eutopic and healthy endometrium. We report common pathogenic mechanisms between DENs and AD, namely excessive macrophage accumulation, fibrosis, and irregular angiogenesis. Our results further support the notion of DENs and AD being linked at the histological level.
Immune Therapies for Myelodysplastic Syndromes and Acute Myeloid Leukemia

Simple Summary Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are bone marrow cancers that have a poor prognosis. They have traditionally been treated with chemotherapy with limited success, and stem cell transplant, which many patients are too frail to receive. Perturbations in the immune system play a role in the development of MDS and AML. Recently, there has been progress in understanding how the immune system can be harnessed to treat these cancers. Effective immune therapies for MDS and AML have been developed at a rapid pace, including novel immune checkpoint inhibitor antibodies, bispecific T-cell-engaging antibodies, antibody drug conjugates, vaccine therapies, and cellular therapeutics including chimeric antigen receptor T-cells and natural killer cells. This review article highlights advances in this field for the practicing clinician to aid in understanding new developments for treating patients with MDS and AML. Abstract Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are hematologic malignancies arising from the bone marrow. Despite recent advances in treating these diseases, patients with higher-risk MDS and AML continue to have a poor prognosis with limited survival. It has long been recognized that there is an immune component to the pathogenesis of MDS and AML, but until recently, immune therapies have played a limited role in treating these diseases. Immune suppressive therapy exhibits durable clinical responses in selected patients with MDS, but the question of which patients are most suitable for this treatment remains unclear. Over the past decade, there has been remarkable progress in identifying genomic features of MDS and AML, which has led to an improved discernment of the molecular pathogenesis of these diseases. An improved understanding of immune and inflammatory molecular mechanisms of MDS and AML have also recently revealed novel therapeutic targets. Emerging treatments for MDS and AML include monoclonal antibodies such as immune checkpoint inhibitors, bispecific T-cell-engaging antibodies, antibody drug conjugates, vaccine therapies, and cellular therapeutics including chimeric antigen receptor T-cells and NK cells. In this review, we provide an overview of the current understanding of immune dysregulation in MDS and AML and an update on novel immune therapies for these bone marrow malignancies.
Factors Associated with E-Cigarette Escalation among High School Students: A Review of the Literature

Background: E-cigarette use has been identified as a behaviour of concern among adolescents, and ever and daily use among this population has increased recently. The purpose of this review was to summarize the relevant studies investigating the frequency and intensity of e-cigarette use in adolescents and the factors associated with these patterns of use. Methods: A scoping search of two databases was conducted to identify longitudinal studies examining escalating e-cigarette use among adolescents. Escalating e-cigarette use could refer to an increasing frequency or intensity of use over time. Articles were screened for relevance. Studies that met inclusion criteria were included for synthesis. Results: Five articles were included for synthesis. All five articles were longitudinal studies taking place in the United States between 2013 and 2017. Age, gender, cost of e-cigarettes, use of cigarettes, polysubstance use, and e-liquid nicotine concentration were associated with escalation of e-cigarette use. Conclusions: A paucity of information exists regarding the escalation of e-cigarette use among adolescents. Given the changing popularity of devices, additional updated evidence is needed to understand the factors associated with the escalation of e-cigarette use among adolescents, which can be used to inform local and national programs and policies.
The complete chloroplast genome sequence of Elaeocarpus decipiens (Elaeocarpaceae)

Abstract Elaeocarpus decipiens F. B. Forbes and Hemsl is an evergreen tree native to East Asia. Here, we sequenced and reported the complete chloroplast genome of E. decipiens for the first time. In the present work, the complete chloroplast (cp) genome sequence of E. decipiens was characterized by Illumina pair-end sequencing. The genome was 158,148 bp in total length, including a large single-copy (LSC) region of 85,702 bp, a small single-copy (SSC) region of 17,672 bp, and a pair of invert repeats (IR) regions of 27,387 bp. The plastid genome contained 142 genes including 97 protein-coding genes, 37 tRNA genes, and eight rRNA genes. Phylogenetic analysis based on 13 chloroplast genomes indicates that E. decipiens is closely related to Elaeocarpus bracean in Elaeocarpacea.
Molecular Functions and Pathways of Plastidial Starch Phosphorylase (PHO1) in Starch Metabolism: Current and Future Perspectives

Starch phosphorylase is a member of the GT35-glycogen-phosphorylase superfamily. Glycogen phosphorylases have been researched in animals thoroughly when compared to plants. Genetic evidence signifies the integral role of plastidial starch phosphorylase (PHO1) in starch biosynthesis in model plants. The counterpart of PHO1 is PHO2, which specifically resides in cytosol and is reported to lack L80 peptide in the middle region of proteins as seen in animal and maltodextrin forms of phosphorylases. The function of this extra peptide varies among species and ranges from the substrate of proteasomes to modulate the degradation of PHO1 in Solanum tuberosum to a non-significant effect on biochemical activity in Oryza sativa and Hordeum vulgare. Various regulatory functions, e.g., phosphorylation, protein–protein interactions, and redox modulation, have been reported to affect the starch phosphorylase functions in higher plants. This review outlines the current findings on the regulation of starch phosphorylase genes and proteins with their possible role in the starch biosynthesis pathway. We highlight the gaps in present studies and elaborate on the molecular mechanisms of phosphorylase in starch metabolism. Moreover, we explore the possible role of PHO1 in crop improvement.
Bacterial Luciferases from Vibrio harveyi and Photobacterium leiognathi Demonstrate Different Conformational Stability as Detected by Time-Resolved Fluorescence Spectroscopy

Detecting the folding/unfolding pathways of biological macromolecules is one of the urgent problems of molecular biophysics. The unfolding of bacterial luciferase from Vibrio harveyi is well-studied, unlike that of Photobacterium leiognathi, despite the fact that both of them are actively used as a reporter system. The aim of this study was to compare the conformational transitions of these luciferases from two different protein subfamilies during equilibrium unfolding with urea. Intrinsic steady-state and time-resolved fluorescence spectra and circular dichroism spectra were used to determine the stages of the protein unfolding. Molecular dynamics methods were applied to find the differences in the surroundings of tryptophans in both luciferases. We found that the unfolding pathway is the same for the studied luciferases. However, the results obtained indicate more stable tertiary and secondary structures of P. leiognathi luciferase as compared to enzyme from V. harveyi during the last stage of denaturation, including the unfolding of individual subunits. The distinctions in fluorescence of the two proteins are associated with differences in the structure of the C-terminal domain of α-subunits, which causes different quenching of tryptophan emissions. The time-resolved fluorescence technique proved to be a more effective method for studying protein unfolding than steady-state methods.
An Exploratory Survey of Mental Health Social Work in Europe

This article reports on an exploratory study comparing mental health social work (MHSW) in Europe. There has been very limited previous research comparing approaches to MHSW in Europe and so the aim of the study was to develop a better understanding of the similarities and differences between and, where relevant, within countries (referred to as jurisdictions). An online survey was distributed mainly through existing European networks and social media to seek information on the role, nature, extent and context of MHSW in a range of European jurisdictions. Conducted during the COVID-19 pandemic, there were 158 responses from 10 jurisdictions. Data were analyzed using thematic analysis. From this analysis, four main themes were identified, relating to: role; law, policy and education; the distinctive contribution made by MHSW; and the key challenges for MHSW. The study demonstrates that MHSW, although it is described and provided in different ways and is confined by a range of factors, plays an important role in mental health services across jurisdictions. There are also interesting differences between contexts, especially in the balance of therapeutic, legal and specialist/generic approaches, some of which reflect the World Health Organisation’s vision and objectives for mental health. Lastly, the study illustrates a need and provides a valuable basis for further comparative and collaborative work to define MHSW and enhance the contributions it makes.
Optimization, Equilibrium and Kinetic Modeling of Methylene Blue Removal from Aqueous Solutions Using Dry Bean Pods Husks Powder

In this research, dry bean pods husks (DBPH) were used as an adsorbent material after minimum processing (without chemical substances consumption and without thermal treatment) to remove methylene blue from aqueous solutions. The adsorbent surface characteristics were investigated using SEM and FTIR analysis. For maximum removal efficiency, several parameters that influence the dye adsorption were optimized using the Taguchi method. Equilibrium and kinetic modeling, along with thermodynamic studies, were conducted to elucidate the adsorption mechanism. Taguchi experimental design showed that the factor with the highest influence was the adsorbent dose, with a percent contribution established by the ANOVA analysis of 40.89%. Langmuir isotherm and pseudo-second order kinetic model characterizes the adsorption process. The maximum adsorption capacity, 121.16 (mg g−1), is higher than other similar adsorbents presented in scientific literature. Thermodynamic parameters indicate a spontaneous, favorable and endothermic adsorption process, and their values show that physical adsorption is involved in the process. The obtained results, and the fact that adsorbent material is inexpensive and easily available, indicate that DBPH powder represents an effective absorbent for treating waters containing methylene blue. Additionally, the Taguchi method is very suitable to optimize the process.
Characterisation of Gel-Forming Mucins Produced In Vivo and In Ex Vivo Conjunctival Explant Cultures

One key element to the health of the ocular surface encompasses the presence of gel-forming mucins in the pre-ocular tear film. Conjunctival goblet cells are specialized epithelial cells that secrete mucins necessary for tear film stability and general homeostasis. Their dysfunction can be linked to a range of ocular surface inflammation disorders and chronic injuries. To obtain new perspectives and angles to tackle mucin deficiency, the need for an accurate evaluation of their presence and corresponding mucin secretion in ex vivo conjunctival cultures has become a requisite. In vitro, goblet cells show a significant decrease in the production and secretion of gel-forming mucins, accompanied by signs of dedifferentiation or transdifferentiation. Explant cultures on laminin-treated CLP-PEG hydrogels can, however, support the production of gel-forming mucins. Together, we challenge the current paradigm to evaluate the presence of cultured goblet cells solely based on their general mucin (MUC) content through imaging analyses, showing the need for additional techniques to assess the functionality of goblet cells. In addition, we broadened the gel-forming mucin profile of in vivo goblet cells with MUC5B and MUC6, while MUC2 and MUC6 is added to the profile of cultured goblet cells.
Deep Jump Learning for Off-Policy Evaluation in Continuous Treatment Settings

We consider off-policy evaluation (OPE) in continuous treatment settings, such as personalized dose-finding. In OPE, one aims to estimate the mean outcome under a new treatment decision rule using historical data generated by a different decision rule. Most existing works on OPE focus on discrete treatment settings. To handle continuous treatments, we develop a novel estimation method for OPE using deep jump learning. The key ingredient of our method lies in adaptively discretizing the treatment space using deep discretization, by leveraging deep learning and multi-scale change point detection. This allows us to apply existing OPE methods in discrete treatments to handle continuous treatments. Our method is further justified by theoretical results, simulations, and a real application to Warfarin Dosing.
Orion: Automatic Repair for Network Programs

Debugging imperative network programs is a challenging task for developers because understanding various network modules and complicated data structures is typically time-consuming. To address the challenge, this paper presents an automated technique for repairing network programs from unit tests. Specifically, given as input a faulty network program and a set of unit tests, our approach localizes the fault through symbolic reasoning, and synthesizes a patch such that the repaired program can pass all unit tests. It applies domain-specific abstraction to simplify network data structures and utilizes modular analysis to facilitate function summary reuse for symbolic analysis. We implement the proposed techniques in a tool called Orion and evaluate it on 10 benchmarks adapted from real-world software-defined networking controllers. The evaluation results demonstrate the effectiveness and efficiency of Orion for repairing network program.
Accumulation phenomenon of dipole-dipole interaction induced by dark Rydberg atoms

We experimentally observed an accumulative type of nonlinear attenuation and distortion of slow light in a laser-cooled electromagnetically-induced-transparency (EIT) medium with the Rydberg state of |32D5/2〉. The present effect of attenuation and distortion was caused by the dipole-dipole interaction between Rydberg atoms in a weak-interaction regime, i.e., the mean distance between Rydberg atoms was far greater than the dipole blockade radius. Our observation can be attributed to the atoms self-accumulated in dark Rydberg states other than those in the bright Rydberg state |32D5/2〉 driven by the coupling field. We performed three different experiments to verify the above hypothesis, to confirm the existence of the dark Rydberg states, and to measure the decay rate from the bright to dark Rydberg states. In the theoretical model, we included the decay process from the bright to dark Rydberg states and the DDI effect induced by both the bright and dark Rydberg atoms. All the experimental data of slow light taken at various probe Rabi frequencies were in good agreement with the theoretical predictions based on the model. The systematic study presented in this work provides a better understanding of the Rydberg-EIT system.
S3PRL-VC: Open-Source Voice Conversion Framework with Self-Supervised Speech Representations

This paper introduces S3PRL-VC, an open-source voice conversion (VC) framework based on the S3PRL toolkit. In the context of recognition-synthesis VC, self-supervised speech representation (S3R) is valuable in its potential to replace the expensive supervised representation adopted by state-of-the-art VC systems. Moreover, we claim that VC is a good probing task for S3R analysis. In this work, we provide a series of in-depth analyses by benchmarking on the two tasks in VCC2020, namely intra-/cross-lingual any-to-one (A2O) VC, as well as an any-to-any (A2A) setting. We also provide comparisons between not only different S3Rs but also top systems in VCC2020 with supervised representations. Systematic objective and subjective evaluation were conducted, and we show that S3R is comparable with VCC2020 top systems in the A2O setting in terms of similarity, and achieves state-of-the-art in S3R-based A2A VC. We believe the extensive analysis, as well as the toolkit itself, contribute to not only the S3R community but also the VC community. The codebase is now open-sourced1.
Appointments: A More Effective Commitment Device for Health Behaviors

Health behaviors are plagued by self-control problems, and commitment devices are frequently proposed as a solution. We show that a simple alternative works even better: appointments. We randomly offer HIV testing appointments and financial commitment devices to high-risk men in Malawi. Appointments are much more effective than financial commitment devices, more than doubling testing rates. In contrast, most men who take up financial commitment devices lose their investments. Appointments address procrastination without the potential drawback of commitment failure, and also address limited memory problems. Appointments have the potential to increase demand for healthcare in the developing world.
SmashEx: Smashing SGX Enclaves Using Exceptions

Exceptions are a commodity hardware functionality which is central to multi-tasking OSes as well as event-driven user applications. Normally, the OS assists the user application by lifting the semantics of exceptions received from hardware to program-friendly user signals and exception handling interfaces. However, can exception handlers work securely in user enclaves, such as those enabled by Intel SGX, where the OS is not trusted by the enclave code? In this paper, we introduce a new attack called SmashEx which exploits the OS-enclave interface for asynchronous exceptions in SGX. It demonstrates the importance of a fundamental property of safe atomic execution that is required on this interface. In the absence of atomicity, we show that asynchronous exception handling in SGX enclaves is complicated and prone to re-entrancy vulnerabilities. Our attacks do not assume any memory errors in the enclave code, side channels, or application-specific logic flaws. We concretely demonstrate exploits that cause arbitrary disclosure of enclave private memory and code-reuse (ROP) attacks in the enclave. We show reliable exploits on two widely-used SGX runtimes, Intel SGX SDK and Microsoft Open Enclave, running OpenSSL and cURL libraries respectively. We tested a total of 14 frameworks, including Intel SGX SDK and Microsoft Open Enclave, 10 of which are vulnerable. We discuss how the vulnerability manifests on both SGX1-based and SGX2-based platforms. We present potential mitigation and long-term defenses for SmashEx.