Miracle-dz/UniFAR-FTUs huggingface dataset:
PREX1 Protein Function Is Negatively Regulated Downstream of Receptor Tyrosine Kinase Activation by p21-activated Kinases (PAKs)*

Downstream of receptor tyrosine kinase and G protein-coupled receptor (GPCR) stimulation, the phosphatidylinositol 3,4,5-trisphosphate (PIP3)-dependent Rac exchange factor (PREX) family of guanine nucleotide exchange factors (GEFs) activates Rho GTPases, leading to important roles for PREX proteins in numerous cellular processes and diseases, including cancer. PREX1 and PREX2 GEF activity is activated by the second messengers PIP3 and Gβγ, and further regulation of PREX GEF activity occurs by phosphorylation. Stimulation of receptor tyrosine kinases by neuregulin and insulin-like growth factor 1 (IGF1) leads to the phosphorylation of PREX1; however, the kinases that phosphorylate PREX1 downstream of these ligands are not known. We recently reported that the p21-activated kinases (PAKs), which are activated by GTP-bound Ras-related C3 botulinum toxin substrate 1 (Rac1), mediate the phosphorylation of PREX2 after insulin receptor activation. Here we show that certain phosphorylation events on PREX1 after insulin, neuregulin, and IGF1 treatment are PAK-dependent and lead to a reduction in PREX1 binding to PIP3. Like PREX2, PAK-mediated phosphorylation also negatively regulates PREX1 GEF activity. Furthermore, the onset of PREX1 phosphorylation was delayed compared with the phosphorylation of AKT, supporting a model of negative feedback downstream of PREX1 activation. We also found that the phosphorylation of PREX1 after isoproterenol and prostaglandin E2-mediated GPCR activation is partially PAK-dependent and likely also involves protein kinase A, which is known to reduce PREX1 function. Our data point to multiple mechanisms of PREX1 negative regulation by PAKs within receptor tyrosine kinase and GPCR-stimulated signaling pathways that have important roles in diseases such as diabetes and cancer.
The Death of Sertoli Cells and the Capacity to Phagocytize Elongated Spermatids During Testicular Regression due to Short Photoperiod in Syrian Hamster (Mesocricetus auratus)1

ABSTRACT In the Syrian hamster (Mesocricetus auratus), an animal that displays testicular regression due to short photoperiod, germ cells are removed by apoptosis during this process and the apoptotic remains are phagocytized by Sertoli cells. The aim of this work was to investigate morphologically whether the testicular regression process due to short photoperiod leads to the apoptosis of Sertoli cells, and whether, during testicular regression, the elongated spermatids are eliminated through phagocytosis by Sertoli cells. To this end, we studied testis sections during testicular regression in Syrian hamster subjected to short photoperiod by means of several morphological techniques using conventional light microscopy (hematoxylin and eosin [H&E], semi-thin section vimentin, immunohistochemistry, SBA lectin, and TUNEL staining), fluorescence microscopy, and transmission electron microscopy (TEM). H&E and semi-thin sections identified Sertoli cells with a degenerated morphology. Greater portion of Sertoli cells that were positive for TUNEL staining were observed especially during the mild regression (MR) and strong regression (SR) phases. In addition, TEM identified the characteristic apoptotic changes in the nucleus and cytoplasm of Sertoli cells. Moreover, during testicular regression and using light microscopy, some elongated spermatids were seen in basal position next to the Sertoli cell nucleus. This Sertoli phagocytic activity was higher in MR and SR phases. TEM confirmed this to be the result of the phagocytic activity of Sertoli cells. In conclusion, during testicular regression in Syrian hamster due to short photoperiod, when germ cells are known to be lost through apoptosis, there is morphological evidences that Sertoli cells are also lost through apoptosis, while some elongated spermatids are phagocytized and eliminated by the Sertoli cells.
Expression Profiling Reveals Developmentally Regulated lncRNA Repertoire in the Mouse Male Germline1

ABSTRACT In mammals, the transcriptome of large noncoding RNAs (lncRNAs) is believed to be greater than that of messenger RNAs (mRNAs). Some lncRNAs, especially large intergenic noncoding RNAs (lincRNAs), participate in epigenetic regulation by binding chromatin-modifying protein complexes and regulating protein-coding gene expression. Given that epigenetic regulation plays a critical role in male germline development, we embarked on expression profiling of both lncRNAs and mRNAs during male germline reprogramming and postnatal development using microarray analyses. We identified thousands of lncRNAs and hundreds of lincRNAs that are either up- or downregulated at six critical time points during male germ cell development. In addition, highly regulated lncRNAs were correlated with nearby (<30 kb) mRNA gene clusters, which were also significantly up- or downregulated. Large ncRNAs can be localized to both the nucleus and cytoplasm, with nuclear lncRNAs mostly associated with key components of the chromatin-remodeling protein complexes. Our data indicate that expression of lncRNAs is dynamically regulated during male germline development and that lncRNAs may function to regulate gene expression at both transcriptional and posttranscriptional levels via genetic and epigenetic mechanisms.
Calcium-Oxidant Signaling Network Regulates AMP-activated Protein Kinase (AMPK) Activation upon Matrix Deprivation

The AMP-activated protein kinase (AMPK) has recently been implicated in anoikis resistance. However, the molecular mechanisms that activate AMPK upon matrix detachment remain unexplored. In this study, we show that AMPK activation is a rapid and sustained phenomenon upon matrix deprivation, whereas re-attachment to the matrix leads to its dephosphorylation and inactivation. Because matrix detachment leads to loss of integrin signaling, we investigated whether integrin signaling negatively regulates AMPK activation. However, modulation of focal adhesion kinase or Src, the major downstream components of integrin signaling, failed to cause a corresponding change in AMPK signaling. Further investigations revealed that the upstream AMPK kinases liver kinase B1 (LKB1) and Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) contribute to AMPK activation upon detachment. In LKB1-deficient cells, we found AMPK activation to be predominantly dependent on CaMKKβ. We observed no change in ATP levels under detached conditions at early time points suggesting that rapid AMPK activation upon detachment was not triggered by energy stress. We demonstrate that matrix deprivation leads to a spike in intracellular calcium as well as oxidant signaling, and both these intracellular messengers contribute to rapid AMPK activation upon detachment. We further show that endoplasmic reticulum calcium release-induced store-operated calcium entry contributes to intracellular calcium increase, leading to reactive oxygen species production, and AMPK activation. We additionally show that the LKB1/CaMKK-AMPK axis and intracellular calcium levels play a critical role in anchorage-independent cancer sphere formation. Thus, the Ca2+/reactive oxygen species-triggered LKB1/CaMKK-AMPK signaling cascade may provide a quick, adaptable switch to promote survival of metastasizing cancer cells.
Discourse(s) of emotion within medical education: the ever‐present absence

Context Emotion in medical education rests between the idealised and the invisible, sitting uneasily at the intersection between objective fact and subjective values. Examining the different ways in which emotion is theorised within medical education is important for a number of reasons. Most significant is the possibility that ideas about emotion can inform a broader understanding of issues related to competency and professionalism.
Permission-Based Malware Detection System for Android Using Machine Learning Techniques

Mobile applications create their own security and privacy models through permission-based models. Some applications may request extra permissions that they do not need but may use for suspicious activities. The aim of this study is to identify those spare permissions requested and use this information in the security and privacy approach, which uses static and code analysis together and applies them to the existing datasets; then the results are compared and accuracy level is determined. Classification is made with an accuracy rate of 91.95%.
Epidermal Growth Factor (EGF) Sustains In Vitro Primordial Follicle Viability by Enhancing Stromal Cell Proliferation via MAPK and PI3K Pathways in the Prepubertal, but Not Adult, Cat Ovary1

ABSTRACT This study examined the influences of epidermal growth factor (EGF) and growth differentiation factor 9 (GDF9) on in vitro viability and activation of primordial follicles in the ovarian tissue of prepubertal (age, <6 mo) versus adult (age, >8 mo) cats. Ovarian cortical slices were cultured in medium containing EGF and/or GDF9 for 14 days. EGF, but not GDF9, improved (P < 0.05) follicle viability in prepubertal donors in a dose-dependent fashion. Neither EGF nor GDF9 enhanced follicle viability in ovarian tissue from adults, and neither factor activated primordial follicles regardless of age group. We then explored how EGF influenced primordial follicles in the prepubertal donors by coincubation with an inhibitor of EGF receptor (AG1478), mitogen-activated protein kinase (MAPK; U0126), or phosphoinositide 3-kinase (PI3K; LY294002). EGF enhanced (P < 0.05) MAPK and AKT phosphorylation, follicle viability, and stromal cell proliferation. These effects were suppressed (P < 0.05) when the tissue was cultured with this growth factor combined with each inhibitor. To identify the underlying influence of age in response to EGF, we assessed cell proliferation and discovered a greater thriving stromal cell population in prepubertal compared to adult tissue. We conclude that EGF plays a significant role in maintaining intraovarian primordial follicle viability (but without promoting activation) in the prepubertal cat. The mechanism of action is via stimulation of MAPK and PI3K signaling pathways that, in turn, promote ovarian cell proliferation. Particularly intriguing is that the ability of cat ovarian cells to multiply in reaction to EGF is age-dependent and highly responsive in prepubertal females.
Tissue-Specific Changes in Molecular Clocks During the Transition from Pregnancy to Lactation in Mice1

ABSTRACT Circadian clocks regulate homeostasis and mediate responses to stressors. Lactation is one of the most energetically demanding periods of an adult female's life. Peripartum changes occur in almost every organ so the dam can support neonatal growth through milk production while homeostasis is maintained. How circadian clocks are involved in adaptation to lactation is currently unknown. The abundance and temporal pattern of core clock genes' expression were measured in suprachiasmatic nucleus, liver, and mammary from late pregnant and early lactation mice. Tissue-specific changes in molecular clocks occurred between physiological states. Amplitude and robustness of rhythms increased in suprachiasmatic nucleus and liver. Mammary rhythms of core molecular clock genes were suppressed. Attenuated rhythms appeared to be a physiological adaptation of mammary to lactation, because manipulation of timing of suckling resulting in significant differences in plasma prolactin and corticosterone had no effect on amplitude. Analysis of core clock proteins revealed that the stoichiometric relationship between positive (CLOCK) and negative (PER2) components remained 1:1 in liver but was increased to 4:1 in mammary during physiological transition. Induction of differentiation of mammary epithelial cell line HC11 with dexamethasone, insulin, and prolactin resulted in similar stoichiometric changes among positive and negative clock regulators, and prolactin induced phase shifts in HC11 Arntl expression rhythm. Data support that distinct mechanisms drive periparturient changes in mammary clock. Stoichiometric change in clock regulators occurs with gland differentiation. Suppression of mammary clock gene expression rhythms represents a physiological adaptation to suckling cues. Adaptations in mammary clock are likely needed in part to support suckling demands of neonates.
Object-based image analysis supported by data mining to discriminate large areas of soybean

ABSTRACT This research aimed to analyze the possibility to estimate and automatically map large areas of soybean cultivation through the use of MODIS (Moderate-Resolution Imaging Spectroradiometer) images. Two major techniques were used: GEOgraphic-Object-Based Image Analysis (GEOBIA) and Data Mining (DM). In order to obtain the images, the segmentation algorithm implemented by Definiens Developer was used. A decision tree (DT) was created from a training set previously prepared. Time-series of images from the MODIS sensor aboard the Terra satellite were acquired in order to represent the wide variation of the vegetation pattern along the soybean crop cycle. The time-series data were used only for the CEI index. Furthermore, to compare the results obtained from GEOBIA, the slicing technique was used at the CEI level. After the training, the DT was applied to the vegetation indices generating the thematic map of the spatial distribution of soybean. In accordance with the error matrix and kappa parameter analysis, tests for statistical significance were created. Results indicate that the classification achieved by Kappa coefficients is 0.76. In short, the obtained results proved that combining vegetation indices and time-series data using GEOBIA return promising results for mapping soybean plantation on a regional scale.
Defining reproductively isolated units in a cryptic and syntopic species complex using mitochondrial and nuclear markers: the brooding brittle star, Amphipholis squamata (Ophiuroidea)

At a time when biodiversity is threatened, we are still discovering new species, and particularly in the marine realm. Delimiting species boundaries is the first step to get a precise idea of diversity. For sympatric species which are morphologically undistinguishable, using a combination of independent molecular markers is a necessary step to define separate species. Amphipholis squamata, a cosmopolitan brittle star, includes several very divergent mitochondrial lineages. These lineages appear totally intermixed in the field and studies on morphology and colour polymorphism failed to find any diagnostic character. Therefore, these mitochondrial lineages may be totally interbreeding presently. To test this hypothesis, we characterized the genetic structure of the complex in the French Mediterranean coast using sequences of mitochondrial DNA (16S) and for the first time, several nuclear DNA markers (introns and microsatellites). The data revealed six phylogenetic lineages corresponding to at least four biological species. These sibling species seem to live in syntopy. However, they seem to display contrasted levels of genetic diversity, suggesting they have distinct demographic histories and/or life‐history traits. Genetic differentiation and isolation‐by‐distance within the French Mediterranean coasts are revealed in three lineages, as expected for a species without a free larval phase. Finally, although recombinant nuclear genotypes are common within mitochondrial lineages, the data set displays a total lack of heterozygotes, suggesting a very high selfing rate, a feature likely to have favoured the formation of the species complex.
Identifying the source of species invasions: sampling intensity vs. genetic diversity

Population geneticists and community ecologists have long recognized the importance of sampling design for uncovering patterns of diversity within and among populations and in communities. Invasion ecologists increasingly have utilized phylogeographical patterns of mitochondrial or chloroplast DNA sequence variation to link introduced populations with putative source populations. However, many studies have ignored lessons from population genetics and community ecology and are vulnerable to sampling errors owing to insufficient field collections. A review of published invasion studies that utilized mitochondrial or chloroplast DNA markers reveals that insufficient sampling could strongly influence results and interpretations. Sixty per cent of studies sampled an average of less than six individuals per source population, vs. only 45% for introduced populations. Typically, far fewer introduced than source populations were surveyed, although they were sampled more intensively. Simulations based on published data forming a comprehensive mtDNA haplotype data set highlight and quantify the impact of the number of individuals surveyed per source population and number of putative source populations surveyed for accurate assignment of introduced individuals. Errors associated with sampling a low number of individuals are most acute when rare source haplotypes are dominant or fixed in the introduced population. Accuracy of assignment of introduced individuals is also directly related to the number of source populations surveyed and to the degree of genetic differentiation among them (FST). Incorrect interpretations resulting from sampling errors can be avoided if sampling design is considered before field collections are made.
Simultaneous Gene Deletion of Gata4 and Gata6 Leads to Early Disruption of Follicular Development and Germ Cell Loss in the Murine Ovary1

ABSTRACT Granulosa cell formation and subsequent follicular assembly are important for ovarian development and function. Two members of the GATA family of transcription factors, GATA4 and GATA6, are expressed in ovarian somatic cells early in development, and their importance in adult ovarian function has been recently highlighted. In this study, we demonstrated that the embryonic loss of Gata4 and Gata6 expression within the ovary results in a strong down-regulation of genes involved in the ovarian developmental pathway (Fst and Irx3) as well as diminished expression of the pregranulosa and granulosa cell markers SPRR2 and FOXL2, respectively. Postnatal ovaries deficient in both Gata genes show impaired somatic cell proliferation and arrested follicular development at the primordial stage, where oocytes are either enclosed by one layer of squamous granulosa cells or remain in germ cell nests/clusters. Furthermore, germ cell nests and primordial follicles are predominantly localized to the central region of the Sf1Cre; Gata4flox/flox Gata6flox/flox ovaries, where the boundary between the medulla and cortex is almost nonexistent. Lastly, most of the oocytes are lost early in development in conditional double mutant ovaries, which confirms the importance of normally differentiated granulosa cells as supporting cells for oocyte survival. Thus, both GATA4 and GATA6 proteins are fundamental regulators of granulosa cell differentiation and proliferation, and consequently of proper follicular assembly during normal ovarian development and function.
Obesity During Pregnancy Disrupts Placental Morphology, Cell Proliferation, and Inflammation in a Sex-Specific Manner Across Gestation in the Mouse1

ABSTRACT It is well-accepted that maternal obesity affects fetal development to elevate the risk of offspring disease, but how this happens is unclear. Understanding placental alterations during gestation as a consequence of maternal obesity is critical to understanding the impact of maternal obesity on fetal programming. Here, we used histological criteria, flow cytometry, quantitative PCR, and multiplex cytokine assays to examine changes in cell proliferation and inflammation in the placenta during gestation in a mouse model of maternal high-fat diet-induced obesity. We focused on mouse mid- to late gestation (approximately human late first and third trimester) because previous literature has indicated that this is when important regulators of metabolism, including that of the brain and endocrine pancreas, are forming. These studies were undertaken in order to understand how maternal obesity changes the placenta during this period, which might suggest a causal link to later-life metabolic dysfunction. We found that labyrinth thickness and cell proliferation were decreased at both pregnancy stages in obese compared to normal weight pregnancies. Inflammation was also altered in late pregnancy with increased macrophage activation and elevated cytokine gene expression in the placenta as well as increased abundance of some cytokines in the fetal circulation in obese compared to normal weight pregnancies. These changes in macrophage activation and cytokine gene expression were of greater magnitude and significance in placentas accompanying male fetuses. These data provide insight into placental changes in obesity and identify potential links between placental inflammation and programming of offspring disease by maternal obesity.
Blue Light-excited Light-Oxygen-Voltage-sensing Domain 2 (LOV2) Triggers a Rearrangement of the Kinase Domain to Induce Phosphorylation Activity in Arabidopsis Phototropin1*

Phototropin1 is a blue light (BL) receptor in plants and shows BL-dependent kinase activation. The BL-excited light-oxygen-voltage-sensing domain 2 (LOV2) is primarily responsible for the activation of the kinase domain; however, the molecular mechanism by which conformational changes in LOV2 are transmitted to the kinase domain remains unclear. Here, we investigated BL-induced structural changes of a minimum functional fragment of Arabidopsis phototropin1 composed of LOV2, the kinase domain, and a linker connecting the two domains using small-angle x-ray scattering (SAXS). The fragment existed as a dimer and displayed photoreversible SAXS changes reflected in the radii of gyration of 42.9 Å in the dark and 48.8 Å under BL irradiation. In the dark, the molecular shape reconstructed from the SAXS profiles appeared as two bean-shaped lobes in a twisted arrangement that was 170 Å long, 80 Å wide, and 50 Å thick. The molecular shape under BL became slightly elongated from that in the dark. By fitting the crystal structure of the LOV2 dimer and a homology model of the kinase domain to their inferred shapes, the BL-dependent change could be interpreted as the positional shift in the kinase domain relative to that of the LOV2 dimer. In addition, we found that lysine 475, a functionally important residue, in the N-terminal region of LOV2 plays a critical role in transmitting the structural changes in LOV2 to the kinase domain. The interface between the domains is critical for signaling, suitably changing the structure to activate the kinase in response to conformational changes in the adjoining LOV2.
Ultrafiltration in Acute Heart Failure

Congestion is the predominant cause of more than 1 million annual heart failure hospitalisations and recurrent fluid overload predicts poor outcomes. Unresolved congestion trumps serum creatinine increases in predicting adverse heart failure outcomes. No pharmacological approach for acute heart failure has reduced these deleterious consequences. Simplified ultrafiltration devices permit fluid removal in lower acuity hospital settings, but results regarding safety and efficacy have been variable. However, adjustment of ultrafiltration rates to patients’ vital signs and renal function has been associated with more effective decongestion and fewer heart failure events. Many aspects of ultrafiltration, including patient selection, fluid removal rates, venous access, prevention of therapy-related complications and costs, require further investigation.