Miracle-dz/UniFAR-FTUs huggingface dataset:
Investigating a cluster of vulvar cancers in young women: distribution of human papillomavirus and HPV-16 variants in vulvar dysplastic or neoplastic biopsies.

BACKGROUND A high incidence of vulvar cancer, and its precursor lesion, high-grade vulvar intraepithelial neoplasia (VIN) has been identified in young Indigenous women living in the Arnhem Land region of the Northern Territory (NT) of Australia. This clustering is restricted to women aged <50 years, suggesting that oncogenic human papillomavirus (HPV) is a key causal factor. This study compared the HPV genotype prevalence, HPV-16 variant distribution and p16(INK4a)expression in stored vulvar cancer and high-grade VIN biopsy specimens from women residing in Arnhem Land, with specimens taken from Indigenous and non-Indigenous women in other regions of NT where there is no observed increase in vulvar cancer incidence. METHODS Twenty high-grade VIN and 10 invasive cancer biopsies were assessed from Arnhem Land along with 24 high-grade VIN and 10 invasive cancer biopsies from other regions of NT. RESULTS Biopsies from Arnhem Land were similar to those from other regions in the detection of high-risk (HR) or possible HR HPV (VIN: 95% and 84% respectively for Arnhem Land and other regions, P=0.356; invasive cancer: 100% and 80%, P=0.473), HPV-16 (VIN: 60% and 80%, P=0.364; invasive cancer: 70% and 70%, P=1.0) and p16(INK4a) expression (VIN: 90% and 84%, P=0.673; invasive cancer: 100% and 80%, P=0.474). All HPV-16 variants were of the European prototype. CONCLUSION Comparison of biopsies revealed no significant difference in the frequency of oncogenic HPVs or HPV-16 variant types between Arnhem Land and other regions, suggesting another cofactor in this cluster.
Differential learning impairments produced by prenatal exposure to ionizing radiation in mice.

PURPOSE To investigate the behavioural effects of prenatal irradiation on different days of gestation on the performance of two learning tasks by adult mice. MATERIALS AND METHODS CD1 mice were exposed in utero to 1 Gy of 250 kV X-rays on gestational days 13, 15 or 18. Other animals were sham-exposed. Male mice were tested as adults in a radial arm maze on two learning tasks considered dependent upon either spatial memory or visual associative memory. RESULTS Performance of the animals on the tasks was a function of the day on which exposure occurred. Compared with sham-exposed animals, exposure on day 18 produced a highly significant deficit in performance on the spatial task, and a small improvement in the visually cued task. Exposure on day 15 produced no deficit in performance on the spatial task, but a highly significant deficit in the cued task. Exposure on day 13 produced no significant deficits on either task. CONCLUSIONS These differential effects on performance appear to be consistent with radiation-induced insult to different memory systems within the developing mouse brain. These and further studies will help provide better estimates of the risks of radiation at different times during gestation on cognitive function in humans.
Conservation of the threatened species Pulsatilla vulgaris Mill. (pasqueflower) is aided by reproductive system and polyploidy.

Population loss due to habitat disturbance is a major concern in biodiversity conservation. Here we investigate the genetic causes of the demographic decline observed in English populations of P ulsatilla vulgaris and the consequences for conservation. Using ten nuclear microsatellite markers, we compare genetic variation in wild populations with restored and seed-regenerated populations (674 samples). Emergence of genetic structure and loss of allelic variation in natural populations is not as evident as expected from demographic trends. Restored populations show genetic variation comparable to their source populations and, in general, to the wild ones. Genetic homogeneity is observed in regeneration trials, although some alleles not captured in source populations are detected. We infer that polyploidy, longevity and clonal reproduction have provided P. vulgaris with the standing genetic variation necessary to make the species resilient to the effects of demographic decline, suggesting that the use of multiple sources for reintroduction may be beneficial to mimic natural gene flow and the availability of multiple allele copies typical of polyploid species.
Molecular Cloning, DNA Sequence Analysis, and Biochemical Characterization of a Novel 65-kDa FK506-binding Protein (FKBP65) *

We have identified a mouse gene encoding a 65-kDa protein (FKBP65) that shares homology with members of the FK506-binding protein (FKBP) class of immunophilins. Predicted amino acid sequence shows that this protein shares significant homology with FKBP12 (46%), FKBP13 (43%), FKBP25 (35%), and FKBP52 (26%). FKBP65 contains four predicted peptidylprolyl cis-trans-isomerase (PPIase) signature domains, and, although similar in size, is distinct from FKBP52 (also identified as FKBP59, hsp56, or HBI), which contains three FKBP12-like PPIase domains. With N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide as the substrate, recombinant FKBP65 is shown to accelerate the isomerization of the prolyl peptide bond with a catalytic efficiency similar to other family members. This isomerization activity is inhibited by FK506 and rapamycin, but is not sensitive to Cyclosporin A. Based on Northern blot analysis, FKBP65 mRNA transcripts are present in lung, spleen, heart, brain, and testis. A polyclonal antibody, raised against a COOH-terminal peptide (amino acid residues 566-581), was used to immunoprecipitate FKBP65 from NIH3T3 cells and demonstrate that FKBP65 is a glycoprotein. In addition, [P]orthophosphate labeling experiments show that FKBP65 is also a phosphoprotein. These results suggest that FKBP65 is a new FKBP family member.
Current Mechanistic and Pharmacodynamic Understanding of Melanocortin-4 Receptor Activation

In this work we summarize our understanding of melanocortin 4 receptor (MC4R) pathway activation, aiming to define a safe and effective therapeutic targeting strategy for the MC4R. Delineation of cellular MC4R pathways has provided evidence for distinct MC4R signaling events characterized by unique receptor activation kinetics. While these studies remain narrow in scope, and have largely been explored with peptidic agonists, the results provide a possible correlation between distinct ligand groups and differential MC4R activation kinetics. In addition, when a set of small-molecule and peptide MC4R agonists are compared, evidence of biased signaling has been reported. The results of such mechanistic studies are discussed.
Use of calcium channel blockers as antihypertensives in relation to mortality and cancer incidence: a population‐based observational study

Treatment with blood pressure lowering drugs may reduce morbidity and mortality. However, the efficacy and effectiveness may differ between antihypertensive agents. The current investigation aimed to compare mortality and cancer incidence in hypertensive patients treated with calcium channel blockers (CCB) or with other antihypertensive drugs (AHD).
Joint-specific power loss after eccentric exercise.

UNLABELLED Previous investigators have reported changes in maximal power after eccentric exercise. The influence of eccentric joint-specific power absorption on subsequent concentric joint-specific power production during multijoint actions has not been reported. PURPOSE Our purposes were to determine the extent to which ankle, knee, and hip joint actions absorbed power during eccentric cycling (ECCcyc) and to evaluate changes in power produced by those joint actions during subsequent maximal concentric cycling (CONcyc). We hypothesized that joint actions that absorbed the most power during ECCcyc would exhibit the greatest reductions in power during subsequent maximal CONcyc. METHODS Nineteen cyclists performed baseline trials of maximal single-leg CONcyc immediately before and 24 h after acute single-leg ECCcyc (5 min, 40% maximum single-leg CONcyc power). Pedal forces and limb kinematics were determined with a force-sensing pedal and instrumented spatial linkage system, respectively. Joint-specific powers were calculated using inverse dynamics and averaged over complete crank revolutions and over extension and flexion phases. RESULTS The largest power-absorbing actions during ECCcyc were eccentric knee extensor activity (-185 +/- 12 W) followed by eccentric hip extensor activity (-92 +/- 12 W). Power absorbed through ankle joint actions was small (-10 +/- 2 W). At 24 h, pedal power produced during maximal CONcyc was reduced by 11% +/- 3% relative to baseline. Compared with baseline, knee extension power was reduced by 19% +/- 0 7%, whereas hip extension power did not differ. CONCLUSIONS Power absorbed through eccentric knee extension actions significantly reduced knee extension power produced during subsequent maximal CONcyc. Even with reduced knee extensor function, participants were able to deliver 89% of their baseline power to the environment. These results have implications for individuals who must continue to perform multijoint activities after eccentric exercise.
Graphene-based silicon modulators

Silicon photonics is a promising technology to address the demand for dense and integrated next-generation optical interconnections due to its complementary-metal-oxide-semiconductor (CMOS) compatibility. However, one of the key building blocks, the silicon modulator, suffers from several drawbacks, including a limited bandwidth, a relatively large footprint, and high power consumption. The graphene-based silicon modulator, which benefits from the excellent optical properties of the two-dimensional graphene material with its unique band structure, has significantly advanced the above critical figures of merit. In this work, we review the state-of-the-art graphene-based silicon modulators operating in various mechanisms, i.e., thermal-optical, electro-optical, and plasmonic. It is shown that graphene-based silicon modulators possess the potential to have satisfactory characteristics in intra- and inter-chip connections.
Robustness of a flatness based controller against parametric uncertainties for a class of under-actuated planar manipulators

Differential flatness provides a systematic approach to plan and control feasible trajectories for underactuated nonlinear systems. Previously [1], the authors have developed a methodology to design a class of under-actuated planar manipulators to be differentially flat. This paper investigates robustness of this flatness based control with respect to parametric uncertainties. Existing literature for robustness in this regard addresses fully actuated systems and underactuated systems where the flat output state does not depend on system parameters. In both these scenarios, the flat output state (with respect to which the controller is designed) is directly available from sensor measurements. However, in general for an under-actuated differentially flat system, the flat output state depends on the measurable original system state through an invertible transformation containing system parameters. In such a scenario with parametric uncertainty, the flat output states can not be measured exactly. This paper addresses robustness against parametric uncertainties in this scenario for a specific class of planar under-actuated manipulators. It is shown that if the transformation is known accurately and only the dynamic model is uncertain a robust control strategy can guarantee exponential stability. It is also shown that in the presence of uncertainties in the transformation, the tracking error can be bounded from above. The effectiveness of this robust control strategy is demonstrated through simulations with a 3-DOF robot.
A Double-Bromodomain Protein, FSH-S, Activates the Homeotic Gene Ultrabithorax through a Critical Promoter-Proximal Region

ABSTRACT More than a dozen trithorax group (trxG) proteins are involved in activation of Drosophila HOX genes. How they act coordinately to integrate signals from distantly located enhancers is not fully understood. The female sterile (1) homeotic (fs(1)h) gene is one of the trxG genes that is most critical for Ultrabithorax (Ubx) activation. We show that one of the two double-bromodomain proteins encoded by fs(1)h acts as an essential factor in the Ubx proximal promoter. First, overexpression of the small isoform FSH-S, but not the larger one, can induce ectopic expression of HOX genes and cause body malformation. Second, FSH-S can stimulate Ubx promoter in cultured cells through a critical proximal region in a bromodomain-dependent manner. Third, purified FSH-S can bind specifically to a motif within this region that was previously known as the ZESTE site. The physiological relevance of FSH-S is ascertained using transgenic embryos containing a modified Ubx proximal promoter and chromatin immunoprecipitation. In addition, we show that FSH-S is involved in phosphorylation of itself and other regulatory factors. We suggest that FSH-S acts as a critical component of a regulatory circuitry mediating long-range effects of distant enhancers.
The Adaptive Immune Role of Metallothioneins in the Pathogenesis of Diabetic Cardiomyopathy: Good or Bad.

Diabetes is a metabolic disorder characterized by hyperglycemia, resulting in low-grade systemic inflammation. Diabetic cardiomyopathy (DCM) is a common complication among diabetes patients, and the mechanism underlying its induction of cardiac remodeling and dysfunction remains unclear. Numerous experimental and clinical studies suggested that adaptive immunity, especially T lymphocyte-mediated immunity, plays a potentially important role in in the pathogenesis of diabetes and DCM. Metallothioneins (MTs), cysteine-rich metal-binding proteins, have antioxidant properties. Some potential mechanisms underlying the cardioprotective effects of MTs include the role of MTs in calcium regulation, zinc homeostasis, insulin sensitization, and antioxidant activity. Moreover, metal homeostasis, especially MT-regulated zinc homeostasis, is essential for immune function. This review discusses aberrant immune regulation in diabetic heart disease with respect to endothelial insulin resistance and the effects of hyperglycemia and hyperlipidemia on tissues and the different effects of intracellular and extracellular MTs on adaptive immunity. This review shows that intracellular MTs are involved in naïve T cell activation and reduce Treg polarization, while extracellular MTs promote proliferation and survival in naïve T cells and Treg polarization but inhibit their activation, thus revealing potential therapeutic strategies targeting the regulation of immune cell function by MTs.
Curcumin and Heme Oxygenase: Neuroprotection and Beyond

Curcumin is a natural polyphenol component of Curcuma longa Linn, which is currently considered one of the most effective nutritional antioxidants for counteracting free radical-related diseases. Several experimental data have highlighted the pleiotropic neuroprotective effects of curcumin, due to its activity in multiple antioxidant and anti-inflammatory pathways involved in neurodegeneration. Although its poor systemic bioavailability after oral administration and low plasma concentrations represent restrictive factors for curcumin therapeutic efficacy, innovative delivery formulations have been developed in order to overwhelm these limitations. This review provides a summary of the main findings involving the heme oxygenase/biliverdin reductase system as a valid target in mediating the potential neuroprotective properties of curcumin. Furthermore, pharmacokinetic properties and concerns about curcumin’s safety profile have been addressed.
An analysis of false turn-on mechanism on high-frequency power devices

In high efficiency and high temperature industrial applications, wide bandgap semiconductor devices, such as: Gallium Nitride (GaN) and Silicon Carbide (SiC), are getting great attention due to their outstanding performance. However, a false turn-on phenomenon can be produced by the switching noise because wide bandgap devices have low threshold voltage. Consequently, the efficiency of a switched-mode power supply using these devices can be decreased. This paper analyzes the gate noise performance using experimental tests and circuit simulations focusing on the parasitic parameters of the power devices. Additionally, this analysis was conducted on the base of the theoretical calculation using an equivalent circuit modeling. As a result, it was obtained that Si MOSFETs and GaN HEMT have different false turn-on mechanism.
Calcineurin B-Like Proteins CBL4 and CBL10 Mediate Two Independent Salt Tolerance Pathways in Arabidopsis

In Arabidopsis, the salt overly sensitive (SOS) pathway, consisting of calcineurin B-like protein 4 (CBL4/SOS3), CBL-interacting protein kinase 24 (CIPK24/SOS2) and SOS1, has been well defined as a crucial mechanism to control cellular ion homoeostasis by extruding Na+ to the extracellular space, thus conferring salt tolerance in plants. CBL10 also plays a critical role in salt tolerance possibly by the activation of Na+ compartmentation into the vacuole. However, the functional relationship of the SOS and CBL10-regulated processes remains unclear. Here, we analyzed the genetic interaction between CBL4 and CBL10 and found that the cbl4 cbl10 double mutant was dramatically more sensitive to salt as compared to the cbl4 and cbl10 single mutants, suggesting that CBL4 and CBL10 each directs a different salt-tolerance pathway. Furthermore, the cbl4 cbl10 and cipk24 cbl10 double mutants were more sensitive than the cipk24 single mutant, suggesting that CBL10 directs a process involving CIPK24 and other partners different from the SOS pathway. Although the cbl4 cbl10, cipk24 cbl10, and sos1 cbl10 double mutants showed comparable salt-sensitive phenotype to sos1 at the whole plant level, they all accumulated much lower Na+ as compared to sos1 under high salt conditions, suggesting that CBL10 regulates additional unknown transport processes that play distinct roles from the SOS1 in Na+ homeostasis.
Environmental Toxicology and Chemistry

The aquatic bioconcentration of a chemical is typically determined using conventional fish tests. To foster the approach of alternatives to animal testing, a combination of computational models and in vitro substrate depletion bioassays (e.g., primary hepatocytes) can be used. One recently developed in vitro assay is the three‐dimensional (3D) hepatic spheroid model from rainbow trout (Oncorhynchus mykiss). The aim of the present study was to evaluate the metabolic competence of the 3D spheroids from rainbow trout when exposed to pyrene, using 2 different sampling procedures (SP1 and SP2). The results were compared with previously published intrinsic clearance (CL) results from S9 fractions and primary hepatocyte assays. Extraction of pyrene using SP1 suggested that the spheroids had depleted 33% of the pyrene within 4 h of exposure, reducing to 91% after 30 h. However, when applying SP2 a substantial amount (36%) of the pyrene was bound to the exposure vial within 2 h, decreasing after 6 h of exposure. Formation of hydroxypyrene‐glucuronide (OH‐PYR‐Glu) was obtained throughout the study, displaying the metabolic competence of the 3D spheroids. The 2 sampling procedures yielded different CLin vitro, where pyrene depletion using SP2 was very similar to published studies using primary hepatocytes. The 3D spheroids demonstrated reproducibile, log‐linear biotransformation of pyrene and displayed formation of OH‐PYR‐Glu, indicating their metabolic competence for 30 h or more. Environ Toxicol Chem 2019;38:1738–1747. © 2019 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.
Advances in Regenerative Stem Cell Therapy in Androgenic Alopecia and Hair Loss: Wnt Pathway, Growth-Factor, and Mesenchymal Stem Cell Signaling Impact Analysis on Cell Growth and Hair Follicle Development

The use of stem cells has been reported to improve hair regrowth in several therapeutic strategies, including reversing the pathological mechanisms, that contribute to hair loss, regeneration of hair follicles, or creating hair using the tissue-engineering approach. Although various promising stem cell approaches are progressing via pre-clinical models to clinical trials, intraoperative stem cell treatments with a one-step procedure offer a quicker result by incorporating an autologous cell source without manipulation, which may be injected by surgeons through a well-established clinical practice. Many authors have concentrated on adipose-derived stromal vascular cells due to their ability to separate into numerous cell genealogies, platelet-rich plasma for its ability to enhance cell multiplication and neo-angiogenesis, as well as human follicle mesenchymal stem cells. In this paper, the significant improvements in intraoperative stem cell approaches, from in vivo models to clinical investigations, are reviewed. The potential regenerative instruments and functions of various cell populaces in the hair regrowth process are discussed. The addition of Wnt signaling in dermal papilla cells is considered a key factor in stimulating hair growth. Mesenchymal stem cell-derived signaling and growth factors obtained by platelets influence hair growth through cellular proliferation to prolong the anagen phase (FGF-7), induce cell growth (ERK activation), stimulate hair follicle development (β-catenin), and suppress apoptotic cues (Bcl-2 release and Akt activation).
Employees’ Perceptions of CSR, Work Engagement, and Organizational Citizenship Behavior: The Mediating Effects of Organizational Justice

Corporate social responsibility (CSR) at the individual level has emerged as an important field of research. However, a more comprehensive understanding of how CSR affects employee work engagement and organizational citizenship behavior (OCB) is still lacking. Based on social exchange theory, we examine the effects of employees’ perceptions of CSR on OCB and work engagement as well as the mediating mechanism of distributive and procedural justice, based on data collected from 350 employees working in the banking sector of Pakistan. Our study suggests that employees’ perceptions of CSR positively predict OCB and work engagement, and that work engagement is positively related to OCB. Both distributive and procedural justice positively mediate the effects of employees’ perceptions of CSR on OCB and work engagement.
Arsenic, Organic Foods, and Brown Rice Syrup

Background: Rice can be a major source of inorganic arsenic (Asi) for many sub-populations. Rice products are also used as ingredients in prepared foods, some of which may not be obviously rice based. Organic brown rice syrup (OBRS) is used as a sweetener in organic food products as an alternative to high-fructose corn syrup. We hypothesized that OBRS introduces As into these products. Objective: We determined the concentration and speciation of As in commercially available brown rice syrups and in products containing OBRS, including toddler formula, cereal/energy bars, and high-energy foods used by endurance athletes. Methods: We used inductively coupled plasma mass spectrometry (ICP-MS) and ion chromatography coupled to ICP-MS to determine total As (Astotal) concentrations and As speciation in products purchased via the Internet or in stores in the Hanover, New Hampshire, area. Discussion: We found that OBRS can contain high concentrations of Asi and dimethyl-arsenate (DMA). An “organic” toddler milk formula containing OBRS as the primary ingredient had Astotal concentrations up to six times the U.S. Environmental Protection Agency safe drinking water limit. Cereal bars and high-energy foods containing OBRS also had higher As concentrations than equivalent products that did not contain OBRS. Asi was the main As species in most food products tested in this study. Conclusions: There are currently no U.S. regulations applicable to As in food, but our findings suggest that the OBRS products we evaluated may introduce significant concentrations of Asi into an individual’s diet. Thus, we conclude that there is an urgent need for regulatory limits on As in food.