Miracle-dz/UniFAR-FTUs huggingface dataset:
VITAMIN D BINDING PROTEIN AND 25-HYDROXYVITAMIN D LEVELS: EMERGING CLINICAL APPLICATIONS.

The precursor of the active form of vitamin D, 25-hydroxyvitamin D (25(OH)D), is recognized as the optimal indicator of vitamin D status. Vitamin D3 undergoes conversion through a multitude of enzymatic reactions described within the paper, and vitamin D levels are dependent on many factors including the vitamin D binding protein (DBP). The free hormone hypothesis postulates that protein-bound hormones are not biologically available and that unbound hormones are biologically active. The majority of circulating 25(OH)D and 1,25-dihydroxyvitamin D is tightly bound to DBP and albumin, with less than 1% circulating in an unbound form. As a result, factors affecting DBP alter the interpretation of 25(OH)D levels. The aim of this review is to assess the current methodology used to measure total and free 25(OH)D, and DBP. Additionally, we analyze the effects of other endocrine hormones and disease processes on DBP levels and subsequently, the interpretation of 25(OH)D levels. ABBREVIATIONS CF = cystic fibrosis DBP = vitamin D binding protein ELISA = enzyme-linked immunosorbent assay ESLD = end-stage liver disease HC = hormone contraceptives iPTH = intact parathyroid hormone LC-MS = liquid chromatography-mass spectrometry MS = multiple sclerosis 25(OH)D = 25-hydroxyvitamin D PHPT = primary hyperparathyroidism RIA = radioimmunoassay.
SODIUM GLUCOSE COTRANSPORTER 2 AND DIPEPTIDYL PEPTIDASE-4 INHIBITION: PROMISE OF A DYNAMIC DUO.

OBJECTIVE This article reviews evidence supporting sodium glucose cotransporter 2 (SGLT2) inhibitor and dipeptidyl peptidase-4 (DPP-4) inhibitor combination therapy for management of type 2 diabetes mellitus (T2DM). METHODS We conducted a nonsystematic review of the literature focusing on single-pill or fixed-dose combinations of SGLT2 inhibitors and DPP-4 inhibitors available in the United States. RESULTS SGLT2 inhibitors and DPP-4 inhibitors have complementary mechanisms of action that address several of the underlying pathophysiologic abnormalities present in T2DM without overlapping toxicities. The combination of these 2 agents has several advantages including a low risk of hypoglycemia, the potential for weight loss, the ability to coformulate into a pill with once-daily administration, and the possibility to use with other classes of glucose-lowering agents. Cardiovascular outcomes trials reported to date support the safety of the DPP-4 class and suggest possible cardioprotective effects for SGLT2 inhibitors - at least based on the first reported study that used empagliflozin. Recent clinical evidence shows that SGLT2 inhibitor/DPP-4 inhibitor therapy is an effective combination for T2DM treatment, providing glycated hemoglobin (HbA1c) reductions of 1.1 to 1.5%, and weight reductions of approximately 2 kg when added to metformin, which is its primary place in therapy. CONCLUSION The combination of an SGLT2 inhibitor/DPP-4 inhibitor is a safe and effective treatment choice for patients with T2DM who are unable to obtain adequate glycemic control with metformin therapy, cannot use metformin, or have a higher baseline HbA1c. ABBREVIATIONS BP = blood pressure; CI = confidence interval; CVOT = cardiovascular outcomes; DKA = diabetic ketoacidosis; DPP-4 = dipeptidyl peptidase-4; EXAMINE = EXamination of cArdiovascular outcoMes with alogliptiN versus standard of carE in patients with type 2 diabetes mellitus and acute coronary syndrome; FDA = Food and Drug Administration; HbA1c = glycated hemoglobin; HR = hazard ratio; MACE = major adverse cardiovascular events; SAVOR-TIMI 53 = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Type 2 Diabetes Mellitus; SBP = systolic blood pressure; SGLT2 = sodium glucose cotransporter 2; TECOS = Trial to Evaluate Cardiovascular Outcomes after Treatment with Sitagliptin; T2DM = type 2 diabetes mellitus; XR = extended release.
Fungal spores: A critical review of the toxicological and epidemiological evidence as a basis for occupational exposure limit setting

Fungal spores are ubiquitous in the environment. However, exposure levels in workplaces where mouldy materials are handled are much higher than in common indoor and outdoor environments. Spores of all tested species induced inflammation in experimental studies. The response to mycotoxin-producing and pathogenic species was much stronger. In animal studies, nonallergic responses dominated after a single dose. Allergic responses also occurred, especially to mycotoxin-producing and pathogenic species, and after repeated exposures. Inhalation of a single spore dose by subjects with sick building syndrome indicated no observed effect levels of 4 × 103 Trichoderma harzianum spores/m3 and 8 × 103 Penicillium chrysogenum spores/m3 for lung function, respiratory symptoms, and inflammatory cells in the blood. In asthmatic patients allergic to Penicillium sp. or Alternaria alternata, lowest observed effect levels (LOELs) for reduced airway conductance were 1 × 104 and 2 × 104 spores/m3, respectively. In epidemiological studies of highly exposed working populations lung function decline, respiratory symptoms and airway inflammation began to appear at exposure levels of 105 spores/m3. Thus, human challenge and epidemiological studies support fairly consistent LOELs of approximately 105 spores/m3 for diverse fungal species in nonsensitised populations. Mycotoxin-producing and pathogenic species have to be detected specifically, however, because of their higher toxicity.
The carcinogenicity of dietary acrylamide intake: A comparative discussion of epidemiological and experimental animal research

Since 2002, it is known that the probable human carcinogen acrylamide is present in commonly consumed carbohydrate-rich foods, such as French fries and potato chips. In this review, the authors discuss the body of evidence on acrylamide carcinogenicity from both epidemiological and rodent studies, including variability, strengths and weaknesses, how both types of evidence relate, and possible reasons for discrepancies. In both rats and humans, increased incidences of various cancer types were observed. In rats, increased incidences of mammary gland, thyroid tumors and scrotal mesothelioma were observed in both studies that were performed. In humans, increased risks of ovarian and endometrial cancers, renal cell cancer, estrogen (and progesterone) receptor–positive breast cancer, and oral cavity cancer (the latter in non-smoking women) were observed. Some cancer types were found in both rats and humans, e.g., endometrial cancer (observed in one of the two rat studies), but there are also some inconsistencies. Interestingly, in humans, some indications for inverse associations were observed for lung and bladder cancers in women, and prostate and oro- and hypopharynx cancers in men. These latter observations indicate that genotoxicity may not be the only mechanism by which acrylamide causes cancer. The estimated risks based on the epidemiological studies for the sites for which a positive association was observed were considerably higher than those based on extrapolations from the rat studies. The observed pattern of increased risks in the rat and epidemiological studies and the decreased risks in the epidemiological studies suggests that acrylamide might influence hormonal systems, for which rodents may not be good models.
Autophagy and lysosomal related protein expression patterns in human glioblastoma

Glioblastoma cells are resistant to apoptotic stimuli with autophagic death prevailing under cytotoxic stress. Autophagy interfering agents may represent a new strategy to test in combination with chemo-radiation. We investigated the patterns of expression of autophagy related proteins (LC3A, LC3B, p62, Beclin 1, ULK1 and ULK2) in a series of patients treated with post-operative radiotherapy. Experiments with glioblastoma cell lines (T98 and U87) were also performed to assess autophagic response under conditions simulating the adverse intratumoral environment. Glioblastomas showed cytoplasmic overexpression of autophagic proteins in a varying extent, so that cases could be grouped into low and high expression groups. 10/23, 5/23, 13/23, 5/23, 8/23 and 9/23 cases examined showed extensive expression of LC3A, LC3B, Beclin 1, Ulk 1, Ulk 2 and p62, respectively. Lysosomal markers Cathepsin D and LAMP2a, as well as the lyososomal biogenesis transcription factor TFEB were frequently overexpressed in glioblastomas (10/23, 11/23, and 10/23 cases, respectively). TFEB was directly linked with PTEN, Cathepsin D, HIF1α, LC3B, Beclin 1 and p62 expression. PTEN was also significantly related with LC3B but not LC3A expression, in both immunohistochemistry and gene expression analysis. Confocal microscopy in T98 and U87 cell lines showed distinct identity of LC3A and LC3B autophagosomes. The previously reported stone-like structure (SLS) pattern of LC3 expression was related with prognosis. SLS were inducible in glioblastoma cell lines under exposure to acidic conditions and 2DG mediated glucose antagonism. The present study provides the basis for autophagic characterization of human glioblastoma for further translational studies and targeted therapy trials.
1,3-Butadiene: II. Genotoxicity profile

1,3-Butadiene’s (BD’s) major electrophilic metabolites 1,2-epoxy-3-butene (EB), 1,2-dihydroxy-3,4-epoxybutane (EBD), and 1,2,3,4-diepoxybutane (DEB) are responsible for both its mutagenicity and carcinogenicity. EB, EBD, and DEB are DNA reactive, forming a variety of adducts. All three metabolites are genotoxic in vitro and in vivo, with relative mutagenic potencies of DEB >> EB > EBD. DEB also effectively produces gene deletions and chromosome aberrations. BD’s greater mutagenicity and carcinogenicity in mice over rats as well as its failure to induce chromosome-level mutations in vivo in rats appear to be due to greater production of DEB in mice. Concentrations of EB and DEB in vivo in humans are even lower than in rats. Although most studies of BD-exposed humans have failed to find increases in gene mutations, one group has reported positive findings. Reasons for these discordant results are examined. BD-related chromosome aberrations have never been demonstrated in humans except for the possible production of micronuclei in lymphocytes of workers exposed to extremely high levels of BD in the workplace. The relative potencies of the BD metabolites, their relative abundance in the different species, and the kinds of mutations they can induce are major considerations in BD’s overall genotoxicity profile.
Expression, regulation and function of Egr1 during implantation and decidualization in mice

Abstract Early growth response gene 1 (Egr1), a zinc finger transcriptional factor, plays an important role in regulating cell proliferation, differentiation and angiogenesis. Current data have shown that Egr1 is involved in follicular development, ovulation, luteinization and placental angiogenesis. However, the expression, regulation and function of Egr1 in mouse uterus during embryo implantation and decidualization are poorly understood. Here we showed that Egr1 was strongly expressed in the subluminal stroma surrounding the implanting blastocyst on day 5 of pregnancy. Injection of Egr1 siRNA into the mouse uterine horn could obviously reduce the number of implanted embryos and affect the uterine vascular permeability. Further study found that Egr1 played a role through influencing the expression of cyclooxygenase-2 (Cox-2), microsomal prostaglandin E synthase 1 (mPGES-1), vascular endothelial growth factor (Vegf), transformation related protein 53 (Trp53) and matrix metallopeptidase 9 (Mmp9) genes in the process of mouse embryo implantation. Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) might direct the expression of Egr1 in the uterine stromal cells. Under in vivo and in vitro artificial decidualization, Egr1 expression was significantly decreased. Overexpression of Egr1 downregulated the expression of decidual marker decidual/trophoblast PRL-related protein (Dtprp) in the uterine stromal cells, while inhibition of Egr1 upregulated the expression of Dtprp under in vitro decidualization. Estrogen and progesterone could regulate the expression of Egr1 in the ovariectomized mouse uterus and uterine stromal cells. These results suggest that Egr1 may be essential for embryo implantation and decidualization.
Lack of centrioles and primary cilia in STIL−/− mouse embryos

Although most animal cells contain centrosomes, consisting of a pair of centrioles, their precise contribution to cell division and embryonic development is unclear. Genetic ablation of STIL, an essential component of the centriole replication machinery in mammalian cells, causes embryonic lethality in mice around mid gestation associated with defective Hedgehog signaling. Here, we describe, by focused ion beam scanning electron microscopy, that STIL−/− mouse embryos do not contain centrioles or primary cilia, suggesting that these organelles are not essential for mammalian development until mid gestation. We further show that the lack of primary cilia explains the absence of Hedgehog signaling in STIL−/− cells. Exogenous re-expression of STIL or STIL microcephaly mutants compatible with human survival, induced non-templated, de novo generation of centrioles in STIL−/− cells. Thus, while the abscence of centrioles is compatible with mammalian gastrulation, lack of centrioles and primary cilia impairs Hedgehog signaling and further embryonic development.
Adequacy of discharge summaries prepared by junior medical residents in a university hospital

Discharge summaries are intended to transfer important clinical information from inpatient to outpatient settings and between hospital admissions. Complete, accurate, and timely discharge summaries can communicate important information back to the outpatient (OPD) physician, prevent adverse events and reduce readmission to hospital. However, discharge summaries are not always given the priority it deserves. Too often, discharge summaries contain insufficient or unnecessary information and fail to reach the OPD physician in time for the patient’s follow-up visit. We evaluated dis-charge summaries produced by first-year medical residents (R1) for their completeness and accuracy. Consecutive dis-charge summaries prepared by R1 residents for patients discharged from internal medicine wards were retrospectively eva-luated by two independent reviewers for presence and accuracy of essential items described by the Joint Commission for Hospital Accreditation. One-hundred and thirty-two discharge summaries were assessed for completeness and accuracy. Most items were incompletely reported with a given item missing in 2.3% - 91.7% of all discharge summaries. Inaccuracies of discharge summaries when compared to the patient chart as a reference standard ranged from 8.5% for final diagnosis to 50.9% for anticipated problems and suggested interventions with a mean of 29.6 + 13.3%. Only 18.2% of the discharge summaries were written within 48 hours of patient discharge (p < 0.001). The availability of a finalized (typed and signed) discharge summary at the first post-discharge visit was low (12.1%) and remained poor at 4 weeks (50.8%). Conclusion: Discharge summaries prepared by R1 physicians are grossly inadequate at documenting most of the essential domains described by the Joint Commission for Hospital Accreditation. Our findings will aid in the development of educational interventions for residents.
Endocrine disrupting chemicals and sexual behaviors in fish – a critical review on effects and possible consequences

Endocrine disrupting chemicals (EDCs) enter aquatic ecosystems through discharged effluents, mainly from wastewater treatment works and diffuse run off from land, and affect a wide range of aquatic biota, including fish. Evidence for altered physiology in fish as a consequence of endocrine disruption is global, with some of the most widely reported effects on sexual development and function. In recent years, research has shown that fish behaviors can also be affected by EDCs which potentially has wide implications for individual fitness and population level outcomes. This review presents a critical assessment on reported effects of EDCs on behavior in fish, focusing on behaviors associated with reproduction. We investigate commonalities and differences in sexual behaviors between fish species most commonly applied in ecotoxicology, drawing out common principles for impacts of EDCs and then reviewing the evidence for, and implications of, disruptions of these behaviors after exposures to EDCs. In an analysis of the reported effects of exposure to the estrogen ethinylestradiol, we show that life-stage at exposure is a key factor determining behavioral responses of affected populations. EDC-induced changes in behavior occur at similar concentrations as for established biomarker responses (e.g. vitellogenin induction for estrogens), indicating behavior is equally sensitive (and noninvasive) as an indicator of EDC exposure. Adopting behaviors in fish as indicators of chemical exposure and effects, however, still has many technical and interpretation challenges and there is very little information available on how behaviors under laboratory conditions equate with those occurring in wild populations.
Critical analysis of endocrine disruptive activity of triclosan and its relevance to human exposure through the use of personal care products

Abstract This review examines the mammalian and human literature pertaining to the potential endocrine disruptive effects of triclosan (TCS). Dietary exposure to TCS consistently produces a dose-dependent decrease in serum thyroxine (T4) in rats without any consistent change in TSH or triiodothyronine (T3). Human studies reveal no evidence that the TCS exposure through personal care product use affects the thyroid system. TCS binds to both androgen and estrogen receptors in vitro with low affinity and evokes diverse responses (e.g., agonist, antagonist, or none) in steroid receptor transfected cell-based reporter assays. Two of three studies in rats have failed to show that TCS exposure suppresses male reproductive function in vivo. Three of four studies have failed to show that TCS possesses estrogenic (or uterotrophic) activity in rats. However, two studies reported that, while TCS lacks estrogenic activity, it can amplify the action of estrogen in vivo. The in vitro, in vivo, and epidemiologic studies reviewed herein show little evidence that TCS adversely affects gestation or postpartum development of offspring. Furthermore, previously reported toxicity testing in a variety of mammalian species shows little evidence that TCS adversely affects thyroid function, male and female reproductive function, gestation, or postpartum development of offspring. Finally, doses of TCS reported to produce hypothyroxinemia, and occasional effects on male and female reproduction, gestation, and offspring in animal studies are several orders of magnitude greater than the estimated exposure levels of TCS in humans. Overall, little evidence exists that TCS exposure through personal care product use presents a risk of endocrine disruptive adverse health effects in humans.
Actin filament nucleation and elongation factors – structure–function relationships

The spontaneous and unregulated polymerization of actin filaments is inhibited in cells by actin monomer-binding proteins such as profilin and Tβ4. Eukaryotic cells and certain pathogens use filament nucleators to stabilize actin polymerization nuclei, whose formation is rate-limiting. Known filament nucleators include the Arp2/3 complex and its large family of nucleation promoting factors (NPFs), formins, Spire, Cobl, VopL/VopF, TARP and Lmod. These molecules control the time and location for polymerization, and additionally influence the structures of the actin networks that they generate. Filament nucleators are generally unrelated, but with the exception of formins they all use the WASP-Homology 2 domain (WH2 or W), a small and versatile actin-binding motif, for interaction with actin. A common architecture, found in Spire, Cobl and VopL/VopF, consists of tandem W domains that bind three to four actin subunits to form a nucleus. Structural considerations suggest that NPFs–Arp2/3 complex can also be viewed as a specialized form of tandem W-based nucleator. Formins are unique in that they use the formin-homology 2 (FH2) domain for interaction with actin and promote not only nucleation, but also processive barbed end elongation. In contrast, the elongation function among W-based nucleators has been “outsourced” to a dedicated family of proteins, Eva/VASP, which are related to WASP-family NPFs.
Diversity of DNA methyltransferases that recognize asymmetric target sequences

DNA methyltransferases (MTases) are a group of enzymes that catalyze the methyl group transfer from S-adenosyl-L-methionine in a sequence-specific manner. Orthodox Type II DNA MTases usually recognize palindromic DNA sequences and add a methyl group to the target base (either adenine or cytosine) on both strands. However, there are a number of MTases that recognize asymmetric target sequences and differ in their subunit organization. In a bacterial cell, after each round of replication, the substrate for any MTase is hemimethylated DNA, and it therefore needs only a single methylation event to restore the fully methylated state. This is in consistent with the fact that most of the DNA MTases studied exist as monomers in solution. Multiple lines of evidence suggest that some DNA MTases function as dimers. Further, functional analysis of many restriction-modification systems showed the presence of more than one or fused MTase genes. It was proposed that presence of two MTases responsible for the recognition and methylation of asymmetric sequences would protect the nascent strands generated during DNA replication from cognate restriction endonuclease. In this review, MTases recognizing asymmetric sequences have been grouped into different subgroups based on their unique properties. Detailed characterization of these unusual MTases would help in better understanding of their specific biological roles and mechanisms of action. The rapid progress made by the genome sequencing of bacteria and archaea may accelerate the identification and study of species- and strain-specific MTases of host-adapted bacteria and their roles in pathogenic mechanisms.
Physiotherapy for the sporting dog

Canine Sports medicine is a fast-growing sub speciality of the veterinary profession and there are increased opportunities for veterinary physiotherapists to share their skills. This article considers how principles of athletic selection, preparation and conditioning are applied to dogs, and gives a brief overview of physiotherapy principles in the management of a common soft tissue injury: hamstring strain.
Plasmid segregation: how to survive as an extra piece of DNA

Non-essential extra-chromosomal DNA elements such as plasmids are responsible for their own propagation in dividing host cells, and one means to ensure this is to carry a miniature active segregation system reminiscent of the mitotic spindle. Plasmids that are maintained at low numbers in prokaryotic cells have developed a range of such active partitioning systems, which are characterized by an impressive simplicity and efficiency and which are united by the use of dynamic, nucleotide-driven filaments to separate and position DNA molecules. A comparison of different plasmid segregation systems reveals (i) how unrelated filament-forming and DNA-binding proteins have been adopted and modified to create a range of simple DNA segregating complexes and (ii) how subtle changes in the few components of these DNA segregation machines has led to a remarkable diversity in the molecular mechanisms of closely related segregation systems. Here, our current understanding of plasmid segregation systems is reviewed and compared with other DNA segregation systems, and this is extended by a discussion of basic principles of plasmid segregation systems, evolutionary implications and the relationship between an autonomous DNA element and its host cell.