Miracle-dz/UniFAR-FTUs huggingface dataset:
Eukaryotic MCM Proteins: Beyond Replication Initiation

SUMMARY The minichromosome maintenance (or MCM) protein family is composed of six related proteins that are conserved in all eukaryotes. They were first identified by genetic screens in yeast and subsequently analyzed in other experimental systems using molecular and biochemical methods. Early data led to the identification of MCMs as central players in the initiation of DNA replication. More recent studies have shown that MCM proteins also function in replication elongation, probably as a DNA helicase. This is consistent with structural analysis showing that the proteins interact together in a heterohexameric ring. However, MCMs are strikingly abundant and far exceed the stoichiometry of replication origins; they are widely distributed on unreplicated chromatin. Analysis of mcm mutant phenotypes and interactions with other factors have now implicated the MCM proteins in other chromosome transactions including damage response, transcription, and chromatin structure. These experiments indicate that the MCMs are central players in many aspects of genome stability.
Requirement of Endogenous Stem Cell Factor and Granulocyte-Colony-Stimulating Factor for IL-17-Mediated Granulopoiesis1

IL-17 is a novel, CD4+ T cell-restricted cytokine. In vivo, it stimulates hematopoiesis and causes neutrophilia consisting of mature granulocytes. In this study, we show that IL-17-mediated granulopoiesis requires G-CSF release and the presence or induction of the transmembrane form of stem cell factor (SCF) for optimal granulopoiesis. However, IL-17 also protects mice from G-CSF neutralization-induced neutropenia. G-CSF neutralization completely reversed IL-17-induced BM progenitor expansion, whereas splenic CFU-GM/CFU-granulocyte-erythrocyte-megakaryocyte-monocyte was only reduced by 50% in both Sl/Sld and littermate control mice. Thus, there remained a significant SCF/G-CSF-independent effect of IL-17 on splenic granulopoiesis, resulting in a preservation of mature circulating granulocytes. IL-17 is a cytokine that potentially interconnects lymphocytic and myeloid host defense and may have potential for therapeutic development.
Changes in pre-diagnostic serum C-reactive protein concentrations and ovarian cancer risk: a longitudinal study.

BACKGROUND Evidence suggests that inflammation may be associated with increased risk of ovarian cancer but there is paucity of studies investigating this association, especially using over-time changes in inflammatory biomarkers. MATERIALS AND METHODS We conducted a prospective population-based case-control study nested within the Finnish Maternity Cohort (FMC). Within the FMC, 170 women with ovarian cancer who had donated serum samples to the cohort twice, ≥1 year apart, before cancer diagnoses were identified. One control per case was matched for age, parity and sampling date. RESULTS Comparing the highest with lowest tertiles, the odds ratio (OR) of ovarian cancer using the first set of serum samples (mean lag time to cancer diagnosis 9.0 years) was 1.62 [95% confidence interval (CI) 0.93-2.83]. However, analysis conducted using the second set of serum samples donated closer to cancer diagnosis (mean lag time 6.4 years) revealed a significantly increased risk of ovarian cancer comparing extreme tertiles of C-reactive protein (CRP) concentrations; OR 1.96 (95% CI 1.11-3.4). Over time, increases in individuals' CRP concentrations were also associated with increased risk; OR 1.90 (95% CI 1.12-3.23). CONCLUSION The results suggest that inflammation may precede ovarian cancer since increasing CRP concentrations, both across tertiles and longitudinally at the individual level, were associated with increased risk.
Transitional Care for Older Adults with Chronic Illnesses as a Vulnerable Population: Theoretical Framework and Future Directions in Nursing.

PURPOSE Effective transitional care is needed to improve the quality of life in older adult patients with chronic illness and avoid discontinuity of care and adverse events. The aim of this article is to provide an overview of the key features, broader implications, and the utility of Meleis' transition theory intended for the transitional care of older adults with chronic illnesses. We present the role of nurse in the context of transitional care and propose future directions to increase the quality of nursing care. METHODS The online databases Cumulative Index of Nursing and Allied Health Literature, MEDLINE, and Science Direct were searched for relevant literature published since 1970 along with textbooks regarding nursing theory. RESULTS An evaluation of the usefulness of transition theory based on transitional care in older adult patients with chronic illnesses is provided. Healthy transition should be the expected standard of nursing care for older adults across all healthcare settings. CONCLUSION Nurses need to contribute to the development of transitional care for vulnerable populations; however, transition theory needs to be enhanced through additional theoretical work and repeated evaluations of the applicability in areas of transitional care.
Passive Immunotherapies Protect WRvFire and IHD-J-Luc Vaccinia Virus-Infected Mice from Lethality by Reducing Viral Loads in the Upper Respiratory Tract and Internal Organs

ABSTRACT Whole-body bioimaging was employed to study the effects of passive immunotherapies on lethality and viral dissemination in BALB/c mice challenged with recombinant vaccinia viruses expressing luciferase. WRvFire and IHD-J-Luc vaccinia viruses induced lethality with similar times to death following intranasal infection, but WRvFire replicated at higher levels than IHD-J-Luc in the upper and lower respiratory tracts. Three types of therapies were tested: licensed human anti-vaccinia virus immunoglobulin intravenous (VIGIV); recombinant anti-vaccinia virus immunoglobulin (rVIG; Symphogen, Denmark), an investigational product containing a mixture of 26 human monoclonal antibodies (HuMAbs) against mature virion (MV) and enveloped virion (EV); and HuMAb compositions targeting subsets of MV or EV proteins. Bioluminescence recorded daily showed that pretreatment with VIGIV (30 mg) or with rVIG (100 μg) on day −2 protected mice from death but did not prevent viral replication at the site of inoculation and dissemination to internal organs. Compositions containing HuMAbs against MV or EV proteins were protective in both infection models at 100 μg per animal, but at 30 μg, only anti-EV antibodies conferred protection. Importantly, the t statistic of the mean total fluxes revealed that viral loads in surviving mice were significantly reduced in at least 3 sites for 3 consecutive days (days 3 to 5) postchallenge, while significant reduction for 1 or 2 days in any individual site did not confer protection. Our data suggest that reduction of viral replication at multiple sites, including respiratory tract, spleen, and liver, as monitored by whole-body bioluminescence can be used to predict the effectiveness of passive immunotherapies in mouse models.
Continuing the search for dyslexia genes on 6p

This study is a continuation and extension of the work with Orton Developmental Dyslexia (DD) pedigrees [Grigorenko et al., 1997 ; 2000 , Grigorenko et al., 2001 ]. This study utilized an extended sample (N = 176) and a well‐saturated map of chromosome 6p (30 markers). Six phenotypes were constructed to span a range of dyslexia‐related cognitive processes. These phenotypes were: (1) Phonemic Awareness (of spoken words); (2) Phonological Decoding (of printed nonwords); (3) Rapid Automatized Naming (of colored squares or object drawings); (4) Single Word Reading (orally, of printed real words); (5) Phonemic Awareness/Decoding/Single‐Word Reading pathway; and (6) Phonemic Awareness/Rapid Naming/Single‐Word Reading pathway. The study resulted in two major findings. First, considering the distributions of the genetic linkage indicators across all phenotypes examined, there appear to be three regions of interest (around markers D6S109, D6S1261, and in the D6S105–D6S265 region). Any of these regions could serve as a starting point in the search for specific gene candidates contributing to the manifestation of DD, yet they all might be echo peaks of a single peak, the boundary of which is difficult to establish due to the limited power of this sample. Second, the DD‐related linkage in 6p21.3 appears to be most closely related to the manifestations of DD through phonemic awareness and single‐word reading deficits. © 2003 Wiley‐Liss, Inc.
Effect of cessation and resumption of static hamstring muscle stretching on joint range of motion.

STUDY DESIGN Single group repeated measures. OBJECTIVES To determine the effects of cessation and resumption of a hamstring muscle stretching protocol on knee range of motion (ROM). BACKGROUND It is generally accepted that stretching exercises result in an increase in ROM. The ability to maintain ROM once stretching has ceased and the ability to regain ROM after resumption of the stretching exercise is not well-known. METHODS AND MEASURES Evaluated the effect of 6 weeks of static hamstring stretching, 4 weeks with cessation from stretching, and 6 weeks with resumption of stretching on knee ROM in 18 inactive college students (12 men, 6 women, mean age 21.0 years). The hamstring stretching consisted of 2 30-second stretches per day, 5 days per week. Knee ROM was measured before and after each of the above phases with an active knee extension test. RESULTS Mean knee ROM increased after the initial stretching period (143+/-11 to 152+/-9 degrees), decreased to baseline following the cessation period (145+/-8 degrees) and again increased following the resumption of stretching but was not different from the initial gains (154+/-10 degrees). Unlike the stretch limb, the control limb ROM did not change over the 4 measurement times. CONCLUSIONS There was no retention of knee ROM 4 weeks following a 6-week stretching protocol and a subsequent stretching period did not enhance the gain of knee ROM over the initial stretching period.
Kinetics of the Ultrastructural Changes in Apoptotic Chondrocytes from an Osteoarthrosis Rat Model: A Window of Comparison to the Cellular Mechanism of Apoptosis in Human Chondrocytes

It is conceivable that apoptosis plays a relevant role in the pathogenesis of osteoarthrosis. We have dissected certain ultrastructural changes in apoptosis when comparing chondrocytes from the rat osteoarthrosis-induced model to those of human osteoarthrosis. Chondrocytes displayed a typical ultrastructural pattern prevailing according to the days following osteoarthrosis induction. These notable modifications included cell shape changes, a distinctive nuclear chromatin condensation, prominent Golgi and rough endoplasmic reticulum (RER), an increased cytosol osmiophilic reaction, matrix vesicles blebbing from the plasma membrane, and cell fragmentation, with the consequent formation of apoptotic bodies. In addition, small particles and fibers were seen engulfed inside chondrocytes in vacuoles, which may well be related to phagocytosis. Similar modifications were observed in human osteoarthrosic cartilage, predominantly those linked to late stages in the rat model. Interestingly, we observed a peculiarly arranged structure inside a chondrocyte's mitochondrion. It consisted of aggregated particles (5-8 nm diameter) forming rounded granules (38-50 nm diameter) lined up between double membranes, probably cristae, running parallel to the long axis of the mitochondrion. All these changes could be linked to different stages in chondrocytes´ apoptotic cell death in osteoarthrosic rat cartilage, similar to what happen in humans. The study of the cellular mechanism of apoptosis facilitates the understanding of the process and might shed additional light on the potential role of apoptotic chondrocyte in osteoarthrosis pathogenesis.
Glucagon-Like Peptide 1(7-36) Amide Stimulates Exocytosis in Human Pancreatic β-Cells by Both Proximal and Distal Regulatory Steps in Stimulus-Secretion Coupling

The effect of glucagon-like peptide 1(7–36) amide [GLP-l(7–36) amide] on membrane potential, wholecell ATP-sensitive potassium channel (KATP) and Ca2+ currents, cytoplasmic Ca2+ concentration, and exocytosis was explored in single human β-cells. GLP-1(7–36) amide induced membrane depolarization that was associated with inhibition of whole-cell KATP current. In addition, GLP-l(7–36) amide (and forskolin) produced greater than fourfold potentiation of Ca2+-dependent exocytosis. The latter effect resulted in part (40%) from acceleration of Ca2+ influx through voltage-dependent (L-type) Ca2+ channels. More importantly, GLP- 1(7–36) amide (via generation of cyclic AMP and activation of protein kinase A) potentiated exocytosis at a site distal to a rise in the cytoplasmic Ca2+ concentration. Photorelease of caged cAMP produced a two- to threefold potentiation of exocytosis when the cytoplasmic Ca2+ concentrations were clamped at >170 nmol/1. The effect of GLP-1(7–36) amide was antagonized by the islet hormone somatostatin. Similar effects on membrane potential, ion conductances, and exocytosis were observed with glucose-dependent insulinotropic polypeptide (GIP), the second major incretin. The present data suggest that the strong insulinotropic action of GLP-1(7–36) amide and GIP in humans results from its interaction with several proximal as well as distal important regulatory steps in the stimulus-secretion coupling.
Norepinephrine amplifies angiotensin II-induced vasoconstriction in rabbit femoral artery.

Several reports have focused on the ability of angiotensin II to amplify vascular contractile responses to norepinephrine, but none have determined whether norepinephrine enhances angiotensin II-induced vasoconstriction. Measuring isometric contraction in isolated rabbit femoral artery rings, we have found that the angiotensin II-induced contractile response was amplified in the presence of a threshold contraction to norepinephrine, as manifested by a 2.9-fold leftward shift of the midpoint of the concentration-response curve with no change in the maximal response. This amplification was attenuated markedly by nifedipine (0.1 microM), a calcium channel antagonist, implicating calcium channel activation in the amplification phenomenon. Precontracting the smooth muscle with a threshold concentration of angiotensin II had no enhancing effect on further angiotensin responses, indicating that the norepinephrine-induced amplification was due to a specific action of norepinephrine, rather than to a precontraction itself. In experiments in which the angiotensin II response was diminished by the presence of the noncompetitive angiotensin II antagonist [Sar1 Ala8]angiotensin II (0.3 microM), norepinephrine affected the angiotensin II response primarily by increasing the maximal response attainable. Prazosin (0.1 microM) both blocked the norepinephrine threshold contraction and abolished completely the amplification. However, when the norepinephrine concentration was increased until a threshold contraction was elicited in the presence of a fixed concentration of prazosin, amplification of the angiotensin II response was restored. These results indicate that norepinephrine exerts its amplifying effect on angiotensin II via activation of alpha-1 adrenoceptors. (ABSTRACT TRUNCATED AT 250 WORDS)
Prevalence of human papillomavirus infection in women in the Autonomous Region of Inner Mongolia: A population‐based study of a Chinese ethnic minority

Human papillomavirus (HPV) is one of the most common sexually transmitted infectious pathogens. Persistent infection has been linked to cancer development, in particular to cervical cancer. This study aims to investigate the epidemiology of HPV infection in women in Inner Mongolia of China and to dissect the disparities between the Han and Mongolian ethnic populations. Cervical cell samples from 5655 women (17‐68 years old) were collected during routine gynecologic examination. HPV infection was established using the HPV GenoArray kit detecting 21 HPV genotypes. The overall HPV prevalence was 14.5%. HPV16 (5.0%), HPV58 (2.2%), and HPV52 (1.5%) are the most common genotypes. Of the 21 genotypes investigated, high‐risk HPV genotypes dominate in all age groups. HPV16 and HPV58 are the most common genotypes in patients with cervical lesions. HPV prevalence among Han women is 11.5% and the most common genotypes are HPV16 (4%) and HPV58 (2.1%). HPV prevalence is significantly higher in Mongolian women (32.6%), with the most common genotypes being HPV16 (10.7%), HPV31 (7.1%), and HPV52 (4.3%). The multiple infection rate in Mongolian participants (14.9%) is also higher than that of Han participants (4.3%). Urbanization, the number of sex partners, and PAP history appear as risk factors for HPV infection in Han, but not in Mongolian participants. HPV infection is highly prevalent in women in Inner Mongolia, China. HPV16 remains the most common genotype in this area. However, there are clear ethnical disparities in respect to the HPV epidemiology between the Han and Mongolian population.
When skin talks: whitening strategies used in higher education*

Abstract This paper aims to identify the ‘whitening’ strategies used by undergraduate students in a developing country with strong levels of ethno-racial discrimination and social mobility. We adopt a critical, constructivist theoretical perspective and a qualitative approach, in the design and analysis, for which we use three instruments: surveys, focus groups and the Q-Methodology. We find that students use several ‘whitening’ strategies (e.g. wearing expensive clothing, improving their diction and managing their bodies) in order to shield against the ethno-racial discrimination they face, and protect from the negative effects it imposes on their personal, academic and employment outcomes. Our findings also reveal that race is redefined in such a way that it involves more than just the skin colour, a process that is enabled by a relatively high degree of social mobility, experienced in the wake of a booming economy.
Positive Allosteric Modulation of the Glucagon-like Peptide-1 Receptor by Diverse Electrophiles*

Therapeutic intervention to activate the glucagon-like peptide-1 receptor (GLP-1R) enhances glucose-dependent insulin secretion and improves energy balance in patients with type 2 diabetes mellitus. Studies investigating mechanisms whereby peptide ligands activate GLP-1R have utilized mutagenesis, receptor chimeras, photo-affinity labeling, hydrogen-deuterium exchange, and crystallography of the ligand-binding ectodomain to establish receptor homology models. However, this has not enabled the design or discovery of drug-like non-peptide GLP-1R activators. Recently, studies investigating 4-(3-benzyloxyphenyl)-2-ethylsulfinyl-6-(trifluoromethyl)pyrimidine (BETP), a GLP-1R-positive allosteric modulator, determined that Cys-347 in the GLP-1R is required for positive allosteric modulator activity via covalent modification. To advance small molecule activation of the GLP-1R, we characterized the insulinotropic mechanism of BETP. In guanosine 5′-3-O-(thio)triphosphate binding and INS1 832-3 insulinoma cell cAMP assays, BETP enhanced GLP-1(9–36)-NH2-stimulated cAMP signaling. Using isolated pancreatic islets, BETP potentiated insulin secretion in a glucose-dependent manner that requires both the peptide ligand and GLP-1R. In studies of the covalent mechanism, PAGE fluorography showed labeling of GLP-1R in immunoprecipitation experiments from GLP-1R-expressing cells incubated with [3H]BETP. Furthermore, we investigated whether other reported GLP-1R activators and compounds identified from screening campaigns modulate GLP-1R by covalent modification. Similar to BETP, several molecules were found to enhance GLP-1R signaling in a Cys-347-dependent manner. These chemotypes are electrophiles that react with GSH, and LC/MS determined the cysteine adducts formed upon conjugation. Together, our results suggest covalent modification may be used to stabilize the GLP-1R in an active conformation. Moreover, the findings provide pharmacological guidance for the discovery and characterization of small molecule GLP-1R ligands as possible therapeutics.
Risk Aversion and Overbidding in First Price Sealed Bid Auctions: New Experimental Evidence

Bidding above the risk-neutral Nash equilibrium in first price sealed bid auctions has traditionally been ascribed to risk aversion. Later studies, however, offer other explanations and even argue that risk aversion plays no or a minor role. In a novel experimental design, we directly test the relationship between risk aversion and overbidding by systematically varying the distribution of risk attitudes in auction markets. We find a significant relationship between our measure of risk aversion and overbidding. (JEL D44, C91).
Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

Significance Amyloid plaques, a key feature of Alzheimer’s disease brain pathology, comprise an extracellular β-amyloid core surrounded by tissue enriched in lysosome-like organelles. As a foundation for understanding the mechanisms that drive amyloid plaque formation, we have elucidated the cellular origins and molecular composition of such organelles. The majority of the lysosomes at amyloid plaques reside within swollen neuronal axons. Interestingly, these organelles contain low levels of multiple luminal lysosomal proteases and closely resemble a lysosome subpopulation that naturally occurs in distal neuronal processes. These results suggest that extracellular β-amyloid deposits cause a local impairment in retrograde axonal transport, leading to the accumulation of lysosome precursors and a blockade in their further maturation that has implications for both β-amyloid production and clearance. Through a comprehensive analysis of organellar markers in mouse models of Alzheimer’s disease, we document a massive accumulation of lysosome-like organelles at amyloid plaques and establish that the majority of these organelles reside within swollen axons that contact the amyloid deposits. This close spatial relationship between axonal lysosome accumulation and extracellular amyloid aggregates was observed from the earliest stages of β-amyloid deposition. Notably, we discovered that lysosomes that accumulate in such axons are lacking in multiple soluble luminal proteases and thus are predicted to be unable to efficiently degrade proteinaceous cargos. Of relevance to Alzheimer’s disease, β-secretase (BACE1), the protein that initiates amyloidogenic processing of the amyloid precursor protein and which is a substrate for these proteases, builds up at these sites. Furthermore, through a comparison between the axonal lysosome accumulations at amyloid plaques and neuronal lysosomes of the wild-type brain, we identified a similar, naturally occurring population of lysosome-like organelles in neuronal processes that is also defined by its low luminal protease content. In conjunction with emerging evidence that the lysosomal maturation of endosomes and autophagosomes is coupled to their retrograde transport, our results suggest that extracellular β-amyloid deposits cause a local impairment in the retrograde axonal transport of lysosome precursors, leading to their accumulation and a blockade in their further maturation. This study both advances understanding of Alzheimer’s disease brain pathology and provides new insights into the subcellular organization of neuronal lysosomes that may have broader relevance to other neurodegenerative diseases with a lysosomal component to their pathology.