Miracle-dz/UniFAR-FTUs huggingface dataset:
Longitudinal Recordings Reveal Transient Increase of Alpha/Low-Beta Power in the Subthalamic Nucleus Associated With the Onset of Parkinsonian Rest Tremor

Functional magnetic resonance imaging studies suggest that different subcortico-cortical circuits control different aspects of Parkinsonian rest tremor. The basal ganglia were proposed to drive tremor onset, and the cerebellum was suggested to be responsible for tremor maintenance (“dimmer-switch” hypothesis). Although several electrophysiological correlates of tremor have been described, it is currently unclear whether any of these is specific to tremor onset or maintenance. In this study, we present data from a single patient measured repeatedly within 2 years after implantation of a deep brain stimulation (DBS) system capable of recording brain activity from the target. Local field potentials (LFPs) from the subthalamic nucleus and the scalp electroencephalogram were recorded 1 week, 3 months, 6 months, 1 year, and 2 years after surgery. Importantly, the patient suffered from severe rest tremor of the lower limbs, which could be interrupted voluntarily by repositioning the feet. This provided the unique opportunity to record many tremor onsets in succession. We found that tremor onset and tremor maintenance were characterized by distinct modulations of subthalamic oscillations. Alpha/low-beta power increased transiently immediately after tremor onset. In contrast, beta power was continuously suppressed during tremor maintenance. Tremor maintenance was additionally associated with subthalamic and cortical power increases around individual tremor frequency. To our knowledge, this is the first evidence of distinct subthalamic LFP modulations in tremor onset and tremor maintenance. Our observations suggest the existence of an acceleration signal for Parkinsonian rest tremor in the basal ganglia, in line with the “dimmer-switch” hypothesis.
Computational Molecular Phenotypic Analysis of PTPN22 (W620R), IL6R (D358A), and TYK2 (P1104A) Gene Mutations of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disorder of bone joints caused by the complex interplay between several factors like body physiology, the environment with genetic background. The recent meta-analysis of GWAS has expanded the total number of RA-associated loci to more than 100, out of which approximately ∼97% (98 variants) loci are located in non-coding regions, and the other ∼3% (3 variants) are in three different non-HLA genes, i.e., TYK2 (Prp1104Ala), IL6R (Asp358Ala), and PTPN22 (Trp620Arg). However, whether these variants prompt changes in the protein phenotype with regards to its stability, structure, and interaction with other molecules, remains unknown. Thus, we selected the three clinically pathogenic variants described above, as positive controls and applied diverse computational methods to scrutinize if those mutations cause changes in the protein phenotype. Both wild type and mutant protein structures of PTPN22 (W620R), IL6R (D358A), and TYK2 (P1104A) were modeled and studied for structural deviations. Furthermore, we have also studied the secondary structure characteristics, solvent accessibility and stability, and the molecular interaction deformities caused by the amino acid substitutions. We observed that simple nucleotide predictions of SIFT, PolyPhen, CADD and FATHMM yields mixed findings in screening the RA-missense variants which showed a ≥P-value threshold of 5 × 10−8 in genome wide association studies. However, structure-based analysis confirms that mutant structures shows subtle but significant changes at their core regions, but their functional domains seems to lose wild type like functional interaction. Our findings suggest that the multidirectional computational analysis of clinically potential RA-mutations could act as a primary screening step before undertaking functional biology assays.
Using mixed methods research in medical education: basic guidelines for researchers

Context Mixed methods research involves the collection, analysis and integration of both qualitative and quantitative data in a single study. The benefits of a mixed methods approach are particularly evident when studying new questions or complex initiatives and interactions, which is often the case in medical education research. Basic guidelines for when to use mixed methods research and how to design a mixed methods study in medical education research are not readily available.
An Intein-based Strategy for the Production of Tag-free Huntingtin Exon 1 Proteins Enables New Insights into the Polyglutamine Dependence of Httex1 Aggregation and Fibril Formation*

The first exon of the Huntingtin protein (Httex1) is one of the most actively studied Htt fragments because its overexpression in R6/2 transgenic mice has been shown to recapitulate several key features of Huntington disease. However, the majority of biophysical studies of Httex1 are based on assessing the structure and aggregation of fusion constructs where Httex1 is fused to large proteins, such as glutathione S-transferase, maltose-binding protein, or thioredoxin, or released in solution upon in situ cleavage of these proteins. Herein, we report an intein-based strategy that allows, for the first time, the rapid and efficient production of native tag-free Httex1 with polyQ repeats ranging from 7Q to 49Q. Aggregation studies on these proteins enabled us to identify interesting polyQ-length-dependent effects on Httex1 oligomer and fibril formation that were previously not observed using Httex1 fusion proteins or Httex1 proteins produced by in situ cleavage of fusion proteins. Our studies revealed the inability of Httex1–7Q/15Q to undergo amyloid fibril formation and an inverse correlation between fibril length and polyQ repeat length, suggesting possible polyQ length-dependent differences in the structural properties of the Httex1 aggregates. Altogether, our findings underscore the importance of working with tag-free Httex1 proteins and indicate that model systems based on non-native Httex1 sequences may not accurately reproduce the effect of polyQ repeat length and solution conditions on Httex1 aggregation kinetics and structural properties.
An enhanced anonymous and unlinkable user authentication and key agreement protocol for TMIS by utilization of ECC

The telecare medicine information systems (TMISs) not only help patients to receive incessant health care services but also assist the medical staffs to access patients' electronic health records anytime and from anywhere via Internet. Since the online communications are exposed to numerous security threats, the mutual authentication and key agreement between patients and the medical servers are of prime significance. During the recent years, various user authentication schemes have been suggested for the TMISs. Nonetheless, most of them are susceptible to some known attacks or have high computational cost. Newly, an effective remote user authentication and session key agreement protocol has been introduced by Ravanbakhsh and Nazari for health care systems. Besides the nice contributions of their work, we found that it has two security weaknesses, namely, known session‐specific temporary information attack and lack of perfect forward secrecy. As a result, to overcome these deficiencies, this paper suggests a novel anonymous and unlinkable user authentication and key agreement scheme for TMISs using the elliptic curve cryptosystem (ECC). We have evaluated the security of the proposed scheme by applying the automated validation of internet security protocols and applications (AVISPA) tool with the intention of indicating that our scheme can satisfy the vital security features. In addition, we have compared the proposed protocol with related schemes to show that it has a proper level of performance. The obtained results demonstrate that the new scheme is more preferable considering both efficiency and security criteria.
Directly Activating the Integrin αIIbβ3 Initiates Outside-In Signaling by Causing αIIbβ3 Clustering*

αIIbβ3 activation in platelets is followed by activation of the tyrosine kinase c-Src associated with the carboxyl terminus of the β3 cytosolic tail. Exogenous peptides designed to interact with the αIIb transmembrane (TM) domain activate single αIIbβ3 molecules in platelets by binding to the αIIb TM domain and causing separation of the αIIbβ3 TM domain heterodimer. Here we asked whether directly activating single αIIbβ3 molecules in platelets using the designed peptide anti-αIIb TM also initiates αIIbβ3-mediated outside-in signaling by causing activation of β3-associated c-Src. Anti-αIIb TM caused activation of β3-associated c-Src and the kinase Syk, but not the kinase FAK, under conditions that precluded extracellular ligand binding to αIIbβ3. c-Src and Syk are activated by trans-autophosphorylation, suggesting that activation of individual αIIbβ3 molecules can initiate αIIbβ3 clustering in the absence of ligand binding. Consistent with this possibility, incubating platelets with anti-αIIb TM resulted in the redistribution of αIIbβ3 from a homogenous ring located at the periphery of discoid platelets into nodular densities consistent with clustered αIIbβ3. Thus, these studies indicate that not only is resting αIIbβ3 poised to undergo a conformational change that exposes its ligand-binding site, but it is poised to rapidly assemble into intracellular signal-generating complexes as well.
The Effect of Parachlorophenylalanine and Active Immunization Against Vasoactive Intestinal Peptide on Reproductive Activities of Broiler Breeder Hens Photostimulated with Green Light1

ABSTRACT Photostimulation of retinal photoreceptors appears to inhibit reproductive activity in birds. In the present study, the involvement of serotonin and vasoactive intestinal peptide was investigated in relation to reproductive failure associated with retinal photostimulation. Hens at 23 wk of age were divided into six rooms equipped with individual cages. At 24 wk of age, three rooms were photostimulated (14L:10D) with white light (control). Three rooms had two parallel lighting systems, red (660 nm) and green (560 nm), which were both on during 6 h of the 14-h light period. Upon photostimulation, the red light was turned off after 6 h, and the green light was left on for a total of 14 h (Green). Five hens from each room served as controls, five hens were immunized against vasoactive intestinal peptide, and five hens received parachlorophenylalanine, an inhibitor of serotonin biosynthesis. Parachlorophenylalanine treatment increased reproductive performance and mRNA expression of GnRH-I, LH-beta and FSH-beta (P < 0.05) in the Green group to levels which did not differ from those of the White (control) group. Immunization against vasoactive intestinal peptide reduced plasma concentration and pituitary mRNA expression of prolactin but did not affect expression of gonadal axis genes. Collectively, the results suggest that retinal photostimulation inhibits the reproductive axis through serotonin and not through vasoactive intestinal peptide.
Chronic Hypoxia Differentially Up-Regulates Protein Kinase C-Mediated Ovine Uterine Arterial Contraction via Actin Polymerization Signaling in Pregnancy1

ABSTRACT Chronic hypoxia (CH) during pregnancy is associated with increased uterine vascular tone. The present study tested the hypothesis that CH up-regulates protein kinase C (PKC)-mediated actin polymerization, resulting in enhanced uterine vascular contraction in pregnancy. Uterine arteries were isolated from nonpregnant (NPUA) and near-term (∼140 days of gestation) pregnant (PUA) sheep that had been maintained at sea level (∼300 m) or exposed to high altitude (3801 m) hypoxia for 110 days. In normoxic animals, the induced contractions by the PKC activator phorbol 12,13-dibutyrate (PDBu) were greater in NPUA than in PUA, which was abrogated by an actin polymerization inhibitor cytochalasin B (Cyto B). In hypoxic animals, PDBu-induced contractions were significantly increased in PUA but not in NPUA, which was inhibited by Cyto B. In contrast, neither pregnancy nor hypoxia affected Cyto B-mediated inhibition of norepinephrine (NE)-induced contractions. Prolonged ex vivo treatment of NPUA with 17beta-estradiol and progesterone significantly attenuated PDBu-induced actin polymerization and contractions, and the hormonal treatment did not alter the inhibitory effect of Cyto B on PDBu- or NE-induced contractions in either normoxic or hypoxic animals. 2-(2-Amino-3-methoxyphenyl)-4H-1-benzopyran-4-one potentiated PDBu-mediated actin polymerization and enhanced PDBu-induced contractions of PUA in normoxic but not hypoxic animals, which was abrogated by Cyto B. The results suggest that chronic hypoxia during pregnancy causes attenuation of steroid hormone-mediated ERK1/2 signaling and results in increased actin polymerization and uterine vascular tone, linking gestational hypoxia to aberrant uteroplacental circulation.
Prevalence of Bovine Trypanosomosis and its Vector Density in Daramallo District, South Western Ethiopia -

The study was carried out from September 2010 to March 2011 in Daramallo district of Gamo Gofa Zone, South Western Ethiopia to assess the prevalence of trypanosomosis and apparent density of tsetse fly in the study area. The methods employed during the study were buffy coat technique for parasitological study and deploying trap for the collection of tsetse flies. A total of 248 cattle were randomly selected from the study population and examined for parasitological study. An overall prevalence of trypanosomosis in the study area was 23.0%. Out of positive cases, Trypanosome congolense (93.0%) was the dominant trypanosome species followed by Trypanosome vivax (5.3%) and mixed (Trypanosome congolense and Trypanosome vivax) (1.8%). The prevalence difference did not show statistical significance (P>0.05) between age groups, and similarly, the same scenario was observed between sex groups. The prevalence of trypanosomosis on the bases of body condition was 58.4% for poor, and 10.5% for medium. Agonizingly, no positive case was recorded among animals of good body condition. There was statistically significant difference (P<0.05) in infection rate among animals of different body condition. Mean packed cell volume (PCV) of parasitaemic cattle (20.94%) was significantly (P< 0.05) lower than that of aparasitaemic cattle (23.59%). About 41 traps were deployed for 48 hours for collection of tsetse fly. A total of 1607 flies were collected from a study area, of which higher density for tsetse fly 1570 (19.14 flies per trap per day) followed by 27 Stomoxy and 12 Tabanus. Generally, this survey showed that trypanosomosis is still a core problem for livestock production of the study area. Therefore, more attention should be given to the control of both the disease and its vectors.
Regulated Wnt/Beta-Catenin Signaling Sustains Adult Spermatogenesis in Mice1

ABSTRACT The importance of Wnt signaling for postnatal testis function has been previously studied in several mouse models, with chronic pathway disruption addressing its function in Sertoli cells and in postmeiotic germ cells. While chronic beta-catenin deletion in Sertoli cells does not profoundly affect testis development, new data indicate that Wnt signaling is required at multiple stages of spermatogenesis. We used two mouse models that allow acute disruption of Wnt signaling to explore the importance of regulated Wnt pathway activity for normal germ cell development in adult male mice. Short-term induction of mutations in Adenomatous polyposis coli (Apc) and beta-catenin (Ctnnbl), which increase and decrease Wnt signaling levels, were generated in AhCre Apcfl/fl and AhCre Ctnnb1fl/fl mice, respectively. Each exhibited a distinct phenotype of disrupted spermatogenesis that was evident within 24 h and persisted for up to 4 days. Outcomes included germ cell apoptosis and rapid loss and altered blood-testis barrier protein distribution and morphology. The functional significance of nuclear localized beta-catenin protein in spermatocytes and round spermatids, indicative of active Wnt signaling, was highlighted by the profound loss of postmitotic germ cells in both models. Developmentally regulated Wnt signaling mediators identified through transcriptional profiling of wild-type and AhCre Ctnnb1fl/fl mouse testes identified Wnt receptors (e.g., Fzd4) and ligands (e.g., Wnt3, Wnt3a, Wnt5b, Wnt7a, and Wnt8b). This demonstration that Wnt signaling control is essential for adult spermatogenesis supports the growing understanding that its disruption may underpin certain cases of male infertility.
Maternal Undernutrition in Cows Impairs Ovarian and Cardiovascular Systems in Their Offspring1

ABSTRACT Severe prenatal undernutrition is usually associated with low birth weights in offspring and disorders including hypertension, obesity, and diabetes. Whether alterations in maternal nutrition insufficient to impair birth weight or prenatal growth impact the cardiovascular, stress, or metabolic systems is unknown. In addition, little is known about the effects of maternal dietary restriction on development of the reproductive system in mammals. Here, we use the bovine model, which has a gestational length and birth rate similar to humans, to show that offspring from nutritionally restricted dams (during the first trimester) were born with identical birth weights and had similar postnatal growth rates (to 95 wk of age), puberty, glucose metabolism, and responses to stress compared to offspring from control mothers. However, an increase in maternal testosterone concentrations was detected during dietary restriction, and these dams had offspring with a diminished ovarian reserve (as assessed by a reduction in antral follicle count, reduced concentrations of anti-Müllerian hormone, and increased follicle-stimulating hormone concentrations), enlarged aorta, and increased arterial blood pressure compared with controls. Our study links transient maternal undernutrition and enhanced maternal androgen production with a diminished ovarian reserve as well as potential suboptimal fertility, enlarged aortic trunk size, and enhanced blood pressure independent of alterations in birth weight, postnatal growth, or stress response and glucose tolerance. The implications are that relatively mild transient reductions in maternal nutrition during the first trimester of pregnancy (even those that do not affect gross development) should be avoided to ensure healthy development of reproductive and cardiovascular systems in offspring.
l-Carnitine Supplementation During Vitrification of Mouse Oocytes at the Germinal Vesicle Stage Improves Preimplantation Development Following Maturation and Fertilization In Vitro

ABSTRACT Oocyte cryopreservation is important for assisted reproductive technologies (ART). Although cryopreservation of metaphase II (MII) oocytes has been successfully used, MII oocytes are vulnerable to the damage inflicted by the freezing procedure. Cryopreservation of germinal vesicle stage oocytes (GV-oocytes) is an alternative choice; however, blastocyst development from GV-oocytes is limited largely due to the need for in vitro maturation (IVM). Herein, we evaluated the effects of l-carnitine (LC) supplementation during vitrification and thawing of mouse GV-oocytes, IVM, and embryo culture on preimplantation development after in vitro fertilization (IVF). We first compared the rate of embryonic development from the oocytes that had been collected at the GV stage from three mouse strains, (B6.DBA)F1, (B6.C3H)F1, and B6, and processed for IVM and IVF, as well as that from the oocytes matured in vivo, i.e. ovulated (IVO). Our results demonstrated that the rate of blastocyst development was the highest in the (B6.DBA)F1 strain and the lowest in the B6 strain. We then supplemented the IVM medium with 0.6 mg/ml LC. The rate of blastocyst development improved in the B6 but not in the (B6.DBA)F1 strain. Vitrification of GV-oocytes in the basic medium alone reduced the rate of blastocyst development in both of those mouse strains. LC supplementation to the IVM medium alone did not change the percentage of blastocyst development. However, LC supplementation to both vitrification and IVM media significantly improved blastocyst development to the levels comparable with those obtained from vitrified/thawed IVO oocytes in both of the (B6.DBA)F1 and B6 strains. We conclude that LC supplementation during vitrification is particularly efficient in improving the preimplantation development from the GV-oocytes that otherwise have lower developmental competence in culture.
Enhanced Uterine Artery Stiffness in Aged Pregnant Relaxin Mutant Mice Is Reversed with Exogenous Relaxin Treatment1

ABSTRACT Pregnancy is associated with a progressive remodeling of the uterine artery. This adaptation is influenced by local and systemic pregnancy-dependent factors. We recently demonstrated that the peptide hormone relaxin mediates uterine artery remodeling in late pregnant rats. The objective of this study in relaxin gene knockout (Rln−/−) mice was to test the hypothesis that relaxin deficiency throughout pregnancy disrupts uterine artery remodeling, an effect that is exacerbated by aging and reversed with relaxin treatment. Passive mechanical wall properties and extracellular matrix components were measured using pressure myography, quantitative PCR, and zymography in uterine arteries from pregnant wild-type (Rln+/+) and Rln−/− mice aged 5 and 8 mo on Days 12.5 and 17.5 pregnancy. In a second study, 8-mo-old Rln−/− mice received either placebo or human recombinant relaxin subcutaneously for 5 days from Day 12.5 pregnancy. Relaxin deficiency in pregnancy did not alter uterine artery remodeling in young mice. However, remodeling was impaired in older pregnant Rln−/− mice, resulting in significantly stiffer uterine arteries. Uterine arteries of aged Rln−/− pregnant mice had increased expression of elastin, whereas several matrix metalloproteinases and cell adhesion molecules were decreased relative to Rln+/+ mice. Fetal weight was also significantly reduced in Rln−/− mice in late pregnancy in both young and old dams, whereas placental weight was unchanged. Arterial stiffness and reduced fetal weight were reversed after relaxin treatment. In conclusion, relaxin deficiency compromises uterine artery remodeling in older pregnant females, increasing the risk of pregnancy complications such as hypertension and intrauterine growth restriction.
Oocyte-Secreted Growth Differentiation Factor 9 Inhibits BCL-2-Interacting Mediator of Cell Death-Extra Long Expression in Porcine Cumulus Cell1

ABSTRACT Oocyte-secreted factors (OSFs) maintain the low incidence of cumulus cell apoptosis. In this report, we described that the presence of oocytes suppressed the expression of proapoptotic protein BCL-2-interacting mediator of cell death-extra long (BIMEL) in porcine cumulus cells. Atretic (terminal deoxynu cleotidyl transferase dUTP nick end labeling-positive) cumulus cells strongly expressed BIMEL protein. The healthy cumulus- oocyte complex exhibited a low BIMEL expression in cumulus cell while the removal of oocyte led to an about 2.5-fold (P < 0.5) increased expression in oocytectomized complex (OOX). Coculturing OOXs with denuded oocytes decreased BIMEL expression to the normal level. The similar expression pattern could also be achieved in OOXs treated with exogenous recombinant mouse growth differentiation factor 9 (GDF9), a well-characterized OSF. This inhibitory action of GDF9 was prevented by the addition of a phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. Luciferase assay further demonstrated that BIM gene expression was forkhead box O3a (FOXO3a)-dependent because mutation of FOXO3a-binding site on the BIM promoter inhibited luciferase activities. Moreover, the activity of BIM promoter encompassing the FOXO3a-binding site could be regulated by GDF9. Additionally, we found that GDF9 elevated the levels of phosphorylated AKT and FOXO3a, and this process was independent of the SMAD signal pathway. Taken together, we concluded that OSFs, particularly GDF9, maintained the low level of BIMEL expression in cumulus cell through activation of the PI3K/FOXO3a pathway.