Miracle-dz/UniFAR-FTUs huggingface dataset:
Deregulation of the p57-E2F1-p53 Axis Results in Nonobstructive Hydrocephalus and Cerebellar Malformation in Mice

ABSTRACT The cyclin-dependent kinase inhibitor (CKI) p57Kip2 plays a pivotal role in cell cycle arrest during development, in particular, in the regulation of the entry of proliferating progenitors into quiescence. The gene encoding p57 undergoes genomic imprinting, and impairment of the regulation of p57 expression results in various developmental anomalies in humans and mice. We now show that p57 is expressed predominantly in the subcommissural organ and cerebellar interneurons in the mouse brain and that mice with brain-specific deletion of the p57 gene (Kip2) manifest prominent nonobstructive hydrocephalus as well as cerebellar malformation associated with the loss of Pax2-positive interneuron precursors and their descendants, including Golgi cells and γ-aminobutyric acid-containing neurons of the deep cerebellar nuclei. These abnormalities were found to be attributable to massive apoptosis of precursor cells in the developing brain. The morphological defects of the p57-deficient mice were corrected by knock-in of the gene for the related CKI p27Kip1 at the Kip2 locus. The abnormalities were also prevented by additional genetic ablation of p53 or E2F1. Our results thus implicate p57 in cell cycle arrest in the subcommissural organ and Pax2-positive interneuron precursors, with the lack of p57 resulting in induction of p53-dependent apoptosis due to hyperactivation of E2F1.
Regulation of MDM2 E3 Ligase Activity by Phosphorylation after DNA Damage

ABSTRACT MDM2 is a major regulator of p53 by acting as a ubiquitin E3 ligase. The central acidic domain and C-terminal RING domain of MDM2 are both indispensable for ubiquitination of p53. Our previous study suggested that ATM phosphorylation of MDM2 near the C terminus inhibits RING domain oligomerization, resulting in p53 stabilization after DNA damage. We present here evidence that these modifications allosterically regulate the functions of both acidic domain and RING domain of MDM2. Using chemical cross-linking, we show that the MDM2 RING domain forms oligomers including dimer and higher-order complexes in vivo. RING domain dimerization efficiency is negatively regulated by upstream sequence. ATM-mediated phosphorylation of the upstream sequence further inhibits RING dimerization. Forced oligomerization of MDM2 partially overcomes the inhibitory effect of phosphorylation and stimulates p53 ubiquitination. Furthermore, the ability of MDM2 acidic domain to bind p53 core domain and induce p53 misfolding are also suppressed by the same C-terminal ATM sites after DNA damage. These results suggest that the acidic domain and RING domain of MDM2 are both allosterically coupled to the intervening ATM sites, which enables the same modification to regulate multiple MDM2 functions critical for p53 ubiquitination.
Raft Protein Clustering Alters N-Ras Membrane Interactions and Activation Pattern

ABSTRACT The trafficking, membrane localization, and lipid raft association of Ras proteins, which are crucial oncogenic mediators, dictate their isoform-specific biological responses. Accordingly, their spatiotemporal dynamics are tightly regulated. While extensively studied for H- and K-Ras, such information on N-Ras, an etiological oncogenic factor, is limited. Here, we report a novel mechanism regulating the activation-dependent spatiotemporal organization of N-Ras, its modulation by biologically relevant stimuli, and isoform-specific effects on signaling. We combined patching/immobilization of another membrane protein with fluorescence recovery after photobleaching (patch-FRAP) and FRAP beam size analysis to investigate N-Ras membrane interactions. Clustering of raft-associated proteins, either glycosylphosphatidylinositol-anchored influenza virus hemagglutinin (HA-GPI) or fibronectin receptors, selectively enhanced the plasma membrane-cytoplasm exchange of N-Ras–GTP (preferentially associated with raft domains) in a cholesterol-dependent manner. Electron microscopy (EM) analysis showed N-Ras–GTP localization in cholesterol-sensitive clusters, from which it preferentially detached upon HA-GPI cross-linking. HA-GPI clustering enhanced the Golgi compartment (GC) accumulation and signaling of epidermal growth factor (EGF)-stimulated N-Ras–GTP. Notably, the cross-linking-mediated enhancement of N-Ras–GTP exchange and GC accumulation depended strictly on depalmitoylation. We propose that the N-Ras activation pattern (e.g., by EGF) is altered by raft protein clustering, which enhances N-Ras–GTP raft localization and depalmitoylation, entailing its exchange and GC accumulation following repalmitoylation. This mechanism demonstrates a functional signaling role for the activation-dependent differential association of Ras isoforms with raft nanodomains.
Dual Nature of Translational Control by Regulatory BC RNAs

ABSTRACT In higher eukaryotes, increasing evidence suggests, gene expression is to a large degree controlled by RNA. Regulatory RNAs have been implicated in the management of neuronal function and plasticity in mammalian brains. However, much of the molecular-mechanistic framework that enables neuronal regulatory RNAs to control gene expression remains poorly understood. Here, we establish molecular mechanisms that underlie the regulatory capacity of neuronal BC RNAs in the translational control of gene expression. We report that regulatory BC RNAs employ a two-pronged approach in translational control. One of two distinct repression mechanisms is mediated by C-loop motifs in BC RNA 3′ stem-loop domains. These C-loops bind to eIF4B and prevent the factor's interaction with 18S rRNA of the small ribosomal subunit. In the second mechanism, the central A-rich domains of BC RNAs target eIF4A, specifically inhibiting its RNA helicase activity. Thus, BC RNAs repress translation initiation in a bimodal mechanistic approach. As BC RNA functionality has evolved independently in rodent and primate lineages, our data suggest that BC RNA translational control was necessitated and implemented during mammalian phylogenetic development of complex neural systems.
Cdc7-Dbf4 Is a Gene-Specific Regulator of Meiotic Transcription in Yeast

ABSTRACT Meiosis divides the chromosome number of the cell in half by having two rounds of chromosome segregation follow a single round of chromosome duplication. The first meiotic division is unique in that homologous pairs of sister chromatids segregate to opposite poles. Recent work in budding and fission yeast has shown that the cell cycle kinase, Cdc7-Dbf4, is required for many meiosis-specific chromosomal functions necessary for proper disjunction at meiosis I. This work reveals another role for Cdc7 in meiosis as a gene-specific regulator of the global transcription factor, Ndt80, which is required for exit from pachytene and entry into the meiotic divisions in budding yeast. Cdc7-Dbf4 promotes NDT80 transcription by relieving repression mediated by a complex of Sum1, Rfm1, and a histone deacetylase, Hst1. Sum1 exhibits meiosis-specific Cdc7-dependent phosphorylation, and mass spectrometry analysis reveals a dynamic and complex pattern of phosphorylation events, including four constitutive cyclin-dependent kinase (Cdk1) sites and 11 meiosis-specific Cdc7-Dbf4-dependent sites. Analysis of various phosphorylation site mutants suggests that Cdc7 functions with both Cdk1 and the meiosis-specific kinase Ime2 to control this critical transition point during meiosis.
The National Sleep Foundation

Abstract The National Sleep Foundation (NSF) Web site is a comprehensive source of timely, authoritative information about sleep, specific sleep problems and disorders, and the issues associated with them. In Spanish and English, with resources for health consumers and health care professionals, this Web site meets a broad range of information needs.
Relationships between upper extremity performance and unified Parkinson`s disease rating scale-motor exam

Objective: Clinical measures that quantify upper extremity function are needed for the accurate evaluation of patients and to plan an intervention strategy. The purpose of this study was to examine the relationship between the Unified Parkinson’s Disease Rating Scale (UPDRS)-Motor Exam and upper extremity performance as a quantifying clinical tool of upper extremity function in persons with Parkinson’s disease. Design: Cross-sectional study. Methods: Thirty-two idiopathic Parkinson’s Disease persons participated in this study. To investigate the relationship between the UPDRS-motor exam, Box and Block test (BBT), and Action Research Arm Test (ARAT) by two physical therapists. The examination took up to 1 hour, and the participants were invited to rest between each clinical measure in order to minimize the effects of fatigue. Clinical measures were assessed while the subjects were in the “on” phase of their medication cycle, generally 1-3 hour after taking their anti-Parkinson’s medications. Results: In more affected side, the UPDRS-motor exam was significantly negative correlated with the BBT (p<0.05) but it was not significantly correlated with the ARAT. In less affected side, only positively correlation was significantly shown between BBT and ARAT (p<0.05). On the other hand, between BBT and ARAT were not significantly correlated with the UPDRS-motor exam. Conclusions: The UPDRS-motor exam is effective tool which was significantly correlated with manual dexterity in more affected upper extremity. But The UPDRS-motor exam is not effective tool in less affected upper extremity.
Genome-Wide Profiling of Liver X Receptor, Retinoid X Receptor, and Peroxisome Proliferator-Activated Receptor α in Mouse Liver Reveals Extensive Sharing of Binding Sites

ABSTRACT The liver X receptors (LXRs) are nuclear receptors that form permissive heterodimers with retinoid X receptor (RXR) and are important regulators of lipid metabolism in the liver. We have recently shown that RXR agonist-induced hypertriglyceridemia and hepatic steatosis in mice are dependent on LXRs and correlate with an LXR-dependent hepatic induction of lipogenic genes. To further investigate the roles of RXR and LXR in the regulation of hepatic gene expression, we have mapped the ligand-regulated genome-wide binding of these factors in mouse liver. We find that the RXR agonist bexarotene primarily increases the genomic binding of RXR, whereas the LXR agonist T0901317 greatly increases both LXR and RXR binding. Functional annotation of putative direct LXR target genes revealed a significant association with classical LXR-regulated pathways as well as peroxisome proliferator-activated receptor (PPAR) signaling pathways, and subsequent chromatin immunoprecipitation-sequencing (ChIP-seq) mapping of PPARα binding demonstrated binding of PPARα to 71 to 88% of the identified LXR-RXR binding sites. The combination of sequence analysis of shared binding regions and sequential ChIP on selected sites indicate that LXR-RXR and PPARα-RXR bind to degenerate response elements in a mutually exclusive manner. Together, our findings suggest extensive and unexpected cross talk between hepatic LXR and PPARα at the level of binding to shared genomic sites.
Putative Brain Networks Underlying Repetitive Negative Thinking and Comorbid Internalizing Problems in Autism

Many high-functioning individuals with autism spectrum disorder (ASD) also experience depression and anxiety, yet little is known about mechanisms underlying this comorbidity. Repetitive negative thinking (RNT) about self-referential information is a transdiagnostic cognitive vulnerability factor that may account for the relationship between these two classes of symptoms. We propose a model where negative self-referential processing and cognitive inflexibility interact to increase risk for RNT, leading to internalizing problems in ASD. Examination of interactions within and between two well-characterized large-scale brain networks, the default mode network and the salience network, may provide insights into neurobiological mechanisms underlying RNT in ASD. We summarize previous literature supporting this model, emphasizing moving toward understanding RNT as a factor accounting for the high rates of internalizing problems in ASD. Future research avenues include understanding heterogeneity in clinical presentation and treating cognitive flexibility and RNT to reduce comorbid internalizing problems in ASD.
Viral Factors Reveal a Role for REF/Aly in Nuclear RNA Stability

ABSTRACT TREX is a conserved multiprotein complex that is necessary for efficient mRNA export to the cytoplasm. In Saccharomyces cerevisiae, the TREX complex is additionally implicated in RNA quality control pathways, but it is unclear whether this function is conserved in mammalian cells. The Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57 protein binds and recruits the TREX component REF/Aly to viral mRNAs. Here, we demonstrate that REF/Aly is recruited to the KSHV noncoding polyadenylated nuclear (PAN) RNA by ORF57. This recruitment correlates with ORF57-mediated stabilization of PAN RNA, suggesting that REF/Aly promotes nuclear RNA stability. Further supporting this idea, tethering REF/Aly to PAN RNA is sufficient to increase the nuclear abundance and half-life of PAN RNA but is not sufficient to promote its export. Interestingly, REF/Aly appears to protect the poly(A) tail from deadenylation, and REF/Aly-stabilized transcripts are further adenylated over time, consistent with previous reports linking poly(A) tail length with nuclear RNA surveillance. These studies show that REF/Aly can stabilize nuclear RNAs independently of their export and support a broader conservation of RNA quality control mechanisms from yeast to humans.
Analysis of Oral Reactions to Dilantin-Sodium

The more widespread use of dilantin-sodium in the treatment of convulsive disorders has stimulated a demand for dental consultations to interpret the significance of the oral reactions encountered. That dilantin often produces changes in the gingival tissues is unchallenged, but no uniformity of opinion exists concerning their incidence, categories, or the features that distinguish them from other abnormalities of the gingivae. This report, based on a two year study of 62 patients in the Neurologic Clinic of the Mount Sinai Hospital, and on an analysis of the literature, is intended to assist the dental clinician by clarifying these points. A working classification of the lesions produced by dilantin is offered, and the essentials of differential diagnosis, the role of aggravating factors and the indicated scope of treatment are discussed. When, in 1938, Merritt and Putnam (1) introduced dilantin-sodium for the treatment of epilepsy, certain toxic reactions of the drug were already recognized, which resembled those following the administration of other barbiturates. Kimball and Horan (2) divided these manifestations into (a) acute toxic reactions, notably cutaneous rashes and evidences of damage to the nervous system, and (b) late reactions due to chronic irritation, of which the most prominent were gingival hypertrophy, and recurrent gastritis. The incidence of gingival changes as reported by several investigators shows a striking disparity (Table I), readily explained by two persisting variables. Statistics were compiled largely by internists rather than stomatologists, and therefore finely shaded differences in the gingival picture may easily have been overlooked. Secondly, observations in no instance were based on patients selected according to the period of time covered by the administration of dilantin. Yet in our studies, the percentage of gingival alterations noted, in fact, the entire clinical picture, often changed after prolonged dosage. Many patients were observed who showed little alteration after one year, but developed marked hypertrophy during the second year of treatment. Carrying this point to a legitimate conclusion, inasmuch as the maximum period that any patient has received dilantin does not yet exceed four years, it is probable that changes in greater degree will be noted in the future.
SIGNIFICANCE OF BACTEREMIA CAUSED BY STAPHYLOCOCCUS AUREUS: A STUDY OF ONE HUNDRED AND TWENTY-TWO CASES AND A REVIEW OF THE LITERATURE CONCERNED WITH EXPERIMENTAL INFECTION IN ANIMALS

Within recent years there has been an increasing interest in the various aspects of infections caused in both man and animals by Staphylococcus aureus. In order to gather more information concerning the factors that influence the course of these infections in man, we have studied a group of 122 cases of bacteremia in which the causative agent was Staph. aureus. We were especially interested in analyzing these cases in the light of experimental infections as they have been produced in animals by numerous investigators. ANALYSIS OF CASES The 122 cases were observed at the Boston City Hospital over a seven year period. In all cases, the patients had demonstrable bacteremia on one or more occasions and the clinical course was entirely consistent with a severe infection. In only 22 cases did the patients recover, a fatality rate of 81.97 per cent. Seasonal and Sex Incidence. —There was no peak of
Radio wave penetration into urban buildings in small cells and microcells

We performed 950 and 1800 MHz CW-measurements of radio wave propagation into various urban buildings in small-cell and microcell propagation scenarios in Vienna. We introduced a new empirical building penetration model that accounted for the power outdoors in a more detailed way than simpler previous ones. In both urban cell types, radio coverage of buildings can successfully be estimated from (i) measured or modelled signal strength on street level and from (ii) wall attenuation parameters. In comparison to small cells, street canyon microcells exhibited, due to predominantly grazing incidence, much higher penetration loss values. <<ETX>>
Comparison of Femoral Anteversion Angle and Determination of Reliability Measured at Three Different Anatomical References of the Tibial Crest During the Trochanteric Prominence Angle Test

The trochanteric prominence angle test (TPAT) has been used to measure the femoral anteversion angle between the tibial crest and the vertical line. However, the exact anatomical reference of the tibial crest has not yet been identified in the literature. Thus, the purposes of this research were twofold: first, to compare the femoral anteversion angle measured at three different anatomical references of the tibial crest (the proximal tibial crest, the proximal third of tibial crest, and the proximal half of tibial crest) and, second, to determine inter-and intra-rater reliabilities of the femoral anteversion angle measured at these three different anatomical references of the tibial crest during the TPAT. We recruited 14 healthy subjects, and a total of 28 legs were examined. The TPAT was measured using a digital inclinometer. A 1-way repeated-measure analysis of variance was used to compare the femoral anteversion angle measured at three different anatomical references of the tibial crest, and intraclass correlation coefficients (ICCs) were calculated to determine reliability. The femoral anteversion angle measured at the proximal tibial crest was significantly higher than that at the proximal third of the tibial crest and the proximal half of the tibial crest. The inter-and intra-rater reliabilities of femoral anteversion angle were measured at three anatomic references of the tibial crest were all found to be high during the TPAT (ICC=.9 0~.98). In conclusion, clinicians should recognize that the different degrees of the femoral anteversion angle could be measured when different anatomical references of the tibial crest were used, and that reliabilities were high when an exact anatomical reference of the tibial crest was used during the TPAT.
Informal communications networking among health professionals: a study of gp-uk

The use of electronic mail (email) has increased greatly over the last few years, not only in the wider world but also within the medical community, particularly in the general practitioner (GP) sector. Email discussion lists have proliferated, and this study looks at one month’s postings from such a list (gp-uk) through author and content analyses, and assesses its value as considered by members of the discussion list. A general overview shows that, although classified as an academic list, the use is more of a ‘buddy’ support network given over to general chat and humour, as well as providing almost instant worldwide opinion and information on practice. Given the professional background of the membership, a surprising finding is the fact that clinical discussion does not figure as the highest valued aspect of the discussion list: that position is taken by its humorous aspects. The overwhelming benefit offered through the use of gp-uk is the access to like-minded professionals worldwide who have taken to the advantages of computer networking technology and computer-mediated communication (CMC).
Alternative Splicing Controls the Mechanisms of FAK Autophosphorylation

ABSTRACT Focal adhesion kinase (FAK) is activated following integrin engagement or stimulation of transmembrane receptors. Autophosphorylation of FAK on Tyr-397 is a critical event, allowing binding of Src family kinases and activation of signal transduction pathways. Tissue-specific alternative splicing generates several isoforms of FAK with different autophosphorylation rates. Despite its importance, the mechanisms of FAK autophosphorylation and the basis for differences between isoforms are not known. We addressed these questions using isoforms of FAK expressed in brain. Autophosphorylation of FAK+, which is identical to that of “standard” FAK, was intermolecular in transfected cells, although it did not involve the formation of stable multimeric complexes. Coumermycin-induced dimerization of gyrase B-FAK+ chimeras triggered autophosphorylation of Tyr-397. This was independent of cell adhesion but required the C terminus of the protein. In contrast, the elevated autophosphorylation of FAK+6,7, the major neuronal splice isoform, was not accounted for by transphosphorylation. Specifically designed immune precipitate kinase assays confirmed that autophosphorylation of FAK+ was intermolecular, whereas autophosphorylation of FAK+6,7 or FAK+7 was predominantly intramolecular and insensitive to the inhibitory effects of the N-terminal domain. Our results clarify the mechanisms of FAK activation and show how alternative splicing can dramatically alter the mechanism of autophosphorylation of a protein kinase.
Mitotic Cyclins Regulate Telomeric Recombination in Telomerase-Deficient Yeast Cells

ABSTRACT Telomerase-deficient mutants of Saccharomyces cerevisiae can survive death by senescence by using one of two homologous recombination pathways. The Rad51 pathway amplifies the subtelomeric Y′ sequences, while the Rad50 pathway amplifies the telomeric TG1-3 repeats. Here we show that telomerase-negative cells require Clb2 (the major B-type cyclin in this organism), in association with Cdc28 (Cdk1), to generate postsenescence survivors at a normal rate. The Rad50 pathway was more sensitive to the absence of Clb2 than the Rad51 pathway. We also report that telomerase RAD50 RAD51 triple mutants still generated postsenescence survivors. This novel Rad50- and Rad51-independent pathway of telomeric recombination also appeared to be controlled by Clb2. In telomerase-positive cells, a synthetic growth defect between mutations in CLB2 and RAD50 or in its partners in the conserved MRX complex, MRE11 and XRS2, was observed. This genetic interaction was independent of Mre11 nuclease activity but was dependent on a DNA repair function. The present data reveal an unexpected role of Cdc28/Clb2 in telomeric recombination during telomerase-independent maintenance of telomeres. They also uncover a functional interaction between Cdc28/Clb2 and MRX during the control of the mitotic cell cycle.