Miracle-dz/UniFAR-FTUs huggingface dataset:
Long non-coding RNA ChRO1 facilitates ATRX/DAXX-dependent H3.3 deposition for transcription-associated heterochromatin reorganization

Abstract Constitutive heterochromatin undergoes a dynamic clustering and spatial reorganization during myogenic differentiation. However the detailed mechanisms and its role in cell differentiation remain largely elusive. Here, we report the identification of a muscle-specific long non-coding RNA, ChRO1, involved in constitutive heterochromatin reorganization. ChRO1 is induced during terminal differentiation of myoblasts, and is specifically localized to the chromocenters in myotubes. ChRO1 is required for efficient cell differentiation, with global impacts on gene expression. It influences DNA methylation and chromatin compaction at peri/centromeric regions. Inhibition of ChRO1 leads to defects in the spatial fusion of chromocenters, and mislocalization of H4K20 trimethylation, Suv420H2, HP1, MeCP2 and cohesin. In particular, ChRO1 specifically associates with ATRX/DAXX/H3.3 complex at chromocenters to promote H3.3 incorporation and transcriptional induction of satellite repeats, which is essential for chromocenter clustering. Thus, our results unveil a mechanism involving a lncRNA that plays a role in large-scale heterochromatin reorganization and cell differentiation.
Origin of first cells at terrestrial, anoxic geothermal fields

All cells contain much more potassium, phosphate, and transition metals than modern (or reconstructed primeval) oceans, lakes, or rivers. Cells maintain ion gradients by using sophisticated, energy-dependent membrane enzymes (membrane pumps) that are embedded in elaborate ion-tight membranes. The first cells could possess neither ion-tight membranes nor membrane pumps, so the concentrations of small inorganic molecules and ions within protocells and in their environment would equilibrate. Hence, the ion composition of modern cells might reflect the inorganic ion composition of the habitats of protocells. We attempted to reconstruct the “hatcheries” of the first cells by combining geochemical analysis with phylogenomic scrutiny of the inorganic ion requirements of universal components of modern cells. These ubiquitous, and by inference primordial, proteins and functional systems show affinity to and functional requirement for K+, Zn2+, Mn2+, and phosphate. Thus, protocells must have evolved in habitats with a high K+/Na+ ratio and relatively high concentrations of Zn, Mn, and phosphorous compounds. Geochemical reconstruction shows that the ionic composition conducive to the origin of cells could not have existed in marine settings but is compatible with emissions of vapor-dominated zones of inland geothermal systems. Under the anoxic, CO2-dominated primordial atmosphere, the chemistry of basins at geothermal fields would resemble the internal milieu of modern cells. The precellular stages of evolution might have transpired in shallow ponds of condensed and cooled geothermal vapor that were lined with porous silicate minerals mixed with metal sulfides and enriched in K+, Zn2+, and phosphorous compounds.
Predictive value of primary care made clinical diagnosis of chronic obstructive pulmonary disease (COPD) with secondary care specialist diagnosis based on spirometry performed in a lung function laboratory

Aim To define the predictive value of clinical diagnosis of chronic obstructive pulmonary disease (COPD) or suspected COPD in primary care patients with spirometric criteria for diagnosis. Background The diagnosis of COPD is usually made clinically but often not confirmed by diagnostic testing. Recent initiatives have called for universal spirometry testing in primary care to diagnose and monitor such patients the implications of this policy on diagnostic accuracy are not as yet known. Methods Retrospective comparative analysis of 677 consecutive primary care referrals to a district general hospital lung function laboratory for spirometry, March 1998 to December 2006. Findings Five hundred and three of 677 patients referred for open access spirometry had a primary care clinical diagnosis or suspected diagnosis of COPD. When compared with NICE spirometric criteria for diagnosis of COPD, 141 patients (28%) had normal spirometry, 46 (9%) had reversible airflow obstruction and 14 (3%) a restrictive pattern of spirometry. The positive predictive value of a primary care clinical diagnosis of COPD was 0.62 for patients referred for assessment of severity and 0.56 for those referred for diagnostic testing. Clinical suspicion of COPD in this sample was not confirmed by spirometry in a high proportion of referred patients. The introduction of the widespread use of spirometry for confirmation of primary care clinician made COPD diagnosis have important implications for both individual patients and primary care service planning.
Population pharmacokinetics of clindamycin orally and intravenously administered in patients with osteomyelitis.

AIMS This study was performed to describe clindamycin, administered either orally or intravenously, concentration-time courses to patients with osteomyelitis, to study the effects of different covariates on clindamycin pharmacokinetics and to simulate an optimized administration scheme. METHODS Clindamycin concentrations were measured in 50 patients. A total of 122 plasma concentrations were available (58 from oral administration and 64 from i.v. infusion). A population pharmacokinetic model was developed with MONOLIX 4 software. RESULTS A one compartment model adequately described the data. Clindamycin clearance increased significantly with body weight (BW). The typical population estimates (interindividual variability) for clearance, volume of distribution and absorption rate constant were 16.2 l h(-1) (0.39), 70.2 l and 0.92 h(-1) , respectively. The bioavailability of the oral form was estimated to be 87.6%. According to BW, theoretical doses needed to reach a C(min) of 2 mg l(-1) were then calculated. CONCLUSIONS The current recommendation of 600 mg three times daily seems to be effective up to 75 kg but the dose should be raised to 900 mg three times daily thereafter. These assumptions should be prospectively confirmed.
High-throughput VDJ sequencing for quantification of minimal residual disease in chronic lymphocytic leukemia and immune reconstitution assessment

The primary cause of poor outcome following allogeneic hematopoietic cell transplantation (HCT) for chronic lymphocytic leukemia (CLL) is disease recurrence. Detection of increasing minimal residual disease (MRD) following HCT may permit early intervention to prevent clinical relapse; however, MRD quantification remains an uncommon diagnostic test because of logistical and financial barriers to widespread use. Here we describe a method for quantifying CLL MRD using widely available consensus primers for amplification of all Ig heavy chain (IGH) genes in a mixture of peripheral blood mononuclear cells, followed by high-throughput sequencing (HTS) for disease-specific IGH sequence quantification. To achieve accurate MRD quantification, we developed a systematic bioinformatic methodology to aggregate cancer clone sequence variants arising from systematic and random artifacts occurring during IGH-HTS. We then compared the sensitivity of IGH-HTS, flow cytometry, and allele-specific oligonucleotide PCR for MRD quantification in 28 samples collected from 6 CLL patients following allogeneic HCT. Using amplimer libraries generated with consensus primers from patient blood samples, we demonstrate the sensitivity of IGH-HTS with 454 pyrosequencing to be 10−5, with a high correlation between quantification by allele-specific oligonucleotide PCR and IGH-HTS (r = 0.85). From the same dataset used to quantify MRD, IGH-HTS also allowed us to profile IGH repertoire reconstitution after HCT—information not provided by the other MRD methods. IGH-HTS using consensus primers will broaden the availability of MRD quantification in CLL and other B cell malignancies, and this approach has potential for quantitative evaluation of immune diversification following transplant and nontransplant therapies.
Electronic Transport via Proteins

A central vision in molecular electronics is the creation of devices with functional molecular components that may provide unique properties. Proteins are attractive candidates for this purpose, as they have specific physical (optical, electrical) and chemical (selective binding, self‐assembly) functions and offer a myriad of possibilities for (bio‐)chemical modification. This Progress Report focuses on proteins as potential building components for future bioelectronic devices as they are quite efficient electronic conductors, compared with saturated organic molecules. The report addresses several questions: how general is this behavior; how does protein conduction compare with that of saturated and conjugated molecules; and what mechanisms enable efficient conduction across these large molecules? To answer these questions results of nanometer‐scale and macroscopic electronic transport measurements across a range of organic molecules and proteins are compiled and analyzed, from single/few molecules to large molecular ensembles, and the influence of measurement methods on the results is considered. Generalizing, it is found that proteins conduct better than saturated molecules, and somewhat poorer than conjugated molecules. Significantly, the presence of cofactors (redox‐active or conjugated) in the protein enhances their conduction, but without an obvious advantage for natural electron transfer proteins. Most likely, the conduction mechanisms are hopping (at higher temperatures) and tunneling (below ca. 150–200 K).
Cells test substrate rigidity by local contractions on submicrometer pillars

Cell growth and differentiation are critically dependent upon matrix rigidity, yet many aspects of the cellular rigidity-sensing mechanism are not understood. Here, we analyze matrix forces after initial cell–matrix contact, when early rigidity-sensing events occur, using a series of elastomeric pillar arrays with dimensions extending to the submicron scale (2, 1, and 0.5 μm in diameter covering a range of stiffnesses). We observe that the cellular response is fundamentally different on micron-scale and submicron pillars. On 2-μm diameter pillars, adhesions form at the pillar periphery, forces are directed toward the center of the cell, and a constant maximum force is applied independent of stiffness. On 0.5-μm diameter pillars, adhesions form on the pillar tops, and local contractions between neighboring pillars are observed with a maximum displacement of ∼60 nm, independent of stiffness. Because mutants in rigidity sensing show no detectable displacement on 0.5-μm diameter pillars, there is a correlation between local contractions to 60 nm and rigidity sensing. Localization of myosin between submicron pillars demonstrates that submicron scale myosin filaments can cause these local contractions. Finally, submicron pillars can capture many details of cellular force generation that are missed on larger pillars and more closely mimic continuous surfaces.
The Influence of Relationship Status on HPV Vaccine Decision-Making among Young Adult Women

ix CHAPTER 1: INTRODUCTION . 1 Background . 1 Statement of Need . 3 Public Health Significance . 6 Specific Aims and Research Questions . 8 Implications.8 Definition of Key Terms . 11 CHAPTER 2: LITERATURE REVIEW . 12 Human Papillomavirus.12 HPV Epidemiology . 12 Health Outcomes Associated with HPV . 13 Cancer . 13 Genital warts . 15 Recurrent respiratory papillomatosis . 15 HPV Vaccination . 15 HPV Vaccination Guidelines . 16 Health Implications of the HPV Vaccine.18 Economic Implications of the HPV Vaccine . 18 HPV Vaccine Policies in the United States . 21 HPV Vaccination Rates . 22 Factors Influencing HPV Vaccination . 24 Macros level factors . 24 Provider recommendation . 25 Factors among adolescents . 25 Factors among young adult males.26 Factors Influencing HPV Vaccination among Young Adult Females . 26 Intrapersonal Barriers and Facilitators . 30 Demographic characteristics . 30
Structural basis for the enhanced stability of highly fluorinated proteins

Noncanonical amino acids have proved extremely useful for modifying the properties of proteins. Among them, extensively fluorinated (fluorous) amino acids seem particularly effective in increasing protein stability; however, in the absence of structural data, the basis of this stabilizing effect remains poorly understood. To address this problem, we solved X-ray structures for three small proteins with hydrophobic cores that are packed with either fluorocarbon or hydrocarbon side chains and compared their stabilities. Although larger, the fluorinated residues are accommodated within the protein with minimal structural perturbation, because they closely match the shape of the hydrocarbon side chains that they replace. Thus, stability increases seem to be better explained by increases in buried hydrophobic surface area that accompany fluorination than by specific fluorous interactions between fluorinated side chains. This finding is illustrated by the design of a highly fluorinated protein that, by compensating for the larger volume and surface area of the fluorinated side chains, exhibits similar stability to its nonfluorinated counterpart. These structure-based observations should inform efforts to rationally modulate protein function using noncanonical amino acids.
Stretchable Energy‐Harvesting Tactile Electronic Skin Capable of Differentiating Multiple Mechanical Stimuli Modes

The first stretchable energy-harvesting electronic-skin device capable of differentiating and generating energy from various mechanical stimuli, such as normal pressure, lateral strain, bending, and vibration, is presented. A pressure sensitivity of 0.7 kPa(-1) is achieved in the pressure region <1 kPa with power generation of tens of μW cm(-2) from a gentle finger touch.
Loss of DNA methylation affects the recombination landscape in Arabidopsis

During sexual reproduction, one-half of the genetic material is deposited in gametes, and a complete set of chromosomes is restored upon fertilization. Reduction of the genetic information before gametogenesis occurs in meiosis, when cross-overs (COs) between homologous chromosomes secure an exchange of their genetic information. COs are not evenly distributed along chromosomes and are suppressed in chromosomal regions encompassing compact, hypermethylated centromeric and pericentromeric DNA. Therefore, it was postulated that DNA hypermethylation is inhibitory to COs. Here, when analyzing meiotic recombination in mutant plants with hypomethylated DNA, we observed unexpected and counterintuitive effects of DNA methylation losses on CO distribution. Recombination was further promoted in the hypomethylated chromosome arms while it was inhibited in heterochromatic regions encompassing pericentromeric DNA. Importantly, the total number of COs was not affected, implying that loss of DNA methylation led to a global redistribution of COs along chromosomes. To determine by which mechanisms altered levels of DNA methylation influence recombination—whether directly in cis or indirectly in trans by changing expression of genes encoding recombination components—we analyzed CO distribution in wild-type lines with randomly scattered and well-mapped hypomethylated chromosomal segments. The results of these experiments, supported by expression profiling data, suggest that DNA methylation affects meiotic recombination in cis. Because DNA methylation exhibits significant variation even within a single species, our results imply that it may influence the evolution of plant genomes through the control of meiotic recombination.
Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade

The transthyretin amyloidoses (ATTR) are invariably fatal diseases characterized by progressive neuropathy and/or cardiomyopathy. ATTR are caused by aggregation of transthyretin (TTR), a natively tetrameric protein involved in the transport of thyroxine and the vitamin A–retinol-binding protein complex. Mutations within TTR that cause autosomal dominant forms of disease facilitate tetramer dissociation, monomer misfolding, and aggregation, although wild-type TTR can also form amyloid fibrils in elderly patients. Because tetramer dissociation is the rate-limiting step in TTR amyloidogenesis, targeted therapies have focused on small molecules that kinetically stabilize the tetramer, inhibiting TTR amyloid fibril formation. One such compound, tafamidis meglumine (Fx-1006A), has recently completed Phase II/III trials for the treatment of Transthyretin Type Familial Amyloid Polyneuropathy (TTR-FAP) and demonstrated a slowing of disease progression in patients heterozygous for the V30M TTR mutation. Herein we describe the molecular and structural basis of TTR tetramer stabilization by tafamidis. Tafamidis binds selectively and with negative cooperativity (Kds ∼2 nM and ∼200 nM) to the two normally unoccupied thyroxine-binding sites of the tetramer, and kinetically stabilizes TTR. Patient-derived amyloidogenic variants of TTR, including kinetically and thermodynamically less stable mutants, are also stabilized by tafamidis binding. The crystal structure of tafamidis-bound TTR suggests that binding stabilizes the weaker dimer-dimer interface against dissociation, the rate-limiting step of amyloidogenesis.
Searching in axial and 3D CT visualisations

Traditional diagnostic modalities have been, for the most part, static two-dimensional images displayed on film or computer screen. More recent diagnostic modalities are solely computer-based and consist of large data-sets of multiple images. Image perception and visual search using these new modalities are complicated by the need to interact with the computer in order to navigate through the data. This paper reports the late-breaking results from two small studies into visual search within two types of CT Colonography (CTC) visualisations. The twelve novice observers in the study were taking part in a week-long course in CTC and were tested at the beginning and end of the course. A number of expert observers were also recorded. The two visualisations used in the study were 2D axial view and 3D colon fly-through. In both cases, searching was performed by inspecting the colon wall, but by two distinct mechanisms. The first study recorded observer eye-gaze and image navigation in a CTC axial view. The search strategy was to follow the lumen of the colon and detect abnormalities in the colon wall. The observer used the physical computer interface to navigate through the set of axial images to perform this task. The 3D fly-through study recorded observer eye-gaze whilst watching a recording of a computed flight through the colon lumen. Unlike the axial view there was no computer control, so inspection of the colon surface was dictated by the speed of flight through the colon.
MicroRNA-200a serves a key role in the decline of progesterone receptor function leading to term and preterm labor

During pregnancy, uterine quiescence is maintained by increased progesterone receptor (PR) activity, but labor is facilitated by a series of events that impair PR function. Previously, we discovered that miR-200 family members serve as progesterone (P4)-modulated activators of contraction-associated genes in the pregnant uterus. In this study, we identified a unique role for miR-200a to enhance the local metabolism of P4 in myometrium and, thus, decrease PR function during the progression toward labor. miR-200a exerts this action by direct repression of STAT5b, a transcriptional repressor of the P4-metabolizing enzyme 20α-hydroxysteroid dehydrogenase (20α-HSD). We observed that miR-200a expression increased and STAT5b expression coordinately decreased in myometrium of mice as they progressed to labor and in laboring myometrium from pregnant women. These changes were associated with a dramatic increase in expression and activity of 20α-HSD in laboring myometrium from mouse and human. Notably, overexpression of miR-200a in cultured human myometrial cells (hTERT-HM) suppressed STAT5b and increased 20α-HSD mRNA levels. In uterine tissues of ovariectomized mice injected with P4, miR-200 expression was significantly decreased, STAT5b expression was up-regulated, and 20α-HSD mRNA was decreased, but in 15 d postcoitum pregnant mice injected with the PR antagonist RU486, preterm labor was associated with increased miR-200a, decreased STAT5b, and enhanced 20α-HSD expression. Taken together, these findings implicate miR-200a as an important regulator of increased local P4 metabolism in the pregnant uterus near term and provide insight into the importance of miR-200s in the decline in PR function leading to labor.
Relationship of protoporphyrin IX synthesis to photodynamic effects by 5‐aminolaevulinic acid and its esters on various cell lines derived from the skin

Background 5‐Aminolaevulinic acid (ALA) and its esters act as precursors to the fluorescent photosensitizer protoporphyrin IX (PpIX) in photodynamic therapy (PDT). There is little information about how ALA and its esters induce PpIX synthesis and photodynamic effects in cell lines derived from the skin.
Lesiones Endoscópicas del Tracto Digestivo Alto en Pacientes con Insuficiencia Renal Crónica Terminal

INTRODUCCION: La Insuficiencia Renal Cronica Terminal (IRCT) ocasiona alteraciones a nivel sistemico, y entre ellas, las relacionadas al aparato digestivo manifestadas por sintomatologia variada y responsable de significativa morbi-mortalidad. El objetivo principal del estudio fue determinar las alteraciones endoscopicas del tracto digestivo superior mas frecuentes en los pacientes con IRCT. MATERIAL Y METODOS: Se desarrollo un estudio descriptivo y retrospectivo en pacientes mayores de 18 anos con diagnostico de IRCT incluidos en el Programa de Hemodialisis del Hospital Central FAP, desde Enero del 2000 a Febrero del 2007, con estudio de endoscopia alta realizada durante el mismo periodo de tiempo, revisandose las respectivas historias clinicas para la recoleccion de variables demograficas, clinicas y endoscopicas. RESULTADOS: Se estudiaron 54 pacientes. La edad promedio fue 73.2 anos, siendo mas frecuente en varones con una relacion M/F de 1.45. La poblacion tenia en promedio 32 meses de diagnostico de IRCT y valores promedio de urea y creatinina serica en 94.4 y 3.9 mg/dl respectivamente. Solo el 37.1% de los pacientes fueron sintomaticos. La indicacion mas frecuente del estudio endoscopico fue la hemorragia digestiva alta (29.6%). Los hallazgos endoscopicos mas prevalentes fueron las erosiones gastricas (35.2%), eritema parcelar antral (27.8%), ulcera gastrica (24.1%) y erosiones duodenales (18.5%). El diagnostico histopatologico predominante fue la gastritis cronica superficial (65.8%). La infeccion por Helicobacter pylori estuvo presente en el 38.6% de los pacientes estudiados. CONCLUSIONES. - Las alteraciones endoscopicas del tracto digestivo superior mas frecuentes en los pacientes con IRCT fueron las erosiones gastricas, eritema parcelar antral, ulcera gastrica y erosiones duodenales.