Miracle-dz/UniFAR-FTUs huggingface dataset:
The histone chaperone sNASP binds a conserved peptide motif within the globular core of histone H3 through its TPR repeats

Eukaryotic chromatin is a complex yet dynamic structure, which is regulated in part by the assembly and disassembly of nucleosomes. Key to this process is a group of proteins termed histone chaperones that guide the thermodynamic assembly of nucleosomes by interacting with soluble histones. Here we investigate the interaction between the histone chaperone sNASP and its histone H3 substrate. We find that sNASP binds with nanomolar affinity to a conserved heptapeptide motif in the globular domain of H3, close to the C-terminus. Through functional analysis of sNASP homologues we identified point mutations in surface residues within the TPR domain of sNASP that disrupt H3 peptide interaction, but do not completely disrupt binding to full length H3 in cells, suggesting that sNASP interacts with H3 through additional contacts. Furthermore, chemical shift perturbations from 1H-15N HSQC experiments show that H3 peptide binding maps to the helical groove formed by the stacked TPR motifs of sNASP. Our findings reveal a new mode of interaction between a TPR repeat domain and an evolutionarily conserved peptide motif found in canonical H3 and in all histone H3 variants, including CenpA and have implications for the mechanism of histone chaperoning within the cell.
Medical Management of Endometriosis

Current approved medical therapies for endometriosis rely on drugs that suppress ovarian steroids and induce a hypoestrogenic state, which determines the atrophy of the ectopic endometrium. Gonadotropin-releasing hormone analogs such as danazol, progestogens and estrogen–progestin combinations have all proven effective in relieving pain and reducing the extent of endometriotic implants. However, symptoms often recur after discontinuation of therapy and hypoestrogenism-related side effects limit the long-term use of most medications. Recently, knowledge of the pathogenesis of endometriosis, particularly at the molecular level, has grown substantially, providing a rational basis for the development of new drugs with precise targets that may be safely administered over the long term.
HERSCHEL OBSERVATIONS OF EXTRAORDINARY SOURCES: ANALYSIS OF THE HIFI 1.2 THz WIDE SPECTRAL SURVEY TOWARD ORION KL II. CHEMICAL IMPLICATIONS

We present chemical implications arising from spectral models fit to the Herschel/HIFI spectral survey toward the Orion Kleinmann-Low nebula (Orion KL). We focus our discussion on the eight complex organics detected within the HIFI survey utilizing a novel technique to identify those molecules emitting in the hottest gas. In particular, we find the complex nitrogen bearing species CH3CN, C2H3CN, C2H5CN, and NH2CHO systematically trace hotter gas than the oxygen bearing organics CH3OH, C2H5OH, CH3OCH3, and CH3OCHO, which do not contain nitrogen. If these complex species form predominantly on grain surfaces, this may indicate N-bearing organics are more difficult to remove from grain surfaces than O-bearing species. Another possibility is that hot (Tkin ∼ 300 K) gas phase chemistry naturally produces higher complex cyanide abundances while suppressing the formation of O-bearing complex organics. We compare our derived rotation temperatures and molecular abundances to chemical models, which include gas-phase and grain surface pathways. Abundances for a majority of the detected complex organics can be reproduced over timescales ≳105 years, with several species being underpredicted by less than 3σ. Derived rotation temperatures for most organics, furthermore, agree reasonably well with the predicted temperatures at peak abundance. We also find that sulfur bearing molecules that also contain oxygen (i.e., SO, SO2, and OCS) tend to probe the hottest gas toward Orion KL, indicating the formation pathways for these species are most efficient at high temperatures.
Stratified operational semantics for safety and correctness of the region calculus

The region analysis of Tofte and Talpin is an attempt to determine statically the life span of dynamically allocated objects. But the calculus is at once intuitively simple, yet deceptively subtle, and previous theoretical analyses have been frustratingly complex: no analysis has revealed and explained in simple terms the connection between the subleties of the calculus and the imperative features it builds on. We present a novel approach for proving safety and correctness of a simplified version of the region calculus. We give a stratified operational semantics, composed of a highlevel semantics dealing with the conceptual difficulties of effect annotations, and a low-level one with explicit operations on a region-indexed store. The main results of the paper are a proof simpler than previous ones, and a modular approach to type safety and correctness. The flexibility of this approach is demonstrated by the simplicity of the extension to the full calculus with type and region polymorphism.
Leveraging data and structure in ontology integration

There is a great deal of research on ontology integration which makes use of rich logical constraints to reason about the structural and logical alignment of ontologies. There is also considerable work on matching data instances from heterogeneous schema or ontologies. However, little work exploits the fact that ontologies include both data and structure. We aim to close this gap by presenting a new algorithm (ILIADS) that tightly integrates both data matching and logical reasoning to achieve better matching of ontologies. We evaluate our algorithm on a set of 30 pairs of OWL Lite ontologies with the schema and data matchings found by human reviewers. We compare against two systems - the ontology matching tool FCA-merge [28] and the schema matching tool COMA++ [1]. ILIADS shows an average improvement of 25% in quality over FCA-merge and a 11% improvement in recall over COMA++.
Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome

The role of the adaptive immune response in controlling the growth and recurrence of human tumors has been controversial. We characterized the tumor-infiltrating immune cells in large cohorts of human colorectal cancers by gene expression profiling and in situ immunohistochemical staining. Collectively, the immunological data (the type, density, and location of immune cells within the tumor samples) were found to be a better predictor of patient survival than the histopathological methods currently used to stage colorectal cancer. The results were validated in two additional patient populations. These data support the hypothesis that the adaptive immune response influences the behavior of human tumors. In situ analysis of tumor-infiltrating immune cells may therefore be a valuable prognostic tool in the treatment of colorectal cancer and possibly other malignancies.
A 6200-Year Environmental History of the Pearl River Marsh, Louisiana.

An 8.81 m sediment core from the fresh marsh area of the Pearl River delta was examined for pollen, diatom, and organic content, to reconstruct the history of the lateHolocene environmental changes. The data show that prior to 5900 years B.P., the coring site was occupied by a swamp forest. Afterwards, the swamp was replaced by a marsh vegetation as a result of postglacial transgression. Since 5900 years B.P. the marsh has remained brackish for most of the time, characterized by abundant marine diatoms and brackish marsh pollen. However, the brackish water environment was interrupted at least two times when the local salinity became low enough to support oligohaline communities. The two regressions correspond to C-14 dates of 3400 to 2200, and 1400 to 1100 years B.P. The most prominent regression is the one from 3400 to 2200 years B.P., which is correlatable with a major neoglacial event. This regression is also compatible with the results of sea level studies in other areas of the U.S. The study results indicate that there were more large fluvial discharge layers during the time of the midHolocene than during the late-Holocene. This probably corresponds to a climatic regime of increased precipitation during the the mid-Holocene. These results support the climate modeling prediction of increased precipitation
Economic Diversity in Medical Education

Providing access to higher education across all income groups is a national priority. This analysis assessed the performance, career choice, and educational indebtedness of medical college students whose educational pursuits were assisted by the provision of financial support. The study looked at designated outcomes (academic performance, specialty choice, accumulated debt) in relation to the independent variable, family (parental) income, of 1,464 students who graduated from Jefferson Medical College between 1992 and 2002. Students were classified into groups of high, moderate, and low income based on their parental income. During the basic science years, the high-income group performed better; however, in the clinical years, performance measures were similar. Those in the high-income group tended to pursue surgery, while those in the low-income group preferred family medicine. The mean of accumulated educational debt was significantly higher for the low-income group. The study provides support for maintaining economic diversity in medical education.
Characterization of an Unconventional Rhodopsin from the Freshwater Actinobacterium Rhodoluna lacicola

ABSTRACT Rhodopsin-encoding microorganisms are common in many environments. However, knowing that rhodopsin genes are present provides little insight into how the host cells utilize light. The genome of the freshwater actinobacterium Rhodoluna lacicola encodes a rhodopsin of the uncharacterized actinorhodopsin family. We hypothesized that actinorhodopsin was a light-activated proton pump and confirmed this by heterologously expressing R. lacicola actinorhodopsin in retinal-producing Escherichia coli. However, cultures of R. lacicola did not pump protons, even though actinorhodopsin mRNA and protein were both detected. Proton pumping in R. lacicola was induced by providing exogenous retinal, suggesting that the cells lacked the retinal cofactor. We used high-performance liquid chromatography (HPLC) and oxidation of accessory pigments to confirm that R. lacicola does not synthesize retinal. These results suggest that in some organisms, the actinorhodopsin gene is constitutively expressed, but rhodopsin-based light capture may require cofactors obtained from the environment. IMPORTANCE Up to 70% of microbial genomes in some environments are predicted to encode rhodopsins. Because most microbial rhodopsins are light-activated proton pumps, the prevalence of this gene suggests that in some environments, most microorganisms respond to or utilize light energy. Actinorhodopsins were discovered in an analysis of freshwater metagenomic data and subsequently identified in freshwater actinobacterial cultures. We hypothesized that actinorhodopsin from the freshwater actinobacterium Rhodoluna lacicola was a light-activated proton pump and confirmed this by expressing actinorhodopsin in retinal-producing Escherichia coli. Proton pumping in R. lacicola was induced only after both light and retinal were provided, suggesting that the cells lacked the retinal cofactor. These results indicate that photoheterotrophy in this organism and others may require cofactors obtained from the environment.
Assessment of prenatal exposure to ethanol by meconium analysis: results of an Italian multicenter study.

BACKGROUND This study estimated in 7 Italian cities the prevalence of prenatal exposure to ethanol by determining fatty acid ethyl esters (FAEEs; palmitic, palmitoleic, stearic, oleic, linoleic, linolenic, and arachidonic esters) and ethyl glucuronide (EtG) in neonatal meconium samples. METHODS A total of 607 meconium samples were obtained from neonatal wards of 7 public hospitals: Verona and San Daniele del Friuli in the northeast of the country, Reggio Emilia in the middle east, Florence and Rome in the center, and Naples and Crotone in the southwest of the peninsula. Meconium biomarkers were assessed by a validated methodology using liquid chromatography-tandem mass spectrometry and the results categorized using the accepted cutoff of 2 nmol/g total amount of 7 FAEEs and 2 nmol/g EtG, to differentiate between heavy maternal ethanol use during pregnancy and occasional or no use at all. RESULTS On the basis of the above-reported cutoffs, the overall prevalence of newborns prenatally exposed to maternal ethanol was 7.9%: 0% in Verona, 4.0% in San Daniele del Friuli, 4.9% in Naples, 5.0% in Florence, 6.2% in Crotone, up to 10.6% in Reggio Emilia, and 29.4% in Rome. Low maternal education level and younger maternal age were associated with biomarker scores over the cutoff. There was also a significant correlation between the highest percentage of prenatal exposure in the capital and certain maternal sociodemographic characteristics. CONCLUSIONS These results indicate considerable variability in the prevalence of fetal exposure to ethanol in different Italian cities, as determined by the objective measurement of biomarkers in meconium. These data, together with previous ones obtained in Barcelona, Spain, indicate that gestational ethanol exposure is widespread, at least in parts of Europe.
Alterations of Functional and Structural Networks in Schizophrenia Patients with Auditory Verbal Hallucinations

Background: There have been many attempts at explaining the underlying neuropathological mechanisms of auditory verbal hallucinations (AVH) in schizophrenia on the basis of regional brain changes, with the most consistent findings being that AVH are associated with functional and structural impairments in auditory and speech-related regions. However, the human brain is a complex network and the global topological alterations specific to AVH in schizophrenia remain unclear. Methods: Thirty-five schizophrenia patients with AVH, 41 patients without AVH, and 50 healthy controls underwent resting-state functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI). The whole-brain functional and structural networks were constructed and analyzed using graph theoretical approaches. Inter-group differences in global network metrics (including small-world properties and network efficiency) were investigated. Results: We found that three groups had a typical small-world topology in both functional and structural networks. More importantly, schizophrenia patients with and without AVH exhibited common disruptions of functional networks, characterized by decreased clustering coefficient, global efficiency and local efficiency, and increased characteristic path length; structural networks of only schizophrenia patients with AVH showed increased characteristic path length compared with those of healthy controls. Conclusion: Our findings suggest that less “small-worldization” and lower network efficiency of functional networks may be an independent trait characteristic of schizophrenia, and regularization of structural networks may be the underlying pathological process engaged in schizophrenic AVH symptom expression.
Predictors of dexmedetomidine-associated hypotension in critically ill patients

Background: Dexmedetomidine is commonly used for sedation in the Intensive Care Unit (ICU), and its use may be associated with hypotension. We sought to determine predictors of dexmedetomidine-associated hypotension. Methods: Retrospective, single-center study of 283 ICU patients in four adults ICUs over a 12 month period. Univariate analyses were performed to determine factors associated with dexmedetomidine-related hypotension. Risk factors significant at the 0.20 level in the univariate analysis were considered for inclusion into a step-wise multiple logistical regression model. Results: Hypotension occurred in 121 (42.8%) patients with a median mean arterial pressure (MAP) nadir of 54 mmHg. Univariate analyses showed an association between hypotension and age (P = 0.03), Acute Physiology and Chronic Health Evaluation II (APACHE II) score (P = 0.02), baseline MAP (<0.001), admission to the cardiothoracic ICU (P = 0.05), history of coronary artery disease (P = 0.02), and postcardiac surgery (P = 0.0009). Admission to the medical ICU was associated with a decrease in development in hypotension (P = 0.03). There was a trend for hypotension with weight (P = 0.09) and history of congestive heart failure (P = 0.12) Only MAP prior to initiation (odds ratio [OR] 0.97, 95% confidence interval [95% CI] 0.95–0.99;P < 0.0001), APACHE II scores (OR 1.06, 95% CI 1.01–1.12;P= 0.017), and history of coronary artery disease (OR 0.48, 95% CI 0.26–0.90,P= 0.022) were independently associated with hypotension by multivariable analysis. Conclusions: Dexmedetomidine-associated hypotension is common. Preexisting low blood pressure, history of coronary artery disease, and higher acuity were identified as independent risk factors for dexmedetomidine-associated hypotension.
Nuclear interferon-inducible protein 16 promotes silencing of herpesviral and transfected DNA

Significance Cells have evolved mechanisms to silence foreign DNA to prevent the expression of foreign genes within them. In mammalian cells, this involves the assembly of heterochromatin on foreign DNAs such as viral or transfected DNA. Herpesviruses have evolved strategies to counteract these host mechanisms to express their own genes. Herein we demonstrate that the nuclear DNA sensor IFN-inducible protein 16 (IFI16) is involved in the host silencing response to foreign DNA. IFI16 promotes the assembly of heterochromatin on herpesviral DNA and inhibition of viral immediate–early gene expression and replication. This silencing effect is also observed on transfected plasmid DNAs. Therefore, our results indicate that IFI16 is broadly involved in the cellular response to foreign DNA. Mammalian cells have evolved mechanisms to silence foreign DNA introduced by viruses or by transfection. Upon herpesviral infection of cells, the viral genome is chromatinized in an attempt by the host cell to restrict expression of the viral genome. HSV ICP0 acts to counter host-intrinsic and innate responses to viral infection. We have found that nuclear interferon (IFN)-inducible protein 16 (IFI16) acts as a restriction factor against ICP0-null herpes simplex virus 1 (HSV-1) to limit viral replication and immediate–early gene expression. IFI16 promoted the addition of heterochromatin marks and the reduction of euchromatin marks on viral chromatin. IFI16 also restricted the expression of plasmid DNAs introduced by transfection but did not restrict SV40 DNA introduced into the cellular nucleus in the form of nucleosomal chromatin by viral infection. These results argue that IFI16 restricts unchromatinized DNA when it enters the cell nucleus by promoting the loading of nucleosomes and the addition of heterochromatin marks. Furthermore, these results indicate that IFI16 provides a broad surveillance role against viral and transfected DNA by promoting restriction of gene expression from the exogenous DNA and inducing innate immune responses.
Regulation of motor neuron subtype identity by repressor activity of Mnx class homeodomain proteins

In the developing spinal cord, motor neurons acquire columnar subtype identities that can be recognized by distinct profiles of homeodomain transcription factor expression. The mechanisms that direct the differentiation of motor neuron columnar subtype from an apparently uniform group of motor neuron progenitors remain poorly defined. In the chick embryo, the Mnx class homeodomain protein MNR2 is expressed selectively by motor neuron progenitors, and has been implicated in the specification of motor neuron fate. We show here that MNR2 expression persists in postmitotic motor neurons that populate the median motor column (MMC), whereas its expression is rapidly extinguished from lateral motor column (LMC) neurons and from preganglionic autonomic neurons of the Column of Terni (CT). The extinction of expression of MNR2, and the related Mnx protein HB9, from postmitotic motor neurons appears to be required for the generation of CT neurons but not for LMC generation. In addition, MNR2 and HB9 are likely to mediate the suppression of CT neuron generation that is induced by the LIM HD protein Lim3. Finally, MNR2 appears to regulate motor neuron identity by acting as a transcriptional repressor, providing further evidence for the key role of transcriptional repression in motor neuron specification.
Hydrogen peroxide relaxes porcine coronary arteries by stimulating BKCachannel activity.

It has been known for a number of years that neutrophils and macrophages secrete H2O2while fighting disease, and the levels obtained within the vasculature under these conditions can reach several hundred micromolar. Because the effect of H2O2on vascular smooth muscle is not fully understood, the present study examined the cellular effects of H2O2on coronary arteries. Under normal ionic conditions, H2O2relaxed arteries that were precontracted with prostaglandin F2α or histamine (EC50 = 252 ± 22 μM). The effect of H2O2was concentration dependent and endothelium independent. In contrast, H2O2did not relax arteries contracted with 80 mM KCl, suggesting involvement of K+ channels. Single-channel patch-clamp recordings revealed that H2O2increased the activity of the large-conductance (119 pS), Ca2+- and voltage-activated K+(BKCa) channel. This response was mimicked by arachidonic acid and inhibited by eicosatriynoic acid, a lipoxygenase blocker, suggesting involvement of leukotrienes. Further studies on intact arteries demonstrated that eicosatriynoic acid not only blocked the vasodilatory response to H2O2but unmasked a vasoconstrictor effect that was reversed by blocking cyclooxygenase activity with indomethacin. These findings identify a novel effector molecule, the BKCachannel, which appears to mediate the vasodilatory effect of H2O2, and suggest that a single signaling pathway, arachidonic acid metabolism, can mediate the vasodilatory and vasoconstrictor effects of H2O2and possibly other reactive oxygen species.