Miracle-dz/UniFAR-FTUs huggingface dataset:
Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor ranolazine

Pathological conditions linked to imbalances in oxygen supply and demand (for example, ischaemia, hypoxia and heart failure) are associated with disruptions in intracellular sodium ([Na+]i) and calcium ([Ca2+]i) concentration homeostasis of myocardial cells. A decreased efflux or increased influx of sodium may cause cellular sodium overload. Sodium overload is followed by an increased influx of calcium through sodium-calcium exchange. Failure to maintain the homeostasis of [Na+]i and [Ca2+]i leads to electrical instability (arrhythmias), mechanical dysfunction (reduced contractility and increased diastolic tension) and mitochondrial dysfunction. These events increase ATP hydrolysis and decrease ATP formation and, if left uncorrected, they cause cell injury and death. The relative contributions of various pathways (sodium channels, exchangers and transporters) to the rise in [Na+]i remain a matter of debate. Nevertheless, both the sodium-hydrogen exchanger and abnormal sodium channel conductance (that is, increased late sodium current (INa)) are likely to contribute to the rise in [Na+]i. The focus of this review is on the role of the late (sustained/persistent) INa in the ionic disturbances associated with ischaemia/hypoxia and heart failure, the consequences of these ionic disturbances, and the cardioprotective effects of the antianginal and anti-ischaemic drug ranolazine. Ranolazine selectively inhibits late INa, reduces [Na+]i-dependent calcium overload and attenuates the abnormalities of ventricular repolarisation and contractility that are associated with ischaemia/reperfusion and heart failure. Thus, inhibition of late INa can reduce [Na+]i-dependent calcium overload and its detrimental effects on myocardial function.
Long-term results of laparoscopic gastrectomy for gastric cancer: a large-scale case-control and case-matched Korean multicenter study.

PURPOSE The oncologic outcomes of laparoscopy-assisted gastrectomy for the treatment of gastric cancer have not been evaluated. The aim of this study is to validate the efficacy and safety of laparoscopic gastrectomy for gastric cancer in terms of long-term survival, morbidity, and mortality retrospectively. PATIENTS AND METHODS The study group comprised 2,976 patients who were treated with curative intent either by laparoscopic gastrectomy (1,477 patients) or open gastrectomy (1,499 patients) between April 1998 and December 2005. The long-term 5-year actual survival analysis in case-control and case-matched population was conducted using the Kaplan-Meier method. The morbidity and mortality and learning curves were evaluated. RESULTS In the case-control study, the overall survival, disease-specific survival, and recurrence-free survival (median follow-up period, 70.8 months) were not statistically different at each cancer stage with the exception of an increased overall survival rate for patients with stage IA cancer treated via laparoscopy (laparoscopic group; 95.3%, open group: 90.3%; P < .001). After matching using a propensity scoring system, the overall survival, disease-specific survival, and recurrence-free survival rates were not statistically different at each stage. The morbidity of the case-matched group was 15.1% in the open group and 12.5% in the laparoscopic group, which also had no statistical significance (P = .184). The mortality rate was also not statistically significant (0.3% in the open group and 0.5% in the laparoscopic group; P = 1.000). The mean learning curve was 42. CONCLUSION The long-term oncologic outcomes of laparoscopic gastrectomy for patients with gastric cancer were comparable to those of open gastrectomy in a large-scale, multicenter, retrospective clinical study.
Socioeconomic differences in cancer survival.

STUDY OBJECTIVE--The aim was to investigate the relationship between socioeconomic status and cancer survival. DESIGN--This was a prospective study, linking census and vital registration records for an approximate 1% representative sample of those enumerated in England and Wales in the 1971 census. SETTING--The study population is nationwide. PARTICIPANTS--The study sample consists of 250,588 men and 262,484 women. During 1971-81, 17,844 cases of cancer were registered, and of those registered, 13,532 died during 1971-1983. MEASUREMENTS AND MAIN RESULTS--Socioeconomic status was assessed in terms of housing tenure. Council tenants, the low socioeconomic group, had poorer survival than owner occupiers, the high socioeconomic group, for the combined group of all neoplasms, and for 11 out of 13 neoplasms examined in males, and 12 out of 15 neoplasms examined in females. Differences were found irrespective of age, cause of death and prognosis of the cancer. Survival analysis by length of follow up indicated that council tenants were more likely to present at a later stage than owner occupiers. CONCLUSIONS--Wide survival differentials were observed between socioeconomic groups. Differences in survival for cancers of poor prognosis (eg, oesophagus, pancreas, lung) where treatment has little effect, cannot be attributed to socioeconomic differences in treatment. The survival differences for cancers of good prognosis (eg, corpus uteri, bladder, skin) could, in part, be due to differences in treatment. It is probable that delay in seeking care is one of the major contributing causes.
Top-Down Republicanism in the South: A View from the Local Level

WITH THE EMERGENCE of Trent Lott from Mississippi as majority leader in the U.S. Senate in 1996 to complement the House leadership of Speaker Newt Gringrich,1 the realignment of southern congressional leadership, it seemed, was complete. The shift of the Democratic “solid South” to a Republican presidential stronghold has been well documented (Black and Black 1992). Carmines and Stimson (1989) note that racial issues have recreated politics in the South. They argue that when President Johnson aligned the Democratic Party with the Civil Rights movement in 1964–65, the stage was set for Republican realignment. Although racial issues prompted Republican realignment, economic and societal change in the South cemented it. The shift of the southern economy from an agricultural base to a modern technological and industrial base created an opportunity for the Republican Party to capture not only social conservatives but also nonnative economic conservatives (Black and Black 1987); that is, voters who are not southern natives but who have brought with them to the South
DNA replication stress induces deregulation of the cell cycle events in root meristems of Allium cepa.

BACKGROUND AND AIMS Prolonged treatment of Allium cepa root meristems with changing concentrations of hydroxyurea (HU) results in either premature chromosome condensation or cell nuclei with an uncommon form of biphasic chromatin organization. The aim of the current study was to assess conditions that compromise cell cycle checkpoints and convert DNA replication stress into an abnormal course of mitosis. METHODS Interphase-mitotic (IM) cells showing gradual changes of chromatin condensation were obtained following continuous 72 h treatment of seedlings with 0·75 mm HU (without renewal of the medium). HU-treated root meristems were analysed using histochemical stainings (DNA-DAPI/Feulgen; starch-iodide and DAB staining for H(2)O(2) production), Western blotting [cyclin B-like (CBL) proteins] and immunochemistry (BrdU incorporation, detection of γ-H2AX and H3S10 phosphorylation). KEY RESULTS Continuous treatment of onion seedlings with a low concentration of HU results in shorter root meristems, enhanced production of H(2)O(2), γ-phosphorylation of H2AX histones and accumulation of CBL proteins. HU-induced replication stress gives rise to axially elongated cells with half interphase/half mitotic structures (IM-cells) having both decondensed and condensed domains of chromatin. Long-term HU treatment results in cell nuclei resuming S phase with gradients of BrdU labelling. This suggests a polarized distribution of factors needed to re-initiate stalled replication forks. Furthermore, prolonged HU treatment extends both the relative time span and the spatial scale of H3S10 phosphorylation known in plants. CONCLUSIONS The minimum cell length and a threshold level of accumulated CBL proteins are both determining factors by which the nucleus attains commitment to induce an asynchronous course of chromosome condensation. Replication stress-induced alterations in an orderly route of the cell cycle events probably reflect a considerable reprogramming of metabolic functions of chromatin combined with gradients of morphological changes spread along the nucleus.
Embryonic development of in vitro matured and in vitro fertilized dog oocytes

In several studies, early cleavage stage canine embryos have been derived from in vitro fertilized oocytes cultured under various conditions. Despite these results, IVF protocols for canine oocytes have yielded low fertilization rates. In this study, Experiment I compared the effects of tissue culture medium (TCM)‐199 supplemented with either (A) 1 μg/ml estradiol or (B) 20 μg/ml estradiol + 1 μg/ml human somatotropin (hST) on the in vitro nuclear maturation rate of canine oocytes. Meiotic progression to the metaphase I and II (MI/MII) stages at 72 hr of in vitro culture (IVC) was 10.2% (11/108) in medium A versus 14.1% (30/142) in medium B (P = 0.802). In Experiment II, cleavage rate was determined among oocytes recovered from ovaries of bitches at different reproductive stages. Oocytes (n = 888) were retrieved from bitches at the follicular, anestrous, and luteal stages and selected for high morphological quality. Oocytes were matured for 48 hr in TCM‐199 supplemented with 1 μg/ml hST + 20 μg/ml estradiol. Oocytes were in vitro fertilized with fresh canine spermatozoa that had been isolated on a Percoll gradient, and were cultured in synthetic oviduct fluid (SOF) medium with bovine serum albumin (BSA; 4 mg/ml) up to 5 days in 5% CO2 in air at 37°C. A proportion of oocytes (30.6%) with identifiable nuclear material had cytoplasm penetrated or fertilized by sperm. The percentage of oocytes developing into early stage embryos was 10.1% (27/267). Although pronuclear development was observed to be higher for oocytes recovered at the follicular phase, the cleavage rate was similar among oocytes recovered from bitches at the follicular, anestrus, and luteal stages. There was no correlation between the proportion of capacitated or acrosome reacted spermatozoa and pronuclei formation and/or percent cleavage. It was concluded that TCM‐199 supplemented with 1 μg/ml hST and estradiol (20 μg/ml) supports nuclear and cytoplasmic maturation of canine oocytes. In this study, meiotic competence was verified by the in vitro production (IVP) and development of embryos up to the 8 cell‐stage. Furthermore, the results indicate that, under the described conditions and despite the influence of reproductive status of the bitch on the developmental competence of in vitro fertilized oocytes to the pronuclei stage, cleavage was independent of donor's reproductive estrous cycle stage. Mol. Reprod. Dev. 67:215–223, 2004. © 2004 Wiley‐Liss, Inc.
Chem-seq permits identification of genomic targets of drugs against androgen receptor regulation selected by functional phenotypic screens

Significance The emergence of powerful new chemical library-screening approaches and the generation of new types of chemical structures makes novel methods available to link candidate chemicals to potential target genes, e.g., as in the interaction with and effects on chromatin-bound targets. Here we report a method that can provide the genome-wide location of a candidate drug. One such synthetic chemical, SD70—first identified in a screen for inhibitors of tumor translocation events—was resynthesized with a tag permitting a ChIP-sequencing–like analysis, referred to as “Chemical affinity capture and massively parallel DNA sequencing (Chem-seq). ” As a consequence of finding its recruitment on androgen receptor-bound functional enhancers, we were able to demonstrate that SD70 could inhibit the prostate cancer cell transcriptional program, in part by inhibition of the demethylase KDM4C. Understanding the mechanisms by which compounds discovered using cell-based phenotypic screening strategies might exert their effects would be highly augmented by new approaches exploring their potential interactions with the genome. For example, altered androgen receptor (AR) transcriptional programs, including castration resistance and subsequent chromosomal translocations, play key roles in prostate cancer pathological progression, making the quest for identification of new therapeutic agents and an understanding of their actions a continued priority. Here we report an approach that has permitted us to uncover the sites and mechanisms of action of a drug, referred to as “SD70,” initially identified by phenotypic screening for inhibitors of ligand and genotoxic stress-induced translocations in prostate cancer cells. Based on synthesis of a derivatized form of SD70 that permits its application for a ChIP-sequencing–like approach, referred to as “Chem-seq,” we were next able to efficiently map the genome-wide binding locations of this small molecule, revealing that it largely colocalized with AR on regulatory enhancers. Based on these observations, we performed the appropriate global analyses to ascertain that SD70 inhibits the androgen-dependent AR program, and prostate cancer cell growth, acting, at least in part, by functionally inhibiting the Jumonji domain-containing demethylase, KDM4C. Global location of candidate drugs represents a powerful strategy for new drug development by mapping genome-wide location of small molecules, a powerful adjunct to contemporary drug development strategies.
Analysis of the mitochondrial DNA genome in the peripheral blood leukocytes of HIV-infected patients with or without lipoatrophy

Objective To investigate the molecular mechanisms of nucleoside analogue reverse transcriptase inhibitor (NRTI)-associated mitochondrial dysfunction. Methods Peripheral blood samples were collected from 10 healthy individuals, 10 HIV-infected, NRTI-treated patients with lipoatrophy, and four HIV-infected patients naive to all antiretrovirals. DNA was isolated from the leukocytes and the mitochondrial genome analyzed for DNA depletion, deletions and point mutations. Results We were not able to detect mitochodrial DNA (mtDNA) depletion, deletions, or DNA rearrangements in any of the specimens, including one from a patient with fulminant lactic acidosis. A complete analysis of the entire mitochondrial genome by temporal temperature gradient gel electrophoresis revealed several nucleotide substitutions in blood mtDNA of several HIV infected patients. Conclusion We found no evidence for NRTI-associated mtDNA depletion or gross mtDNA mutations in leukocytes of HIV-infected patients, regardless of their treatment history. Thus, either NRTI-induced mutations in mtDNA are tissue-specific or alternatively, pre-existent mtDNA variations in HIV disease predispose to the development of clinically apparent mitochondrial dysfunction during NRTI therapy. The significance of mtDNA variations in the development of mitochondrial-related clinical conditions in HIV patients with or without NRTI therapy is to be further investigated.
Bounds on price of anarchyon linear cost functions

The price of anarchy (POA) is a quite powerful tool to characterize the efficiency loss of competition on networks. In this paper, we derive a bound for POA for the case that the cost function is linear but asymmetric. The result is a generalization of that of Han et. al. in the sense that the involved matrix is only assumed to be positive semidefinite, but not positive definite. Consequently, the range of application of the result is widened. We give two simple examples to illustrate our result.
Two conformational states of Candida rugosa lipase

The structure of Candida rugosa lipase in a new crystal form has been determined and refined at 2.1 Å resolution. The lipase molecule was found in an inactive conformation, with the active site shielded from the solvent by a part of the polypeptide chain — the flap. Comparison of this structure with the previously determined “open” form of this lipase, in which the active site is accessible to the solvent and presumably the substrate, shows that the transition between these 2 states requires only movement of the flap. The backbone NH groups forming the putative oxyanion hole do not change position during this rearrangement, indicating that this feature is preformed in the inactive state. The 2 lipase conformations probably correspond to states at opposite ends of the pathway of interfacial activation. Quantitative analysis indicates a large increase of the hydrophobic surface in the vicinity of the active site. The flap undergoes a flexible rearrangement during which some of its secondary structure refolds. The interactions of the flap with the rest of the protein change from mostly hydrophobic in the inactive form to largely hydrophilic in the “open” conformation. Although the flap movement cannot be described as a rigid body motion, it has very definite hinge points at Glu 66 and at Pro 92. The rearrangement is accompanied by a cis‐trans isomerization of this proline, which likely increases the energy required for the transition between the 2 states, and may play a role in the stabilization of the active conformation at the water/lipid interface. Carbohydrate attached at Asn 351 also provides stabilization for the open conformation of the flap.
Deepest Known Plant Life Discovered on an Uncharted Seamount

The discovery of abundant autotrophic macrophytes living below 200 meters indicates their importance to primary productivity, food webs, sedimentary processes, and as reef builders in clear oceanic waters. Estimates concerning minimum light levels for macroalgal photosynthesis and macrophytic contributions to the biology and geology of tropical insular and continental borderlands must now be revised.
Attributing Corporate Responsibility for Sexual Harassment

This study examines circumstances under which observers might consider an organization to have responsibility for its employees’ actions, based on their reading of a scenario of sexual harassment. By changing the details of the scenario, we examine the influence of (a) the harasser’s organizational role (i.e., a supervisor or coworker), (b) the existence of corporate sexual harassment policies, and (c) the company’s past responses to sexual harassment complaints. The results suggested that the harasser’s organizational role is the most important factor for predicting whether an individual would consider pressing a sexual harassment claim. Respondents’ assessment that the victim should make a claim is higher when the harasser is an immediate supervisor rather than a nonsupervisory coworker. Perceived organizational responsibility is also a direct predictor of intent to make a claim. The results provide a clearer understanding of when an individual is more likely to favor making a claim in response to perceived sexual harassment. The practical implications include the following: (a) Sexual harassment training for supervisors is important because their sexual harassment is most likely to lead to a legal claim, (b) antisexual harassment policies have the effect of reducing the likelihood that a victim will perceive the organization as responsible for failing to prevent a supervisor’s action, and (c) organizations should make clear their opposition to sexual harassment both to discourage harassers and to divert a victim’s attribution for responsibility away from the organization if an incident takes place.
Complete remission of refractory, ulcerated, primary cutaneous CD30+ anaplastic large cell lymphoma following brentuximab vedotin therapy.

Primary cutaneous CD30 + anaplastic large cell lympho-mas (pc-ALCL) belong to the group of rare, non-mycosis fungoides T-cell lymphomas (1). Similar to lymphomatoid papulosis the characteristic immunohistochemical finding of pc-ALCL is CD30-positivity of infiltrating neoplastic T cells. To date, only limited data is available on the treatment of pc-ALCL and current recommendations are largely based on case reports and small cohort studies (2). Surgical excision and/or radiotherapy are usually performed in limited disease. In cases of disseminated disease, multi-agent chemotherapy has shown good effects, but is accompanied with high toxicity and high recurrence rates. Herein, we report a case of refractory, widespread pc-ALCL that was successfully treated with brentuximab vedotin. A 56-year-old Caucasian man was initially referred to our department with a solid erythematous nodule 4 cm in diameter located in the left popliteal region. The patient's further medical history included coronary heart disease, peripheral arterial disease, and hyperuricemia. Histopathological evaluation of a lesional biopsy showed diffuse lymphocytic infiltrations of primarily large anaplastic cells within the entire dermis. Immunohistochemical analysis revealed CD4-, CD5-, and CD30-positivity in more than 70% and expression of Ki-67 in more than 50% of infiltrating cells (Fig. 1). The lymphocytes showed a loss of CD3 expression and were negative for anaplastic lymphoma kinase-1 (ALK-1) and T-cell beta chain antigen receptor F1 (beta F-1). CD8 was punctually expressed by small nuclei lymphocytic cells. At this time, there was no evidence for extracutaneous disease. Based on the clinical and histopathological findings, a diagnosis of CD30 + pc-ALCL was made and the tumour was completely excised. Seven months later the patient presented with a new nodule located at the preexisting scar as well as palpable, enlarged lymph nodes in the left inguinal region. Histological analysis of the lesions showed secondary infiltration of the CD30 + pc-ALCL (the histological evaluation of 5 out of 8 removed lymph nodes showed loss of normal lymph node architecture as well as large amounts of tumour infiltrates consisting of large, anaplastic, proliferating, CD30 + lymphoid cells). Complete computed tomography (CT) scan and bone marrow biopsy were unremarkable. We decided to initiate radiation therapy of the popliteal and inguinal area as well as low-dose therapy with methotrexate (15 mg/week). However, new skin lesions and lymph node metastases developed within a few weeks. Subsequent inguinal lymphadenectomy, a second course of radiation therapy, low-dose interferon alpha, bexarotene, and 6 cycles of mono-chemotherapy with gemcitabine did not result …
Molecular mechanisms of cell recruitment to inflammatory sites: general and tissue-specific pathways.

The observation that circulating leucocytes adhere to and migrate across the vascular endothelium was first made 70 yr ago; this was noted to occur without breach of the endothelial barrier, suggesting the presence of complex regulatory mechanisms [1]. More recently, in a series of classic experiments, Gowans and Knight observed that lymphocytes isolated from the rat thoracic duct homed rapidly back to lymph nodes and secondary lymphoid organs upon reinjection: furthermore, it was noted that this occurred across the distinctly shaped endothelial cells of the postcapillary venules [2]. Since then we have learnt much about the molecular basis of leucocyte extravasation and the regulatory mechanisms involved. In this review we will describe molecular interactions involved in the stages of leucocyte recruitment and extravasation into the tissues. We will also describe the specific molecular interactions that allow the selective recruitment of tissue-specific leucocytes to inflammatory sites. Finally, we will emphasize the central role that adhesion molecules have in the development of the inflammatory response by drawing from examples of human disease, and describe recent progress in the therapeutic targeting of these molecules with particular reference to inflammatory arthritis.