Miracle-dz/UniFAR-FTUs huggingface dataset:
Novel Carbapenem Antibiotics for Parenteral and Oral Applications: In Vitro and In Vivo Activities of 2-Aryl Carbapenems and Their Pharmacokinetics in Laboratory Animals

ABSTRACT SM-295291 and SM-369926 are new parenteral 2-aryl carbapenems with strong activity against major causative pathogens of community-acquired infections such as methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae (including penicillin-resistant strains), Streptococcus pyogenes, Enterococcus faecalis, Klebsiella pneumoniae, Moraxella catarrhalis, Haemophilus influenzae (including β-lactamase-negative ampicillin-resistant strains), and Neisseria gonorrhoeae (including ciprofloxacin-resistant strains), with MIC90s of ≤1 μg/ml. Unlike tebipenem (MIC50, 8 μg/ml), SM-295291 and SM-369926 had no activity against hospital pathogens such as Pseudomonas aeruginosa (MIC50, ≥128 μg/ml). The bactericidal activities of SM-295291 and SM-369926 against penicillin-resistant S. pneumoniae and β-lactamase-negative ampicillin-resistant H. influenzae were equal or superior to that of tebipenem and greater than that of cefditoren. The therapeutic efficacies of intravenous administrations of SM-295291 and SM-369926 against experimentally induced infections in mice caused by penicillin-resistant S. pneumoniae and β-lactamase-negative ampicillin-resistant H. influenzae were equal or superior to that of tebipenem and greater than that of cefditoren, respectively, reflecting their in vitro activities. SM-295291 and SM-369926 showed intravenous pharmacokinetics similar to those of meropenem in terms of half-life in monkeys (0.4 h) and were stable against human dehydropeptidase I. SM-368589 and SM-375769, which are medoxomil esters of SM-295291 and SM-369926, respectively, showed good oral bioavailability in rats, dogs, and monkeys (4.2 to 62.3%). Thus, 2-aryl carbapenems are promising candidates that show an ideal broad spectrum for the treatment of community-acquired infections, including infections caused by penicillin-resistant S. pneumoniae and β-lactamase-negative ampicillin-resistant H. influenzae, have low selective pressure on antipseudomonal carbapenem-resistant nosocomial pathogens, and allow parenteral, oral, and switch therapies.
The present and future disease burden of hepatitis C virus (HCV) infection with today's treatment paradigm

The disease burden of hepatitis C virus (HCV) is expected to increase as the infected population ages. A modelling approach was used to estimate the total number of viremic infections, diagnosed, treated and new infections in 2013. In addition, the model was used to estimate the change in the total number of HCV infections, the disease progression and mortality in 2013–2030. Finally, expert panel consensus was used to capture current treatment practices in each country. Using today's treatment paradigm, the total number of HCV infections is projected to decline or remain flat in all countries studied. However, in the same time period, the number of individuals with late‐stage liver disease is projected to increase. This study concluded that the current treatment rate and efficacy are not sufficient to manage the disease burden of HCV. Thus, alternative strategies are required to keep the number of HCV individuals with advanced liver disease and liver‐related deaths from increasing.
Stimulation of colorectal cancer cell line growth by ET-1 and its inhibition by ETA antagonists

BACKGROUND The vasoactive peptide endothelin 1 (ET-1) acts via two receptors, endothelin receptors A (ETA) and B (ETB). ET-1 is overexpressed by human cancers in vivo and in vitro and may be mitogenic for cancer cells. METHOD To elucidate if ET-1 is a growth regulator the following were investigated in human colorectal cancer cell lines (LIM1215 and HT29): ET-1 production by ELISA; ET receptor expression using radioligand autoradiographic techniques; and responsiveness to ET-1, and to ETA and ETB antagonism by growth measurements. RESULTS ET-1 was produced by LIM1215 and HT29 cells (21.3 and 41.7 fmol/ml/106 cells (24 hours); 22.6 and 71.7 fmol/ml/106 cells (48 hours), respectively). ETA and ETB receptors were expressed by both cell lines. Addition of ET-1 resulted in a dose dependent increase in cell numbers which was significant at 10−8–10−9 M for LIM1215, with the greatest increase at 10−8 M (32.7% and 28.4% increase above controls at 48 hours and 72 hours; p<0.05) and at 10−8–10−9 M for HT29, with the greatest increase at 10−9 M (13.4% and 15.7% increase above controls at 48 hours and 72 hours; p<0.05). ETAantagonists BQ123 and BQ610, but not the ETB antagonist BQ788, inhibited ET-1 induced proliferation of both LIM1215 and HT29 (p<0.05). CONCLUSION ET-1 can stimulate the proliferation of colorectal cancer cell lines via the ETA, but not the ETB, receptor.
Urbanization and human health

SUMMARY Urbanization involves a physical change in which increasing proportions of populations live in urban settings, however defined. It also implies considerable changes in the ways in which these people live, how they earn their livelihoods, the food which they eat, and the wide range of environmental factors to which they are exposed. There is another underlying assumption that, increasingly, urban populations will be more healthy than their rural counterparts and that higher levels of urbanization will equate with better health status. This paper discusses some of the assumptions underlying this contention. It takes issue with certain of them, particularly the assumption that urbanization affects the health of all residents equally. It is manifestly evident that in many cities, particularly in the developing world, the poor are exposed to greater risks and have much lower health status than their richer neighbours. In addition, whilst urban residents may theoretically have a better access to health care and services than do residents in many rural areas, and whilst many indicators of health do appear better in more highly urbanized societies than ones less so, there are caveats. The paper introduces the concept of epidemiological transition, which suggests that, whilst life expectancy might be higher in many urbanized countries and in certain cities, the inhabitants are often merely suffering from different forms of ill-health, often chronic or degenerative, rather than infective. In certain cities in middle-income countries, residents, particularly the poor, are exposed to a double risk of both infection and chronic degenerative ailments. The paper concludes with a consideration of more general recent statements from the World Health Organization among others, on the impact of urbanization on health. The ‘Healthy Cities’ project is also discussed. WHO identifies a range of general determinants of urban health: physical, social, cultural and environmental. Many represent the by-products of modernization and especially industrialization. It is emphasized that urbanization, and the concentration of human beings into new areas in particular, can bring exposure to new risk factors for large numbers of people. The growth of infectious and parasitic disease in some urban settings must therefore be recognized, as must the emergence of chronic diseases, with the concomitant need for investment in new types of health and social care. However, a number of constraints militate against the achievement of improved urban health, especially in developing countries. The paper concludes by considering some important constraints: the very scale of urban health problems; the impacts of structural adjustment programmes which cut public expenditure on environmental health, health services and nutrition, thereby increasing the vulnerability of the poor; urban management problems; lack of political will; and the difficulties of measuring change in health and effects of policies.
International legal concept of “effective control” of foreign territories and lessons for Azerbaijan and Ukraine

In today's conditions, when the appetite of the aggressor remains unlimited, but one wants to appear civilized, new forms of occupation (hybrid occupation) arise, one of which receives the definition of «effective control». This concept is developed in the decisions of the European Court of Human Rights (ECHR), and in the future – in the resolutions of the Parliamentary Assembly of the Council of Europe (PACE). The concept proceeds from the fact that the notion of territorial jurisdiction is closely related to the state's ability to exercise real control over the territory. When a state does not exercise authority over part of its territory, which may occur as a result of armed occupation by another state that controls the territory, the responsibility for observing human rights in that territory rests with such a controlling state. Since this form of occupation concerns both Azerbaijan and Ukraine, and this is fixed in the legal documents of international institutions, it is advisable to draw certain parallels for the extraction of necessary lessons.
Advanced diagnostics in Renal Mass using Optical Coherence Tomography: a preliminary report

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The ZIIR Element of the Epstein-Barr Virus BZLF1 Promoter Plays a Central Role in Establishment and Maintenance of Viral Latency

ABSTRACT The Epstein-Barr virus (EBV) BZLF1 gene encodes the immediate-early (IE) protein Zta, which plays a central role in regulating the switch between viral latency and lytic replication. A silencing element, ZIIR, is located between the ZID and ZII positive regulatory elements in the BZLF1 promoter Zp. We report here the phenotypes of variants of EBV strain B95.8 containing base substitution mutations in this ZIIR element. HEK293 cells infected with ZIIR mutant (ZIIRmt) virus produced at least 20-fold more viral IE Zta and Rta and early (E) EAD protein than did cells infected with the parental wild-type (WT) virus, leading to viral DNA replication and production of infectious virus. However, ZIIR mutant virus was 1/10 as efficient as WT virus in establishing proliferating B-cell clones following infection of human primary blood B cells. The ZIIRmt-infected lymphoblastoid cell lines (LCLs) that did grow out exhibited a phenotype similar to the one observed in 293 cells, including marked overproduction of IE and E gene products relative to WT-infected LCLs and lytic replication of the viral genome. Incubation of the ZIIRmt-infected LCLs with the chemical inducer 12-O-tetradecanoyl-phorbol-13-acetate (TPA) led to much greater activation of Zp than did the same treatment of WT- or ZVmt-infected LCLs. Furthermore, a protein kinase C (PKC) inhibitor, bis-indolylmaleimide, eliminated this activation by TPA. Thus, we conclude that ZIIR is a potent silencing element of Zp; it plays a key role in establishment and maintenance of EBV latency by inhibiting activation of Zp through the PKC signal transduction pathway.
Habitat Segregation and Biochemical Activities of Marine Members of the Family Vibrionaceae

A comparative study of marine members of the family Vibrionaceae with the technique of numerical taxonomy revealed habitat segregation as well as a cosmopolitan nature of species distribution among the vibrios in different marine environments. The bacterial strains analyzed were isolated from seawater, sediments, phyto- and zooplankton, and fish in the Indian Ocean, the South and East China Sea, and West Pacific Ocean, and coastal areas of Japan. A total of 155 morphological, physiological, and biochemical tests were carried out for each of 405 strains examined. The results showed that most of the large taxonomical clusters which emerged from the computation corresponded to ecological groups which have particular niches. For instance, each group of seawater vibrios inhabited a particular water layer of limited depth range, in spite of the fact that strains of the group were isolated from sampling locations spread over a wide area from the Indian Ocean to Japanese coast. Various vibrio groups showed remarkable differences in their physiological and biochemical activities, and the activities of each group seemed to correspond with its ecological niche. The strains which inhabited surface-water layers grew fast and actively utilized many high-molecular-weight organic compounds and carbohydrates that are derived from fresh, easily degradable organic matter present in the surface waters, whereas the middle- and deep-water vibrios did not decompose most of the high-molecular-weight organic compounds except chitin but, rather, utilized some carbohydrates and organic acids which seemed to be derived from refractory particulate organic matter present in the deeper waters.
NetLogo Based Model for VANET Behaviors Dynamic Research

The meanings and contents of the vehicular networks simulation research are addressed. By the discussion of self-organization characteristics and the interaction between a large numbers of self-organizing vehicles, a new vehicle mobility model based on the true scene of the participants is proposed that is P-AOC modeling method. It aims to obtain a more profound comprehension of the complex behavior working mechanism of the vehicle in the VANET environment and be able to faithfully reproduce the real VANET scene. The emergent behavior and sudden existing behaviors of VANET entities are well reflected and this helps for safety driving and warning timely.
Alendronate Attenuates Eosinophilic Airway Inflammation Associated with Suppression of Th2 Cytokines, Th17 Cytokines, and Eotaxin-2

Bisphosphonates (BPs) have been widely used to treat osteoporosis. They act by inhibiting farnesyl diphosphate synthase in the mevalonate pathway. This resembles the action of statins, whose immune-modulating effect has recently been highlighted. In contrast, the effect of BPs on immune responses has not been elucidated well. In this study, we examined the effect of alendronate (ALN), a nitrogen-containing BP, on allergic airway inflammation in a mouse model. BALB/c mice were sensitized twice with OVA and challenged three times with nebulized OVA to induce eosinophilic airway inflammation. ALN was administered by an intragastric tube before each inhalation. ALN strongly suppressed airway eosinophilia and Th2, as well as Th17 cytokine production in the lung. ALN also attenuated eotaxin-2 production in the lung. Immunohistochemistry demonstrated that the major cell source of eotaxin-2 was peribronchial/perivascular macrophages, and flow cytometrical studies confirmed that ALN decreased eotaxin-2 expression in these macrophages. Furthermore, ALN attenuated eotaxin-2 production from mouse pleural macrophages and human monocyte/macrophage-like THP-1 cells in vitro. These results suggest that ALN suppressed Ag-induced airway responses in the mouse model. The suppression of eotaxin-2 production from macrophages appears to be one of ALN’s immunomodulatory effects, whereas the mechanism by which ALN suppressed Th2 and Th17 responses could not be fully elucidated in this study. Although a clinical study should be conducted, ALN could be a novel therapeutic option for asthma.
Positive and Negative Information Transfers from Management

We examine positive and negative information transfers associated with management earnings and revenue forecasts. Positive information transfers are due to industry commonalities whereas negative information transfers are caused by competitive shifts. We argue that positive and negative intraindustry information transfers offset each other and lead to an overall finding of no information transfers even though they exist. We also conjecture that the type of information transfers from the same management forecast can be positive or negative based on the characteristics of the information receiver. We hypothesize positive information transfers to nonrival firms and negative information transfers to rivals. Consistent with our prediction, we find negative (positive) information transfers between forecasting firms and nonforecasting rival (nonrival) firms in the same industry. Through analyses using competitors identified by Hoover's and 10-K reports, we show more general evidence of
THE CLINICAL ASSESSMENT OF BINOCULAR VISION BEFORE AND AFTER A WORKING DAY *

Abstract— This paper looks at the clinical investigative and measurement procedures used in assessing binocular vision at the beginning of a normal working day and compared with the same procedures carried out in the afternoon which included several hours of close work. In 84 young adults, it was found that dissociated heterophoria, associated heterophoria and fixation disparity increased. This was accompanied by visual symptoms. It is likely that any decompensation of heterophoria is worse at the end of a working day. The results of this investigation raise the question of the value of some clinical tests for binocular assessment carried out at the beginning of the day.
A Modified Stability Analysis of Two-Dimensional Linear Time Invariant Discrete Systems within the Unity-Shifted Unit Circle

This paper proposes a method to ascertain the stability of two dimensional linear time invariant discrete system within the shifted unit circle which is represented by the form of characteristic equation. Further an equivalent single dimensional characteristic equation is formed from the two dimensional characteristic equation then the stability formulation in the left half of Z-plane, where the roots of characteristic equation f(Z) = 0 should lie within the shifted unit circle. The coefficient of the unit shifted characteristic equation is suitably arranged in the form of matrix and the inner determinants are evaluated using proposed Jury’s concept. The proposed stability technique is simple and direct. It reduces the computational cost. An illustrative example shows the applicability of the proposed scheme.
A myristylated membrane protein encoded by the vaccinia virus L1R open reading frame is the target of potent neutralizing monoclonal antibodies.

We identified a protein component of the intracellular mature vaccinia virion membrane that is a target of a potent neutralizing monoclonal antibody, 7D11, obtained from Alan L Schmaljohn. By immunofluorescent and electron microscopic analysis, MAb 7D11 was found to stain intracytoplasmic viral factories, virion membranes in cell sections, and the surface of negatively stained preparations of purified virions. The MAb 7D11 antigen, which is synthesized at late times in infection, has apparent molecular masses of 25 and 29 kDa under nonreducing and reducing conditions, respectively. The membrane antigen was most efficiently extracted from virions by NP40 detergent in combination with a reducing agent; in addition, the protein partitioned exclusively into the detergent phase when extracted with Triton X-114. Although the N-terminus of the immunoaffinity-purified protein was blocked, sequence analysis of trypic peptides revealed that the MAb 7D11 antigen was identical to the myristylated protein encoded by the L1R open reading frame previously described by C.A. Franke, E.M. Wilson, and D.E. Hruby (1990, J. Virol. 64, 5988-5996). Validation of this genetic assignment was provided by the ability of MAb 7D11 to immunoprecipitate a [3H]myristic acid-labeled product of the expected molecular weight from infected cells. In addition, we discovered that the previously described neutralizing monoclonal antibody 2D5 (Y. Ichihashi, T. Takahashi, and M. Oie, 1994, Virology 202, 834-843) also recognizes the L1R protein.
Alteration of the ERK5 pathway by hydroxysafflor yellow A blocks expression of MEF2C in activated hepatic stellate cells in vitro: Potential treatment for hepatic fibrogenesis

Abstract Context: Hepatic fibrosis ultimately leads to cirrhosis if not treated effectively. Hepatic stellate cells (HSC) are a main mediator of hepatic fibrosis through the accumulation of extracellular matrix proteins. Suppression activation of passaged HSC has been proposed as therapeutic strategies for the treatment and prevention of hepatic fibrosis. Objective: To evaluate the effect of hydroxysafflor yellow A (HSYA), an active chemical compound derived from the flowers of Carthamus tinctorius L. (Compositae), on HSC inhibition, and to begin elucidating underlying mechanisms. Materials and methods: Primary HSCs were isolated from rats by in situ pronase/collagenase perfusion. Culture-activated HSCs were treated with or without HSYA at 30 μM in the presence or absence of PD98059 for 48 h, and then cell proliferation was measured by MTS assays. Messenger RNA (mRNA) expression was quantified by polymerase chain reaction, and protein was quantified by Western blots or enzyme-linked immunosorbent assays. Results: HSYA significantly inhibits culture-activated HSC proliferation in a dose-dependent and time-dependent manner with an IC50 value of 112.79 μM. HSYA (30 μM) induce the suppression of HSC activation, as indicated by decreases in contents of type I alpha collagen in HSC-cultured media and expression of α-smooth muscle actin protein in culture-activated HSC by 55 and 71%, respectively. HSYA (30 μM) also caused significant decreases in mRNA expression of type III alpha collagen in HSC by 28%. HSYA (30 μM) suppresses myocyte enhancer factor 2 C (MEF2C) expression both at its mRNA and protein levels by 60 and 61%, respectively. Further study demonstrated that HSYA (30 μM) caused significant decreases in p-ERK5 by 49%. Blocking extracellular signal-regulated protein kinase 5 (ERK5) activity by XMD 8--92, an ERK5 inhibitor, markedly abrogated the inhibitive effects of HSYA on HSC activation, and blocked the HSYA-mediated MEF2C down-regulation. Conclusions: HSYA suppress HSC activation by ERK5-mediated MEF2C down-regulation and makes it a potential candidate for prevention and treatment of hepatic fibrogenesis.
Defining the role of T cell‐derived leptin in the modulation of hepatic or intestinal inflammation in mice

The role of leptin in the immune system has been well established. While adipocytes represent the major source, leptin production by lymphocytes, infiltrating at the site of inflammation, was recently demonstrated. However, the significance of this locally released leptin remains unresolved. In the present study, two models in which absence of leptin‐signalling is associated with protection were employed: the model of ConA‐induced hepatitis and the CD4+CD45Rbhigh transfer model of colitis. For the ConA model, scid mice were reconstituted with either WT or leptin‐deficient (ob/ob) CD4+ T cells. Eight weeks post transfer, ConA was injected and serum ALT, TNFα, leptin as well as liver mononuclear cell activation and histological signs of inflammation were evaluated. No difference between recipients of WT or ob/ob cells was observed for any of the parameters evaluated. In the second model, either WT or ob/ob CD4+CD45Rbhigh cells were transferred into scid mice. No histological differences were detected, although recipients of ob/ob cells showed higher weight loss compared to recipients of WT cells. Spontaneous production of IL‐6 from colon cultures obtained from recipients of ob/ob cells was reduced compared to recipients of WT cells, whereas stimulation of lamina propria lymphocytes with leptin resulted in a higher IFNγ release in recipients of ob/ob cells compared to recipients of WT cells. In conclusion, the present study provides evidence that T cell‐derived leptin does not play a major role in the regulation of the inflammatory process, indicating that the adipose tissue is the critical player in the immune‐modulating effects of leptin.