bluuebunny/crossref_metadata_2025_split huggingface dataset:
Changes in the Plasmodial Surface Anion Channel Reduce Leupeptin Uptake and Can Confer Drug Resistance in
Plasmodium falciparum
-Infected Erythrocytes
Authors: Lisk Godfrey , Pain Margaret , Gluzman Ilya Y. , Kambhampati Shivkumar , Furuya Tetsuya , Su Xin-zhuan , Fay Michael P. , Goldberg Daniel E. , Desai Sanjay A. 
Published: April 2008

ABSTRACT
Cysteine protease inhibitors kill malaria parasites and are being pursued for development as antimalarial agents. Because they have multiple targets within bloodstream-stage parasites, workers have assumed that resistance to these inhibitors would not be acquired easily. In the present study, we used in vitro selection to generate a parasite resistant to growth inhibition by leupeptin, a broad-profile cysteine and serine protease inhibitor. Resistance was not associated with upregulation of cysteine protease activity, reduced leupeptin sensitivity of this activity, or expression level changes for putative cysteine or serine proteases in the parasite genome. Instead, it was associated with marked changes in the plasmodial surface anion channel (PSAC), an ion channel on infected erythrocytes that functions in nutrient and bulky organic solute uptake. Osmotic fragility measurements, electrophysiological recordings, and leupeptin uptake studies revealed selective reductions in organic solute permeability via PSAC, altered single-channel gating, and reduced inhibitor affinity. These changes yielded significantly reduced leupeptin uptake and could fully account for the acquired resistance. PSAC represents a novel route for the uptake of bulky hydrophilic compounds acting against intraerythrocytic parasite targets. Drug development based on such compounds should proceed cautiously in light of possible resistance development though the selection of PSAC mutants.
Trypanocidal and Leishmanicidal Activities of Sesquiterpene Lactones from
Ambrosia tenuifolia
Sprengel (Asteraceae)
Authors: Sülsen Valeria P. , Frank Fernanda M. , Cazorla Silvia I. , Anesini Claudia A. , Malchiodi Emilio L. , Freixa Blanca , Vila Roser , Muschietti Liliana V. , Martino Virginia S. 
Published: April 2008

ABSTRACT

Bioassay-guided fractionation of the organic extract of
Ambrosia tenuifolia
Sprengel (Asteraceae) led to the isolation of two bioactive sesquiterpene lactones with significant trypanocidal and leishmanicidal activities. By spectroscopic methods (
1
H- and
13
C-nuclear magnetic resonance, distortionless enhancement by polarization transfer, correlated spectroscopy, heteronuclear multiple-quantum coherence, electron impact-mass spectrometry, and infrared spectroscopy), these compounds were identified as psilostachyin and peruvin. Both compounds showed a marked in vitro trypanocidal activity against
Trypanosoma cruzi
epimastigotes with 50% inhibitory concentration (IC
50
) values of less than 2 μg/ml. Psilostachyin exerted a significant in vitro activity against the trypomastigote forms of
T. cruzi
(IC
50
, 0.76 μg/ml) and was selected for in vivo testing. Psilostachyin-treated mice had a survival of 100% and lower parasitemia values than control mice. Both compounds were also tested on
Leishmania
sp. promastigotes: psilostachyin (IC
50
, 0.12 μg/ml) and peruvin (IC
50
, 0.39 μg/ml) exerted significant leishmanicidal activities. This is the first time that the trypanocidal and leishmanicidal activities of these compounds have been reported. The selectivity index (SI) was employed to evaluate the cytotoxic effect of lactones on T lymphocytes. Although the SIs of both compounds were high for
T. cruzi
epimastigotes, psilostachyin was more selective against trypomastigotes (SI, 33.8) while peruvin showed no specificity for this parasite. Both compounds presented high selectivity for
Leishmania
spp. The results shown herein suggest that psilostachyin and peruvin could be considered potential candidates for the development of new antiprotozoal agents against Chagas' disease and leishmaniasis.
In Vitro Evaluation of CBR-2092, a Novel Rifamycin-Quinolone Hybrid Antibiotic: Microbiology Profiling Studies with Staphylococci and Streptococci
Authors: Robertson Gregory T. , Bonventre Eric J. , Doyle Timothy B. , Du Qun , Duncan Leonard , Morris Timothy W. , Roche Eric D. , Yan Dalai , Lynch A. Simon 
Published: April 2008

ABSTRACT

We present data from antimicrobial assays performed in vitro that pertain to the potential clinical utility of a novel rifamycin-quinolone hybrid antibiotic, CBR-2092, for the treatment of infections mediated by gram-positive cocci. The MIC
90
s for CBR-2092 against 300 clinical isolates of staphylococci and streptococci ranged from 0.008 to 0.5 μg/ml. Against
Staphylococcus aureus
, CBR-2092 exhibited prolonged postantibiotic effects (PAEs) and sub-MIC effects (SMEs), with values of 3.2, 6.5, and >8.5 h determined for the PAE (3× MIC), SME (0.12× MIC), and PAE-SME (3× MIC/0.12× MIC) periods, respectively. Studies of genetically defined mutants of
S. aureus
indicate that CBR-2092 is not a substrate for the NorA or MepA efflux pumps. In minimal bactericidal concentration and time-kill studies, CBR-2092 exhibited bactericidal activity against staphylococci that was retained against rifampin- or intermediate quinolone-resistant strains, with apparent paradoxical cidal characteristics against rifampin-resistant strains. In spontaneous resistance studies, CBR-2092 exhibited activity consistent with balanced contributions from its composite pharmacophores, with a mutant prevention concentration of 0.12 μg/ml and a resistance frequency of <10
−12
determined at 1 μg/ml in agar for
S. aureus
. Similarly, CBR-2092 suppressed the emergence of preexisting rifamycin resistance in time-kill studies undertaken at a high cell density. In studies of the intracellular killing of
S. aureus
, CBR-2092 exhibited prolonged bactericidal activity that was superior to the activities of moxifloxacin, rifampin, and a cocktail of moxifloxacin and rifampin. Overall, CBR-2092 exhibited promising activity in a range of antimicrobial assays performed in vitro that pertain to properties relevant to the effective treatment of serious infections mediated by gram-positive cocci.
Use of Gene Dosage Effects for a Whole-Genome Screen To Identify
Mycobacterium marinum
Macrophage Infection Loci
Authors: Park Bonggoo , Subbian Selvakumar , El-Etr Sahar H. , Cirillo Suat L. G. , Cirillo Jeffrey D. 
Published: April 2008

ABSTRACT

We recently identified two loci,
mel1
and
mel2
, that affect macrophage infection by
Mycobacterium marinum
. The ability of these loci to confer enhanced infection in trans is presumably due to gene dosage effects since their presence on plasmids increases expression from five- to eightfold. Reasoning that this phenomenon would allow identification of other mycobacterial genes involved in macrophage infection, we conducted a screen of an
M. marinum
DNA library that provides 2.6-fold coverage of the entire genome for clones that affect macrophage infection. Our preliminary screen identified 76 plasmids that carry loci affecting macrophage infection. We eliminated plasmids that do not confer the expected phenotype when retransformed (70%), that have identical physical maps (5%), or that carry either of the
mel1
or
mel2
loci (14%) from further consideration. Four loci that confer enhanced infection (
mel
) and four that confer repressed infection (
mrl
) of macrophages were identified, and two of each group were chosen for detailed analysis. Saturating transposon mutagenesis was used to identify the loci responsible, and
M. marinum
mutants were constructed in the genes involved. We expect these genes to provide insight into how mycobacteria parasitize macrophages, an important component of innate immunity.
The Active-Site Cysteinyls and Hydrophobic Cavity Residues of ResA Are Important for CytochromecMaturation inBacillus subtilis
Authors: Hodson Christopher T. C. , Lewin Allison , Hederstedt Lars , Le Brun Nick E. 
Published: May 2008

ABSTRACTResA is an extracytoplasmic membrane-bound thiol-disulfide oxidoreductase required for cytochromecmaturation inBacillus subtilis. Previous biochemical and structural studies have revealed that the active-site cysteinyls cycle between oxidized and reduced states with a low reduction potential and that, upon reduction, a hydrophobic cavity forms close to the active site. Here we report in vivo studies of ResA-deficientB. subtiliscomplemented with a series of ResA variants. Using a range of methods to analyze the cellular cytochromeccontent, we demonstrated (i) that the N-terminal transmembrane segment of ResA serves principally to anchor the protein to the cytoplasmic membrane but also plays a role in mediating the activity of the protein; (ii) that the active-site cysteines are important for cytochromecmaturation activity; (iii) that Pro141, which forms part of the hydrophobic cavity and which adopts acisconformation, plays an important role in protein stability; (iv) that Glu80, which lies at the base of the hydrophobic cavity, is important for cytochromecmaturation activity; and, finally, (v) that Pro141 and Glu80 ResA mutant variants promote selective maturation of low levels of onec-type cytochrome, subunit II of the cytochromecoxidasecaa3, indicating that this apocytochrome is distinct from the other three endogenousc-type cytochromes ofB. subtilis.
State Responsibility for Climate Change Damages
Authors: Voigt Christina 
Published: April 2008

AbstractThe Intergovernmental Panel on Climate Change (IPCC) outlined in its Fourth Assessment Report (2007) various consequences of continuing greenhouse gas emissions into the atmosphere. The effects include the loss of land and property, health and ecological damages, threats to human security and potential human casualties. The question which this article seeks to address is whether and how international law is equipped to deal with complex global challenges such as climate change. Special focus is given to the law on state responsibility and its capacity to deal with damages that are caused by a changing climate. In this context, the following legal issues will be examined: Can states be held responsible under international law for current or future climate change damages? Is there an obligation under public international law to prevent and to compensate for such damages? Especially the determination of a primary obligation to prevent harm, acting with due diligence, the question of causality and the determination of legal consequences are considered. As the examples given by the IPCC show, there will be an increasing need to address the issue of compensation for climate damages. Justice, fairness and international, national and human security require international law to adjust and live up to these challenges.
Human Rights Indicators for Assessing State Compliance with International Human Rights
Authors: de Beco Gauthier 
Published: April 2008

AbstractThis article discusses human rights indicators for assessing state compliance with international human rights. It analyses the use of human rights indicators before treaty bodies, how human rights aspects are to be integrated into these indicators and what conceptual framework must be developed for their establishment. The article also examines the different kinds of data required for human rights indicators, the way in which indicators relating to both civil and political and economic, social and cultural rights could be developed as well as the types of human rights indicators that could be used. The article concludes with how to make human rights indicators a useful instrument for monitoring state compliance with international human rights.
The Role of Persistent Objection in International Humanitarian Law
Authors: Guldahl Camilla 
Published: April 2008

AbstractThe publication of the ICRC Customary International Humanitarian Law encouraged a debate on the role of the doctrine of persistent objection in international humanitarian law. After setting out the background and meaning of this doctrine, this article will use the examples of belligerent reprisals against civilians and the protection of the environment in light of the use of nuclear weapons to show that although persistent objection is relied upon in international humanitarian law, the dictates of the principles of humanity and public conscience mean that it is less accepted and respected than in other areas of international law. This despite the fact that there are no express limitations on the application of this doctrine to international humanitarian law.
International Law, US Foreign Policy and Post-9/11 Islamic Fundamentalism: The Legal Status of the 'War on Terror'
Authors: Rehman Javaid , Ghosh Saptarshi 
Published: April 2008

AbstractThe days immediately after 11 September 2001 saw considerable tension, anger and anxiety. These politically charged days witnessed significant activity within the United Nations and various agencies of international law. The world community rightly condemned the 9/11 attacks as cowardly actions and an unforgivable crime against humanity. The entire global public opinion expressed sympathy for the victims of 9/11 and empathised with the people of the United States. The show of human solidarity as well as the Resolutions within the United Nations were the responses from the international community and international law to the terrorist attacks on the United States. It becomes, therefore, quite ironic that the enormity of the 9/11 human tragedy was used by the United States government to undermine the established norms, practices, principles and framework of international law. Over the past six years, the United States foreign policy has continued to violate international law and brutalise human dignity. This paper critically examines the systematic violation of international norms under the banner of 'war on terror'. It takes the view that the 'war on terror' has had exactly the effect which it proclaimed to prevent-namely the growth of radicalisation, terrorism and Islamic extremism.
The UN Human Rights Obligations and Immunity: An Oxymoron Casting a Shadow on the Transitional Administrations in Kosovo and East Timor
Authors: Werzer Julia 
Published: April 2008

AbstractOn the basis of the transitional administrations in Kosovo and East Timor, this article analyzes the compatibility of the UN human rights obligations with the wide scope of immunity enjoyed by the organization and its officials. By focusing on the right to a fair trial (and especially the right of access to a court), the author submits that the almost absolute lack of judicial mechanisms to review acts of UN transitional administrations violates the local population's human rights. Although institutions such as an Ombudsperson or a Human Rights Advisory Panel (in Kosovo) have been established, they do not constitute means of protection that are reasonable alternatives to independent and impartial courts. As a corollary, the international responsibility of the United Nations is entailed.
Elements of Nordic Practice 2005–2006: Finland
Authors: Rainne Juha 
Published: April 2008

AbstractThis report includes selected parts of Finnish state practice in the field of international law in 2005 and 2006. The activities during this period were dominated by Finland's Presidency of the European Union (EU) in the second half of 2006. The report comprises state practice related, inter alia, to humanitarian law, international tribunals, international sanctions, measures to combat terrorism and the work of the Sixth Committee of the UN General Assembly. Special attention is paid to the activities that took place in the field of international law during the Finnish EU Presidency.
Artifacts and Original Intent: A Cross-Cultural Perspective on the Design Stance
Authors: Barrett H. Clark , Laurence Stephen , Margolis Eric 
Published: April 2008

AbstractHow do people decide what category an artifact belongs to? Previous studies have suggested that adults and, to some degree, children, categorize artifacts in accordance with the design stance, a categorization system which privileges the designer's original intent in making categorization judgments. However, these studies have all been conducted in Western, technologically advanced societies, where artifacts are mass produced. In this study, we examined intuitions about artifact categorization among the Shuar, a hunter-horticulturalist society in the Amazon region of Ecuador. We used a forced-choice method similar to previous studies, but unlike these studies, our scenarios involved artifacts that would be familiar to the Shuar. We also incorporated a community condition to examine the possible effect of community consensus on how artifacts are categorized. The same scenarios were presented to university student participants in the UK. Across populations and conditions, participants tended to categorize artifacts in terms of a creator's intent as opposed to a differing current use. This lends support to the view that the design stance may be a universal feature of human cognition. However, we conclude with some thoughts on the limitations of the present method for studying artifact concepts.
When Minds Migrate: Conceptualizing Spirit Possession
Authors: Cohen Emma , Barrett Justin 
Published: April 2008

AbstractTo investigate possible cognitive factors influencing the cross-cultural incidence of spirit possession concepts and to develop a more refined understanding of the precise contours of 'intuitive mind-body dualism' (Bloom, 2004), two studies were conducted that explored adults' intuitions about the relationship between minds and bodies. Specifically, the studies explored how participants reason about the effects of a hypothetical mind-migration across a range of behaviours. Both studies used hypothetical mind-transfer scenarios in which the mind of one person ("Beth") is transferred into the body of another person ("Ann"). Participants were asked to reason about the new post-transfer person's behaviours and aptitudes. In Study 1, participants (n=25) were provided with a scale on which they indicated their answers; in Study 2, participants (n=26) responded to open-ended questions. In both studies, the majority of participants reasoned that while the post-transfer person's performance on physical tasks (e.g., sprinting) would be similar to the host (i.e., Ann) performance on mental tasks (e.g., story-telling) would be similar to the person whose mind has been transferred (i.e., Beth). Further, participants tended to assume a complete displacement of minds, such that the post-transfer person's performance on mental task items was reasoned to be identical to incoming person's performance normally. The relevance of these findings for explaining the variable incidence and spread of different possession concepts is discussed.
Some Cognitive Origins of Cultural Order
Authors: Malley Brian , Knight Nicola 
Published: April 2008

AbstractThe nature of cultural organization remains an open anthropological question. Although we eschew any simplistic global reductionism, here we argue that three organizational features of culture, its systematicity; the recurrence of distinctions across semantic, conceptual and practical boundaries; and the 'bleeding' of properties between associated concepts, may find their origin in fundamental operating principles of the human mind: respectively, the cognitive principle of relevance, the decompositionality of cognitive processing and the network structure of semantic memory. The reframing of some features of culture in cognitive terms may open up some ethnographic observations, so far resistant to anthropological explanation, to new avenues for theory and relevant data from other disciplines.
Recurrence of Bear Restoration Symbolism: Minusinsk Basin Evenki and Basin-Plateau Ute
Authors: McNeil Lynda 
Published: April 2008

AbstractBy combining ethnographic and evolutionary psychological approaches, this paper compares adaptive strategies of two groups of hunter-gatherers colonizing marginal environments, one in Southern Siberia (Minusinsk Basin) and the other in North America (Great Basin and Colorado Plateau). The biological and cultural survival of Southern Siberian (Evenki) and Basin-Plateau (Numic) hunter-gatherers depended upon developing a complex of social and symbolic strategies, including ritual, oral narratives and rock art. These symbolic representations, which emerged in response to reproductive and somatic demands, appear to have been preserved and transmitted inter-generationally, and to have recurred cross-culturally above chance.
Dualism Revisited: Body vs. Mind vs. Soul
Authors: Richert Rebekah , Harris Paul 
Published: April 2008

AbstractA large, diverse sample of adults was interviewed about their conception of the ontological and functional properties of the mind as compared to the soul. The existence of the mind was generally tied to the human lifecycle of conception, birth, growth and death, and was primarily associated with cognitive as opposed to spiritual functions. In contrast, the existence of the soul was less systematically tied to the lifecycle and frequently associated with spiritual as opposed to cognitive functions. Participants were also asked about three ethical issues: stem cell research, life support for patients in a persistent vegetative state and cloning. As expected, participants' beliefs about the ontology and function of the soul were linked to their judgments about these ethical issues whereas their beliefs about the mind were unrelated. Overall, the findings show that many adults do not espouse a simple body-mind dualism, and any tendency toward such dualism is unlikely to explain their beliefs in an afterlife. Instead, afterlife beliefs appear to be associated with the idea of an immaterial essence, potentially dissociable from the biology of life and death.
Policing Sex: Explaining Demons in the Cognitive Economies of Religion
Authors: Braxton Donald 
Published: April 2008

AbstractThis article offers a cognitive theory of religious postulations of demonic beings in religious systems. I suggest a significant tension between a biological inheritance of moderate sexual promiscuity and the culturally imposed ideal of exclusive monogamy generates the salience of libidinous supernatural agents to human minds. I review sexual selection theory as applied to humans, the sexual proclivities of demonic cultural constructs, and survey the literature on demonic beings in religious systems. I offer statistical evidence of groupings of demon beliefs around the chief tension points suggested by sexual selection theory. I end with suggestions for further empirical testing of the theory.
Vocal Emotion Recognition Across Disparate Cultures
Authors: Bryant Gregory , Barrett H. Clark 
Published: April 2008

AbstractThere exists substantial cultural variation in how emotions are expressed, but there is also considerable evidence for universal properties in facial and vocal affective expressions. This is the first empirical effort examining the perception of vocal emotional expressions across cultures with little common exposure to sources of emotion stimuli, such as mass media. Shuar hunter-horticulturalists from Amazonian Ecuador were able to reliably identify happy, angry, fearful and sad vocalizations produced by American native English speakers by matching emotional spoken utterances to emotional expressions portrayed in pictured faces. The Shuar performed similarly to English speakers who heard the same utterances in a content-filtered condition. These data support the hypothesis that vocal emotional expressions of basic affective categories manifest themselves in similar ways across quite disparate cultures.