Genetic and Modifiable Risk Factors Contributing to Cisplatin-Induced Toxicities

Effective administration of traditional cytotoxic chemotherapy is often limited by off-target toxicities. This clinical dilemma is epitomized by cisplatin, a platinating agent that has potent antineoplastic activity due to its affinity for DNA and other intracellular nucleophiles. Despite its efficacy against many adult-onset and pediatric malignancies, cisplatin elicits multiple off-target toxicities that can not only severely impact a patient’s quality of life, but also lead to dose reductions or the selection of alternative therapies that can ultimately affect outcomes. Without an effective therapeutic measure by which to successfully mitigate many of these symptoms, there have been attempts to identify a priori those individuals who are more susceptible to developing these sequelae through studies of genetic and nongenetic risk factors. Older age is associated with cisplatin induced ototoxicity, neurotoxicity and nephrotoxicity. Traditional genome-wide association studies have identified single nucleotide polymorphisms in ACYP2 and WFS1 associated with cisplatin-induced hearing loss. However, validating associations between specific genotypes and cisplatin-induced toxicities with enough stringency to warrant clinical application remains challenging. This review summarizes the current state of knowledge with regard to specific adverse sequelae following cisplatin-based therapy with a focus on ototoxicity, neurotoxicity, nephrotoxicity, myelosuppression and nausea/emesis. We discuss variables (genetic and nongenetic) contributing to these detrimental toxicities, and currently available means to prevent or treat their occurrence

Intraspecific variability modulates interspecific variability in animal organismal stoichiometry.

Interspecific differences in organismal stoichiometry (OS) have been documented in a wide range of animal taxa and are of significant interest for understanding evolutionary patterns in OS. In contrast, intraspecific variation in animal OS has generally been treated as analytical noise or random variation, even though available data suggest intraspecific variability in OS is widespread. Here, we assess how intraspecific variation in OS affects inferences about interspecific OS differences using two co-occurring Neotropical fishes: Poecilia reticulata and Rivulus hartii. A wide range of OS has been observed within both species and has been attributed to environmental differences among stream systems. We assess the contributions of species identity, stream system, and the interactions between stream and species to variability in N:P, C:P, and C:N. Because predation pressure can impact the foraging ecology and life-history traits of fishes, we compare predictors of OS between communities that include predators, and communities where predators are absent. We find that species identity is the strongest predictor of N:P, while stream or the interaction of stream and species contribute more to the overall variation in C:P and C:N. Interspecific differences in N:P, C:P, and C:N are therefore not consistent among streams. The relative contribution of stream or species to OS qualitatively changes between the two predation communities, but these differences do not have appreciable effects in interspecific patterns. We conclude that although species identity is a significant predictor of OS, intraspecific OS is sometimes sufficient to overwhelm or obfuscate interspecific differences in OS

Governing the Empire. Provincial Administration in the Almohad Caliphate (1224-1269): Critical Edition, Translation, and Study of Manuscript 4752 of the Ḥasaniyya Library in Rabat Containing 77 Taqādīm ("Appointments")

traduction anglaise Travis BruceGoverning Empire is a study, accompanied by a re-edition and a French translation, of maǧmūʿ Yaḥyá, the " compendium of Yaḥyá ", manuscript 4752 in the Library ḥasaniyya in Rabat. This little volume, the surviving copy of which dates from the 16th-17th centuries, reproduces a formulary composed in the late 13th century by Yaḥyá al-Ḫaḏūǧ, a man of letters living at the time of the demise of the Almohad Empire in 1269. It contains 77 acts of appointment of provincial officials, governors, military chiefs, chiefs of Arab tribes, tax-collectors and judges, written between 1224 and 1269. Of this total, 73 acts (two of them identical) concern the Almohad Empire, especially the Maghrebian part, and four concern the anti-Almohad principality of Ibn Hūd al-Mutawakkil of Murcia (r. 1228-1238) in the Iberian Peninsula. The acts reproduced by Yaḥyá belong to the highly codified genre of chancery literature. Written most frequently in rhyming prose (saǧʿ) and intended for proclamation in the great mosques of the Empire, they obey rules of composition and follow rhetorical, syntactical and linguistic procedures which place them --as the compiler asserts-- in the sphere of the adab, that is literature, or more generally the culture of the "man of good breeding". Partaking of poetry, sermon, oratory, normative literature and religious discourse, the appointments reproduced there are the expression of a sovereign order, the Almohad imperial order, or the anti-Almohad order of the Hūdi principality of Murcia. Set down in writing and rendered anonymous through the quasi-systematic deletion of proper names, toponyms and dates, these acts were neutralized for the use of successive specialists in the language of power. Performative as they were, they came to be accepted as models and thus were absorbed into the ever-growing thesaurus of reference texts. This pragmatic collection is the last vestige of the most important indigenous authority in the history of the Maghreb. Governing Empire begins by retracing the political history of the Almohad Empire and the stages through which a territory and an authority were built up. It recalls the ideological, political and religious foundations which made Ibn Tūmart possible to unify the Maghreb and al-Andalus in the mid-12th century in the service of a dynasty of Berber origin. ʿAbd al-Mu'min (r. 1130-1162) and his descendants, the Mu'minids, mobilised the strength of the tribes of the time, Berber and Arab, to impose a dogma devised by the greatest of contemporary thinkers. Living witnesses of the islamization and arabization of the Maghreb, this dynasty resolved to reorganize the structures of power and authority to its own advantage. The Almohad sovereigns, who had assumed the title of Caliph in consonance with their pretension to guide all the peoples of Islam (umma), in the manner of the Muʿtazilite in 9th-century Iraq, claimed for themselves the authority to interpret divine law. To that end, jurists and wise men were separated from the interpretative process that the Malikite school had reserved to them since the 9th century, and they were reduced to judicial tasks or enrolled in the chancery services. The literature that the chancery produced, of which the manuscript presented, re-edited and translated here is one of the fundamental examples, plainly reveals this reversal of the relationships of authority between the religious knowledge of the ulemas and the political power of the caliphs. The organization of the "compendium of Yaḥyá", which is presented in the second part, throws light on the original ideological concepts predominating at the close of the Almohad era: thus, military and fiscal functions, which belong to the political order --governors, army generals, admirals of the fleet and tax collectors-- are clearly set apart from the judicial functions pertaining to the judges. Law-making devolved upon the sovereign, the sole authorized interpreter of divine law as embodied in the Qur'an and Tradition. The task of creating positive law thus rested entirely with the Caliph-imām, heir to the founder of the Almohad movement, Ibn Tūmart (d. 1130) -- the guide inspired by God, "impeccable imām and acknowledged Mahdī". The tasks assigned to the appointed functionaries, the counsels and orders given them, and the instructions addressed to subjects, all clearly reflect the organic conception of society and of imperial authority that characterized the Almohad ideology. That ideology was revolutionary inasmuch as it clearly departed from functionalist approaches, like that implicit in the al-Aḥkām al-Sulṭāniyya wa l-Wilāyat al-Dīniyya ("The Ordinances of Government") of al-Māwardī (d. 1058). The careful edition and the French translation of Yaḥyá's formulary in the third part of Governing Empire give a good idea of the breadth of literary talent demanded of chancery secretaries, veritable craftsmen of language, simply to produce the decrees of power. The infinite stylistic and lexical variations combine adherence to rigid codes of chancery language with the kind of poetic and rhetorical innovations characteristic of great works of literature. This work on the language of power, at once laborious and skilled, bureaucratic and poetic, puts a voice to a specific authority --the authority of the Almohad caliphs, rooted in a particular time and place: the 13th-century Maghreb. The posthumous compilation of these performative utterances abstracts the language of power and sets Almohad history, dogma and order in the context of the corpus of timeless Islamic authorities. This formulary thus affords a glimpse of the specific nature of and the role played by administrative archives in the mediaeval Muslim world and throws light on the exceptional intricacy of Islamic imperial bureaucracies as exemplified by their chancery, the dīwān al-inšā', literally the "bureau of creation"

Rim-functionalized cryptophane-111 derivatives via heterocapping, and their xenon complexes

International audienceCapping of cyclotriphenolene (3a) by the more available cyclotriguaiacylene (3c) or trisbromocyclotriphenolene (3b) gives the first rim-functionalized cryptophane-111 derivatives. Crystal structures of the xenon complexes reveal high cavity packing coefficients and unprecedentedly short Xe...C contacts

Regulation of development by Rx genes

The paired-like homeobox-containing gene Rx has a critical role in the eye development of several vertebrate species including Xenopus, mouse, chicken, medaka, zebrafish and human. Rx is initially expressed in the anterior neural region of developing embryos, and later in the retina and ventral hypothalamus. Abnormal regulation or function of Rx results in severe abnormalities of eye formation. Overexpression of Rx in Xenopus and zebrafish embryos leads to overproliteration of retinal cells. A targeted elimination of Rx in mice results in a lack of eye formation. Mutations in Rx genes are the cause of the mouse mutation eyeless (ey1), the medaka temperature sensitive mutation eyeless (el) and the zebrafish mutation chokh. In humans, mutations in Rx lead to anophthalmia. All of these studies indicate that Rx genes are key factors in vertebrate eye formation. Because these results cannot be easily reconciled with the most popular dogmas of the field, we offer our interpretation of eye development and evolution

Pursuing Racial Equity in Suburban High Schools: How Informal School Leaders Rise to the Challenge of Addressing Racial Inequity

This qualitative study examines the experiences of three informal teacher leaders in diversifying suburban high schools as they developed strategies to address racial inequity at their schools. Each participant in this study represented a distinct racial identity (Asian-American, Latino, white) with varying degrees of personal and professional race consciousness and positionality at their schools. Our study is framed by Banks (2014) theory of multicultural education, which suggests that schools must attend to five elements of school culture and practice in order to practice authentic multicultural education. With support from university faculty, the teacher leaders identified culturally responsive pedagogy and inclusive curriculum strategies to address the problem of inequitable learning conditions in their schools. We found that informal leaders in schools represent an often untapped resource who can energize and guide colleagues in targeted equity strategies that support broader macro-level diversity, equity and inclusion programs. This study explores the steps that three diversifying suburban schools took to demonstrate a commitment toward racial equity for BIPOC students, and how informal teacher leaders navigated the work with administration, colleagues, students, and community. We hope in this study to shed light on the commitments, policies, and practices that schools might develop to reflect a more democratic, inclusive learning environment for all students but particularly for BIPOC students and especially in places where they represent the minority in the school and do not feel that their voices are heard

Infectious Diseases

This article is made available for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.Pulmonary infections are caused by a wide range of pathogenic microorganisms, including bacteria, viruses, fungi, and parasites. The most common lung infections in immunocompetent hosts are caused by pyogenic bacteria (e.g., Streptococcus pneumoniae), common respiratory viruses, and mycoplasma. These infections are usually diagnosed by clinical and microbiologic studies, including cultures and serology tests. Lung biopsy is rarely used in these diagnoses. Patients with life-threatening pneumonia, especially those who are immunocompromised, are more likely to undergo lung biopsy to rule out unusual infections not easily diagnosed using conventional microbiologic methods and for which treatment strategies may be different. Pathogens more likely to be diagnosed using lung biopsy for which there are characteristic pathologic changes are highlighted in this chapter and listed in Table 4.1

Associations between food group intakes and circulating insulin-like growth factor-I in the UK Biobank: a cross-sectional analysis

PURPOSE: Circulating insulin-like growth factor-I (IGF-I) concentrations have been positively associated with risk of several common cancers and inversely associated with risk of bone fractures. Intakes of some foods have been associated with increased circulating IGF-I concentrations; however, evidence remains inconclusive. Our aim was to assess cross-sectional associations of food group intakes with circulating IGF-I concentrations in the UK Biobank. METHODS: At recruitment, the UK Biobank participants reported their intake of commonly consumed foods. From these questions, intakes of total vegetables, fresh fruit, red meat, processed meat, poultry, oily fish, non-oily fish, and cheese were estimated. Serum IGF-I concentrations were measured in blood samples collected at recruitment. After exclusions, a total of 438,453 participants were included in this study. Multivariable linear regression was used to assess the associations of food group intakes with circulating IGF-I concentrations. RESULTS: Compared to never consumers, participants who reported consuming oily fish or non-oily fish ≥ 2 times/week had 1.25 nmol/L (95% confidence interval:1.19–1.31) and 1.16 nmol/L (1.08–1.24) higher IGF-I concentrations, respectively. Participants who reported consuming poultry ≥ 2 times/week had 0.87 nmol/L (0.80–0.94) higher IGF-I concentrations than those who reported never consuming poultry. There were no strong associations between other food groups and IGF-I concentrations. CONCLUSIONS: We found positive associations between oily and non-oily fish intake and circulating IGF-I concentrations. A weaker positive association of IGF-I with poultry intake was also observed. Further research is needed to understand the mechanisms which might explain these associations

BCX4430 – A broad-spectrum antiviral adenosine nucleoside analog under development for the treatment of Ebola virus disease

SummaryThe adenosine nucleoside analog BCX4430 is a direct-acting antiviral drug under investigation for the treatment of serious and life-threatening infections from highly pathogenic viruses, such as the Ebola virus. Cellular kinases phosphorylate BCX4430 to a triphosphate that mimics ATP; viral RNA polymerases incorporate the drug's monophosphate nucleotide into the growing RNA chain, causing premature chain termination. BCX4430 is active in vitro against many RNA viral pathogens, including the filoviruses and emerging infectious agents such as MERS-CoV and SARS-CoV. In vivo, BCX4430 is active after intramuscular, intraperitoneal, and oral administration in a variety of experimental infections. In nonclinical studies involving lethal infections with Ebola virus, Marburg virus, Rift Valley fever virus, and Yellow Fever virus, BCX4430 has demonstrated pronounced efficacy. In experiments conducted in several models, both a reduction in the viral load and an improvement in survival were found to be related to the dose of BCX4430. A Phase 1 clinical trial of intramuscular administration of BCX4430 in healthy subjects is currently ongoing