An accurate scheme to solve cluster dynamics equations using a Fokker-Planck approach

We present a numerical method to accurately simulate particle size distributions within the formalism of rate equation cluster dynamics. This method is based on a discretization of the associated Fokker-Planck equation. We show that particular care has to be taken to discretize the advection part of the Fokker-Planck equation, in order to avoid distortions of the distribution due to numerical diffusion. For this purpose we use the Kurganov-Noelle-Petrova scheme coupled with the monotonicity-preserving reconstruction MP5, which leads to very accurate results. The interest of the method is highlighted on the case of loop coarsening in aluminum. We show that the choice of the models to describe the energetics of loops does not significantly change the normalized loop distribution, while the choice of the models for the absorption coefficients seems to have a significant impact on it

Progress towards the total synthesis of hamigerans C and D: a direct approach to an elaborated 6-7-5 carbocyclic core

The hamigeran family of natural products has been the target of numerous synthetic efforts because of its biological activity and interesting structural properties. Herein, we disclose our efforts toward the synthesis of hamigerans C and D, unique among the initially isolated members because of their 6-7-5 carbocyclic core. Our approach directly targets this tricyclic motif by sequential Negishi and Heck coupling reactions, yielding an advanced intermediate with all necessary carbons and sufficient functionality poised for completion of the synthesis of these two natural products

IN SEARCH OF ADEQUATE FAITH: RELIGIOUS SKEPTICISM IN GERMAN LETTERS (1750-1800)

The following dissertation, “In Search of Adequate Faith: Religious Skepticism in German Letters (1750–1800),” is an interdisciplinary study exploring the religious writings of Klopstock, Lessing, and Novalis. During the mid- to late-eighteenth century the struggle to articulate a distinctly modern faith becomes audible across the literary and aesthetic works of writers who were committed to making the biblical tradition more appealing to an increasingly skeptical age. Rather than driving a wedge between sacred and secular cultures, these writers promised greater spiritual cohesion. Instead of simply yielding to the authority of tradition and scripture, their works strove to articulate more adequate means of forging religious bonds. This study investigates how a number of writers turned the spirit of religion into a weapon, which precipitated a second reformation in the latter half of the eighteenth century. How did literature and aesthetics challenge the authority of the five Lutheran Solae? How might they offer more effective strategies for reconciling faith and reason than philosophy and theology? What role did material and visual culture play in mediating religious experience at this time? To answer these questions, I analyze a constellation of documents associated with each writer. My first chapter interrogates the poetic methodology of Klopstock’s Der Messias by exploring his extensive amplification of the New Testament figure Doubting Thomas. In my analysis, Klopstock's poetics inadvertently reproduce Thomas’ tragic “mistake” by doubting the efficacy of unaided scripture to communicate religious truth; a doubt that he attempts to resolve by intensifying the reader’s affective experience of the gospel narratives. My second chapter argues that Lessing develops a more powerful defense against religious skepticism than Klopstock by appealing to the spirit of religion rather than to the authority of its letter. By reorienting faith around the spirit of religion, Lessing sparks a Copernican turn in religious consciousness that helped emancipate modern believers from theological regimes that had become increasingly normative in their approach to the letter of scripture. My final chapter considers how Novalis confronts the ways in which Lessing and the Protestant tradition deminishes the value of sensible forms of religious mediation by “spiritualizing” modern faith. Unlike Lessing, Novalis insists that revealed knowledge demands material mediation like images and symbols in order to (re)shape and (re)generate religious experience

Ring-Contraction Strategy for the Practical, Scalable, Catalytic Asymmetric Synthesis of Versatile γ-Quaternary Acylcyclopentenes

Contraction action! A simple protocol for the catalytic asymmetric synthesis of highly functionalized γ-quaternary acylcyclopentenes (see schematic) in up to 91 % overall yield and 92 % ee has been developed. The reaction sequence employs a palladium-catalyzed enantioselective alkylation reaction and exploits the unusual stability of β-hydroxy cycloheptanones to achieve a general and robust method for performing two-carbon ring contractions

Progress towards the total synthesis of hamigerans C and D: a direct approach to an elaborated 6-7-5 carbocyclic core

The hamigeran family of natural products has been the target of numerous synthetic efforts because of its biological activity and interesting structural properties. Herein, we disclose our efforts toward the synthesis of hamigerans C and D, unique among the initially isolated members because of their 6-7-5 carbocyclic core. Our approach directly targets this tricyclic motif by sequential Negishi and Heck coupling reactions, yielding an advanced intermediate with all necessary carbons and sufficient functionality poised for completion of the synthesis of these two natural products

Vertical transmission of HIV among pregnant women who initially had false–negative rapid HIV tests in four South African antenatal clinics

INTRODUCTION : There is a risk of mother-to-child transmission of HIV (MTCT) during pregnancy and breastfeeding. The aim of this study was to assess vertical transmission of HIV among pregnant women who initially had false–negative rapid HIV tests in South African antenatal care (ANC) clinics. METHODS : Pregnant participants were enrolled in a diagnostic study that used nucleic acid amplification testing (NAAT) to screen for early HIV infection among individuals who tested negative on rapid HIV tests used at the point-of-care (POC) facilities. Participants were enrolled from four ANC clinics in the Tshwane district of South Africa. All NAAT-positive participants were recalled to the clinics for further management. Vertical transmission was assessed among exposed infants whose HIV polymerase chain reaction (PCR) results were available. RESULTS : This study enrolled 8208 pregnant participants who tested negative on rapid HIV tests between 2013 and 2016. Their median age was 26 years (interquartile range [IQR]: 23–30). NAAT detected HIV infections in 0.6% (n = 49; 95% confidence interval {CI}: 0.5–0.8) of all study participants. The distribution of these infections among the four clinics ranged from 0.3%– 1.1%, but this was not statistically significant (p = 0.07). Forty-seven participants (95.9%) were successfully recalled and referred for antiretroviral treatment initiation as part of prevention of MTCT (PMTCT). Most women with newly diagnosed HIV infection presented for the first ANC visit in the second (61.9%, n = 26) and third (31.0%, n = 13) trimesters. HIV PCR results were available for thirty-two infants, three of whom tested positive (9.4%; 95% CI: 1.98–25.02). CONCLUSIONS : This study showed that supplemental HIV testing for pregnant women led to earlier linkage to the PMTCT programme. Inaccurate diagnosis of HIV infection at ANC clinics is likely to undermine the efforts of eliminating MTCT particularly in HIV-endemic settings.S1 Table. Characteristics of participants diagnosed with early or chronic HIV infection. Initial tests were performed from samples obtained at enrolment (i.e. after a negative rapid HIV test result). HIV viral load (VL) tests were performed first to screen for HIV infection, and all the serology tests were performed later. Follow-up (F/U) VL was only performed for participants who had an initial VL <5000 copies/ml [16]. Pt ID = participant’s study identity, F = female, gen = generation, ELISA = enzyme-linked immunosorbent assay, W. Blot = Western Blot, LAg = limiting antigen, Insuf = insufficient, LT = long term (chronic) infection, --- = not available (participant did not return for follow-up), + = positive,— = negative. Units: HIV VL = copies/ml; p24 antigen = cut-off index (COI); Genscreen ELISA = sample cut-off (S/CO); LAg avidity = normalized optical density (OD-n); LAg avidity <1.5 OD-n = early infection; LAg avidity >1.5 OD-n = LT (chronic) infection. ¥ = participant 6738 was previously misclassified as having chronic infection [16], but testing on her follow-up sample revealed low avidity antibodies consistent with early infection; this was confirmed on repeat testing of 6738 sample. P24 antigen, W. Blot and F/U LAg were not performed for the last participants identified with newly diagnosed HIV infection owing to cost limitations. This also applies to the F/U VL for participant 1692, as this was supposed to have been performed according to the diagnostic study protocol [14].This work was supported by SHM - South African Medical Research Council – Self Initiated Research (SA MRC-SIR) grant; SHM - Discovery Foundation grant; SHM - Hamilton Naki Clinical Scholarship; and TCQ - The Division of Intramural Research, NIAID, NIH.SHM - South African Medical Research Council – Self Initiated Research (SA MRC-SIR) grant; SHM - Discovery Foundation grant; SHM - Hamilton Naki Clinical Scholarship; and TCQ - The Division of Intramural Research, NIAID, NIH.http://www.plosone.orgam2020Internal Medicin

Vertical transmission of HIV among pregnant women who initially had false–negative rapid HIV tests in four South African antenatal clinics

INTRODUCTION : There is a risk of mother-to-child transmission of HIV (MTCT) during pregnancy and breastfeeding. The aim of this study was to assess vertical transmission of HIV among pregnant women who initially had false–negative rapid HIV tests in South African antenatal care (ANC) clinics. METHODS : Pregnant participants were enrolled in a diagnostic study that used nucleic acid amplification testing (NAAT) to screen for early HIV infection among individuals who tested negative on rapid HIV tests used at the point-of-care (POC) facilities. Participants were enrolled from four ANC clinics in the Tshwane district of South Africa. All NAAT-positive participants were recalled to the clinics for further management. Vertical transmission was assessed among exposed infants whose HIV polymerase chain reaction (PCR) results were available. RESULTS : This study enrolled 8208 pregnant participants who tested negative on rapid HIV tests between 2013 and 2016. Their median age was 26 years (interquartile range [IQR]: 23–30). NAAT detected HIV infections in 0.6% (n = 49; 95% confidence interval {CI}: 0.5–0.8) of all study participants. The distribution of these infections among the four clinics ranged from 0.3%– 1.1%, but this was not statistically significant (p = 0.07). Forty-seven participants (95.9%) were successfully recalled and referred for antiretroviral treatment initiation as part of prevention of MTCT (PMTCT). Most women with newly diagnosed HIV infection presented for the first ANC visit in the second (61.9%, n = 26) and third (31.0%, n = 13) trimesters. HIV PCR results were available for thirty-two infants, three of whom tested positive (9.4%; 95% CI: 1.98–25.02). CONCLUSIONS : This study showed that supplemental HIV testing for pregnant women led to earlier linkage to the PMTCT programme. Inaccurate diagnosis of HIV infection at ANC clinics is likely to undermine the efforts of eliminating MTCT particularly in HIV-endemic settings.S1 Table. Characteristics of participants diagnosed with early or chronic HIV infection. Initial tests were performed from samples obtained at enrolment (i.e. after a negative rapid HIV test result). HIV viral load (VL) tests were performed first to screen for HIV infection, and all the serology tests were performed later. Follow-up (F/U) VL was only performed for participants who had an initial VL <5000 copies/ml [16]. Pt ID = participant’s study identity, F = female, gen = generation, ELISA = enzyme-linked immunosorbent assay, W. Blot = Western Blot, LAg = limiting antigen, Insuf = insufficient, LT = long term (chronic) infection, --- = not available (participant did not return for follow-up), + = positive,— = negative. Units: HIV VL = copies/ml; p24 antigen = cut-off index (COI); Genscreen ELISA = sample cut-off (S/CO); LAg avidity = normalized optical density (OD-n); LAg avidity <1.5 OD-n = early infection; LAg avidity >1.5 OD-n = LT (chronic) infection. ¥ = participant 6738 was previously misclassified as having chronic infection [16], but testing on her follow-up sample revealed low avidity antibodies consistent with early infection; this was confirmed on repeat testing of 6738 sample. P24 antigen, W. Blot and F/U LAg were not performed for the last participants identified with newly diagnosed HIV infection owing to cost limitations. This also applies to the F/U VL for participant 1692, as this was supposed to have been performed according to the diagnostic study protocol [14].This work was supported by SHM - South African Medical Research Council – Self Initiated Research (SA MRC-SIR) grant; SHM - Discovery Foundation grant; SHM - Hamilton Naki Clinical Scholarship; and TCQ - The Division of Intramural Research, NIAID, NIH.SHM - South African Medical Research Council – Self Initiated Research (SA MRC-SIR) grant; SHM - Discovery Foundation grant; SHM - Hamilton Naki Clinical Scholarship; and TCQ - The Division of Intramural Research, NIAID, NIH.http://www.plosone.orgam2020Internal Medicin

The anthelmintic praziquantel is a human serotoninergic G-protein-coupled receptor ligand

Schistosomiasis is a debilitating tropical disease caused by infection with parasitic blood flukes. Approximately 260 million people are infected worldwide, underscoring the clinical and socioeconomic impact of this chronic infection. Schistosomiasis is treated with the drug praziquantel (PZQ), which has proved the therapeutic mainstay for over three decades of clinical use. However, the molecular target(s) of PZQ remain undefined. Here we identify a molecular target for the antischistosomal eutomer - (R)-PZQ - which functions as a partial agonist of the human serotoninergic 5HT2B receptor. (R)-PZQ modulation of serotoninergic signaling occurs over a concentration range sufficient to regulate vascular tone of the mesenteric blood vessels where the adult parasites reside within their host. These data establish (R)-PZQ as a G-protein-coupled receptor ligand and suggest that the efficacy of this clinically important anthelmintic is supported by a broad, cross species polypharmacology with PZQ modulating signaling events in both host and parasite

Palladium-catalyzed asymmetric alkylation in the synthesis of cyclopentanoid and cycloheptanoid core structures bearing all-carbon quaternary stereocenters

General catalytic asymmetric routes toward cyclopentanoid and cycloheptanoid core structures embedded in numerous natural products have been developed. The central stereoselective transformation in our divergent strategies is the enantioselective decarboxylative alkylation of seven-membered β-ketoesters to form α-quaternary vinylogous esters. Recognition of the unusual reactivity of β-hydroxyketones resulting from the addition of hydride or organometallic reagents enabled divergent access to y-quaternary acylcyclopentenes through a ring contraction pathway or y-quaternary cycloheptenones through a carbonyl transposition pathway. Synthetic applications of these compounds were explored through the preparation of mono-, bi-, and tricyclic derivatives that can serve as valuable intermediates for the total synthesis of complex natural products. This work complements our previous work with cyclohexanoid systems