Chemical characterization of oligosaccharides in the milk of six species of New and Old World monkeys.

Human and great ape milks contain a diverse array of milk oligosaccharides, but little is known about the milk oligosaccharides of other primates, and how they differ among taxa. Neutral and acidic oligosaccharides were isolated from the milk of three species of Old World or catarrhine monkeys (Cercopithecidae: rhesus macaque (Macaca mulatta), toque macaque (Macaca sinica) and Hamadryas baboon (Papio hamadryas)) and three of New World or platyrrhine monkeys (Cebidae: tufted capuchin (Cebus apella) and Bolivian squirrel monkey (Saimiri boliviensis); Atelidae: mantled howler (Alouatta palliata)). The milks of these species contained 6-8% total sugar, most of which was lactose: the estimated ratio of oligosaccharides to lactose in Old World monkeys (1:4 to 1:6) was greater than in New World monkeys (1:12 to 1:23). The chemical structures of the oligosaccharides were determined mainly by (1)H-NMR spectroscopy. Oligosaccharides containing the type II unit (Gal(β1-4)GlcNAc) were found in the milk of the rhesus macaque, toque macaque, Hamadryas baboon and tufted capuchin, but oligosaccharides containing the type I unit (Gal(β1-3)GlcNAc), which have been found in human and many great ape milks, were absent from the milk of all species studied. Oligosaccharides containing Lewis x (Gal(β1-4)[Fuc(α1-3)]GlcNAc) and 3-fucosyl lactose (3-FL, Gal(β1-4)[Fuc(α1-3)]Glc) were found in the milk of the three cercopithecid monkey species, while 2-fucosyl lactose (5'-FL, Fuc(α1-2)Gal(β1-4)Glc) was absent from all species studied. All of these milks contained acidic oligosaccharides that had N-acetylneuraminic acid as part of their structures, but did not contain oligosaccharides that had N-glycolylneuraminic acid, in contrast to the milk or colostrum of great apes which contain both types of acidic oligosaccharides. Two GalNAc-containing oligosaccharides, lactose 3'-O-sulfate and lacto-N-novopentaose I (Gal(β1-3)[Gal(β1-4)GlcNAc(β1-6)]Gal(β1-4)Glc) were found only in the milk of rhesus macaque, hamadryas baboon and tufted capuchin, respectively. Further research is needed to determine the extent to which the milk oligosaccharide patterns observed among these taxa represent wider phylogenetic trends among primates and how much variation occurs among individuals or species.

Reckoning With Apartheid: The Conundrum of Working Through the Past, An Introduction

From April 26-29, 1994, South Africa held its first universal, democratic elections. Witnessed by the world, South Africans of all races waited patiently in line to cast their ballots, signaling the official and symbolic birth of the “new” South Africa. The subsequent years, marked initially with euphoric hopes for racial healing enabled by institutional processes such as the Truth and Reconciliation Commission (TRC), have instead, most recently, inspired deep concern about epidemic levels of HIV/AIDS, violent crime, state corruption, and unbridled market reforms directed at everything from property to bodies to babies. Now, seemingly beleaguered state officials deploy the mantra “TINA” (There Is No Alternative [to neoliberal development]) to fend off criticism of growing income and wealth disparities. To coincide, more or less, with the anniversary of 1994—less to commemorate than to signal something about the trajectory of the past twenty years—we are proposing an interdisciplinary, special theme section of Comparative Studies in South Asia, Africa, and the Middle East (CSSAAME) entitled “The Haunted Present: Reckoning After Apartheid” (tentative title). The special theme section is framed around questions of reckoning in the double sense of both a moral and practical accounting for historical injury alongside the challenges and failures of the no-longer “new” South Africa. Against accounts depicting the liberation era as non-violent and peaceable, more nuanced analysis we argue suggests not only that South Africa’s “revolution” was marked by both collective and individual violence—on the part of the state and the liberation movements—but that reckoning with the present demands of scholars, the media, and cultural commentators that they begin to grapple more fully with the dimensions and different figurations of South Africa’s violent colonial history. Indeed, violence and reckoning appear as two central forces in contemporary South African political, economic, and social life. In response, we are driven to pose the following questions: In the post-apartheid period, what forms of (individual, structural) violence have come to bear on South African life? How does this violence reckon with apartheid and its legacies? Does it in fact reckon with the past? How can we or should we think about violence as a response to the (failed?) reckoning of state initiatives like the TRC? What has enabled or enables aesthetic forms—literature, photography, plastic arts, and other modes of expressive culture—to respond to the difficulties of South Africa’s ongoing transition? What, in fact, would a practice or ethic of reckoning defined in the following way look like? ˈrekəniNG/ noun: • the action or process of calculating or estimating something: last year was not, by any reckoning, a particularly good one; the system of time reckoning in Babylon • a person’s view, opinion, or judgment: by ancient reckoning, bacteria are plants • archaic, a bill or account, or its settlement • the avenging or punishing of past mistakes or misdeeds: the fear of being brought to reckoning there will be a terrible reckoning (Oxford English Dictionary) Looking back on the period, just before 1994, is sobering indeed. At the time, many saw in the energies and courage of those fighting for liberation the possibilities of a post-racial, post-conflict society. Yet as much as the new was ushered in, old apartheid forms lingered. Recalling Nadine Gordimer’s invocation of Gramsci’s “morbid symptoms” more and more it seems “the old is dying and the new cannot be born” (Gramsci cited in Gordimer 1982). And even as the new began to emerge other forces—both internal and external to South Africa—redefined the conditions for transformation. The so-called “new” South Africa, as Jennifer Wenzel has argued, was really more than anything “the changing face of old oppressions” (Wenzel 2009:159). The implications for our special theme section of CSSAAME are many. We begin by exploring the gender, race, and class dimensions of contemporary South African life by way of its literatures, histories, and politics, its reversion to custom, the claims of ancestors on the living, in brief, the various cultural expressive modes in which contemporary South Africa reckons with its past and in so doing accounts, day by day, for the ways in which the present can be lived, pragmatically. This moves us some distance from the exercise in “truth and reconciliation” of the earlier post-transition years to consider more fully the nature of post-conflict, the suturing of old enmities in the present, and the ways of resolving those lingering suspicions both ordinary and the stuff of the dark night of the soul (Nelson 2009:xv).

Reckoning With Apartheid: The Conundrum of Working Through the Past

From April 26-29, 1994, South Africa held its first universal, democratic elections. Witnessed by the world, South Africans of all races waited patiently in line to cast their ballots, signaling the official and symbolic birth of the “new” South Africa. The subsequent years, marked initially with euphoric hopes for racial healing enabled by institutional processes such as the Truth and Reconciliation Commission (TRC), have instead, most recently, inspired deep concern about epidemic levels of HIV/AIDS, violent crime, state corruption, and unbridled market reforms directed at everything from property to bodies to babies. Now, seemingly beleaguered state officials deploy the mantra “TINA” (There Is No Alternative [to neoliberal development]) to fend off criticism of growing income and wealth disparities. To coincide, more or less, with the anniversary of 1994—less to commemorate than to signal something about the trajectory of the past twenty years—we are proposing an interdisciplinary, special theme section of Comparative Studies in South Asia, Africa, and the Middle East (CSSAAME) entitled “The Haunted Present: Reckoning After Apartheid” (tentative title). The special theme section is framed around questions of reckoning in the double sense of both a moral and practical accounting for historical injury alongside the challenges and failures of the no-longer “new” South Africa. Against accounts depicting the liberation era as non-violent and peaceable, more nuanced analysis we argue suggests not only that South Africa’s “revolution” was marked by both collective and individual violence—on the part of the state and the liberation movements—but that reckoning with the present demands of scholars, the media, and cultural commentators that they begin to grapple more fully with the dimensions and different figurations of South Africa’s violent colonial history. Indeed, violence and reckoning appear as two central forces in contemporary South African political, economic, and social life. In response, we are driven to pose the following questions: In the post-apartheid period, what forms of (individual, structural) violence have come to bear on South African life? How does this violence reckon with apartheid and its legacies? Does it in fact reckon with the past? How can we or should we think about violence as a response to the (failed?) reckoning of state initiatives like the TRC? What has enabled or enables aesthetic forms—literature, photography, plastic arts, and other modes of expressive culture—to respond to the difficulties of South Africa’s ongoing transition? What, in fact, would a practice or ethic of reckoning defined in the following way look like? ˈrekəniNG/ noun: • the action or process of calculating or estimating something: last year was not, by any reckoning, a particularly good one; the system of time reckoning in Babylon • a person’s view, opinion, or judgment: by ancient reckoning, bacteria are plants • archaic, a bill or account, or its settlement • the avenging or punishing of past mistakes or misdeeds: the fear of being brought to reckoning there will be a terrible reckoning (Oxford English Dictionary) Looking back on the period, just before 1994, is sobering indeed. At the time, many saw in the energies and courage of those fighting for liberation the possibilities of a post-racial, post-conflict society. Yet as much as the new was ushered in, old apartheid forms lingered. Recalling Nadine Gordimer’s invocation of Gramsci’s “morbid symptoms” more and more it seems “the old is dying and the new cannot be born” (Gramsci cited in Gordimer 1982). And even as the new began to emerge other forces—both internal and external to South Africa—redefined the conditions for transformation. The so-called “new” South Africa, as Jennifer Wenzel has argued, was really more than anything “the changing face of old oppressions” (Wenzel 2009:159). The implications for our special theme section of CSSAAME are many. We begin by exploring the gender, race, and class dimensions of contemporary South African life by way of its literatures, histories, and politics, its reversion to custom, the claims of ancestors on the living, in brief, the various cultural expressive modes in which contemporary South Africa reckons with its past and in so doing accounts, day by day, for the ways in which the present can be lived, pragmatically. This moves us some distance from the exercise in “truth and reconciliation” of the earlier post-transition years to consider more fully the nature of post-conflict, the suturing of old enmities in the present, and the ways of resolving those lingering suspicions both ordinary and the stuff of the dark night of the soul (Nelson 2009:xv).

The Function and Regulation of Photobodies in Phytochrome Signaling

Light is a critical environmental signal that regulates every phase of the plant life cycle, from germination to floral initiation. Of the many light receptors in the model plant Arabidopsis thaliana, the red- and far-red light-sensing phytochromes (phys) are arguably the best studied, but the earliest events in the phy signaling pathway remain poorly understood. One of the earliest phy signaling events is the translocation of photoactivated phys from the cytoplasm to the nucleus, where they localize to subnuclear foci termed photobodies; in continuous light, photobody localization correlates closely with the light-dependent inhibition of embryonic stem growth. Despite a growing body of evidence supporting the biological significance of photobodies in light signaling, photobodies have also been shown to be dispensable for seedling growth inhibition in continuous light, so their physiological importance remains controversial; additionally, the molecular components that are required for phy localization to photobodies are largely unknown. The overall goal of my dissertation research was to gain insight into the early steps of phy signaling by further defining the role of photobodies in this process and identifying additional intragenic and extragenic requirements for phy localization to photobodies.

Even though the domain structure of phys has been extensively studied, not all of the intramolecular requirements for phy localization to photobodies are known. Previous studies have shown that the entire C-terminus of phys is both necessary and sufficient for their localization to photobodies. However, the importance of the individual subdomains of the C-terminus is still unclear. For example a truncation lacking part of the most C-terminal domain, the histidine kinase-related domain (HKRD), can still localize to small photobodies in the light and behaves like a weak allele. However, a point mutation within the HKRD renders the entire molecule completely inactive. To resolve this discrepancy, I explored the hypothesis that this point mutation might impair the dimerization of the HKRD; dimerization has been shown to occur via the C-terminus of phy and is required for more efficient signaling. I show that this point mutation impairs nuclear localization of phy as well as its subnuclear localization to photobodies. Additionally, yeast-two-hybrid analysis shows that the wild-type HKRD can homodimerize but that the HKRD containing the point mutation fails to dimerize with both itself and with wild-type HKRD. These results demonstrate that dimerization of the HKRD is required for both nuclear and photobody localization of phy.

Studies of seedlings grown in diurnal conditions show that photoactivated phy can persist into darkness to repress seedling growth; a seedling's growth rate is therefore fastest at the end of the night. To test the idea that photobodies could be involved in regulating seedling growth in the dark, I compared the growth of two transgenic Arabidopsis lines, one in which phy can localize to photobodies (PBG), and one in which it cannot (NGB). Despite these differences in photobody morphology, both lines are capable of transducing light signals and inhibiting seedling growth in continuous light. After the transition from red light to darkness, the PBG line was able to repress seedling growth, as well as the accumulation of the growth-promoting, light-labile transcription factor PHYTOCHROME INTERACTING FACTOR 3 (PIF3), for eighteen hours, and this correlated perfectly with the presence of photobodies. Reducing the amount of active phy by either reducing the light intensity or adding a phy-inactivating far-red pulse prior to darkness led to faster accumulation of PIF3 and earlier seedling growth. In contrast, the NGB line accumulated PIF3 even in the light, and seedling growth was only repressed for six hours; this behavior was similar in NGB regardless of the light treatment. These results suggest that photobodies are required for the degradation of PIF3 and for the prolonged stabilization of active phy in darkness. They also support the hypothesis that photobody localization of phys could serve as an instructive cue during the light-to-dark transition, thereby fine-tuning light-dependent responses in darkness.

In addition to determining an intragenic requirement for photobody localization and further exploring the significance of photobodies in phy signaling, I wanted to identify extragenic regulators of photobody localization. A recent study identified one such factor, HEMERA (HMR); hmr mutants do not form large photobodies, and they are tall and albino in the light. To identify other components in the HMR-mediated branch of the phy signaling pathway, I performed a forward genetic screen for suppressors of a weak hmr allele. Surprisingly, the first three mutants isolated from the screen were alleles of the same novel gene, SON OF HEMERA (SOH). The soh mutations rescue all of the phenotypes associated with the weak hmr allele, and they do so in an allele-specific manner, suggesting a direct interaction between SOH and HMR. Null soh alleles, which were isolated in an independent, tall, albino screen, are defective in photobody localization, demonstrating that SOH is an extragenic regulator of phy localization to photobodies that works in the same genetic pathway as HMR.

In this work, I show that dimerization of the HKRD is required for both the nuclear and photobody localization of phy. I also demonstrate a tight correlation between photobody localization and PIF3 degradation, further establishing the significance of photobodies in phy signaling. Finally, I identify a novel gene, SON OF HEMERA, whose product is necessary for phy localization to photobodies in the light, thereby isolating a new extragenic determinant of photobody localization. These results are among the first to focus exclusively on one of the earliest cellular responses to light - photobody localization of phys - and they promise to open up new avenues into the study of a poorly understood facet of the phy signaling pathway.

Essays on the Role of Government Incentives in the Private Provision of Social Goods

The economic rationale for public intervention into private markets through price mechanisms is twofold: to correct market failures and to redistribute resources. Financial incentives are one such price mechanism. In this dissertation, I specifically address the role of financial incentives in providing social goods in two separate contexts: a redistributive policy that enables low income working families to access affordable childcare in the US and an experimental pay-for-performance intervention to improve population health outcomes in rural India. In the first two papers, I investigate the effects of government incentives for providing grandchild care on grandmothers’ short- and long-term outcomes. In the third paper, coauthored with Manoj Mohanan, Grant Miller, Katherine Donato, and Marcos Vera-Hernandez, we use an experimental framework to consider the the effects of financial incentives in improving maternal and child health outcomes in the Indian state of Karnataka.

Grandmothers provide a significant amount of childcare in the US, but little is known about how this informal, and often uncompensated, time transfer impacts their economic and health outcomes. The first two chapters of this dissertation address the impact of federally funded, state-level means-tested programs that compensate grandparent-provided childcare on the retirement security of older women, an economically vulnerable group of considerable policy interest. I use the variation in the availability and generosity of childcare subsidies to model the effect of government payments for grandchild care on grandmothers’ time use, income, earnings, interfamily transfers, and health outcomes. After establishing that more generous government payments induce grandmothers to provide more hours of childcare, I find that grandmothers adjust their behavior by reducing their formal labor supply and earnings. Grandmothers make up for lost earnings by claiming Social Security earlier, increasing their reliance on Supplemental Security Income (SSI) and reducing financial transfers to their children. While the policy does not appear to negatively impact grandmothers’ immediate economic well-being, there are significant costs to the state, in terms of both up-front costs for care payments and long-term costs as a result of grandmothers’ increased reliance on social insurance.

The final paper, The Role of Non-Cognitive Traits in Response to Financial Incentives: Evidence from a Randomized Control Trial of Obstetrics Care Providers in India, is coauthored with Manoj Mohanan, Grant Miller, Katherine Donato and Marcos Vera-Hernandez. We report the results from “Improving Maternal and Child Health in India: Evaluating Demand and Supply Side Strategies” (IMACHINE), a randomized controlled experiment designed to test the effectiveness of supply-side incentives for private obstetrics care providers in rural Karnataka, India. In particular, the experimental design compares two different types of incentives: (1) those based on the quality of inputs providers offer their patients (inputs contracts) and (2) those based on the reduction of incidence of four adverse maternal and neonatal health outcomes (outcomes contracts). Along with studying the relative effectiveness of the different financial incentives, we also investigate the role of provider characteristics, preferences, expectations and non-cognitive traits in mitigating the effects of incentive contracts.

We find that both contract types input incentive contracts reduce rates of post-partum hemorrhage, the leading cause of maternal mortality in India by about 20%. We also find some evidence of multitasking as output incentive contract providers reduce the level of postnatal newborn care received by their patients. We find that patient health improvements in response to both contract types are concentrated among higher trained providers. We find improvements in patient care to be concentrated among the lower trained providers. Contrary to our expectations, we also find improvements in patient health to be concentrated among the most risk averse providers, while more patient providers respond relatively little to the incentives, and these difference are most evident in the outputs contract arm. The results are opposite for patient care outcomes; risk averse providers have significantly lower rates of patient care and more patient providers provide higher quality care in response to the outputs contract. We find evidence that overconfidence among providers about their expectations about possible improvements reduces the effectiveness of both types of incentive contracts for improving both patient outcomes and patient care. Finally, we find no heterogeneous response based on non-cognitive traits.

Assessing Surveillance Elements of the Zanzibar Malaria Elimination Program to Support Malaria Elimination in Zanzibar

Though significant progress has been made through control efforts in recent years, malaria remains a leading cause of morbidity and mortality throughout the world, with 3.2 billion people at risk of developing the disease. Zanzibar is currently pursuing malaria elimination through the Zanzibar Malaria Elimination Program (ZAMEP), and is working toward a goal of no locally acquired malaria cases by 2018. A comprehensive and well functioning malaria surveillance program is central to achieving this goal. Under ZAMEP’s current surveillance strategy, District Malaria Surveillance Officers (DMSOs) respond to malaria case notifications through the reactive case detection (RACD) system. Three malaria screening and treatment strategies are undertaken in response to this system, including household-level (HSaT), focal-level (FSaT), and mass-level (MSaT). Each strategy is triggered by a different case threshold and tests different-sized populations. The aims of this study were to (1) assess the cost effectiveness of three malaria screening and treatment strategies; (2) assess the timeliness and completeness of ZAMEP’s RACD system; (3) and qualitatively explore the roles of DMSOs.

Screening disposition and budget information for 2014 screening and treatment strategies was analyzed to determine prevalence rates in screened populations and the cost effectiveness of each strategy. Prevalence rates within the screened population varied by strategy: 6.1 percent in HSaT, 1.2 percent in FSaT, and 0.9 percent in MSaT. Of the various costing scenarios considering cost per person screened, MSaT was the most cost-effective, with costs ranging from $9.57 to $12.57 per person screened. Of the various costing scenarios considering cost per case detected, HSaT was the most cost-effective, at $385.51 per case detected.

Case data from 2013 through mid-2015 was used to assess the timeliness and completeness of the RACD system. The average number of RACD activities occurring within 48 hours of notification improved slightly between 2013 and the first half of 2015, from 90.7 percent to 93.1 percent. The average percentage of household members screened during RACD also increased over the same time period, from 84 percent in 2013 to 89.9 percent in the first half of 2015.

Interviews with twenty DMSOs were conducted to gain insights into the challenges to malaria elimination both from the health system and the community perspectives. Major themes discussed in the interviews include the need for additional training, inadequate information capture at health facility, resistance to household testing, transportation difficulties, inadequate personnel during the high transmission season, and community misinformation.

Zanzibar is now considered a low transmission setting, making elimination feasible, but also posing new challenges to achieving this goal. The findings of this study provide insight into how surveillance activities can be improved to support the goal of malaria elimination in Zanzibar. Key changes include reevaluating the use of MSaT activities, improving information capture at health facilities, hiring additional DMSOs during the high transmission season, and improving community communication.