Browsing by Author "Dhar, Nisha"

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    Association between serum zinc level and dynamics of Group B Streptococcus colonisation among pregnant women in South Africa
    (University of the Witwatersrand, Johannesburg, 2024) Dhar, Nisha; Madhi, Shabir A
    Background Maternal colonisation by Group B Streptococcus (GBS) is a major risk factor for early onset invasive GBS disease among newborns. Zinc micronutrient plays a critical role in several biological processes that are essential to prevent bacterial colonisation and/or invasion. The aim of this study was to investigate the association of serum zinc levels with GBS rectovaginal new acquisition and clearance from 20 to 37+ weeks gestation in pregnant women. Methods Vaginal and rectal GBS colonisation was determined at 20–25 weeks (visit-1), followed by 3 subsequent visits at 5–6 weeks intervals, until 37–40 weeks gestation (visit-4). Serum was collected at visit-1 and visit-4 and serum zinc was estimated by inductively coupled plasma mass spectrometry. “New acquisition” group was defined as participants for whom GBS culture was negative at visit-1 and acquired GBS in one of the subsequent visits. Participants not colonised with GBS at any visits were categorized as GBS “persistently uncolonised”. Participants who remained colonised throughout all study visits were defined as “persistently colonised” group. GBS “clearance group” included participants who were colonised at enrolment (visit-1) and in whom GBS colonisation cleared by last visit (visit-4). Results Participants in persistently un-colonised group had significantly higher zinc geometric mean concentration (GMC) at visit-1 compared with those who had new acquisition (20.18 µmol/L; 95%CI 17.99-22.64 vs 13.68 µmol/L; 95%CI 12.59-14.87, p=0.03). Higher zinc concentration in the persistently un-colonised group when compared with new acquisition group was significantly associated with lower odds of GBS rectovaginal acquisition [Odds ratio (OR) 0.15, p=0.001]. The lowest zinc threshold significantly associated with 45% lower odds of new acquisition was ≥15 umol/L (27.2% in new acquisition vs 40.5% in persistently un-colonised; OR 0.55; 95%CI 0.31- 0.96; p=0.03). Furthermore, zinc concentration was higher among women in clearance group compared with those in persistently colonised group (20.03 µmol/L; 95%CI 16.54-24.27 vs 16.45 µmol/L; 95%CI 13.32-20.31, p=0.04). Conclusion There was an inverse association between serum zinc levels in pregnant women and odds of GBS acquisition in those not initially colonised. Zinc supplementation in early pregnancy could reduce risk of invasive GBS disease in their newborns
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    The molecular evolution of complexity at the origin of life
    (2016-10-25) Dhar, Nisha
    A widely accepted hypothesis for the origin of life is that it was based on catalytic RNA or ribozymes (the RNA world hypothesis). In this paradigm, one of the earliest and essential functions for an RNA based life to emerge was polymerisation. Although polymerisation activity has been demonstrated in extant and engineered ribozymes, these molecules are large and too complex to have formed spontaneously in the prebiotic world. Furthermore, the evolution and stability of RNA based life would have required a pool of diverse complex ribozymes. An understanding of the basic mechanistic processes implicated in the emergence of a minimal polymerase and diverse complex molecules from small oligomers remains a major gap. This project examined the ligation activity of a polymerase and its smaller derivatives with random oligonucleotide substrates and revealed how the molecular dynamics of ligation would have affected the evolution of complexity in the early stages of an RNA world. The size and structural complexity of a minimal polymerase (called R18 polymerase ribozyme) was reduced in a stepwise fashion. All RNA constructs were examined for self-ligation function with 24 random oligonucleotide substrates (each 35 nucleotides long) in the absence of experimentally designed base pairing. The smallest element (40 nucleotides long) was able to non-specifically ligate substrates to its own end, however, with low efficiency. A gradual increase in specificity for the substrates and overall functional efficiency was observed with an increase in structural complexity of the ribozymes. The most complex R18 polymerase ligated only selected substrate variants to itself, although with much greater efficiency than the smaller constructs. These findings suggest that the complexity in a primitive molecular system increased in a modular fashion via ligases. Furthermore, general compatibility of the ligases with the substrates was a mechanism for increase in the molecular complexity and functionality. The inverse correlation between functional flexibility and efficiency with increase in structural complexity of the catalysts points to a molecular trade-off. In the ecology of the RNA world, this molecular trade-off would have been central to ribozyme population stability and for the development of functional specialisation. The findings in this project point to a form of hypercycle composed of a complementary set of processes stabilised by inherent molecular trade-offs. Such a hypercycle is suggested to facilitate the emergence of a stable molecular network and a replicative unit essential for life to begin.