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1.  Implications of a 3.472–3.333 Gyr-old subaerial microbial mat from the Barberton greenstone belt, South Africa for the UV environmental conditions on the early Earth 
Modelling suggests that the UV radiation environment of the early Earth, with DNA weighted irradiances of about three orders of magnitude greater than those at present, was hostile to life forms at the surface, unless they lived in specific protected habitats. However, we present empirical evidence that challenges this commonly held view. We describe a well-developed microbial mat that formed on the surface of volcanic littoral sediments in an evaporitic environment in a 3.5–3.3 Ga-old formation from the Barberton greenstone belt. Using a multiscale, multidisciplinary approach designed to strongly test the biogenicity of potential microbial structures, we show that the mat was constructed under flowing water by 0.25 μm filaments that produced copious quantities of extracellular polymeric substances, representing probably anoxygenic photosynthesizers. Associated with the mat is a small colony of rods–vibroids that probably represent sulphur-reducing bacteria. An embedded suite of evaporite minerals and desiccation cracks in the surface of the mat demonstrates that it was periodically exposed to the air in an evaporitic environment. We conclude that DNA-damaging UV radiation fluxes at the surface of the Earth at this period must either have been low (absorbed by CO2, H2O, a thin organic haze from photo-dissociated CH4, or SO2 from volcanic outgassing; scattered by volcanic, and periodically, meteorite dust, as well as by the upper layers of the microbial mat) and/or that the micro-organisms exhibited efficient gene repair/survival strategies.
doi:10.1098/rstb.2006.1896
PMCID: PMC1664690  PMID: 17008224
Early Mid Archaean; Barberton; microfossils; littoral zone; UV environment
2.  Geological constraints on detecting the earliest life on Earth: a perspective from the Early Archaean (older than 3.7 Gyr) of southwest Greenland 
At greater than 3.7 Gyr, Earth's oldest known supracrustal rocks, comprised dominantly of mafic igneous with less common sedimentary units including banded iron formation (BIF), are exposed in southwest Greenland. Regionally, they were intruded by younger tonalites, and then both were intensely dynamothermally metamorphosed to granulite facies (the highest pressures and temperatures generally encountered in the Earth's crust during metamorphism) in the Archaean and subsequently at lower grades until about 1500 Myr ago. Claims for the first preserved life on Earth have been based on the occurrence of greater than 3.8 Gyr isotopically light C occurring as graphite inclusions within apatite crystals from a 5 m thick purported BIF on the island of Akilia. Detailed geologic mapping and observations there indicate that the banding, first claimed to be depositional, is clearly deformational in origin. Furthermore, the mineralogy of the supposed BIF, being dominated by pyroxene, amphibole and quartz, is unlike well-known BIF from the Isua Greenstone Belt (IGB), but resembles enclosing mafic and ultramafic igneous rocks modified by metasomatism and repeated metamorphic recrystallization. This scenario parsimoniously links the geology, whole-rock geochemistry, 2.7 Gyr single crystal zircon ages in the unit, an approximately 1500 Myr age for apatites that lack any graphite, non-MIF sulphur isotopes in the unit and an inconclusive Fe isotope signature. Although both putative body fossils and carbon-12 enriched isotopes in graphite described at Isua are better explained by abiotic processes, more fruitful targets for examining the earliest stages in the emergence of life remain within greater than 3.7 Gyr IGB, which preserves BIF and other rocks that unambiguously formed at Earth's surface.
doi:10.1098/rstb.2006.1836
PMCID: PMC1578730  PMID: 16754603
Archaean; origin of life; Greenland; geochemistry; isotope geochemistry; geology
3.  Antiquity of the biological sulphur cycle: evidence from sulphur and carbon isotopes in 2700 million-year-old rocks of the Belingwe Belt, Zimbabwe. 
Sulphur and carbon isotopic analyses on small samples of kerogens and sulphide minerals from biogenic and non-biogenic sediments of the 2.7 x 10(9) years(Ga)-old Belingwe Greenstone Belt (Zimbabwe) imply that a complex biological sulphur cycle was in operation. Sulphur isotopic compositions display a wider range of biological fractionation than hitherto reported from the Archaean. Carbon isotopic values in kerogen record fractionations characteristic of rubisco activity methanogenesis and methylotrophy and possibly anoxygenic photosynthesis. Carbon and sulphur isotopic fractionations have been interpreted in terms of metabolic processes in 2.7 Ga prokaryote mat communities, and indicate the operation of a diverse array of metabolic processes. The results are consistent with models of early molecular evolution derived from ribosomal RNA.
doi:10.1098/rspb.2000.1338
PMCID: PMC1088579  PMID: 11209879
4.  The Emergence of Environmental Homeostasis in Complex Ecosystems 
PLoS Computational Biology  2013;9(5):e1003050.
The Earth, with its core-driven magnetic field, convective mantle, mobile lid tectonics, oceans of liquid water, dynamic climate and abundant life is arguably the most complex system in the known universe. This system has exhibited stability in the sense of, bar a number of notable exceptions, surface temperature remaining within the bounds required for liquid water and so a significant biosphere. Explanations for this range from anthropic principles in which the Earth was essentially lucky, to homeostatic Gaia in which the abiotic and biotic components of the Earth system self-organise into homeostatic states that are robust to a wide range of external perturbations. Here we present results from a conceptual model that demonstrates the emergence of homeostasis as a consequence of the feedback loop operating between life and its environment. Formulating the model in terms of Gaussian processes allows the development of novel computational methods in order to provide solutions. We find that the stability of this system will typically increase then remain constant with an increase in biological diversity and that the number of attractors within the phase space exponentially increases with the number of environmental variables while the probability of the system being in an attractor that lies within prescribed boundaries decreases approximately linearly. We argue that the cybernetic concept of rein control provides insights into how this model system, and potentially any system that is comprised of biological to environmental feedback loops, self-organises into homeostatic states.
Author Summary
Life on Earth is perhaps greater than three and a half billion years old and it would appear that once it started it never stopped. During this period a number of dramatic shocks and drivers have affected the Earth. These include the impacts of massive asteroids, runaway climate change and increases in brightness of the Sun. Has life on Earth simply been lucky in withstanding such perturbations? Are there any self-regulating or homeostatic processes operating in the Earth system that would reduce the severity of such perturbations? If such planetary processes exist, to what extent are they the result of the actions of life? In this study, we show how the regulation of environmental conditions can emerge as a consequence of life's effects. If life is both affected by and affects it environment, then this coupled system can self-organise into a robust control system that was first described during the early cybernetics movement around the middle of the twentieth century. Our findings are in principle applicable to a wide range of real world systems - from microbial mats to aquatic ecosystems up to and including the entire biosphere.
doi:10.1371/journal.pcbi.1003050
PMCID: PMC3656095  PMID: 23696719
5.  Microbially Induced Sedimentary Structures Recording an Ancient Ecosystem in the ca. 3.48 Billion-Year-Old Dresser Formation, Pilbara, Western Australia 
Astrobiology  2013;13(12):1103-1124.
Abstract
Microbially induced sedimentary structures (MISS) result from the response of microbial mats to physical sediment dynamics. MISS are cosmopolitan and found in many modern environments, including shelves, tidal flats, lagoons, riverine shores, lakes, interdune areas, and sabkhas. The structures record highly diverse communities of microbial mats and have been reported from numerous intervals in the geological record up to 3.2 billion years (Ga) old. This contribution describes a suite of MISS from some of the oldest well-preserved sedimentary rocks in the geological record, the early Archean (ca. 3.48 Ga) Dresser Formation, Western Australia. Outcrop mapping at the meter to millimeter scale defined five sub-environments characteristic of an ancient coastal sabkha. These sub-environments contain associations of distinct macroscopic and microscopic MISS. Macroscopic MISS include polygonal oscillation cracks and gas domes, erosional remnants and pockets, and mat chips. Microscopic MISS comprise tufts, sinoidal structures, and laminae fabrics; the microscopic laminae are composed of primary carbonaceous matter, pyrite, and hematite, plus trapped and bound grains. Identical suites of MISS occur in equivalent environmental settings through the entire subsequent history of Earth including the present time. This work extends the geological record of MISS by almost 300 million years. Complex mat-forming microbial communities likely existed almost 3.5 billion years ago. Key Words: Archean—Biofilms—Microbial mats—Early Earth—Evolution. Astrobiology 13, 1103–1124.
doi:10.1089/ast.2013.1030
PMCID: PMC3870916  PMID: 24205812
6.  Environmental arsenic contamination and its health effects in a historic gold mining area of the Mangalur greenstone belt of Northeastern Karnataka, India 
Journal of hazardous materials  2012;262:1048-1055.
This report summarizes recent findings of environmental arsenic (As) contamination and the consequent health effects in a community located near historic gold mining activities in the Mangalur greenstone belt of Karnataka, India. Arsenic contents in water, hair, nail, soil and food were measured by FI-HG-AAS. Elemental analyses of soils were determined by ICP-MS (inductively coupled plasma-mass spectrometry). Of 59 tube-well water samples, 79% had As above 10 μg L−1 (maximum 303 μg L−1). Of 12 topsoil samples, six were found to contain As greater than 2000 mg kg−1 possibly indicating the impact of mine tailings on the area. All hair and nail samples collected from 171 residents contained elevated As. Arsenical skin lesions were observed among 58.6% of a total 181 screened individuals. Histopathological analysis of puncture biopsies of suspected arsenical dermatological symptoms confirmed the diagnosis in 3 out of 4 patients. Based on the time-course of arsenic-like symptoms reported by the community as well as the presence of overt arsenicosis, it is hypothesized that the primary route of exposure in the study area was via contaminated groundwater; however, the identified high As content in residential soil could also be a significant source of As exposure via ingestion. Additional studies are required to determine the extent as well as the relative contribution of geologic and anthropogenic factors in environmental As contamination in the region. This study report is to our knowledge one of the first to describe overt arsenicosis in this region of Karnataka, India as well as more broadly an area with underlying greenstone geology and historic mining activity.
doi:10.1016/j.jhazmat.2012.10.002
PMCID: PMC4089497  PMID: 23228450
Arsenic; Groundwater; Greenstone; Gold mine; Karnataka; Arsenical skin lesions
7.  Cesarean Section and Rate of Subsequent Stillbirth, Miscarriage, and Ectopic Pregnancy: A Danish Register-Based Cohort Study 
PLoS Medicine  2014;11(7):e1001670.
Louise Kenny and colleagues conduct a population-based cohort study in Denmark to assess the likelihood of stillbirth, miscarriage, and ectopic pregnancy following cesarean section compared to women who gave birth by vaginal delivery.
Please see later in the article for the Editors' Summary
Background
With cesarean section rates increasing worldwide, clarity regarding negative effects is essential. This study aimed to investigate the rate of subsequent stillbirth, miscarriage, and ectopic pregnancy following primary cesarean section, controlling for confounding by indication.
Methods and Findings
We performed a population-based cohort study using Danish national registry data linking various registers. The cohort included primiparous women with a live birth between January 1, 1982, and December 31, 2010 (n = 832,996), with follow-up until the next event (stillbirth, miscarriage, or ectopic pregnancy) or censoring by live birth, death, emigration, or study end. Cox regression models for all types of cesarean sections, sub-group analyses by type of cesarean, and competing risks analyses for the causes of stillbirth were performed. An increased rate of stillbirth (hazard ratio [HR] 1.14, 95% CI 1.01, 1.28) was found in women with primary cesarean section compared to spontaneous vaginal delivery, giving a theoretical absolute risk increase (ARI) of 0.03% for stillbirth, and a number needed to harm (NNH) of 3,333 women. Analyses by type of cesarean section showed similarly increased rates for emergency (HR 1.15, 95% CI 1.01, 1.31) and elective cesarean (HR 1.11, 95% CI 0.91, 1.35), although not statistically significant in the latter case. An increased rate of ectopic pregnancy was found among women with primary cesarean overall (HR 1.09, 95% CI 1.04, 1.15) and by type (emergency cesarean, HR 1.09, 95% CI 1.03, 1.15, and elective cesarean, HR 1.12, 95% CI 1.03, 1.21), yielding an ARI of 0.1% and a NNH of 1,000 women for ectopic pregnancy. No increased rate of miscarriage was found among women with primary cesarean, with maternally requested cesarean section associated with a decreased rate of miscarriage (HR 0.72, 95% CI 0.60, 0.85). Limitations include incomplete data on maternal body mass index, maternal smoking, fertility treatment, causes of stillbirth, and maternally requested cesarean section, as well as lack of data on antepartum/intrapartum stillbirth and gestational age for stillbirth and miscarriage.
Conclusions
This study found that cesarean section is associated with a small increased rate of subsequent stillbirth and ectopic pregnancy. Underlying medical conditions, however, and confounding by indication for the primary cesarean delivery account for at least part of this increased rate. These findings will assist women and health-care providers to reach more informed decisions regarding mode of delivery.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Globally, increasing numbers of babies are being delivered by cesarean section (a surgical operation in which the baby is delivered through a cut made in the mother's abdomen and womb) instead of naturally through their mother's vagina. In England in 2010, for example, nearly 25% of all babies were delivered by cesarean section (also called C-section) compared to only 2% in the 1950s; in China and some parts of South America cesarean rates are now between 40% and 50%. A cesarean section is usually performed when a vaginal birth would endanger the life of the mother or her unborn child because, for example, the baby is in the wrong position. Some cesareans are performed as emergency procedures, but others are planned in advance when the need for the operation becomes clear during pregnancy (an elective cesarean). Some planned cesarean sections are also undertaken because the mother has requested a cesarean delivery in the absence of any medical reasons for such a delivery.
Why Was This Study Done?
Cesarean sections save lives but do they have any negative impacts on the outcome of subsequent pregnancies? With so many cesarean sections being undertaken, it is important to be sure that the procedure does not increase the rates of subsequent miscarriage, stillbirth, or ectopic pregnancy. Miscarriage—the loss of a fetus (developing baby) that is unable to survive independently—is the commonest complication of early pregnancy, affecting about one in five women who know they are pregnant. Stillbirth is fetal death after about 20–24 weeks of pregnancy; the exact definition of stillbirth varies between countries. About four million stillbirths occur each year worldwide. Ectopic pregnancy—development of the fetus outside the womb—occurs in 1%–2% of all pregnancies. In this population-based cohort study, the researchers investigate the rates of subsequent stillbirth, miscarriage, and ectopic pregnancy following a cesarean section among women living in Denmark. A population-based cohort study determines the baseline characteristics of the individuals in a population, and then follows the population over time to see whether specific characteristics are associated with specific outcomes.
What Did the Researchers Do and Find?
The researchers obtained data for 832,996 women from Danish national registers about their first live birth (including whether they had a cesarean) then followed the women (again using the registers) until they had a stillbirth, miscarriage, or ectopic pregnancy, or a second live birth. The researchers used these data and statistical models to estimate the risk of stillbirth, miscarriage, and ectopic pregnancy following a cesarean compared to a spontaneous vaginal delivery after controlling for the possibility that the cesarean was performed because of an indication that might increase the risk of a subsequent event (confounding). Women who had had a cesarean had a 14% increased risk of a stillbirth in their next pregnancy compared to women who had had a vaginal delivery, corresponding to an absolute risk increase of 0.03%. In other words, 3,333 women would need to have a cesarean to result in one extra stillbirth in subsequent pregnancy (a “number needed to harm” of 3,333). Compared to vaginal delivery, having a cesarean increased the risk of a subsequent ectopic pregnancy by 9% (an absolute risk increase of 0.1% and a number needed to harm of 1,000) but did not increase the rate of subsequent miscarriages.
What Do These Findings Mean?
These findings show that, among women living in Denmark, cesarean section is associated with a slightly increased rate of subsequent stillbirth and ectopic pregnancy. Part of this increase can be accounted for by underlying medical conditions and by confounding by the indication for the primary cesarean section. The accuracy of these findings may be affected by limitations in the study such as incomplete data on some factors (for example, the smoking history of the mother) that might have affected the risk of stillbirth, miscarriage, and ectopic pregnancy, and by misclassification or underreporting of the study outcomes. Given the global increase in cesarean rates, these findings suggest that cesarean delivery is not associated with an increased rate of subsequent stillbirth, miscarriage, or ectopic pregnancy, an important finding for both expectant mothers and health-care professionals that nonetheless needs to be confirmed in further large-scale studies. Finally, these findings highlight the need for women to consider all their options thoroughly before requesting a cesarean section on non-medical grounds.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001670.
The American Congress of Obstetricians and Gynecologists provides patient fact sheets on cesarean birth, miscarriage, and ectopic pregnancy
The US-based non-profit Nemours Foundation provides information about cesarean sections, miscarriage and stillbirth, and ectopic pregnancy (in English and Spanish)
The UK National Health Service Choices website provides information for patients about cesarean section, miscarriage, stillbirth, and ectopic pregnancy
MedlinePlus provides links to additional resources about cesarean section, miscarriage, stillbirth, and ectopic pregnancy (in English and Spanish)
The UK non-profit organization Healthtalkonline provides personal stories about cesarean delivery, miscarriage, and stillbirth
doi:10.1371/journal.pmed.1001670
PMCID: PMC4077571  PMID: 24983970
8.  Light-Dependant Biostabilisation of Sediments by Stromatolite Assemblages 
PLoS ONE  2008;3(9):e3176.
For the first time we have investigated the natural ecosystem engineering capacity of stromatolitic microbial assemblages. Stromatolites are laminated sedimentary structures formed by microbial activity and are considered to have dominated the shallows of the Precambrian oceans. Their fossilised remains are the most ancient unambiguous record of early life on earth. Stromatolites can therefore be considered as the first recognisable ecosystems on the planet. However, while many discussions have taken place over their structure and form, we have very little information on their functional ecology and how such assemblages persisted despite strong eternal forcing from wind and waves. The capture and binding of sediment is clearly a critical feature for the formation and persistence of stromatolite assemblages. Here, we investigated the ecosystem engineering capacity of stromatolitic microbial assemblages with respect to their ability to stabilise sediment using material from one of the few remaining living stromatolite systems (Highborne Cay, Bahamas). It was shown that the most effective assemblages could produce a rapid (12–24 h) and significant increase in sediment stability that continued in a linear fashion over the period of the experimentation (228 h). Importantly, it was also found that light was required for the assemblages to produce this stabilisation effect and that removal of assemblage into darkness could lead to a partial reversal of the stabilisation. This was attributed to the breakdown of extracellular polymeric substances under anaerobic conditions. These data were supported by microelectrode profiling of oxygen and calcium. The structure of the assemblages as they formed was visualised by low-temperature scanning electron microscopy and confocal laser microscopy. These results have implications for the understanding of early stromatolite development and highlight the potential importance of the evolution of photosynthesis in the mat forming process. The evolution of photosynthesis may have provided an important advance for the niche construction activity of microbial systems and the formation and persistence of the stromatolites which came to dominate shallow coastal environments for 80% of the biotic history of the earth.
doi:10.1371/journal.pone.0003176
PMCID: PMC2526175  PMID: 18781202
9.  Diversity, Distribution and Hydrocarbon Biodegradation Capabilities of Microbial Communities in Oil-Contaminated Cyanobacterial Mats from a Constructed Wetland 
PLoS ONE  2014;9(12):e114570.
Various types of cyanobacterial mats were predominant in a wetland, constructed for the remediation of oil-polluted residual waters from an oil field in the desert of the south-eastern Arabian Peninsula, although such mats were rarely found in other wetland systems. There is scarce information on the bacterial diversity, spatial distribution and oil-biodegradation capabilities of freshwater wetland oil-polluted mats. Microbial community analysis by Automated Ribosomal Spacer Analysis (ARISA) showed that the different mats hosted distinct microbial communities. Average numbers of operational taxonomic units (OTUsARISA) were relatively lower in the mats with higher oil levels and the number of shared OTUsARISA between the mats was <60% in most cases. Multivariate analyses of fingerprinting profiles indicated that the bacterial communities in the wetland mats were influenced by oil and ammonia levels, but to a lesser extent by plant density. In addition to oil and ammonia, redundancy analysis (RDA) showed also a significant contribution of temperature, dissolved oxygen and sulfate concentration to the variations of the mats’ microbial communities. Pyrosequencing yielded 282,706 reads with >90% of the sequences affiliated to Proteobacteria (41% of total sequences), Cyanobacteria (31%), Bacteriodetes (11.5%), Planctomycetes (7%) and Chloroflexi (3%). Known autotrophic (e.g. Rivularia) and heterotrophic (e.g. Azospira) nitrogen-fixing bacteria as well as purple sulfur and non-sulfur bacteria were frequently encountered in all mats. On the other hand, sequences of known sulfate-reducing bacteria (SRBs) were rarely found, indicating that SRBs in the wetland mats probably belong to yet-undescribed novel species. The wetland mats were able to degrade 53–100% of C12–C30 alkanes after 6 weeks of incubation under aerobic conditions. We conclude that oil and ammonia concentrations are the major key players in determining the spatial distribution of the wetland mats’ microbial communities and that these mats contribute directly to the removal of hydrocarbons from oil field wastewaters.
doi:10.1371/journal.pone.0114570
PMCID: PMC4267807  PMID: 25514025
10.  Risk of pulmonary tuberculosis relative to silicosis and exposure to silica dust in South African gold miners [published erratum appears in Occup Environ Med 1999 Mar;56(3):215-6] 
OBJECTIVES: To investigate the following questions. (1) Is silica dust on its own, without the presence of silicosis, associated with an increased risk of pulmonary tuberculosis (PTB) in workers exposed to silica dust? (2) In the absence of silicosis is the excess risk dose related? (3) What is the predominant chronological sequence between the development of PTB and the development of silicosis after the end of exposure to dust? METHODS: A cohort of 2255 white South African gold miners has been followed up from 1968 to 1971, when they were 45-55 years of age, to 31 December 1995 for the incidence of PTB. During the follow up 1592 (71%) men died. Of these, 1296 (81%) had a necropsy done at the National Centre for Occupational Health (NCOH) to determine the presence of silicosis and PTB. The incidence of PTB in the cohort was studied relative to cumulative exposure to dust and the onset of silicosis. For the miners with necropsy, the incidence for PTB was studied relative to the severity of silicosis found at necropsy. RESULTS: There were 115 subjects who developed PTB. The total person- years of follow up was 39,319. For the whole cohort, the factors associated with increased risk of PTB were cumulative exposure to dust (mg/m3.y) (the adjusted rate ratio (RR) 1.07; (95% confidence interval (95% CI) 1.04 to 1.10)), silicosis diagnosed radiologically (3.96 (2.59 to 6.06)), and tobacco pack-years (1.02 (1.01 to 1.03)). The RR (95% CI) for PTB increased with increasing quartiles of cumulative exposure to dust 1.0, 1.51 (0.78 to 2.91), 2.35 (1.28 to 4.32), and 3.22 (1.75 to 5.90). In miners who did not have radiologically diagnosed silicosis (n = 1934, PTB = 74), the adjusted RR (95% CI) for PTB and cumulative exposure to dust was 1.10 (1.06 to 1.13), and increased with quartiles of cumulative exposure to dust as 1.00, 1.46 (0.70 to 3.03), 2.67 (1.37 to 5.23), and 4.01 (2.04 to 7.88). For the subjects who had a necropsy (n = 1296, PTB = 70), the adjusted RR (95% CI) for PTB increased with the severity of silicosis found at necropsy; 1.0 for no silicosis, 1.88 (0.97 to 3.64) for negligible, 2.69 (1.35 to 5.37) for slight, and 2.30 (1.16 to 4.58) for moderate or marked silicosis. For subjects who had a necropsy and no silicosis (n = 577, PTB = 18), the adjusted RR (95% CI) increased slightly with quartiles of cumulative dust 1.0, 1.11 (0.31 to 4.00), 1.42 (0.43 to 4.72), and 1.38 (0.33 to 5.62). CONCLUSION: Exposure to silica dust is a risk factor for the development of PTB in the absence of silicosis, even after exposure to silica dust ends. The risk of PTB increases with the presence of silicosis, and in miners without radiological silicosis, with quartiles of exposure to dust. The severity of silicosis diagnosed at necropsy was associated with increasing risk of PTB and even < 5 nodules--that is, undetectable radiologically--was associated with an increased risk of PTB. The diagnosis of PTB was on average 7.6 years after the end of exposure to dust, at around 60 years of age. The onset of radiological silicosis preceded the diagnosis of PTB in 90.2% of the cases with PTB who had silicosis. The results have implications for medical surveillance of workers exposed to silica dust after the end of exposure.
 
PMCID: PMC1757613  PMID: 9816385
11.  Mortality in Patients with HIV-1 Infection Starting Antiretroviral Therapy in South Africa, Europe, or North America: A Collaborative Analysis of Prospective Studies 
PLoS Medicine  2014;11(9):e1001718.
Analyzing survival in HIV treatment cohorts, Andrew Boulle and colleagues find mortality rates in South Africa comparable to or better than those in North America by 4 years after starting antiretroviral therapy.
Please see later in the article for the Editors' Summary
Background
High early mortality in patients with HIV-1 starting antiretroviral therapy (ART) in sub-Saharan Africa, compared to Europe and North America, is well documented. Longer-term comparisons between settings have been limited by poor ascertainment of mortality in high burden African settings. This study aimed to compare mortality up to four years on ART between South Africa, Europe, and North America.
Methods and Findings
Data from four South African cohorts in which patients lost to follow-up (LTF) could be linked to the national population register to determine vital status were combined with data from Europe and North America. Cumulative mortality, crude and adjusted (for characteristics at ART initiation) mortality rate ratios (relative to South Africa), and predicted mortality rates were described by region at 0–3, 3–6, 6–12, 12–24, and 24–48 months on ART for the period 2001–2010. Of the adults included (30,467 [South Africa], 29,727 [Europe], and 7,160 [North America]), 20,306 (67%), 9,961 (34%), and 824 (12%) were women. Patients began treatment with markedly more advanced disease in South Africa (median CD4 count 102, 213, and 172 cells/µl in South Africa, Europe, and North America, respectively). High early mortality after starting ART in South Africa occurred mainly in patients starting ART with CD4 count <50 cells/µl. Cumulative mortality at 4 years was 16.6%, 4.7%, and 15.3% in South Africa, Europe, and North America, respectively. Mortality was initially much lower in Europe and North America than South Africa, but the differences were reduced or reversed (North America) at longer durations on ART (adjusted rate ratios 0.46, 95% CI 0.37–0.58, and 1.62, 95% CI 1.27–2.05 between 24 and 48 months on ART comparing Europe and North America to South Africa). While bias due to under-ascertainment of mortality was minimised through death registry linkage, residual bias could still be present due to differing approaches to and frequency of linkage.
Conclusions
After accounting for under-ascertainment of mortality, with increasing duration on ART, the mortality rate on HIV treatment in South Africa declines to levels comparable to or below those described in participating North American cohorts, while substantially narrowing the differential with the European cohorts.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
AIDS has killed about 36 million people since the first recorded case of the disease in 1981, and a similar number of people (including 25 million living in sub-Saharan Africa) are currently infected with HIV, the virus that causes AIDS. HIV destroys immune system cells (including CD4 cells, a type of lymphocyte), leaving infected individuals susceptible to other serious infections. Early in the AIDS epidemic, HIV-positive people usually died within 10 years of becoming infected. In 1996, effective antiretroviral therapy (ART) became available and, for people living in high-income countries, HIV infection became a chronic condition. But ART was expensive, so HIV/AIDS remained largely untreated and fatal in resource-limited countries. Then, in 2003, the international community began to work towards achieving universal access to ART. By the end of 2012, nearly two-thirds of HIV-positive people (nearly 10 million individuals) living in low- and middle-income countries who were eligible for treatment because their CD4 cell count had fallen below 350/mm3 blood or because they had developed an AIDS-defining condition were receiving treatment.
Why Was This Study Done?
It is known that a larger proportion of HIV-positive patients starting ART die during the first year of treatment in sub-Saharan Africa than in Europe and North America. This difference arises in part because patients in resource-limited settings tend to have lower CD4 counts when they start treatment than patients in wealthy countries. However, the lack of reliable data on mortality (death) in resource-limited settings has made it hard to compare longer-term outcomes in different settings. Information on the long-term outcomes of HIV-positive patients receiving ART in resource-limited countries is needed to guide the development of appropriate health systems and treatment regimens in these settings. In this collaborative analysis of prospective cohort studies, the researchers compare mortality up to 4 years on ART in South Africa, Europe, and North America. A prospective cohort study follows a group of individuals over time to see whether differences in specific characteristics at the start of the study affect subsequent outcomes. A collaborative analysis combines individual patient data from several studies.
What Did the Researchers Do and Find?
The researchers combined data from four South Africa cohorts of HIV-positive patients starting ART included in the International Epidemiologic Databases to Evaluate AIDS South African (IeDEA-SA) collaboration with data from six North American cohorts and nine European cohorts included in the ART Cohort Collaboration (ART-CC). The South African cohorts were chosen because unusually for studies undertaken in countries in sub-Saharan Africa the vital status of patients (whether they had died) who had been lost to follow-up in these cohorts could be obtained from the national population register. Patients in South Africa began treatment with more advanced disease (indicated by a lower average CD4 count) than patients in Europe or North America. Notably, high early mortality after starting ART in South Africa occurred mainly in patients starting ART with a CD4 count below 50 cells/mm3. The cumulative mortality after 4 years of ART was 16.6%, 4.7%, and 15.3% in South Africa, Europe, and North America, respectively. After adjusting for patient characteristics at ART initiation, the mortality rate among patients beginning ART was initially lower in Europe and North American than in South Africa. However, although the adjusted mortality rate in Europe remained lower than the rate in South Africa, the rate in North America was higher than that in South Africa between 24 and 48 months on ART.
What Do These Findings Mean?
Although the linkage to national vital registration systems (databases of births and deaths) undertaken in this collaborative analysis is likely to have greatly reduced bias due to under-ascertainment of mortality, the accuracy of these findings may still be limited by differences in how this linkage was undertaken in different settings. Nevertheless, these findings suggest that mortality among HIV-infected patients receiving ART in South Africa, although initially higher than in Europe and North America, rapidly declines with increasing duration on ART and, after 4 years of treatment, approaches the rate seen in high-income settings. Intriguingly, these findings also highlight the relatively higher late mortality in North America compared to either Europe or South Africa, a result that needs to be investigated to explore the extent to which differences in mortality ascertainment, patient characteristics and comorbidities, or health systems and treatment regimens contribute to variations in outcomes among HIV-positive patients in various settings.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001718.
This study is further discussed in a PLOS Medicine Perspective by Agnes Binagwaho and colleagues
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on universal access to ART, on HIV and AIDS in sub-Saharan Africa, and on HIV and AIDS in South Africa (in English and Spanish)
The World Health Organization provides information on all aspects of HIV/AIDS (in several languages); its 2013 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infections: recommendations for a public health approach are available
The 2013 UNAIDS World AIDS Day Report provides up-to-date information about the AIDS epidemic and efforts to halt it
Information about the International Epidemiologic Databases to Evaluate AIDS South African (IeDEA-SA) collaboration and about the ART Cohort Collaboration is available
Personal stories about living with HIV/AIDS are available through Avert, Nam/aidsmap, and Healthtalkonline
doi:10.1371/journal.pmed.1001718
PMCID: PMC4159124  PMID: 25203931
12.  Cell evolution and Earth history: stasis and revolution 
This synthesis has three main parts. The first discusses the overall tree of life and nature of the last common ancestor (cenancestor). I emphasize key steps in cellular evolution important for ordering and timing the major evolutionary innovations in the history of the biosphere, explaining especially the origins of the eukaryote cell and of bacterial flagella and cell envelope novelties. Second, I map the tree onto the fossil record and discuss dates of key events and their biogeochemical impact. Finally, I present a broad synthesis, discussing evidence for a three-phase history of life. The first phase began perhaps ca 3.5 Gyr ago, when the origin of cells and anoxic photosynthesis generated the arguably most primitive prokaryote phylum, Chlorobacteria (=Chloroflexi), the first negibacteria with cells bounded by two acyl ester phospholipid membranes. After this ‘chlorobacterial age’ of benthic anaerobic evolution protected from UV radiation by mineral grains, two momentous quantum evolutionary episodes of cellular innovation and microbial radiation dramatically transformed the Earth's surface: the glycobacterial revolution initiated an oxygenic ‘age of cyanobacteria’ and, as the ozone layer grew, the rise of plankton; immensely later, probably as recently as ca 0.9 Gyr ago, the neomuran revolution ushered in the ‘age of eukaryotes’, Archaebacteria (arguably the youngest bacterial phylum), and morphological complexity. Diversification of glycobacteria ca 2.8 Gyr ago, predominantly inhabiting stratified benthic mats, I suggest caused serial depletion of 13C by ribulose 1,5-bis-phosphate caboxylase/oxygenase (Rubisco) to yield ultralight late Archaean organic carbon formerly attributed to methanogenesis plus methanotrophy. The late origin of archaebacterial methanogenesis ca 720 Myr ago perhaps triggered snowball Earth episodes by slight global warming increasing weathering and reducing CO2 levels, to yield runaway cooling; the origin of anaerobic methane oxidation ca 570 Myr ago reduced methane flux at source, stabilizing Phanerozoic climates. I argue that the major cellular innovations exhibit a pattern of quantum evolution followed by very rapid radiation and then substantial stasis, as described by Simpson. They yielded organisms that are a mosaic of extremely conservative and radically novel features, as characterized by De Beer's phrase ‘mosaic evolution’. Evolution is not evenly paced and there are no real molecular clocks.
doi:10.1098/rstb.2006.1842
PMCID: PMC1578732  PMID: 16754610
neomura; snowball Earth; archaebacteria; eobacteria; eukaryote origin; glycobacteria
13.  Quorum Sensing in Extreme Environments 
Life : Open Access Journal  2013;3(1):131-148.
Microbial communication, particularly that of quorum sensing, plays an important role in regulating gene expression in a range of organisms. Although this phenomenon has been well studied in relation to, for example, virulence gene regulation, the focus of this article is to review our understanding of the role of microbial communication in extreme environments. Cell signaling regulates many important microbial processes and may play a pivotal role in driving microbial functional diversity and ultimately ecosystem function in extreme environments. Several recent studies have characterized cell signaling in modern analogs to early Earth communities (microbial mats), and characterization of cell signaling systems in these communities may provide unique insights in understanding the microbial interactions involved in function and survival in extreme environments. Cell signaling is a fundamental process that may have co-evolved with communities and environmental conditions on the early Earth. Without cell signaling, evolutionary pressures may have even resulted in the extinction rather than evolution of certain microbial groups. One of the biggest challenges in extremophile biology is understanding how and why some microbial functional groups are located where logically they would not be expected to survive, and tightly regulated communication may be key. Finally, quorum sensing has been recently identified for the first time in archaea, and thus communication at multiple levels (potentially even inter-domain) may be fundamental in extreme environments.
doi:10.3390/life3010131
PMCID: PMC4187201  PMID: 25371335
quorum sensing; extremophiles; microbial communication
14.  Clonal Waves of Neisseria Colonisation and Disease in the African Meningitis Belt: Eight- Year Longitudinal Study in Northern Ghana 
PLoS Medicine  2007;4(3):e101.
Background
The Kassena-Nankana District of northern Ghana lies in the African “meningitis belt” where epidemics of meningococcal meningitis have been reoccurring every eight to 12 years for the last 100 years. The dynamics of meningococcal colonisation and disease are incompletely understood, and hence we embarked on a long-term study to determine how levels of colonisation with different bacterial serogroups change over time, and how the patterns of disease relate to such changes.
Methods and Findings
Between February 1998 and November 2005, pharyngeal carriage of Neisseria meningitidis in the Kassena-Nankana District was studied by twice-yearly colonisation surveys. Meningococcal disease was monitored throughout the eight-year study period, and patient isolates were compared to the colonisation isolates. The overall meningococcal colonisation rate of the study population was 6.0%. All culture-confirmed patient isolates and the majority of carriage isolates were associated with three sequential waves of colonisation with encapsulated (A ST5, X ST751, and A ST7) meningococci. Compared to industrialised countries, the colonising meningococcal population was less constant in genotype composition over time and was genetically less diverse during the peaks of the colonisation waves, and a smaller proportion of the isolates was nonserogroupable. We observed a broad age range in the healthy carriers, resembling that of meningitis patients during large disease epidemics.
Conclusions
The observed lack of a temporally stable and genetically diverse resident pharyngeal flora of meningococci might contribute to the susceptibility to meningococcal disease epidemics of residents in the African meningitis belt. Because capsular conjugate vaccines are known to impact meningococcal carriage, effects on herd immunity and potential serogroup replacement should be monitored following the introduction of such vaccines.
An analysis of pharyngeal carriage of meningococci in one district of Ghana examined the features of the isolates that might contribute to the susceptibility to meningococcal epidemics in the African meningitis belt.
Editors' Summary
Background.
Bacterial meningitis is a rare but often fatal infection of the meninges—the thin membrane around the brain and the spinal cord. It can be caused by several types of bacteria, but meningococcal meningitis, which is caused by Neisseria meningitidis, is the most common form of bacterial meningitis in children and the second most common form in adults. About 10% of healthy people have N. meningitidis growing in their nose and throat; the bacteria are spread by exposure to infected respiratory secretions. In these “carriers,” the immune system keeps the bug in check but sometimes this surveillance fails, N. meningitidis enters the bloodstream and travels to the brain, where it infects the meninges and causes inflammation. The symptoms of meningococcal meningitis are sudden fever, headache, and a stiff neck and, even if strong antibiotics are given quickly, 10%–15% of patients die.
Why Was This Study Done?
Outbreaks of meningococcal meningitis occur all over the world, but the highest burden of disease is in the African meningitis belt, which stretches across sub-Saharan Africa from Senegal to Ethiopia. Here, localized epidemics of meningococcal meningitis occur every eight to 12 years during the dry season. Control of these epidemics relies on their early detection followed by mass immunization. This approach can be hard to implement in countries with limited resources, but the introduction of other control measures (for example, routine childhood immunization) requires an understanding of how the spread of different strains of N. meningitides through the community causes periodic epidemics. In this study, the researchers have studied the long-term dynamics of colonization by N. meningitidis and the occurrence of meningococcal meningitis in one region of the African meningitis belt.
What Did the Researchers Do and Find?
The researchers took throat swabs twice a year from people living in rural northern Ghana for eight years. They tested each swab for N. meningitidis and determined the serogroup of the bacteria they found. Bacterial serogroups differ only in terms of the antigens (molecules recognized by the immune system) that they express; N. meningitidis is classified into 13 serogroups based on the sugars that coat its surface. The researchers also used DNA sequencing to group the bacterial isolates into genoclouds—genetically closely related groups of meningococci represented by a sequence type (ST) number. Finally, they monitored meningococcal disease throughout the study and determined the serogroup and genocloud of patient isolates. Their results show colonization of 6% of the study population by N. meningitidis and reveal three consecutive waves of colonization and disease characterized by the presence of a serogroup A ST5 genocloud, a serogroup X ST751 genocloud, and finally a serogroup A ST7 genocloud. Colonizing bacteria isolated in this study in Ghana, the researchers report, changed their genotype more frequently but were less genetically diverse than those isolated in industrialized countries. In addition, the commonest serogroups of N. meningitidis in carriers in Ghana were disease-causing serogroups, whereas in industrialized countries these serogroups are rarely seen in carriers. However, non-groupable bacteria (bacteria that lack surface sugars), although common in industrialized countries, were rare in Ghana.
What Do These Findings Mean?
These findings begin to explain why epidemics of meningococcal meningitis are common in the African meningitis belt. Because there isn't a stable, genetically diverse population of N. meningitidis in carriers, the immune systems of people living here may not be optimally prepared to deal with new bacterial clones that arrive in the region, and this lack of immunity could result in frequent epidemics. However, because the researchers took relatively few samples every six months from one small area of the meningitis belt, the genetic diversity of N. meningitidis over the whole region might be considerably greater than that colonizing the study population. Nevertheless, the description of successive waves of meningococci colonization in Ghana has important implications for the proposed introduction of childhood vaccination against meninogococcal disease in the African meningitis belt. If this vaccination program goes ahead, warn the researchers, it will be essential to monitor which strains of N. meningitidis are colonizing the population and to have emergency plans ready to deal with any emerging disease-causing serogroups that are not covered by the vaccine.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040101.
The Web sites of the institutions at which this research was performed, the Swiss Tropical Institute and the Navrongo Health Research Centre, provide more information about the programs
The World Health Organization provides information on meningococcal disease, including the African meningitis belt (in English, Spanish, Chinese, Russian, and Arabic)
Information on meningitis and vaccines and their potential use in Africa is available from the Meningitis Vaccine Project (in English and French)
Medline Plus has encyclopedia pages on meningococcal meningitis
The US Centers for Disease Control and Prevention provides information on meningococcal disease (in English and Spanish)
doi:10.1371/journal.pmed.0040101
PMCID: PMC1831736  PMID: 17388665
15.  Hydrogen production in photosynthetic microbial mats in the Elkhorn Slough estuary, Monterey Bay 
The ISME Journal  2011;6(4):863-874.
Hydrogen (H2) release from photosynthetic microbial mats has contributed to the chemical evolution of Earth and could potentially be a source of renewable H2 in the future. However, the taxonomy of H2-producing microorganisms (hydrogenogens) in these mats has not been previously determined. With combined biogeochemical and molecular studies of microbial mats collected from Elkhorn Slough, Monterey Bay, California, we characterized the mechanisms of H2 production and identified a dominant hydrogenogen. Net production of H2 was observed within the upper photosynthetic layer (0–2 mm) of the mats under dark and anoxic conditions. Pyrosequencing of rRNA gene libraries generated from this layer demonstrated the presence of 64 phyla, with Bacteriodetes, Cyanobacteria and Proteobacteria dominating the sequences. Sequencing of rRNA transcripts obtained from this layer demonstrated that Cyanobacteria dominated rRNA transcript pyrotag libraries. An OTU affiliated to Microcoleus spp. was the most abundant OTU in both rRNA gene and transcript libraries. Depriving mats of sunlight resulted in an order of magnitude decrease in subsequent nighttime H2 production, suggesting that newly fixed carbon is critical to H2 production. Suppression of nitrogen (N2)-fixation in the mats did not suppress H2 production, which indicates that co-metabolic production of H2 during N2-fixation is not an important contributor to H2 production. Concomitant production of organic acids is consistent with fermentation of recently produced photosynthate as the dominant mode of H2 production. Analysis of rRNA % transcript:% gene ratios and H2-evolving bidirectional [NiFe] hydrogenase % transcript:% gene ratios indicated that Microcoelus spp. are dominant hydrogenogens in the Elkhorn Slough mats.
doi:10.1038/ismej.2011.142
PMCID: PMC3309353  PMID: 22011721
microbial mats; fermentation; hydrogen; hydrogenase; Microcoleus spp.; pyrotags
16.  Polyamine Analogues Bind Human Serum Albumin 
Biomacromolecules  2007;8(10):3177-3183.
Polyamine analogues show antitumor activity in experimental models and their ability to alter activity of cytotoxic chemotherapeutic agents in breast cancer is well documented. Association of polyamines with nucleic acids and protein is included in their mechanism of action. The aim of this study was to examine the interaction of human serum albumin (HSA) with several polyamine analogues such as 1,11-diamino-4,8-diazaundecane (333), 3,7,11,15-tetrazaheptadecane.4HCl (BE-333) and 3,7,11,15,19-pentazahenicosane.5HCl (BE-3333) in aqueous solution at physiological conditions, using a constant protein concentration and various polyamine contents (μM to mM). FTIR, UV-visible and CD spectroscopic methods were used to determine the polyamine binding mode and the effects of polyamine complexation on protein stability and secondary structure.
Structural analysis showed that polyamines bind non-specifically (H-bonding) via polypeptide polar groups with binding constants of K333 = 9.30 × 103 M−1, KBE-333 = 5.63 × 102 M−1 and KBE-3333 = 3.66 × 102 M−1. The protein secondary structure showed major alterations with reduction of α-helix from 55% (free protein) to 43–50% and increase of β-sheet from 17% (free protein) to 29–36% in the 333-, BE-333- and BE-3333 complexes, indicating a partial protein unfolding upon polyamine interaction. HSA structure was less perturbed by polyamine analogues than those of the biogenic polyamines.
doi:10.1021/bm700697a
PMCID: PMC2548305  PMID: 17887793
polyamine analogues; protein; HSA; binding mode; secondary structure; FTIR; CD spectroscopy
17.  Elimination of HIV in South Africa through Expanded Access to Antiretroviral Therapy: A Model Comparison Study 
PLoS Medicine  2013;10(10):e1001534.
Using nine structurally different models, Jan Hontelez and colleagues investigate timeframes for HIV elimination in South Africa using a universal test and treat strategy.
Please see later in the article for the Editors' Summary
Background
Expanded access to antiretroviral therapy (ART) using universal test and treat (UTT) has been suggested as a strategy to eliminate HIV in South Africa within 7 y based on an influential mathematical modeling study. However, the underlying deterministic model was criticized widely, and other modeling studies did not always confirm the study's finding. The objective of our study is to better understand the implications of different model structures and assumptions, so as to arrive at the best possible predictions of the long-term impact of UTT and the possibility of elimination of HIV.
Methods and Findings
We developed nine structurally different mathematical models of the South African HIV epidemic in a stepwise approach of increasing complexity and realism. The simplest model resembles the initial deterministic model, while the most comprehensive model is the stochastic microsimulation model STDSIM, which includes sexual networks and HIV stages with different degrees of infectiousness. We defined UTT as annual screening and immediate ART for all HIV-infected adults, starting at 13% in January 2012 and scaled up to 90% coverage by January 2019. All models predict elimination, yet those that capture more processes underlying the HIV transmission dynamics predict elimination at a later point in time, after 20 to 25 y. Importantly, the most comprehensive model predicts that the current strategy of ART at CD4 count ≤350 cells/µl will also lead to elimination, albeit 10 y later compared to UTT. Still, UTT remains cost-effective, as many additional life-years would be saved. The study's major limitations are that elimination was defined as incidence below 1/1,000 person-years rather than 0% prevalence, and drug resistance was not modeled.
Conclusions
Our results confirm previous predictions that the HIV epidemic in South Africa can be eliminated through universal testing and immediate treatment at 90% coverage. However, more realistic models show that elimination is likely to occur at a much later point in time than the initial model suggested. Also, UTT is a cost-effective intervention, but less cost-effective than previously predicted because the current South African ART treatment policy alone could already drive HIV into elimination.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 34 million people (mostly in low- and middle-income countries) are currently infected with HIV, the virus that causes AIDS, and every year another 2.5 million people become infected. HIV, which is usually transmitted through unprotected sex with an infected partner, gradually destroys CD4 lymphocytes and other immune system cells, leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, people infected with HIV often died within ten years of infection. Then, in 1996, antiretroviral therapy (ART) became available, and, for people living in affluent countries, HIV/AIDS became a chronic condition. However, ART was expensive, so HIV/AIDS remained a fatal condition for people living in resource-limited countries. In 2006, the international community set a target of achieving universal ART coverage by 2010, and ART programs were initiated in many resource-limited countries. Although universal ART coverage has still not been achieved in South Africa, where nearly 6 million people are HIV-positive, 80% of people in need of ART were receiving a World Health Organization–recommended ART regimen by October 2012.
Why Was This Study Done?
ART is usually started when a person's CD4 count falls below 350 cells/µl blood, but it is thought that treatment of all HIV-positive individuals, regardless of their CD4 count, could reduce HIV transmission by reducing the infectiousness of HIV-positive individuals (“treatment as prevention”). Might it be possible, therefore, to eliminate HIV by screening everyone annually for infection and treating all HIV-positive individuals immediately? In 2009, a mathematical modeling study suggested that seven years of universal test and treat (UTT) could eliminate HIV in South Africa. The deterministic (nonrandom) model used in that study has been widely criticized, however, and some subsequent modeling studies have reached different conclusions, probably because of differences in the models' structures and in the assumptions built into them. A better understanding of the reasons for the discrepancies between models would help policy-makers decide whether to introduce UTT, so, here, the researchers developed several increasingly complex and realistic models of the South African HIV epidemic and used these models to predict the long-term impact of UTT in South Africa.
What Did the Researchers Do and Find?
The researchers developed nine structurally different mathematical models of the South African HIV epidemic based on the STDSIM framework, a stochastic microsimulation model that simulates the life course of individuals in a dynamic network of sexual contacts and in which events such as HIV infection are random processes. The simplest model, which resembled the original deterministic model, was extended by sequentially adding in factors such as different HIV transmission rates at different stages of HIV infection and up-to-date assumptions regarding the ability of ART to reduce HIV infectiousness. All the models replicated the prevalence of HIV in South Africa (the proportion of the population that was HIV-positive) between 1990 and 2010, and all predicted that UTT (defined as annual screening of individuals age 15+ years and immediate ART for all HIV-infected adults starting in 2012 and scaled up to 90% coverage by 2019) would result in HIV elimination (less than one new infection per 1,000 person-years). However, whereas the simplest model predicted that UTT would eliminate HIV after seven years, the more complex, realistic models predicted elimination at much later time points. Importantly, the most comprehensive model predicted that, although elimination would be reached after about 17 years of UTT, the current strategy of ART initiation for HIV-positive individuals at a CD4 cell count at or below 350 cells/µl would also lead to HIV elimination, albeit ten years later than UTT.
What Do These Findings Mean?
These findings confirm previous predictions that UTT could eliminate HIV in South Africa, but the development of more realistic models than those used in the past suggests that HIV elimination would occur substantially later than originally predicted. Importantly, the most comprehensive model suggests that HIV could be eliminated in South Africa using the current strategy for ART treatment alone. As with all modeling studies, the accuracy of these findings depends on the assumptions built into the models and on the structure of the models. Thus, although these findings support the use of UTT as an intervention to eliminate HIV, more research with comprehensive models that incorporate factors such as data from ongoing trials of treatment as prevention is needed to determine the population-level impact and overall cost-effectiveness of UTT.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001534.
This study is further discussed in a PLOS Medicine Perspective by Ford and Hirnschall
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on HIV and AIDS in South Africa, on HIV treatment as prevention and the possibility of HIV elimination (in English and Spanish)
The 2012 UNAIDS World AIDS Day Report provides up-to-date information about the AIDS epidemic and efforts to halt it
The World Health Organization provides information about universal access to AIDS treatment (in several languages); its 2010 ART guidelines can be downloaded
The PLOS Medicine Collection Investigating the Impact of Treatment on New HIV Infections provides more information about HIV treatment as prevention
Personal stories about living with HIV/AIDS are available through Avert, through NAM/aidsmap, and through the charity website Healthtalkonline
doi:10.1371/journal.pmed.1001534
PMCID: PMC3805487  PMID: 24167449
18.  A Rhinocerotid Skull Cooked-to-Death in a 9.2 Ma-Old Ignimbrite Flow of Turkey 
PLoS ONE  2012;7(11):e49997.
Background
Preservation of fossil vertebrates in volcanic rocks is extremely rare. An articulated skull (cranium and mandible) of a rhinoceros was found in a 9.2±0.1 Ma-old ignimbrite of Cappadocia, Central Turkey. The unusual aspect of the preserved hard tissues of the skull (rough bone surface and brittle dentine) allows suspecting a peri-mortem exposure to a heating source.
Methodology/Principal Findings
Here we describe and identify the skull as belonging to the large two-horned rhinocerotine Ceratotherium neumayri, well-known in the late Miocene of the Eastern Mediterranean Province. Gross structural features and microscopic changes of hard tissues (bones and teeth) are then monitored and compared to the results of forensic and archaeological studies and experiments focusing on heating effects, in order to reconstruct the hypothetical peri-mortem conditions. Macroscopic and microscopic structural changes on compact bones (canaliculi and lamellae vanished), as well as partial dentine/cementum disintegration, drastic enamel-dentine disjunctions or microscopic cracks affecting all hard dental tissues (enamel, cementum, and dentine) point to continued exposures to temperatures around 400–450°C. Comparison to other cases of preservation of fossil vertebrates within volcanic rocks points unambiguously to some similarity with the 79 AD Plinian eruption of the Vesuvius, in Italy.
Conclusions/Significance
A 9.2±0.1 Ma-old pyroclastic density current, sourced from the Çardak caldera, likely provoked the instant death of the Karacaşar rhino, before the body of the latter experienced severe dehydration (leading to the wide and sustainable opening of the mouth), was then dismembered within the pyroclastic flow of subaerial origin, the skull being separated from the remnant body and baked under a temperature approximating 400°C, then transported northward, rolled, and trapped in disarray into that pyroclastic flow forming the pinkish Kavak-4 ignimbrite ∼30 km North from the upper Miocene vent.
doi:10.1371/journal.pone.0049997
PMCID: PMC3503723  PMID: 23185510
19.  Biogenic and Synthetic Polyamines Bind Cationic Dendrimers 
PLoS ONE  2012;7(4):e36087.
Biogenic polyamines are essential for cell growth and differentiation, while polyamine analogues exert antitumor activity in multiple experimental model systems, including breast and lung cancer. Dendrimers are widely used for drug delivery in vitro and in vivo. We report the bindings of biogenic polyamines, spermine (spm), and spermidine (spmd), and their synthetic analogues, 3,7,11,15-tetrazaheptadecane.4HCl (BE-333) and 3,7,11,15,19-pentazahenicosane.5HCl (BE-3333) to dendrimers of different compositions, mPEG-PAMAM (G3), mPEG-PAMAM (G4) and PAMAM (G4). FTIR and UV-visible spectroscopic methods as well as molecular modeling were used to analyze polyamine binding mode, the binding constant and the effects of polyamine complexation on dendrimer stability and conformation. Structural analysis showed that polyamines bound dendrimers through both hydrophobic and hydrophilic contacts with overall binding constants of Kspm-mPEG-G3 = 7.6×104 M−1, Kspm-mPEG-PAMAM-G4 = 4.6×104 M−1, Kspm-PAMAM-G4 = 6.6×104 M−1, Kspmd-mPEG-G3 = 1.0×105 M−1, Kspmd-mPEG-PAMAM-G4 = 5.5×104 M−1, Kspmd-PAMAM-G4 = 9.2×104 M−1, KBE-333-mPEG-G3 = 4.2×104 M−1, KBe-333-mPEG-PAMAM-G4 = 3.2×104 M−1, KBE-333-PAMAM-G4 = 3.6×104 M−1, KBE-3333-mPEG-G3 = 2.2×104 M−1, KBe-3333-mPEG-PAMAM-G4 = 2.4×104 M−1, KBE-3333-PAMAM-G4 = 2.3×104 M−1. Biogenic polyamines showed stronger affinity toward dendrimers than those of synthetic polyamines, while weaker interaction was observed as polyamine cationic charges increased. The free binding energies calculated from docking studies were: −3.2 (spermine), −3.5 (spermidine) and −3.03 (BE-3333) kcal/mol, with the following order of binding affinity: spermidine-PAMAM-G-4>spermine-PAMMAM-G4>BE-3333-PAMAM-G4 consistent with spectroscopic data. Our results suggest that dendrimers can act as carrier vehicles for delivering antitumor polyamine analogues to target tissues.
doi:10.1371/journal.pone.0036087
PMCID: PMC3338638  PMID: 22558341
20.  Population Vulnerability and Disability in Kenya's Tsetse Fly Habitats 
Background
Human African Trypanosomiasis (HAT), also referred to as sleeping sickness, and African Animal Trypanosomaisis (AAT), known as nagana, are highly prevalent parasitic vector-borne diseases in sub-Saharan Africa. Humans acquire trypanosomiasis following the bite of a tsetse fly infected with the protozoa Trypanosoma brucei (T.b.) spp. –i.e., T.b. gambiense in West and Central Africa and T.b. rhodesiense in East and Southern Africa. Over the last decade HAT diagnostic capacity to estimate HAT prevalence has improved in active case-finding areas but enhanced passive surveillance programs are still lacking in much of rural sub-Saharan Africa.
Methodology/Principal Findings
This retrospective-cross-sectional study examined the use of national census data (1999) to estimate population vulnerability and disability in Kenya's 7 tsetse belts to assess the potential of HAT-acquired infection in those areas. A multilevel study design estimated the likelihood of disability in individuals, nested within households, nested within tsetse fly habitats of varying levels of poverty. Residents and recent migrants of working age were studied. Tsetse fly's impact on disability was conceptualised via two exposure pathways: directly from the bite of a pathogenic tsetse fly resulting in HAT infection or indirectly, as the potential for AAT takes land out of agricultural production and diseased livestock leads to livestock morbidity and mortality, contributing to nutritional deficiencies and poverty. Tsetse belts that were significantly associated with increased disability prevalence were identified and the direct and indirect exposure pathways were evaluated.
Conclusions/Significance
Incorporating reports on disability from the national census is a promising surveillance tool that may enhance future HAT surveillance programs in sub-Saharan Africa. The combined burdens of HAT and AAT and the opportunity costs of agricultural production in AAT areas are likely contributors to disability within tsetse-infested areas. Future research will assess changes in the spatial relationships between high tsetse infestation and human disability following the release of the Kenya 2009 census at the local level.
Author Summary
The tsetse fly's influence on human health occurs through direct and indirect exposure pathways. Directly, the fly is a vector for the disease human African trypanosomiasis (HAT), which it spreads to nearly 18,000 new victims each year. Indirectly, the fly is a vector for African Animal Trypanosomaisis (AAT) also known as nagana, which restricts agricultural production, limiting the availability of food and contributing to impoverished conditions across rural sub-Saharan Africa. This historical study used 1999 census data to determine the prevalence of disability among residents and migrants living within Kenya's 7 tsetse fly belts. The results showed that the HAT transmission cycle may differ for residents and migrants with mechanisms leading to exposures that are environmentally driven for residents and economically driven for migrants. The combined burdens of HAT and AAT and the opportunity costs of agricultural production in AAT areas are potential contributors to disability within these tsetse-infested areas. Incorporating reports on disability from the national census appears to be an important surveillance tool that would enhance future HAT surveillance programs in sub-Saharan Africa.
doi:10.1371/journal.pntd.0000957
PMCID: PMC3035673  PMID: 21347453
21.  Timescales of Growth Response of Microbial Mats to Environmental Change in an Ice-Covered Antarctic Lake 
Biology  2013;2(1):151-176.
Lake Vanda is a perennially ice-covered, closed-basin lake in the McMurdo Dry Valleys, Antarctica. Laminated photosynthetic microbial mats cover the floor of the lake from below the ice cover to >40 m depth. In recent decades, the water level of Lake Vanda has been rising, creating a “natural experiment” on development of mat communities on newly flooded substrates and the response of deeper mats to declining irradiance. Mats in recently flooded depths accumulate one lamina (~0.3 mm) per year and accrue ~0.18 µg chlorophyll-a cm−2 y−1. As they increase in thickness, vertical zonation becomes evident, with the upper 2-4 laminae forming an orange-brown zone, rich in myxoxanthophyll and dominated by intertwined Leptolyngbya trichomes. Below this, up to six phycobilin-rich green/pink-pigmented laminae form a subsurface zone, inhabited by Leptolyngbya, Oscillatoria and Phormidium morphotypes. Laminae continued to increase in thickness for several years after burial, and PAM fluorometry indicated photosynthetic potential in all pigmented laminae. At depths that have been submerged for >40 years, mats showed similar internal zonation and formed complex pinnacle structures that were only beginning to appear in shallower mats. Chlorophyll-a did not change over time and these mats appear to represent resource-limited “climax” communities. Acclimation of microbial mats to changing environmental conditions is a slow process, and our data show how legacy effects of past change persist into the modern community structure.
doi:10.3390/biology2010151
PMCID: PMC4009872  PMID: 24832656
cyanobacteria; benthic communities; microbial mat; environmental change; Antarctic lake
22.  Early anaerobic metabolisms 
Before the advent of oxygenic photosynthesis, the biosphere was driven by anaerobic metabolisms. We catalogue and quantify the source strengths of the most probable electron donors and electron acceptors that would have been available to fuel early-Earth ecosystems. The most active ecosystems were probably driven by the cycling of H2 and Fe2+ through primary production conducted by anoxygenic phototrophs. Interesting and dynamic ecosystems would have also been driven by the microbial cycling of sulphur and nitrogen species, but their activity levels were probably not so great. Despite the diversity of potential early ecosystems, rates of primary production in the early-Earth anaerobic biosphere were probably well below those rates observed in the marine environment. We shift our attention to the Earth environment at 3.8 Gyr ago, where the earliest marine sediments are preserved. We calculate, consistent with the carbon isotope record and other considerations of the carbon cycle, that marine rates of primary production at this time were probably an order of magnitude (or more) less than today. We conclude that the flux of reduced species to the Earth surface at this time may have been sufficient to drive anaerobic ecosystems of sufficient activity to be consistent with the carbon isotope record. Conversely, an ecosystem based on oxygenic photosynthesis was also possible with complete removal of the oxygen by reaction with reduced species from the mantle.
doi:10.1098/rstb.2006.1906
PMCID: PMC1664682  PMID: 17008221
Archaean; evolution; hydrogen; anoxygenic photosynthesis; iron; metabolism
23.  New Rapid Diagnostic Tests for Neisseria meningitidis Serogroups A, W135, C, and Y 
PLoS Medicine  2006;3(9):e337.
Background
Outbreaks of meningococcal meningitis (meningitis caused by Neisseria meningitidis) are a major public health concern in the African “meningitis belt,” which includes 21 countries from Senegal to Ethiopia. Of the several species that can cause meningitis, N. meningitidis is the most important cause of epidemics in this region. In choosing the appropriate vaccine, accurate N. meningitidis serogroup determination is key. To this end, we developed and evaluated two duplex rapid diagnostic tests (RDTs) for detecting N. meningitidis polysaccharide (PS) antigens of several important serogroups.
Methods and Findings
Mouse monoclonal IgG antibodies against N. meningitidis PS A, W135/Y, Y, and C were used to develop two immunochromatography duplex RDTs, RDT1 (to detect serogroups A and W135/Y) and RDT2 (to detect serogroups C and Y). Standards for Reporting of Diagnostic Accuracy criteria were used to determine diagnostic accuracy of RDTs on reference strains and cerebrospinal fluid (CSF) samples using culture and PCR, respectively, as reference tests. The cutoffs were 105 cfu/ml for reference strains and 1 ng/ml for PS. Sensitivities and specificities were 100% for reference strains, and 93.8%–100% for CSF serogroups A, W135, and Y in CSF. For CSF serogroup A, the positive and negative likelihood ratios (± 95% confidence intervals [CIs]) were 31.867 (16.1–63.1) and 0.065 (0.04–0.104), respectively, and the diagnostic odds ratio (± 95% CI) was 492.9 (207.2–1,172.5). For CSF serogroups W135 and Y, the positive likelihood ratio was 159.6 (51.7–493.3) Both RDTs were equally reliable at 25 °C and 45 °C.
Conclusions
These RDTs are important new bedside diagnostic tools for surveillance of meningococcus serogroups A and W135, the two serogroups that are responsible for major epidemics in Africa.
There are several strains ofNeisseria meningitidis that can cause seasonal outbreaks of meningitis in Africa. Treatment of patients and containment of the epidemic through vaccination depends on which strain is responsible. The new dipstick tests described here are accurate and suitable for storage and use in resource-poor settings.
Editors' Summary
Background
Bacterial meningitis, a potentially deadly infection of tissues that line the brain and spinal cord, affects over 1 million people each year. Patients with bacterial meningitis usually have fever, headache, and stiff neck, and may become unconscious and die if the disease is not treated within hours. Most cases of bacterial meningitis occur in Africa, particularly in the arid savannah region south of the Sahara known as the Sahel, where epidemic outbreaks of meningitis occur periodically. This region, also called the “meningitis belt,” extends from Senegal and adjacent coastal countries in West Africa across the continent to Ethiopia. Although most outbreaks tend to occur in the dry season, they differ in frequency in different areas of the meningitis belt, and may involve any of several kinds of bacteria. One of the major causes of epidemic meningitis is Neisseria meningitidis, a meningococcus bacterium that exists in several different groups. Group A has been a common cause of epidemic meningitis in Africa, and some outbreaks were due to group C. More recently, group W135 has emerged as an epidemic strain. In addition to prompt diagnosis and treatment of individual cases, effective public health strategies for controlling meningococcal meningitis include rapid identification of outbreaks and determination of the type of bacteria involved, followed by mass vaccination of people in the surrounding area without delay. Vaccines are chosen on the basis of the responsible meningococcal serogroup: either the inexpensive bivalent vaccine A/C or the expensive, less readily available trivalent vaccine A/C/W135. Before the advent of W135 as an epidemic clone, bivalent vaccine was applied in the meningitis belt without identification of the serogroup. With the appearance of the W135 strain in 2003, however, the determination of serogroup before vaccination is important to select an effective vaccine and avoid misspending of limited funds.
Why Was This Study Done?
Because there are few laboratories in the affected countries and epidemiological surveillance systems are inadequate, it is difficult for health authorities to mount a rapid and effective vaccination campaign in response to an outbreak. In addition, because the two main bacteria (meningococcus and pneumococcus) that cause meningitis require different antibiotic treatments, it is important for doctors to find out quickly which bacteria is causing an individual case. The authors of this study wanted to develop a rapid and easy test that can tell whether meningococcus is the cause of a particular case of meningitis, and if so, which group of meningococcus is involved. As most outbreaks in the meningitis belt occur in rural areas that are distant from well-equipped medical laboratories, it was necessary to develop a test that can be carried out at the patient's bedside by nurses, does not require refrigeration or laboratory equipment, and is highly accurate in distinguishing among the different groups of meningococcus.
What Did the Researchers Do and Find?
The researchers have developed a rapid test to determine whether a patient's meningitis is caused by one of the four most common groups of meningococcus circulating in Africa. The test is done on the patient's spinal fluid, which is obtained by a lumbar puncture (spinal tap) as part of the usual evaluation of a patient thought to have meningitis. The test uses two paper strips, also called dipsticks (one for groups A and W135/Y, and the other for groups C and Y), that can be placed in two separate tubes of the patient's spinal fluid. After several minutes, the appearance of red lines on the dipsticks shows whether one of the four groups of meningococcus is present. The dipsticks can be produced in large quantities and relatively cheaply. The researchers showed that the test dipsticks are stable for weeks in hot weather, and are therefore practical for bedside use in resource-poor settings. They examined the test on stored spinal fluid from patients in Niger and found that the dipstick test was able to identify the correct group of meningococcus more than 95% of the time for the three groups represented in these specimens (the results were compared to a standard DNA test or culture that are highly accurate for identifying the type of bacteria present but much more complicated and expensive).
What Do These Findings Mean?
The new dipstick test for meningococcal meningitis represents a major advance for health-care workers in remote locations affected by meningitis epidemics. This test can be stored without refrigeration and used at bedside in the hot temperatures typical of the African savannah during the meningitis season. The dipsticks are easier to use than currently available test kits, give more rapid results, and are more accurate in telling the difference between group Y and the increasingly important group W135. Further research is needed to determine whether the test can be used with other clinical specimens (such as blood or urine), and whether the test is dependable for detecting group C meningococcus, which is common in Europe but rare in Africa. Nonetheless, the dipstick test promises to be an important tool for guiding individual treatment decisions as well as public health actions, including vaccine selection, against the perennial threat of epidemic meningitis.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030337.
World Health Organization fact sheet on meningococcal meningitis
PATH Meningitis Vaccine Project
US Centers for Disease Control and Prevention page on meningococcal disease
doi:10.1371/journal.pmed.0030337
PMCID: PMC1563501  PMID: 16953658
24.  Increased Toxoplasma gondii positivity relative to age in 125 Scottish sheep flocks; evidence of frequent acquired infection 
Veterinary Research  2011;42(1):121.
Toxoplasma gondii seroprevalence was determined in 3333 sheep sera from 125 distinct sheep flocks in Scotland, with the majority of flocks being represented by 27 samples, which were collected between July 2006 and August 2008. The selected farms give a representative sample of 14 400 sheep holdings identified in the Scottish Government census data from 2004. Overall T. gondii seroprevalence, at individual sheep level, was determined to be 56.6%; each flock tested, had at least a single positive animal and in four flocks all ewes tested positive. The seroprevalence of sheep increased from 37.7% in one year old stock to 73.8% in ewes that were older than six years, showing that acquired infections during the life of the animals is frequent and that environmental contamination by T. gondii oocysts must be significant. The median within-flock seroprevalence varied significantly across Scotland, with the lowest seroprevalence of 42.3% in the South and the highest seroprevalence of 69.2% in the far North of Scotland and the Scottish Islands, while the central part of Scotland had a seroprevalence of 57.7%. This distribution disequilibrium may be due to the spread and survival of oocysts on pasture and lambing areas. A questionnaire accompanying sampling of flocks identified farms that used Toxovax®, a commercial vaccine that protects sheep from abortion due to T. gondii infection. Only 24.7% of farmers used the vaccine and the vaccine did not significantly affect the within flock seroprevalence for T. gondii. The implications for food safety and human infection are discussed.
doi:10.1186/1297-9716-42-121
PMCID: PMC3284422  PMID: 22189159
25.  A Novel Lineage of Proteobacteria Involved in Formation of Marine Fe-Oxidizing Microbial Mat Communities 
PLoS ONE  2007;2(8):e667.
Background
For decades it has been recognized that neutrophilic Fe-oxidizing bacteria (FeOB) are associated with hydrothermal venting of Fe(II)-rich fluids associated with seamounts in the world's oceans. The evidence was based almost entirely on the mineralogical remains of the microbes, which themselves had neither been brought into culture or been assigned to a specific phylogenetic clade. We have used both cultivation and cultivation-independent techniques to study Fe-rich microbial mats associated with hydrothermal venting at Loihi Seamount, a submarine volcano.
Methodology/Principle Findings
Using gradient enrichment techniques, two iron-oxidizing bacteria, strains PV-1 and JV-1, were isolated. Chemolithotrophic growth was observed under microaerobic conditions; Fe(II) and Fe0 were the only energy sources that supported growth. Both strains produced filamentous stalk-like structures composed of multiple nanometer sized fibrils of Fe-oxyhydroxide. These were consistent with mineralogical structures found in the iron mats. Phylogenetic analysis of the small subunit (SSU) rRNA gene demonstrated that strains PV-1 and JV-1 were identical and formed a monophyletic group deeply rooted within the Proteobacteria. The most similar sequence (85.3% similarity) from a cultivated isolate came from Methylophaga marina. Phylogenetic analysis of the RecA and GyrB protein sequences confirmed that these strains are distantly related to other members of the Proteobacteria. A cultivation-independent analysis of the SSU rRNA gene by terminal-restriction fragment (T-RF) profiling showed that this phylotype was most common in a variety of microbial mats collected at different times and locations at Loihi.
Conclusions
On the basis of phylogenetic and physiological data, it is proposed that isolate PV-1T ( = ATCC BAA-1019: JCM 14766) represents the type strain of a novel species in a new genus, Mariprofundus ferrooxydans gen. nov., sp. nov. Furthermore, the strain is the first cultured representative of a new candidatus class of the Proteobacteria that is widely distributed in deep-sea environments, Candidatus ζ (zeta)-Proteobacteria cl. nov.
doi:10.1371/journal.pone.0000667
PMCID: PMC1930151  PMID: 17668050

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