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1.
Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator 总被引:11,自引:0,他引:11
Hunter CJ Dejam A Blood AB Shields H Kim-Shapiro DB Machado RF Tarekegn S Mulla N Hopper AO Schechter AN Power GG Gladwin MT 《Nature medicine》2004,10(10):1122-1127
The blood anion nitrite contributes to hypoxic vasodilation through a heme-based, nitric oxide (NO)-generating reaction with deoxyhemoglobin and potentially other heme proteins. We hypothesized that this biochemical reaction could be harnessed for the treatment of neonatal pulmonary hypertension, an NO-deficient state characterized by pulmonary vasoconstriction, right-to-left shunt pathophysiology and systemic hypoxemia. To test this, we delivered inhaled sodium nitrite by aerosol to newborn lambs with hypoxic and normoxic pulmonary hypertension. Inhaled nitrite elicited a rapid and sustained reduction ( approximately 65%) in hypoxia-induced pulmonary hypertension, with a magnitude approaching that of the effects of 20 p.p.m. NO gas inhalation. This reduction was associated with the immediate appearance of NO in expiratory gas. Pulmonary vasodilation elicited by aerosolized nitrite was deoxyhemoglobin- and pH-dependent and was associated with increased blood levels of iron-nitrosyl-hemoglobin. Notably, from a therapeutic standpoint, short-term delivery of nitrite dissolved in saline through nebulization produced selective, sustained pulmonary vasodilation with no clinically significant increase in blood methemoglobin levels. These data support the concept that nitrite is a vasodilator acting through conversion to NO, a process coupled to hemoglobin deoxygenation and protonation, and evince a new, simple and inexpensive potential therapy for neonatal pulmonary hypertension. 相似文献
2.
Although the development of early warning systems for malaria has been advocated by international agencies and academic researchers for many years, practical progress in this area has been relatively modest. In two recent articles, Thomson et al. provide new evidence that models of malaria incidence that incorporate monitored or predicted climate can provide early warnings of epidemics one to five months in advance in semi-arid areas. Although the potential benefits of these models in terms of improved management of epidemics are clear, several technical and practical hurdles still need to be overcome before the models can be widely integrated into routine malaria-control strategies. 相似文献
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Ethiopian mitochondrial DNA heritage: tracking gene flow across and around the gate of tears 总被引:6,自引:1,他引:5
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Kivisild T Reidla M Metspalu E Rosa A Brehm A Pennarun E Parik J Geberhiwot T Usanga E Villems R 《American journal of human genetics》2004,75(5):752-770
Approximately 10 miles separate the Horn of Africa from the Arabian Peninsula at Bab-el-Mandeb (the Gate of Tears). Both historic and archaeological evidence indicate tight cultural connections, over millennia, between these two regions. High-resolution phylogenetic analysis of 270 Ethiopian and 115 Yemeni mitochondrial DNAs was performed in a worldwide context, to explore gene flow across the Red and Arabian Seas. Nine distinct subclades, including three newly defined ones, were found to characterize entirely the variation of Ethiopian and Yemeni L3 lineages. Both Ethiopians and Yemenis contain an almost-equal proportion of Eurasian-specific M and N and African-specific lineages and therefore cluster together in a multidimensional scaling plot between Near Eastern and sub-Saharan African populations. Phylogeographic identification of potential founder haplotypes revealed that approximately one-half of haplogroup L0–L5 lineages in Yemenis have close or matching counterparts in southeastern Africans, compared with a minor share in Ethiopians. Newly defined clade L6, the most frequent haplogroup in Yemenis, showed no close matches among 3,000 African samples. These results highlight the complexity of Ethiopian and Yemeni genetic heritage and are consistent with the introduction of maternal lineages into the South Arabian gene pool from different source populations of East Africa. A high proportion of Ethiopian lineages, significantly more abundant in the northeast of that country, trace their western Eurasian origin in haplogroup N through assorted gene flow at different times and involving different source populations. 相似文献
4.
Mitochondrial DNA variation reveals maternal origins and demographic dynamics of Ethiopian indigenous goats 总被引:1,自引:0,他引:1
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Getinet Mekuriaw Tarekegn Kassahun Tesfaye Okeyo Ally Mwai Appolinaire Djikeng Tadelle Dessie Josephine Birungi Sarah Osama Netsanet Zergaw Alubel Alemu Gloria Achieng Jack Tutah Collins Mutai Joyce Njuguna Joram M. Mwacharo 《Ecology and evolution》2018,8(3):1543-1553
The Horn of Africa forms one of the two main historical entry points of domestics into the continent and Ethiopia is particularly important in this regard. Through the analysis of mitochondrial DNA (mtDNA) d‐loop region in 309 individuals from 13 populations, we reveal the maternal genetic variation and demographic dynamics of Ethiopian indigenous goats. A total of 174 variable sites that generated 231 haplotypes were observed. They defined two haplogroups that were present in all the 13 study populations. Reference haplotypes from the six globally defined goat mtDNA haplogroups show the two haplogroups present in Ethiopia to be A and G, the former being the most predominant. Although both haplogroups are characterized by an increase in effective population sizes (Ne) predating domestication, they also have experienced a decline in Ne at different time periods, suggesting different demographic histories. We observed seven haplotypes, six were directly linked to the central haplotypes of the two haplogroups and one was central to haplogroup G. The seven haplotypes were common between Ethiopia, Kenya, Egypt, and Saudi Arabia populations, suggesting common maternal history and the introduction of goats into East Africa via Egypt and the Arabian Peninsula, respectively. While providing new mtDNA data from a historically important region, our results suggest extensive intermixing of goats mediated by human socio‐cultural and economic interactions. These have led to the coexistence of the two haplogroups in different geographic regions in Ethiopia resulting in a large caprine genetic diversity that can be exploited for genetic improvement. 相似文献
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Patrick Baenyi Simon Joseph Owino Junga Getinet Mekuriaw Tarekegn Eunice Machuka Christian Keambou Tiambo Dorine Kabange Katunga Musale M. Dieudinn Roger Vumilia Kizungu Joel Winyo Ochieng Roger Pelle 《Ecology and evolution》2022,12(3)
This study aimed at assessing haplotype diversity and population dynamics of three Congolese indigenous goat populations that included Kasai goat (KG), small goat (SG), and dwarf goat (DG) of the Democratic Republic of Congo (DRC). The 1169 bp d‐loop region of mitochondrial DNA (mtDNA) was sequenced for 339 Congolese indigenous goats. The total length of sequences was used to generate the haplotypes and evaluate their diversities, whereas the hypervariable region (HVI, 453 bp) was analyzed to define the maternal variation and the demographic dynamic. A total of 568 segregating sites that generated 192 haplotypes were observed from the entire d‐loop region (1169 bp d‐loop). Phylogenetic analyses using reference haplotypes from the six globally defined goat mtDNA haplogroups showed that all the three Congolese indigenous goat populations studied clustered into the dominant haplogroup A, as revealed by the neighbor‐joining (NJ) tree and median‐joining (MJ) network. Nine haplotypes were shared between the studied goats and goat populations from Pakistan (1 haplotype), Kenya, Ethiopia and Algeria (1 haplotype), Zimbabwe (1 haplotype), Cameroon (3 haplotypes), and Mozambique (3 haplotypes). The population pairwise analysis (FST ) indicated a weak differentiation between the Congolese indigenous goat populations. Negative and significant (p‐value <.05) values for Fu''s Fs (−20.418) and Tajima''s (−2.189) tests showed the expansion in the history of the three Congolese indigenous goat populations. These results suggest a weak differentiation and a single maternal origin for the studied goats. This information will contribute to the improvement of the management strategies and long‐term conservation of indigenous goats in DRC. 相似文献
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Judith G. Makombu Francesca Stomeo Pius M. Oben Eldridge Tilly Opiyo O. Stephen Benedicta O. Oben Evans K. Cheruiyot Getinet Mekuriaw Tarekegn Paul Zango Atem E. Egbe Abigail Ndagyong Eric Mialhe Jules R. Ngueguim Fidalis D. N. Mujibi 《Ecology and evolution》2019,9(24):14217-14233
Macrobrachium (Bate, 1868) is a large and cosmopolitan crustacean genus of high economic importance worldwide. We investigated the morphological and molecular identification of freshwater prawns of the genus Macrobrachium in South, South West, and Littoral regions of Cameroon. A total of 1,566 specimens were examined morphologically using a key described by Konan (Diversité morphologique et génétique des crevettes des genres Atya Leach, 1816 et Macrobrachium Bate, 1868 de Côte d'Ivoire, 2009, Université d'Abobo Adjamé, Côte d'Ivoire), leading to the identification of seven species of Macrobrachium: M. vollenhovenii (Herklots, 1857); M. macrobrachion (Herklots, 1851); M. sollaudii (De Man, 1912); M. dux (Lenz, 1910); M. chevalieri (Roux, 1935); M. felicinum (Holthuis, 1949); and an undescribed Macrobrachium species M. sp. To validate the genetic basis of the identified species, 94 individuals representing the species were selected and subjected to genetic characterization using 1,814 DArT markers. The admixture analysis revealed four groups: M. vollenhovenii and M. macrobrachion; M. chevalieri; M. felicinum and M. sp; and M. dux and M. sollaudii. But, the principal component analysis (PCA) separated M. sp and M. felicinum to create additional group (i.e., five groups). Based on these findings, M. vollenhovenii and M. macrobrachion may be conspecific, as well as M. dux and M. sollaudii, while M. felicinum and M. sp seems to be different species, suggesting a potential conflict between the morphological identification key and the genetic basis underlying speciation and species allocation for Macrobrachium. These results are valuable in informing breeding design and genetic resource conservation programs for Macrobrachium in Africa. 相似文献
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Shanat Baig Vishy Veeranna Shaun Bolton Nicola Edwards Jeremy W. Tomlinson Konstantinos Manolopoulos John Moran Richard P. Steeds Tarekegn Geberhiwot 《BMC endocrine disorders》2018,18(1):88
Background
Alström syndrome (ALMS) is a very rare autosomal recessive monogenic disorder caused by a mutation in the ALMS1 gene and characterised by childhood onset obesity, dyslipidaemia, advanced non-alcoholic fatty liver disease, diabetes and extreme insulin resistance. There is evidence of multi-organ fibrosis in ALMS and severity of the disease often leads to organ failure with associated morbidities, resulting in reduced life expectancy. There are no specific treatments for this disease, and current management consists of only symptomatic therapies. PBI-4050 is a new molecular entity with demonstrated anti-inflammatory and anti-fibrotic activities in preclinical models, including animal models of human diseases characterized by progressive fibrosis in the kidney, heart, liver and lungs. Moreover, completed Phase 2 studies in type 2 diabetes mellitus with metabolic syndrome and idiopathic pulmonary fibrosis further support the anti-inflammatory and anti-fibrotic activity of PBI-4050. Together, these data suggest that PBI-4050 has the potential to treat the pathological inflammatory and fibrotic features of ALMS. The aim of this study is to evaluate the safety and anti-inflammatory & anti-fibrotic activities of PBI-4050 in subjects with ALMS.Methods
This is a Phase 2, single-centre, single-arm, open-label trial. A total of 18 patients with ALMS will be enrolled to receive PBI-4050 at a total daily oral dose of 800?mg for an initial 24?weeks with continuation for an additional 36 or 48?weeks. Standard assessments of safety include adverse events, clinical laboratory tests, vital signs, physical examination and electrocardiograms. Efficacy assessments include adipose tissue biopsy, hyperinsulinaemic-euglycaemic glucose clamp, adipose tissue microdialysis, liver transient elastography, liver and cardiac magnetic resonance imaging, and laboratory blood tests.Discussion
This is the first clinical study of PBI-4050 in subjects with ALMS. Given the rarity and complexity of the disease, a single-centre, single-arm, open-label design has been chosen to maximise subject exposure and increase the likelihood of achieving our study endpoints. The results will provide valuable safety and preliminary evidence of the effects of PBI-4050 in ALMS, a rare heterogeneous disease associated with progressive fibrosis and premature mortality.Trial registration
The trial is registered on ClinicalTrials.gov (Identifier; NCT02739217, February 2016) and European Union Drug Regulating Authorities Clinical Trials (EudraCT Number 2015–001625-16, Sept 2015).10.
Lucy van Dorp David Balding Simon Myers Luca Pagani Chris Tyler-Smith Endashaw Bekele Ayele Tarekegn Mark G. Thomas Neil Bradman Garrett Hellenthal 《PLoS genetics》2015,11(8)
The Ari peoples of Ethiopia are comprised of different occupational groups that can be distinguished genetically, with Ari Cultivators and the socially marginalised Ari Blacksmiths recently shown to have a similar level of genetic differentiation between them (F
ST ≈ 0.023 − 0.04) as that observed among multiple ethnic groups sampled throughout Ethiopia. Anthropologists have proposed two competing theories to explain the origins of the Ari Blacksmiths as (i) remnants of a population that inhabited Ethiopia prior to the arrival of agriculturists (e.g. Cultivators), or (ii) relatively recently related to the Cultivators but presently marginalized in the community due to their trade. Two recent studies by different groups analysed genome-wide DNA from samples of Ari Blacksmiths and Cultivators and suggested that genetic patterns between the two groups were more consistent with model (i) and subsequent assimilation of the indigenous peoples into the expanding agriculturalist community. We analysed the same samples using approaches designed to attenuate signals of genetic differentiation that are attributable to allelic drift within a population. By doing so, we provide evidence that the genetic differences between Ari Blacksmiths and Cultivators can be entirely explained by bottleneck effects consistent with hypothesis (ii). This finding serves as both a cautionary tale about interpreting results from unsupervised clustering algorithms, and suggests that social constructions are contributing directly to genetic differentiation over a relatively short time period among previously genetically similar groups. 相似文献