To reveal phenotypic and functional genomic patterns of mitonuclear adaptation, a laboratory adaptation study with
nematodes was conducted in which independently evolving lines were initiated from a ...low-fitness mitochondrial electron transport chain (ETC) mutant,
Following 60 generations of evolution in large population sizes with competition for food resources, two distinct classes of lines representing different degrees of adaptive response emerged: a low-fitness class that exhibited minimal or no improvement compared to the
mutant ancestor, and a high-fitness class containing lines that exhibited partial recovery of wild-type fitness. Many lines that achieved higher reproductive and competitive fitness levels were also noted to evolve high frequencies of males during the experiment, consistent with adaptation in these lines having been facilitated by outcrossing. Whole-genome sequencing and analysis revealed an enrichment of mutations in loci that occur in a
-centric region of the
interactome and could be classified into a small number of functional genomic categories. A highly nonrandom pattern of mitochondrial DNA mutation was observed within high-fitness
lines, with parallel fixations of nonsynonymous base substitutions within genes encoding NADH dehydrogenase subunits I and VI. These mitochondrial gene products reside within ETC complex I alongside the nuclear-encoded GAS-1 protein, suggesting that rapid adaptation of select
recovery lines was driven by fixation of compensatory mitochondrial mutations.
Abstract
A mutation-accumulation (MA) experiment with Caenorhabditis elegans nematodes was conducted in which replicate, independently evolving lines were initiated from a low-fitness mitochondrial ...electron transport chain mutant, gas-1. The original intent of the study was to assess the effect of electron transport chain dysfunction involving elevated reactive oxygen species production on patterns of spontaneous germline mutation. In contrast to results of standard MA experiments, gas-1 MA lines evolved slightly higher mean fitness alongside reduced among-line genetic variance compared with their ancestor. Likewise, the gas-1 MA lines experienced partial recovery to wildtype reactive oxygen species levels. Whole-genome sequencing and analysis revealed that the molecular spectrum but not the overall rate of nuclear DNA mutation differed from wildtype patterns. Further analysis revealed an enrichment of mutations in loci that occur in a gas-1-centric region of the C. elegans interactome, and could be classified into a small number of functional-genomic categories. Characterization of a backcrossed four-mutation set isolated from one gas-1 MA line revealed this combination to be beneficial on both gas-1 mutant and wildtype genetic backgrounds. Our combined results suggest that selection favoring beneficial mutations can be powerful even under unfavorable population genetic conditions, and agree with fitness landscape theory predicting an inverse relationship between population fitness and the likelihood of adaptation.
Mutation is a fundamental process that drives evolutionary change; however, most new mutations are deleterious for organismal fitness and can readily propagate within populations under a broad range ...of conditions. Mutational processes able to counteract deleterious mutation accumulation include: 1) reversion mutation back to wildtype, 2) acquisition of generally beneficial mutations, and 3) compensatory mutations that specifically mitigate the effects of previously-acquired deleterious mutations through epistasis. The potential for any of these mutation types alters our expectations for the impact of deleterious mutation in populations, but since the fitness effects of individual mutations are rarely characterized, the relative importance of beneficial and compensatory epistatic mutations is unknown. In this thesis, I characterized the nuclear mutations that arose in a previous mutation accumulation (MA) experiment using Caenorhabditis elegans nematodes, in which mutations were allowed to accumulate under extreme drift conditions in replicate, independently evolving lines initiated from a low-fitness mitochondrial electron transport chain (ETC) mutant, gas-1. In contrast to the results of typical MA experiments, gas-1 MA lines improved fitness slightly compared to their ancestor. Here, I find that the gas-1 MA lines demonstrate little increase in among-line variance and that the gas-1 MA nuclear mutations are more narrowly functionally defined than wildtype MA nuclear mutations. When combined with evidence for zygotic or post zygotic selection these data suggest that selection—both purifying and positive—can be an extremely powerful force even in conditions of extreme genetic drift. Furthermore, functional characterization of a four-mutation set isolated from one of the gas-1 MA lines on gas-1 and wildtype backgrounds shows fitness improvements on both backgrounds. This beneficial four-mutation set is associated with a decrease in steady-state endogenous ROS on the gas-1 background while exhibiting no effect on wildtype. I also find that steady-state ATP levels associated with the beneficial four-mutation set decreased compared to wildtype suggesting that fermentation may be metabolic strategy to cope with increase oxidative stress. These findings suggest that we can detect and characterize specific genetic changes that lead to a partial recovery of fitness and phenotype in a low-fitness ETC-deficient mutant strain of C. elegans. I extended my thesis to include analyses of fitness and phenotype of 24 replicate lineages of the gas-1 ETC mutant evolved in large population (n = 1000) sizes for 60 generations—conditions optimal for selection and fitness recovery (RC). I find that two distinct gas-1 RC fitness groups emerged: one group with significantly higher average fitness than the ancestor and containing two lines that exceeded wildtype fitness levels, and another group with more modest and non-significant fitness gains. Interestingly, many lines in the first group were observed to generate appreciable numbers of males during experimental evolution—consistent with evolution of outcrossing either accompanying or driving rapid fitness recovery. Bioinformatic functional analyses of the nuclear mutations that arose in the gas-1 RC lines show the availability of potentially more paths to fitness recovery for large populations than small ones. Combined, these data allow us to identify patterns in selection and drift in gas-1 recovery under MA and RC (recovery) conditions. My research advances our understanding of the genetic bases of adaptive evolution under extremely unfavorable population genetic conditions and how mitochondrial dysfunction affects evolutionary dynamics.
Traumatic brain injury (TBI) associated with temporal bone fractures causing ipsilateral hearing loss is not uncommon. But contralateral sensorineural hearing loss (SNHL) in the absence of temporal ...bone fractures is not frequently encountered or looked for in TBI patients. A simple bed side tuning fork test followed by a formal audiogram underscore the importance of pre-emptive assessment to prevent a permanent handicap. We report a case of a young man with no prior ear disease or comorbidities, who sustained traumatic brain injury with right parieto-temporal hemorrhagic contusion and cervical myelopathy following a two-wheeler fall. Although, there was no evidence of temporal bone fractures, he developed sudden profound deafness on the contralateral side of the brain injury. Evaluation and treatment for the same were initially delayed as the management solely focused on his neurological complaints and as the hearing loss was contralateral it was perceived to be unrelated to his brain injury. We want to highlight the importance of thorough evaluation and screening for bilateral hearing loss in patients with TBI irrespective of the presence or absence of temporal bone fractures to initiate appropriate management. We also want to add our patient to the very few such cases reported in the literature. We analyzed these cases and reviewed the possible pathophysiological mechanisms behind this entity.
To evaluate the efficacy and safety of intranasal midazolam and chloral hydrate syrup for procedural sedation in children.
Prospective randomized placebo-controlled trial (double blind, double ...dummy).
Tertiary care hospital over 18 months.
Eighty-two children, 1 to 6 years old, undergoing auditory brainstem response testing were randomized to receive either intranasal midazolam with oral placebo or chloral hydrate syrup with placebo nasal spray. Intranasal midazolam was delivered at 0.5 mg/kg (100 mcg per spray) and oral syrup at 50 mg/kg. Children not sedated at 30 minutes had a second dose at half the initial dose. The primary outcomes measured were safety and efficacy. Secondary outcomes were time to onset of sedation, parental separation, nature of parental separation, parental satisfaction, audiologist's satisfaction, time to recovery, and number of attempts.
Forty-one children were in each group, and no major adverse events were noted. The chloral hydrate group showed earlier onset of sedation (66%) compared with the intranasal midazolam group (33%). Significant difference in time to recovery was noted in the chloral hydrate group (78 minutes) versus the intranasal midazolam group (108 minutes). The parents' and audiologist's satisfaction was higher for chloral hydrate (95% and 75%) than for intranasal midazolam (49% and 29%, respectively). Overall, sedation was 95% with chloral hydrate versus 51% with intranasal midazolam. Both drugs maintained sedation.
Intranasal midazolam and chloral hydrate are both safe and efficacious for pediatric procedural sedation. Chloral hydrate was superior to intranasal midazolam, with an earlier time to onset of sedation, a faster recovery, better satisfaction among parents and the audiologist, and successful sedation.
Background: The natural history of HIV infection in early disease is not affected by pregnancy. In later stages there may be rapid disease progression leading to adverse pregnancy outcomes. ...Prevalence of HIV in India is 0.3% in pregnant women. With the advent of PPTCT, there have been a decline in the adverse pregnancy outcomes but still few adversities are reported. Aim of the study was to assess the various pregnancy outcomes in HIV positive women and the effects of antiretroviral therapy (ART).Methods: A retrospective analytical study conducted from July 2017-June 2019 on HIV infected pregnant women. Their maternal age, CD4 count at diagnosis of HIV, after postpartum, mode of delivery, birth weight and HIV status of baby were noted and analyzed. Results: 18 HIV infected pregnant women were included. Their mean age was 25.6 years. 12 patients were in 2nd trimester and the rest in 1st trimester. All were on triple-drug (TEL) regimen. Three were diagnosed with HIV prior to conception and were already on ART. Remaining were detected at the time of ANC visit. All cases fall under stage I WHO clinical staging. Out of the 18 pregnant, two delivered by LSCS and the rest by normal delivery. All were term deliveries, with mean birth weight of 2.82 kg. One HIV infected baby was born by LSCS. The mean CD4 count at the time of diagnosis of HIV was 389 and at postpartum was 508. Overall, there was seen to be an increase in CD4 count without any adverse effects during ART.Conclusions: Prompt HIV diagnosis and ART initiation during antenatal period can have good pregnancy outcome and thereby reducing transmission to children.
Background: Stigma about STDs (sexually transmitted diseases) may influence an individual’s decision to disclose information about his/her sexual behaviour to health care practitioners as well as to ...their sex partners. This leads to a continued transmission of sexually transmitted infections (STI) and greater probability of adverse sequelae. Thus, care seeking interval may be regarded as an indirect measure of stigma associated with STI. The aim of this study is to assess healthcare-seeking behaviour of patients and the factors associated with its delay.Methods: This was a cross-sectional study conducted over a period of 1 year in STD OP of Government Stanley medical college, Chennai which included all symptomatic STD Patients who came to OP. The data were collected using a semi-structured questionnaire. The statistical package SPSS (version 16) was used for analysis.Results: The study included 492 males and 517 females who presented with STD related symptoms. Nearly 54% of patients sought care after 7 days of onset of symptoms. In that 52% of patients reported their delay to be due to fear of disclosure about their symptoms, 19% had self treatment, 12% of them expected spontaneous resolution, 8% had lack of awareness about their symptoms and the remaining 9% reported various other causes.Conclusions: Fear of stigmatisation has a positive association with increased care seeking interval in STDs. Addressing concerns about stigma and educating the public about timely heath care could help reduce the complications of STDs among high risk adult population thereby improving the quality of patient’s life.
The groundbreaking 3-time Eisner Award-winning graphic novel, now available digitally for the first time! Join us as we explore this missing piece of Jim Henson's career in a celebration of his ...creative process, gorgeously brought to life by acclaimed illustrator Ramon K. Perez (Wolverine and the X-Men, Spider Man: Year One). Discovered in the Archives of The Jim Henson Company, Tale of Sand is an original graphic novel adaptation of an unproduced, feature-length screenplay written by Jim Henson and his frequent writing partner, Jerry Juhl. Tale of Sand follows scruffy everyman, Mac, who wakes up in an unfamiliar town, and is chased across the desert of the American Southwest by all manners of man and beast of unimaginable proportions. Produced with the complete blessing of Henson co-CEO Lisa Henson, Tale of Sand was hailed as a groundbreaking achievement upon release, winning the Eisner Awards for Best Graphic Album, Best Penciller/Inker, and Best Production Design, as well as winning the Harvey Awards for Best Graphic Novel and Best Artist.
Background： Despite its variety of potential applications, the wide implementation of infrared technology in cattle production faces technical, environmental and biological challenges similar to ...other indicators of metabolic state. Nine trials, divided into three classes （technological, environmental and biological factors） were conducted to illustrate the influence of these factors on body surface temperature assessed through infrared imaging. Results： Evaluation of technological factors indicated the following： measurements of body temperatures were strongly repeatable when taken within 0 s; appropriateness of differing infrared camera technologies was influenced by distance to the target; and results were consistent when analysis of thermographs was compared between judges. Evaluation of environmental factors illustrated that wind and debris caused decreases in body surface temperatures without affecting metabolic rate; additionally, body surface temperature increased due to sunlight but returned to baseline values within minutes of shade exposure. Examination/investigation/exploration of animal factors demonstrated that exercise caused an increase in body surface temperature and metabolic rate. Administration of sedative and anti-sedative caused changes on body surface temperature and metabolic rate, and during late pregnancy a foetal thermal imprint was visible through abdominal infrared imaging. Conclusion： The above factors should be considered in order to standardize operational procedures for taking thermographs, thereby optimizing the use of such technology in cattle operations.
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