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BioRxiv : the Preprint Server For... Jun 2024Mitochondria are central to cellular metabolism; hence, their dysfunction contributes to a wide array of human diseases including cancer, cardiopathy, neurodegeneration,...
Mitochondria are central to cellular metabolism; hence, their dysfunction contributes to a wide array of human diseases including cancer, cardiopathy, neurodegeneration, and heritable pathologies such as Barth syndrome. Cardiolipin, the signature phospholipid of the mitochondrion promotes proper cristae morphology, bioenergetic functions, and directly affects metabolic reactions carried out in mitochondrial membranes. To match tissue-specific metabolic demands, cardiolipin typically undergoes an acyl tail remodeling process with the final step carried out by the phospholipid-lysophospholipid transacylase tafazzin. Mutations in the gene are the primary cause of Barth syndrome. Here, we investigated how defects in cardiolipin biosynthesis and remodeling impact metabolic flux through the tricarboxylic acid cycle and associated pathways in yeast. Nuclear magnetic resonance was used to monitor in real-time the metabolic fate of C -pyruvate in isolated mitochondria from three isogenic yeast strains. We compared mitochondria from a wild-type strain to mitochondria from a Δ strain that lacks tafazzin and contains lower amounts of unremodeled cardiolipin, and mitochondria from a Δ strain that lacks cardiolipin synthase and cannot synthesize cardiolipin. We found that the C-label from the pyruvate substrate was distributed through about twelve metabolites. Several of the identified metabolites were specific to yeast pathways, including branched chain amino acids and fusel alcohol synthesis. Most metabolites showed similar kinetics amongst the different strains but mevalonate and α-ketoglutarate, as well as the NAD+/NADH couple measured in separate nuclear magnetic resonance experiments, showed pronounced differences. Taken together, the results show that cardiolipin remodeling influences pyruvate metabolism, tricarboxylic acid cycle flux, and the levels of mitochondrial nucleotides.
PubMed: 38948727
DOI: 10.1101/2024.06.18.599628 -
BioRxiv : the Preprint Server For... Jun 2024Spinocerebellar Ataxia Type 8 (SCA8) is an inherited neurodegenerative disease caused by a bidirectionally expressed CTG●CAG expansion mutation in the ATXN-8 and...
Spinocerebellar Ataxia Type 8 (SCA8) is an inherited neurodegenerative disease caused by a bidirectionally expressed CTG●CAG expansion mutation in the ATXN-8 and ATXN8-OS genes. While primarily a motor disorder, psychiatric and cognitive symptoms have been reported. It is difficult to elucidate how the disease alters brain function in areas with little or no degeneration producing both motor and cognitive symptoms. Using transparent polymer skulls and CNS-wide GCaMP6f expression, we studied neocortical networks throughout SCA8 progression using wide-field Ca2+ imaging in a transgenic mouse model of SCA8. We observed that neocortical networks in SCA8+ mice were hyperconnected globally which led to network configurations with increased global efficiency and centrality. At the regional level, significant network changes occurred in nearly all cortical regions, however mainly involved sensory and association cortices. Changes in functional connectivity in anterior motor regions worsened later in the disease. Near perfect decoding of animal genotype was obtained using a generalized linear model based on canonical correlation strengths between activity in cortical regions. The major contributors to decoding were concentrated in the somatosensory, higher visual and retrosplenial cortices and occasionally extended into the motor regions, demonstrating that the areas with the largest network changes are predictive of disease state.
PubMed: 38948725
DOI: 10.1101/2024.06.20.599947 -
BioRxiv : the Preprint Server For... Jun 2024Flagella are highly complex rotary molecular machines that enable bacteria to not only migrate to optimal environments but to also promote range expansion,...
Flagella are highly complex rotary molecular machines that enable bacteria to not only migrate to optimal environments but to also promote range expansion, competitiveness, virulence, and antibiotic survival. Flagellar motility is an energy-demanding process, where the sum of its production (biosynthesis) and operation (rotation) costs has been estimated to total ∼10% of the entire energy budget of an cell. The acquisition of such a costly adaptation process is expected to secure short-term benefits by increasing competitiveness and survival, as well as long-term evolutionary fitness gains. While the role of flagellar motility in bacterial survival has been widely reported, its direct influence on the rate of evolution remains unclear. We show here that both production and operation costs contribute to elevated mutation frequencies. Our findings suggest that flagellar movement may be an important player in tuning the rate of bacterial evolution.
PubMed: 38948722
DOI: 10.1101/2024.06.21.600093 -
BioRxiv : the Preprint Server For... Jun 2024Uveal coloboma, a developmental eye defect, is caused by failed development of the optic fissure, a ventral structure in the optic stalk and cup where axons exit the eye...
BACKGROUND
Uveal coloboma, a developmental eye defect, is caused by failed development of the optic fissure, a ventral structure in the optic stalk and cup where axons exit the eye and vasculature enters. The Hedgehog (Hh) signaling pathway regulates optic fissure development: loss-of-function mutations in the Hh receptor produce overactive Hh signaling and can result in coloboma. We previously proposed a model where overactive Hh signaling disrupts optic fissure formation by upregulating transcriptional targets acting both cell- and non-cell-autonomously. Here, we examine the Netrin family of secreted ligands as candidate Hh target genes.
RESULTS
We find multiple Netrin ligands upregulated in the zebrafish mutant during optic fissure development. Using a gain-of-function approach to overexpress Netrin in a spatiotemporally specific manner, we find that or overexpression is sufficient to cause coloboma and disrupt wild-type optic fissure formation. We used loss-of-function alleles, CRISPR/Cas9 mutagenesis, and morpholino knockdown to test if loss of Netrin can rescue coloboma in the mutant: loss of genes does not rescue the mutant phenotype.
CONCLUSION
These results suggest that Netrin is sufficient but not required to disrupt optic fissure formation downstream of overactive Hh signaling in the mutant.
KEY FINDINGS
Overactive Hedgehog signaling in the mutant causes increased netrin expression Spatiotemporally specific overexpression of netrin1a and netrin1b can cause coloboma Spatiotemporally specific overexpression of netrin1a can disrupt optic fissure and stalk formation as well as optic stalk cell morphology, similar to the mutant Loss of netrin ligands in the mutant does not rescue the phenotype.
PubMed: 38948711
DOI: 10.1101/2024.06.18.599642 -
Frontiers in Veterinary Science 2024lice are an extensive parasitic concern in goat populations worldwide, posing significant economic and health risks. This study examined the identification of alleles...
INTRODUCTION
lice are an extensive parasitic concern in goat populations worldwide, posing significant economic and health risks. This study examined the identification of alleles of resistance to pyrethroid and mutations in samples obtained from goats in five provinces in western and northwestern Iran.
METHODS
Morphological and molecular techniques were employed to identify the louse species. Molecular identification methods and gene sequencing were used to identify resistance-associated mutations in the voltage-gated sodium channel (VGSC) gene.
RESULTS AND DISCUSSION
The results revealed that six amino acid substitutions, including threonine-to-isoleucine (T917I), leucine-to-phenylalanine (L920F), isoleucine-to-phenylalanine (I927F), phenylalanine-to-alanine (F928A), valine-to-arginine (V929R), and arginine-to-leucine (R930L) mutations, were present in the VGSC gene of lice from various regions of Iran. These findings suggest the potential for pyrethroid resistance development in this louse species, highlighting the importance of integrated pest management (IPM) strategies. Such strategies, which combine selective insecticides, regular grooming, and environmental sanitation, are crucial for effectively managing infestations and preserving the efficacy of pyrethroids for pest control. Moreover, the emergence of novel kdr mutations underscores the need for ongoing research into the molecular mechanisms underlying these mutations. This research is vital for developing strategies to combat pyrethroid resistance and maintaining the efficacy of insecticides in controlling lice.
PubMed: 38948670
DOI: 10.3389/fvets.2024.1380328 -
Journal of Family Medicine and Primary... May 2024Sickle cell disease (SCD) is a disorder marked by a single-point mutation in the beta-globin gene. Hydroxyurea is a globally accepted disease-modifying agent that sounds...
BACKGROUND
Sickle cell disease (SCD) is a disorder marked by a single-point mutation in the beta-globin gene. Hydroxyurea is a globally accepted disease-modifying agent that sounds to be effective in managing clinically and probably preventing complications of SCD. The current study aims to document the morbidity pattern and impact of Hydroxyurea therapy in the Outpatient Department of Sickle Cell Institute, Raipur.
MATERIALS AND METHODS
This cross-sectional study was conducted among randomly selected sixty-five patients (adults and children above six years). After obtaining informed consent, relevant data were collected in a predesigned pretested questionnaire. The appropriate statistical exercise was applied for the interpretation of results and inferences.
RESULTS
Acute febrile illness 54 (83%) and 53 (81.5%) reported pain crisis observed to have the most common morbidity among the study subjects, followed by 55.4% (36), 33 (50.8%) jaundice and difficulty breathing, respectively. Joint pain was the most commonly observed complaint, particularly at the knee joint (76.9%). Other complaints such as hand-foot syndrome (24.6%), epistaxis (27.7%), and acute chest syndrome (21.5%). Vaso-occlusive crisis (72.4%), difficulty in walking (60.0%) and eyesight (35.4%), leg ulcers (9.2%), and dactylitis (3.1%) were also documented as clinical manifestations among study participants. Less than half (44.46%) had an awareness about SCD. Hydroxyurea therapy was highly significant in improving the patient's clinical picture ( < 0.01), especially following the frequency of hospitalization and the requirement for blood transfusion.
CONCLUSION
Pain crisis is the most common morbidity among study participants with a low level of knowledge about SCD with febrile illness. Hydroxyurea therapy was found to be quite effective as a disease-modifying therapy, especially for reducing the frequency of blood transfusion and lowering hospitalization rates among SCD patients.
PubMed: 38948632
DOI: 10.4103/jfmpc.jfmpc_1490_23 -
Journal of Family Medicine and Primary... May 2024The rapid spread and mutation rate of severe acute respiratory syndrome corona virus (SARS-CoV2) demands continuous monitoring in terms of genomic and serosurvival. The...
INTRODUCTION
The rapid spread and mutation rate of severe acute respiratory syndrome corona virus (SARS-CoV2) demands continuous monitoring in terms of genomic and serosurvival. The current study is designed to track the seroprevalence of health care workers (HCWs) postvaccination, as they may be more susceptible to contracting the SARS-CoV-2 infection compared to the general population.
OBJECTIVE
The objective was to identify the seroprevalence rate for SARS-CoV-2 immunoglobulin G (IgG) antibody (N, S1, S2) amongst HCWs of various levels of exposure working in a tertiary care teaching hospital in Puducherry.
MATERIALS AND METHODS
The present study followed a nonprobability consecutive sampling technique, which involved 216 study participants HCWs from the hospital. IgG antibody levels were measured using EUROIMMUNE Anti SARS-COV-2 ELISA KIT (IG g) ELISA at two points: firstly, 2 weeks after the second dose of vaccination, followed by 2 weeks after the booster dose.
RESULTS
Out of the total 216 participants enrolled in the survey, there were 140 males and 76 females, and the maximum number of candidates studied were in the 41-50 age group. Almost 46.7% of the HCWs who participated in the study were seropositive for SARS-CoV-2 in the case of those who were high-risk exposed, while only 30.4% were amongst those who were low-risk exposed. The proportion of study participants who became seropositive increased considerably after the booster dose (65.7%), from 38.0% when tested three months after infection.
CONCLUSION
A significant increase in antibody titres amongst high-risk HCWs postboost vaccination demands continuous monitoring of soluble IgG levels for recommendations of vaccination schedules.
PubMed: 38948592
DOI: 10.4103/jfmpc.jfmpc_1488_23 -
Evolutionary Applications Jul 2024The Seychelles magpie-robin's (SMR) five island populations exhibit some of the lowest recorded levels of genetic diversity among endangered birds, and high levels of...
The Seychelles magpie-robin's (SMR) five island populations exhibit some of the lowest recorded levels of genetic diversity among endangered birds, and high levels of inbreeding. These populations collapsed during the 20th century, and the species was listed as Critically Endangered in the IUCN Red List in 1994. An assisted translocation-for-recovery program initiated in the 1990s increased the number of mature individuals, resulting in its downlisting to Endangered in 2005. Here, we explore the temporal genomic erosion of the SMR based on a dataset of 201 re-sequenced whole genomes that span the past ~150 years. Our sample set includes individuals that predate the bottleneck by up to 100 years, as well as individuals from contemporary populations established during the species recovery program. Despite the SMR's recent demographic recovery, our data reveal a marked increase in both the genetic load and realized load in the extant populations when compared to the historical samples. Conservation management may have reduced the intensity of selection by increasing juvenile survival and relaxing intraspecific competition between individuals, resulting in the accumulation of loss-of-function mutations (i.e. severely deleterious variants) in the rapidly recovering population. In addition, we found a 3-fold decrease in genetic diversity between temporal samples. While the low genetic diversity in modern populations may limit the species' adaptability to future environmental changes, future conservation efforts (including IUCN assessments) may also need to assess the threats posed by their high genetic load. Our computer simulations highlight the value of translocations for genetic rescue and show how this could halt genomic erosion in threatened species such as the SMR.
PubMed: 38948538
DOI: 10.1111/eva.13739 -
Frontiers in Pharmacology 2024To evaluate the cost-effectiveness of sotorasib versus docetaxel in non-small cell lung cancer (NSCLC) patients with KRAS mutation from the China and United...
PURPOSE
To evaluate the cost-effectiveness of sotorasib versus docetaxel in non-small cell lung cancer (NSCLC) patients with KRAS mutation from the China and United States'social perspective.
MATERIALS AND METHODS
A Markov model that included three states (progression-free survival, post-progression survival, and death) was developed. Incremental cost-effectiveness ratio (ICER), quality-adjusted life-year (QALY), and incremental QALY were calculated for the two treatment strategies. One-way sensitivity analysis was used to investigate the factors that had a greater impact on the model results, and tornado diagrams were used to present the results. Probabilistic sensitivity analysis was performed with 1,000 Monte Carlo simulations. Assume distributions based on parameter types and randomly sample all parameter distributions each time., The results were presented as cost-effectiveness acceptable curves.
RESULTS
This economic evaluation of data from the CodeBreak 200 randomized clinical trial. In China, sotorasib generated 0.44 QAYL with a total cost of $84372.59. Compared with docetaxel, the ICER value of sotorasib was $102701.84/QALY, which was higher than willingness to pay (WTP), so sotorasib had no economic advantage. In the US, sotorasib obtained 0.35 QALY more than docetaxel, ICER was $15,976.50/QALY, which was more than 1 WTP but less than 3 WTP, indicating that the increased cost of sotorasib was acceptable. One-way sensitivity analysis showed that the probability of sotorasib having economic benefits gradually increased when the cost of follow-up examination was reduced in China. And there was no influence on the conclusions within the range of changes in China. When the willingness to pay (WTP) exceeds $102,500, the probability of sotorasib having cost effect increases from 0% to 49%.
CONCLUSION
Sotorasib had a cost effect from the perspective in the United States. However, sotorasib had no cost effect from the perspective in China, and only when the WTP exceeds $102,500, the probability of sotorasib having cost effect increases from 0% to 49%.
PubMed: 38948474
DOI: 10.3389/fphar.2024.1348688 -
Frontiers in Pharmacology 2024Unfortunately, ovarian cancer is still diagnosed most often only in an advanced stage and is also the most lethal gynecological cancer. Another problem is the fact that... (Review)
Review
Unfortunately, ovarian cancer is still diagnosed most often only in an advanced stage and is also the most lethal gynecological cancer. Another problem is the fact that treated patients have a high risk of disease recurrence. Moreover, ovarian cancer is very diverse in terms of molecular, histological features and mutations. Many patients may also develop platinum resistance, resulting in poor response to subsequent lines of treatment. To improve the prognosis of patients with ovarian cancer, it is expected to make better existing and implement new, promising treatment methods. Targeted therapies seem very promising. Currently, bevacizumab - a VEGF inhibitor and therapy with olaparib - a polyADP-ribose polymerase inhibitor are approved. Other methods worth considering in the future include: folate receptor α, immune checkpoints or other immunotherapy methods. To improve the treatment of ovarian cancer, it is also important to ameliorate the determination of molecular features to describe and understand which group of patients will benefit most from a given treatment method. This is important because a larger group of patients treated for ovarian cancer can have a greater chance of surviving longer without recurrence.
PubMed: 38948462
DOI: 10.3389/fphar.2024.1416555