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PloS One 2024A web application, GTExome, is described that quickly identifies, classifies, and models missense mutations in commonly expressed human proteins. GTExome can be used to...
A web application, GTExome, is described that quickly identifies, classifies, and models missense mutations in commonly expressed human proteins. GTExome can be used to categorize genomic mutation data with tissue specific expression data from the Genotype-Tissue Expression (GTEx) project. Commonly expressed missense mutations in proteins from a wide range of tissue types can be selected and assessed for modeling suitability. Information about the consequences of each mutation is provided to the user including if disulfide bonds, hydrogen bonds, or salt bridges are broken, buried prolines introduced, buried charges are created or lost, charge is swapped, a buried glycine is replaced, or if the residue that would be removed is a proline in the cis configuration. Also, if the mutation site is in a binding pocket the number of pockets and their volumes are reported. The user can assess this information and then select from available experimental or computationally predicted structures of native proteins to create, visualize, and download a model of the mutated protein using Fast and Accurate Side-chain Protein Repacking (FASPR). For AlphaFold modeled proteins, confidence scores for native proteins are provided. Using this tool, we explored a set of 9,666 common missense mutations from a variety of tissues from GTEx and show that most mutations can be modeled using this tool to facilitate studies of protein-protein and protein-drug interactions. The open-source tool is freely available at https://pharmacogenomics.clas.ucdenver.edu/gtexome/.
Topics: Humans; Mutation, Missense; Genome, Human; Models, Molecular; Software; Internet; Proteins
PubMed: 38814966
DOI: 10.1371/journal.pone.0303604 -
PLoS Biology May 2024Zebrafish are popular research organisms selected for laboratory use due in part to widespread availability from the pet trade. Many contemporary colonies of laboratory...
Zebrafish are popular research organisms selected for laboratory use due in part to widespread availability from the pet trade. Many contemporary colonies of laboratory zebrafish are maintained in aquaculture facilities that monitor and aim to curb infections that can negatively affect colony health and confound experiments. The impact of laboratory control on the microbial constituents associated with zebrafish in research environments compared to the pet trade are unclear. Diseases of unknown causes are common in both environments. We conducted a metatranscriptomic survey to broadly compare the zebrafish-associated microbes in pet trade and laboratory environments. We detected many microbes in animals from the pet trade that were not found in laboratory animals. Cohousing experiments revealed several transmissible microbes including a newly described non-enveloped, double-stranded RNA virus in the Birnaviridae family we name Rocky Mountain birnavirus (RMBV). Infections were detected in asymptomatic animals from the pet trade, but when transmitted to laboratory animals RMBV was associated with pronounced antiviral responses and hemorrhagic disease. These experiments highlight the pet trade as a distinct source of diverse microbes that associate with zebrafish and establish a paradigm for the discovery of newly described pathogenic viruses and other infectious microbes that can be developed for study in the laboratory.
Topics: Animals; Zebrafish; Fish Diseases; Pets; Animals, Laboratory; Aquaculture
PubMed: 38814944
DOI: 10.1371/journal.pbio.3002606 -
JAMA Network Open May 2024Standard of care for unresectable locally advanced non-small cell lung cancer (NSCLC) involves definitive chemoradiotherapy followed by maintenance therapy with...
IMPORTANCE
Standard of care for unresectable locally advanced non-small cell lung cancer (NSCLC) involves definitive chemoradiotherapy followed by maintenance therapy with durvalumab. However, the cost of durvalumab has been cited as a barrier to its use in various health systems.
OBJECTIVE
To evaluate the cost-effectiveness of durvalumab vs placebo as maintenance therapy in patients with unresectable stage III NSCLC from 4 international payer perspectives (US, Brazil, Singapore, and Spain).
DESIGN, SETTING, AND PARTICIPANTS
In this economic evaluation, a Markov model was designed to compare the lifetime cost-effectiveness of maintenance durvalumab for unresectable stage III NSCLC with that of placebo, using 5-year outcomes data from the PACIFIC randomized placebo-controlled trial. Individual patient data were extracted from the PACIFIC, KEYNOTE-189, ADAURA, ALEX, and REVEL randomized clinical trials to develop a decision-analytic model to determine the cost-effectiveness of durvalumab compared with placebo maintenance therapy over a 10-year time horizon. Direct costs, adverse events, and patient characteristics were based on country-specific payer perspectives and demographic characteristics. The study was conducted from June 1, 2022, through December 27, 2023.
MAIN OUTCOMES AND MEASURES
Life-years, quality-adjusted life years (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs) were estimated at country-specific willingness-to-pay thresholds ([data reported in US$] US: $150 000 per QALY; Brazil: $22 251 per QALY; Singapore: $55 288 per QALY, and Spain: $107 069 per QALY). One-way and probabilistic sensitivity analyses were performed to account for parameters of uncertainty. A cost-threshold analysis was also performed.
RESULTS
The US base-case model found that treatment with durvalumab was associated with an increased cost of $114 394 and improved effectiveness of 0.50 QALYs compared with placebo, leading to an ICER of $228 788 per QALY. Incremental cost-effectiveness ratios, according to base-case models, were $141 146 for Brazil, $153 461 for Singapore, and $125 193 for Spain. Durvalumab price adjustments to the PACIFIC data improved cost-effectiveness in Singapore, with an ICER of $45 164. The model was most sensitive to the utility of durvalumab.
CONCLUSIONS AND RELEVANCE
In this cost-effectiveness analysis of durvalumab as maintenance therapy for unresectable stage III NSCLC, the therapy was found to be cost-prohibitive from the perspective of various international payers according to country-specific willingness-to-pay thresholds per QALY. The findings of the study suggest that discounted durvalumab acquisition costs, as possible in Singapore, might improve cost-effectiveness globally.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Cost-Benefit Analysis; Lung Neoplasms; Antibodies, Monoclonal; Brazil; Spain; Quality-Adjusted Life Years; Male; Singapore; Female; United States; Middle Aged; Neoplasm Staging; Aged; Antineoplastic Agents, Immunological; Markov Chains; Cost-Effectiveness Analysis
PubMed: 38814640
DOI: 10.1001/jamanetworkopen.2024.13938 -
European Annals of Allergy and Clinical... May 2024
PubMed: 38813919
DOI: 10.23822/EurAnnACI.1764-1489.343 -
Turkish Journal of Medical Sciences 2024This study investigated serum, vitreous, and anterior chamber fluid electrolyte changes, corneal thickness (CT), corneal volume (CV), anterior chamber volume (ACV), and...
BACKGROUND/AIM
This study investigated serum, vitreous, and anterior chamber fluid electrolyte changes, corneal thickness (CT), corneal volume (CV), anterior chamber volume (ACV), and anterior chamber depth (ACD) as an auxiliary diagnostic method in the identification of drowning in fresh or salt water.
MATERIALS AND METHODS
The study used 35 healthy, adult, male, white New Zealand rabbits, seperated into five groups (control, saltwater drowning (SWD), saltwater immersion (SWI), freshwater drowning (FWD), freshwater immersion (FWI)). CT, CV, ACV, and ACD measurements were made with Pentacam topography at 0, 2, and 4 h in all groups. Magnesium (mg), sodium (Na), and chlorine (Cl) were measured in the blood at 0 and 2 h, and in blood, vitreous fluid, and humor aqueous at 4 h.
RESULTS
It was determined that CT, CV, ACV, and ACD are not of great value in drowning diagnosis and are affected by the fresh or salt water rather than drowning. Vitreous Na, Cl, and Mg levels are ineffective in determining drowning after one h. Anterior chamber fluid may provide valuable information in the differentiation freshwater - saltwater drownings at the 4th h in corpses retrieved from water.
CONCLUSION
Anterior chamber fluid Na and Cl levels, especially in corpses removed from salt water, can be an easily used test that can help diagnose drowning.
Topics: Animals; Rabbits; Drowning; Male; Fresh Water; Vitreous Body; Anterior Chamber; Sodium; Magnesium; Chlorine; Cornea; Seawater; Aqueous Humor; Immersion
PubMed: 38812651
DOI: 10.55730/1300-0144.5764 -
Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles.Genome Medicine May 2024We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney,...
BACKGROUND
We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney, caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative mode of action, wherein an increased level of AFF3 resulted in pathological effects.
METHODS
Evolutionary constraints suggest that other modes-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be damaging variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants.
RESULTS
We identified an individual with a KINSSHIP-like phenotype carrying a de novo partial duplication of AFF3 further strengthening the hypothesis that an increased level of AFF3 is pathological. We also detected seventeen individuals displaying a milder syndrome with either heterozygous Loss-of-Function (LoF) or biallelic missense variants in AFF3. Consistent with semi-dominance, we discovered three patients with homozygous LoF and one compound heterozygote for a LoF and a missense variant, who presented more severe phenotypes than their heterozygous parents. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA, confirming their association with the ablation of aff3. Conversely, some of the human AFF3 mRNAs carrying missense variants identified in affected individuals did not rescue these phenotypes. Overexpression of mutated AFF3 mRNAs in zebrafish embryos produced a significant increase of abnormal larvae compared to wild-type overexpression further demonstrating deleteriousness. To further assess the effect of AFF3 variation, we profiled the transcriptome of fibroblasts from affected individuals and engineered isogenic cells harboring + / + , KINSSHIP/KINSSHIP, LoF/ + , LoF/LoF or KINSSHIP/LoF AFF3 genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the KINSSHIP/KINSSHIP or the LoF/LoF lines. While the same pathways are affected, only about one third of the differentially expressed genes are common to the homozygote datasets, indicating that AFF3 LoF and KINSSHIP variants largely modulate transcriptomes differently, e.g. the DNA repair pathway displayed opposite modulation.
CONCLUSIONS
Our results and the high pleiotropy shown by variation at this locus suggest that minute changes in AFF3 function are deleterious.
Topics: Humans; Animals; Zebrafish; Transcriptome; Intellectual Disability; Phenotype; Female; Male; Mutation, Missense; Loss of Function Mutation
PubMed: 38811945
DOI: 10.1186/s13073-024-01339-y -
BMC Plant Biology May 2024Salinity stress, an ever-present challenge in agriculture and environmental sciences, poses a formidable hurdle for plant growth and productivity in saline-prone regions...
Salinity stress, an ever-present challenge in agriculture and environmental sciences, poses a formidable hurdle for plant growth and productivity in saline-prone regions worldwide. Therefore, this study aimed to explore the effectiveness of trehalose and mannitol induce salt resistance in wheat seedlings. Wheat grains of the commercial variety Sakha 94 were divided into three groups : a group that was pre-soaked in 10 mM trehalose, another group was soaked in 10 mM mannitol, and the last was soaked in distilled water for 1 hour, then the pre soaked grains cultivated in sandy soil, each treatment was divided into two groups, one of which was irrigated with 150 mM NaCl and the other was irrigated with tap water. The results showed that phenols content in wheat seedlings increased and flavonoids reduced due to salt stress. Trehalose and mannitol cause slight increase in total phenols content while total flavonoids were elevated highy in salt-stressed seedlings. Furthermore, Trehalose or mannitol reduced salt-induced lipid peroxidation. Salt stress increases antioxidant enzyme activities of guaiacol peroxidase (G-POX), ascorbate peroxidase (APX), and catalase (CAT) in wheat seedlings, while polyphenol oxidase (PPO) unchanged. Trehalose and mannitol treatments caused an increase in APX, and CAT activities, whereas G-POX not altered but PPO activity were decreased under salt stress conditions. Molecular docking confirmed the interaction of Trehalose or mannitol with peroxidase and ascorbic peroxidase enzymes. Phenyl alanine ammonia layase (PAL) activity was increased in salt-stressed seedlings. We can conclude that pre-soaking of wheat grains in 10 mM trehalose or mannitol improves salinity stress tolerance by enhancing antioxidant defense enzyme and/or phenol biosynthesis, with docking identifying interactions with G-POX, CAT, APX, and PPO.
Topics: Triticum; Trehalose; Seedlings; Mannitol; Salt Tolerance; Molecular Docking Simulation; Antioxidants; Salt Stress; Flavonoids; Phenols
PubMed: 38811894
DOI: 10.1186/s12870-024-04964-2 -
Nature Communications May 2024Evolution results from the interaction of stochastic and deterministic processes that create a web of historical contingency, shaping gene content and organismal...
Evolution results from the interaction of stochastic and deterministic processes that create a web of historical contingency, shaping gene content and organismal function. To understand the scope of this interaction, we examine the relative contributions of stochasticity, determinism, and contingency in shaping gene inactivation in 34 lineages of endosymbiotic bacteria, Sodalis, found in parasitic lice, Columbicola, that are independently undergoing genome degeneration. Here we show that the process of genome degeneration in this system is largely deterministic: genes involved in amino acid biosynthesis are lost while those involved in providing B-vitamins to the host are retained. In contrast, many genes encoding redundant functions, including components of the respiratory chain and DNA repair pathways, are subject to stochastic loss, yielding historical contingencies that constrain subsequent losses. Thus, while selection results in functional convergence between symbiont lineages, stochastic mutations initiate distinct evolutionary trajectories, generating diverse gene inventories that lack the functional redundancy typically found in free-living relatives.
Topics: Symbiosis; Genome, Bacterial; Evolution, Molecular; Stochastic Processes; Animals; Phylogeny; Enterobacteriaceae; Mutation
PubMed: 38811551
DOI: 10.1038/s41467-024-48784-2 -
Science Advances May 2024Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on...
Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit ), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit ), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.
Topics: Humans; Colorectal Neoplasms; Anti-Inflammatory Agents, Non-Steroidal; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Aspirin; Receptors, Prostaglandin E, EP4 Subtype; Male; Genetic Predisposition to Disease; Female; Case-Control Studies; Middle Aged; Genetic Loci; Aged
PubMed: 38809988
DOI: 10.1126/sciadv.adk3121 -
Science Advances May 2024Water purification via interfacial solar steam generation exhibits promising potential. However, salt crystallization on evaporators reduces solar absorption and...
Water purification via interfacial solar steam generation exhibits promising potential. However, salt crystallization on evaporators reduces solar absorption and obstructs water supply. To address it, a waffle-shaped solar evaporator (WSE) has been designed. WSE is fabricated via a zinc-assisted pyrolysis route, combining low-cost biomass carbon sources, recyclable zinc, and die-stamping process. This route enables cost-effective production without the need of sophisticated processing. As compared to conventional plane-shaped evaporators, WSE is featured by extra sidewalls for triggering the convection with the synergistic solute and thermal Marangoni effects. Consequently, WSE achieves spontaneous salt rejection and durable evaporation stability. It has demonstrated continuous operation for more than 60 days in brine without fouling.
PubMed: 38809973
DOI: 10.1126/sciadv.adk1113