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1.
Biomed Pharmacother ; 175: 116668, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38701565

ABSTRACT

The combination of radiation treatment and chemotherapy is currently the standard for management of cancer patients. However, safe doses do not often provide effective therapy, then pre-treated patients are forced to repeat treatment with often already increased tumor resistance to drugs and irradiation. One of the solutions we suggest is to improve primary course of radiation treatment via enhancing radiosensitivity of tumors by magnetic-guided iron oxide nanoparticles (magnetite). We obtained spherical heparinized iron oxide nanoparticles (hIONPs, ∼20 nm), characterized it by TEM, Infrared spectroscopy and DLS. Then hIONPs cytotoxicity was assessed for colon cancer cells (XTT assay) and cellular uptake of nanoparticles was analyzed with X-ray fluorescence. Combination of ionizing radiation (IR) and hIONPs in vitro caused an increase of G2/M arrest of cell cycle, mitotic errors and decrease in survival (compared with samples exposed to IR and hIONPs separately). The promising results were shown for magnetic-guided hIONPs in CT26-grafted BALB/C mice: the combination of intravenously administrated hIONPs and IR showed 20,8% T/C ratio (related to non-treated mice), while single radiation had no shown significant decrease in tumor growth (72,4%). Non-guided by magnets hIONPs with IR showed 57,9% of T/C. This indicates that ultra-small size and biocompatible molecule are not the key to successful nano-drug design, in each case, delivery technologies need to be improved when transferred to in vivo model.


Subject(s)
Colonic Neoplasms , Heparin , Magnetic Iron Oxide Nanoparticles , Mice, Inbred BALB C , Radiation-Sensitizing Agents , Animals , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Colonic Neoplasms/radiotherapy , Magnetic Iron Oxide Nanoparticles/chemistry , Radiation-Sensitizing Agents/pharmacology , Radiation-Sensitizing Agents/chemistry , Radiation-Sensitizing Agents/administration & dosage , Humans , Mice , Cell Line, Tumor , Heparin/chemistry , Heparin/pharmacology , Magnetite Nanoparticles/chemistry , Xenograft Model Antitumor Assays , Cell Survival/drug effects
2.
Micromachines (Basel) ; 15(5)2024 Apr 24.
Article in English | MEDLINE | ID: mdl-38793134

ABSTRACT

This paper is devoted to the study of CMOS IC parameter degradation during reliability testing. The paper presents a review of literature data on the issue of the reliability of semiconductor devices and integrated circuits and the types of failures leading to the degradation of IC parameters. It describes the tests carried out on the reliability of controlled parameters of integrated circuit TPS54332, such as quiescent current, quiescent current in standby mode, resistance of the open key, and instability of the set output voltage in the whole range of input voltages and in the whole range of load currents. The calculated values of activation energies and acceleration coefficients for different test temperature regimes are given. As a result of the work done, sample rejection tests have been carried out on the TPS54332 IC under study. Experimental fail-safe tests were carried out, with subsequent analysis of the chip samples by the controlled parameter quiescent current. On the basis of the obtained experimental values, the values of activation energy and acceleration coefficient at different temperature regimes were calculated. The dependencies of activation energy and acceleration coefficient on temperature were plotted, which show that activation energy linearly increases with increasing temperature, while the acceleration coefficient, on the contrary, decreases. It was also found that the value of the calculated activation energy of the chip is 0.1 eV less than the standard value of the activation energy.

3.
Proc Biol Sci ; 291(2023): 20240537, 2024 May.
Article in English | MEDLINE | ID: mdl-38747705

ABSTRACT

The noasaurid ceratosaur Kiyacursor longipes gen. et sp. nov. is described based on a fragmentary skeleton including cervical vertebra, pectoral girdle, humerus and hind limbs from the Lower Cretaceous (Aptian) Ilek Formation at Shestakovo 1 locality in Western Siberia, Russia. This is the first ceratosaur from the Early Cretaceous of Asia, extending the stratigraphic range of Ceratosauria by 40 Myr on that continent. Kiyacursor shares unique hind limb proportions with Elaphrosaurus and Limusaurus, suggesting improved cursorial ability. These taxa show an ostrich-like specialization of the pes, with a large third metatarsal and greatly reduced second metatarsal. By contrast, all other fast running non-avian theropod dinosaurs have an arctometatarsalian pes, with the third metatarsal strongly reduced proximally. The new taxon lived in the Early Cretaceous ecosystem containing a number of other Jurassic relics, such as stem salamanders, protosuchian and shartegosuchid crocodyliforms, tritylodontid synapsids and docodontan mammaliaforms.


Subject(s)
Dinosaurs , Fossils , Animals , Dinosaurs/anatomy & histology , Dinosaurs/classification , Fossils/anatomy & histology , Siberia , Biological Evolution
4.
Int J Mol Sci ; 25(7)2024 Mar 25.
Article in English | MEDLINE | ID: mdl-38612476

ABSTRACT

The review introduces the stages of formation and experimental confirmation of the hypothesis regarding the mutual potentiation of neuroprotective effects of hypoxia and hypercapnia during their combined influence (hypercapnic hypoxia). The main focus is on the mechanisms and signaling pathways involved in the formation of ischemic tolerance in the brain during intermittent hypercapnic hypoxia. Importantly, the combined effect of hypoxia and hypercapnia exerts a more pronounced neuroprotective effect compared to their separate application. Some signaling systems are associated with the predominance of the hypoxic stimulus (HIF-1α, A1 receptors), while others (NF-κB, antioxidant activity, inhibition of apoptosis, maintenance of selective blood-brain barrier permeability) are mainly modulated by hypercapnia. Most of the molecular and cellular mechanisms involved in the formation of brain tolerance to ischemia are due to the contribution of both excess carbon dioxide and oxygen deficiency (ATP-dependent potassium channels, chaperones, endoplasmic reticulum stress, mitochondrial metabolism reprogramming). Overall, experimental studies indicate the dominance of hypercapnia in the neuroprotective effect of its combined action with hypoxia. Recent clinical studies have demonstrated the effectiveness of hypercapnic-hypoxic training in the treatment of childhood cerebral palsy and diabetic polyneuropathy in children. Combining hypercapnic hypoxia with pharmacological modulators of neuro/cardio/cytoprotection signaling pathways is likely to be promising for translating experimental research into clinical medicine.


Subject(s)
Neuroprotection , Neuroprotective Agents , Child , Humans , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Hypercapnia , Carbon Dioxide , Hypoxia
5.
Neurol Res ; : 1-11, 2024 Apr 21.
Article in English | MEDLINE | ID: mdl-38643375

ABSTRACT

INTRODUCTION: Experimental studies on animals have demonstrated a higher neuroprotective efficacy of hypercapnic hypoxia compared to normocapnic hypoxia. Respiratory training with hypercapnic hypoxia has shown a positive impact on the functional state of the nervous system in children with cerebral palsy (CP). It can be presumed that the combined effect of moderate hypercapnia and hypoxia will be promising for clinical application within the context of early rehabilitation after ischemic stroke. METHODS: A randomized triple-blind placebo-controlled study was conducted on 102 patients with ischemic stroke, aged 63.07 ± 12.1 years. All patients were diagnosed with ischemic stroke based on neuroimaging criteria and/or clinical criteria within the 48-72 hour timeframe. The experimental group (n = 50) underwent daily respiratory training with hypercapnic hypoxia (FetCO2 5-6%, FetO2 15-16%) using the 'Carbonic' device for 7-11 sessions of 20 minutes each day during the treatment process. The control group (placebo, n = 52) underwent training on a similar device modified for breathing atmospheric air. Neurological examinations were conducted on all patients before the study and on the day after completing the training course. RESULTS: The standard treatment demonstrated effectiveness in terms of neurological status scales in both groups. Intermittent exposure to hypercapnic hypoxia proved more effective in improving neurological function indicators in patients compared to the placebo group: NIHSS scale scores were 40% lower than in the placebo group (p < 0.001); mRS scale scores were 35% lower (p < 0.001); B-ADL-I and RMI indices were higher by 26% (p < 0.01) and 36% (p < 0.001), respectively; MoCA scale results were 13% higher (p < 0.05); HADS and BDI-II scale scores were lower by 35% (p < 0.05) and 25% (p < 0.05), respectively. The increase in MMSE scale scores in the intervention group was 54% higher (p < 0.001), and MoCA scale scores increased by 25% (p < 0.001). CONCLUSION: Respiratory training with hypercapnic hypoxia improves the functional state of the nervous system in patients with ischemic stroke. After conducting further clarifying studies, hypercapnic hypoxia can be considered as an effective method of neurorehabilitation, which can be used as early as 48-72 hours after the onset of stroke.

6.
Org Biomol Chem ; 22(13): 2643-2653, 2024 03 27.
Article in English | MEDLINE | ID: mdl-38456317

ABSTRACT

Thienylallylamines, readily accessible from the corresponding thienyl aldehydes, react with maleic and trifluoromethylmaleic anhydrides leading to the formation of acids with a thieno[2,3-f]isoindole core. The reaction sequence involves two successive steps: acylation of the nitrogen atom of the initial allylamine and the intramolecular Diels-Alder vinylarene (IMDAV) reaction. The scope and limitations of the proposed method were thoroughly investigated. It has been revealed with the aid of X-ray analysis and DFT calculations that the key step, the IMDAV reaction, proceeds through an exo-transition state, giving rise to the exclusive formation of a single diastereomer of the target heterocycle. The obtained functionally substituted thieno[2,3-f]isoindole carboxylic acids are potentially useful substrates for further transformations and bioscreening. The antimicrobial evaluation of the obtained compounds revealed that 1-oxo-2-(3-(trifluoromethyl)phenyl)hexahydrobenzo[4,5]thieno[2,3-f]isoindole-10-carboxylic acid is the most active sample in the synthesized library. It exhibits antibacterial activity against sensitive strains of Gram-positive bacteria, including S. aureus, Enterococcus faecium, Bacillus cereus, and Micrococcus luteus, as well as the Gram-negative bacteria E. coli and Pseudomonas fluorescens, with MIC values ranging from 4 to 64 µg mL-1. 9-Oxo-8-phenyloctahydronaphtho[2,1-d]thieno[2,3-f]isoindole-10-carboxylic acid showed antifungal activity against yeast culture C. albicans with a MIC value of 32 µM.


Subject(s)
Escherichia coli , Staphylococcus aureus , Microbial Sensitivity Tests , Anti-Bacterial Agents/chemistry , Carboxylic Acids , Isoindoles
7.
Vaccines (Basel) ; 12(2)2024 Jan 26.
Article in English | MEDLINE | ID: mdl-38400113

ABSTRACT

The emergence of SARS-CoV-2 mutant variants has posed a significant challenge to both the prevention and treatment of COVID-19 with anti-coronaviral neutralizing antibodies. The latest viral variants demonstrate pronounced resistance to the vast majority of human monoclonal antibodies raised against the ancestral Wuhan variant. Less is known about the susceptibility of the evolved virus to camelid nanobodies developed at the start of the pandemic. In this study, we compared nanobody repertoires raised in the same llama after immunization with Wuhan's RBD variant and after subsequent serial immunization with a variety of RBD variants, including that of SARS-CoV-1. We show that initial immunization induced highly potent nanobodies, which efficiently protected Syrian hamsters from infection with the ancestral Wuhan virus. These nanobodies, however, mostly lacked the activity against SARS-CoV-2 omicron-pseudotyped viruses. In contrast, serial immunization with different RBD variants resulted in the generation of nanobodies demonstrating a higher degree of somatic mutagenesis and a broad range of neutralization. Four nanobodies recognizing distinct epitopes were shown to potently neutralize a spectrum of omicron variants, including those of the XBB sublineage. Our data show that nanobodies broadly neutralizing SARS-CoV-2 variants may be readily induced by a serial variant RBD immunization.

8.
Biomed Rep ; 20(3): 37, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38343660

ABSTRACT

Proteasome inhibitor bortezomib is an anticancer agent approved for treatment of multiple myeloma and mantle cell lymphoma. However, its application in other types of cancer, primarily in solid tumors, is limited due to poor pharmacokinetics, inefficient tissue penetration, low stability and frequent adverse effects. In the present study, a novel micellar nano-scaled delivery system was manufactured, composed of amphiphilic poly(N-vinylpyrrolidone) nanoparticles loaded with bortezomib. Similar nanoparticles loaded with prothionamide, a drug without anticancer effect, were used as control. The size and zeta potential of the obtained polymeric micelles were measured by dynamic light scattering. Bortezomib-loaded micelles exhibited significant cytotoxic activity in vitro in monolayer tumor cell cultures (IC50 ~6.5 µg/ml) and in 3D multicellular tumor spheroids (IC50 ~8.5 µg/ml) of human glioblastoma cell lines U87 and T98G. Additionally, the toxic effects in vivo were studied in zebrafish Danio rerio embryos, with an estimated 50% lethal concentration of 0.1 mg/ml. Considering that bortezomib and other molecules from the class of proteasome inhibitors are potent antitumor agents, nanodelivery approach can help reduce adverse effects and expand the range of its applications for treatment of various oncological diseases.

9.
Nanomaterials (Basel) ; 14(2)2024 Jan 11.
Article in English | MEDLINE | ID: mdl-38251128

ABSTRACT

This work explored the zinc nanoparticles obtained by the one-stage induction flow levitation method. A 10 kW tube generator with an operating frequency of 440 kHz was used. The process used 8 mm diameter zinc granules (2 g weight) with a purity of 99.9%. Zinc wire was fed to replace the evaporated metal from the granule surface. This method productivity was 30 g/h of nanoparticles. In addition, various methods were used to characterize the resulting nanoparticles: scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-Ray fluorescence analysis (XRF), dynamic light scattering (DLS), porosimetry and inductively coupled plasma atomic emission spectroscopy (ICP-MS). The resulting nanoparticle size, determined by SEM and porosimetry, was 350 nm, while the size of the primary crystallites was 21 nm. The amount of impurities in the resulting nanoparticles did not exceed 1000 ppm.

10.
Alzheimers Dement ; 20(2): 1123-1136, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37881831

ABSTRACT

INTRODUCTION: The National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site Alzheimer's Genomics Database (GenomicsDB) is a public knowledge base of Alzheimer's disease (AD) genetic datasets and genomic annotations. METHODS: GenomicsDB uses a custom systems architecture to adopt and enforce rigorous standards that facilitate harmonization of AD-relevant genome-wide association study summary statistics datasets with functional annotations, including over 230 million annotated variants from the AD Sequencing Project. RESULTS: GenomicsDB generates interactive reports compiled from the harmonized datasets and annotations. These reports contextualize AD-risk associations in a broader functional genomic setting and summarize them in the context of functionally annotated genes and variants. DISCUSSION: Created to make AD-genetics knowledge more accessible to AD researchers, the GenomicsDB is designed to guide users unfamiliar with genetic data in not only exploring but also interpreting this ever-growing volume of data. Scalable and interoperable with other genomics resources using data technology standards, the GenomicsDB can serve as a central hub for research and data analysis on AD and related dementias. HIGHLIGHTS: The National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) offers to the public a unique, disease-centric collection of AD-relevant GWAS summary statistics datasets. Interpreting these data is challenging and requires significant bioinformatics expertise to standardize datasets and harmonize them with functional annotations on genome-wide scales. The NIAGADS Alzheimer's GenomicsDB helps overcome these challenges by providing a user-friendly public knowledge base for AD-relevant genetics that shares harmonized, annotated summary statistics datasets from the NIAGADS repository in an interpretable, easily searchable format.


Subject(s)
Alzheimer Disease , United States , Humans , Alzheimer Disease/genetics , Genome-Wide Association Study , National Institute on Aging (U.S.) , Genomics , Databases, Factual , Genetic Predisposition to Disease/genetics
11.
Sci Rep ; 13(1): 22963, 2023 Dec 27.
Article in English | MEDLINE | ID: mdl-38151506

ABSTRACT

Deep-ocean sediments, similarly to seawater, are important reservoirs of 137Cs, an anthropogenic radionuclide with a relatively long half-live found in the Earth system. To better understand the geochemical behaviour of 137Cs in the ocean, we examined the temporal changes of 137Cs activity concentrations in the overlying waters and in sediments from the Far Eastern Seas (Sea of Japan, SOJ, and Okhotsk Sea, OS) during the period of 1998-2021. The 137Cs activity levels showed exponential changes during the observed period. The decay-corrected change rates of 137Cs in deep waters of SOJ exhibited a slow increase, while 137Cs levels in seawater and sediment in OS decreased gradually. This reflects a topographical difference, as SOJ is a semi-closed sea, whereas OS receives continuously inflow of subarctic waters. It was confirmed that 137Cs released after the Fukushima Dai-ichi Nuclear Power Plant accident was rapidly transported into the deep waters of the SOJ. To elucidate the transfer processes of 137Cs from seawater to sediment, we discussed the temporal changes of the partition coefficients (Kd) of 137Cs between the overlying water and the surface sediment. In shallow areas (< 1500 m water depth), Kd values were almost constant within the sampling periods, although the temporal changes in the Kd values occurred in deeper waters (> 2500 m depth). The Kd values increased with increasing depth, which may reflect a pressure effect as a possible mechanism. These findings suggest that chemical processes may be important factors controlling the transport of 137Cs between seawater and sediment, although more complicated phenomena occurred in deep waters and sediments of the SOJ (> 3000 m depth).

12.
Bioinformatics ; 39(11)2023 11 01.
Article in English | MEDLINE | ID: mdl-37947320

ABSTRACT

SUMMARY: Preparing functional genomic (FG) data with diverse assay types and file formats for integration into analysis workflows that interpret genome-wide association and other studies is a significant and time-consuming challenge. Here we introduce hipFG (Harmonization and Integration Pipeline for Functional Genomics), an automatically customized pipeline for efficient and scalable normalization of heterogenous FG data collections into standardized, indexed, rapidly searchable analysis-ready datasets while accounting for FG datatypes (e.g. chromatin interactions, genomic intervals, quantitative trait loci). AVAILABILITY AND IMPLEMENTATION: hipFG is freely available at https://bitbucket.org/wanglab-upenn/hipFG. A Docker container is available at https://hub.docker.com/r/wanglab/hipfg.


Subject(s)
Genome-Wide Association Study , Software , Genomics , Chromatin , Quantitative Trait Loci
13.
Int J Mol Sci ; 24(19)2023 Sep 28.
Article in English | MEDLINE | ID: mdl-37834155

ABSTRACT

The development of brain in vitro models requires the application of novel biocompatible materials and biopolymers as scaffolds for controllable and effective cell growth and functioning. The "ideal" brain in vitro model should demonstrate the principal features of brain plasticity like synaptic transmission and remodeling, neurogenesis and angiogenesis, and changes in the metabolism associated with the establishment of new intercellular connections. Therefore, the extracellular scaffolds that are helpful in the establishment and maintenance of local microenvironments supporting brain plasticity mechanisms are of critical importance. In this review, we will focus on some carbohydrate metabolites-lactate, pyruvate, oxaloacetate, malate-that greatly contribute to the regulation of cell-to-cell communications and metabolic plasticity of brain cells and on some resorbable biopolymers that may reproduce the local microenvironment enriched in particular cell metabolites.


Subject(s)
Biocompatible Materials , Brain , Biocompatible Materials/pharmacology , Brain/physiology , Neurogenesis , Biopolymers , Morphogenesis
14.
Int J Mol Sci ; 24(16)2023 Aug 17.
Article in English | MEDLINE | ID: mdl-37629078

ABSTRACT

In recent times, there has been a significant increase in researchers' interest in the functions of microRNAs and the role of these molecules in the pathogenesis of many multifactorial diseases. This is related to the diagnostic and prognostic potential of microRNA expression levels as well as the prospects of using it in personalized targeted therapy. This review of the literature analyzes existing scientific data on the involvement of microRNAs in the molecular and cellular mechanisms underlying the development of pathologies such as Alzheimer's disease, cerebral ischemia and reperfusion injury, and dysfunction of the blood-brain barrier.


Subject(s)
Alzheimer Disease , MicroRNAs , Humans , MicroRNAs/genetics , Epigenesis, Genetic , Alzheimer Disease/genetics , Blood-Brain Barrier , Signal Transduction/genetics
15.
Naturwissenschaften ; 110(4): 40, 2023 Aug 02.
Article in English | MEDLINE | ID: mdl-37530873

ABSTRACT

Eutriconodonta are an important group of early crown mammals with a wide distribution in the Jurassic-Cretaceous of the Northern Hemisphere and few occurrences in the Southern Hemisphere. Three taxa of eutriconodontans are known from the Early Cretaceous high-latitude Teete vertebrate assemblage in Yakutia, Russia: Sangarotherium aquilonium (Eutriconodonta incertae sedis), Gobiconodon sp. A (large), and Gobiconodon sp. B (small) (Gobiconodontidae). These three taxa are based on four specimens and indicate a remarkable taxonomic diversity of eutriconodontans at this locality. The coexistence of two Gobiconodon species, large and small, is characteristic for several Early Cretaceous vertebrate assemblages in Asia. Gobiconodon sp. A from the Teete locality is the largest species of this genus known from Asia, but is smaller than the North American G. ostromi. The spreading of Gobiconodon from Asia to North America likely occurred during the Aptian-Albian faunal dispersal event. The discovery of Gobiconodon in the Teete locality is further evidence for a dispersal route via Beringia from Asia to North America which previously has been postulated based on the occurrence of Asian dinosaur taxa in western North America at this time. The questionable record of Gobiconodon from Europe and its lack from eastern North America make a dispersal from Asia to North America via Europe less probable.


Subject(s)
Dinosaurs , Fossils , Animals , Asia , Russia , Mammals , Dinosaurs/anatomy & histology , Phylogeny
16.
bioRxiv ; 2023 May 12.
Article in English | MEDLINE | ID: mdl-37425787

ABSTRACT

Centromeres are genomic regions that coordinate accurate chromosomal segregation during mitosis and meiosis. Yet, despite their essential function, centromeres evolve rapidly across eukaryotes. Centromeres are often the sites of chromosomal breaks which contribute to genome shuffling and promote speciation by inhibiting gene flow. How centromeres form in strongly host-adapted fungal pathogens has yet to be investigated. Here, we characterized the centromere structures in closely related species of mammalian-specific pathogens of the fungal phylum of Ascomycota. Methods allowing reliable continuous culture of Pneumocystis species do not currently exist, precluding genetic manipulation. CENP-A, a variant of histone H3, is the epigenetic marker that defines centromeres in most eukaryotes. Using heterologous complementation, we show that the Pneumocystis CENP-A ortholog is functionally equivalent to CENP-ACnp1 of Schizosaccharomyces pombe. Using organisms from a short-term in vitro culture or infected animal models and ChIP-seq, we identified centromeres in three Pneumocystis species that diverged ~100 million years ago. Each species has a unique short regional centromere (< 10kb) flanked by heterochromatin in 16-17 monocentric chromosomes. They span active genes and lack conserved DNA sequence motifs and repeats. CENP-C, a scaffold protein that links the inner centromere to the kinetochore appears dispensable in one species, suggesting a kinetochore rewiring. Despite the loss of DNA methyltransferases, 5-methylcytosine DNA methylation occurs in these species, though not related to centromere function. These features suggest an epigenetic specification of centromere function.

17.
Nat Commun ; 14(1): 4082, 2023 07 10.
Article in English | MEDLINE | ID: mdl-37429841

ABSTRACT

Three types of DNA methyl modifications have been detected in bacterial genomes, and mechanistic studies have demonstrated roles for DNA methylation in physiological functions ranging from phage defense to transcriptional control of virulence and host-pathogen interactions. Despite the ubiquity of methyltransferases and the immense variety of possible methylation patterns, epigenomic diversity remains unexplored for most bacterial species. Members of the Bacteroides fragilis group (BFG) reside in the human gastrointestinal tract as key players in symbiotic communities but also can establish anaerobic infections that are increasingly multi-drug resistant. In this work, we utilize long-read sequencing technologies to perform pangenomic (n = 383) and panepigenomic (n = 268) analysis of clinical BFG isolates cultured from infections seen at the NIH Clinical Center over four decades. Our analysis reveals that single BFG species harbor hundreds of DNA methylation motifs, with most individual motif combinations occurring uniquely in single isolates, implying immense unsampled methylation diversity within BFG epigenomes. Mining of BFG genomes identified more than 6000 methyltransferase genes, approximately 1000 of which were associated with intact prophages. Network analysis revealed substantial gene flow among disparate phage genomes, implying a role for genetic exchange between BFG phages as one of the ultimate sources driving BFG epigenome diversity.


Subject(s)
Bacteriophages , Methyltransferases , Humans , Methyltransferases/genetics , Bacteroides fragilis/genetics , Epigenomics , DNA Methylation/genetics , Bacteriophages/genetics , Bacteroides , Epigenesis, Genetic
18.
medRxiv ; 2023 Jul 08.
Article in English | MEDLINE | ID: mdl-37461624

ABSTRACT

Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer's Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6,728 African American, 8,899 Hispanic (HIS), and 3,232 East Asian individuals, performing within-ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identified 13 loci with cross-ancestry associations including known loci at/near CR1 , BIN1 , TREM2 , CD2AP , PTK2B , CLU , SHARPIN , MS4A6A , PICALM , ABCA7 , APOE and two novel loci not previously reported at 11p12 ( LRRC4C ) and 12q24.13 ( LHX5-AS1 ). Reflecting the power of diverse ancestry in GWAS, we observed the SHARPIN locus using 7.1% the sample size of the original discovering single-ancestry GWAS (n=788,989). We additionally identified three GWS ancestry-specific loci at/near ( PTPRK ( P =2.4×10 -8 ) and GRB14 ( P =1.7×10 -8 ) in HIS), and KIAA0825 ( P =2.9×10 -8 in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest with P adjusted =1.6×10 -4 ) and the classical complement pathway ( P adjusted =1.3×10 -3 ). Genes at/near our novel loci have known roles in neuronal development ( LRRC4C, LHX5-AS1 , and PTPRK ) and insulin receptor activity regulation ( GRB14 ). These findings provide compelling support for using traditionally-underrepresented populations for gene discovery, even with smaller sample sizes.

19.
Plant Physiol Biochem ; 200: 107761, 2023 Jul.
Article in English | MEDLINE | ID: mdl-37209454

ABSTRACT

Forest trees are subjected to multiple stressors during their long lifetime and therefore require effective and finely regulated stress-protective systems. Stressors can induce protective systems either directly or with the involvement of stress memory mechanisms. Stress memory has only begun to be uncovered in model plants and is unexplored in coniferous species. Therefore, we studied the possible role of stress memory in the regulation of the accumulation of stress-protective compounds (heat shock proteins, dehydrins, proline) in the needles of naturally grown Scots pine and Norway spruce trees subjected to the subsequent action of long-term (multiyear) and short-term (seasonal) water shortages. Although the water deficit was relatively mild, it significantly influenced the pattern of expression of stress memory-related heat shock factor (HSF) and SWI/SNF genes, indicating the formation of stress memory in both species. In spruce, dehydrin accumulation was increased by water shortage in a manner compatible with Type II stress memory. The accumulation of HSP40 in spruce needles was positively influenced by long-term water shortage, but this increase was unlikely to be of biological importance due to the concomitant decrease in HSP70, HSP90 and HSP101 accumulation. Finally, proline accumulation was negatively influenced by short-term water deficit in spruce. In pine, no one protective compound accumulated in response to water stress. Taken together, the results indicate that the accumulation of stress-protective compounds was generally independent of stress memory effects both in pine and in spruce.


Subject(s)
Picea , Pinus sylvestris , Pinus , Droughts , Picea/metabolism , Seedlings/metabolism , Pinus sylvestris/metabolism
20.
bioRxiv ; 2023 Apr 25.
Article in English | MEDLINE | ID: mdl-37162864

ABSTRACT

Preparing functional genomic (FG) data with diverse assay types and file formats for integration into analysis workflows that interpret genome-wide association and other studies is a significant and time-consuming challenge. Here we introduce hipFG, an automatically customized pipeline for efficient and scalable normalization of heterogenous FG data collections into standardized, indexed, rapidly searchable analysis-ready datasets while accounting for FG datatypes (e.g., chromatin interactions, genomic intervals, quantitative trait loci).

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