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Science (New York, N.Y.) Jun 2024Polycystic ovary syndrome (PCOS), a prevalent reproductive disorder in women of reproductive age, features androgen excess, ovulatory dysfunction, and polycystic...
Polycystic ovary syndrome (PCOS), a prevalent reproductive disorder in women of reproductive age, features androgen excess, ovulatory dysfunction, and polycystic ovaries. Despite its high prevalence, specific pharmacologic intervention for PCOS is challenging. In this study, we identified artemisinins as anti-PCOS agents. Our finding demonstrated the efficacy of artemisinin derivatives in alleviating PCOS symptoms in both rodent models and human patients, curbing hyperandrogenemia through suppression of ovarian androgen synthesis. Artemisinins promoted cytochrome P450 family 11 subfamily A member 1 (CYP11A1) protein degradation to block androgen overproduction. Mechanistically, artemisinins directly targeted lon peptidase 1 (LONP1), enhanced LONP1-CYP11A1 interaction, and facilitated LONP1-catalyzed CYP11A1 degradation. Overexpression of LONP1 replicated the androgen-lowering effect of artemisinins. Our data suggest that artemisinin application is a promising approach for treating PCOS and highlight the crucial role of the LONP1-CYP11A1 interaction in controlling hyperandrogenism and PCOS occurrence.
Topics: Animals; Female; Humans; Mice; Rats; Androgens; Artemisinins; Cholesterol Side-Chain Cleavage Enzyme; Disease Models, Animal; Hyperandrogenism; Mitochondrial Proteins; Ovary; Polycystic Ovary Syndrome; Proteolysis; Mice, Inbred C57BL; Young Adult; Adult; Rats, Sprague-Dawley; ATP-Dependent Proteases
PubMed: 38870290
DOI: 10.1126/science.adk5382 -
The Science of the Total Environment Sep 2024The widespread use of chemical disinfectants and antibiotics poses a major threat to food safety and human health. However, the mechanisms of co-transmission of...
The widespread use of chemical disinfectants and antibiotics poses a major threat to food safety and human health. However, the mechanisms of co-transmission of antimicrobial resistance genes (ARGs) and biocides and metal resistance genes (BMRGs) of foodborne pathogens in the food chain is still unclear. This study isolated 343 E. coli strains from animal-derived foods in Beijing and incorporated online data of human-derived E. coli strains from NCBI. Our results demonstrated a relatively uniform distribution of strains from various regions in Beijing, indicating a lack of region-specific clustering. Additionally, predominant sequence types varied between food- and human-derived strains, suggesting a preference for different hosts and environments. Phenotypic association analysis showed that the chlorine disinfectants peroxides had a significant positive correlation with tetracyclines. Many more ARGs and BMRGs were enriched in human-associated E. coli compared with those in chicken- and pork-origin. The quaternary ammonium compounds (QACs) resistance gene qacEΔ1 had a strong correlation with aminoglycoside resistance gene aadA5, folate pathway antagonist resistance gene dfrA17, sul1 and macrolide resistance gene mph(A). The correlation results indicated a significant association between the copper resistance gene cluster pco and the silver resistance gene cluster sil. Coexistence of many resistance genes was observed within the qacEΔ1 gene structure, with qacEΔ1-sul1 being the most common combination. Our findings demonstrated that the epidemiological spread of resistance is affected by a combination of heavy metals, disinfectants and antibiotic use, suggesting that the prevention and control strategies of antimicrobial resistance need to be multifaceted and comprehensive.
Topics: Disinfectants; Anti-Bacterial Agents; Humans; Escherichia coli; Beijing; Drug Resistance, Bacterial; Food Microbiology; Animals; China
PubMed: 38866143
DOI: 10.1016/j.scitotenv.2024.173888 -
Journal of Infection in Developing... May 2024Global monitoring of severe acute respiratory syndrome related coronavirus 2 (SARS-CoV-2) genetic sequences and associated metadata is essential for coronavirus disease...
INTRODUCTION
Global monitoring of severe acute respiratory syndrome related coronavirus 2 (SARS-CoV-2) genetic sequences and associated metadata is essential for coronavirus disease 2019 (COVID-19) response. Therefore, Sanger's partial genome sequencing technique was used to monitor the circulating variants of SARS-CoV-2 in Cameroon.
METHODOLOGY
Nasopharyngeal specimen was collected from persons suspected of SARS-CoV-2 following the national guidelines between January and December 2021. All specimens with cycle threshold (Ct) below 30 after amplification were eligible for sequencing of the partial spike (S) gene of SARS-CoV-2 using the Sanger sequencing method.
RESULTS
During the year 2021, 1481 real time reverse transcriptase polymerase chain reaction (RT-PCR) SARS-CoV-2 positive samples were selected for partial sequencing of the S gene of SARS-CoV-2. Amongst these, 878 yielded good sequencing products. A total of 231 probable variants (26.3%) were identified. The variants were mainly represented by Delta (70.6%), Alpha (15.6%), Omicron (7.4%), Beta (3.5%), Mu (1.7%) and Gamma (0.4%). Phylogenetic analysis of the probable variants from Cameroon with reference strains confirmed that all prior and current variants of concern (VOC) clustered with their respective reference sequences.
CONCLUSIONS
The surveillance strategy implemented in Cameroon, based on partial sequencing of the S gene enabled identification of the major circulating variants and provided information on the distribution of these variants, which contributed to implementing public health measures to control disease spread in the country.
Topics: Humans; Cameroon; SARS-CoV-2; Spike Glycoprotein, Coronavirus; COVID-19; Male; Female; Adult; Adolescent; Child; Middle Aged; Young Adult; Child, Preschool; Nasopharynx; Aged; Phylogeny; Infant
PubMed: 38865404
DOI: 10.3855/jidc.18155 -
Alzheimer's & Dementia : the Journal of... Jun 2024Frontotemporal lobar degeneration (FTLD) encompasses behavioral variant frontotemporal dementia (bvFTD), progressive supranuclear palsy, corticobasal...
INTRODUCTION
Frontotemporal lobar degeneration (FTLD) encompasses behavioral variant frontotemporal dementia (bvFTD), progressive supranuclear palsy, corticobasal syndrome/degeneration, and primary progressive aphasias (PPAs). We cross-validated fluid biomarkers and neuroimaging.
METHODS
Seven fluid biomarkers from cerebrospinal fluid and serum were related to atrophy in 428 participants including these FTLD subtypes, logopenic variant PPA (lvPPA), Alzheimer's disease (AD), and healthy subjects. Atrophy was assessed by structural magnetic resonance imaging and atlas-based volumetry.
RESULTS
FTLD subtypes, lvPPA, and AD showed specific profiles for neurofilament light chain, phosphorylated heavy chain, tau, phospho-tau, amyloid beta from serum/cerebrospinal fluid, and brain atrophy. Neurofilaments related to regional atrophy in bvFTD, whereas progranulin was associated with atrophy in semantic variant PPA. Ubiquitin showed no effects.
DISCUSSION
Results specify biomarker and atrophy patterns in FTLD and AD supporting differential diagnosis. They identify neurofilaments and progranulin in interaction with structural imaging as promising candidates for monitoring disease progression and therapy.
HIGHLIGHTS
Study cross-validated neuroimaging and fluid biomarkers in dementia. Five kinds of frontotemporal lobar degeneration and two variants of Alzheimer's disease. Study identifies disease-specific fluid biomarker and atrophy profiles. Fluid biomarkers and atrophy interact in a disease-specific way. Neurofilaments and progranulin are proposed as biomarkers for diagnosis and therapy.
PubMed: 38865340
DOI: 10.1002/alz.13863 -
Zhonghua Yi Xue Za Zhi Jun 2024To prepare interleukin-1β-targeted nanoantibodies and observe their effects on apoptosis in hypoxic cardiomyocyte of mice. Using DNA recombination technology, the...
To prepare interleukin-1β-targeted nanoantibodies and observe their effects on apoptosis in hypoxic cardiomyocyte of mice. Using DNA recombination technology, the pET-16b and pHEN1 expression vectors were used to construct the prokaryotic expression plasmids of interleukin-1β-targeted nanobodies (pET-16b-4G6M-VHH, pET-16b-5BVP-VHH, pET-16b-5MVZ-VHH, pHEN1-4G6M-VHH, pHEN1-5BVP-VHH and pHEN1-5MVZ-VHH, where VHH is a variable domain of heavy chain antibody, 4G6M-VHH, 5BVP-VHH, 5MVZ-VHH were three interleukin-1β-targeted nanoantibodies respectively). The constructed plasmids were transferred into Rosetta2 (DE3) for induction of expression and nickel column purification, respectively. The sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting were employed to identify the expression product and purified product, and the enzyme-linked immune sorbent assay (ELISA) was performed to determine their affinity. The cardiomyocyte hypoxia model was used with the highest affinity IL-1β-targeted nanobody (pHEN1-5MVZ-VHH), and cell survival and apoptosis rates were detected (the experiment was divided into normal control group, hypoxia model group, blank plasmid group and 12.5, 25.0, 50.0 μg/ml pHEN1-5MVZ-VHH treatment groups). SDS-PAGE and Western blotting results showed that the anti-interleukin-1β (IL-1β) nanobodies with a relative molecular mass of about 15 000 were successfully obtained. Likewise, ELISA results found that the nanobodies expressed in pHEN1 vector group had higher affinity for IL-1β antigen compared with pET-16b vector group (4G6M-VHH group: 3.20±0.03 vs 1.20±0.03, <0.001; 5BVP-VHH group: 3.18±0.06 vs 1.21±0.02, <0.001; 5MVZ-VHH group: 3.38±0.05 vs 1.62±0.04, <0.001). Additionally, the results of cell survival assay and apoptosis assay detected that compared with the hypoxia model group, HL-1 cell activity was significantly increased in the 25.0 μg/ml and 50.0 μg/ml pHEN1-5MVZ-VHH treatment groups [(75.55±2.23)% vs (46.90±2.51)%, <0.001; (74.36±1.96)% vs (46.90±2.51)%, <0.001], and apoptosis rate was significantly reduced [(6.83±0.27)% vs (10.24±0.76)%, <0.001; (6.68±0.38)% vs (10.24±0.76)%, <0.001]. 4G6M-VHH, 5BVP-VHH, and 5MVZ-VHH are expressed by both pET-16b and pHEN1 expression vectors and the nanobodies produced by the pHEN1 vector display enhanced antigen affinity. Furthermore, in hypoxic cardiomyocytes, pHEN1-5MVZ-VHH treatment reduces cell apoptosis.
Topics: Animals; Interleukin-1beta; Mice; Apoptosis; Myocytes, Cardiac; Single-Domain Antibodies; Plasmids; Escherichia coli; Hypoxia
PubMed: 38858217
DOI: 10.3760/cma.j.cn112137-20231223-01469 -
One Health (Amsterdam, Netherlands) Jun 2024In recent years, aerosols have been recognized as a prominent medium for the transmission of antibiotic-resistant bacteria and genes. Among these, particles with a...
In recent years, aerosols have been recognized as a prominent medium for the transmission of antibiotic-resistant bacteria and genes. Among these, particles with a particle size of 2 μm (PM) can directly penetrate the alveoli. However, the presence of antibiotic-resistant genes in aerosols from pet hospitals and the potential risks posed by antibiotic-resistant bacteria in these aerosols to humans and animals need to be investigated. In this study, cefotaxime-resistant bacteria were collected from 5 representative pet hospitals in Changchun using a Six-Stage Andersen Cascade Impactor. The distribution of bacteria in each stage was analyzed, and bacteria from stage 5 and 6 were isolated and identified. Minimal inhibitory concentrations of isolates against 12 antimicrobials were determined using broth microdilution method. Quantitative Polymerase Chain Reaction was employed to detect resistance genes and mobile genetic elements that could facilitate resistance spread. The results indicated that ARBs were enriched in stage 5 (1.1-2.1 μm) and stage 3 (3.3-4.7 μm) of the sampler. A total of 159 isolates were collected from stage 5 and 6. Among these isolates, the genera spp. (51%), spp. (19%), and spp. (14%) were the most prevalent. The isolates exhibited the highest resistance to tetracycline and the lowest resistance to cefquinome. Furthermore, 56 (73%) isolates were multidrug-resistant. Quantitative PCR revealed the expression of 165 genes in these isolates, with mobile genetic elements showing the highest expression levels. In conclusion, PM from pet hospitals harbor a significant number of antibiotic-resistant bacteria and carry mobile genetic elements, posing a potential risk for alveolar infections and the dissemination of antibiotic resistance genes.
PubMed: 38855194
DOI: 10.1016/j.onehlt.2024.100765 -
Molecular Cancer Jun 2024Intestinal metaplasia (IM) is classified into complete intestinal metaplasia (CIM) and incomplete intestinal metaplasia (IIM). Patients diagnosed with IIM face an...
BACKGROUND
Intestinal metaplasia (IM) is classified into complete intestinal metaplasia (CIM) and incomplete intestinal metaplasia (IIM). Patients diagnosed with IIM face an elevated susceptibility to the development of gastric cancer, underscoring the critical need for early screening measures. In addition to the complexities associated with diagnosis, the exact mechanisms driving the progression of gastric cancer in IIM patients remain poorly understood. OLFM4 is overexpressed in several types of tumors, including colorectal, gastric, pancreatic, and ovarian cancers, and its expression has been associated with tumor progression.
METHODS
In this study, we used pathological sections from two clinical centers, biopsies of IM tissues, precancerous lesions of gastric cancer (PLGC) cell models, animal models, and organoids to explore the role of OLFM4 in IIM.
RESULTS
Our results show that OLFM4 expression is highly increased in IIM, with superior diagnostic accuracy of IIM when compared to CDX2 and MUC2. OLFM4, along with MYH9, was overexpressed in IM organoids and PLGC animal models. Furthermore, OLFM4, in combination with Myosin heavy chain 9 (MYH9), accelerated the ubiquitination of GSK3β and resulted in increased β-catenin levels through the Wnt signaling pathway, promoting the proliferation and invasion abilities of PLGC cells.
CONCLUSIONS
OLFM4 represents a novel biomarker for IIM and could be utilized as an important auxiliary means to delimit the key population for early gastric cancer screening. Finally, our study identifies cell signaling pathways involved in the progression of IM.
Topics: Humans; Metaplasia; Glycogen Synthase Kinase 3 beta; Animals; beta Catenin; Mice; Myosin Heavy Chains; Disease Progression; Stomach Neoplasms; Female; Wnt Signaling Pathway; Cell Proliferation; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Disease Models, Animal; Male; Organoids
PubMed: 38849840
DOI: 10.1186/s12943-024-02016-9 -
Mikrochimica Acta Jun 2024CRISPR/Cas system has been widely applied in the assay of disease-related nucleic acids. However, it is still challenging to use CRISPR/Cas system to detect multiple...
CRISPR/Cas system has been widely applied in the assay of disease-related nucleic acids. However, it is still challenging to use CRISPR/Cas system to detect multiple nucleic acids at the same time. Herein, we combined the preponderance of DNA logic circuit, label-free, and CRISPR/Cas technology to construct a label-free "AND" logical gate for multiple microRNAs detection with high specificity and sensitivity. With the simultaneous input of miRNA-155 and miRNA-141, the logic gate starts, and the activation chain of Cas12a is destroyed; thus, the activity is inhibited and the fluorescence of the signal probe ssDNA-AgNCs is turned on. The detection limit of this method for simultaneous quantitative detection of double target is 84 fmol/L (S/N = 3). In this "AND" logic gate, it is only necessary for the design of a simple DNA hairpin probe, which is inexpensive and easy, and since this method involves only one signal output, the data processing is very simple. What is more important, in this strategy two types of microRNAs can be monitored simultaneously by only using CRISPR/Cas12a and a type of crRNA, which offers a new design concept for the exploitation of single CRISPR/Cas system for multiple nucleic acid assays.
Topics: MicroRNAs; CRISPR-Cas Systems; Humans; Limit of Detection; CRISPR-Associated Proteins; Endodeoxyribonucleases; Metal Nanoparticles; Biosensing Techniques; DNA, Single-Stranded; Bacterial Proteins; DNA
PubMed: 38849560
DOI: 10.1007/s00604-024-06452-8 -
Brain : a Journal of Neurology Jun 2024Intracellular trafficking involves an intricate machinery of motor complexes including the dynein complex to shuttle cargo for autophagolysosomal degradation. Deficiency...
Intracellular trafficking involves an intricate machinery of motor complexes including the dynein complex to shuttle cargo for autophagolysosomal degradation. Deficiency in dynein axonemal chains as well as cytoplasmic light and intermediate chains have been linked with ciliary dyskinesia and skeletal dysplasia. The cytoplasmic dynein 1 heavy chain protein (DYNC1H1) serves as a core complex for retrograde trafficking in neuronal axons. Dominant pathogenic variants in DYNC1H1 have been previously implicated in peripheral neuromuscular disorders (NMD) and neurodevelopmental disorders (NDD). As heavy-chain dynein is ubiquitously expressed, the apparent selectivity of heavy-chain dyneinopathy for motor neuronal phenotypes remains currently unaccounted for. Here, we aimed to evaluate the full DYNC1H1-related clinical, molecular and imaging spectrum, including multisystem features and novel phenotypes presenting throughout life. We identified 47 cases from 43 families with pathogenic heterozygous variants in DYNC1H1 (aged 0-59 years) and collected phenotypic data via a comprehensive standardized survey and clinical follow-up appointments. Most patients presented with divergent and previously unrecognized neurological and multisystem features, leading to significant delays in genetic testing and establishing the correct diagnosis. Neurological phenotypes include novel autonomic features, previously rarely described behavioral disorders, movement disorders, and periventricular lesions. Sensory neuropathy was identified in nine patients (median age of onset 10.6 years), of which five were only diagnosed after the second decade of life, and three had a progressive age-dependent sensory neuropathy. Novel multisystem features included primary immunodeficiency, bilateral sensorineural hearing loss, organ anomalies, and skeletal manifestations, resembling the phenotypic spectrum of other dyneinopathies. We also identified an age-dependent biphasic disease course with developmental regression in the first decade and, following a period of stability, neurodegenerative progression after the second decade of life. Of note, we observed several cases in whom neurodegeneration appeared to be prompted by intercurrent systemic infections with double-stranded DNA viruses (Herpesviridae) or single-stranded RNA viruses (Ross-River fever, SARS-CoV-2). Moreover, the disease course appeared to be exacerbated by viral infections regardless of age and/or severity of NDD manifestations, indicating a role of dynein in anti-viral immunity and neuronal health. In summary, our findings expand the clinical, imaging, and molecular spectrum of pathogenic DYNC1H1 variants beyond motor neuropathy disorders and suggest a life-long continuum and age-related progression due to deficient intracellular trafficking. This study will facilitate early diagnosis and improve counselling and health surveillance of affected patients.
PubMed: 38848546
DOI: 10.1093/brain/awae183 -
MethodsX Jun 2024We present a lightweight tool for clonotyping and measurable residual disease (MRD) assessment in monoclonal lymphoproliferative disorders. It is a translational method...
SWIGH-SCORE: A translational light-weight approach in computational detection of rearranged immunoglobulin heavy chain to be used in monoclonal lymphoproliferative disorders.
We present a lightweight tool for clonotyping and measurable residual disease (MRD) assessment in monoclonal lymphoproliferative disorders. It is a translational method that enables computational detection of rearranged immunoglobulin heavy chain gene sequences.•The clonotyping tool emphasizes parallelization and applicability across sequencing platforms.•The algorithm is based on an adaptation of the Smith-Waterman algorithm for local alignment of reads generated by 2nd and 3rd generation of sequencers.For method validation, we demonstrate the targeted sequences of immunoglobulin heavy chain genes from diagnostic bone marrow using serial dilutions of CD138+ plasma cells from a patient with multiple myeloma. Sequencing libraries from diagnostic samples were prepared for the three sequencing platforms, Ion S5 (Thermo Fisher Scientific), MiSeq (Illumina), and MinION (Oxford Nanopore), using the LymphoTrack assay. Basic quality filtering was performed, and a Smith-Waterman-based algorithm was developed in shell and C for clonotyping and MRD assessment using FASTQ data files. Performance is demonstrated across the three different sequencing platforms.
PubMed: 38846434
DOI: 10.1016/j.mex.2024.102741