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The 2019 COVID-19 pandemic outbreak has caused a global public health emergency. In addition to preventing the spread of the disease, restrictions such as school closures may reduce children and adolescents' opportunities for physical activity and increase the prevalence of sedentary behaviour. However, the current evidence regarding the effects of COVID-19 on physical activity and sedentary behaviour in children and adolescents is insufficiently clear. A total of five databases were searched. In addition, grey literature, reference list and registries were also checked. A total of 26 studies were included in the systematic review. Total physical activity, moderate to vigorous physical activity, sedentary and ST were analysed separately using random effects models. Additionally, this study also used meta-analysis to investigate the differences between boys and girls, objective measures and subjective measures, cross-sectional studies and longitudinal studies. Results: The results of the meta-analysis showed that children and adolescents had a significant decrease in total physical activity (SMD= -0.76, 95% CI= -1.46 to -0.06, I2= 99.5%), moderate to vigorous physical activity (SMD= -0.36, 95% CI= -0.6 to -0.11, I2= 94.7%), sedentary behaviour (SMD= 1.44, 95% CI= 0.31 to 2.56, I2= 98.6%), and a significant increase in screen time (SMD= 0.75, 95% CI= 0.49 to 1.02, I2= 97.3%). Meta-analysis results showed a significant decline in moderate to vigorous physical activity in boys, but no change was found in girls. However, results from the systematic review suggested that girls are more likely to develop more screen time than boys. Children and adolescents' physical activity and sedentary behaviour are negatively impacted by restrictions associated with Covid-19. In addition, girls' screen time is more likely to increase than boys'.

This study utilizes grounded theory methodology to conduct an in-depth analysis based on interviews with 24 sports master's students, aiming to explore the enhancement pathways for academic capabilities in this demographic within China. The findings highlight several key factors affecting these capabilities: individual factors, mentorship, and environmental conditions. Specifically, graduate funding and living conditions directly impact the academic capabilities of sports master's students, whereas the extent of institutional focus and the level of school support along with geographical factors have a latent effect. Additionally, the role of mentors is found to modulate and enhance these environmental conditions. Proposed developmental pathways include: 1) Stimulating internal drivers by emphasizing the integration of extensive and intensive literature reviews to strengthen and implement theoretical research foundations; 2) Boosting external drivers through enhancing mentor-student interactions to foster positive relational development; 3) Building supportive environmental conditions by actively coordinating life and research funding aspects to fully enhance academic capabilities.

Information processing systems in sports and training applications are backboned by artificial intelligence for non-human intervening and accurate analysis. The fitness, performance, etc. outcomes are delivered by the system through learning implications over the different inputs. However, the recommendation/ prediction outcomes are down-surged in analyzing similar information due to learning complexity and non-adaptable outcome. Therefore, the problem is resolved by fragmenting and processing the information using a similarity measure. Therefore, this method is named as Sliced-Information Processing with Analogous Learning (SIP-AL). In this method, a neural network is used for deciding the processing feature for better accuracy. In the contrary case of down-surges, the information slicing based on an analogous point is performed. This prevents the continuity between redundant and continuous data preventing errors.

Abstract Neutrophil extracellular traps (NETs) have garnered attention for their dual role in host defense and tumor promotion. With their involvement documented across a spectrum of tumors, their influence on the progression of cholangiocarcinoma (CCA) is of paramount interest. We employed immunohistochemistry and immunofluorescence to detect NET deposition in CCA tissues. Through in vitro and in vivo investigation, including CCA organoid and transposon-based models in PAD4 KO mice, we explored the effects of NETs on cell proliferation and metastasis. Molecular insights were gained through RNA sequencing, enzyme linked immunosorbent assay, and chromatin immunoprecipitation. Elevated intratumoral NET deposition within CCA tissues was associated with poor survival. The influence of NETs on CCA proliferation, migration and invasion was primarily mediated by NET-DNA. RNA sequencing unveiled the activation of the NFκB signaling pathway due to NET-DNA stimulation. NET-DNA pull-down assay coupled with mass spectrometry revealed the interaction between NET-DNA and αV integrin (ITGAV), culmination in the activation of the NFκB pathway. Furthermore, NET-DNA directly upregulated the expression of VEGF-A in cancer cells. The study unequivocally establishes NETs as facilitators of CCA progression, orchestrating proliferation, metastasis, and angiogenesis through ITGAV/NFκB pathway activation. This novel insight positions NETs as prospective therapeutic targets for managing CCA patients. By implementing a variety of methodologies and drawing intricate connections between NETs, DNA interactions, and signaling pathways, this research expands our comprehension of the complex interplay between the immune system and cancer progression, offering promising avenues for intervention.

A single crystal of potassium tantalum niobate was chosen to deposit high quality diamond thin films by microwave plasma chemical vapor deposition (MPCVD) techniques. The surface morphologies and microstructures of the as-deposited diamond films were characterized by XRD, SEM, and Raman spectroscopy. The photocatalytic properties of the samples were studied. A TaC transition layer was identified during the deposition of diamond. Additionally, it was observed that as the deposition time prolonged, the quality of the diamond film improved. All film samples showed good ability to degrade Rhodamine B, with the degradation rate of the film deposited for 12 h being 0.29 times higher, corresponding to a 1.6 times greater degrading speed of Rhodamine B compared to the film deposited for 3 h. This research introduces a novel substrate for depositing polycrystalline diamond and explores its application in photocatalysis.

BackgroundThe converter stations of high-voltage direct current (HVDC) transmission lines generate special total electric fields. At present, few investigations have been conducted on total electric fields in the workplace of converter stations from an perspective of occupational health. ObjectiveTo understand the current situation of total electric field strength in the workplace of converter stations. MethodsUsing purposive sampling, a calibrated HDEM-1 direct current (DC) total electric field strength measurement system was used to measure the total electric fields of 12 converter stations serving 6 DC lines in Southeast and Southwest China according to the Measurement method for total electric field strength and ion current density of the converter stations and DC transmission lines (DL/T 1089—2008). The results were evaluated according to occupational exposure limits recommended by The limits of electromagnetic environment at ±800 kV UHV DC converter station (DL/T 275—2012), the American Conference of Governmental Industrial Hygienists (ACGIH), and the International Commission on Non-Ionizing Radiation Protection (ICNIRP). ResultsA total of 615 check points were planned, the total electric field strength was 0.05-37.05 kV·m−1, and the median was 10.45 kV·m−1. The total electric field strength of 39 check points (6.3%) exceeded 25 kV·m−1 (the limits of ACGIH and ICNIRP), and the total electric field strength of 12 check points (2.0%) exceeded 30 kV·m−1 (the limit of DL/T 275—2012). There were statistically significant differences in the total electric field strength values and the proportions of exceeding 25 kV·m−1 between the neutral regions and the positive regions and between the neutral regions and the negative regions (P < 0.01). The proportion of total electric field strength exceeding 30 kV·m−1 in the negative regions was higher than that in the positive regions (P < 0.01). There were no significant differences in the total electric field strength of converter stations at different voltage levels and different altitudes (P > 0.05). There were no significant differences in the proportions of total electric field exceeding 25 kV·m−1 and exceeding 30 kV·m−1 in converter stations at different voltage levels and different altitudes (P > 0.05). ConclusionThe total electric field in some workplace of converter stations exceeds selected limits. Converter station operators may be exposed to high-strength total electric field for a short time.

Objective: The aim of this study was to investigate the relationship between exercise and gut Microbiome and to assess its possible causality.Methods: Using Mendelian randomization (MR) research methods, we collected genetic data from different populations, including genetic variants associated with relative abundance or presence of microbial taxa as instrumental variables. At the same time, we extracted results related to obesity and gut Microbiome from existing relevant studies and used inverse variance weighting (IVW), weighted median, and MR-Egger regression to assess the causal relationship between obesity and gut Microbiome. We plotted forest plots and scatter plots of the association between obesity and gut Microbiome.Results: Gut Microbiome was positively associated with obesity, and four bacterial genera (Akkermansia, RuminococcaceaeUCG011, Holdemania, and Intestinimonas) were associated with obesity according to inverse variance-weighted estimation in at least one MR method. Inverse variance weighted estimation showed that obesity was associated with obesity in Akkermansia (OR = 0.810, 95% CI 0.608–1.079, p = 0.04), RuminococcaceaeUCG011 (OR = 1.238, 95% CI 0. 511–2.999, p = 0.04), Holdemania Intestinimonas (OR = 1.214, 95% CI 1.002–1.470, p = 0.03), and Intestinimonas (OR = 0.747, 95% CI 0.514–1.086, p = 0.01) had a relevant effect. Obesity decreased the abundance of Akkermansia, Intestinimonas microbiome and increased the abundance of RuminococcaceaeUCG011, Holdemania microbiome.Conclusion: The results of this study, conducted using a two-sample Mendelian randomization method, suggest a causal relationship between obesity and intestinal microbiome. Obesity decreased the abundance of Akkermansia, Intestinimonas microbiome and increased the abundance of RuminococcaceaeUCG011, Holdemania microbiome. More randomized controlled trials are necessary to elucidate the protective effects of exercise on gut Microbiome and its unique protective mechanisms.

AbstractHepatocellular carcinoma (HCC) is a malignant tumor leading cancer-associated high mortality worldwide. Unfortunately, the most commonly used drug therapeutics not only lack of target ability and efficiency, but also exhibit severe systemic toxicity to normal tissues. Thus, effective and targeted nanodrug of HCC therapy is emerging as a more important issue. Here, we design and develop the novel nanomicelles, namely Mannose-polyethylene glycol 600-Nitroimidazole (Man-NIT). This micelle compound with high purity comprise two parts, which can self-assemble into nanoscale micelle. The outer shell is selected mannose as hydrophilic moiety, while the inner core is nitroimidazole as hydrophobic moiety. In the cell experiment, Man-NIT was more cellular uptake by HCCLM3 cells due to the mannose modification. Mannose as a kind of glucose transporter 1 (GLUT1) substrate, can specifically recognize and bind to over-expressed GLUT1 on carcinoma cytomembrane. The nitroimidazole moiety of Man-NIT was reduced by the over-expressed nitroreductase with reduced nicotinamide adenine dinucleotide phosphate (NADPH) as the cofactor, resulting in transient deletion of NADPH and glutathione (GSH). The increase of reactive oxygen species (ROS) in HCCLM3 cells disturbed the balance of redox, and finally caused the death of tumor cells. Additional in vivo experiment was conducted using twenty-four male BALB/c nude mice to build the tumor model. The results showed that nanomicelles were accumulated in the liver of mice. The tumor size and pathological features were obviously improved after nanomicelles treatment. It indicates that namomicelles have a tumor inhibition effect, especially Man-NIT, which may be a potential nanodrug of chemotherapeutics for HCC therapy.

Semiconductor devices generally take advantage of the charge of electrons, whereas magnetic materials are used for recording information involving electron spin. To make use of both charge and spin of electrons in semiconductors, a high concentration of magnetic elements can be introduced in nonmagnetic III-V semiconductors to make magnetic semiconductor. In this work, Fe-Diamond was obtained with low solubility by modified microwave plasma chemical vapor deposition technique. Magnetic measurements revealed that the magnetic transition temperature from paramagnetic to ferromagnetic-like is above room temperature. The bandgap of Fe-Diamond is calculated to be 1.65 eV, which indicates that Fe-Diamond is a room temperature diluted ferromagnetic semiconductor.

IntroductionPituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides.MethodsFollowing the identification of a loss-of-function variant (p.Arg703Gln) in the peptidylglycine a-amidating monooxygenase (PAM) gene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated PA kindreds for PAM variants. Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis.ResultsIn germline DNA, we detected seven heterozygous, likely pathogenic missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with growth hormone excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally tested in vitro for protein expression and trafficking by Western blotting, splicing by minigene assays, and amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of the PAM gene and rare PAM SNVs with diagnoses linked to pituitary gland hyperfunction.ConclusionThe identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.

Human alveolar and tracheobronchial epithelial air liquid interface (ALI) tissues are used as models to examine cellular responses to SARS-CoV-2 and influenza A virus infections and as antiviral drug screening assay platforms.

In addition to being associated with allergic diseases, parasites, bacteria, and venoms, a growing body of research indicates that mast cells and their mediators can regulate liver disease progression. When mast cells are activated, they degranulate and release many mediators, such as histamine, tryptase, chymase, transforming growth factor-β1 (TGF-β1), tumor necrosis factor–α(TNF-α), interleukins cytokines, and other substances that mediate the progression of liver disease. This article reviews the role of mast cells and their secretory mediators in developing hepatitis, cirrhosis and hepatocellular carcinoma (HCC) and their essential role in immunotherapy. Targeting MC infiltration may be a novel therapeutic option for improving liver disease progression.

Drug delivery system (DDS) realizes the drug delivery process through the drug carrier. As an important part of DDS, the selection of the drug carrier material is extremely critical, which requires the carrier material to possess excellent biocompatibility and targeting and not affect the pharmacological action of the drug. As one of the endogenous extracellular vesicles, exosomes are 30–100 nm in diameter, which are considered a new generation of a natural nanoscale delivery system. Exosomes secreted by different types of cells carry signaling molecules (such as proteins and nucleic acid) playing an important role in cell behaviors. Owing to their ability to specialize in intercellular communication, exosomes provide a distinctive method to deliver therapeutic drugs to target cells. In this concept, exosomes as the natural liposomes carry endogenous biomolecules, have excellent biocompatibility, and could be loaded with cargo both in vivo and in vitro. In addition, modifications by genetic and/or chemical engineering to part of the exosome surface or complement the desired natural effect may enhance the targeting with drug loading capability. Notably, exosomes weakly react with serum proteins prolonging cargo half-life. Overall, exosomes as natural carriers integrate the superiority of synthetic nanocarriers and cellular communication while precluding their limitations, which provides novel and reliable methods for drug delivery and treatment. Our review focuses on the therapeutic potentials and clinical values of exosomes as a carrier of drug delivery system in multiple diseases, including cancer, nervous, immune, and skeletal system diseases.

IntroductionAdrenocortical hyperplasia and adrenal rest tumor (ART) formation are common in congenital adrenal hyperplasia (CAH). Although driven by excessive corticotropin, much is unknown regarding the morphology and transformation of these tissues. Our study objective was to characterize CAH-affected adrenals and ART and compare with control adrenal and gonadal tissues.Patients/MethodsCAH adrenals, ART and control tissues were analyzed by histology, immunohistochemistry, and transcriptome sequencing. We investigated protein expression of the ACTH receptor (MC2R), steroidogenic (CYP11B2, CYP11B1, CYB5A) and immune (CD20, CD3, CD68) biomarkers, and delta-like 1 homolog (DLK1), a membrane bound protein broadly expressed in fetal and many endocrine cells. RNA was isolated and gene expression was analyzed by RNA sequencing (RNA-seq) followed by principle component, and unsupervised clustering analyses.ResultsBased on immunohistochemistry, CAH adrenals and ART demonstrated increased zona reticularis (ZR)-like CYB5A expression, compared to CYP11B1, and CYP11B2, markers of zona fasciculata and zona glomerulosa respectively. CYP11B2 was mostly absent in CAH adrenals and absent in ART. DLK1 was present in CAH adrenal, ART, and also control adrenal and testis, but was absent in control ovary. Increased expression of adrenocortical marker MC2R, was observed in CAH adrenals compared to control adrenal. Unlike control tissues, significant nodular lymphocytic infiltration was observed in CAH adrenals and ART, with CD20 (B-cell), CD3 (T-cell) and CD68 (macrophage/monocyte) markers of inflammation. RNA-seq data revealed co-expression of adrenal MC2R, and testis-specific INSL3, HSD17B3 in testicular ART indicating the presence of both gonadal and adrenal features, and high expression of DLK1 in ART, CAH adrenals and control adrenal. Principal component analysis indicated that the ART transcriptome was more similar to CAH adrenals and least similar to control testis tissue.ConclusionsCAH-affected adrenal glands and ART have similar expression profiles and morphology, demonstrating increased CYB5A with ZR characteristics and lymphocytic infiltration, suggesting a common origin that is similarly affected by the abnormal hormonal milieu. Immune system modulators may play a role in tumor formation of CAH.

Abstract Scolytinae (bark beetle) is one of the most detrimental pests on the Chongming Island. It is desirable to understand the behaviour of the Scolytinae throughout its life cycle. Behaviour studies regarding mass attacks, mating behaviour and chemical control have been frequently reported in literature. However, little research could be found regarding the life of Scolytinae in the larval stage, especially for beetles in the field. In this paper, we analyse the tunnel map beneath the tree bark, since it is a potential source of information on the population size, egg gallery and larval development. We propose four hypotheses including synchronous larval growth (SLG), outward normal direction (OND), communication and repulsion (CR) and individual differences(ID), then employ the methods of curve fitting and differential equation modelling to mathematically reconstruct the tunnel map. Furthermore, we introduce the Frechet distance to measure the similarity of curves. Numerical simulation shows that the reconstructed tunnel map closely matches the collected sample.

La-related protein 4 (LARP4) directly binds both poly(A) and poly(A)-binding protein (PABP). LARP4 was shown to promote poly(A) tail (PAT) lengthening and stabilization of individual mRNAs presumably by protection from deadenylation (Mattijssen et al., 2017). We developed a nucleotide resolution transcriptome-wide, single molecule SM-PAT-seq method. This revealed LARP4 effects on a wide range of PAT lengths for human mRNAs and mouse mRNAs from LARP4 knockout (KO) and control cells. LARP4 effects are clear on long PAT mRNAs but become more prominent at 30–75 nucleotides. We also analyzed time courses of PAT decay transcriptome-wide and for ~200 immune response mRNAs. This demonstrated accelerated deadenylation in KO cells on PATs < 75 nucleotides and phasing consistent with greater PABP dissociation in the absence of LARP4. Thus, LARP4 shapes PAT profiles throughout mRNA lifespan with impact on mRNA decay at short lengths known to sensitize PABP dissociation in response to deadenylation machinery.

The understanding on the response of aluminum alloy to direct lightning currents is needed for lightning protection. Four typical lightning current components, which are the first return stroke current, subsequent return stroke current, continuing current in the stroke intervals, and long continuing current, are simulated to investigate their damage effects on Al alloy 3003 material by laboratory experiments. The damage morphology on alloy's surface and the microstructure in cross section are observed with high-resolution scanning electron microscope. Elemental composition changes of alloy material are measured by an X-ray energy dispersive spectrometer. Indentation hardness tests are conducted to measure the changes in alloy's micro-hardness. Then, the damage characteristics and mechanisms of the alloy are analyzed by comparing the experimental results under different current parameters of lightning components. The results show that, in response to the first return stroke current component, a thin oxide layer and cracks are formed on the alloy's surface. The cracks are initiated by the broken of the oxide layer. Under the continuing current component in the stroke intervals, the dendritic crystals appear and grow in the direction of temperature decrease inside the material. In response to the long continuing current component, uneven solidification induced cracks are formed. The over-burn phenomenon also occurs and lots of hydrogen evolution porosities appear. As a response to the subsequent return stroke current, the damage pattern on alloy's surface is dominated by pits, and the thickness of the damaged layer is typically 15 μm.

Understanding the physiology and pathology of an organ composed of a variety of cell populations depends critically on genome-wide information on each cell type. Here, we report single-cell transcriptome profiling of over 6,800 freshly dispersed anterior pituitary cells from postpubertal male and female rats. Six pituitary-specific cell types were identified based on known marker genes and characterized: folliculostellate cells and hormone-producing corticotrophs, gonadotrophs, thyrotrophs, somatotrophs, and lactotrophs. Also identified were endothelial and blood cells from the pituitary capillary network. The expression of numerous developmental and neuroendocrine marker genes in both folliculostellate and hormone-producing cells supports that they have a common origin. For several genes, the validity of transcriptome analysis was confirmed by qRT-PCR and single cell immunocytochemistry. Folliculostellate cells exhibit impressive transcriptome diversity, indicating their major roles in production of endogenous ligands and detoxification enzymes, and organization of extracellular matrix. Transcriptome profiles of hormone-producing cells also indicate contributions toward those functions, while also clearly demonstrating their endocrine function. This survey highlights many novel genetic markers contributing to pituitary cell type identity, sexual dimorphism, and function, and points to relationships between hormone-producing and folliculostellate cells.

We report the 5.1 Mb noncontiguous draft genome of Afipia septicemium strain OHSU_II, isolated from blood of a female patient. The genome consists of 5,087,893 bp circular chromosome with no identifiable autonomous plasmid with a G + C content of 61.09% and contains 4898 protein-coding genes and 49 RNA genes including 3 rRNA genes and 46 tRNA genes.

To study the basic law of negative corona discharge in solid particle-air two-phase flow, corona discharge experiments in a needle-plate electrode system at different voltage levels and different wind speed were carried out in the wind tunnel. In this paper, the change law of average current and current waveform were analyzed, and the observed phenomena were systematically explained from the perspectives of airflow, particle charging, and particle motion with the help of PIV (particle image velocity) measurements and ultraviolet observations.

The efficiency of hybrid seed production can be improved by increasing the percentage of exserted stigma, which is closely related to the stigma length in rice. In the chromosome segment substitute line (CSSL) population derived from Nipponbare (recipient) and Kasalath (donor), a single CSSL (SSSL14) was found to show a longer stigma length than that of Nipponbare. The difference in stigma length between Nipponbare and SSSL14 was controlled by one locus (qSTL3). Using 7,917 individuals from the SSSL14/Nipponbare F2 population, the qSTL3 locus was delimited to a 19.8-kb region in the middle of the short arm of chromosome 3. Within the 19.8-kb chromosome region, three annotated genes (LOC_Os03g14850, LOC_Os03g14860 and LOC_Os03g14880) were found in the rice genome annotation database. According to gene sequence alignments in LOC_Os03g14850, a transition of G (Nipponbare) to A (Kasalath) was detected at the 474-bp site in CDS. The transition created a stop codon, leading to a deletion of 28 amino acids in the deduced peptide sequence in Kasalath. A T-DNA insertion mutant (05Z11CN28) of LOC_Os03g14850 showed a longer stigma length than that of wild type (Zhonghua 11), validating that LOC_Os03g14850 is the gene controlling stigma length. However, the Kasalath allele of LOC_Os03g14850 is unique because all of the alleles were the same as that of Nipponbare at the 474-bp site in the CDS of LOC_Os03g14850 among the investigated accessions with different stigma lengths. A gene-specific InDel marker LQ30 was developed for improving stigma length during rice hybrid breeding by marker-assisted selection.

Cultures previously set up for isolation of mycoplasmal agents from blood of patients with poorly-defined illnesses, although not yielding positive results, were cryopreserved because of suspicion of having low numbers of unknown microbes living in an inactive state in the broth. We re-initiated a set of 3 cultures for analysis of the "uncultivable" or poorly-grown microbes using NGS technology. Broth of cultures from 3 blood samples, submitted from OHSU between 2000 and 2004, were inoculated into culture flasks containing fresh modified SP4 medium and kept at room temperature (RT), 30°C and 35°C. The cultures showing evidence of microbial growth were expanded and subjected to DNA analysis by genomic sequencing using Illumina MiSeq. Two of the 3 re-initiated blood cultures kept at RT after 7-8 weeks showed evidence of microbial growth that gradually reached into a cell density with detectable turbidity. The microbes in the broth when streaked on SP4 agar plates produced microscopic colonies in ∼ 2 weeks. Genomic studies revealed that the microbes isolated from the 2 blood cultures were a novel Afipia species, tentatively named Afipia septicemium. Microbes in the 3(rd) culture (OHSU_III) kept at RT had a limited level of growth and could not reach a plateau with high cell density. Genomic sequencing identified the microbe in the culture as a previously unknown species of Bradyrhizobium bacteria. This study reports on the isolation of novel Afipia and Bradyrhizobium species. Isolation of Bradyrhizobium species bacteria has never been reported in humans. The study also reveals a previously unrecognized nature of hematogenous infections by the 2 unique groups of Bradyrhizobiaceae. Our studies show that improvement of culture system plus effective use of NGS technology can facilitate findings of infections by unusual microbes in patients having poorly-defined, sometimes mysterious illnesses.

We recently isolated and discovered new Bradyrhizobiaceae microbes from the cryopreserved culture broth of blood samples from 3 patients with poorly defined illnesses using modified SP4 media and culture conditions coupled with genomic sequencing. Using a similar protocol, we studied a previously cryopreserved culture broth of blood sample from a patient who had succumbed to an acute onset of fulminant pulmonary illness. We report that two phases of microbial growth were observed in the re-initiated culture. Biochemical and genomic characterization revealed microbes isolated from the first phase of growth were new Afipia species of Bradyrhizobiaceae, tentatively named A. cberi with a ~ 5 MB chromosome that was different from those of all previously known Afipia microbes including the newly discovered A. septicemium. The microbes isolated from the second phase of growth were prominent sugar assimilators, novel Phyllobacteriaceae, phylogenetically most closely related to Mesorhizobium and tentatively named M. hominis with a ~ 5.5 MB chromosome. All A. cberi isolates carry a circular ~ 140 KB plasmid. Some M. hominis isolates possess a circular ~ 412 KB plasmid that can be lost in prolonged culture or passage. No antibiotics resistant genes could be identified in both of the A. cberi and M. hominis plasmids. Antibiotic susceptibility studies using broth culture systems revealed isolates of A. cberi could be sensitive to some antibiotics, but all isolates of M. hominis were resistant to essentially all tested antibiotics. However, the cell-free antibiotics susceptibility test results may not be applicable to clinical treatment against the microbes that are known to be capable of intracellular growth. It remains to be determined if the 2 previously unknown Rhizobiales were indeed pathogenic and played a role in the pulmonary disease process in this patient. Specific probes and methods will be developed to re-examine the diseased lungs from patient's autopsy.

The orphan nuclear receptor Nur77 is emerging as an attractive target for cancer therapy, and activating Nur77's non-genotypic anticancer function has demonstrated strong therapeutic potential. However, few Nur77 site B ligands have been identified as excellent anticancer compounds. There are no co-crystal structures of effective anticancer agents at Nur77 site B, which greatly limits the development of novel Nur77 site B ligands. Moreover, the lack of pharmaceutical ligands restricts Nur77's therapeutic proof of concept. Herein, we developed a first-in-class Nur77 site B ligand (NB1) that significantly inhibited cancer cells by mediating the Nur77/Bcl-2-related apoptotic effect at mitochondria. The X-ray crystallography suggests that NB1 is bound to the Nur77 site B with a distinct binding mode. Importantly, NB1 showed favorable pharmacokinetic profiles and safety, as evidenced by its good oral bioavailability in rats and lack of mortality, bodyweight loss, and pathological damage at the 512.0 mg/kg dose in mice. Furthermore, oral administration of NB1 demonstrated remarkable in vivo anticancer efficacy in an MDA-MB-231 xenograft model. Together, our work discovers NB1 as a new generation Nur77 ligand that activates the Nur77/Bcl-2 apoptotic pathway with a safe and effective cancer therapeutic potency.

Abstract Background Magnetic Resonance Imaging (MRI) is extensively utilized in clinical diagnostics and medical research, yet the imaging process is often compromised by noise interference. This noise arises from various sources, leading to a reduction in image quality and subsequently hindering the accurate interpretation of image details by clinicians. Traditional denoising methods typically assume that noise follows a Gaussian distribution, thereby neglecting the more complex noise types present in MRI images, such as Rician noise. As a result, denoising remains a challenging and practical task. Method The main research work of this paper focuses on modifying mask information based on a global mask mapper. The mask mapper samples all blind spot pixels on the denoised image and maps them to the same channel. By incorporating perceptual loss, it utilizes all available information to improve performance while avoiding identity mapping. During the denoising process, the model may mistakenly remove some useful information as noise, resulting in a loss of detail in the denoised image. To address this issue, we train a generative adversarial network (GAN) with adaptive hybrid attention to restore the detailed information in the denoised MRI images. Result The two-stage model NRAE shows an improvement of nearly 1.4 dB in PSNR and approximately 0.1 in SSIM on clinical datasets compared to other classic models. Specifically, compared to the baseline model, PSNR is increased by about 0.6 dB, and SSIM is only 0.015 lower. From a visual perspective, NRAE more effectively restores the details in the images, resulting in richer and clearer representation of image details. Conclusion We have developed a deep learning-based two-stage model to address noise issues in medical MRI images. This method not only successfully reduces noise signals but also effectively restores anatomical details. The current results indicate that this is a promising approach. In future work, we plan to replace the current denoising network with more advanced models to further enhance performance.

Introduction: Pituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides.. Methods: Following the identification of a loss-of-function variant (p.Arg703Gln) in the peptidylglycine a-amidating monooxygenase (PAM) gene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated PA kindreds for PAM variants. Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis.. Results: In germline DNA, we detected seven heterozygous, likely pathogenic missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with growth hormone excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally tested in vitro for protein expression and trafficking by Western blotting, splicing by minigene assays, and amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of the PAM gene and rare PAM SNVs with diagnoses linked to pituitary gland hyperfunction. Conclusion: The identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function. [ABSTRACT FROM AUTHOR]