Regeneration of the human segmentation clock in somitoids in vitro.

Each vertebrate species appears to have a unique timing mechanism for forming somites along the vertebral column, and the process in human remains poorly understood at the molecular level due to technical and ethical limitations. Here, we report the reconstitution of human segmentation clock by direct reprogramming. We first reprogrammed human urine epithelial cells to a presomitic mesoderm (PSM) state capable of long-term self-renewal and formation of somitoids with an anterior-to-posterior axis. By inserting the RNA reporter Pepper into HES7 and MESP2 loci of these iPSM cells, we show that both transcripts oscillate in the resulting somitoids at ~5 h/cycle. GFP-tagged endogenous HES7 protein moves along the anterior-to-posterior axis during somitoid formation. The geo-sequencing analysis further confirmed anterior-to-posterior polarity and revealed the localized expression of WNT, BMP, FGF, and RA signaling molecules and HOXA-D family members. Our study demonstrates the direct reconstitution of human segmentation clock from somatic cells, which may allow future dissection of the mechanism and components of such a clock and aid regenerative medicine.

Low temperature inhibits anthocyanin accumulation in strawberry fruit by activating FvMAPK3-induced phosphorylation of FvMYB10 and degradation of Chalcone Synthase 1.

Low temperature causes poor coloration of strawberry (Fragaria sp.) fruits, thus greatly reducing their commercial value. Strawberry fruits accumulate anthocyanins during ripening, but how low temperature modulates anthocyanin accumulation in plants remains largely unknown. We identified MITOGEN-ACTIVATED PROTEIN KINASE3 (FvMAPK3) as an important negative regulator of anthocyanin accumulation that mediates the poor coloration of strawberry fruits in response to low temperature. FvMAPK3 activity was itself induced by low temperature, leading to the repression of anthocyanin accumulation via two mechanisms. Activated FvMAPK3 acted as the downstream target of MAPK KINASE4 (FvMKK4) and SUCROSE NONFERMENTING1-RELATED KINASE2.6 (FvSnRK2.6) to phosphorylate the transcription factor FvMYB10 and reduce its transcriptional activity. In parallel, FvMAPK3 phosphorylated CHALCONE SYNTHASE1 (FvCHS1) to enhance its proteasome-mediated degradation. These results not only provide an important reference to elucidate the molecular mechanisms underlying low-temperature-mediated repression of anthocyanin accumulation in plants, but also offer valuable candidate genes for generating strawberry varieties with high tolerance to low temperature and good fruit quality.

SlJAZ10 and SlJAZ11 mediate dark-induced leaf senescence and regeneration.

During evolutionary adaptation, the mechanisms for self-regulation are established between the normal growth and development of plants and environmental stress. The phytohormone jasmonate (JA) is a key tie of plant defence and development, and JASMONATE-ZIM DOMAIN (JAZ) repressor proteins are key components in JA signalling pathways. Here, we show that JAZ expression was affected by leaf senescence from the transcriptomic data. Further investigation revealed that SlJAZ10 and SlJAZ11 positively regulate leaf senescence and that SlJAZ11 can also promote plant regeneration. Moreover, we reveal that the SlJAV1-SlWRKY51 (JW) complex could suppress JA biosynthesis under normal growth conditions. Immediately after injury, SlJAZ10 and SlJAZ11 can regulate the activity of the JW complex through the effects of electrical signals and Ca2+ waves, which in turn affect JA biosynthesis, causing a difference in the regeneration phenotype between SlJAZ10-OE and SlJAZ11-OE transgenic plants. In addition, SlRbcs-3B could maintain the protein stability of SlJAZ11 to protect it from degradation. Together, SlJAZ10 and SlJAZ11 not only act as repressors of JA signalling to leaf senescence, but also regulate plant regeneration through coordinated electrical signals, Ca2+ waves, hormones and transcriptional regulation. Our study provides critical insights into the mechanisms by which SlJAZ11 can induce regeneration.

Missense mutation of ISL1 (E283D) is associated with the development of type 2 diabetes.

AIMS/HYPOTHESIS: Mutations in Isl1, encoding the insulin enhancer-binding protein islet-1 (ISL1), may contribute to attenuated insulin secretion in type 2 diabetes mellitus. We made an Isl1E283D mouse model to investigate the disease-causing mechanism of diabetes mellitus. METHODS: The ISL1E283D mutation (c. 849A>T) was identified by whole exome sequencing on an early-onset type 2 diabetes family and then the Isl1E283D knockin (KI) mouse model was created and an IPGTT and IPITT were conducted. Glucose-stimulated insulin secretion (GSIS), expression of Ins2 and other ISL1 target genes and interacting proteins were evaluated in isolated pancreas islets. Transcriptional activity of Isl1E283D was evaluated by cell-based luciferase reporter assay and electrophoretic mobility shift assay, and the expression levels of Ins2 driven by Isl1 wild-type (Isl1WT) and Isl1E283D mutation in rat INS-1 cells were determined by RT-PCR and western blotting. RESULTS: Impaired GSIS and elevated glucose level were observed in Isl1E283D KI mice while expression of Ins2 and other ISL1 target genes Mafa, Pdx1, Slc2a2 and the interacting protein NeuroD1 were downregulated in isolated islets. Transcriptional activity of the Isl1E283D mutation for Ins2 was reduced by 59.3%, and resulted in a marked downregulation of Ins2 expression when it was overexpressed in INS-1 cells, while overexpression of Isl1WT led to an upregulation of Ins2 expression. CONCLUSIONS/INTERPRETATION: Isl1E283D mutation reduces insulin expression and secretion by regulating insulin and other target genes, as well as its interacting proteins such as NeuroD1, leading to the development of glucose intolerance in the KI mice, which recapitulated the human diabetic phenotype. This study identified and highlighted the Isl1E283D mutation as a novel causative factor for type 2 diabetes, and suggested that targeting transcription factor ISL1 could offer an innovative avenue for the precise treatment of human type 2 diabetes.

Human papillomavirus-driven head and neck cancers in Japan during 2008-2009 and 2018-2019: The BROADEN study.

There is limited understanding of epidemiology and time trends of human papilloma virus (HPV)-driven head and neck cancers (HNC) in Japan, especially outside of the oropharynx. To assess HPV-driven HNC, a non-interventional study (BROADEN) of HNC patients diagnosed in 2008-2009 and 2018-2019 was conducted in Japan. Adult patients with oropharyngeal, nasopharyngeal, laryngeal, hypopharyngeal or oral cavity cancers were included in this study. HPV was centrally tested using p16INK4a immunohistochemistry, HPV-DNA PCR and HPV E6*I mRNA. HPV attributability required positivity in at least two tests (p16INK4a immunohistochemistry, HPV-DNA PCR, HPV E6*I mRNA) in the oropharynx, and HPV-DNA and HPV E6*I mRNA positivity for non-oropharynx sites. Nineteen hospitals included a total of 1108 patients, of whom 981 had valid samples. Men accounted for 82% of HNC diagnoses. Patients in the earlier cohort were younger and included a higher percentage of smokers. There was an increasing trend of HPV-driven oropharyngeal cancer over the last decade, from 44.2% to 51.7%. HPV attribution in nasopharyngeal cancers was 3.2% in 2008-2009 and 7.5% in 2018-2019; and 4.4% and 0% for larynx respectively. In total, 95.2% of HPV-driven HNC were attributed to HPV genotypes included in the 9-valent HPV vaccine being HPV16 the most prominent genotype. These results suggest that an epidemiologic shift is happening in Japan, with a decrease in smoking and alcohol use and an increase in HPV-driven HNC. The increasing trend of HPV-driven HNC in Japan highlights the need for preventive strategies to mitigate the rise of HPV-driven HNC.

Metabolism of novel potential syntrophic acetate-oxidizing bacteria in thermophilic methanogenic chemostats.

Acetate is a major intermediate in the anaerobic digestion of organic waste to produce CH4. In methanogenic systems, acetate degradation is carried out by either acetoclastic methanogenesis or syntrophic degradation by acetate oxidizers and hydrogenotrophic methanogens. Due to challenges in the isolation of syntrophic acetate-oxidizing bacteria (SAOB), the diversity and metabolism of SAOB and the mechanisms of their interactions with methanogenic partners are not fully characterized. In this study, the in situ activity and metabolic characteristics of potential SAOB and their interactions with methanogens were elucidated through metagenomics and metatranscriptomics. In addition to the reported SAOB classified in the genera Tepidanaerobacter, Desulfotomaculum, and Thermodesulfovibrio, we identified a number of potential SAOB that are affiliated with Clostridia, Thermoanaerobacteraceae, Anaerolineae, and Gemmatimonadetes. The potential SAOB possessing the glycine-mediated acetate oxidation pathway dominates SAOB communities. Moreover, formate appeared to be the main product of the acetate degradation by the most active potential SAOB. We identified the methanogen partner of these potential SAOB in the acetate-fed chemostat as Methanosarcina thermophila. The dominated potential SAOB in each chemostat had similar metabolic characteristics, even though they were in different fatty-acid-fed chemostats. These novel syntrophic lineages are prevalent and may play critical roles in thermophilic methanogenic reactors. This study expands our understanding of the phylogenetic diversity and in situ biological functions of uncultured syntrophic acetate degraders and presents novel insights into how they interact with methanogens.IMPORTANCECombining reactor operation with omics provides insights into novel uncultured syntrophic acetate degraders and how they perform in thermophilic anaerobic digesters. This improves our understanding of syntrophic acetate degradation and contributes to the background knowledge necessary to better control and optimize anaerobic digestion processes.

OsEIN2-OsEIL1/2 pathway negatively regulates chilling tolerance by attenuating OsICE1 function in rice.

Low temperature severely affects rice development and yield. Ethylene signal is essential for plant development and stress response. Here, we reported that the OsEIN2-OsEIL1/2 pathway reduced OsICE1-dependent chilling tolerance in rice. The overexpressing plants of OsEIN2, OsEIL1 and OsEIL2 exhibited severe stress symptoms with excessive reactive oxygen species (ROS) accumulation under chilling, while the mutants (osein2 and oseil1) and OsEIL2-RNA interference plants (OsEIL2-Ri) showed the enhanced chilling tolerance. We validated that OsEIL1 and OsEIL2 could form a heterxodimer and synergistically repressed OsICE1 expression by binding to its promoter. The expression of OsICE1 target genes, ROS scavenging- and photosynthesis-related genes were downregulated by OsEIN2 and OsEIL1/2, which were activated by OsICE1, suggesting that OsEIN2-OsEIL1/2 pathway might mediate ROS accumulation and photosynthetic capacity under chilling by attenuating OsICE1 function. Moreover, the association analysis of the seedling chilling tolerance with the haplotype showed that the lower expression of OsEIL1 and OsEIL2 caused by natural variation might confer chilling tolerance on rice seedlings. Finally, we generated OsEIL2-edited rice with an enhanced chilling tolerance. Taken together, our findings reveal a possible mechanism integrating OsEIN2-OsEIL1/2 pathway with OsICE1-dependent cascade in regulating chilling tolerance, providing a practical strategy for breeding chilling-tolerant rice.

Bio-inspired foveal super-resolution method for multi-focal-length images based on local gradient constraints.

Most existing super-resolution (SR) imaging systems, inspired by the bionic compound eye, utilize image registration and reconstruction algorithms to overcome the angular resolution limitations of individual imaging systems. This article introduces a multi-aperture multi-focal-length imaging system and a multi-focal-length image super-resolution algorithm, mimicking the foveal imaging of the human eye. Experimental results demonstrate that with the proposed imaging system and an SR imaging algorithm inspired by the human visual system, the proposed method can enhance the spatial resolution of the foveal region by up to 4 × compared to the original acquired image. These findings validate the effectiveness of the proposed imaging system and computational imaging algorithm in enhancing image texture and spatial resolution.

Joint constraints of guided filtering based confidence and nonlocal sparse tensor for color polarization super-resolution imaging.

This paper introduces a camera-array-based super-resolution color polarization imaging system designed to simultaneously capture color and polarization information of a scene in a single shot. Existing snapshot color polarization imaging has a complex structure and limited generalizability, which are overcome by the proposed system. In addition, a novel reconstruction algorithm is designed to exploit the complementarity and correlation between the twelve channels in acquired color polarization images for simultaneous super-resolution (SR) imaging and denoising. We propose a confidence-guided SR reconstruction algorithm based on guided filtering to enhance the constraint capability of the observed data. Additionally, by introducing adaptive parameters, we effectively balance the data fidelity constraint and the regularization constraint of nonlocal sparse tensor. Simulations were conducted to compare the proposed system with a color polarization camera. The results show that color polarization images generated by the proposed system and algorithm outperform those obtained from the color polarization camera and the state-of-the-art color polarization demosaicking algorithms. Moreover, the proposed algorithm also outperforms state-of-the-art SR algorithms based on deep learning. To evaluate the applicability of the proposed imaging system and reconstruction algorithm in practice, a prototype was constructed for color polarization image acquisition. Compared with conventional acquisition, the proposed solution demonstrates a significant improvement in the reconstructed color polarization images.

An Atlas of Dietary Intakes and Medication Uses on Risk of Bladder Cancer: A Wide-Angle Mendelian Randomization Analysis.

BACKGROUND: Observational studies suggests that diets and medications affect bladder cancer (BC) development, which are subject to confounding and difficult to make causal inference. Here we aimed to investigate whether those observational associations are causal and determining the potential directions and pathways. METHODS: We used 2-sample Mendelian randomization (MR) analysis to assess associations of dietary intakes, medication uses and molecules with BC risk. Genetic summary data were derived from participants of predominantly European ancestry with rigorous instruments selection, where univariable MR, mediation MR and multivariable MR were performed. RESULTS: The results of univariable MR showed 4 dietary intakes and 4 medication uses having a protective effect on BC, while 4 circulating metabolites, 440 circulating proteins and 2 gut microbes were observed to be causally associated with BC risk. Through mediation MR, we found 572 analytes showing consistent mediating effects between dietary intakes or medication uses and BC risk. Furthermore, 9 out of 16 diet-medication pairs showed significant interactions and alterations on BC when consumed jointly. CONCLUSION: In summary, the findings obtained from the current study have important implications for informing prevention strategies that point to potential lifestyle interventions or medication prescriptions to reduce the risk of developing BC.HighlightsThe current study extends observational literature in showing the importance of diets and medications on bladder cancer prevention.The associations of diets and medications on bladder cancer prevention might be through circulating metabolites, circulating proteins and gut microbiotaOur results provide a new understanding of interactions in certain diet-medication pairs which should be taken into account by both physicians and patients during the development of a treatment strategy.

Multi-omics association study of hexadecane degradation in haloarchaeal strain Halogranum rubrum RO2-11.

Haloarchaea with the capacity to degrade alkanes is promising to deal with petroleum pollution in hypersaline environments. However, only a limited number of haloarchaeal species are investigated, and their pathway and mechanism for alkane degradation remain unclear. In this study, Halogranum rubrum RO2-11, a haloarchaeal strain, verified the ability to degrade kerosene and hexadecane in 184 g/L NaCl, with 53% and 52% degradation rates after 9 and 4 days, respectively. Genome sequencing and gene annotation indicated that strain RO2-11 possesses a complete potential alkane-degrading pathway, of which alkane hydroxylases may include CYP450, AlmA, and LadA. Transcriptome and metabolome analyses revealed that the upregulation of related genes in TCA cycle, lysine biosynthesis, and acetylation may help improve hexadecane degradation. Additionally, an alternative degrading pathway of hexadecane based on dual-terminal ß-oxidation may occur in strain RO2-11. It is likely to be the first report of alkane degradation by the genus Halogranum, which may be helpful for applications of oil-pollution bioremediation under high-salt conditions.

Psychache status and associated contributing factors among the Hakka elderly in Fujian, China.

BACKGROUND: Little is known about the state of psychological distress of the elderly in China, and research on specific subgroups such as Hakka older adults is almost lacking. This study investigates psychache and associated factors among Hakka elderly in Fujian, China. METHODS: The data analysed in this study were derived from China's Health-Related Quality of Life Survey for Older Adults 2018. The Chinese version of the Psychache Scale (PAS) was used to assess the frequency and intensity of psychache in Hakka older adults. Generalized linear regression analysis was conducted to identify the main socio-demographic factors associated with psychache overall and its frequency and intensity. RESULTS: A total of 1,262 older adults participated, with mean scores of 18.27 ± 6.88 for total PAS, 12.50 ± 4.79 for PAS-Frequency and 5.77 ± 2.34 for PAS-Intensity. On average, females scored higher than males on PAS-Frequency (ß = 0.84, 95% CI = 0.34, 1.35) and PAS-Intensity (ß = 0.48, 95% CI = 0.22, 0.73). Older adults currently living in towns (ß = -2.18, 95% CI = -2.81, -1.54), with their spouse only (ß = -3.71, 95% CI = -4.77, -2.65), or with children (ß = -3.24, 95% CI = -4.26, -2.22) were more likely to score lower on PAS-Frequency. Conversely, older adults who were regular sleepers (ß = -1.19, 95% CI =-1.49, -0.88) or lived with their spouse only (ß = -1.25, 95% CI = -1.78, -0.72) were more likely to score lower on PAS-Intensity. CONCLUSION: Among Hakka elderly, we found a higher frequency and greater intensity of psychache in females, those with poor health status, irregular sleepers, rural residents, solo dwellers, those with below CNY 10,000 in personal savings, and the medically uninsured. The study's findings indicate that policymakers should give more attention to the susceptible population and implement practical interventions to reduce their psychological burden.

Exoskeleton rehabilitation robot training for balance and lower limb function in sub-acute stroke patients: a pilot, randomized controlled trial.

PURPOSE: This pilot study aimed to investigate the effects of REX exoskeleton rehabilitation robot training on the balance and lower limb function in patients with sub-acute stroke. METHODS: This was a pilot, single-blind, randomized controlled trial. Twenty-four patients with sub-acute stroke (with the course of disease ranging from 3 weeks to 3 months) were randomized into two groups, including a robot group and a control group. Patients in control group received upright bed rehabilitation (n = 12) and those in robot group received exoskeleton rehabilitation robot training (n = 12). The frequency of training in both groups was once a day (60 min each) for 5 days a week for a total of 4 weeks. Besides, the two groups were evaluated before, 2 weeks after and 4 weeks after the intervention, respectively. The primary assessment index was the Berg Balance Scale (BBS), whereas the secondary assessment indexes included the Fugl-Meyer Lower Extremity Motor Function Scale (FMA-LE), the Posture Assessment Scale for Stroke Patients (PASS), the Activities of Daily Living Scale (Modified Barthel Index, MBI), the Tecnobody Balance Tester, and lower extremity muscle surface electromyography (sEMG). RESULTS: The robot group showed significant improvements (P < 0.05) in the primary efficacy index BBS, as well as the secondary efficacy indexes PASS, FMA-LE, MBI, Tecnobody Balance Tester, and sEMG of the lower limb muscles. Besides, there were a significant differences in BBS, PASS, static eye-opening area or dynamic stability limit evaluation indexes between the robotic and control groups (P < 0.05). CONCLUSIONS: This is the first study to investigate the effectiveness of the REX exoskeleton rehabilitation robot in the rehabilitation of patients with stroke. According to our results, the REX exoskeleton rehabilitation robot demonstrated superior potential efficacy in promoting the early recovery of balance and motor functions in patients with sub-acute stroke. Future large-scale randomized controlled studies and follow-up assessments are needed to validate the current findings. CLINICAL TRIALS REGISTRATION: URL: https://www.chictr.org.cn/index.html.Unique identifier: ChiCTR2300068398.

Development and effectiveness of a BOPPPS teaching model-based workshop for community pharmacists training.

BACKGROUND/AIM: With the pharmaceutical innovation and clinical knowledge updating, the continuing education and on-the-job training are extremely important for improving community pharmacists' professional competence. Previous training often adopted traditional lecture-based teaching, and the efficacy was limited. The aim of this study is to develop a new strategy for community pharmacist training. METHODS: Based on the BOPPPS (Bridge-in, Objective, Pre-assessment, Participatory Learning, Post-assessment and Summary) teaching model and workshop method, a continuing on-the-job training program was constructed. Participates were randomly and evenly divided into two groups by random number table method. Twenty-four community pharmacists in total completed all training contents and evaluation components in this study. Twelve pharmacists in experimental group were trained via this new BOPPPS-based workshop, while others still adopted traditional didactic lecture-based approaches. RESULTS: After training, quantitative examination combined with clinical pharmacy practice tests were carried out to evaluate the effectiveness and outcomes of two training groups. For written exam, the total scores from the BOPPPS-based workshop group (82.67 ± 4.70) was higher than that of traditional lectured-base group (73.75 ± 6.15) (P < 0.001). Encouragingly, compared with the results of practical ability assessment from traditional training group (71.75 ± 4.75), the pharmacists receiving BOPPPS-based workshop training presented more excellent performance (78.25 ± 5.03), which displayed statistically significant differences (P < 0.01). In addition, an anonymous questionnaire was used to survey trainees' feelings after completing this continuing education program. The results revealed that the BOPPPS-based workshop can bring a better learning experience than traditional lecture-based training, and the percentages of positive response to each item were more than 91.7%. CONCLUSIONS: Through multi-dimensional evaluation, it was suggested that our BOPPPS-based workshop achieved desired training effects. Moreover, our research also demonstrated that this strategy had advantages of stimulating inspiration, autonomous learning, team-work spirit and pharmacy practice improvement. It may provide a reference of innovative training method for community pharmacists.

Response of fulvic acid linking to redox characteristics on methane and short-chain fatty acids in anaerobic digestion of chicken manure.

Fulvic acids (FAs) is formed during the bioconversion of organic matter (OM) to biogas during anaerobic digestion (AD) and has a complex structure and redox function. However, the evolutionary mechanisms of FAs during AD and its interactions with acid and methane production have not been sufficiently investigated, especially at different stages of AD. Intermittent AD experiments by chicken manure and rice husk showed significant structural changes and reduced aromatization of FAs (e.g., O-H stretch6, 14.10-0%; SR, 0.22-0.60). The electron donating capacity (EDC) [9.76-45.39 µmole-/(g C)] and electron accepting capacity (EAC) [2.55-5.20 µmole-/(g C)] of FAs showed a tendency of decreasing and then increasing, and FAs had a stronger electron transfer capacity (ETC) in the methanogenic stage. Correlation analysis showed that the EDC of FAs was influenced by their own structure (C-O stretch2, C-H bend1, C-H bend4, and N-H bend) and also had an inhibitory effect on propionic production, which further inhibited acetic production. The EAC of FAs was affected by molecular weight and had a promoting effect on methane production. Structural equation modelling identified three possible pathways for AD. The C-O stretch2 structure of FAs alone inhibits the production of propionic. In addition, pH can directly affect the EDC of FAs. This study provides a theoretical basis for the structural and functional evolution of FAs in AD of chicken manure on the mechanism of methane production.

Alpha oscillations track content-specific working memory capacity.

Though the neural basis of working memory (WM) capacity is often studied by exploiting inter-individual differences, capacity may also differ across memory materials within a given individual. Here, we exploit the content-dependence of WM capacity as a novel approach to investigate the oscillatory correlates of WM capacity, focusing on posterior 9-12 Hz alpha activity during retention. We recorded scalp electroencephalography (EEG) while male and female human participants performed WM tasks with varying memory loads (2 vs. 4 items) and materials (English letters vs. regular shapes vs. abstract shapes). First, behavioural data confirmed that memory capacity was fundamentally content-dependent: capacity for abstract shapes plateaued at around two, while the participants could remember more letters and regular shapes. Critically, content-specific capacity was paralleled in the degree of attenuation of EEG-alpha activity that plateaued in a similar, content-specific, manner. While we observed greater alpha attenuation for higher loads for all materials, we found larger load effects for letters and regular shapes than for abstract shapes - consistent with our behavioural data showing a lower capacity plateau for abstract shapes. Moreover, when only considering 2-item trials, alpha attenuation was greater for abstract shapes - where 2-items were close to the capacity plateau - than for other materials. Multivariate decoding of alpha-activity patterns reinforced these findings. Finally, for each material, load effects on capacity (K) and alpha attenuation were correlated across individuals. Our results demonstrate that alpha oscillations track memory capacity in a content-specific manner and track not just the number of items, but also their complexity.SIGNIFICANCE STATEMENTWorking memory (WM) is limited in its capacity. We show that capacity is not fixed for an individual but is rather memory-content dependent. Moreover, we used this as a novel approach to investigate the neural basis of WM capacity with EEG. We found that both behavioural capacity estimates and neural oscillations in the alpha band varied with memory loads and materials. The critical finding is a capacity plateau of approximately two items only for the more complex materials, accompanied by a similar plateau in the EEG alpha attenuation. The load effects on capacity and alpha attenuation were furthermore correlated across individuals for each of the materials. Our results demonstrate that alpha oscillations track the content-specific nature of WM capacity.

Characterization of ALTO-encoding circular RNAs expressed by Merkel cell polyomavirus and trichodysplasia spinulosa polyomavirus.

Circular RNAs (circRNAs) are a conserved class of RNAs with diverse functions, including serving as messenger RNAs that are translated into peptides. Here we describe circular RNAs generated by human polyomaviruses (HPyVs), some of which encode variants of the previously described alternative large T antigen open reading frame (ALTO) protein. Circular ALTO RNAs (circALTOs) can be detected in virus positive Merkel cell carcinoma (VP-MCC) cell lines and tumor samples. CircALTOs are stable, predominantly located in the cytoplasm, and N6-methyladenosine (m6A) modified. The translation of MCPyV circALTOs into ALTO protein is negatively regulated by MCPyV-generated miRNAs in cultured cells. MCPyV ALTO expression increases transcription from some recombinant promoters in vitro and upregulates the expression of multiple genes previously implicated in MCPyV pathogenesis. MCPyV circALTOs are enriched in exosomes derived from VP-MCC lines and circALTO-transfected 293T cells, and purified exosomes can mediate ALTO expression and transcriptional activation in MCPyV-negative cells. The related trichodysplasia spinulosa polyomavirus (TSPyV) also expresses a circALTO that can be detected in infected tissues and produces ALTO protein in cultured cells. Thus, human polyomavirus circRNAs are expressed in human tumors and infected tissues and express proteins that have the potential to modulate the infectious and tumorigenic properties of these viruses.

The effects of the interaction of genetic predisposition with lifestyle factors on bladder cancer risk.

OBJECTIVES: To investigate the association of polygenic risk score (PRS) and bladder cancer (BC) risk and whether this PRS can be offset by a healthy lifestyle. METHODS: Individuals with BC (n = 563) and non-BC controls (n = 483 957) were identified in the UK Biobank, and adjusted Cox regression models were used. A PRS was constructed based on 34 genetic variants associated with BC development, while a healthy lifestyle score (HLS) was constructed based on three lifestyle factors (i.e., smoking, physical activity, and diet). RESULTS: Overall, a negative interaction was observed between the PRS and the HLS (P = 0.02). A 7% higher and 28% lower BC risk per 1-standard deviation (SD) increment in PRS and HLS were observed, respectively. A simultaneous increment of 1 SD in both HLS and PRS was associated with a 6% lower BC risk. In addition, individuals with a high genetic risk and an unfavourable lifestyle showed an increased BC risk compared to individuals with low genetic risk and a favourable lifestyle (hazard ratio 1.55, 95% confidence interval 1.16-1.91; P for trend <0.001). Furthermore, population-attributable fraction (PAF) analysis showed that 12%-15% of the BC cases might have been prevented if individuals had adhered to a healthy lifestyle. CONCLUSION: This large-scale cohort study shows that a genetic predisposition combined with unhealthy behaviours have a joint negative effect on the risk of developing BC. Behavioural lifestyle changes should be encouraged for people through comprehensive, multifactorial approaches, although high-risk individuals may be selected based on genetic risk.

Stereospecific recognition of a chiral centre over multiple flexible covalent bonds by 19F-NMR.

High performance in chiral recognition by a reactive 19F-tag was demonstrated for a variety of enantiomers. The analytes with up to five flexible covalent bonds from the chiral center can be discriminated by a sensitive chiral reporter manifested in the 19F-NMR spectrum. Simultaneous identification of chiral amines in a mixture and high accuracy ee determination were achieved.

Linking Redox Characteristics to Dissolved Organic Matter Derived from Different Biowaste Composts: A Theoretical Modeling Approach Based on FT-ICR MS Analysis.

Compost dissolved organic matter (DOM) is a complex mixture of redox-active organic molecules that impact various biogeochemical processes in soil environments. However, the impact of chemical complexity (heterogeneity and chemodiversity) on the electron accepting capacity (EAC) and electron donating capacity (EDC) of DOM molecules remains unclear, which hinders our ability to predict their environmental behavior and redox properties. In this study, the applicability of Vienna Soil Organic Matter Modeler 2 (VSOMM2) to the composting system based on the FT-ICR MS data has been validated. A molecular modeling approach using VSOMM2 and Schrödinger software was developed to quantitatively assess the redox sites and molecular interactions of compost DOM. Compost DOM molecules are categorized into three distinct groups based on their heterogeneous origins. In addition, we have developed 18 molecular models of compost DOM based on the links of molecules to EAC/EDC. Finally, Ar-OH, quinone, Ar-SH, and Ar-NH2 were identified as the redox sites; noncovalent contacts, H bonds, salt bridges, and aromatic-H bonds might be significant electronic transmission channels of compost DOM. Our findings contribute to the development of precise regulatory methods for functional molecules within compost DOM, providing the fine standards for composts matching specific ecosystem service requirements.