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Abstract Background The additive model of inheritance assumes that heterozygotes (Aa) are exactly intermediate in respect to homozygotes (AA and aa). While this model is commonly used in single-locus genetic association studies, significant deviations from additivity are well-documented and contribute to phenotypic variance across many traits and systems. This assumption can introduce type I and type II errors by overestimating or underestimating the effects of variants that deviate from additivity. Alternative genotype encoding strategies have been explored to account for different inheritance patterns, but they often incur significant computational or methodological costs. To address these challenges, we introduce PAGER (Phenotype Adjusted Genotype Encoding and Ranking), an efficient pre-processing method that encodes each genetic variant based on normalized mean phenotypic differences between diallelic genotype classes (AA, Aa, and aa). This approach more accurately reflects each variant’s true inheritance model, improving model precision while minimizing the costs associated with alternative encoding strategies. Results Through extensive benchmarking on SNPs simulated with both binary and continuous phenotypes, we demonstrate that PAGER accurately represents various inheritance patterns (including additive, dominant, recessive, and heterosis), achieves levels of statistical power that meet or exceed other encoding strategies, and attains computation speeds up to 55 times faster than a similar method, EDGE. We also apply PAGER to publicly available real-world data and identify a novel, relevant putative QTL associated with body mass index in rats (Rattus norvegicus) that is not detected with the additive model. Conclusions Overall, we show that PAGER is an efficient genotype encoding approach that can uncover sources of missing heritability and reveal novel insights in the study of complex traits while incurring minimal costs.

Background and aimsUltrasound derived carotid intima-media thickness (cIMT) is valuable for cardiovascular risk stratification. We assessed the relative importance of traditional atherosclerosis risk factors and plasma proteins in predicting cIMT measured nearly a decade later.MethodWe examined 6,136 UK Biobank participants with 1,461 proteins profiled using the proximity extension assay applied to their baseline blood draw who subsequently underwent a cIMT measurement. We implemented linear regression, stepwise Akaike Information Criterion-based, and the least absolute shrinkage and selection operator (LASSO) models to identify potential proteomic as well as non-proteomic predictors. We evaluated our model performance using the proportion variance explained (R2).ResultThe mean time from baseline assessment to cIMT measurement was 9.2 years. Age, blood pressure, and anthropometric related variables were the strongest predictors of cIMT with fat-free mass index of the truncal region being the strongest predictor among adiposity measurements. A LASSO model incorporating variables including age, assessment center, genetic risk factors, smoking, blood pressure, trunk fat-free mass index, apolipoprotein B, and Townsend deprivation index combined with 97 proteins achieved the highest R2 (0.308, 95% C.I. 0.274, 0.341). In contrast, models built with proteins alone or non-proteomic variables alone explained a notably lower R2 (0.261, 0.228–0.294 and 0.260, 0.226–0.293, respectively). Chromogranin b (CHGB), Cystatin-M/E (CST6), leptin (LEP), and prolargin (PRELP) were the proteins consistently selected across all models.ConclusionPlasma proteins add to the clinical and genetic risk factors in predicting a cIMT measurement. Our findings implicate blood pressure and extracellular matrix-related proteins in cIMT pathophysiology.

The central areas of many Chinese cities have experienced large-scale urbanization in recent decades, a trend that is affecting the quality of life of residents and posing challenges to the sustainable development of urban ecosystems. Hence, it is vital to conduct assessments of urban ecosystems’ health conditions to ensure their sustainability. In this study, the spatial and temporal dynamics of ecosystem health in the central city of Wuhan were analyzed using the Vigor-Organization-Resilience-Service (VORS) model. The sensitivity of ecosystem health at different scales was also investigated using hierarchical health assessment delineation and random forest regression methods. The results showed that the composite index of ecosystem health has been declining since 2000, highlighting the negative impacts of shrinking ecological space, declining service capacity and urban expansion. Health zoning divides areas into five categories. Meanwhile, the health zones are located in areas of dense shrubs, cropland and water bodies on the edge of the central city, while the weak zones are mainly in the core of the city, which is 99.33 % impervious surface. The main factors influencing ecosystem health, including impervious surface area, water bodies and topography, vary from region to region. The study proposes targeted ecological management strategies for different health zones in Wuhan, emphasizing ecosystem protection and providing guidance for sustainable urban development.

Jianghan Plain is an important grain-producing area in China, and the transformation of the natural environment by the long-term polder activities of the people in this area has created a characteristic polder landscape. After 2000, urbanization has led to the destruction of ecosystems in these polder landscapes, especially in sensitive areas at the urban–rural interface. ESP can help mitigate this threat by systematically identifying and connecting ecologically significant areas to enhance ecosystem stability and sustainability. In this paper, taking Dongxihu Polder as an example, we apply multi-source remote sensing data to develop LER and LUC models. Combining these with MCR model, we construct an ESP for Dongxihu Polder. The study shows that (1) the growth of LER and LUC in Dongxihu Polder is characterized by “strong dynamics, high complexity and weak protection”, which is closely related to the urban expansion of the urban–rural boundary area; (2) Watersheds, woodlands, and farmlands play an important role in controlling LERs and LUCs, so we identified 33 ecologically important source areas that are mainly concentrated in these regions; (3) In this paper, 46 ecological strategic nodes and 16 ecological corridors were extracted to construct the Dongxihu Polder ESP of “one ring, five axes, multiple points and multiple chains”, and suggested specific optimization strategies. The study provides feasible ecological management policy recommendations for the protection as well as sustainable development of Dongxihu Polder.

People with long COVID are those who still have symptoms, signs, and conditions after the initial phase of infection of SARS-CoV-2. The incidence of long COVID varies among regions—31% in North America, 44% in Europe, and 51% in Asia, which is challenging the healthcare system, but there is limited guidelines for its treatment. With more and more nationwide projects funded by the government such as the RECOVER initiative in the United States and National Institute for Health Research funding in the United Kingdom, an increasing number of ongoing clinical trials are investigating the efficacy of diverse therapies on reversing long COVID. After searching the World Health Organization International Clinical Trial Registry Platform, 587 clinical studies are identified as long COVID studies. Among these, 312 studies (53.2%) are testing potential therapies. Most of the long COVID trials were conducted in the United States (58 trials [18.6%]), followed by India (55 trials [17.6%]), and Spain (20 trials [6.4%]). Interventions in these clinical trials include physical exercise, rehabilitation therapy, behavioral therapy, and pharmacological therapies including herbs, paxlovid, and fluvoxamine. These trials are aiming to deal with these long COVID symptoms and signs including fatigue, decreased pulmonary function, reduced cognitive function, and others. To date, only 11 of these 312 studies have published their results that were not confirmative, unfortunately. Future studies should be designed to address sleep disorders which were seldomly included in registered clinical studies. Moreover, interventions aimed at treating the underlying pathophysiology of long COVID are also necessary but currently lacking.

Abstract Background Chronic back pain affected 619 million people globally in 2020 which accounts for a heavy disease burden causing tremendous productivity losses. Current therapies including ibuprofen, duloxetine, and opioids might cause side effects and even severe drug use disorders. Therefore, a non‐pharmacologic therapy with better or equivalent efficacy and fewer side effects is needed. Methods We did a multi‐center, single‐blinded, randomized, positive drug controlled, clinical trial. Patients with chronic back pain in moderate severity were randomized into receiving hot stone massage or flurbiprofen plaster group. Both interventions were 2 weeks with a follow‐up of 4 weeks. The primary outcome was the change in the score of the Global Pain Scale (GPS) from baseline to week 2. Secondary outcomes included Numerical Rating Scale (NRS), Chronic Pain Acceptance Questionnaire (CPAQ), Pain Self‐Efficacy Questionnaire (PSEQ), Hospital Anxiety and Depression Scale (HADS), and Short Form‐36 (SF36) from baseline to week 2 and week 6. Exploratory outcome assessment included the muscle thickness measured by ultrasound. Any adverse event was monitored throughout the study period. Results A total of 120 patients were enrolled in this trial. At 2 weeks GPS decreased significantly in the hot stone massage group compared to the flurbiprofen group (difference between groups = ‐8.1 points, 95% confidence interval [CI] ‐15.8 to ‐0.3, p = 0.047). Moreover, hot stone massage also showed more improvement at 2 weeks compared to flurbiprofen, including NRS (‐0.5 points, 95% CI ‐1.0 to ‐0.1, p = 0.029), PSEQ (5.4 points, 95% CI 0.5 to 10.2, p = 0.030), and mental component of Short Form‐36 (SF‐36) (1.7 points, 95% CI 0.4 to 2.9, p = 0.010), but not in CPAQ (p = 0.131), HADS (p = 0.303 for depression, p = 0.399 for anxiety), or SF‐36 (p = 0.129 for physical component, p = 0.246 for social component, p = 0.076 for fatigue component). A total of two participants in the hot stone massage group reported mild pain on skin surface when receiving the procedure at the first intervention session.

The uncertainty and correlation of energy prices pose challenges to the planning and operation of park-level integrated energy systems. Especially, the extreme scenarios in both electricity and natural gas prices would result in significant economic losses, which have not been fully studied in the planning of park-level integrated energy systems. In this regard, this paper proposes a conditional-value-at-risk-based planning method for the park-level integrated energy system that considers both the extreme scenarios of energy prices and the correlation between the electricity price and natural gas price. First, the Gaussian mixture model is used to model the probability distribution function of the electricity price and natural gas price with high accuracy. Then, the Frank-Copula function is adopted to model the correlation between energy prices in different energy markets. Furthermore, a novel scenario generation method preserving extreme scenarios of energy prices is proposed, where extreme price scenarios are identified in the scenario generation process and subsequently preserved in scenario reduction. Finally, a conditional-value-at-risk-based planning model is proposed to optimize the overall investment and operation costs of the park-level integrated energy system, where the operational risks introduced by renewable generation and energy markets are effectively handled by the conditional value at risk. Case studies demonstrate that compared with the model without the consideration of extreme scenarios of energy prices, the potential risk loss of the proposed model is reduced by 3% in the same generated scenarios. The proposed model is more beneficial in enhancing the system’s resilience to the risk.

In the context of global climate change, drought and soil salinity are some of the most devastating abiotic stresses affecting agriculture today. PYL proteins are essential components of abscisic acid (ABA) signaling and play critical roles in responding to abiotic stressors, including drought and salt stress. Although PYL genes have been studied in many species, their roles in responding to abiotic stress are still unclear in the sunflower. In this study, 19 HaPYL genes, distributed on 15 of 17 chromosomes, were identified in the sunflower. Fragment duplication is the main cause of the expansion of PYL genes in the sunflower genome. Based on phylogenetic analysis, HaPYL genes were divided into three subfamilies. Members in the same subfamily share similar protein motifs and gene exon-intron structures, except for the second subfamily. Tissue expression patterns suggested that HaPYLs serve different functions when responding to developmental and environmental signals in the sunflower. Exogenous ABA treatment showed that most HaPYLs respond to an increase in the ABA level. Among these HaPYLs, HaPYL2a, HaPYL4d, HaPYL4g, HaPYL8a, HaPYL8b, HaPYL8c, HaPYL9b, and HaPYL9c were up-regulated with PEG6000 treatment and NaCl treatment. This indicates that they may play a role in resisting drought and salt stress in the sunflower by mediating ABA signaling. Our findings provide some clues to further explore the functions of PYL genes in the sunflower, especially with regards to drought and salt stress resistance.

IntroductionChronic musculoskeletal pain bothers the quality of life for approximately 1.71 billion people worldwide. Although pharmacological therapies play an important role in controlling chronic pain, overuse of opioids, persistent or recurrent symptoms, and pain-related disability burden still need to be addressed. Heat-stone massage is using the heated stone to stimulate muscles and ligaments followed by massage for relax, which can potentially treat the chronic musculoskeletal pain. To determine the efficacy and safety of heat-stone massage for patients with chronic musculoskeletal pain is needed.Methods and analysisThis multicenter, 2-arm, randomized, positive drug-controlled trial will include a total of 120 patients with chronic musculoskeletal pain. The intervention group will receive a 2 week heat-stone massage, 3 times per week, whereas the control group will receive the flurbiprofen plaster twice per day for 2 weeks. The primary end point is the change in Global Pain Scale from baseline to the end of the 2 week intervention. The secondary outcomes include the pain severity (Numerical Rating Scale), pain acceptance (Chronic Pain Acceptance Questionnaire), self-management (Health Education Impact Questionnaire), self-efficacy (Pain Self-Efficacy Questionnaire), anxiety and depression (Hospital Anxiety and Depression Scale), quality of life (Short Form-36). The intention-to-treat dataset will be used for analysis.DiscussionThe pain management remains the research topic that patients always pay close attention to. This will be the first randomized clinical trial to evaluate whether heat-stone massage, a non-pharmacological therapy, is effective in the chronic musculoskeletal pain management. The results will provide evidence for new option of daily practice.Clinical trial registrationWorld Health Organization Chinese Clinical Trial Registry [ChiCTR2200065654; https://www.chictr.org.cn/showproj.html?proj=185403]; International Traditional Medicine Clinical Trial Registry [ITMCTR2022000104; http://itmctr.ccebtcm.org.cn/en-US/Home/ProjectView?pid=51776b6f-77b8-4811-9b5a-a0fec10f2cee].

Summary: Relapse of acute myeloid leukemia (AML) remains a significant concern due to persistent leukemia-initiating stem cells (LICs) that are typically not targeted by most existing therapies. Using a murine AML model, human AML cell lines, and patient samples, we show that AML LICs are sensitive to endogenous and exogenous cyclopentenone prostaglandin-J (CyPG), Δ12-PGJ2, and 15d-PGJ2, which are increased upon dietary selenium supplementation via the cyclooxygenase-hematopoietic PGD synthase pathway. CyPGs are endogenous ligands for peroxisome proliferator-activated receptor gamma and GPR44 (CRTH2; PTGDR2). Deletion of GPR44 in a mouse model of AML exacerbated the disease suggesting that GPR44 activation mediates selenium-mediated apoptosis of LICs. Transcriptomic analysis of GPR44−/− LICs indicated that GPR44 activation by CyPGs suppressed KRAS-mediated MAPK and PI3K/AKT/mTOR signaling pathways, to enhance apoptosis. Our studies show the role of GPR44, providing mechanistic underpinnings of the chemopreventive and chemotherapeutic properties of selenium and CyPGs in AML.

This study aimed to isolate and identify a ligninolytic bacterium from the rumen of buffalo (Bubalus bubalis) and investigate its effects as a silage additive for whole-plant rape. Three lignin-degradation strains were isolated from the buffalo rumen, with AH7-7 being chosen for further experiments. Strain AH7-7, with acid tolerance and a 51.4% survival rate at pH 4, was identified as Bacillus cereus. It exhibited a lignin-degradation rate of 20.5% after being inoculated in a lignin-degrading medium for 8 days. We divided the rape into four groups according to the various additive compositions to examine the fermentation quality, nutritional value, and bacterial community after ensiling: Bc group (inoculated with B. cereus AH7-7 3.0 × 106 CFU g FW−1), Blac group (inoculated with B. cereus AH7-7 1.0 × 106 CFU g FW−1, L. plantarum 1.0 × 106 CFU g FW−1, and L. buchneri 1.0 × 106 CFU g FW−1), Lac group (inoculated with L. plantarum 1.5 × 106 CFU g FW−1 and L. buchneri 1.5 × 106 CFU g FW−1), and Ctrl group (no additives). After 60 days of fermentation, the application of B. cereus AH7-7 was potent in modulating the fermentation quality of silage, especially when combined with L. plantarum and L. buchneri, as indicated by lower dry matter loss and higher contents of crude protein, water-soluble carbohydrate, and lactic acid. Furthermore, treatments with the B. cereus AH7-7 additive decreased the contents of acid detergent lignin, cellulose, and hemicellulose. The B. cereus AH7-7 additive treatments reduced the bacterial diversity and optimized the bacterial community compositions of silage, with an increase in the relative abundance of beneficial Lactobacillus and a decrease in the relative abundance of undesirable Pantoea and Erwinia. Functional prediction revealed that inoculation with B. cereus AH7-7 could increase the cofactors and vitamins metabolism, amino acid metabolism, translation, replication and repair, and nucleotide metabolism, while decreasing the carbohydrate metabolism, membrane transport, and energy metabolism. In brief, B. cereus AH7-7 improved the microbial community, fermentation activity, and ultimately the quality of silage. The ensiling with B. cereus AH7-7, L. plantarum, and L. buchneri combination is an effective and practical strategy to improve the fermentation and nutrition preservation of rape silage.

The high levels of bile acids are a critical factor in hepatorenal syndrome. Organic solute transporter α/β (Ostα/β) participate in bile acids reabsorption in the kidney. Fucoidan has the great potential in protecting against liver and kidney injury. However, whether Ostα/β increase bile acids reabsorption in bile duct ligature (BDL)-induced hepatorenal syndrome and the blockade of fucoidan are still not clear. Male mice that received BDL were given to fucoidan (at 12.5, 25 and 50 ​mg/kg) through intraperitoneal injection once daily for three weeks. The serum, liver and kidney samples of these experimental mice were collected to carry out biochemical, pathological and Western blot analysis. In this study, fucoidan significantly lowered serum activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), decreased serum levels of uric acid, creatinine and uric nitrogen, restored the deregulation of the renal urate transporter 1 (URAT1), organic anion transporter 1 (OAT1), and organic cation/carnitine transporter 1/2 (OCTN1/2), consistence with alleviation BDL-induced liver and kidney dysfunction, inflammation and fibrosis in mice. Furthermore, fucoidan significantly hampered Ostα/β and reduced bile acids reabsorption in BDL-induced mice, protected against AML12 and HK-2 ​cells injury in vitro. These results demonstrate that fucoidan alleviates BDL-induced hepatorenal syndrome through inhibition Ostα/β to reduce bile acids reabsorption in mice. Therefore, suppression of Ostα/β by fucoidan may be a novel strategy for attenuating hepatorenal syndrome.

IntroductionThe rapid development of the farming industry has increased the amount of manure produced by livestock and poultry, causing increasingly prominent environmental pollution problems. In recent years, due to the increase in conventional bedding material costs, an increasing number of farmers choose to use harmless recycled manure as bedding. Manure bedding treatment of farms can not only solve the problem of manure pollution, but also resource utilization of manure and cost savings.MethodsThis study compared the effects of five microbial agents (Microbial agents A, B, C, E, F) on buffalo manure bedding treatment by testing the temperature, moisture content, pH, microbial bacteria distribution of buffalo manure ectopic fermentation, and screened the lowest cost and most effective agent. The changes of microbial bacteria distribution in different periods of bedding treatment were also detected.ResultsAgent A was eliminated because of poor fermentation effect and low fermentation temperature, which could not achieve the effect of harmless treatment. The other four agents of bacteria achieved a harmless effect, but the bedding treatment effect of agent F was significantly better than agent E, B, and C. In terms of the cost of agents: the cost of agent F required for fermenting 100m³ buffalo manure was the lowest, 1000yuan, followed by E (1200yuan), C (1750yuan), and B (1980yuan). In the process of ectopic fermentation bedding treatment of buffalo manure, Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, and Chloroflexi were the major bacteria used. The process was divided into three periods; the heating period - high temperature period - cooling period, the high temperature period could reach more than 75°C, and a large number of pathogenic bacteria and harmful bacteria, and other miscellaneous bacteria in the pile were degraded, their species diversity was reduced, and the structure of bacterial flora had significant differences in different treatment periods. In conclusion, this study has provided a guide for the resource utilization of manure in cattle farms and the reduction of manure pollution to the environment.

The present study aims to evaluate the effects of prepartum maternal supplementation of Capsicum oleoresin (CAP) on colostrum quality and growth performance in newborn buffalo calves. Twelve multiparous buffaloes were randomly assigned to two groups starting from 4 weeks prepartum: the control group with a basal diet (CON) and the treatment group with a basal diet supplemented with 20 mg CAP/kg dry matter (CAP20). After birth, all calves were weighed and received colostrum from their respective dam directly within 2 h. After that, calves received pasteurized milk and starter feed till 56 days of age. The results showed that CAP increased lactose (P < 0.05) in colostrum, and it tended to increase monounsaturated fatty acids; however, it decreased colostrum urea nitrogen (P < 0.10). CAP did not affect colostrum yield and immunoglobulin G and M concentrations. The weekly starter intake was not affected by maternal CAP supplementation during the first 6 weeks of life. There was an increasing tendency in weekly starter intake from weeks 7 and 8 (P < 0.10) in CAP20 compared with CON. At 7 days of age, calves in CAP20 had higher immunoglobulin G (P < 0.05) and a decreased tendency in calves' serum glucose compared with CON. Additionally, maternal CAP supplementation increased calves' serum β-hydroxybutyric acid (P < 0.05) and tended to increase total protein (P < 0.10), while decreased non-esterified fatty acids (P < 0.05) at 56 days of age. Calves in CAP20 had higher final withers height, final heart girth, average withers height, and average heart girth than the CON (P < 0.05). These results suggest that maternal CAP supplementation could improve colostrum quality and positively affect the performance of buffalo calves.

The harnessing and utilization of tidal current energy have emerged as prominent topics in scientific inquiry, due to their vast untapped resource potential, leading to numerous investigations into the efficacy of hydrokinetic turbines under various operational conditions. This paper delineates the wake field characteristics and performance of horizontal axis tidal stream turbines under the influence of support structures, using a comprehensively blade-resolved computational fluid dynamics (CFDs) model that employs Reynolds-averaged Navier–Stokes (RANS) equations in combination with the RNG k-ε turbulence model. To achieve this, the study utilized experimental tank tests and numerical simulations to investigate the distribution characteristics and recuperative principles of the turbine’s wake field. The velocity distribution and energy augmentation coefficient of the wake field showed strong agreement with the experimental results. To further assess the effect of support structures on the flow field downstream of the unit and its performance, the hydrodynamic attributes of the turbine wake field were analyzed with and without support structures. The interference elicited by the support structure modified the velocity distribution of the near-wake flow field, resulting in a 4.41% decrease in the turbine’s power coefficient (Cp), significantly impacting the turbine’s instantaneous performance.

Leaf anthracnose (LA) and anthracnose crown rot (ACR) represent serious fungal diseases that pose significant threats to strawberry production. To characterize the pathogen diversity associated with above diseases, 100 strawberry plants, including varieties of “Hongjia,” “Zhangji,” and “Tianxianzui,” were sampled from Jiande and Zhoushan, the primary plantation regions of Zhejiang province, China. A total of 309 Colletotrichum isolates were isolated from crown (150 isolates) and leaves (159 isolates) of affected samples. Among these, 100 isolates obtained from the plants showing both LA and CR symptoms were selected randomly for further characterization. Based on the morphological observations combined with phylogenetic analysis of multiple genes (ACT, ITS, CAL, GAPDH, and CHS), all the 100 tested isolates were identified as C. gloeosporioides species complex, including 91 isolates of C. siamense, 8 isolates of C. fructicola causing both LA and ACR, and one isolate of C. aenigma causing ACR. The phenotypic characteristics of these isolated species were investigated using the BIOLOG phenotype MicroArray (PM) and a total of 950 different metabolic phenotype were tested, showing the characteristics among these isolates and providing the theoretical basis for pathogenic biochemistry and metabolism. The pathogenicity tests showed that even the same Colletotrichum species isolated from different diseased tissues (leaves or crowns) had significantly different pathogenicity toward strawberry leaves and crown. C. siamense isolated from diseased leaves (CSLA) was more aggressive than C. siamense isolated from rotted crown (CSCR) during the infection on “Zhangji” leaves. Additionally, C. fructicola isolated from affected leaf (CFLA) caused more severe symptoms on the leaves of four strawberry varieties compared to C. fructicola isolated from diseased crown (CFCR). For crown rot, the pathogenicity of CSCR was higher than that of CSLA.

This paper proposes a dual-harmonic pole-changing (PC) motor with split permanent magnet (PM) poles (DHPCM-SPMPs). By adopting a split PM pole structure, the amplitude of the third PM flux density is increased greatly. Therefore, when a PC winding is adopted to couple with the fundamental and third PM flux density components, respectively, the proposed motor can work as a PC PM motor to satisfy operating demands of electric tractors. The design and effect of the proposed split PM pole structure is introduced first. The winding topology is then designed according to the slot vector diagrams of the two PM flux density components, and the PC operation can be realized by electric switches. Aiming at a torque ratio design objective, the PM structure parameters can be determined based on mathematical derivation, and the speed-widening capability is proved based on the operation characteristic analysis. Finally, the electromagnetic performance of the DHPCM-SPMPs is investigated and compared by finite element analysis, which shows the high torque capability in eight-pole mode and the wide speed range in twenty-four-pole mode benefiting from the PC operation.

Assumptions are made about the genetic model of single nucleotide polymorphisms (SNPs) when choosing a traditional genetic encoding: additive, dominant, and recessive. Furthermore, SNPs across the genome are unlikely to demonstrate identical genetic models. However, running SNP-SNP interaction analyses with every combination of encodings raises the multiple testing burden. Here, we present a novel and flexible encoding for genetic interactions, the elastic data-driven genetic encoding (EDGE), in which SNPs are assigned a heterozygous value based on the genetic model they demonstrate in a dataset prior to interaction testing. We assessed the power of EDGE to detect genetic interactions using 29 combinations of simulated genetic models and found it outperformed the traditional encoding methods across 10%, 30%, and 50% minor allele frequencies (MAFs). Further, EDGE maintained a low false-positive rate, while additive and dominant encodings demonstrated inflation. We evaluated EDGE and the traditional encodings with genetic data from the Electronic Medical Records and Genomics (eMERGE) Network for five phenotypes: age-related macular degeneration (AMD), age-related cataract, glaucoma, type 2 diabetes (T2D), and resistant hypertension. A multi-encoding genome-wide association study (GWAS) for each phenotype was performed using the traditional encodings, and the top results of the multi-encoding GWAS were considered for SNP-SNP interaction using the traditional encodings and EDGE. EDGE identified a novel SNP-SNP interaction for age-related cataract that no other method identified: rs7787286 (MAF: 0.041; intergenic region of chromosome 7)-rs4695885 (MAF: 0.34; intergenic region of chromosome 4) with a Bonferroni LRT p of 0.018. A SNP-SNP interaction was found in data from the UK Biobank within 25 kb of these SNPs using the recessive encoding: rs60374751 (MAF: 0.030) and rs6843594 (MAF: 0.34) (Bonferroni LRT p: 0.026). We recommend using EDGE to flexibly detect interactions between SNPs exhibiting diverse action.

POEMS syndrome is a rare multisystem disease associated with an underlying plasma cell disorder. Its name is an acronym for peripheral neuropathy (P), endocrinopathy (E), organomegaly (O), monoclonal plasma cell proliferative disorder (M), and skin changes (S). This case report describes a patient with POEMS syndrome who presented with progressive fatigue and numbness in the lower extremities. Initially, the patient was erroneously diagnosed with diabetes and diabetic peripheral neuropathy because of the endocrinopathy associated with POEMS syndrome. After a second hospitalization, the patient was diagnosed with POEMS syndrome and recovered with alkylator therapy and a peripheral blood stem cell transplant. The patient’s overall condition was improved at the 1-year follow-up. POEMS syndrome should be considered if a patient presents with endocrinopathy and unexplained peripheral neuropathy.

Colorectal cancer (CRC) is a common cancer worldwide, with a lower 5-years survival rate. Recently, long non-coding RNAs (lncRNAs) have been well-studied as the oncogenes or the tumor suppressors in multiple malignancies, including CRC. However, their biological functions and potential mechanisms in human cancer remain unclear. Here, we evaluated the expression of TDRKH-AS1 in CRC tissues and identified its potential targets. We found that TDRKH-AS1 is upregulated in majority of CRC patients, which is also significantly correlated with their malignant characteristics and their dismal prognoses. The high expression of TDRKH-AS1 can promote cancer cell proliferation substantially and invasion based on in vitro experiments. We also recognized that the TDRKH-AS1 targets the β-catenin in the Wnt signaling pathway to exert its carcinogenic activity. TDRKH-AS1 could serve as a promising prognostic predictor and a potential therapeutic target for further early diagnoses and treatments via a non-invasive method.

The development of the nanosized delivery systems with targeting navigation and efficient cargo release for cancer therapy has attracted great attention in recent years. Herein, a folic acid (FA) modified PEGylated polycaprolactone containing ditelluride linkage was synthesized through a facile coupling reaction. The hydrophobic doxorubicin (DOX) can be encapsulated into the polymeric micelles, and such nanoparticles (F-TeNPDOX) exhibited redox-responsive drug release under abundant glutathione (GSH) condition due to the degradation of ditelluride bonds. In addition, flow cytometric analyses showed that the FA ligands on F-TeNPDOX could facilitate their cellular uptake in 4T1 breast cancer cells. Therefore, F-TeNPDOX led to the promoted drug accumulation and enhanced growth inhibition on 4T1 tumor in vivo. The obtained results suggest F-TeNPDOX excellent potential as nanocarriers for anticancer drug delivery.

Epistasis analysis elucidates the effects of gene-gene interactions (G×G) between multiple loci for complex traits. However, the large computational demands and the high multiple testing burden impede their discoveries. Here, we illustrate the utilization of two methods, main effect filtering based on individual GWAS results and biological knowledge-based modeling through Biofilter software, to reduce the number of interactions tested among single nucleotide polymorphisms (SNPs) for 15 cardiac-related traits and 14 fatty acids. We performed interaction analyses using the two filtering methods, adjusting for age, sex, body mass index (BMI), waist-hip ratio, and the first three principal components from genetic data, among 2,824 samples from the Ludwigshafen Risk and Cardiovascular (LURIC) Health Study. Using Biofilter, one interaction nearly met Bonferroni significance: an interaction between rs7735781 in XRCC4 and rs10804247 in XRCC5 was identified for venous thrombosis with a Bonferroni-adjusted likelihood ratio test (LRT) p: 0.0627. A total of 57 interactions were identified from main effect filtering for the cardiac traits G×G (10) and fatty acids G×G (47) at Bonferroni-adjusted LRT p < 0.05. For cardiac traits, the top interaction involved SNPs rs1383819 in SNTG1 and rs1493939 (138kb from 5' of SAMD12) with Bonferroni-adjusted LRT p: 0.0228 which was significantly associated with history of arterial hypertension. For fatty acids, the top interaction between rs4839193 in KCND3 and rs10829717 in LOC107984002 with Bonferroni-adjusted LRT p: 2.28×10-5 was associated with 9-trans 12-trans octadecanoic acid, an omega-6 trans fatty acid. The model inflation factor for the interactions under different filtering methods was evaluated from the standard median and the linear regression approach. Here, we applied filtering approaches to identify numerous genetic interactions related to cardiac-related outcomes as potential targets for therapy. The approaches described offer ways to detect epistasis in the complex traits and to improve precision medicine capability.

The water buffalo (Bubalus bubalis) is known for its unique utilization of low-quality fibrous feeds and outstanding digestion performance, highlighting its role as an animal model in studying fiber fractions degradation. Among roughage, lignin attracted wide attention in ruminant nutrition studies, which affects animal digestibility. Therefore, the present study aims to investigate the functional relation between three lignin monomeric compositions of coniferyl alcohol (G), ρ-coumaryl alcohol (H) and sinapyl alcohol (S) and ruminal fiber degradation in water buffalo. Hence, three female water buffaloes (Nili-Ravi × Mediterranean, five years old, 480 ± 20 kg) were assigned for an in vivo study by utilizing the nylon-bag method, examining eight kinds of roughage. All the experimental roughage types were analyzed for the effective degradability (ED) of neutral detergent fiber (NDF), acid detergent fiber (ADF), acid detergent lignin (ADL), cellulose (CEL) and hemicellulose (HC) fractions. Then, prediction models for the roughage fiber degradation were established based on the characteristics of lignin monomer content. The results showed that S, S/G and S/(G+S+H) were positively correlated with the ED of NDF, ADF, CEL and HC; H/S was negatively correlated. For the effective degradability of ADL (ADLD), S and S/(G+S+H) were positively correlated with it; H, H/G, H/S and H/(G+S+H) were negatively correlated. The model with the highest fitting degree was ADLD = 0.161 − 1.918 × H + 3.152 × S (R2 = 0.758, p < 0.01). These results indicated that the lignin monomer composition is closely related to the utilization rate of roughage fiber. S-type lignin monomer plays a vital role in the fiber degradation of roughage. The experiment found the effect of lignin monomer composition on the degradation of fiber fractions using buffalo as the experimental animal and constructed prediction models, providing a scientific basis for building a new technological method using lignin composition to evaluate buffalo roughage. Furthermore, the capacity of ADL degradation of buffalo was proved in this experiment. In order to further explore the ability of lignin degradation by the buffalo, the DNA of rumen microorganisms was extracted for sequencing. The top three composition of rumen microorganisms at the genus level were Prevotella_1, 226, Rikenellaceae_RC9_gut_group and Ruminococcaceae_UCG-011. Six strains with lignin degradation ability were screened from buffalo rumen contents. This experiment also revealed that the buffalos possess rumen microorganisms with lignin degradation potential.

While genome-wide association studies are an established method of identifying genetic variants associated with disease, environment-wide association studies (EWAS) highlight the contribution of nongenetic components to complex phenotypes. However, the lack of high-throughput quality control (QC) pipelines for EWAS data lends itself to analysis plans where the data are cleaned after a first-pass analysis, which can lead to bias, or are cleaned manually, which is arduous and susceptible to user error. We offer a novel software, CLeaning to Analysis: Reproducibility-based Interface for Traits and Exposures (CLARITE), as a tool to efficiently clean environmental data, perform regression analysis, and visualize results on a single platform through user-guided automation. It exists as both an R package and a Python package. Though CLARITE focuses on EWAS, it is intended to also improve the QC process for phenotypes and clinical lab measures for a variety of downstream analyses, including phenome-wide association studies and gene-environment interaction studies. With the goal of demonstrating the utility of CLARITE, we performed a novel EWAS in the National Health and Nutrition Examination Survey (NHANES) (N overall Discovery=9063, N overall Replication=9874) for body mass index (BMI) and over 300 environment variables post-QC, adjusting for sex, age, race, socioeconomic status, and survey year. The analysis used survey weights along with cluster and strata information in order to account for the complex survey design. Sixteen BMI results replicated at a Bonferroni corrected p < 0.05. The top replicating results were serum levels of g-tocopherol (vitamin E) (Discovery Bonferroni p: 8.67x10-12, Replication Bonferroni p: 2.70x10-9) and iron (Discovery Bonferroni p: 1.09x10-8, Replication Bonferroni p: 1.73x10-10). Results of this EWAS are important to consider for metabolic trait analysis, as BMI is tightly associated with these phenotypes. As such, exposures predictive of BMI may be useful for covariate and/or interaction assessment of metabolic-related traits. CLARITE allows improved data quality for EWAS, gene-environment interactions, and phenome-wide association studies by establishing a high-throughput quality control infrastructure. Thus, CLARITE is recommended for studying the environmental factors underlying complex disease.

[Objectives] This study was conducted to evaluate the protective effect of polysaccharides from Enteromorpha prolifera (PEP) on mice with hepatorenal syndrome induced by carbon tetrachloride. [Methods] A mouse hepatorenal syndrome model was induced by carbon tetrachloride. The serum levels of lipid, total antioxidant capacity, liver and kidney function, pathological changes of liver and kidney were selected to clarity the effectiveness of PEP on hepatorenal syndrome in mice. [Results] PEP effectively 10w ?ered the serum levels of lipid, increased total antioxidant capacity, improved liver and kidney injury, and alleviated pathological changes of liver and kidney of mice induced by carbon tetrachloride. [Conclusions] PEP has a potent preventive effect on hepatorenal syndrome induced by carbon tetrachloride in mice, which provides theoretical support for future clinical application of PEP. [ABSTRACT FROM AUTHOR]