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To quantitatively evaluate blood-brain barrier (BBB) permeability in the perihaematomal region of spontaneous intracerebral haemorrhage (ICH) and investigate the association between the alterations in cerebral blood flow and BBB permeability around the haematoma.Spontaneous ICH patients underwent unenhanced computed tomography (CT) and CT perfusion (CTP) simultaneously. Haematoma volume was measured on CT. The values of cerebral haemodynamic parameters including cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), time to peak (TTP), and permeability-surface area product (PS) were measured in the perihaematomal region and the contralateral mirror region, and then relative values were calculated for statistical analysis. Linear regression was used to evaluate associations between BBB permeability and variables.A total of 87 ICH patients were included in this study. The focally elevated BBB permeability was observed in the perihaematomal region in ICH patients. Linear regression showed that reduced rCBF (β = -0.379, p=0.001) and increased rCBV (β = 0.412, p=0.000) correlated independently with increased relative PS (rPS) value in deep ICH, while only increased rCBV (β = 0.423, p=0.071) correlated to increased rPS value in patients with lobar ICH.BBB permeability is focally elevated in the region around the haematoma. Cerebral haemodynamic alterations are associated with increased BBB permeability. Cerebral hypoperfusion may aggravate BBB compromise, and a compensatory increase in CBV may lead to reperfusion injury on BBB.

Dysbiotic oral microbiota has been associated with multiple sclerosis. However, the role and mechanism of oral microbiota in the development of multiple sclerosis are still elusive. Here, we demonstrated that ligature-induced periodontitis (LIP) aggravated experimental autoimmune encephalomyelitis (EAE) in mice, and this was likely dependent on the expansion of T helper 17 (Th17) cells. LIP increased the splenic richness of Enterobacter sp., which was able to induce the expansion of splenic Th17 cells and aggravate EAE in mice. LIP also led to enrichment of Erysipelotrichaceae sp. in the gut and increased Th17 cells in the large intestinal lamina propria of EAE mice. Fecal microbiota transplantation from EAE mice with LIP also promoted EAE symptoms. In conclusion, periodontitis exacerbates EAE, likely through ectopic colonization of oral pathobionts and expansion of Th17 cells.

Lactobacillus paracasei SLP 16 was obtained from liquor cellar mud, and it was analysed by genome sequencing on Illumina Hiseqq platform. Then the biological information of L. paracasei SLP16 was analysed by ExPasy (website), and the toxin safety of the strain SLP 16 was analysed by PSI/PHI in the virulence factor database VFDB. Through the second-generation DNA sequencing platform technology, the whole genome information of L. paracasei SLP16 was obtained, which showed that the genome size of the strain SLP 16 was 2·65 mol l−1, and the GC content of the strain SLP 16 was 46·9%. And a total of 3131 genes were detected, including 3067 genes encoding protein and 63 genes encoding RNA. Whole genome analysis showed that L. paracasei SLP16 had five coding genes of F0F1-ATPase, four coding genes of Na+/H+ antiporter and three coding genes of A-ATPase, which were closely related to the acid tolerance of lactic acid bacteria (LAB). Whole genome analysis of L. paracasei SLP16 showed that SLP 16 had only one CFA synthetic coding gene, and no important BSH coding gene; however, it had F0F1-ATPase, Na+/H+ antiporter and several two-component regulatory systems, and which were related to bile salt tolerance of LAB. Safety evaluation in L. paracasei SLP16 showed that it did not have the virulence factor coding gene related to toxin. Common antibiotic sensitivity tests showed that L. paracasei SLP16 was resistant to compounds such as sulfamethoxazole, ciprofloxacin, gentamicin and lincomycin. In summary, L. paracasei SLP16 had coding genes closely related to acid tolerance and bile salt tolerance, and no coding gene of virulence factors related to toxins, and few kinds of resistant antibiotics. Therefore, whole genome analysis showed that L. paracasei SLP16 was a safe probiotic strain that can be safely applied.

Background Advanced testing methodologies and measurement techniques to identify complex deformation and failure at high strain rates have drawn increasing attention in recent years. Objective The objective of the current study is the development of a novel combined tension–torsion split Hopkinson bar (TTHB) conceived to generate a combination of tensile and torsional stress waves in a single loading case, and to measure material data representative of real case impact scenarios. Methods An energy store and release mechanism was employed to generate both the longitudinal and shear waves via the rapid release of a bespoke clamp assembly. A parametric study of the material and geometry of the clamp was implemented via numerical simulations to optimise critical aspects of the wave generation. Thin-walled tube specimens made of two metallic materials were utilised to examine the capability of the developed TTHB system by comparing the experimental measurements with those obtained from conventional split Hopkinson tension and torsion bars. Results The experimental results demonstrate that the synchronisation of the longitudinal and torsional waves was achieved within 15 microseconds. Different wave rise time were obtained via the controlled release of the clamp using fracture pins of various materials. The analysis indicates that the developed TTHB is capable of characterising the dynamic behaviour of materials under tension, torsion, as well as under a wide range of complex stress states. Conclusions The presented apparatus, testing and analysis methods allow for the direct population of the dynamic failure stress envelopes of engineering materials and for the accurate evaluation of existing and novel constitutive models.

Advanced additive manufacturing techniques have been recently used to tackle the two fundamental challenges of biodegradable Fe-based bone-substituting materials, namely low rate of biodegradation and insufficient bioactivity. While additively manufactured porous iron has been somewhat successful in addressing the first challenge, the limited bioactivity of these biomaterials hinder their progress towards clinical application. Herein, we used extrusion-based 3D printing for additive manufacturing of iron-matrix composites containing silicate-based bioceramic particles (akermanite), thereby addressing both of the abovementioned challenges. We developed inks that carried iron and 5, 10, 15, or 20 vol% of akermanite powder mixtures for the 3D printing process and optimized the debinding and sintering steps to produce geometrically-ordered iron-akermanite composites with an open porosity of 69–71%. The composite scaffolds preserved the designed geometry and the original α-Fe and akermanite phases. The in vitro biodegradation rates of the composites were improved as much as 2.6 times the biodegradation rate of geometrically identical pure iron. The yield strengths and elastic moduli of the scaffolds remained within the range of the mechanical properties of the cancellous bone, even after 28 days of biodegradation. The composite scaffolds (10–20 vol% akermanite) demonstrated improved MC3T3-E1 cell adhesion and higher levels of cell proliferation. The cellular secretion of collagen type-1 and the alkaline phosphatase activity on the composite scaffolds (10–20 vol% akermanite) were, respectively higher than and comparable to Ti6Al4V in osteogenic medium. Taken together, these results clearly show the potential of 3D printed porous iron-akermanite composites for further development as promising bone substitutes. Statement of significance: Porous iron matrix composites containing akermanite particles were produced by means of multi-material additive manufacturing to address the two fundamental challenges associated with biodegradable iron-based biomaterials, namely very low rate of biodegradation and insufficient bioactivity. Our porous iron-akermanite composites exhibited enhanced biodegradability and superior bioactivity compared to porous monolithic iron scaffolds. The murine bone cells proliferated on the composite scaffolds, and secreted the collagen type-1 matrix that stimulated bony-like mineralization. The results show the exceptional potential of the developed porous iron-based composite scaffolds for application as bone substitutes.

Traditional Chinese medicine (TCM) has played a pivotal role in maintaining the health of people, and the intrinsic quality of TCM is directly related to the clinical efficacy. The medicinal ingredients of TCM are derived from the secondary metabolites of plant metabolism and are also the result of the coordination of various physiological activities in plants. Arbuscular mycorrhizal fungi (AMF) are among the most ubiquitous plant mutualists that enhance the growth and yield of plants by facilitating the uptake of nutrients and water. Symbiosis of AMF with higher plants promotes growth and helps in the accumulation of secondary metabolites. However, there is still no systematic analysis and summation of their roles in the application of TCM, biosynthesis and accumulation of active substances of herbs, as well as the mechanisms. AMF directly or indirectly affect the accumulation of secondary metabolites of TCM, which is the focus of this review. First, in this review, the effects of AMF symbiosis on the content of different secondary metabolites in TCM, such as phenolic acids, flavonoids, alkaloids and terpenoids, are summarized. Moreover, the mechanism of AMF regulating the synthesis of secondary metabolites was also considered, in combination with the establishment of mycorrhizal symbionts, response mechanisms of plant hormones, nutritional elements and expression of key enzyme their activities. Finally, combined with the current application prospects for AMF in TCM, future in-depth research is planned, thus providing a reference for improving the quality of TCM. In this manuscript, we review the research status of AMF in promoting the accumulation of secondary metabolites in TCM to provide new ideas and methods for improving the quality of TCM.

Rationale: Genetic variation has a substantial contribution to chronic obstructive pulmonary disease (COPD) and lung function measurements. Heritability estimates using genome-wide genotyping data can be biased if analyses do not appropriately account for the nonuniform distribution of genetic effects across the allele frequency and linkage disequilibrium (LD) spectrum. In addition, the contribution of rare variants has been unclear. Objectives: We sought to assess the heritability of COPD and lung function using whole-genome sequence data from the Trans-Omics for Precision Medicine program. Methods: Using the genome-based restricted maximum likelihood method, we partitioned the genome into bins based on minor allele frequency and LD scores and estimated heritability of COPD, FEV1% predicted and FEV1/FVC ratio in 11 051 European ancestry and 5853 African-American participants. Measurements and Main Results: In European ancestry participants, the estimated heritability of COPD, FEV1% predicted and FEV1/FVC ratio were 35.5%, 55.6% and 32.5%, of which 18.8%, 19.7%, 17.8% were from common variants, and 16.6%, 35.8%, and 14.6% were from rare variants. These estimates had wide confidence intervals, with common variants and some sets of rare variants showing a statistically significant contribution (P-value

(+)-Valencene is a bioactive sesquiterpene that can be used for flavoring and fragrances, and microbial production provides an alternative sustainable access. However, the complexity of cellular metabolism makes it challenging for its high-level production. Here, we report the global rewiring cellular metabolism for

Funding Acknowledgements Type of funding sources: None. Background Previous research on atrial fibrillation (AF)-related healthcare cost is limited by claims-derived categorization of AF diagnosis and does not assess for incremental differences in cost based on degree of AF burden. Objective To directly assess the incremental cost of device detected AF (ddAF), and compare relative costs among cohorts with no AF, paroxysmal AF (pAF), persistent AF (PeAF), and permanent AF (PermAF) in patients with cardiac implantable electronic devices (CIED) capable of sensitive and continuous atrial arrhythmia detection. Methods Using the de-identified Optum® Clinformatics® U.S. claims database (2015 to 2020) linked with the Medtronic CareLink® database, we identified CIED patients that transmitted data ≥6 months post-implant (baseline period). Annualized per-patient costs in follow up were analyzed from insurance claims and adjusted to 2020 US Dollars. Total costs were compared between patients with no AF and those with device detected pAF, PeAF and PermAF. Analyses were adjusted for geographical region, insurance type, CHA2DS2-VASc Score, and implant year. Results Of the 21,391 patients (72.9±10.9 yrs; 56.3% male) analyzed, 7,798 (36.5%) had ddAF. Among these, 5,966 (76.5%) were pAF (avg burden 2.9±8.6%), 1,145 (14.7%) were PeAF (avg burden 47.2±29.9%), and 687 (8.8%) were PermAF (avg burden 99.3±0.7%). Patients with ddAF had higher overall annualized total healthcare costs than those without ddAF (fig). The incremental annualized increased cost in those with ddAF was $12,789 ± $161,749 per patient. Patients with pAF, PeAF and PermAF all had higher adjusted healthcare costs than those without AF (p for all Conclusions In the present analysis of CIED patients, ddAF was associated with increased healthcare costs after adjustment for clinical and demographic covariates. Among those with ddAF, patients with PeAF had the highest healthcare costs. Preventing development of AF, and progression to PeAF, may reduce healthcare costs.

The secondary palate forms from two lateral primordia called the palatal shelves which form a contact in the midline, become adherent at the fusing interface (medial edge epithelia, MEE) and subsequently fuse. The gene encoding transforming growth factor-ß3 (Tgfb3) is strongly and specifically expressed in MEE cells. Our previous study suggested that Tgfb3 expression is controlled via upstream cis-regulatory elements in and around the neighboring Ift43 gene. Another study suggested that the canonical Wnt signaling via ß-Catenin is responsible for the MEE-specific Tgfb3 gene expression, since deletion of the Ctnnb1 gene by a commonly used Keratin 14-Cre (K14Cre) mouse line almost completely abolished Tgfb3 expression in the MEE resulting in cleft palate. Here, we wanted to analyze whether Tcf/Lef consensus binding sites located in the previously identified regions of the Ift43 gene are responsible for the spatiotemporal control of Tgfb3 expression during palatogenesis. We show that contrary to the previous report, deletion of the Ctnnb1 gene in basal MEE cells by the K14Cre driver (the same K14Cre mouse line was used as in the previous study referenced above) does not affect the MEE-specific Tgfb3 expression or TGFß3-dependent palatal epithelial fusion. All mutant embryos showed a lack of palatal rugae accompanied by other craniofacial defects, e.g., a narrow snout and a small upper lip, while only a small subset (Ctnnb1 mutants displayed a cleft palate. Moreover, the K14Cre:Ctnnb1 embryos showed reduced levels and altered patterns of Shh expression. Our present data imply that epithelial ß-catenin may not be required for MEE-specific Tgfb3 expression or palatal epithelial fusion.

Motivation In a genome-wide association study, analyzing multiple correlated traits simultaneously is potentially superior to analyzing the traits one by one. Standard methods for multivariate genome-wide association study operate marker-by-marker and are computationally intensive. Results We present a sparsity constrained regression algorithm for multivariate genome-wide association study based on iterative hard thresholding and implement it in a convenient Julia package MendelIHT.jl. In simulation studies with up to 100 quantitative traits, iterative hard thresholding exhibits similar true positive rates, smaller false positive rates, and faster execution times than GEMMA’s linear mixed models and mv-PLINK’s canonical correlation analysis. On UK Biobank data with 470 228 variants, MendelIHT completed a three-trait joint analysis (n=185 656) in 20 h and an 18-trait joint analysis (n=104 264) in 53 h with an 80 GB memory footprint. In short, MendelIHT enables geneticists to fit a single regression model that simultaneously considers the effect of all SNPs and dozens of traits. Availability and implementation Software, documentation, and scripts to reproduce our results are available from https://github.com/OpenMendel/MendelIHT.jl.

BackgroundHeart failure (HF) is a serious condition with increasing prevalence, high morbidity, and increased mortality. Obesity is an established risk factor for cardiovascular diseases, including HF. Fluctuation in body mass index (BMI) has shown a higher risk of cardiovascular outcomes. We investigated the association between BMI variability and incident HF.MethodsIn the UK Biobank, we established a prospective cohort after excluding participants with prevalent HF or cancer at enrollment. A total of 99,368 White (British, Irish, and any other white background) participants with ≥ 3 BMI measures during > 2 years preceding enrollment were included, with a median follow-up of 12.5 years. The within-participant variability of BMI was evaluated using standardized standard deviation (SD) and coefficient of variation (CV). The association of BMI variability with incident HF was assessed using Fine and Gray’s competing risk model, and adjusted for age, sex, smoking history, alcohol consumption, diabetes, hypertension, history of heart attack, stroke, atrial fibrillation, lipids, estimated glomerular filtration rate and mean BMI per individual.ResultsIn the fully adjusted model, higher BMI variability measured in both SD and CV were significantly associated with higher risk in HF incidence (SD: Hazard Ratio [HR] 1.05, 95% Confidence Interval [CI] 1.02 - 1.07, p = 0.0002; CV: HR 1.06, 95% CI 1.04 - 1.09, p < 0.0001).ConclusionsLongitudinal health records capture BMI fluctuation, which independently predicts HF incidence. Integration of long-term BMI and other routinely measured health factors may improve risk prediction of HF and other cardiovascular outcomes.

The discovery of the topological states has become a key topic in condensed matter physics with the focus evolving from the Dirac or Weyl points to high-dimension topological states of the nodal lines and nodal surfaces. For a topological material to manifest its quantum properties and become useful in applications, the topological states need to be genuine and clean so that they lie close to the Fermi level without other trivial bands existing at the Fermi level. While a number of high-dimension topological materials are predicted, only a few of them have been synthesized and confirmed and the genuine and clean ones are especially scarce. Here we report the realization of the genuine clean multiple high-dimension topological states in NaAlSi. By performing high-resolution angle-resolved photoemission measurements and band structure calculations, we have observed two sets of nodal surfaces and the formation of two homocentric nodal ring states in NaAlSi. The observed nodal rings are distinct in that the inner one is a type-{\uppercase\expandafter{\romannumeral1}} nodal ring while the outer one is a type-{\uppercase\expandafter{\romannumeral1}} nodal ring embedded with four type-{\uppercase\expandafter{\romannumeral3}} nodal points. All the bands involved in the nodal rings lie very close to the Fermi level with no other trivial bands coexisting at the Fermi level. These observations make NaAlSi a desirable topological material to explore for novel quantum states and exotic properties.

The effect of tearing modes on the confinement of runaway electrons is studied in EAST tokamak. The general tendency of the radial diffusion coeffcient of REs D r is derived based on the time response relation between the tearing modes and runaway electrons. The results indicate that, the magnetic fluctuations of tearing modes will enhance the radial diffusion of runaway electrons when the magnetic island is small. Following the increasing of the magnetic fluctuations of the tearing modes, the formed large magnetic island may weaken the radial diffusion of runaway electrons. The results can be important to understand the confinement of runaway electrons when large magnetic islands exist in the plasma.

Methanol is an ideal feedstock for chemical and biological manufacturing. Constructing an efficient cell factory is essential for producing complex compounds through methanol biotransformation, in which coordinating methanol use and product synthesis is often necessary. In methylotrophic yeast, methanol utilization mainly occurs in peroxisomes, which creates challenges in driving the metabolic flux toward product biosynthesis. Here, we observed that constructing the cytosolic biosynthesis pathway resulted in compromised fatty alcohol production in the methylotrophic yeast Ogataea polymorpha . Alternatively, peroxisomal coupling of fatty alcohol biosynthesis and methanol utilization significantly improved fatty alcohol production by 3.9-fold. Enhancing the supply of precursor fatty acyl-CoA and cofactor NADPH in the peroxisomes by global metabolic rewiring further improved fatty alcohol production by 2.5-fold and produced 3.6 g/L fatty alcohols from methanol under fed-batch fermentation. We demonstrated that peroxisome compartmentalization is helpful for coupling methanol utilization and product synthesis, and with this approach, constructing efficient microbial cell factories for methanol biotransformation is feasible.

Organic scintillators exhibit fast timing, high detection efficiency for fast neutrons and pulse shape discrimination (PSD) capability. PSD is essential in mixed radiation fields, where different types of radiation need to be detected and discriminated. In neutron measurements for nuclear security and non proliferation effective PSD is crucial, because a weak neutron signature needs to be detected in the presence of a strong gamma-ray background. The most commonly used deterministic PSD technique is charge integration (CI). This method requires the optimization of specific parameters to obtain the best gamma-neutron separation. These parameters depend on the scintillating material and light readout device and typically require a lengthy optimization process and a calibration reference measurement with a mixed source. In this paper, we propose a new method based on the scintillation fluorescence physics that enables to find the optimum PSD integration gates using only a gamma-ray emitter. We demonstrate our method using three organic scintillation detectors: deuterated trans-stilbene, small-molecule organic glass, and EJ-309. In all the investigated cases, our method allowed finding the optimum PSD CI parameters without the need of iterative optimization.

OBJECTIVE Anterior lumbar interbody fusion (ALIF) used at the lumbosacral junction provides arthrodesis for several indications. The anterior approach allows restoration of lumbar lordosis, an important goal of surgery. With hyperlordotic ALIF implants, several options may be employed to obtain the desired amount of lordosis. In this study, the authors compared the degree of radiographic lordosis achieved with lordotic and hyperlordotic ALIF implants at the L5–S1 segment. METHODS All patients undergoing L5–S1 ALIF from 2 institutions over a 4-year interval were included. Patients < 18 years of age or those with any posterior decompression or osteotomy were excluded. ALIF implants in the lordotic group had 8° or 12° of inherent lordosis, whereas implants in the hyperlordotic group had 20° or 30° of lordosis. Upright standing radiographs were used to determine all radiographic parameters, including lumbar lordosis, segmental lordosis, disc space lordosis, and disc space height. Separate analyses were performed for patients who underwent single-segment fixation at L5–S1 and for the overall cohort. RESULTS A total of 204 patients were included (hyperlordotic group, 93 [45.6%]; lordotic group, 111 [54.4%]). Single-segment ALIF at L5–S1 was performed in 74 patients (hyperlordotic group, 27 [36.5%]; lordotic group, 47 [63.5%]). The overall mean ± SD age was 61.9 ± 12.3 years; 58.3% of patients (n = 119) were women. The mean number of total segments fused was 3.2 ± 2.6. Overall, 66.7% (n = 136) of patients had supine surgery and 33.3% (n = 68) had lateral surgery. Supine positioning was significantly more common in the hyperlordotic group than in the lordotic group (83.9% [78/93] vs 52.3% [58/111], p < 0.001). After adjusting for differences in surgical positioning, the change in lumbar lordosis was significantly greater for hyperlordotic versus lordotic implants (3.6° ± 7.5° vs 0.4° ± 7.5°, p = 0.048) in patients with single-level fusion. For patients receiving hyperlordotic versus lordotic implants, changes were also significantly greater for segmental lordosis (12.4° ± 7.5° vs 8.4° ± 4.9°, p = 0.03) and disc space lordosis (15.3° ± 5.4° vs 9.3° ± 5.8°, p < 0.001) after single-level fusion at L5–S1. The change in disc space height was similar for these 2 groups (p = 0.23). CONCLUSIONS Hyperlordotic implants provided a greater degree of overall lumbar lordosis restoration as well as L5–S1 segmental and disc space lordosis restoration than lordotic implants. The change in disc space height was similar. Differences in lateral and supine positioning did not affect these parameters.

Methylotrophic yeasts have been widely recognized as a promising host for production of recombinant proteins and value-added chemicals. Promoters for controlled gene expression are critical for construction of efficient methylotrophic yeasts cell factories. Here, we summarized recent advances in characterizing and engineering promoters in methylotrophic yeasts, such as Komagataella phaffii and Ogataea polymorpha. Constitutive and inducible promoters controlled by methanol or other inducers/repressors were introduced to demonstrate their applications in production of proteins and chemicals. Furthermore, efforts of promoter engineering, including site-directed mutagenesis, hybrid promoter, and transcription factor regulation to expand the promoter toolbox were also summarized. This mini-review also provides useful information on promoters for the application of metabolic engineering in methylotrophic yeasts. KEY POINTS: • The characteristics of six methylotrophic yeasts and their promoters are described. • The applications of Komagataella phaffii and Ogataea polymorpha in metabolic engineeringare expounded. • Three promoter engineering strategies are introduced in order to expand the promoter toolbox.

The Finkelstein and Schoenfeld (FS) test is a popular generalized pairwise comparison approach to analyze prioritized composite endpoints (eg, components are assessed in order of clinical importance). Power and sample size estimation for the FS test, however, are generally done via simulation studies. This simulation approach can be extremely computationally burdensome, compounded by increasing number of composite endpoints and with increasing sample size. Here we propose an analytical solution to calculate power and sample size for commonly encountered two-component hierarchical composite endpoints. The power formulas are derived assuming underlying distributions in each of the component outcomes on the population level, which provide a computationally efficient and practical alternative to the standard simulation approach. Monte Carlo simulation results demonstrate that performance of the proposed power formulas are consistent with that of the simulation approach, and have generally desirable objective properties including robustness to mis-specified distributional assumptions. We demonstrate the application of the proposed formulas by calculating power and sample size for the Transthyretin Amyloidosis Cardiomyopathy Clinical Trial.

More indications proved that diet might be involved in the telomere length, a marker of biological aging and chronic diseases. Copper is widely viewed as one of the essential elements in the diet. Therefore, this study aimed to evaluate the relationship between telomere length and dietary copper intake in hypertension and provide a basis for guiding dietary copper intake in patients with hypertension.The data was collected from the National Health and Nutrition Examination Survey (NHANES) in 1999-2000 and 2001-2002. The relevance between telomere length and dietary copper intake in hypertension is assessed using a multivariable linear regression model.We gathered 1,867 participants with hypertension with assessed telomere length and dietary copper intake. We found that one unit increasing log-transformed dietary copper intake in hypertension was significantly associated with longer telomere length base pair (bp) (β = 112.20, 95% confidence interval [CI]: 5.48, 218.92), after controlling for covariates, including age, sex, ethnicity, body mass index (BMI), physical activity, and taking medication for hypertension. For the age group, we found that one unit increasing log-transformed dietary copper in hypertension was associated with longer telomere length (β = 237.95, 95% CI: 114.39, 361.51) in the age group45 years. The grouping was based on whether the participants take medication for hypertension. We found that one unit increasing log-transformed dietary copper in hypertension was associated with longer telomere length (β = 116.47, 95% CI: 0.72, 232.21) in the group that takes medication for hypertension.This study demonstrates that dietary copper intake was associated with longer telomere length in patients with hypertension, which provides evidence for guiding dietary copper intake in patients with hypertension. However, further studies are needed to evaluate the effect of copper supplementation on telomere length in patients with hypertension in well-designed random control studies and prospective studies.

Bio-manufacturing via microbial cell factory requires large promoter library for fine-tuned metabolic engineering. Ogataea polymorpha, one of the methylotrophic yeasts, possesses advantages in broad substrate spectrum, thermal-tolerance, and capacity to achieve high-density fermentation. However, a limited number of available promoters hinders the engineering of O. polymorpha for bio-productions. Here, we systematically characterized native promoters in O. polymorpha by both GFP fluorescence and fatty alcohol biosynthesis. Ten constitutive promoters (PPDH, PPYK, PFBA, PPGM, PGLK, PTRI, PGPI, PADH1, PTEF1 and PGCW14) were obtained with the activity range of 13%–130% of the common promoter PGAP (the promoter of glyceraldehyde-3-phosphate dehydrogenase), among which PPDH and PGCW14 were further verified by biosynthesis of fatty alcohol. Furthermore, the inducible promoters, including ethanol-induced PICL1, rhamnose-induced PLRA3 and PLRA4, and a bidirectional promoter (PMal-PPer) that is strongly induced by sucrose, further expanded the promoter toolbox in O. polymorpha. Finally, a series of hybrid promoters were constructed via engineering upstream activation sequence (UAS), which increased the activity of native promoter PLRA3 by 4.7–10.4 times without obvious leakage expression. Therefore, this study provided a group of constitutive, inducible, and hybrid promoters for metabolic engineering of O. polymorpha, and also a feasible strategy for rationally regulating the promoter strength.

Barriers to implementing infection prevention and control (IPC) practices may be experienced by healthcare workers (HCWs) caring for people with CF (PwCF), PwCF, and their families. We hypothesized that these stakeholders from CF centers with early adoption of the updated 2013 IPC guideline would experience fewer barriers implementing selected recommendations compared to stakeholders from CF centers with delayed adoption.In 2018-2019 we surveyed HCWs and PwCF/parents from 25 CF centers to identify knowledge, attitude, and practice barriers. Each center recruited five HCWs with different occupations. Pediatric centers recruited five parents of children18 years old and five young adults 18-21 years old. Adult centers recruited 10 adults ≥18 years old. We determined respondents' knowledge scores, the proportion who agreed with or perceived health benefits from recommendations, and reported adherence to recommendations.Knowledge scores, perception of health benefits, and adherence to selected practices were similar among participants from centers with early vs. delayed adoption, yet generally lower for inpatient nurses. IPC practitioners were less likely to perceive health benefits from PwCF wearing masks and HCWs wearing gowns and gloves. Among HCWs, 57% educated75% of PwCF/parents about IPC and 43% advised75% of PwCF/parents to avoid socializing with other PwCF. Among PwCF/parents, 69%, 53%, and 56% reported discussions with their care teams about performing hand hygiene, avoiding socialization, or the 2013 IPC guideline, respectively.Our findings suggest opportunities for targeted education for specific HCW occupations and for PwCF and their families.

Recent advances in immunotherapy have fundamentally changed the landscape of cancer treatment by leveraging the specificity and selectivity of the adaptive immune system to kill cancer cells. These successes have ushered in a new wave of research aimed at understanding immune recognition with the hope of developing newer immunotherapies. The advent of clustered regularly interspaced short palindromic repeats (CRISPR) technologies and advancement of multiomics modalities have greatly accelerated the discovery process. Here, we review the current literature surrounding CRISPR screens within the context of tumor immunology, provide essential components needed to conduct immune-specific CRISPR screens, and present avenues for future research.

To investigate the computed tomography (CT) and integrated positron-emission tomography (PET)/CT findings of primary pulmonary lymphoepithelioma-like carcinoma (PLELC).The imaging and histopathological data of 215 patients with PLELC confirmed at histopathology were analysed retrospectively. All patients underwent CT, and 70 underwent PET/CT. None of the cohort had nasopharyngeal lymphoepithelioma-like carcinoma.The PLELC was demonstrated as a solitary nodule/mass in 188 cases (188/215, 87%), multiple nodules/masses in 12 cases (12/215, 6%), lobar or segmental consolidation in 15 cases (15/215, 7%). The tumour showed a well-defined margin in 171 cases (171/215, 80%), lobular sign in 177 cases (177/215, 82%), and spicule sign in 91 cases (91/215, 42%). Most of the cases showed homogeneous density in unenhanced CT (128/215, 60%), and vascular shadows inside the tumour in the arterial stage were found in 105 cases (105/158, 66%). Involvement of the bronchus was found in 154 cases (154/215, 72%). Hilar or mediastinal lymph nodes were enlarged in 160 patients (160/215, 74%). Seventy cases demonstrated avid 2-[PLELC should be suspected when a large, lobulate, well-defined lung tumour with homogeneous density, vascular encasement, and high

To investigate the downstream rim seal gas ingestion characteristics of a 1.5-stage turbine, the URANS equations were solved numerically using the SST turbulence model. The effects of different purge flow rates and the second vane on the ingestion characteristics of the aft cavity and the nonuniform fluctuations of the main gas path pressure are analysed. The results showed that the aft cavity is affected by the combined effects of the blade and the second vane, and the potential field at the leading edge of the second vane greatly influence the airflow variation in the aft cavity, which enhances the ingress of the mainstream into the wheel-space. The front purge flow weakens the egress between the suction side of the blade and the suction side of the second vane. The potential field at the leading edge of the second vane suppresses the nonuniform distribution of airflow in the aft cavity caused by the rotational effect of the blade.

Diabetes-related complications reflect longstanding damage to small and large vessels throughout the body. In addition to the duration of diabetes and poor glycemic control, genetic factors are important contributors to the variability in the development of vascular complications. Early heritability studies found strong familial clustering of both macrovascular and microvascular complications. However, they were limited by small sample sizes and large phenotypic heterogeneity, leading to less accurate estimates. We take advantage of two independent studies—UK Biobank and the Action to Control Cardiovascular Risk in Diabetes trial—to survey the single nucleotide polymorphism heritability for diabetes microvascular (diabetic kidney disease and diabetic retinopathy) and macrovascular (cardiovascular events) complications. Heritability for diabetic kidney disease was estimated at 29%. The heritability estimate for microalbuminuria ranged from 24 to 60% and was 41% for macroalbuminuria. Heritability estimates of diabetic retinopathy ranged from 6 to 33%, depending on the phenotype definition. More severe diabetes retinopathy possessed higher genetic contributions. We show, for the first time, that rare variants account for much of the heritability of diabetic retinopathy. This study suggests that a large portion of the genetic risk of diabetes complications is yet to be discovered and emphasizes the need for additional genetic studies of diabetes complications.

Gradient meshes, an advanced vector graphics primitive, are widely used by designers for creating scalable vector graphics. Traditional variants require a regular rectangular topology, which is a severe design restriction. The more advanced subdivision gradient mesh allows for an arbitrary manifold topology and is based on subdivision techniques to define the resulting colour surface. This also allows the artists to manipulate the geometry and colours at various levels of subdivision. Recent advances allow for the interpolation of both geometry and colour, local detail following edits at coarser subdivision levels and sharp colour transitions. A shortcoming of all existing methods is their dependence on global refinement, which makes them unsuitable for real-time (commercial) design applications. We present a novel method that incorporates the idea of feature-adaptive subdivision and uses approximating patches suitable for hardware tessellation with real-time performance. Further novel features include multiple interaction mechanisms and self-intersection prevention during interactive design/editing.

Background Anterior lumbar interbody fusion (ALIF) and lateral lumbar interbody fusion (LLIF) are commonly performed in separate stages with a change in patient positioning to provide arthrodesis in the lumbar spine. Interest has recently emerged in performing these approaches as a single-stage surgery with the patient in the lateral decubitus position. The objective of this study was to evaluate the technical feasibility of performing minimally invasive anterolateral fixation in a single supine position. Methods Two fresh-frozen cadavers were used and placed supine. Standard minimally invasive anterior access was obtained by the approach surgeon. An ALIF was performed at L5-S1 using standard techniques. A lateral incision was marked over the L4-5 disc space using fluoroscopy. Direct palpation and bimanual dissection were achieved through the same anterior incision, allowing access to the retroperitoneal space. Dilator and retractor docking was performed under fluoroscopic guidance. Direct visualization of the docking hardware through the anterior incision was used to ensure the safety of peritoneal contents and vasculature. The LLIF was then performed using standard techniques at L4-5. Results Plain radiographs confirmed acceptable positioning of both the ALIF and LLIF grafts. No injury to the cadaveric peritoneum, vasculature, or lumbar plexus was observed. A slightly enlarged anterior incision also permitted retroperitoneal access and visualization of the L3-4 disc space. Conclusion This cadaver feasibility study demonstrates that combined minimally invasive ALIF and LLIF procedures may be performed as a single-stage with the patient in the supine position. Clinical consideration and study of this approach are warranted.

International audience; This paper is a contribution to fasten integration of battery pack innovation in commercial Electric Vehicles (EV) through massive digitalization: a seamless process detailed for battery design, battery safety, and battery management. Selected results of studies carried out on the EV value chain from design to recycling steps are presented, highlighting the importance of seamless integration and holistic state of mind when designing EV. Association between experimental and numerical approaches for efficient innovative EV production is crucial to achieve easy commercialisation. Successful forecasting of aging and thermal runaway evolution from single cell failure at module level using such methods illustrates their great potential. Hardware key counterparts under development are also introduced and give an idea of future architecture of EV battery packs and overall improvement of EV energy efficiency. Finally, a flexible and easily modifiable solution for battery electric vehicle (BEV) that allows rapid and cost-effective integration of future innovation is presented. This paper globally illustrates key breakthroughs gained in the context of the collaborative research project named ‘DEMOBASE’, for DEsign and MOdelling for improved BAttery Safety and Efficiency successfully submitted for funding by the European Commission in response to a 2017 call dedicated to ‘Green Vehicles’ under the EU Horizon 2020 work programme “Smart, green and integrated transport”.