NCoR repression of LXRs restricts macrophage biosynthesis of insulin-sensitizing omega 3 fatty acids.

Macrophage-mediated inflammation is a major contributor to obesity-associated insulin resistance. The corepressor NCoR interacts with inflammatory pathway genes in macrophages, suggesting that its removal would result in increased activity of inflammatory responses. Surprisingly, we find that macrophage-specific deletion of NCoR instead results in an anti-inflammatory phenotype along with robust systemic insulin sensitization in obese mice. We present evidence that derepression of LXRs contributes to this paradoxical anti-inflammatory phenotype by causing increased expression of genes that direct biosynthesis of palmitoleic acid and ω3 fatty acids. Remarkably, the increased ω3 fatty acid levels primarily inhibit NF-κB-dependent inflammatory responses by uncoupling NF-κB binding and enhancer/promoter histone acetylation from subsequent steps required for proinflammatory gene activation. This provides a mechanism for the in vivo anti-inflammatory insulin-sensitive phenotype observed in mice with macrophage-specific deletion of NCoR. Therapeutic methods to harness this mechanism could lead to a new approach to insulin-sensitizing therapies.

Adipocyte NCoR knockout decreases PPARγ phosphorylation and enhances PPARγ activity and insulin sensitivity.

Insulin resistance, tissue inflammation, and adipose tissue dysfunction are features of obesity and Type 2 diabetes. We generated adipocyte-specific Nuclear Receptor Corepressor (NCoR) knockout (AKO) mice to investigate the function of NCoR in adipocyte biology, glucose and insulin homeostasis. Despite increased obesity, glucose tolerance was improved in AKO mice, and clamp studies demonstrated enhanced insulin sensitivity in liver, muscle, and fat. Adipose tissue macrophage infiltration and inflammation were also decreased. PPARγ response genes were upregulated in adipose tissue from AKO mice and CDK5-mediated PPARγ ser-273 phosphorylation was reduced, creating a constitutively active PPARγ state. This identifies NCoR as an adaptor protein that enhances the ability of CDK5 to associate with and phosphorylate PPARγ. The dominant function of adipocyte NCoR is to transrepress PPARγ and promote PPARγ ser-273 phosphorylation, such that NCoR deletion leads to adipogenesis, reduced inflammation, and enhanced systemic insulin sensitivity, phenocopying the TZD-treated state.

Selective prebiotic formation of RNA pyrimidine and DNA purine nucleosides.

The nature of the first genetic polymer is the subject of major debate1. Although the 'RNA world' theory suggests that RNA was the first replicable information carrier of the prebiotic era-that is, prior to the dawn of life2,3-other evidence implies that life may have started with a heterogeneous nucleic acid genetic system that included both RNA and DNA4. Such a theory streamlines the eventual 'genetic takeover' of homogeneous DNA from RNA as the principal information-storage molecule, but requires a selective abiotic synthesis of both RNA and DNA building blocks in the same local primordial geochemical scenario. Here we demonstrate a high-yielding, completely stereo-, regio- and furanosyl-selective prebiotic synthesis of the purine deoxyribonucleosides: deoxyadenosine and deoxyinosine. Our synthesis uses key intermediates in the prebiotic synthesis of the canonical pyrimidine ribonucleosides (cytidine and uridine), and we show that, once generated, the pyrimidines persist throughout the synthesis of the purine deoxyribonucleosides, leading to a mixture of deoxyadenosine, deoxyinosine, cytidine and uridine. These results support the notion that purine deoxyribonucleosides and pyrimidine ribonucleosides may have coexisted before the emergence of life5.

An extended conformation of SARS-CoV-2 main protease reveals allosteric targets.

SignificanceThe coronavirus main protease (Mpro) is required for viral replication. Here, we obtained the extended conformation of the native monomer of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Mpro by trapping it with nanobodies and found that the catalytic domain and the helix domain dissociate, revealing allosteric targets. Another monomeric state is termed compact conformation and is similar to one protomer of the dimeric form. We designed a Nanoluc Binary Techonology (NanoBiT)-based high-throughput allosteric inhibitor assay based on structural conformational change. Our results provide insight into the maturation, dimerization, and catalysis of the coronavirus Mpro and pave a way to develop an anticoronaviral drug through targeting the maturation process to inhibit the autocleavage of Mpro.

Investigation on the machinability of polycrystalline ZnSe by elliptical vibration diamond cutting.

Polycrystalline zinc selenide is widely used in advanced optical systems due to its superior optical properties. However, the soft and brittle properties bring a challenge for high-quality surface processing. In recent years, elliptical vibration cutting has been proven as a promising method for machining brittle materials. In the present research, a series of grooving and planning experiments were carried out to investigate the machinability of zinc selenide with elliptical vibration cutting. The removal mechanism was analyzed from fracture characteristics, chip morphology, and phase transformation. The results show that elliptical vibration cutting is effective in suppressing cleavage-induced craters. Reducing the nominal cutting speed is beneficial to inhibit the spring back-induced tearing of grains. A 94-time increase in the critical depth of cut was achieved by vibration trajectory optimization compared to ordinary cutting. Moreover, the influence mechanism of feed on the evolution of surface morphology was revealed. Finally, a zinc selenide microlens array was successfully fabricated. The performance was evaluated by geometric parameter measurements and a multiple imaging test. The findings provide a prospective method for ductile regime machining of zinc selenide.

Characteristics associated with response to subcutaneously administered anti-CGRP monoclonal antibody medications in a real-world community cohort of persons living with migraine: A retrospective clinical and genetic study.

OBJECTIVE: To evaluate response to anti-calcitonin gene-related peptide (CGRP) migraine preventives in a real-world community cohort of persons living with migraine and to identify clinical and genetic characteristics associated with efficacious response. BACKGROUND: Erenumab-aooeb, fremanezumab-vrfm, and galcanezumab-gnlm target CGRP or its receptor; however, many patients are non-responsive. METHODS: In this retrospective clinical and genetic study, we identified 1077 adult patients who satisfied the International Classification of Headache Disorders, 3rd edition, criteria for migraine without aura, migraine with aura, or chronic migraine and who were prescribed an anti-CGRP migraine preventive between May 2018 and May 2021. Screening of 558 patients identified 289 with data at baseline and first follow-up visits; data were available for 161 patients at a second follow-up visit. The primary outcome was migraine days per month (MDM). In 198 genotyped patients, we evaluated associations between responders (i.e., patients with ≥50% reduction in MDM at follow-up) and genes involved in CGRP signaling or pharmacological response, and genetic and polygenic risk scores. RESULTS: The median time to first follow-up was 4.4 (0.9-22) months after preventive start. At the second follow-up, 5.7 (0.9-13) months later, 145 patients had continued on the same preventive. Preventives had strong, persistent effects in reducing MDM in responders (follow-up 1: η2 = 0.26, follow-up 2: η2 = 0.22). At the first but not second follow-up: galcanezumab had a larger effect than erenumab, while no difference was seen at either follow-up between galcanezumab and fremanezumab or fremanezumab and erenumab. The decrease in MDM at follow-up was generally proportional to baseline MDM, larger in females, and increased with months on medication. At the first follow-up only, patients with prior hospitalization for migraine or who had not responded to more preventive regimens had a smaller decrease in MDM. Reasons for stopping or switching a preventive varied between medications and were often related to cost and insurance coverage. At both follow-ups, patient tolerance (1: 92.2% [262/284]; 2: 95.2% [141/145]) and continued use (1: 77.5% [224/289]; 2: 80.6% [116/145]) were high and similar across preventives. Response consistency (always non-responders: 31.7% [46/145]; always responders: 56.5% [82/145], and one-time only responders: 11.7% [17/145]) was also similar across preventives. Non-responder status had nominally significant associations with rs12615320-G in RAMP1 (odds ratio [95% confidence interval]: 4.7 [1.5, 14.7]), and rs4680-A in COMT (0.6[0.4, 0.9]). Non-responders had a lower mean genetic risk score than responders (1.0 vs. 1.1; t(df) = -1.75(174.84), p = 0.041), and the fraction of responders increased with genetic and polygenic risk score percentile. CONCLUSIONS: In this real-world setting, anti-CGRP preventives reduced MDM persistently and had similar and large effect sizes on MDM reduction; however, clinical and genetic factors influenced response.

Novel reference range values for serum testosterone: a cross-sectional study of 200,000 males.

PURPOSE: To better understand the effects of aging, metabolic syndrome, diurnal variation, and seasonal variation on serum testosterone levels in the context of current guideline statements on testosterone deficiency. METHODS: This cross-sectional study utilized the United Kingdom Biobank. Physical examination, anthropomorphic measurements, and laboratory evaluation were performed at the time of enrollment from 2006 to 2010. The primary outcomes were the effect of age, the presence of metabolic syndrome, the time of day, and the month of the year on serum testosterone levels. RESULTS: Among 197,883 included men, the 5th, 25th, 50th, 75th and 95th percentile testosterone levels in men without metabolic syndrome were significantly higher than those in men with metabolic syndrome at every decade of life (p < 0.001). The average testosterone level within each group (men without metabolic syndrome vs. men with) was clinically similar across decade of life (12.43 in 40's 12.29 in 50's 12.24 in 60's vs. 10.69 in 40's 10.56 in 50's 10.63 in 60's respectively). Average testosterone levels decreased with blood draws later in the day ranging from 10.91 to 12.74 nmol/L (p < 0.01). Similarly, there was seasonal variation in serum testosterone ranging from 11.86 to 12.18 nmol/L (p < 0.01). CONCLUSIONS: We found significant variation in serum testosterone according to the presence of metabolic syndrome and time of laboratory draw, but not according to age. These data challenge the prior dogma of age-related hypogonadism and favor an individualized approach towards serum testosterone measurement and interpretation. However, further studies are needed to correlate these population-based data with individuals' hypogonadal symptoms.

Electroacupuncture improves vascular cognitive impairment no dementia: A Randomized Clinical Trial.

BACKGROUND: Electroacupuncture (EA) could represent a clinically effective treatment strategy for patients with vascular cognitive impairment no dementia (VCIND). This randomized trial aims to explore the underlying mechanism of EA in VCIND patients through cognitive function assessment and neuroimaging assessment. METHODS: 140 eligible patients with VCIND were recruited and randomly divided into EA group (n = 70) and Control group (n = 70). The Montreal Cognitive Assessment (MoCA), and the Auditory Verbal Learning Test (AVLT), the Stroop color-naming task (STROOP), and the resting-state functional magnetic resonance imaging assessment. The EA group received treatment for 30 min/day, 5 times/week, for 8 weeks. RESULTS: EA intervention could increase the MoCA score and improve the neutral and consistency response of the STROOP test in VCIND patients (P < 0.05). fMRI functional connectivity analysis showed that, after EA, the default mode network (DMN) function of the posterior cingulate gyrus, left middle frontal gyrus, left anterior cingulate gyrus, left and right superior temporal gyrus, right insula, left precentral gyrus and other brain regions were significantly higher than that in the control group. The functional connectivity between the posterior cingulate gyrus-left middle frontal gyrus and the posterior cingulate gyrus-right superior temporal gyrus was positively correlated with cognitive function (P < 0.05). Gray Matter Volume increased in VCIND after EA(P < 0.05). CONCLUSIONS: EA can increase the functional connectivity between posterior cingulate gyrus-other gyri in VCIND patients. The functional connectivity is positively correlated with cognitive function.

[A Review on Automatic Detection Algorithm for Patient-Ventilator Asynchrony during Mechanical Ventilation].

This study summarizes the application of automatic recognition technologies for patient-ventilator asynchrony (PVA) during mechanical ventilation. In the early stages, the method of setting rules and thresholds relied on manual interpretation of ventilator parameters and waveforms. While these methods were intuitive and easy to operate, they were relatively sensitive in threshold setting and rule selection and could not adapt well to minor changes in patient status. Subsequently, machine learning and deep learning technologies began to emerge and develop. These technologies automatically extract and learn data characteristics through algorithms, making PVA detection more robust and universal. Among them, logistic regression, support vector machines, random forest, hidden Markov models, convolutional autoencoders, long short-term memory networks, one-dimensional convolutional neural networks, etc., have all been successfully used for PVA recognition. Despite the significant advancements in feature extraction through deep learning methods, their demand for labelled data is high, potentially consuming significant medical resources. Therefore, the combination of reinforcement learning and self-supervised learning may be a viable solution. In addition, most algorithm validations are based on a single dataset, so the need for cross-dataset validation in the future will be an important and challenging direction for development.

Structure basis of two nanobodies neutralizing SARS-CoV-2 Omicron variant by targeting ultra-conservative epitopes.

The evolving SARS-CoV-2 Omicron strain has repeatedly caused widespread disease epidemics, and effective antibody drugs continue to be in short supply. Here, we identified a batch of nanobodies with high affinity for receptor binding domain (RBD) of SARS-CoV-2 spike protein, separated them into three classes using high performance liquid chromatography (HPLC), and then resolved the crystal structure of the ternary complexes of two non-competing nanobodies (NB1C6 and NB1B5) with RBD using X-ray crystallography. The structures showed that NB1B5 and NB1C6 bind to the left and right flank of the RBD, respectively, and that the binding epitopes are highly conserved cryptic sites in all SARS-CoV-2 mutant strains, as well as that NB1B5 can effectively block the ACE2. These two nanobodies were covalently linked into multivalent and bi-paratopic formats, and have a high affinity and neutralization potency for omicron, potentially inhibiting viral escape. The binding sites of these two nanobodies are relatively conserved, which help guide the structural design of antibodies targeting future variants of SARS-CoV-2 to combat COVID-19 epidemics and pandemics.

Efficacy of cell-free DNA methylation-based blood test for colorectal cancer screening in high-risk population: a prospective cohort study.

BACKGROUND: Although colonoscopy is the standard screening test for colorectal cancer (CRC), its use is limited by a poor compliance rate, the need for extensive bowel preparation, and the risk of complications. As an alternative, an FDA-approved stool-based DNA test, Cologuard, has demonstrated satisfactory detection performance for CRC, but its compliance rate remains suboptimal, primarily attributable to individuals' reluctance to provide stool samples. METHODS: We developed a noninvasive blood-based CRC test, ColonSecure, based on cell-free DNA containing cancer-specific CpG island methylation patterns. We initially screened publicly available datasets for differentially methylated CpG sites in CRC with prediction potential. Subsequently, we performed two sequential bisulfite-free methylation sequencing on blood samples obtained from CRC patients and non-cancer controls. Through rigorous evaluation of each marker and machine learning-assisted feature selection, we identified 149 hypermethylated markers from over 193,000 CpG sites. These markers were then utilized to construct the ColonSecure model, enabling accurate CRC detection. RESULTS: We validated the efficacy of our cell-free DNA methylation-based blood test for CRC screening with 3493 high-risk individuals identified from 114,136 urban residents. The ColonSecure test identified 89 out of 103 CRC patients diagnosed by the follow-up colonoscopy, outperforming CEA, CRP, and CA19-9 (with a sensitivity of 86.4% compared to 45.6%, 39.8%, and 25.2% for CEA, CRP, and CA19-9 respectively; an AUROC of 0.956 compared to an AUROC of < 0.77 for other methods). CONCLUSION: Our observations emphasize the potential of our multiple cfDNA methylation marker-based test for CRC screening in high-risk populations.

Association of rare, recurrent nonsynonymous variants in the germline of prostate cancer patients of African ancestry.

BACKGROUND: Although men of African ancestry (AA) have the highest mortality rate from prostate cancer (PCa), relatively little is known about the germline variants that are associated with PCa risk in AA men. The goal of this study is to systematically evaluate rare, recurrent nonsynonymous variants across the exome for their association with PCa in AA men. METHODS: Whole exome sequencing (WES) of germline DNA in two AA PCa patient cohorts of Johns Hopkins Hospital (N = 960) and Wayne State University (N = 747) was performed. All nonsynonymous variants present in both case cohorts, with a carrier rate between 0.5% and 1%, were identified. Their carrier rates were compared with rates from 8128 African/African American (AFR) control subjects from The Genome Aggregation Database (gnomAD) using Fisher's exact test. Significant variants, defined as false discovery rate (FDR) adjusted p-value ≤ 0.05, were further evaluated in AA PCa cases (N = 132) and controls (N = 1184) from the UK Biobank (UKB). RESULTS: Two variants reached a pre-specified statistical significance level. The first was p.R14Q in GPRC5C (found in 0.47% of PCa cases and 0.01% of population controls); odds ratio (OR) for PCa was 37.46 (95% confidence interval CI 4.68-299.72), pexact = 7.01E-06, FDR-adjusted p-value = 0.05. The second was p.R511Q in IGF1R (found in 0.53% of PCa cases and 0.01% of population controls); OR for PCa was 21.54 (95%CI 4.65-99.76), pexact = 5.51E-06, FDR-adjusted p-value = 0.05. The mean percentage of African ancestry was similar between variant carriers and noncarriers of each variant, p > 0.05. In the UKB AA men, GPRC5C R14Q was 0.76% and 0.08% in cases and controls, respectively, OR for PCa was 9.00 (95%CI 0.56-145.23), pexact = 0.19. However, IGF1R R511Q was not found in cases or controls. CONCLUSIONS: This WES study identified two rare, recurrent nonsynonymous PCa risk-associated variants in AA. Confirmation in additional large populations of AA PCa cases and controls is required.

Cutting depth-oriented ductile machining of infrared micro-lens arrays by elliptical vibration cutting.

Infrared micro-lens arrays (MLAs) are widely used in advanced optical systems due to their advantages such as low focusing depth and high sensitivity. Elliptical vibration cutting (EVC) is a promising approach for the fabrication of MLAs on infrared brittle materials. However, the mechanism of ductile machining of MLAs prepared by EVC has not been fully elucidated so far. In this paper, based on the vibration intermittent cutting characteristics and the transient material removal state, a ductile machining model of MLAs on brittle material by EVC was established. This model effectively calculates the subsurface damage of the machined surface and realizes the prediction of the critical depth for ductile machining of MLAs. Furthermore, the concave micro-lenses were prepared on single crystal silicon by EVC and ordinary cutting (OC) to verify this model. The results demonstrated that EVC could significantly enhance the critical depth by approximately 4.3 times compared to OC. Microstructural surface damage predominantly occurs at the exit side of the tool cutting. This proposed model accurately predicts the actual critical depth, with an average error of about 7.5%. Additionally, elevating the amplitude in the depth of cut direction could increase the critical depth, but a larger amplitude would inhibit the increase of the critical depth. This study contributes to a better understanding of ductile machining of microstructure on brittle materials and facilitates the process optimization of MLAs fabrication using EVC.

Preparation and characterization of nanobodies targeting SARS-CoV-2 papain-like protease.

Coronavirus Papain-like protease (PLpro) mediates the cleavage of viral polyproteins and assists the virus escaping from innate immune response. Thus, PLpro is an attractive target for the development of broad-spectrum drugs as it has a conserved structure across different coronaviruses. In this study, we purified SARS-CoV-2 PLpro as an immune antigen, constructed a nanobody phage display library, and identified a set of nanobodies with high affinity for SARS-CoV-2. In addition, enzyme activity experiments demonstrated that two nanobodies had a significant inhibitory effect on the PLpro. These nanobodies should therefore be investigated as candidates for the treatment of coronaviruses.

ß-sitosterol targets glucocorticoid receptor to reduce airway inflammation and remodeling in allergic asthma.

INTRODUCTION: In most asthma patients, symptoms are controlled by treatment with glucocorticoid, but long-term or high-dose use can produce adverse effects. Therefore, it is crucial to find new therapeutic strategies. ß-sitosterol could suppress type Ⅱ inflammation in ovalbumin (OVA)-induced mice, but its mechanisms have remained unclear. METHODS: A binding activity of ß-sitosterol with glucocorticoid receptor (GR) was analyzed by molecular docking. Human bronchial epithelial cells (BEAS-2B) and human bronchial smooth muscle cells (HBSMC) were treated with different concentrations (0, 1, 5, 10, 20, and 50 µg/mL) of ß-sitosterol for suitable concentration selection. In transforming growth factor (TGF)-ß1 treated BEAS-2B and HBSMC, cells were treated with 20 µg/mL ß-sitosterol or dexamethasone (Dex) to analyze its possible mechanism. In OVA-induced mice, 2.5 mg/kg ß-sitosterol or Dex administration was performed to analyze the therapeutic mechanism of ß-sitosterol. A GR antagonist RU486 was used to confirm the mechanism of ß-sitosterol in the treatment of asthma. RESULTS: A good binding of ß-sitosterol to GR (score = -8.2 kcal/mol) was found, and the GR expression was upregulated with ß-sitosterol dose increase in BEAS-2B and HBSMC. Interleukin (IL)-25 and IL-33 secretion was significantly decreased by ß-sitosterol in the TGF-ß1-induced BEAS-2B, and the levels of collagen 1A and α-smooth muscle actin (SMA) were reduced in the TGF-ß1-induced HBSMC. In the OVA-challenged mice, ß-sitosterol treatment improved airway inflammation and remodeling through suppressing type Ⅱ immune response and collagen deposition. The therapeutic effects of ß-sitosterol were similar to Dex treatment in vitro and in vivo. RU486 treatment clearly hampered the therapeutic effects of ß-sitosterol in the TGF-ß1-induced cells and OVA-induced mice. CONCLUSION: This study identified that ß-sitosterol binds GR to perform its functions in asthma treatment. ß-sitosterol represent a potential therapeutic drug for allergic asthma.

Bifunctional Thiourea-Catalyzed Enantioselective Aza-Friedel-Crafts Reaction of 3-Aminobenzofurans with Isatin-Derived Ketimines.

A quinine-derived thiourea-promoted enantioselective aza-Friedel-Crafts reaction of 3-aminobenzofurans with isatin-derived ketimines is developed, providing a variety of 3-benzofuran-3-amino-2-oxindoles bearing a quaternary stereocenter with good to excellent yields (72-95%) and moderate to excellent enantioselectivities (48-97%). The synthetic potential of this concise and efficient protocol is revealed by gram-scale preparation and further transformation of the adduct to an optically pure spirocyclic oxindole.

Diagnostic Value of Serum Golgi Protein 73 for Liver Fibrosis: A Systematic Review and Meta-Analysis.

BACKGROUND: The assessment of liver fibrosis has been a critical component in the clinical management of liver diseases. We performed a meta-analysis to evaluate serum Golgi protein 73 (GP73) in the diagnosis of liver fibrosis. METHODS: A literature search was performed in eight databases until July 13, 2022. We strictly searched studies according to inclusion and exclusion criteria, extracted data, and then assessed quality. We pooled the sensitivity, specificity, and other diagnostic estimates of serum GP73 to assess liver fibrosis. Moreover, publication bias, threshold analysis, sensitivity analysis, meta-regression, subgroup analysis, and post-test probability were evaluated. RESULTS: Our research integrated 16 articles including 3,676 patients. Potential publication bias and threshold effect were not found. The pooled sensitivity, specificity, and area under the curve of the summary receiver operating characteristic curve were 0.63, 0.79, and 0.818 for significant fibrosis; 0.77, 0.76, and 0.852 for advanced fibrosis; and 0.80, 0.76, and 0.894 for cirrhosis, respectively. The aetiology was one of the important sources of heterogeneity. CONCLUSION: Serum GP73 was a feasible diagnostic marker for liver fibrosis, which is of great significance for the clinical management of liver diseases.

Association of sickle cell trait with adverse pregnancy outcomes in a population-based cohort.

INTRODUCTION: Sickle cell trait (SCT) is common in African descendants. Its association with several adverse pregnancy outcomes (APOs) has been reported but remains inconsistent. The objectives of this study are to test associations of SCT with APOs in non-Hispanic Black women, including (1) validate the associations of SCT with previously reported APOs, (2) test novel associations of SCT with broad spectrum of APOs, and (3) estimate the attributable risk of SCT for implicated APOs. MATERIAL AND METHODS: This is a retrospective analysis of a prospectively designed population-based cohort. Women/participants were self-reported non-Hispanic Black women from the UK Biobank (UKB). SCT status was determined based on heterozygous Glu6Val in the HBB gene. Several APOs were studied, including four previously reported SCT-associated APOs (preeclampsia, bacteriuria, pregnancy loss, and preterm delivery), and broad conditions related to pregnancy, childbirth, and the puerperium. APOs were curated by experts' peer review and consensus processes. Associations of SCT with APOs were tested by estimating its relative risk and 95% confidence interval (95% CI), adjusting for number of live births and age at first birth. Attributable risk proportion (ARP) and population attributable risk proportion (PARP) of SCT to APOs were estimated. RESULTS: Among the 4057 self-reported non-Hispanic Black women with pregnancy records in the UKB, 581 (14.32%) were SCT carriers. For four previously reported SCT-associated APOs, two were confirmed at a nominal P < 0.05; relative risk (RR) was 2.39 (95% CI 1.09-5.23) for preeclampsia, and 4.85 (95% CI 1.77-13.27) for bacteriuria. SCT contributed substantially to these two APOs among SCT carriers, with attributable risk proportion estimated at 61.00% and 68.96% for preeclampsia and bacteriuria, respectively. SCT also contributed substantially to these two APOs in the population (self-reported Black UK women), with population attributable risk proportion estimated at 18.30% and 24.14% for preeclampsia and bacteriuria, respectively. In addition, novel associations were found for seven other APOs (nominal P < 0.05). CONCLUSIONS: SCT is significantly associated with APOs in this study and contributes substantially to APOs among self-reported Black women in the UK. Confirmation of these findings in independent study populations is required.

Calibration of polygenic risk scores is required prior to clinical implementation: results of three common cancers in UKB.

BACKGROUND: SNP-based polygenic risk scores have recently been adopted in the clinic for risk assessment of some common diseases. Their validity is supported by a consistent trend between their percentile rank and disease risk in populations. However, for clinical use at the individual level, the reliability of score values is necessary considering they are directly used to calculate remaining lifetime risk. OBJECTIVES: We assessed the reliability of polygenic score values to estimate prostate cancer (PCa), breast cancer (BCa) and colorectal cancer (CRC) risk in three incident cohorts from the UK Biobank (n>500 000). METHODS: Cancer-specific Genetic Risk Score (GRS), a well-established population-standardised polygenic risk score, was calculated. RESULTS: A systematic bias was found between estimated risks (GRS values) and observed risks; ß (95% CI) was 0.67 (0.58-0.76), 0.74 (0.65-0.84) and 0.82 (0.75-0.89), respectively, for PCa, BCa and CRC, all significantly lower than 1.00 (perfect calibration), p<0.001. After applying a correction factor derived from a training data set, the ß for corrected GRS values in an independent testing data set were 1.09 (1.05-1.13), 1.00 (0.88-1.12) and 1.08 (0.96-1.21), respectively, for PCa, BCa and CRC. CONCLUSION: Assessing the calibration of polygenic risk scores is necessary and feasible to ensure their reliability prior to clinical implementation.

Random spherical microlens array fabricated by elliptical vibration diamond cutting and molding.

Microlens arrays (MLAs) are widely used in homogenized laser beams due to excellent optical properties. However, the interference effect generated in traditional MLA (tMLA) homogenization will reduce the quality of the homogenized spot. Hence, the random MLA (rMLA) was proposed to reduce the interference effect in the homogenization process. To achieve mass production of these high-quality optical homogenization components, the rMLA with randomness in both period and sag height was proposed first. Subsequently, MLA molds were ultra-precision machined on S316 molding steel by elliptical vibration diamond cutting. Furthermore, the rMLA components were precisely fabricated by applying molding technology. Finally, Zemax simulation and homogenization experiments were carried out to verify the advantage of the designed rMLA.