Evaluating and implementing block jackknife resampling Mendelian randomization to mitigate bias induced by overlapping samples.

Participant overlap can induce overfitting bias into Mendelian randomization (MR) and polygenic risk score (PRS) studies. Here, we evaluated a block jackknife resampling framework for genome-wide association studies (GWAS) and PRS construction to mitigate overfitting bias in MR analyses and implemented this study design in a causal inference setting using data from the UK Biobank. We simulated PRS and MR under three scenarios: (1) using weighted SNP estimates from an external GWAS, (2) using weighted SNP estimates from an overlapping GWAS sample and (3) using a block jackknife resampling framework. Based on a P-value threshold to derive genetic instruments for MR studies (P < 5 × 10-8) and a 10% variance in the exposure explained by all SNPs, block-jackknifing PRS did not suffer from overfitting bias (mean R2 = 0.034) compared with the externally weighted PRS (mean R2 = 0.040). In contrast, genetic instruments derived from overlapping samples explained a higher variance (mean R2 = 0.048) compared with the externally derived score. Overfitting became considerably more severe when using a more liberal P-value threshold to construct PRS (e.g. P < 0.05, overlapping sample PRS mean R2 = 0.103, externally weighted PRS mean R2 = 0.086), whereas estimates using jackknife score remained robust to overfitting (mean R2 = 0.084). Using block jackknife resampling MR in an applied analysis, we examined the effects of body mass index on circulating biomarkers which provided comparable estimates to an externally weighted instrument, whereas the overfitted scores typically provided narrower confidence intervals. Furthermore, we extended this framework into sex-stratified, multivariate and bidirectional settings to investigate the effect of childhood body size on adult testosterone levels.

Research on the tilt-to-length coupling noise suppression method inside the gravitational wave detection telescope.

As an integral component of the laser interferometry measurement system, the tilt-to-length (TTL) coupling noise inside the telescope stands out as a critical noise factor that requires meticulous consideration. In the TianQin project, the non-geometric TTL-coupled noise inside the telescope should be less than 0.22 pm/Hz1/2. Additionally, the wavefront aberration RMS at the small pupil of the telescope needs to be better than 0.0065 λ. These requirements set for the telescope are exceptionally stringent. To address this challenge, this study aims to relax the wavefront aberration requirements by mitigating non-geometric TTL coupling noise, while ensuring the non-geometric TTL coupling noise remains below 0.22 pm/Hz1/2. By controlling the coupling aberration proportion, the wavefront aberration RMS at the small pupil of the telescope can be relaxed to 0.014 λ. Alternatively, optimizing the Gaussian beam waist radius can relax the wavefront aberration RMS to 0.016 λ. By simultaneously utilizing two optimization methods, the wavefront aberration at the small pupil of the telescope can be reduced to 0.033 λ, resulting in an impressive success rate of 91.15% in meeting the noise requirements.

Association between genetically proxied PCSK9 inhibition and prostate cancer risk: A Mendelian randomisation study.

BACKGROUND: Prostate cancer (PrCa) is the second most prevalent malignancy in men worldwide. Observational studies have linked the use of low-density lipoprotein cholesterol (LDL-c) lowering therapies with reduced risk of PrCa, which may potentially be attributable to confounding factors. In this study, we performed a drug target Mendelian randomisation (MR) analysis to evaluate the association of genetically proxied inhibition of LDL-c-lowering drug targets on risk of PrCa. METHODS AND FINDINGS: Single-nucleotide polymorphisms (SNPs) associated with LDL-c (P < 5 × 10-8) from the Global Lipids Genetics Consortium genome-wide association study (GWAS) (N = 1,320,016) and located in and around the HMGCR, NPC1L1, and PCSK9 genes were used to proxy the therapeutic inhibition of these targets. Summary-level data regarding the risk of total, advanced, and early-onset PrCa were obtained from the PRACTICAL consortium. Validation analyses were performed using genetic instruments from an LDL-c GWAS conducted on male UK Biobank participants of European ancestry (N = 201,678), as well as instruments selected based on liver-derived gene expression and circulation plasma levels of targets. We also investigated whether putative mediators may play a role in findings for traits previously implicated in PrCa risk (i.e., lipoprotein a (Lp(a)), body mass index (BMI), and testosterone). Applying two-sample MR using the inverse-variance weighted approach provided strong evidence supporting an effect of genetically proxied inhibition of PCSK9 (equivalent to a standard deviation (SD) reduction in LDL-c) on lower risk of total PrCa (odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.76 to 0.96, P = 9.15 × 10-3) and early-onset PrCa (OR = 0.70, 95% CI = 0.52 to 0.95, P = 0.023). Genetically proxied HMGCR inhibition provided a similar central effect estimate on PrCa risk, although with a wider 95% CI (OR = 0.83, 95% CI = 0.62 to 1.13, P = 0.244), whereas genetically proxied NPC1L1 inhibition had an effect on higher PrCa risk with a 95% CI that likewise included the null (OR = 1.34, 95% CI = 0.87 to 2.04, P = 0.180). Analyses using male-stratified instruments provided consistent results. Secondary MR analyses supported a genetically proxied effect of liver-specific PCSK9 expression (OR = 0.90 per SD reduction in PCSK9 expression, 95% CI = 0.86 to 0.95, P = 5.50 × 10-5) and circulating plasma levels of PCSK9 (OR = 0.93 per SD reduction in PCSK9 protein levels, 95% CI = 0.87 to 0.997, P = 0.04) on PrCa risk. Colocalization analyses identified strong evidence (posterior probability (PPA) = 81.3%) of a shared genetic variant (rs553741) between liver-derived PCSK9 expression and PrCa risk, whereas weak evidence was found for HMGCR (PPA = 0.33%) and NPC1L1 expression (PPA = 0.38%). Moreover, genetically proxied PCSK9 inhibition was strongly associated with Lp(a) levels (Beta = -0.08, 95% CI = -0.12 to -0.05, P = 1.00 × 10-5), but not BMI or testosterone, indicating a possible role for Lp(a) in the biological mechanism underlying the association between PCSK9 and PrCa. Notably, we emphasise that our estimates are based on a lifelong exposure that makes direct comparisons with trial results challenging. CONCLUSIONS: Our study supports a strong association between genetically proxied inhibition of PCSK9 and a lower risk of total and early-onset PrCa, potentially through an alternative mechanism other than the on-target effect on LDL-c. Further evidence from clinical studies is needed to confirm this finding as well as the putative mediatory role of Lp(a).

Synthesis and Bioevaluation of Novel Technetium-99m-Labeled Complexes with Norfloxacin HYNIC Derivatives for Bacterial Infection Imaging.

To seek a novel 99mTc-labeled quinolone derivative for bacterial infection SPECT imaging that aims to lower nontarget organ uptake, a novel norfloxacin 6-hydrazinoicotinamide (HYNIC) derivative (HYNICNF) was designed and synthesized. It was radiolabeled with different coligands, such as tricine, trisodium triphenylphosphine-3,3',3″-trisulfonate (TPPTS), sodium triphenylphosphine-3-monosulfonate (TPPMS), and ethylenediamine-N,N'-diacetic acid (EDDA), to obtain three 99mTc-labeled norfloxacin HYNIC complexes, namely, [99mTc]Tc-tricine-TPPTS-HYNICNF, [99mTc]Tc-tricine-TPPMS-HYNICNF, and [99mTc]Tc-EDDA-HYNICNF. These complexes were purified (RCP > 95%) and evaluated in vitro and in vivo for targeting bacteria. All three complexes are hydrophilic, maintain good stability, and specifically bind Staphylococcus aureus in vitro. The biodistribution in mice with bacterial infection demonstrated that [99mTc]Tc-EDDA-HYNICNF showed a higher abscess uptake and lower nontarget organ uptake and was able to distinguish bacterial infection and sterile inflammation. Single photon emission computed tomography (SPECT) image study in bacterial infection mice showed there was a visible accumulation in the infection site, suggesting that [99mTc]Tc-EDDA-HYNICNF is a potential radiotracer for bacterial infection imaging.

99mTc-CN7DG: A Highly Expected SPECT Imaging Agent of Cancer with Satisfactory Tumor Uptake and Tumor-to-Nontarget Ratios.

A novel glucose derivative (CN7DG) possessing an isonitrile as a coordinating group was synthesized, and 99mTc-CN7DG, which was expected to be a powerful tumor imaging agent for SPECT, was prepared in a kit by the reaction of CN7DG with SnCl2·2H2O and 99mTcO4-. 99mTc-CN7DG exhibited good stability and was transported via glucose transporters. Biodistribution results in mice bearing A549 tumor models showed that 99mTc-CN7DG had a higher uptake at the tumor sites and better tumor/blood and tumor/muscle ratios than did [18F]FDG and 99mTc-CN5DG. SPECT/CT imaging studies showed obvious accumulation in tumor sites, suggesting that 99mTc-CN7DG is a promising candidate for tumor imaging. Because 99mTc and 188Re stand for a "theranostic pair", 188Re-CN7DG is expected to be prepared as a promising agent for tumor therapy.

Radiolabeling and evaluation of a novel [99mTcN]2+ complex with deferoxamine dithiocarbamate as a potential agent for bacterial infection imaging.

In order to find a 99mTc-labeled deferoxamine radiotracer for bacterial infection imaging, deferoxamine dithiocarbamate (DFODTC) was successfully synthesized and it was radiolabeled with [99mTcN]2+ core to prepare the 99mTcN(DFODTC)2 complex. 99mTcN(DFODTC)2 was obtained with high radiochemical purity without further purification. The complex was lipophilic and exhibited good in vitro stability. According to the result of bacterial binding study, the binding of 99mTcN(DFODTC)2 to bacteria was specific. Biodistribution in mice study indicated that 99mTcN(DFODTC)2 had a higher uptake in bacterial infection tissues than in turpentine-induced abscesses at 120 min after injection, which showed that the radiotracer could differentiate between bacterial infection and sterile inflammation. SPECT/CT images showed that there was a clear accumulation in infection sites, suggesting that 99mTcN(DFODTC)2 could be a potential bacterial infection imaging radiotracer.

Design, Synthesis, and Evaluation of Chalcone Derivatives as Multifunctional Agents against Alzheimer's Disease.

Fifteen chalcone derivatives 3a-3o were synthesized, and evaluated as multifunctional agents against Alzheimer's disease. In vitro studies revealed that these compounds inhibited self-induced Aß1-42 aggregation effectively ranged from 45.9-94.5 % at 20 µM, and acted as potential antioxidants. Their structure-activity relationships were summarized. In particular, (2E)-3-[4-(dimethylamino)phenyl]-1-(pyridin-2-yl)prop-2-en-1-one (3g) exhibited an excellent inhibitory activity of 94.5 % at 20 µM, and it could disassemble the self-induced Aß1-42 aggregation fibrils with ratio of 57.1 % at 20 µM concentration. In addition, compound 3g displayed good chelating ability for Cu2+ , and could effectively inhibit and disaggregate Cu2+ -induced Aß aggregation. Moreover, compound 3g exerted low cytotoxicity, significantly reversed Aß1-42 -induced SH-SY5Y cell damage. More importantly, compound 3g remarkably ameliorated scopolamine-induced memory impairment in mice. In summary, all the results revealed compound 3g was a potential multifunctional agent for AD therapy.

Synthesis and evaluation of [99mTcN]2+ core and [99mTcO]3+ core labeled complexes with 4-nitroimidazole xanthate derivative for tumor hypoxia imaging.

A 4-nitroimidazole xanthate ligand (NMXT) was synthesized and radiolabeled with [99mTcN]2+ core and [99mTcO]3+ core to obtain 99mTcN-NMXT and 99mTcO-NMXT, respectively. The two 99mTc-complexes were prepared with high radiochemical purity and had good stability. The partition coefficient results indicated both of them were hydrophilic, and cellular uptake studies showed they exhibited good hypoxic selectivity. From the biodistribution study results, 99mTcO-NMXT showed more favourable tumor uptake (1.73 ± 0.14 ID%/g) and higher tumor/muscle ratio (7.01 ± 0.16) than 99mTcN-NMXT at 4 h post-injection. Single photon emission computed tomography (SPECT) imaging study of 99mTcO-NMXT showed there was a visible accumulation in tumor site, suggesting it would be a promising candidate as a tumor hypoxia imaging agent.

Design, Preparation, and Evaluation of a Novel 99mTcN Complex of Ciprofloxacin Xanthate as a Potential Bacterial Infection Imaging Agent.

In order to seek novel technetium-99m bacterial infection imaging agents, a ciprofloxacin xanthate (CPF2XT) was synthesized and radiolabeled with [99mTcN]2+ core to obtain the 99mTcN-CPF2XT complex, which exhibited high radiochemical purity, hydrophilicity, and good stability in vitro. The bacteria binding assay indicated that 99mTcN-CPF2XT had specificity to bacteria. A study of biodistribution in mice showed that 99mTcN-CPF2XT had a higher uptake in bacterial infection tissues than in turpentine-induced abscesses, indicating that it could distinguish bacterial infection from sterile inflammation. Compared to 99mTcN-CPFXDTC, the abscess/blood and abscess/muscle ratios of 99mTcN-CPF2XT were higher and the uptakes of 99mTcN-CPF2XT in the liver and lung were obviously decreased. The results suggested that 99mTcN-CPF2XT would be a potential bacterial infection imaging agent.

Periodontitis and inflammatory bowel disease: a meta-analysis.

BACKGROUND: Periodontitis was reported to be associated with inflammatory bowel disease (IBD). However, the association between them has not been firmly established in the existing literature. Therefore, this meta-analysis was conducted to evaluate the relationship between periodontitis and IBD. METHODS: Electronic databases were searched for publications up to August 1, 2019 to include all eligible studies. The pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated to determine the association between periodontal disease and IBD using a random or fixed effects model according to heterogeneity. RESULTS: Six eligible studies involving 599 IBD patients and 448 controls were included. The pooled OR between periodontitis and IBD was 3.17 (95% CI: 2.09-4.8) with no heterogeneity observed (I2 = 0.00%). The pooled ORs were 3.64 (95% CI: 2.33-5.67) and 5.37 (95% CI: 3.30-8.74) for the associations between periodontitis and the two sub-categories of IBD, Crohn' s disease and ulcerative colitis, respectively. CONCLUSIONS: The results demonstrated that periodontitis was significantly associated with IBD. However, the mechanisms underlying periodontitis and IBD development are undetermined. Further studies are needed to elucidate this relationship.

Protective role of α2-macroglobulin against jaw osteoradionecrosis in a preclinical rat model.

OBJECTIVE: We have previously demonstrated the effect of alpha-2-macroglobulin (α2M) in the remediation of radiation-induced cellular damage. Here, we investigated the protective effects of α2M in a preclinical rat model of jaw osteoradionecrosis (ORN). METHODS: Eighteen rats were divided randomly into three groups: the control group, the radiation therapy (RT) alone group, and the radiated mandibles pretreated with α2M (α2M + RT) group. One month after radiation, all left molar teeth were extracted. After another 3 months, the animals were sacrificed and body weight, histopathology, microcomputed tomography and immunofluorescence were evaluated in all groups. RESULTS: The RT group showed serious alopecia, bone exposure, inflammation, necrosis, fibrosis, and the absence of new bone formation within the socket. The α2M + RT group exhibited less alopecia than the RT group and slight inflammation and fibrosis in the bone marrow cavity. The cortical bone was similar to normal bone tissue. Interestingly, compared with RT group, serum superoxide dismutase levels in the α2M + RT group increased at the 1th day (P = 0.037), 14th day (P = 0.012), while reactive oxygen species levels clearly decreased at the 1th day (P< 0.001), 14th day (P = 0.007), and 28th day (P = 0.013). CONCLUSIONS: A clinically translational model of jaw ORN was successfully established and the application of α2M prior to radiation protected the bone from being injured by the radiation, possibly related to oxidative stress.

[Pharmacodynamics of Huanglian Jiedu decoction in Alzheimer's disease (AD) model rats and effect on improvement of inflammation microenvironment in brain].

To study the pharmacokinetics of active ingredients (alkaloids, iridoids and flavonoids) in Huanglian Jiedu decoction (HLJDD) in Alzheimer's disease (AD) model rats, and investigate its mechanism in treatment of AD. All of rats were divided into normal control group (n=6), shame operation group (n=6) and model group (n=12). Rats in shame operation group received daily subcutaneous injection of D-galactose (D-gal 50 mg·kg⁻¹) for a total of 45 d to induce subacute aging model. Based on the operation of shame operation group, the rats in model group were given with an injection of Aß25₋35 (4.0 g·L⁻¹)-ibotenic acid (2.0 g·L⁻¹) into the nucleus basalis magnocellularis. Then rats in model group were divided into HLJDD one day administration group (n=6) and HLJDD one week group (n=6). The plasma concentration of alkaloids, iridoid and flavonoids was determined by liquid chromatography tandem mass spectrometry (LC-QQQ-MS) at different time points. The levels of seven inflammatory factors (MIP-2, IL-1ß, IL-2, IL-8, IL-10, IL-13, TNF-α) in cerebrospinalfluid (CSF) were measured by Bio-Plex multi-factor detection technology. Iridoids in AD model rats, with high bioavailability, were easily absorbed and eliminated. The plasma concentration of alkaloid was lower, and the AUC (area under the curve) was higher in HLJDD one week group than that in HLJDD one day group. The plasma concentration-time curves of flavonoids showed obvious bimodal phenomena. After the gastric administration of HLJDD, the inflammatory factors in CSF of AD rats demonstrated a callback trend, including IL-1ß/IL-10 (P<0.05) with significant difference. The pharmacokinetic behaviors of iridoids, alkaloids and flavonoids (41 compounds) in AD model rats were fundamentally elucidated, and HLJDD can improve the central inflammatory status of AD rats by regulating the levels of inflammatory factors.

Design, synthesis, and evaluation of salicyladimine derivatives as multitarget-directed ligands against Alzheimer's disease.

A series of salicyladimine derivatives were designed, synthesized and evaluated as multi-target-directed ligands for the treatment of Alzheimer's disease (AD). Biological activity results demonstrated that some derivatives possessed significant inhibitory activities against amyloid-ß (Aß) aggregation and human monoamine oxidase B (hMAO-B) as well as remarkable antioxidant effects and low cell toxicity. The optimal compound, 5, exhibited excellent potency for inhibition of self-induced Aß1-42 aggregation (91.3±2.1%, 25µM), inhibition of hMAO-B (IC50, 1.73±0.39µM), antioxidant effects (43.4±2.6µM of IC50 by DPPH method, 0.67±0.06 trolox equivalent by ABTS method), metal chelation and BBB penetration. Furthermore, compound 5 had neuroprotective effects against ROS generation, H2O2-induced apoptosis, 6-OHDA-induced cell injury, and a significant in vitro anti-inflammatory activity. Collectively, these findings highlighted that compound 5 was a potential balanced multifunctional neuroprotective agent for the development of anti-AD drugs.

The role and mechanism of action of activin A in neurite outgrowth of chicken embryonic dorsal root ganglia.

Activin A, a member of the transforming growth factor ß (TGFß) superfamily, plays an essential role in neuron survival as a neurotrophic and neuroprotective factor in the central nervous system. However, the effects and mechanisms of action of activin A on the neurite outgrowth of dorsal root ganglia (DRG) remain unclear. In the present study, we found that activin A is expressed in DRG collected from chicken embryos on embryonic day 8 (E8). Moreover, activin A induced neurite outgrowth of the primary cultured DRG and maintained the survival of monolayer-cultured DRG neurons throughout the observation period of ten days. Follistatin (FS), an activin-binding protein, significantly inhibited activin A-induced neurite outgrowth of DRG, but failed to influence the effect of nerve growth factor (NGF) on DRG neurite outgrowth. Furthermore, the results showed that activin A significantly upregulated mRNA expression of activin receptor type IIA (ActRIIA) and calcitonin gene-related peptide (CGRP) in DRG, and stimulated serotonin (5-HT) production from DRG, indicating that activin A might induce DRG neurite outgrowth by promoting CGRP expression and stimulating 5-HT release. These data suggest that activin A plays an important role in the development of DRG in an autocrine or paracrine manner.

Association of transforming growth factor-ß1 T869C, G915C, and C509T gene polymorphisms with rheumatoid arthritis risk.

The association of transforming growth factor-ß1 (TGFß1) is an important signaling pathway factor involving extracellular matrix regulation, and its gene polymorphisms with the risk of rheumatoid arthritis (RA) is currently still fiercely debated. Therefore, this meta-analysis was performed to determine if TGFß1 T869C, G915C, and C509T gene polymorphisms correlate with the risk of developing RA. Association reports were identified from PubMed, Cochrane Library and CBM-disc (China Biological Medicine Database) on 1 May 2013, and eligible studies were recruited and synthesized to identifying patterns among study results. T869C TT genotype in the overall population was associated with increased RA risk (OR = 1.28, 95% CI: 1.02-1.60, p = 0.03). In the sub-group analysis, T869C TT genotype was shown to be a risk factor for RA, and T869C C allele or CC genotype a protective factor against RA disease in Asians, but these associations were not found in Caucasians. Furthermore, TGFß1 C509T TT genotype was distinctly associated with RA susceptibility, but the T allele and CC genotype were not. TGFß1 G915C gene polymorphism was not associated with RA susceptibility. In conclusion, the TT genotype of TGFß1 T869C was associated with RA risk in the overall population and Asians. Furthermore, CC genotype or C allele was determined to be protective factors with respect to the RA risk in the overall population and Asians. Nonetheless, additional studies are required to firmly establish a correlation between the aforementioned polymorphisms and RA risk.

Use of extended vertical lower trapezius island myocutaneous flaps to cover exposed reconstructive plates.

PURPOSE: Plate exposure is the most common complication after reconstruction of oncologic resection using a titanium plate. The outcomes of covering exposed reconstructive plates with extended vertical lower trapezius island myocutaneous flaps (TIMFs) were evaluated. PATIENTS AND METHODS: Twelve instances of exposure of reconstructive plates occurred in patients after segmental mandibulectomy to treat cancer of the oral cavity and oropharynx. The plates were covered with extended vertical lower TIMFs. The site of the primary tumor was the gingiva or mandible in 5 cases, the buccal mucosa in 3, the floor of the mouth in 2, and the base of the tongue in 2. The types of bone defect were hemimandibular in 1 case, central in 2, and lateral in 9. Intraoral, extraoral, and intra- and extraoral exposures occurred in 1, 7, and 4 instances, respectively. Intraorally and extraorally exposed plates were re-covered with skin paddles measuring 6 × 7 to 6 × 23 cm (average, 6.0 × 13.5 cm). Four folded extended vertical lower TIMFs were constructed to cover plates exhibiting intra- and extraoral exposure. RESULTS: All flaps survived. Patients were followed for 12 to 36 months (median duration, 22.8 months). One patient (8.3%) exhibited external plate exposure at 20 months. Nine patients (75.0%) were alive with no evidence of disease at 12 to 36 months, and 2 (16.7%) were alive with disease at 20 to 28 months. One patient (8.3%) died of local recurrence at 23 months. CONCLUSIONS: The use of extended vertical lower TIMFs to cover intraorally, extraorally, or intra- and extraorally exposed plates is reliable.

TET3 Contributes to Exercise-Induced Functional Axon Regeneration and Visual Restoration.

Axons have intrinsically poor regenerative capacity in the mature central nervous system (CNS), leading to permanent neurological impairments in individuals. There is growing evidence that exercise is a powerful physiological intervention that can obviously enhance cell rejuvenate capacity, but its molecular mechanisms that mediate the axonal regenerative benefits remain largely unclear. Using the eye as the CNS model, here it is first indicated that placing mice in an exercise stimulation environment induced DNA methylation patterns and transcriptomes of retinal ganglion cell, promoted axon regeneration after injury, and reversed vision loss in aged mice. These beneficial effects are dependent on the DNA demethylases TET3-mediated epigenetic effects, which increased the expression of genes associated with the regenerative growth programs, such as STAT3, Wnt5a, Klf6. Exercise training also shows with the improved mitochondrial and metabolic dysfunction in retinas and optic nerves via TET3. Collectively, these results suggested that the increased regenerative capacity induced by enhancing physical activity is mediated through epigenetic reprogramming in mouse model of optic nerve injury and in aged mouse. Understanding the molecular mechanism underlying exercise-dependent neuronal plasticity led to the identification of novel targets for ameliorating pathologies associated with etiologically diverse diseases.

Stephaochratidin A, a Rare Stephacidin-Asperochratide Hybrid with Ferroptosis Inhibitory Activity from the Deep-Sea-Derived Aspergillus ochraceus.

One rare stephacidin-asperochratide hybrid, stephaochratidin A (1), was isolated from the deep-sea-derived Aspergillus ochraceus MCCC 3A00521. The relative structure of 1 was determined by comprehensive analyses of its 1D and 2D NMR data as well as HRESIMS data. And the absolute configuration was unambiguously assigned by ECD calculations and the X-ray single-crystal diffraction analysis. Plausible biosynthetic pathway of 1 was proposed. Stephaochratidin A (1) exhibited significant ferroptosis inhibitory activity with the EC50 value of 15.4 µM by downregulating HMOX-1 expression and lipid peroxidation.

[Effects of electromagnetic radiation on health and immune function of operators].

OBJECTIVE: To investigate the effects of electromagnetic radiation on the physiological indices and immune function of operators. METHODS: The general conditions and electromagnetic radiation awareness rate of 205 operators under electromagnetic radiation were evaluated using a self-designed questionnaire. Physical examination, electrocardiography, and routine urine test were performed in these operators. Peripheral blood was collected from the operators under electromagnetic radiation for blood cell counting and biochemical testing, and their peripheral blood lymphocytes were cultured for determination of chromosomal aberrant frequency and micronucleus frequency. The data from these operators (exposure group) were compared with those of 95 ordinary individuals (control group). RESULTS: The chief complaint of giddiness, tiredness, dizziness, and amnesia showed significant differences between the exposure group and control group (P < 0.01), and the difference in headache became larger with an increase in working years. The awareness rate of electromagnetic radiation damage was significantly higher in the exposure group than in the control group. The difference in bradycardia was significant between the two groups (P <0.01), and the incidence was higher with longer working years. Significant differences between the two groups were also found in the numbers of individuals with elevated alanine aminotransferase, total bilirubin, and direct bilirubin (P < 0.01), populations with increased lymphocyte ratio and decreased neutrophil ratio (P < 0.01), populations with positive occult blood, urobilinogen, and bilirubin tests, and the number of individuals with increased micronucleus frequency of cultured peripheral blood lymphocytes (P < 0.01). In addition, the exposure group had significantly increased complement C3 and C4 (P < 0.01), significantly increased IgG (P < 0.05), and significantly decreased IgM (P < 0.01), as compared with the control group. CONCLUSION: Electromagnetic radiation may lead to the changes in physiological indices, genetic effects, and immune function and affect the health and immune function in operators. The adverse effects are increased as the working years increase. So it is important to strengthen occupational protection of operators under electromagnetic radiation.

Efficient Multi-View Clustering via Unified and Discrete Bipartite Graph Learning.

Although previous graph-based multi-view clustering (MVC) algorithms have gained significant progress, most of them are still faced with three limitations. First, they often suffer from high computational complexity, which restricts their applications in large-scale scenarios. Second, they usually perform graph learning either at the single-view level or at the view-consensus level, but often neglect the possibility of the joint learning of single-view and consensus graphs. Third, many of them rely on the k -means for discretization of the spectral embeddings, which lack the ability to directly learn the graph with discrete cluster structure. In light of this, this article presents an efficient MVC approach via unified and discrete bipartite graph learning (UDBGL). Specifically, the anchor-based subspace learning is incorporated to learn the view-specific bipartite graphs from multiple views, upon which the bipartite graph fusion is leveraged to learn a view-consensus bipartite graph with adaptive weight learning. Furthermore, the Laplacian rank constraint is imposed to ensure that the fused bipartite graph has discrete cluster structures (with a specific number of connected components). By simultaneously formulating the view-specific bipartite graph learning, the view-consensus bipartite graph learning, and the discrete cluster structure learning into a unified objective function, an efficient minimization algorithm is then designed to tackle this optimization problem and directly achieve a discrete clustering solution without requiring additional partitioning, which notably has linear time complexity in data size. Experiments on a variety of multi-view datasets demonstrate the robustness and efficiency of our UDBGL approach. The code is available at https://github.com/huangdonghere/UDBGL.