Retinoic acid mitigates the NSC319726-induced spermatogenesis dysfunction through cuproptosis-independent mechanisms.

Copper ionophore NSC319726 has attracted researchers' attention in treating diseases, particularly cancers. However, its potential effects on male reproduction during medication are unclear. This study aimed to determine whether NSC319726 exposure affected the male reproductive system. The reproductive toxicity of NSC319726 was evaluated in male mice following a continuous exposure period of 5 weeks. The result showed that NSC319726 exposure caused testis index reduction, spermatogenesis dysfunction, and architectural damage in the testis and epididymis. The exposure interfered with spermatogonia proliferation, meiosis initiation, sperm count, and sperm morphology. The exposure also disturbed androgen synthesis and blood testis barrier integrity. NSC319726 treatment could elevate the copper ions in the testis to induce cuproptosis in the testis. Copper chelator rescued the elevated copper ions in the testis and partly restored the spermatogenesis dysfunction caused by NSC319726. NSC319726 treatment also decreased the level of retinol dehydrogenase 10 (RDH10), thereby inhibiting the conversion of retinol to retinoic acid, causing the inability to initiate meiosis. Retinoic acid treatment could rescue the meiotic initiation and spermatogenesis while not affecting the intracellular copper ion levels. The study provided an insight into the bio-safety of NSC319726. Retinoic acid could be a potential therapy for spermatogenesis impairment in patients undergoing treatment with NSC319726.

Elevated thyroid stimulating hormone and metabolic syndrome risk in patients with first-episode and drug-naïve major depressive disorder: a large-scale cross-sectional study.

BACKGROUND: Metabolic syndrome (MetS) is common in major depressive disorder (MDD), but its relationship with thyroid hormones remains unclear. We aimed to examine the association of thyroid hormones and MetS in first-episode drug-naïve (FEDN) MDD patients. METHODS: We recruited 1718 unmedicated MDD patients in this cross-sectional study. MetS was defined based on the 2004 Chinese Diabetes Society Criteria. Serum thyroid hormones including free thyroxine (FT4), free triiodothyronine (FT3), thyroid-stimulating hormone (TSH), thyroid peroxidase antibodies (TPOAb), and anti-thyroglobulin (TGAb) were examined. We used the logistic regression model to determine risk factors for MetS and examined the performance of the regression model by using the Area Under the Curve (AUC). In addition, we performed the trend test to test whether the results were robust. RESULTS: The prevalence of MetS in unmedicated MDD patients was 34.4%. MDD patients with MetS had higher levels of serum TSH, TGAb, and TPOAb (all P < 0.001). Concurrently, serum TSH levels were independent risk factors for MetS in MDD patients (OR:1.49, 95%CI: 1.40-1.58), which could also distinguish MDD patients with and without MetS (AUC was 0.77). Additionally, in the trend test, the results also indicated a similar trend when TSH was used as a categorical variable (P for trend < 0.001). CONCLUSIONS: This study suggests that TSH levels were independent risk factors for MetS in FEDN MDD patients (OR:1.49). The examination of thyroid function may contribute to the early detection of MetS.

Concentration-Driven Evolution of Adaptive Artificial Ion Channels or Nanopores with Specific Anticancer Activities.

In nature, ceramides are a class of sphingolipids possessing a unique ability to self-assemble into protein-permeable channels with intriguing concentration-dependent adaptive channel cavities. However, within the realm of artificial ion channels, this interesting phenomenon is scarcely represented. Herein, we report on a novel class of adaptive artificial channels, Pn-TPPs, based on PEGylated cholic acids bearing triphenylphosphonium (TPP) groups as anion binding motifs. Interestingly, the molecules self-assemble into chloride ion channels at low concentrations while transforming into small molecule-permeable nanopores at high concentrations. Moreover, the TPP groups endow the molecules with mitochondria-targeting properties, enabling them to selectively drill holes on the mitochondrial membrane of cancer cells and subsequently trigger the caspase 9 apoptotic pathway. The anticancer efficacies of Pn-TPPs correlate with their abilities to form nanopores. Significantly, the most active ensembles formed by P5-TPP exhibits impressive anticancer activity against human liver cancer cells, with an IC50 value of 3.8 µM. While demonstrating similar anticancer performance to doxorubicin, P5-TPP exhibits a selectivity index surpassing that of doxorubicin by a factor of 16.8.

Non-Covalently Stapled H+ /Cl- Ion Channels Activatable by Visible Light for Targeted Anticancer Therapy.

The development of stimuli-responsive artificial H+ /Cl- ion channels, capable of specifically disturbing the intracellular ion homeostasis of cancer cells, presents an intriguing opportunity for achieving high selectivity in cancer therapy. Herein, we describe a novel family of non-covalently stapled self-assembled artificial channels activatable by biocompatible visible light at 442 nm, which enables the co-transport of H+ /Cl- across the membrane with H+ /Cl- transport selectivity of 6.0. Upon photoirradiation of the caged C4F-L for 10 min, 90 % of ion transport efficiency can be restored, giving rise to a 10.5-fold enhancement in cytotoxicity against human colorectal cancer cells (IC50 =8.5 µM). The mechanism underlying cancer cell death mediated by the H+ /Cl- channels involves the activation of the caspase 9 apoptosis pathway as well as the scarcely reported disruption of the autophagic processes. In the absence of photoirradiation, C4F-L exhibits minimal toxicity towards normal intestine cells, even at a concentration of 200 µM.

Plasma total cholesterol concentration and risk of higher-grade prostate cancer: A nested case-control study and a dose-response meta-analysis.

Our previous publication found an increased risk of higher-grade (Gleason sum ≥7) prostate cancer for men with high total cholesterol concentration (≥200 mg/dl) in the Health Professionals Follow-up Study (HPFS). With additional 568 prostate cancer cases, we are now able to investigate this association in more detail. For the nested case-control study, we included 1260 men newly diagnosed with prostate cancer between 1993 and 2004, and 1328 controls. For the meta-analyses, 23 articles studied the relationship between total cholesterol level and prostate cancer incidence were included. Logistic regression models and dose-response meta-analysis were performed. An increased risk of higher-grade (Gleason sum ≥4 + 3) prostate cancer for high vs low quartile of total cholesterol level was observed in the HPFS (ORmultivariable = 1.56; 95% CI = 1.01-2.40). This finding was compatible with the association noted in the meta-analysis of highest vs lowest group of total cholesterol level, which suggested a moderately increased risk of higher-grade prostate cancer (Pooled RR =1.21; 95%CI: 1.11-1.32). Moreover, the dose-response meta-analysis indicated that an increased risk of higher-grade prostate cancer occurred primarily at total cholesterol levels ≥200 mg/dl, where the RR was 1.04 (95%CI: 1.01-1.08) per 20 mg/dl increase in total cholesterol level. However, total cholesterol concentration was not associated with the risk of prostate cancer overall either in the HPFS or in the meta-analysis. Our primary finding, as well as the result of the meta-analysis suggested a modest increased risk of higher-grade prostate cancer, at total cholesterol concentrations exceeding 200 mg/dl.

Whole-Genome Resequencing of Worldwide Wild and Domestic Sheep Elucidates Genetic Diversity, Introgression, and Agronomically Important Loci.

Domestic sheep and their wild relatives harbor substantial genetic variants that can form the backbone of molecular breeding, but their genome landscapes remain understudied. Here, we present a comprehensive genome resource for wild ovine species, landraces and improved breeds of domestic sheep, comprising high-coverage (∼16.10×) whole genomes of 810 samples from 7 wild species and 158 diverse domestic populations. We detected, in total, ∼121.2 million single nucleotide polymorphisms, ∼61 million of which are novel. Some display significant (P < 0.001) differences in frequency between wild and domestic species, or are private to continent-wide or individual sheep populations. Retained or introgressed wild gene variants in domestic populations have contributed to local adaptation, such as the variation in the HBB associated with plateau adaptation. We identified novel and previously reported targets of selection on morphological and agronomic traits such as stature, horn, tail configuration, and wool fineness. We explored the genetic basis of wool fineness and unveiled a novel mutation (chr25: T7,068,586C) in the 3'-UTR of IRF2BP2 as plausible causal variant for fleece fiber diameter. We reconstructed prehistorical migrations from the Near Eastern domestication center to South-and-Southeast Asia and found two main waves of migrations across the Eurasian Steppe and the Iranian Plateau in the Early and Late Bronze Ages. Our findings refine our understanding of genome variation as shaped by continental migrations, introgression, adaptation, and selection of sheep.

Adherence to the World Cancer Research Fund/American Institute for Cancer Research cancer prevention recommendations throughout the life course and risk of colorectal cancer precursors.

BACKGROUND: Despite the increasing incidence in colorectal cancer (CRC) among the young population, the involvement of modifiable early-life exposures is understudied. METHODS: We prospectively investigated the association of lifestyle score, which measures adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations, in adolescence and adulthood with risk of CRC precursors in 34,509 women enrolled in the Nurses' Health Study II. Participants reported adolescent diet in 1998 and subsequently underwent at least one lower gastrointestinal endoscopy between 1999 and 2015. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression for clustered data. RESULTS: During follow-up (1998-2015), 3036 women had at least one adenoma, and 2660 had at least one serrated lesion. In multivariable analysis, per unit increase in adolescent WCRF/AICR lifestyle score was not associated with risk of total adenoma or serrated lesions, in contrast to adult WCRF/AICR lifestyle score (OR = 0.92, 95% CI: 0.87-0.97, Ptrend = 0.002 for total adenoma; and OR = 0.86, 95% CI: 0.81-0.92, Ptrend < 0.001 for total serrated lesions). CONCLUSION: Adherence to the 2018 WCRF/AICR recommendations during adulthood but not during adolescence was associated with a lower risk of CRC precursors.

The novel CDK9 inhibitor, XPW1, alone and in combination with BRD4 inhibitor JQ1, for the treatment of clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is a highly lethal malignancy with few therapeutic options. Cyclin­dependent kinase 9 (CDK9), a potential therapeutic target of many cancers, has been recently observed to be upregulated in ccRCC patients. Therefore, we aimed to investigate the therapeutic potential of CDK9 in ccRCC and develop a novel CDK9 inhibitor with low toxicity for ccRCC treatment. METHODS: The expression of CDK9 in ccRCC was checked using the online database and tissue microarray analysis. shRNA-mediated CDK9 knockdown and CDK inhibitor were applied to evaluate the effect of CDK9 on ccRCC. Medicinal chemistry methods were used to develop a new CDK9 inhibitor with drugability. RNA-seq and ChIP-seq experiments were conducted to explore the mechanism of action. MTS, western blotting, and colony formation assays were performed to evaluate the anti-ccRCC effects of CDK9 knockdown and inhibition in vitro. The in vivo anti-tumour efficacy was evaluated in a xenograft model. RESULTS: CDK9 is overexpressed and associated with poor survival in ccRCC. Knockdown or inhibition of CDK9 significantly suppressed ccRCC cells. XPW1 was identified as a new potent and selective CDK9 inhibitor with excellent anti-ccRCC activity and low toxicity. In mechanism, XPW1 transcriptionally inhibited DNA repair programmes in ccRCC cells, resulting in an excellent anti-tumour effect. CDK9 and BRD4 were two highly correlated transcriptional regulators in ccRCC patients, and the BRD4 inhibitor JQ1 enhanced XPW1's anti-ccRCC effects in vitro and in vivo. CONCLUSIONS: This work provides valuable insights into the therapeutic potential of CDK9 in ccRCC. The CDK9 inhibitor XPW1 would be a novel therapeutic agent for targeting ccRCC, alone or in rational combinations.

Association of Proton Pump Inhibitor Use With All-Cause and Cause-Specific Mortality.

BACKGROUND & AIMS: The use of proton pump inhibitors (PPIs) has increased rapidly in the past 2 decades. Concerns about the regular use of PPIs contributing to mortality have been raised. METHODS: We conducted a prospective cohort study using data collected from the Nurses' Health Study (2004-2018) and the Health Professionals Follow-up Study (2004-2018). Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% CIs for mortality according to PPI use. We used a modified lag-time approach to minimize reverse causation (ie, protopathic bias). RESULTS: Among 50,156 women and 21,731 men followed for 831,407 person-years and a median of 13.8 years, we documented 22,125 deaths, including 4592 deaths from cancer, 5404 from cardiovascular diseases, and 12,129 deaths from other causes. Compared with nonusers of PPIs, PPI users had significantly higher risks of all-cause mortality (HR, 1.19; 95% CI, 1.13-1.24) and mortality due to cancer (HR, 1.30; 95% CI, 1.17-1.44), cardiovascular diseases (HR, 1.13; 95% CI, 1.02-1.26), respiratory diseases (HR, 1.32; 95% CI, 1.12-1.56), and digestive diseases (HR, 1.50; 95% CI, 1.10-2.05). Upon applying lag times of up to 6 years, the associations were attenuated and no longer statistically significant (all-cause: HR, 1.04; 95% CI, 0.97-1.11; cancer: HR, 1.07; 95% CI, 0.89-1.28; cardiovascular diseases: HR, 0.94; 95% CI, 0.81-1.10; respiratory diseases: HR, 1.20; 95% CI, 0.95-1.50; digestive diseases: HR, 1.38; 95% CI, 0.88-2.18). Longer duration of PPI use did not confer higher risks for all-cause and cause-specific mortality. CONCLUSIONS: After accounting for protopathic bias, PPI use was not associated with higher risks of all-cause mortality and mortality due to major causes.

Being Breastfed in Infancy and Risk of Colorectal Cancer and Precursor Lesions.

BACKGROUND & AIMS: Emerging evidence implicates the importance of perinatal and early-life exposures in colorectal cancer (CRC) development. However, it remains unclear whether being breastfed in infancy is associated with CRC risk in adult life, particularly early adulthood. METHODS: We prospectively investigated the association between history of being breastfed and risk of CRC and its precursor lesions among 66,634 women 46-93 years of age from the Nurses' Health Study and 92,062 women 27-68 years of age from the Nurses' Health Study II. Cox regression and logistic regression for clustered data were used to estimate hazard ratios for CRC and odds ratios for CRC precursors, respectively. RESULTS: During 3.5 million person-years of follow-up, we identified 1490 incident cases of CRC in 2 cohorts. Having been breastfed was associated with a 23% (95% confidence interval [CI], 10% to 38%) increased risk of CRC. The risk of CRC increased with duration of being breastfed (Ptrend < .001). These findings were validated using breastfeeding information from the mothers of a subset of participants. Among younger participants from the Nurses' Health Study II, a significant association was observed between being breastfed and increased risk of high-risk adenomas under 50 years of age (odds ratio, 1.46; 95% CI, 1.16 to 1.83). Consistently, having been breastfed was associated with increased risk of CRC among participants ≤55 years of age (hazard ratio, 1.38; 95% CI, 1.06 to 1.80). CONCLUSIONS: Being breastfed in infancy was associated with increased risk of CRC in adulthood, including among younger adults. However, further research is needed to understand the underlying biological mechanisms, as this association does not establish causation.

Clinical and Genomic Characterization of Interval Colorectal Cancer in 3 Prospective Cohorts.

BACKGROUND & AIMS: Interval colorectal cancers (CRCs), cancers diagnosed after a screening/surveillance examination in which no cancer is detected, and before the date of next recommended examination, reflect an unprecedented challenge in CRC detection and prevention. To better understand this poorly characterized CRC variant, we examined the clinical and mutational characteristics of interval CRCs in comparison with screen detected CRCs. METHODS: We included 1175 CRCs documented in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial and 3661 CRCs in the Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS). Multivariable Cox models were performed to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of death risk. Whole exome sequencing was conducted in 147 PLCO cases and 796 NHS/HPFS cases. RESULTS: A total of 619 deaths (312 CRC-specific) and 2404 deaths (1904 CRC-specific) were confirmed during follow-up of PLCO and NHS/HPFS, respectively. Compared with screen detected CRCs, interval CRCs had a multivariate-adjusted HR (95% CI) of 1.47 (1.21-1.78) for CRC-specific mortality and 1.27 (1.09-1.47) for overall mortality (meta-analysis combining all 3 cohorts). However, we did not observe significant differences in mutational features between interval and screen detected CRCs (false discovery rate adjusted P > .05). CONCLUSION: Interval CRCs had a significantly increased risk of death compared with screen detected CRCs that were not explained by established clinical prognostic factors, including stage at diagnosis. The survival disadvantage of interval CRCs did not appear to be explained by differences in the genomic landscape of tumors characterized by whole exome sequencing.

Molecular Characteristics of Early-Onset Colorectal Cancer According to Detailed Anatomical Locations: Comparison With Later-Onset Cases.

INTRODUCTION: Early-onset colorectal cancer diagnosed before the age of 50 years has been increasing. Likely reflecting the pathogenic role of the intestinal microbiome, which gradually changes across the entire colorectal length, the prevalence of certain tumor molecular characteristics gradually changes along colorectal subsites. Understanding how colorectal tumor molecular features differ by age and tumor location is important in personalized patient management. METHODS: Using 14,004 cases with colorectal cancer including 3,089 early-onset cases, we examined microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF mutations in carcinomas of the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum and compared early-onset cases with later-onset cases. RESULTS: The proportions of MSI-high, CIMP-high, and BRAF -mutated early-onset tumors were lowest in the rectum (8.8%, 3.4%, and 3.5%, respectively) and highest in the ascending colon (46% MSI-high; 15% CIMP-high) or transverse colon (8.6% BRAF -mutated) (all Ptrend <0.001 across the rectum to ascending colon). Compared with later-onset tumors, early-onset tumors showed a higher prevalence of MSI-high status and a lower prevalence of CIMP-high status and BRAF mutations in most subsites. KRAS mutation prevalence was higher in the cecum compared with that in the other subsites in both early-onset and later-onset tumors ( P < 0.001). Notably, later-onset MSI-high tumors showed a continuous decrease in KRAS mutation prevalence from the rectum (36%) to ascending colon (9%; Ptrend <0.001), followed by an increase in the cecum (14%), while early-onset MSI-high cancers showed no such trend. DISCUSSION: Our findings support biogeographical and pathogenic heterogeneity of colorectal carcinomas in different colorectal subsites and age groups.

Health Insurance Coverage and Racial/Ethnic Disparities in US Childhood and Adolescent Cancer Survival.

OBJECTIVE: To evaluate potential effect modification by health insurance coverage on racial and ethnic disparities in cancer survival among US children and adolescents. STUDY DESIGN: Data from 54 558 individuals diagnosed with cancer at ≤ 19 years between 2004 and 2010 were obtained from the National Cancer Database. Cox proportional hazards regression was used for analyses. An interaction term between race/ethnicity and health insurance type was included to examine racial/ethnic disparities in survival by each insurance status category. RESULTS: Racial/ethnic minorities experienced a 14%-42% higher hazard of death compared with non-Hispanic Whites (NHWs) with magnitudes varying by health insurance type (Pinteraction < .001). Specifically, among those reported as privately insured, the hazard of death was higher for non-Hispanic Blacks (NHBs) (hazard ratio [HR] = 1.48, 95% CI: 1.36-1.62), non-Hispanic American Indian/Alaskan Natives (HR = 1.99, 95% CI: 1.36-2.90), non-Hispanic Asians or Pacific Islanders (HR = 1.30, 95% CI: 1.13-1.50), and Hispanics (HR = 1.28, 95% CI: 1.17-1.40) vs NHWs. Racial/ethnic disparities in survival among those reported as covered by Medicaid were present for NHBs (HR = 1.30, 95% CI: 1.19-1.43) but no other racial/ethnic minorities (HR ranges: 0.98∼1.00) vs NHWs. In the uninsured group, the hazard of death for NHBs (HR = 1.68, 95% CI: 1.26-2.23) and Hispanics (HR = 1.27, 95% CI: 1.01-1.61) was higher vs NHWs. CONCLUSIONS: Disparities in survival exist across insurance types, particularly for NHB childhood and adolescent cancer patients vs NHWs with private insurance. These findings provide insights for research and policy, and point to the need for more efforts on promoting health equity while improving health insurance coverage.

Strophiofimbrins A and B: Two Rearranged Norditerpenoids with Novel Tricyclic Carbon Skeletons from Strophioblachia fimbricalyx.

Two rearranged norditerpenoids with novel tricyclic carbon skeletons, strophiofimbrin A (1) and strophiofimbrin B (2), were isolated from Strophioblachia fimbricalyx. Their structures were established by 1D/2D NMR spectroscopy, HRESIMS, quantum chemistry calculations, and X-ray diffraction analyses. 1 and 2 represented the first examples of diterpenoids with unprecedented 5/6/7-fused ring systems. In the proposed biosynthetic pathway, they were suspected to derive from cleistanthane norditerpenoids via ring opening, expansion, cyclization, and rearrangement based on the existence of phenanthrenone and cleistanthane diterpenoids from Strophioblachia and Trigonostemon, two closely related genera of the Euphorbiaceae family. Furthermore, compounds 1 and 2 exhibited significant proliferation inhibition and obvious neuroprotective effects.

Withdrawn: Ticagrelor reduces myocardial cell injury induced by myocardial ischemia/reperfusion in diabetic rats by activating JAK2/STAT3.

The above article from Cell Biology International, published online on 5 December 2022, on Wiley Online Library (https://doi.org/10.1002/cbin.11940), has been withdrawn by agreement between the journal Editor in Chief, Sergio Schenkman, and John Wiley and Sons Ltd. The withdrawal has been agreed due to a technical error at the publisher that caused the article to be mistakenly published online although it had been rejected due to evidence that the peer review process for this paper was manipulated.

Moderate alcohol consumption, types of beverages and drinking pattern with cardiometabolic biomarkers in three cohorts of US men and women.

Underlying mechanisms of the inverse relationship between moderate alcohol consumption and cardiometabolic disorders are unclear. Modification by types of alcoholic beverages consumed and drinking pattern remains understudied. We aimed to provide insight into the mechanisms by examining 14 insulinemic/glycemic, inflammatory and lipid markers. We used cross-sectional data from 15,436 women in the Nurses' Health Study, 19,318 women in the Nurses' Health Study II, and 6872 men in the Health Professionals Follow-up Study. Multivariable linear regression was used to estimate the percentage differences in biomarker concentrations according to alcohol intakes. The average alcohol intake in the combined cohort was 3.3 servings/week. We found a 1 serving/d increment in alcohol intake (14 g ethanol, 44 ml liquor or 355 ml beer or 118 ml wine per day) was associated with a 0.6% lower level of HbA1c, 1.7-3.6% lower proinflammatory markers and 4.2% higher adiponectin, as well as 7.1% higher HDL-cholesterol and 2.1% lower triglyceride with a significant linear trend. Wine, especially red wine, was associated with lower inflammation in particular. Beer had weaker favorable to null associations with blood lipids and adiponectin. Liquor was associated with higher C-peptide and interleukin-6, yet equally associated with lower HbA1c and higher HDL-cholesterol as other beverages. Drinking 3 days or more per week was related to a better biomarker profile than nonregular drinking independent of intake levels. Drinking appeared to have similar associations irrespective whether done with meals or not. Our data indicated moderate alcohol intake, especially if consumed from wine and done regularly, was associated with favorable profiles of insulinemic/glycemic and inflammatory markers and blood lipids.

Effects of High-Definition Transcranial Direct Current Stimulation Targeting the Anterior Cingulate Cortex on the Pain Thresholds: A Randomized Controlled Trial.

BACKGROUND: The majority of existing clinical studies used active transcranial direct current stimulation (tDCS) over superficial areas of the pain neuromatrix to regulate pain, with conflicting results. Few studies have investigated the effect of tDCS on pain thresholds by focusing on targets in deep parts of the pain neuromatrix. METHODS: This study applied a single session of high-definition tDCS (HD-tDCS) targeting the anterior cingulate cortex (ACC) and used a parallel and sham-controlled design to compare the antinociceptive effects in healthy individuals by assessing changes in pain thresholds. Sixty-six female individuals (mean age, 20.5 ± 2.4 years) were randomly allocated into the anodal, cathodal, or sham HD-tDCS groups. The primary outcome of the study was pain thresholds (pressure pain threshold, heat pain threshold, and cold pain threshold), which were evaluated before and after stimulation through the use of quantitative sensory tests. RESULTS: Only cathodal HD-tDCS targeting the ACC significantly increased heat pain threshold (P < 0.05) and pressure pain threshold (P < 0.01) in healthy individuals compared with sham stimulation. Neither anodal nor cathodal HD-tDCS showed significant analgesic effects on cold pain threshold. Furthermore, no statistically significant difference was found in pain thresholds between anodal and sham HD-tDCS (P > 0.38). Independent of HD-tDCS protocols, the positive and negative affective schedule scores were decreased immediately after stimulation compared with baseline. CONCLUSIONS: The present study has found that cathodal HD-tDCS targeting the ACC provided a strong antinociceptive effect (increase in pain threshold), demonstrating a positive biological effect of HD-tDCS.

Investigation on low-loss hollow-core anti-resonant terahertz fiber.

In this work, a hollow-core anti-resonant terahertz (THz) fiber with elliptical cladding and nested tubes is proposed and fabricated. It is an effective way to reduce the loss of THz waves by transmitting them in an air core and breaking the material absorption. After parameter optimization of the initial structure, multiple transmission windows exist in the 0.2-0.8 THz band, where confinement loss is as low as 3.47×10-3cm-1 at 0.8 THz. At 0.2-0.7 THz, confinement losses lie between 10-3 and 10-2cm-1. The 3D printed samples are characterized by a THz time-domain spectroscopy system. Experimental results showed that the designed fiber structure transmits loss coefficients up to 10-2cm-1 in the 0.2-0.8 THz band (the minimum value is located at 0.46 THz, corresponding to a loss coefficient of 0.0284cm-1). The experiments show that the designed THz fiber achieves a good transmission effect.

["Trichosanthis Fructus-Allii Macrostemonis Bulbus" combination inhibits NLRP3 inflammasome activation and reduces inflammatory response in RAW264.7 macrophage by inducing autophagy].

This study aims to explore the effect of "Trichosanthis Fructus-Allii Macrostemonis" combination(GX) on the activation of NOD-, LRR-, and pyrin domain-containing protein 3(NLRP3) inflammasome, the release of inflammatory cytokines, and the level of autophagy in RAW264.7 macrophage damaged by lipopolysaccharide(LPS), and the mechanism of GX against inflammatory response in macrophages. To be specific, LPS was used to induce the injury of RAW264.7 cells. Cell Counting Kit-8(CCK-8) assay was employed to measure the survival rate of cells, and Western blot to detect the protein expression of NLRP3, apoptosis-associated speck-like protein(ASC), cysteine-aspartic acid protease(caspase)-1, interleukin(IL)-18, IL-1ß, microtubule-associated protein light chain 3(LC3)-Ⅱ, and selective autophagy junction protein p62/sequestosome 1 in RAW264.7 macrophages. ELISA was used to measure the levels of IL-18 and IL-1ß in RAW264.7 cells. Transmission electron microscopy was applied to observe the number of autophagosomes in RAW264.7 cells. Immunofulourescence staining was used to detect the expression of LC3-Ⅱ and p62 in RAW264.7 cells. The result showed that GX significantly reduced the protein expression of NLRP3, ASC, and caspase-1 in RAW264.7 cells, significantly increased the protein expression of LC3Ⅱ, decreased the expression of p62, significantly inhibited the secretion of IL-18 and IL-1ß, significantly increased the number of autophagosomes, significantly enhanced the immunofluorescence of LC3Ⅱ, and reduced the immunofluorescence of p62. Furthermore, 3-methyladenine(3-MA) could reverse the inhibitory effect of GX on NLRP3, ASC, and caspase-1 and reduce the release of IL-18 and IL-1ß. In summary, GX can increase of the autophagy activity of RAW264.7 and inhibit the activation of NLRP3 inflammasome, thereby reducing the release of inflammatory cytokines and suppressing inflammatory response in macrophages.

Stability and reproducibility of proteomic profiles in epidemiological studies: comparing the Olink and SOMAscan platforms.

Limited data exist on the performance of high-throughput proteomics profiling in epidemiological settings, including the impact of specimen collection and within-person variability over time. Thus, the Olink (972 proteins) and SOMAscan7Kv4.1 (7322 proteoforms of 6596 proteins) assays were utilized to measure protein concentrations in archived plasma samples from the Nurses' Health Studies and Health Professionals Follow-Up Study. Spearman's correlation coefficients (r) and intraclass correlation coefficients (ICCs) were used to assess agreement between (1) 42 triplicate samples processed immediately, 24-h or 48-h after blood collection from 14 participants; and (2) 80 plasma samples from 40 participants collected 1-year apart. When comparing samples processed immediately, 24-h, and 48-h later, 55% of assays had an ICC/r ≥ 0.75 and 87% had an ICC/r ≥ 0.40 in Olink compared to 44% with an ICC/r ≥ 0.75 and 72% with an ICC/r ≥ 0.40 in SOMAscan7K. For both platforms, >90% of the assays were stable (ICC/r ≥ 0.40) in samples collected 1-year apart. Among 817 proteins measured with both platforms, Spearman's correlations were high (r > 0.75) for 14.7% and poor (r < 0.40) for 44.8% of proteins. High-throughput proteomics profiling demonstrated reproducibility in archived plasma samples and stability after delayed processing in epidemiological studies, yet correlations between proteins measured with the Olink and SOMAscan7K platforms were highly variable.