Discovery of Selective Proteolysis-Targeting Chimera Degraders Targeting PTP1B as Long-Term Hypoglycemic Agents.

PTP1B, a promising target for insulin sensitizers in type 2 diabetes treatment, can be effectively degraded using proteolysis-targeting chimera (PROTAC). This approach offers potential for long-acting antidiabetic agents. We report potent bifunctional PROTACs targeting PTP1B through the E3 ubiquitin ligase cereblon. Western blot analysis showed significant PTP1B degradation by PROTACs at concentrations from 5 nM to 5 µM after 48 h. Evaluation of five highly potent PROTACs revealed compound 75 with a longer PEG linker (23 atoms), displaying remarkable degradation activity after 48 and 72 h, with DC50 values of 250 nM and 50 nM, respectively. Compound 75 induced selective degradation of PTP1B, requiring engagement with both the target protein and CRBN E3 ligase, in a ubiquitination and proteasome-dependent manner. It significantly reduced blood glucose AUC0-2h to 29% in an oral glucose tolerance test and activated the IRS-1/PI3K/Akt signaling pathway in HepG2 cells, showing promise for long-term antidiabetic therapy.

DNA polymerase delta governs parental histone transfer to DNA replication lagging strand.

Chromatin replication is intricately intertwined with the recycling of parental histones to the newly duplicated DNA strands for faithful genetic and epigenetic inheritance. The transfer of parental histones occurs through two distinct pathways: leading strand deposition, mediated by the DNA polymerase ε subunits Dpb3/Dpb4, and lagging strand deposition, facilitated by the MCM helicase subunit Mcm2. However, the mechanism of the facilitation of Mcm2 transferring parental histones to the lagging strand while moving along the leading strand remains unclear. Here, we show that the deletion of Pol32, a nonessential subunit of major lagging-strand DNA polymerase δ, results in a predominant transfer of parental histone H3-H4 to the leading strand during replication. Biochemical analyses further demonstrate that Pol32 can bind histone H3-H4 both in vivo and in vitro. The interaction of Pol32 with parental histone H3-H4 is disrupted through the mutation of the histone H3-H4 binding domain within Mcm2. Our findings identify the DNA polymerase δ subunit Pol32 as a critical histone chaperone downstream of Mcm2, mediating the transfer of parental histones to the lagging strand during DNA replication.

Chlorantraniliprole induces mitophagy, ferroptosis, and cytokine homeostasis imbalance in grass carp (Ctenopharyngodon idella) hepatocytes via the mtROS-mitochondrial fission/fusion axis.

Chlorantraniliprole (CAP) is a bis-amide pesticide used for pest control mainly in agricultural production activities and rice-fish co-culture systems. CAP residues cause liver damage in non-target organism freshwater fish. However, it is unclear whether CAP-exposure-induced liver injury in fish is associated with mitochondrial dysfunction-mediated mitophagy, ferroptosis, and cytokines. Therefore, we established grass carp hepatocyte models exposed to different concentrations of CAP (20, 40, and 80 µM) in vitro. MitoSOX probe, JC-1 staining, immunofluorescence double staining, Fe2+ staining, lipid peroxidation staining, qRT-PCR, and Western blot were used to verify the physiological regulatory mechanism of CAP induced liver injury. In the present study, the CAP-treated groups exhibited down-regulation of antioxidant-related enzyme activities and accumulation of peroxides. CAP treatment induced an increase in mitochondrial reactive oxygen species (mtROS) levels and altered expression of mitochondrial fission/fusion (Drp1, Fis1, Mfn1, Mfn2, and Opa1) genes in grass carp hepatocytes. In addition, mitophagy (Parkin, Pink1, p62, LC3II/I, and Beclin-1), ferroptosis (GPX4, COX2, ACSL4, FTH, and NCOA4), and cytokine (IFN-γ, IL-18, IL-17, IL-6, IL-10, IL-1ß, IL-2, and TNF-α)-related gene expression was significantly altered. Collectively, these findings suggest that CAP exposure drives mitophagy activation, ferroptosis occurrence, and cytokine homeostasis imbalance in grass carp hepatocytes by triggering mitochondrial dysfunction mediated by the mtROS-mitochondrial fission/fusion axis. This study partly explained the physiological regulation mechanism of grass carp hepatocyte injury induced by insecticide CAP from the physiological and biochemical point of view and provided a basis for evaluating the safety of CAP environmental residues to non-target organisms.

Effect of substrate material and abutment geometry on the accuracy of intraoral scanning: An in vitro study.

STATEMENT OF PROBLEM: Digital scanning is gradually replacing conventional impression making, but consensus on how tooth preparation influences the accuracy of intraoral scanning is lacking. PURPOSE: The purpose of this in vitro study was to evaluate the effect of substrate material and abutment geometry on the accuracy of digital casts obtained by intraoral scanning. MATERIAL AND METHODS: The height and total occlusal convergence (TOC) angle were measured in 5 different groups that contained 5 specimens of different materials: natural tooth, cobalt chromium alloy, titanium, zirconium dioxide ceramic, and resin. The specimens were scanned with an industrial scanner to obtain reference data. Each specimen was placed in a maxillary standard dentition model that was assembled in a head simulator. Each dentition model was scanned 10 times with an intraoral scanner (IOS) under operatory lighting conditions to acquire intraoral scanning files for each specimen. All data were imported into a metrology software program and processed. A total of 10 trueness deviations, the mean superimposition results between IOS scanning data and reference data, and precision deviations, the mean superimposition results between IOS scanning data in pairs, were recorded. Two-way analysis of variance (ANOVA) and Tukey multiple comparison test were used to analyze the accuracy of intraoral scanning in relation to the height or TOC angle of the abutment (α=.05). The total means of each substrate material were compared with the Kruskal-Wallis test and Dunn test for multiple comparisons. RESULTS: The accuracy of scanning images was related to material and abutment geometry (P<.05). Bias was larger as abutment height increased with most substrates. Larger TOC angles increased the accuracy of the digital scans. The trueness deviation of translucent materials and the precision deviation of reflective materials were generally larger. CONCLUSIONS: Substrate material and abutment geometry influence the accuracy of intraoral scanning. The accuracy of IOS generally tended to improve with decreasing height and increasing TOC angle and was affected by different substrates.

Update on the Basic Understanding of Fusarium graminearum Virulence Factors in Common Wheat Research.

Wheat is one of the most important food crops, both in China and worldwide. Wheat production is facing extreme stresses posed by different diseases, including Fusarium head blight (FHB), which has recently become an increasingly serious concerns. FHB is one of the most significant and destructive diseases affecting wheat crops all over the world. Recent advancements in genomic tools provide a new avenue for the study of virulence factors in relation to the host plants. The current review focuses on recent progress in the study of different strains of Fusarium infection. The presence of genome-wide repeat-induced point (RIP) mutations causes genomic mutations, eventually leading to host plant susceptibility against Fusarium invasion. Furthermore, effector proteins disrupt the host plant resistance mechanism. In this study, we proposed systematic modification of the host genome using modern biological tools to facilitate plant resistance against foreign invasion. We also suggested a number of scientific strategies, such as gene cloning, developing more powerful functional markers, and using haplotype marker-assisted selection, to further improve FHB resistance and associated breeding methods.

Synthesis and Neuroprotective Evaluation of Substituted Indanone/Benzofuranone and Piperidine Hybrids.

Based on the neuroprotection of butylphthalide and donepezil, a series of indanone/benzofuranone and piperidine hybrids were designed and synthesized for assessment of their neuroprotective activities, aiming to enhance the bioavailability and therapeutic efficacy of natural phthalide analogues. Within this study, it was observed that most indanone derivatives bearing 1-methylpiperidine in the tail segment demonstrated superior neuroprotective effects on the oxygen glucose deprivation/reperfusion (OGD/R)-induced rat primary neuronal cell injury model in vitro compared to benzofuranone compounds. Among the synthesized compounds, 11 (4, 14, 15, 22, 26, 35, 36, 37, 48, 49, and 52) displayed robust cell viabilities in the OGD/R model, along with favorable blood-brain barrier permeability as confirmed by the parallel artificial membrane permeability assay. Notably, compound 4 showed significant neuronal cell viabilities within the concentration range of 3.125 to 100 µM, without inducing cytotoxicity. Further results from in vivo middle cerebral artery occlusion/R experiments revealed that 4 effectively ameliorated ischemia-reperfusion injury, reducing the infarct volume to 18.45% at a dose of 40 mg/kg. This outcome suggested a superior neuroprotective effect compared to edaravone at 20 mg/kg, further highlighting the potential therapeutic efficacy of compound 4 in addressing neurological disorders.

[Retracted] MicroRNA­202 inhibits endometrial stromal cell migration and invasion by suppressing the K­Ras/Raf1/MEK/ERK signaling pathway.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the Transwell invasion assay data shown in Figs. 2C and 4B were strikingly similar to data appearing in different form in a paper by different authors at a different research institute that had already been submitted for publication. Owing to the fact that the contentious data in the above article had already been submitted for publication prior to its submission to International Journal of Molecular Medicine, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a satisfactory reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 46: 2078­2088, 2020; DOI: 10.3892/ijmm.2020.4749].

Attempted retrieval of guidewire fragment using the twisting wire technique causes coronary perfusion: Case report.

RATIONALE: Guidewire fracture is one of the biggest risks of percutaneous coronary intervention, twisting wire technique is very useful for retrieving the fractured wire, but the potential risks have been inadequately reported. Herein, we present a case of retrieval of guidewire fragments using the twisting wire technique that causes coronary perfusion. PATIENT CONCERNS: A 37-year-old male patient was admitted to our hospital for elective percutaneous coronary intervention of the left circumflex coronary artery. CLINICAL FINDINGS: For chronic total occlusion of the distal left circumflex coronary artery, antegrade recanalization by wire escalation, and parallel wire techniques were attempted. However, we shockingly found that the BMW guidewire, anchored in the right coronary artery, spontaneously fractured from the proximal right coronary artery, and a lengthy fragment of the guidewire remained in the coronary. DIAGNOSES, INTERVENTIONS, AND OUTCOMES: Many attempts were made to retrieve the remnant guidewire including the twisting wire technique, which leads to the perforation of the coronary. OUTCOMES: Finally, percutaneous retrieving procedures were stopped in favor of surgical extraction via a small coronary arteriotomy. This procedure was successful. LESSONS: To the best of our knowledge, the present case is the first reported spontaneous fracture of the guidewire. Leaving such a lengthy remnant guidewire in the artery, or leaving stenting over the wire, would impose a high risk of coronary thrombosis, perforation, and embolization. Yet, the perforation of the artery that occurred in this case, which could have had life-threatening consequences, resulted from our attempts to retrieve the guidewire using the twisting wire technique.

Golgi-localized APYRASE 1 is critical for Arabidopsis growth by affecting cell wall integrity under boron deficiency.

Many nucleoside triphosphate-diphosphohydrolases (NTPDases/APYRASEs, APYs) play a key role in modulating extracellular nucleotide levels. However, the Golgi-localized APYs, which help control glycosylation, have rarely been studied. Here, we identified AtAPY1, a gene encoding an NTPDase in the Golgi apparatus, which is required for cell wall integrity and plant growth under boron (B) limited availability. Loss of function in AtAPY1 hindered cell elongation and division in root tips while increasing the number of cortical cell layers, leading to swelling of the root tip and abundant root hairs under low B stress. Further, expression pattern analysis revealed that B deficiency significantly induced AtAPY1, especially in the root meristem and stele. Fluorescent-labeled AtAPY1-GFP localized to the Golgi stack. Biochemical analysis showed that AtAPY1 exhibited a preference of UDP and GDP hydrolysis activities. Consequently, the loss of function in AtAPY1 might disturb the homoeostasis of NMP-driven NDP-sugar transport, which was closely related to the synthesis of cell wall polysaccharides. Further, cell wall-composition analysis showed that pectin content increased and borate-dimerized RG-II decreased in apy1 mutants, along with a decrease in cellulose content. Eventually, altered polysaccharide characteristics presumably cause growth defects in apy1 mutants under B deficiency. Altogether, these data strongly support a novel role for AtAPY1 in mediating responses to low B availability by regulating cell wall integrity.

Dietary patterns, metabolomics and frailty in a large cohort of 120 000 participants.

Objective: To examine the associations of dietary patterns with frailty and whether metabolic signatures (MSs) mediate these associations. Methods: We used UK Biobank data to examine (1) the associations of four dietary patterns (i.e., alternate Mediterranean diet [aMED], Recommended Food Score [RFS], Dietary Approaches to Stop Hypertension [DASH] and Mediterranean-DASH Intervention for Neurodegenerative Delay [MIND] diet) with frailty (measured by the frailty phenotype and the frailty index) using multivariable logistic regression (analytic sample 1: N = 124 261; mean age = 57.7 years), and (2) the mediating role of MSs (weighted sums of the metabolites selected from 168 plasma metabolites using the LASSO algorithm) in the above associations via mediation analysis (analytic sample 2: N = 26 270; mean age = 57.7 years). Results: Four dietary patterns were independently associated with frailty (all P < 0.001). For instance, compared to participants in the lowest tertile for RFS, those in the intermediate (odds ratio [OR]: 0.81; 95% confidence interval [CI]: 0.74, 0.89) and highest (OR: 0.62; 95% CI: 0.56, 0.68) tertiles had a lower risk of frailty. We found that 98, 68, 123 and 75 metabolites were associated with aMED, RFS, DASH and MIND, respectively, including 16 common metabolites (e.g., fatty acids, lipoproteins, acetate and glycoprotein acetyls). The MSs based on these metabolites partially mediated the association of the four dietary patterns with frailty, with the mediation proportion ranging from 26.52% to 45.83%. The results were robust when using another frailty measure, the frailty index. Conclusions: The four dietary patterns were associated with frailty, and these associations were partially mediated by MSs. Adherence to healthy dietary patterns may potentially reduce frailty development by modulating metabolites.

The RING zinc finger protein LbRZF1 promotes salt gland development and salt tolerance in Limonium bicolor.

The recretohalophyte Limonium bicolor thrives in high-salinity environments because salt glands on the above-ground parts of the plant help to expel excess salt. Here, we characterize a nucleus-localized C3HC4 (RING-HC)-type zinc finger protein of L. bicolor named  RING  ZINC  FINGER PROTEIN  1 (LbRZF1). LbRZF1 was expressed in salt glands and in response to NaCl treatment. LbRZF1 showed no E3 ubiquitin ligase activity. The phenotypes of overexpression and knockout lines for LbRZF1 indicated that LbRZF1 positively regulated salt gland development and salt tolerance in L. bicolor. lbrzf1 mutants had fewer salt glands and secreted less salt than did the wild-type, whereas LbRZF1-overexpressing lines had opposite phenotypes, in keeping with the overall salt tolerance of these plants. A yeast two-hybrid screen revealed that LbRZF1 interacted with LbCATALASE2 (LbCAT2) and the transcription factor LbMYB113, leading to their stabilization. Silencing of LbCAT2 or LbMYB113 decreased salt gland density and salt tolerance. The heterologous expression of LbRZF1 in Arabidopsis thaliana conferred salt tolerance to this non-halophyte. We also identified the transcription factor LbMYB48 as an upstream regulator of LbRZF1 transcription. The study of LbRZF1 in the regulation network of salt gland development also provides a good foundation for transforming crops and improving their salt resistance.

A capillary-based centrifugal indicator equipped with in situ pathogenic bacteria culture for fast antimicrobial susceptibility testing.

Antimicrobial resistance has become a major global health threat due to the misuse and overuse of antibiotics. Rapid, affordable, and high-efficiency antimicrobial susceptibility testing (AST) is among the effective means to solve this problem. Herein, we developed a capillary-based centrifugal indicator (CBCI) equipped with an in situ culture of pathogenic bacteria for fast AST. The bacterial incubation and growth were performed by macro-incubation, which seamlessly integrated the capillary indicator. Through simple centrifugation, all the bacterial cells were confined at the nanoliter-level capillary column. The packed capillary column height could linearly reflect the bacterial count, and the minimum inhibitory concentration (MIC) was determined based on the difference in the column height between the drug-added groups and the control group. The AST results could easily be determined by the naked eye or smartphone imaging. Thus, the CBCI realized the combination of macro-bacterial incubation and early micro assessment, which accelerated the phenotypic AST without complex microscopic counting or fluorescent labelling. The whole operation process was simple and easy to use. AST results could be determined for E. coli ATCC strains within 3.5 h, and the output results for clinical samples were consistent with the hospital reports. We expect this AST platform to become a useful tool in limiting antimicrobial resistance, especially in remote/resource-limited areas or in underdeveloped countries.

Mechanistic insights into chemical conditioning on transformation of dissolved organic matter and plant biostimulants production during sludge aerobic composting.

Inorganic coagulants (aluminum and iron salt) are widely used to improve sludge dewaterability, resulting in numerous residues in dewatered sludge. Composting refers to the controlled microbial process that converts organic wastes into fertilizer, and coagulant residues in dewatered sludge can affect subsequent compost efficiency and resource recycling, which remains unclear. This work investigated the effects of two typical metal salt coagulants (poly aluminum chloride [PAC] and poly ferric sulfate [PFS]) conditioning on sludge compost. Our results revealed that PAC conditioning inhibited composting with decreased peak temperature, microbial richness, enzymatic reaction intensities, and compost quality, associated with decreased pH and microbial toxicity of aluminum. Nevertheless, PFS conditioning selectively enriched Pseudoxanthomonas sp. and resulted in more fertile compost with increased peak temperature, enzymatic reaction intensities, and humification degree. Spectroscopy and mass difference analyses indicated that PFS conditioning enhanced reaction intensities of labile biopolymers at the thermophilic stage, mainly comprising hydrolyzation (H2O), dehydrogenation (-H2, -H4), oxidation (+O1H2), and other reactions (i.e., +CH2, C2H4O1, C2H6O1). Unlike the common composting process primarily conducts humification at the cooling stage, PFS conditioning changed the main occurrence stage to the thermophilic stage. Non-targeted metabolomics revealed that indole (a humification intermediate) is responsible for the increased humification degree and indoleacetic acid content in the PFS-conditioned compost, which then promoted compost quality. Plant growth experiments further confirmed that the dissolved organic matter (DOM) in PFS-conditioned compost produced the maximum plant biomass. This study provided molecular-level evidence that PFS conditioning can promote humification and compost fertility during sludge composting, enabling chemical conditioning optimization for sustainable management of sludge.

BDE-47-induced damage prevented by melatonin in grass carp hepatocytes (L8824).

Polybrominated diphenyl ethers (PBDEs) are toxic to organisms with melatonin (MT) providing protection for tissues and cells against these. This study investigates the mechanism of damage of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and the cellular protection of MT on grass carp hepatocytes. Grass carp hepatocytes were exposed to 25 µmol/L BDE-47 and/or 40 µmol/L MT for 24 h before testing. Acridine orange/ethidium bromide (AO/EB) double fluorescence staining results showed that BDE-47 could induce cell apoptosis. The expression levels of the endoplasmic reticulum (ER) stress-related genes ire1, atf4, grp78, perk, and chop were also significantly up-regulated (P < 0.01). The levels of the apoptosis-related genes caspase3, bax, and caspase9 were significantly up-regulated (P < 0.0001), while the level of bcl-2 was significantly down-regulated (P < 0.01). Compared with the BDE-47 group, the BDE-47 + MT group showed reduced levels of ER and apoptosis of hepatocytes, while the expression of the ER stress-related genes ire1, atf4, grp78, perk, and chop and the apoptosis-related genes caspase3, bax, and caspase9 were down-regulated (P < 0.05), and the level of bcl-2 was up-regulated (P < 0.01). In conclusion, BDE-47 can activate ER and apoptosis in grass carp hepatocytes, while MT can reduce these responses.

Sexual Behavior and Perceived Risk for Oropharyngeal Cancer Among Men Who Have Sex With Men: A Psychometric Scale Validation.

BACKGROUND: Men who have sex with men (MSM) are at increased risk for human papillomavirus-associated oropharyngeal cancer (HPV-OPC). The objective of this analysis was to create a psychometrically validated scale to measure perception of risk for HPV-OPC. METHODS: We conducted an exploratory and a confirmatory factor analysis to determine and confirm the latent factor structure. We used a path diagram to evaluate the relationship between the validated scale and perceived risk for HPV-OPC. The model was determined to be a good fit if it met all criteria: root mean square error of approximation ≤0.06, standardized root mean residual ≤0.08, Comparative Fit Index ≥0.90, and Tucker-Lewis Index ≥0.90. We report standardized estimates and 95% confidence intervals. RESULTS: This cross-sectional study recruited 1315 MSM. A majority (73.33%) of MSM had performed fellatio on ≥20 partners, 36.98% had rimmed ≥20 partners, and 5.31% had performed cunnilingus on ≥10 partners in their lifetime.Six sexual history survey items loaded onto 2 latent factors: sexual risk behaviors: class 1 and sexual risk behaviors: class 2. The final model statistics indicated good fit: root mean square error of approximation = 0.064, standardized root mean residual = 0.059, Comparative Fit Index = 0.996, and Tucker-Lewis Index = 0.993. Sexual risk behaviors: class 1 was associated with greater perceived risk for HPV-OPC (0.217; 95% confidence interval, 0.138-0.295). Age, HIV status, HPV vaccination status, and sexual risk behaviors: class 2 were not associated with perceived risk for HPV-OPC. CONCLUSION: Men who have sex with men assessed risk for HPV-OPC based on their lifetime number of cisgender male sexual partners, rimming partners, and fellatio partners but not other sexual behaviors. Men who have sex with men may be responsive to future HPV-OPC educational interventions and opportunities for screening.

Association of the combination of obstructive sleep apnea risk and sleep duration with ideal cardiovascular health metrics in patients undergoing hemodialysis.

BACKGROUND: The purpose of this study was to explore the separate and combined associations of obstructive sleep apnea (OSA) risk and sleep duration with ideal cardiovascular health metrics in hemodialysis (HD) patients. METHODS: 470 HD participants (average: 59.48 ± 12.89 y, 281 men) were included in this study. Sleep duration was measured as self-reported average sleep time during the previous month. The OSA risk was assessed using the STOP-BANG questionnaire. Participants were divided into three groups based on the number of ideal cardiovascular health (CVH) metrics: 0-2,3-4, and 5-7. Ordinal logistic regression was conducted to model the associations of CVH metrics with sleep duration, OSA risk, and their combined effects by adjusting for specific covariates. RESULTS: After adjusting for covariates, short sleep duration (< 7 h) (OR = 0.53; 95% CI [ 0.30, 0.92]) and OSA risk (OR = 0.58; 95% CI [0.32, 0.83]) were negatively associated with better CVH (ideal vs. intermediate; intermediate vs. poor), respectively. For HD patients with both short sleep duration and OSA risk, the odds of ideal CVH metrics were reduced by 72% (odds ratio 0.28 [95% CI 0.13, 0.60]). CONCLUSIONS: Short sleep duration and OSA risk are separately and jointly associated with poor CVH in hemodialysis patients. Suitable interventions for sleep may minimize the risk of developing cardiovascular disease.

Effect of adrenocorticotropic hormone stimulation during adrenal vein sampling for the subtyping of primary aldosteronism: a prospective study.

OBJECTIVE: Adrenal venous sampling (AVS) is key for primary aldosteronism subtype identification. However, the value of adrenocorticotropic hormone (ACTH) stimulation in AVS is still controversial. METHODS: In this prospective study, we investigated the role of continuous ACTH infusion on the performance and interpretation of bilateral simultaneous AVS using a standard protocol in 59 primary aldosteronism patients. We analyzed the selectivity index and lateralization index in AVS pre and post-ACTH and estimated the prognosis of patients who underwent adrenalectomy with different cutoff points of lateralization index post-ACTH. RESULTS: The confirmed success rate of bilateral adrenal vein catheterization increased from 84% pre-ACTH to 95% post-ACTH. Fifty percent of the patients had a decline in lateralization index post-ACTH, 30% of patients showed unilateral primary aldosteronism pre-ACTH but bilateral primary aldosteronism post-ACTH according to lateralization index at least 2 pre-ACTH and lateralization index at least 4 post-ACTH. The outcomes of the patients with primary aldosteronism after adrenalectomy indicated that all patients achieved clinical and biochemical success regardless of lateralization index at least 4 or less than 4 post-ACTH. Receiver operating characteristic curves showed that lateralization index cutoff 2.58 post-ACTH stimulation yielded the best threshold in lateralization with a sensitivity of 73.1% and a specificity of 92.9%. CONCLUSION: ACTH stimulation increased the AVS success rates in patients with primary aldosteronism, reduced lateralization index in some cases and decreased the proportion of identified unilateral primary aldosteronism, resulting in some patients losing the opportunity for disease cure. Compared with lateralization index at least 4, a lower cutoff point of lateralization index at least 2.58 after ACTH stimulation has better accuracy of lateralization diagnosis.

Morphological and quantitative study of the inferior alveolar nerve canal in hemifacial microsomia.

This study aimed to probe into the anatomic course of inferior alveolar nerve canal (IANC) in hemifacial microsomia (HFM) on a large scale, morphological observations and further quantitative study were performed. Patients were classified by Pruzansky-Kaban classification. The anatomic course of IANC was analyzed morphologically with three-dimensional (3D) imaging software among 248 patients. Seven distances between fixed landmarks on both sides were measured for 236 patients. The differences between affected and unaffected sides were compared. Significant differences were found in the entrance (P < 0.001), route (P < 0.001), and exit (P < 0.05) of IANC in type IIb and III HFM. The higher the degree of mandibular deformity was, the higher the incidence of IANC variation was (P < 0.05). The distances in the horizontal aspect of IANC including from mandibular foramen to mental foramen (P < 0.05) and from mental foramen to gonion (P < 0.05) were significantly shorter on the affected side. Abnormalities of the anatomical course of IANC exist in patients with Pruzansky-Kaban type IIb and type III HFM. The reduction of IANC on the affected side in the horizontal distance is more obvious. Three-dimensional imaging assessment is recommended before surgery.

New Insights into Decabromodiphenyl Ether-Induced Splenic Injury in Chickens: Involvement of ROS-Mediated Endoplasmic Reticulum Stress Pathway Triggering Autophagy and Apoptosis.

Decabromodiphenyl ether (BDE-209) is a widely used brominated flame retardant that can easily detach from materials and enter into feed and foodstuffs, posing a serious risk to human and animal health and food safety of animal origin. However, the immunotoxic effects of BDE-209 on the avian spleen and the exact mechanism of the toxicity remain unknown. Therefore, we established an experimental model of BDE-209-exposed chickens and a positive control model of cyclophosphamide-induced immunosuppression in vivo and treated MDCC-MSB-1 cells and chicken splenic primary lymphocytes with BDE-209 in vitro. The results showed that BDE-209 treatment caused morphological and structural abnormalities in the chicken spleens. Mechanistically, indicators related to oxidative stress, endoplasmic reticulum stress (ERS), autophagy, and apoptosis were significantly altered by BDE-209 exposure in both the spleen and lymphocytes, but the use of the N-acetylcysteine or the 4-phenylbutyric acid significantly reversed these changes. In addition, BDE-209 exposure decreased the spleen antimicrobial peptide and immunoglobulin gene expression. In conclusion, the present research revealed that BDE-209 exposure enhanced lymphocyte autophagy and apoptosis in chicken spleen via the ROS-mediated ERS pathway. This signaling cascade regulatory relationship not only opens up a new avenue for studying BDE-209 immunotoxicity but also provides important insights into preventing BDE-209 hazards to animal health.

Impact of individual level uncertainty of lung cancer polygenic risk score (PRS) on risk stratification.

BACKGROUND: Although polygenic risk score (PRS) has emerged as a promising tool for predicting cancer risk from genome-wide association studies (GWAS), the individual-level accuracy of lung cancer PRS and the extent to which its impact on subsequent clinical applications remains largely unexplored. METHODS: Lung cancer PRSs and confidence/credible interval (CI) were constructed using two statistical approaches for each individual: (1) the weighted sum of 16 GWAS-derived significant SNP loci and the CI through the bootstrapping method (PRS-16-CV) and (2) LDpred2 and the CI through posteriors sampling (PRS-Bayes), among 17,166 lung cancer cases and 12,894 controls with European ancestry from the International Lung Cancer Consortium. Individuals were classified into different genetic risk subgroups based on the relationship between their own PRS mean/PRS CI and the population level threshold. RESULTS: Considerable variances in PRS point estimates at the individual level were observed for both methods, with an average standard deviation (s.d.) of 0.12 for PRS-16-CV and a much larger s.d. of 0.88 for PRS-Bayes. Using PRS-16-CV, only 25.0% of individuals with PRS point estimates in the lowest decile of PRS and 16.8% in the highest decile have their entire 95% CI fully contained in the lowest and highest decile, respectively, while PRS-Bayes was unable to find any eligible individuals. Only 19% of the individuals were concordantly identified as having high genetic risk (> 90th percentile) using the two PRS estimators. An increased relative risk of lung cancer comparing the highest PRS percentile to the lowest was observed when taking the CI into account (OR = 2.73, 95% CI: 2.12-3.50, P-value = 4.13 × 10-15) compared to using PRS-16-CV mean (OR = 2.23, 95% CI: 1.99-2.49, P-value = 5.70 × 10-46). Improved risk prediction performance with higher AUC was consistently observed in individuals identified by PRS-16-CV CI, and the best performance was achieved by incorporating age, gender, and detailed smoking pack-years (AUC: 0.73, 95% CI = 0.72-0.74). CONCLUSIONS: Lung cancer PRS estimates using different methods have modest correlations at the individual level, highlighting the importance of considering individual-level uncertainty when evaluating the practical utility of PRS.