Oleic acid availability impacts thymocyte preprogramming and subsequent peripheral Treg cell differentiation.

The nature of activation signals is essential in determining T cell subset differentiation; however, the features that determine T cell subset preference acquired during intrathymic development remain elusive. Here we show that naive CD4+ T cells generated in the mouse thymic microenvironment lacking Scd1, encoding the enzyme catalyzing oleic acid (OA) production, exhibit enhanced regulatory T (Treg) cell differentiation and attenuated development of experimental autoimmune encephalomyelitis. Scd1 deletion in K14+ thymic epithelia recapitulated the enhanced Treg cell differentiation phenotype of Scd1-deficient mice. The dearth of OA permitted DOT1L to increase H3K79me2 levels at the Atp2a2 locus of thymocytes at the DN2-DN3 transition stage. Such epigenetic modification persisted in naive CD4+ T cells and facilitated Atp2a2 expression. Upon T cell receptor activation, ATP2A2 enhanced the activity of the calcium-NFAT1-Foxp3 axis to promote naive CD4+ T cells to differentiate into Treg cells. Therefore, OA availability is critical for preprogramming thymocytes with Treg cell differentiation propensities in the periphery.

The super elongation complex (SEC) mediates phase transition of SPT5 during transcriptional pause release.

Release of promoter-proximally paused RNA Pol II into elongation is a tightly regulated and rate-limiting step in metazoan gene transcription. However, the biophysical mechanism underlying pause release remains unclear. Here, we demonstrate that the pausing and elongation regulator SPT5 undergoes phase transition during transcriptional pause release. SPT5 per se is prone to form clusters. The disordered domain in SPT5 is required for pause release and gene activation. During early elongation, the super elongation complex (SEC) induces SPT5 transition into elongation droplets. Depletion of SEC increases SPT5 pausing clusters. Furthermore, disease-associated SEC mutations impair phase properties of elongation droplets and transcription. Our study suggests that SEC-mediated SPT5 phase transition might be essential for pause release and early elongation and that aberrant phase properties could contribute to transcription abnormality in diseases.

Symbiosis-inspired de novo synthesis of ultrahigh MOF growth mixed matrix membranes for sustainable carbon capture.

Mixed matrix membranes (MMMs) are one of the most promising solutions for energy-efficient gas separation. However, conventional MMM synthesis methods inevitably lead to poor filler-polymer interfacial compatibility, filler agglomeration, and limited loading. Herein, inspired by symbiotic relationships in nature, we designed a universal bottom-up method for in situ nanosized metal organic framework (MOF) assembly within polymer matrices. Consequently, our method eliminating the traditional postsynthetic step significantly enhanced MOF dispersion, interfacial compatibility, and loading to an unprecedented 67.2 wt % in synthesized MMMs. Utilizing experimental techniques and complementary density functional theory (DFT) simulation, we validated that these enhancements synergistically ameliorated CO2 solubility, which was significantly different from other works where MOF typically promoted gas diffusion. Our approach simultaneously improves CO2 permeability and selectivity, and superior carbon capture performance is maintained even during long-term tests; the mechanical strength is retained even with ultrahigh MOF loadings. This symbiosis-inspired de novo strategy can potentially pave the way for next-generation MMMs that can fully exploit the unique characteristics of both MOFs and matrices.

Role of TFEB-autophagy lysosomal pathway in palmitic acid induced renal tubular epithelial cell injury.

Lysosomal dysfunction and impaired autophagic flux are involved in the pathogenesis of lipotoxicity in the kidney. Here, we investigated the role of transcription factor EB (TFEB), a master regulator of autophagy-lysosomal pathway, in palmitic acid induced renal tubular epithelial cells injury. We examined lipid accumulation, autophagic flux, expression of Ps211-TFEB, and nuclear translocation of TFEB in HK-2 cells overloaded with palmitic acid (PA). By utilizing immunohistochemistry, we detected TFEB expression in renal biopsy tissues from patients with diabetic nephropathy and normal renal tissue adjacent to surgically removed renal carcinoma (controls), as well as kidney tissues from rat fed with high-fat diet (HFD) and low-fat diet (LFD). We found significant lipid accumulation, increased apoptosis, accompanied with elevated Ps211-TFEB, decreased nuclear TFEB, reduced lysosome biogenesis and insufficient autophagy in HK-2 cells treated with PA. Kidney tissues from patients with diabetic nephropathy had lower nuclear and total levels of TFEB than that in control kidney tissues. Level of renal nuclear TFEB in HFD rats was also lower than that in LFD rats. Exogenous overexpression of TFEB increased the nuclear TFEB level in HK-2 cells treated with PA, promoted lysosomal biogenesis, improved autophagic flux, reduced lipid accumulation and apoptosis. Our results collectively indicate that PA is a strong inducer for TFEB phosphorylation modification at ser211 accompanied with lower nuclear translocation of TFEB. Impairment of TFEB-mediated lysosomal biogenesis and function by palmitic acid may lead to insufficient autophagy and promote HK-2 cells injury.

A genome-wide association study reveals novel loci and candidate genes associated with plant height variation in Medicago sativa.

BACKGROUND: Plant height (PH) is an important agronomic trait influenced by a complex genetic network. However, the genetic basis for the variation in PH in Medicago sativa remains largely unknown. In this study, a comprehensive genome-wide association analysis was performed to identify genomic regions associated with PH using a diverse panel of 220 accessions of M. sativa worldwide. RESULTS: Our study identified eight novel single nucleotide polymorphisms (SNPs) significantly associated with PH evaluated in five environments, explaining 8.59-12.27% of the phenotypic variance. Among these SNPs, the favorable genotype of chr6__31716285 had a low frequency of 16.4%. Msa0882400, located proximal to this SNP, was annotated as phosphate transporter 3;1, and its role in regulating alfalfa PH was supported by transcriptome and candidate gene association analysis. In addition, 21 candidate genes were annotated within the associated regions that are involved in various biological processes related to plant growth and development. CONCLUSIONS: Our findings provide new molecular markers for marker-assisted selection in M. sativa breeding programs. Furthermore, this study enhances our understanding of the underlying genetic and molecular mechanisms governing PH variations in M. sativa.

Entropy-Driven Morphology Regulation of MAX Phase Solid Solutions with Enhanced Microwave Absorption and Thermal Insulation Performance.

Morphology regulation and composition design have proved to be effective strategies for the fabrication of desirable microwave absorbers. However, it is still challenging to precisely control the microstructure and components of MAX phases. Herein, an entropy-driven approach, a transition from irregular grains (low entropy) to sheet structure (high entropy), is proposed to modulate the morphology of MAX phases. The theoretical calculation indicates that the morphology evolution can be ascribed to the enlarged energy difference between (11_00) and (0001) facets. The enriched structural defects and optimized morphologies yield significant dipolar polarization, interfacial polarization, multiple reflections, and scattering, which all enhance the electromagnetic wave absorption performance of (V0.25 Ti0.25 Cr0.25 Mo0.25 )2 GaC. Specifically, its minimum reflection loss can reach up to -47.12 dB at 12.13 GHz, and the optimal effective absorption bandwidth is 4.56 GHz (2.03 mm). Meanwhile, (V0.25 Ti0.25 Cr0.25 Mo0.25 )2 GaC shows also pronounced thermal insulation properties affording it good reliability in the harsh working environment. This work offers a novel approach to designing and regulating the morphology of the high entropy MAX phase, and also presents an opportunity to elucidate the relationship between entropy and electromagnetic wave absorption performance.

Targeted Modulation of Redox and Immune Homeostasis in Acute Lung Injury Using a Thioether-Functionalized Dendrimer.

Acute lung injury (ALI) is the pathophysiological precursor of acute respiratory distress syndrome. It is characterized by increased oxidative stress and exaggerated inflammatory response that disrupts redox reactions and immune homeostasis in the lungs, thereby posing significant clinical challenges. In this study, an internally functionalized thioether-enriched dendrimer Sr-G4-PEG is developed, to scavenge both proinflammatory cytokines and reactive oxygen species (ROS) and restore homeostasis during ALI treatment. The dendrimers are synthesized using an efficient and orthogonal thiol-ene "click" chemistry approach that involves incorporating thioether moieties within the dendritic architectures to neutralize the ROS. The ROS scavenging of Sr-G4-PEG manifests in its capacity to sequester proinflammatory cytokines. The synergistic effects of scavenging ROS and sequestering inflammatory cytokines by Sr-G4-PEG contribute to redox remodeling and immune homeostasis, along with the modulation of the NLRP3-pyroptosis pathway. Treatment with Sr-G4-PEG enhances the therapeutic efficacy of ALIs by alleviating alveolar bleeding, reducing inflammatory cell infiltration, and suppressing the release of inflammatory cytokines. These results suggest that Sr-G4-PEG is a potent nanotechnological candidate for remodeling redox and immune homeostasis in the treatment of ALIs, demonstrating the great potential of dendrimer-based nanomedicine for the treatment of respiratory pathologies.

Incidence rate of occult lymph node metastasis in clinical T1-2N0M0 small cell lung cancer patients and radiomic prediction based on contrast-enhanced CT imaging: a multicenter study : Original research.

BACKGROUND: This study aimed to explore the incidence of occult lymph node metastasis (OLM) in clinical T1 - 2N0M0 (cT1 - 2N0M0) small cell lung cancer (SCLC) patients and develop machine learning prediction models using preoperative intratumoral and peritumoral contrast-enhanced CT-based radiomic data. METHODS: By conducting a retrospective analysis involving 242 eligible patients from 4 centeres, we determined the incidence of OLM in cT1 - 2N0M0 SCLC patients. For each lesion, two ROIs were defined using the gross tumour volume (GTV) and peritumoral volume 15 mm around the tumour (PTV). By extracting a comprehensive set of 1595 enhanced CT-based radiomic features individually from the GTV and PTV, five models were constucted and we rigorously evaluated the model performance using various metrics, including the area under the curve (AUC), accuracy, sensitivity, specificity, calibration curve, and decision curve analysis (DCA). For enhanced clinical applicability, we formulated a nomogram that integrates clinical parameters and the rad_score (GTV and PTV). RESULTS: The initial investigation revealed a 33.9% OLM positivity rate in cT1 - 2N0M0 SCLC patients. Our combined model, which incorporates three radiomic features from the GTV and PTV, along with two clinical parameters (smoking status and shape), exhibited robust predictive capabilities. With a peak AUC value of 0.772 in the external validation cohort, the model outperformed the alternative models. The nomogram significantly enhanced diagnostic precision for radiologists and added substantial value to the clinical decision-making process for cT1 - 2N0M0 SCLC patients. CONCLUSIONS: The incidence of OLM in SCLC patients surpassed that in non-small cell lung cancer patients. The combined model demonstrated a notable generalization effect, effectively distinguishing between positive and negative OLMs in a noninvasive manner, thereby guiding individualized clinical decisions for patients with cT1 - 2N0M0 SCLC.

Phase separation of RNA-binding protein promotes polymerase binding and transcription.

An RNA-involved phase-separation model has been proposed for transcription control. However, the molecular links that connect RNA to the transcription machinery remain missing. Here we find that RNA-binding proteins (RBPs) constitute half of the chromatin proteome in embryonic stem cells (ESCs), some being colocalized with RNA polymerase (Pol) II at promoters and enhancers. Biochemical analyses of representative RBPs show that the paraspeckle protein PSPC1 inhibits the RNA-induced premature release of Pol II, and makes use of RNA as multivalent molecules to enhance the formation of transcription condensates and subsequent phosphorylation and release of Pol II. This synergistic interplay enhances polymerase engagement and activity via the RNA-binding and phase-separation activities of PSPC1. In ESCs, auxin-induced acute degradation of PSPC1 leads to genome-wide defects in Pol II binding and nascent transcription. We propose that promoter-associated RNAs and their binding proteins synergize the phase separation of polymerase condensates to promote active transcription.

Animal models of heart failure with preserved ejection fraction (HFpEF): from metabolic pathobiology to drug discovery.

Heart failure (HF) with preserved ejection fraction (HFpEF) is currently a preeminent challenge for cardiovascular medicine. It has a poor prognosis, increasing mortality, and is escalating in prevalence worldwide. Despite accounting for over 50% of all HF patients, the mechanistic underpinnings driving HFpEF are poorly understood, thus impeding the discovery and development of mechanism-based therapies. HFpEF is a disease syndrome driven by diverse comorbidities, including hypertension, diabetes and obesity, pulmonary hypertension, aging, and atrial fibrillation. There is a lack of high-fidelity animal models that faithfully recapitulate the HFpEF phenotype, owing primarily to the disease heterogeneity, which has hampered our understanding of the complex pathophysiology of HFpEF. This review provides an updated overview of the currently available animal models of HFpEF and discusses their characteristics from the perspective of energy metabolism. Interventional strategies for efficiently utilizing energy substrates in preclinical HFpEF models are also discussed.

Natural pyrethrins induce cytotoxicity in SH-SY5Y cells and neurotoxicity in zebrafish embryos (Danio rerio).

Natural pyrethrins are widely used in agriculture because of their good insecticidal activity. Meanwhile, natural pyrethrins play an important role in the safety evaluation of pyrethroids as precursors for structural development of pyrethroid insecticides. However, there are fewer studies evaluating the neurological safety of natural pyrethrins on non-target organisms. In this study, we used SH-SY5Y cells and zebrafish embryos to explore the neurotoxicity of natural pyrethrins. Natural pyrethrins were able to induce SH-SY5Y cells damage, as evidenced by decreased viability, cycle block, apoptosis and DNA damage. The apoptotic pathway may be related to the involvement of mitochondria and the results showed that natural pyrethrins induced a rise in Capase-3 viability, Ca2+ overload, a decrease in adenosine triphosphate (ATP) and a collapse of mitochondrial membrane potential in SH-SY5Y cells. Natural pyrethrins may mediate DNA damage in SH-SY5Y cells through oxidative stress. The results showed that natural pyrethrins induced an increase in reactive oxygen species (ROS) levels, superoxide dismutase (SOD) activity, malondialdehyde (MDA) content and catalase (CAT) activity, and induced a decrease in glutathione peroxidase (GPx) activity in SH-SY5Y cells. In vivo, natural pyrethrins induced developmental malformations in zebrafish embryos, which were mainly characterized by pericardial edema and yolk sac edema. Meanwhile, the results showed that natural pyrethrins induced damage to the Huc-GFP axis and disturbed lipid metabolism in the head of zebrafish embryos. Further results showed elevated ROS levels and apoptosis in the head of zebrafish embryos, which corroborated with the results of the cell model. Finally, the results of mRNA expression assay of neurodevelopment-related genes indicated that natural pyrethrins exposure interfered with their expression and led to neurodevelopmental damage in zebrafish embryos. Our study may raise concerns about the neurological safety of natural pyrethrins on non-target organisms.

Basic study on cryopreservation of rat calvarial osteoblasts with different cryoprotectants.

Cryopreservation is a method adopted for storage of autologous skulls. Herein, this current research sought to explore the effects of different cryoprotectants on the biological characteristics of rat calvarial osteoblasts after cryopreservation. Neonatal Sprague-Dawley rats were selected and their skull tissues were isolated. The skull tissues were allocated into the refrigerating-3M, refrigerating-6M, M199-3M, M199-6M, povidone iodine-3M, and povidone iodine-6M groups according to the usage of cryoprotectants and treatment time (month) and the fresh group. Osteoblasts were isolated from skull tissues in each group through digestion. The histomorphology of the skull was evaluated by H&E staining and cell morphology was observed by microscopy. The viability, proliferation, apoptosis, and osteogenic activity of osteoblasts were assessed by trypan blue staining, MTT, flow cytometry, and alkaline phosphatase (ALP) staining. The skull histomorphology and osteoblast morphology were similar between the fresh and refrigerating groups. Osteoblast viability was weakened after cryopreservation. The longer the refrigeration time, the lower the number of living cells and the higher the apoptosis rate. However, cryopreservation using different cryoprotectants did not evidently affect osteoblast proliferation and ALP activity. Different cryoprotectants show no apparent effect on the osteogenic activity of rat calvarial osteoblasts after cryopreservation.

[Analysis of genetic variants and molecular pathogenesis in a Chinese pedigree affected with Multiple epiphyseal dysplasia].

OBJECTIVE: To analyze the genetic variant and molecular pathogenesis in a Chinese pedigree affected with Multiple epiphyseal dysplasia (MED). METHODS: A MED pedigree which had presented at the Beijing Jishuitan Hospital Affiliated to Capital Medical University on September 13, 2020 was selected as the study subject. Clinical data of the pedigree were collected. Peripheral blood samples were drawn from pedigree members for the extraction of genomic DNA. Whole exome sequencing (WES) was carried out for the pedigree. Candidate variant was verified by Sanger sequencing. Wild type and mutant SLC26A2 expression plasmids were constructed and transfected into human primary chondrocytes. The effect of the variants on the protein localization and cell proliferation was determined by immunofluorescence and CCK8 assays. RESULTS: WES and Sanger sequencing revealed that the proband has harbored compound heterozygous variants of the SLC26A2 gene, including a paternally derived c.484G>T (p.Val162Leu) missense variant and a maternally derived c.485_486delTG (p.Val162Glyfs*12) frameshifting variant. The SLC26A2WT and its mutant SLC26A2Val162Leu and SLC26A2Val162Glyfs*12 expression plasmids were distributed in the nuclei and cytoplasm of human primary chondrocytes. Compared with SLC26A2WT, the expressions of SLC26A2Val162Leu and SLC26A2Val162Glyfs*12 were decreased, along with reduced proliferation of human primary chondrocytes. CONCLUSION: The c.484G>T and c.485_486delTG compound heterozygous variants of the SLC26A2 gene may affect the proliferation of human primary chondrocytes and underlay the pathogenesis of MED in this pedigree.

Mannitol inhibits the proliferation of neural stem cell by a p38 mitogen-activated protein kinase-dependent signaling pathway.

PURPOSE: Mannitol is one of the first-line drugs for reducing cerebral edema through increasing the extracellular osmotic pressure. However, long-term administration of mannitol in the treatment of cerebral edema triggers damage to neurons and astrocytes. Given that neural stem cell (NSC) is a subpopulation of main regenerative cells in the central nervous system after injury, the effect of mannitol on NSC is still elusive. The present study aims to elucidate the role of mannitol in NSC proliferation. METHODS: C57 mice were derived from the animal house of Zunyi Medical University. A total of 15 pregnant mice were employed for the purpose of isolating NSCs in this investigation. Initially, mouse primary NSCs were isolated from the embryonic cortex of mice and subsequently identified through immunofluorescence staining. In order to investigate the impact of mannitol on NSC proliferation, both cell counting kit-8 assays and neurospheres formation assays were conducted. The in vitro effects of mannitol were examined at various doses and time points. In order to elucidate the role of Aquaporin 4 (AQP4) in the suppressive effect of mannitol on NSC proliferation, various assays including reverse transcription polymerase chain reaction, western blotting, and immunocytochemistry were conducted on control and mannitol-treated groups. Additionally, the phosphorylated p38 (p-p38) was examined to explore the potential mechanism underlying the inhibitory effect of mannitol on NSC proliferation. Finally, to further confirm the involvement of the p38 mitogen-activated protein kinase-dependent (MAPK) signaling pathway in the observed inhibition of NSC proliferation by mannitol, SB203580 was employed. All data were analyzed using SPSS 20.0 software (SPSS, Inc., Chicago, IL). The statistical analysis among multiple comparisons was performed using one-way analysis of variance (ANOVA), followed by Turkey's post hoc test in case of the data following a normal distribution using a Shapiro-Wilk normality test. Comparisons between 2 groups were determined using Student's t-test, if the data exhibited a normal distribution using a Shapiro-Wilk normality test. Meanwhile, data were shown as median and interquartile range and analyzed using the Mann-Whitney U test, if the data failed the normality test. A p < 0.05 was considered as significant difference. RESULTS: Primary NSC were isolated from the mice, and the characteristics were identified using immunostaining analysis. Thereafter, the results indicated that mannitol held the capability of inhibiting NSC proliferation in a dose-dependent and time-dependent manner using cell counting kit-8, neurospheres formation, and immunostaining of Nestin and Ki67 assays. During the process of mannitol suppressing NSC proliferation, the expression of AQP4 mRNA and protein was downregulated, while the gene expression of p-p38 was elevated by reverse transcription polymerase chain reaction, immunostaining, and western blotting assays. Subsequently, the administration of SB203580, one of the p38 MAPK signaling pathway inhibitors, partially abrogated this inhibitory effect resulting from mannitol, supporting the fact that the p38 MAPK signaling pathway participated in curbing NSC proliferation induced by mannitol. CONCLUSIONS: Mannitol inhibits NSC proliferation through downregulating AQP4, while upregulating the expression of p-p38 MAPK.

Causes and global, regional, and national burdens of traumatic brain injury from 1990 to 2019.

PURPOSE: Traumatic brain injury (TBI), currently a major global public health problem, imposes a significant economic burden on society and families. We aimed to quantify and predict the incidence and severity of TBI by analyzing its incidence, prevalence, and years lived with disability (YLDs). The epidemiological changes in TBI from 1990 to 2019 were described and updated to provide a reference for developing prevention, treatment, and incidence-reducing measures for TBI. METHODS: A secondary analysis was performed on the incidence, prevalence, and YLDs of TBI by sex, age group, and region (n = 21,204 countries and territories) between 1990 and 2019 using the Global Burden of Diseases, Injuries, and Risk Factors Study 2019. Proportions in the age-standardized incidence rate due to underlying causes of TBI and proportions of minor and moderate or severe TBI were also reported. RESULTS: In 2019, there were 27.16 million (95% uncertainty intervals (UI): 23.36 - 31.42) new cases of TBI worldwide, with age-standardized incidence and prevalence rates of 346 per 100,000 population (95% UI: 298-401) and 599 per 100,000 population (95% UI: 573-627), respectively. From 1990 to 2019, there were no significant trends in global age-standardized incidence (estimated annual percentage changes: -0.11%, 95% UI: -0.18% - -0.04%) or prevalence (estimated annual percentage changes: 0.01%, 95% UI: -0.04% - 0.06%). TBI caused 7.08 million (95% UI: 5.00 - 9.59) YLDs in 2019, with age-standardized rates of 86.5 per 100,000 population (95% UI: 61.1 - 117.2). In 2019, the countries with higher incidence rates were mainly distributed in Central Europe, Eastern Europe, and Australia. The 2019 global age-standardized incidence rate was higher in males than in females. The 2019 global incidence of moderate and severe TBI was 182.7 per 100,000 population, accounting for 52.8% of all TBI, with falls and road traffic injuries being the main causes in most regions. CONCLUSIONS: The incidence of moderate and severe TBI was slightly higher in 2019, and TBI still accounts for a significant portion of the global injury burden. The likelihood of moderate to severe TBI and the trend of major injury under each injury cause from 1990 to 2019 and the characteristics of injury mechanisms in each age group are presented, providing a basis for further research on injury causes in each age group and the future establishment of corresponding policies and protective measures.

The discrepancy in timing between synchronous signals and visual stimulation should not be underestimated.

Response latency is a critical parameter in studying human behavior, representing the time interval between the onset of stimulus and the response. However, different time between devices can introduce errors. Serial port synchronization signal can mitigate this, but limited information is available regarding their accuracy. Optical signals offer another option, but the difference in the positioning of optical signals and visual stimuli can introduce errors, and there have been limited reports of error reduction. This study aims to investigate methods for reducing the time errors. We used the Psychtoolbox to generate visual stimuli and serial port synchronization signals to explore their accuracy. Subsequently, we proposed a calibration formula to minimize the error between optical signals and visual stimuli. The findings are as follows: Firstly, the serial port synchronization signal presenting precedes visual stimulation, with a smaller lead time observed at higher refresh rates. Secondly, the lead time increases as the stimulus position deviates to the right and downwards. In Linux and IOPort(), serial port synchronization signals exhibited greater accuracy. Considering the poor accuracy and the multiple influencing factors associated with serial port synchronization signals, it is recommended to use optical signals to complete time synchronization. The results indicate that under the darkening process, the time error is - 0.23 ~ 0.08 ms (mean). This calibration formula can help measure the response latency accurately. This study provides valuable insights for optimizing experimental design and improving the accuracy of response latency. Although it only involves visual stimuli, the methods and results of this study can still serve as a reference.

Investigating the association between serum ADAM/ADAMTS levels and bone mineral density by mendelian randomization study.

PURPOSE: A Disintegrin and Metalloproteinase (ADAM) and A Disintegrin and Metalloproteinase with Thrombospondin Motif (ADAMTS) have been reported potentially involved in bone metabolism and related to bone mineral density. This Mendelian Randomization (MR) analysis was performed to determine whether there are causal associations of serum ADAM/ADAMTS with BMD in rid of confounders. METHODS: The genome-wide summary statistics of four site-specific BMD measurements were obtained from studies in individuals of European ancestry, including forearm (n = 8,143), femoral neck (n = 32,735), lumbar spine (n = 28,498) and heel (n = 426,824). The genetic instrumental variables for circulating levels of ADAM12, ADAM19, ADAM23, ADAMTS5 and ADAMTS6 were retrieved from the latest genome-wide association study of European ancestry (n = 5336 ~ 5367). The estimated causal effect was given by the Wald ratio for each variant, the inverse-variance weighted model was used as the primary approach to combine estimates from multiple instruments, and sensitivity analyses were conducted to assess the robustness of MR results. The Bonferroni-corrected significance was set at P < 0.0025 to account for multiple testing, and a lenient threshold P < 0.05 was considered to suggest a causal relationship. RESULTS: The causal effects of genetically predicted serum ADAM/ADAMTS levels on BMD measurements at forearm, femoral neck and lumbar spine were not statistically supported by MR analyses. Although causal effect of ADAMTS5 on heel BMD given by the primary MR analysis (ß = -0.006, -0.010 to 0.002, P = 0.004) failed to reach Bonferroni-corrected significance, additional MR approaches and sensitivity analyses indicated a robust causal relationship. CONCLUSION: Our study provided suggestive evidence for the causal effect of higher serum levels of ADAMTS5 on decreased heel BMD, while there was no supportive evidence for the associations of ADAM12, ADAM19, ADAM23, and ADAMTS6 with BMD at forearm, femoral neck and lumbar spine in Europeans.

68Ga-FAPI PET/CT for Rheumatoid Arthritis: A Prospective Study.

Background In rheumatoid arthritis (RA), fibroblast-like synoviocyte cells, which are involved in inflammation of the articular cartilage and bone, overexpress fibroblast activation protein (FAP). This is a feature that could be leveraged to improve imaging assessment of disease. Purpose To determine the performance of gallium 68 (68Ga)-labeled FAP inhibitor (FAPI) in assessing joint disease activity of RA and to compare with fluorine 18 (18F) fluorodeoxyglucose (FDG) imaging. Materials and Methods Twenty participants with RA (15 women; mean age, 55 years ± 10 [SD]) were prospectively enrolled from September 2020 to December 2021 and underwent clinical and laboratory assessment of disease activity and dual-tracer PET/CT (68Ga-FAPI and 18F-FDG) imaging. Imaging-derived variables of PET joint count (the number of joints positive for RA at PET) and PET articular index (a sum of the points of the joints using a three-point scale) were correlated to clinical and laboratory variables of disease activity. Results The combined output of both PET/CT techniques helped detect 244 affected joints, all of which showed positive results at 68Ga-FAPI PET/CT. However, fifteen of 244 (6.1%) FAPI-avid joints in six of 20 (30%) participants were not detected at 18F-FDG PET/CT. The maximum standardized uptake value of the most affected joint in each participant was higher in 68Ga-FAPI than in 18F-FDG PET/CT (9.54 ± 4.92 vs 5.85 ± 2.81, respectively; P = .001). The maximum standardized uptake values of the joints at both 68Ga-FAPI and 18F-FDG PET/CT were positively correlated with laboratory evaluation of C-reactive protein levels (r = 0.49 [P = .03] and 0.54 [P = .01], respectively). The PET joint count and PET articular index scores at 68Ga-FAPI PET/CT were also positively correlated with most clinical disease activity variables and radiographic progression of joint damage (P < .05). Conclusion In participants with rheumatoid arthritis who underwent gallium 68 fibroblast activation protein inhibitor PET/CT, the extent of joint involvement correlated with clinical and laboratory variables of disease activity and showed a greater amount and degree of affected joints than at fluorine 18 fluorodeoxyglucose PET/CT. Clinical trial registration no. NCT04514614 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Williams and Ahlman in this issue.

Cancer occurrence after SLE: effects of medication-related factors, disease-related factors and survival from an observational study.

OBJECTIVES: To explore the survival and risk factors for cancer occurrence after SLE (SLE-CA). METHODS: Patients with cancer diagnosed after SLE in Peking Union Medical College Hospital between January 2006 and September 2017 were recruited and followed. Data regarding medication-related and disease-related factors and survival were collected and compared with matched controls. Logistic regressions were applied to identify risk factors. The Kaplan-Meier method with a log-rank test was performed to evaluate survival. RESULTS: Forty-five SLE-CA patients and 128 controls were included, with the most common cancer site being the female genital system. SLE-CA patients were exposed to a higher cumulative dosage of CYC, with less mucocutaneous and haematologic involvement and higher anti-dsDNA positivity. At the time of cancer diagnosis, SLE-CA patients had lower SLEDAI 2000 (SLEDAI-2K), tended to achieve Definitions of Remission in SLE remission and minimal disease activity, but had higher SLICC/ACR Damage Index. Multivariable analysis identified high dosage of CYC [odds ratio (OR) 1.027, 95% CI 1.008, 1.046; P = 0.005] and low SLEDAI-2K at cancer diagnosis (OR 0.756, 95% CI 0.579, 0.986; P = 0.039) as risk factors. Mucocutaneous (OR 0.330, 95% CI 0.110, 0.991; P = 0.048) and haematologic involvement (OR 0.304, 95% CI 0.103, 0.902; P = 0.032) were negatively associated with cancer occurrence after SLE. The 5- and 10-year survival rates in SLE-CA patients were 95.2% and 92.1%, respectively. No significant difference of survival was observed between SLE-CA patients and controls (P = 0.177). CONCLUSION: High dosage of CYC and disease-related factors (low SLEDAI-2K, less mucocutaneous and haematologic involvement) were related factors for cancer occurrence after SLE, while no survival difference was observed.

Identification of QTL for reducing loss of grain yield under salt stress conditions in bi-parental populations derived from wheat landrace Hongmangmai.

KEY MESSAGE: A novel QTL (QSt.nftec-2BL) was mapped to a 0.7 cM interval on chromosome 2B. Plants carrying QSt.nftec-2BL produced higher grain yields by up to 21.4% than otherwise in salinized fields. Wheat yield has been limited by soil salinity in many wheat-growing areas globally. The wheat landrace Hongmangmai (HMM) possesses salt tolerance as it produced higher grain yields than other tested wheat varieties including Early Premium (EP) under salt stresses. To detect QTL underlying this tolerance, wheat cross EP × HMM was chosen to serve as mapping population that was homozygous at Ppd (photoperiod response gene), Rht (reduced plant height gene) and Vrn (vernalization gene); thus, interference with QTL detection by these loci could be minimized. QTL mapping was conducted firstly using 102 recombinant inbred lines (RILs) that were selected from the EP × HMM population (827 RILs) for similarity in grain yield under non-saline condition. Under salt stresses, however, the 102 RILs varied significantly in grain yield. These RILs were genotyped using a 90 K SNP (single nucleotide polymorphism) array; consequently, a QTL (QSt.nftec-2BL) was detected on chromosome 2B. Then, using 827 RILs and new simple sequence repeat (SSR) markers developed according to the reference sequence IWGSC RefSeq v1.0, location of QSt.nftec-2BL was refined to a 0.7 cM (6.9 Mb) interval flanked by SSR markers 2B-557.23 and 2B-564.09. Selection for QSt.nftec-2BL was performed based on the flanking markers using two bi-parental wheat populations. Trials for validating effectiveness of the selection were conducted in salinized fields in two geographical areas and two crop seasons, demonstrating that wheat plants with the salt-tolerant allele in homozygous status at QSt.nftec-2BL produced higher grain yields by up to 21.4% than otherwise.