A TNIP1-driven systemic autoimmune disorder with elevated IgG4.

Whole-exome sequencing of two unrelated kindreds with systemic autoimmune disease featuring antinuclear antibodies with IgG4 elevation uncovered an identical ultrarare heterozygous TNIP1Q333P variant segregating with disease. Mice with the orthologous Q346P variant developed antinuclear autoantibodies, salivary gland inflammation, elevated IgG2c, spontaneous germinal centers and expansion of age-associated B cells, plasma cells and follicular and extrafollicular helper T cells. B cell phenotypes were cell-autonomous and rescued by ablation of Toll-like receptor 7 (TLR7) or MyD88. The variant increased interferon-ß without altering nuclear factor kappa-light-chain-enhancer of activated B cells signaling, and impaired MyD88 and IRAK1 recruitment to autophagosomes. Additionally, the Q333P variant impaired TNIP1 localization to damaged mitochondria and mitophagosome formation. Damaged mitochondria were abundant in the salivary epithelial cells of Tnip1Q346P mice. These findings suggest that TNIP1-mediated autoimmunity may be a consequence of increased TLR7 signaling due to impaired recruitment of downstream signaling molecules and damaged mitochondria to autophagosomes and may thus respond to TLR7-targeted therapeutics.

Class-Switch Recombination Occurs Infrequently in Germinal Centers.

Class-switch recombination (CSR) is a DNA recombination process that replaces the immunoglobulin (Ig) constant region for the isotype that can best protect against the pathogen. Dysregulation of CSR can cause self-reactive BCRs and B cell lymphomas; understanding the timing and location of CSR is therefore important. Although CSR commences upon T cell priming, it is generally considered a hallmark of germinal centers (GCs). Here, we have used multiple approaches to show that CSR is triggered prior to differentiation into GC B cells or plasmablasts and is greatly diminished in GCs. Despite finding a small percentage of GC B cells expressing germline transcripts, phylogenetic trees of GC BCRs from secondary lymphoid organs revealed that the vast majority of CSR events occurred prior to the onset of somatic hypermutation. As such, we have demonstrated the existence of IgM-dominated GCs, which are unlikely to occur under the assumption of ongoing switching.

TLR7 gain-of-function genetic variation causes human lupus.

Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease1-7, evidence of lupus-causing TLR7 gene variants is lacking. Here we describe human systemic lupus erythematosus caused by a TLR7 gain-of-function variant. TLR7 is a sensor of viral RNA8,9 and binds to guanosine10-12. We identified a de novo, previously undescribed missense TLR7Y264H variant in a child with severe lupus and additional variants in other patients with lupus. The TLR7Y264H variant selectively increased sensing of guanosine and 2',3'-cGMP10-12, and was sufficient to cause lupus when introduced into mice. We show that enhanced TLR7 signalling drives aberrant survival of B cell receptor (BCR)-activated B cells, and in a cell-intrinsic manner, accumulation of CD11c+ age-associated B cells and germinal centre B cells. Follicular and extrafollicular helper T cells were also increased but these phenotypes were cell-extrinsic. Deficiency of MyD88 (an adaptor protein downstream of TLR7) rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. Despite prominent spontaneous germinal-centre formation in Tlr7Y264H mice, autoimmunity was not ameliorated by germinal-centre deficiency, suggesting an extrafollicular origin of pathogenic B cells. We establish the importance of TLR7 and guanosine-containing self-ligands for human lupus pathogenesis, which paves the way for therapeutic TLR7 or MyD88 inhibition.

Phytophthora effector PSR1 hijacks the host pre-mRNA splicing machinery to modulate small RNA biogenesis and plant immunity.

Phytophthora effector PSR1 suppresses small RNA (sRNA)-mediated immunity in plants, but the underlying mechanism remains unknown. Here, we show that Phytophthora suppressor of RNA silencing 1 (PSR1) contributes to the pathogenicity of Phytophthora sojae and specifically binds to three conserved C-terminal domains of the eukaryotic PSR1-Interacting Protein 1 (PINP1). PINP1 encodes PRP16, a core pre-mRNA splicing factor that unwinds RNA duplexes and binds to primary microRNA transcripts and general RNAs. Intriguingly, PSR1 decreased both RNA helicase and RNA-binding activity of PINP1, thereby dampening sRNA biogenesis and RNA metabolism. The PSR1-PINP1 interaction caused global changes in alternative splicing (AS). A total of 5,135 genes simultaneously exhibited mis-splicing in both PSR1-overexpressing and PINP1-silenced plants. AS upregulated many mRNA transcripts that had their introns retained. The high occurrence of intron retention in AS-induced transcripts significantly promoted Phytophthora pathogen infection in Nicotiana benthamiana, and this might be caused by the production of truncated proteins. Taken together, our findings reveal a key role for PINP1 in regulating sRNA biogenesis and plant immunity.

GEN1 as a risk factor for human congenital anomalies of the kidney and urinary tract.

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) are prevalent birth defects. Although pathogenic CAKUT genes are known, they are insufficient to reveal the causes for all patients. Our previous studies indicated GEN1 as a pathogenic gene of CAKUT in mice, and this study further investigated the correlation between GEN1 and human CAKUT. METHODS: In this study, DNA from 910 individuals with CAKUT was collected; 26 GEN1 rare variants were identified, and two GEN1 (missense) variants in a non-CAKUT group were found. Mainly due to the stability results of the predicted mutant on the website, in vitro, 10 variants (eight CAKUT, two non-CAKUT) were selected to verify mutant protein stability. In addition, mainly based on the division of the mutation site located in the functional region of the GEN1 protein, 8 variants (six CAKUT, two non-CAKUT) were selected to verify enzymatic hydrolysis, and the splice variant GEN1 (c.1071 + 3(IVS10) A > G) was selected to verify shear ability. Based on the results of in vitro experiments and higher frequency, three sites with the most significant functional change were selected to build mouse models. RESULTS: Protein stability changed in six variants in the CAKUT group. Based on electrophoretic mobility shift assay of eight variants (six CAKUT, two non-CAKUT), the enzymatic hydrolysis and DNA-binding abilities of mutant proteins were impaired in the CAKUT group. The most serious functional damage was observed in the Gen1 variant that produced a truncated protein. A mini-gene splicing assay showed that the variant GEN1 (c.1071 + 3(IVS10) A > G) in the CAKUT group significantly affected splicing function. An abnormal exon10 was detected in the mini-gene splicing assay. Point-mutant mouse strains were constructed (Gen1: c.1068 + 3 A > G, p.R400X, and p.T105R) based on the variant frequency in the CAKUT group and functional impairment in vitro study and CAKUT phenotypes were replicated in each. CONCLUSION: Overall, our findings indicated GEN1 as a risk factor for human CAKUT.

Uncovering eco-friendly design in the ancient bronze goose-and-fish lamp: an unnoticeable gap boosts ventilation.

The bronze goose-and-fish lamp exhibited in the national museum of China is a 2,000-y-old artifact once used for indoor lighting by nobility in the Western Han dynasty (206 BCE TO 25 CE). The beauty of this national treasure arises from its elegant shape vividly showing a goose catching fish with beautiful colors painted over the whole body. Beyond the artistic and historical value, what enchants people most is the eco-design concept of this oil-burning lamp. It is widely believed that the smoke generated by burning animal oil can flow into the goose belly through its long neck, then be absorbed by prefilled water in the belly, hence mitigating indoor air pollution. Although different mechanistic hypotheses such as natural convection and even the siphon effect have been proposed to qualitatively rationalize the above-claimed pollution mitigation function, due to the absence of a true scientific analysis, the definitive mechanism remains a mystery. By rigorous modeling of the nonisothermal fluid flow coupled with convection-diffusion of pollutant within and out of the lamp, we discover that it is the unnoticeable gap between goose body and lamp tray (i.e., an intrinsic feature of the multicompartmental design) that can offer definitive ventilation in the lamp. The ventilation is facilitated by natural convection due to oil burning. Adequate ventilation plays a key role in enabling pollution mitigation, as it allows pollutant to reach the goose belly, travel over and be absorbed by the water.

Integrating single-cell transcriptomics and machine learning to predict breast cancer prognosis: A study based on natural killer cell-related genes.

Breast cancer (BC) is the most commonly diagnosed cancer in women globally. Natural killer (NK) cells play a vital role in tumour immunosurveillance. This study aimed to establish a prognostic model using NK cell-related genes (NKRGs) by integrating single-cell transcriptomic data with machine learning. We identified 44 significantly expressed NKRGs involved in cytokine and T cell-related functions. Using 101 machine learning algorithms, the Lasso + RSF model showed the highest predictive accuracy with nine key NKRGs. We explored cell-to-cell communication using CellChat, assessed immune-related pathways and tumour microenvironment with gene set variation analysis and ssGSEA, and observed immune components by HE staining. Additionally, drug activity predictions identified potential therapies, and gene expression validation through immunohistochemistry and RNA-seq confirmed the clinical applicability of NKRGs. The nomogram showed high concordance between predicted and actual survival, linking higher tumour purity and risk scores to a reduced immune score. This NKRG-based model offers a novel approach for risk assessment and personalized treatment in BC, enhancing the potential of precision medicine.

Gestational diabetes mellitus induces congenital anomalies of the kidney and urinary tract in mice by altering RET/MAPK/ERK pathway.

Gestational diabetes mellitus (GDM) presents a substantial population health concern. Previous studies have revealed that GDM can ultimately influence nephron endowment. In this study, we established a GDM mouse model to investigate the embryological alterations and molecular mechanisms underlying the development of congenital anomalies of the kidney and urinary tract (CAKUT) affected by GDM. Our study highlights that GDM could contribute to the manifestation of CAKUT, with prevalent phenotypes characterized by isolated hydronephrosis and duplex kidney complicated with hydronephrosis in mice. Ectopic ureteric buds (UBs) and extended length of common nephric ducts (CNDs) were noted in the metanephric development stage. The expression of Ret and downstream p-ERK activity were enhanced in UBs, which indicated the alteration of RET/MAPK/ERK pathway may be one of the mechanisms contributing to the increased occurrence of CAKUT associated with GDM.

Unzipping Carbon Nanotubes to Sub-5-nm Graphene Nanoribbons on Cu(111) by Surface Catalysis.

Graphene nanoribbons (GNRs) are promising in nanoelectronics for their quasi-1D structures with tunable bandgaps. The methods for controllable fabrication of high-quality GNRs are still limited. Here a way to generate sub-5-nm GNRs by annealing single-walled carbon nanotubes (SWCNTs) on Cu(111) is demonstrated. The structural evolution process is characterized by low-temperature scanning tunneling microscopy. Substrate-dependent measurements on Au(111) and Ru(0001) reveal that the intermediate strong SWCNT-surface interaction plays a pivotal role in the formation of GNRs.

Preliminary analysis on the characteristics of light absorption coefficients in typical rivers of different river basins across China.

As a vital constituent of water's optical properties, the absorption coefficients influence the distribution of underwater light field, consequently impacting the structures and functional patterns of riverine ecosystems. In this study, the light absorption of non-algal particulates (ad(λ), m-1), phytoplankton (aph(λ), m-1) and CDOM (ag(λ), m-1) of 380 water samples collected from 133 rivers in eight external river basins across China from 2013 to 2023 were examined to determine the optical absorption characteristics. Results showed significant differences in ad(λ), aph(λ) and ag(λ) across different basins. ① The water bodies of eight basins can be categorized into 5 dominant types of absorption coefficients. ② In eastern China, ag(440) exhibited a northeast-high and southwest-low spatial distribution pattern. The Songliao River Basin had the highest ag(440) than other basins. The higher slope S of ag(λ) in rivers compared to lakes and reservoirs confirm river water primarily derive CDOM from external sources, distinguishing them from lakes and reservoirs. ③ The Huaihe and Haihe River Basins had higher ad(440) and aph(440) values, primarily due to lower terrain and human activities, leading to the accumulation of suspended particles and nutrients. And soil erosion from the Loess Plateau caused significant differences in ad(440) between the upper and middle reaches of the Yellow River Basin. These findings hold significant implications for understanding the optical characteristics of rivers in China.

Acid-modified biomass-based N-doped O-rich hierarchical porous carbon as a high-performance electrode for supercapacitors.

In contemporary society, the conversion and efficient utilization of waste biomass and its derivatives are of great significance. Carbonized wood (CW) is an easily accessible and cost-effective green resource, but it has limitations as an electrode material due to its low specific surface area, limited active sites and poor conductivity. Therefore, it is crucial to improve the performance of biomass-based materials by using activation, heteroatom doping and modification methods to enhance the specific surface area and active sites. In this study, we developed acid-modified urea-doped activated carbonized wood (AUACW) with a three-dimensional (3D) porous structure and porosity, achieving a high specific surface area of 1321.3 m2 g-1. In addition, the degree of graphitization (ID/IG = 1.0) provides good conductivity and a large number of active sites, which are conducive to charge transfer and ion diffusion. The increase of nitrogen and oxygen elements enhances the surface wettability of the material and provides additional pseudocapacitance. The specific capacitance of AUACW reaches 435.84 F g-1 at 0.8 A g-1 with a 93.6% capacitance retention after 10 000 cycles in a 1 M KOH electrolyte. More attractively, a symmetrical supercapacitor (SSC) based on AUACW delivers an energy density of 22.61 W h kg-1 at a power density of 533.26 W kg-1. This work demonstrates the promising potential of utilizing waste biomass to develop green and valuable carbon materials for supercapacitors.

Protein-losing enteropathy as a new phenotype in atypical hemolytic uremic syndrome caused by CD46 gene mutation.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a life-threatening thrombotic microangiopathy. Genetic defects in the alternative complement (AP) pathway have been identified in 60-70% of individuals. Eculizumab is recommended as a first-line therapy. METHODS: We collected the clinical data of a pediatric patient with aHUS accompanied by protein-losing enteropathy (PLE). Genetic testing was performed. Related literature on aHUS combined with PLE was reviewed. RESULTS: A 15-year-old Chinese girl was diagnosed with aHUS at 3.7 years of age and experienced five episodes; her symptoms completely resolved with plasma treatment. Severe gastrointestinal symptoms and hypoalbuminemia presented after the first episode, and PLE was diagnosed. A novel homozygous CD46 variant was identified, and FACS revealed significantly decreased CD46 expression. She presented at a recent relapse with persistent GI symptoms and headache and progressed to chronic kidney failure; peritoneal dialysis was initiated. Eculizumab was given 8 months after the last recurrence. Surprisingly, PLE was cured. Afterward, dialysis was discontinued, and eGFR recovered to 44.8 ml/min/1.73 m2. A review of the literature indicated that PLE with thrombosis was caused by CD55 variants via hyperactivation of the AP system. We report an aHUS patient with PLE caused by CD46 variants. Symptoms of both PLE and aHUS were significantly alleviated in our patient and patients with CD55 variants treated with eculizumab, indicating that PLE was a new symptom of aHUS in our patient with a CD46 variant. CONCLUSIONS: Our case expands the phenotype of aHUS caused by a CD46 mutation and provides evidence of the efficacy of eculizumab after a long phase of chronic kidney failure.

Risk factors and outcome of BK polyomavirus infection in pediatric kidney transplantation.

BACKGROUND: BK polyomavirus (BKV) infection is a critical complication hindering graft survival after kidney transplantation. We aimed to investigate the risk factors and outcome of BKV infection in pediatric kidney transplantation. METHODS: The clinical and follow-up data of pediatric kidney transplant recipients at the Children's Hospital of Fudan University from Jan 2015 to June 2023 were retrospectively analyzed. RESULTS: A total of 217 patients were included in the study with mean follow-up time of 24.3 ± 19.9 months. The mean age at transplantation was 9.7 ± 4.2 years. The patient survival rate and graft survival rate were 98.2% and 96.8%, respectively. Twenty-nine patients (13.4%) developed BKV infection, which was detected at 5.8 ± 3.2 months after transplantation. Among these 29 patients with BKV infection, 8 patients (3.6%) developed BKV nephropathy (BKVN), which was diagnosed at 8.3 ± 2.9 months after transplantation, and 2 patients developed graft failure eventually. Compared with the non-BKV infection group (eGFR 76.7 ± 26.1 mL/min/1.73 m2) and BKV infection without BKVN group (eGFR 85.2 ± 23.8 mL/min/1.73 m2), BKVN group had lowest eGFR during follow-up (33.5 ± 11.0 ml/min/1.73 m2, P < 0.001). Younger age at transplant (OR 0.850, 95%CI 0.762-0.948, P = 0.005), CAKUT disease of primary etiology (OR 2.890, 95%CI 1.200-6.961, P = 0.018), and CMV negative recipient serostatus before transplantation (OR 3.698, 95%CI 1.583-8.640, P = 0.003) were independent risk factors for BKV infection. CONCLUSIONS: Incidence of BKV infection is quite high within 12 months after pediatric kidney transplantation and children with BKVN have poor graft function. Younger age at transplant, CAKUT disease, and CMV negative recipient serostatus before transplantation increase the risk of BKV infection after kidney transplantation.

IPNA clinical practice recommendations for the diagnosis and management of children with IgA nephropathy and IgA vasculitis nephritis.

IgA nephropathy and IgA vasculitis with nephritis, albeit rare, represent two relatively frequent glomerular conditions in childhood. Compared to adults, pediatric IgA nephropathy has a more acute presentation, most frequently with synpharyngitic macrohematuria and histologically with more intense inflammation and less intense chronic damage. Management of these conditions is controversial and supported by little high-quality evidence. The paucity of evidence is due to the disease heterogeneity, its inter-ethnic variability, and the difficulty of extrapolating data from adult studies due to the peculiarities of the condition in children. IgA vasculitis with nephritis is a kidney manifestation of a systemic disorder, typical of the pediatric age, in which both the diagnosis of kidney involvement and its management are poorly defined, and an interdisciplinary approach is crucial. Both conditions can have a profound and long-lasting impact on kidney function and the global health of affected children. The International Pediatric Nephrology Association has therefore convened a diverse international group of experts from different disciplines to provide guidance on the recommended management of these conditions in children and to establish common definitions and define priorities for future high-quality, evidence-based collaborative studies for the benefit of children.

USP11 promotes renal tubular cell pyroptosis and fibrosis in UUO mice via inhibiting KLF4 ubiquitin degradation.

The pyroptosis of renal tubular epithelial cells leads to tubular loss and inflammation and then promotes renal fibrosis. The transcription factor Krüppel-like factor 4 (KLF4) can bidirectionally regulate the transcription of target genes. Our previous study revealed that sustained elevation of KLF4 is responsible for the transition of acute kidney injury (AKI) into chronic kidney disease (CKD) and renal fibrosis. In this study, we explored the upstream mechanisms of renal tubular epithelial cell pyroptosis from the perspective of posttranslational regulation and focused on the transcription factor KLF4. Mice were subjected to unilateral ureteral obstruction (UUO) surgery and euthanized on D7 or D14 for renal tissue harvesting. We showed that the pyroptosis of renal tubular epithelial cells mediated by both the Caspase-1/GSDMD and Caspase-3/GSDME pathways was time-dependently increased in UUO mouse kidneys. Furthermore, we found that the expression of the transcription factor KLF4 was also upregulated in a time-dependent manner in UUO mouse kidneys. Tubular epithelial cell-specific Klf4 knockout alleviated UUO-induced pyroptosis and renal fibrosis. In Ang II-treated mouse renal proximal tubular epithelial cells (MTECs), we demonstrated that KLF4 bound to the promoter regions of Caspase-3 and Caspase-1 and directly increased their transcription. In addition, we found that ubiquitin-specific protease 11 (USP11) was increased in UUO mouse kidneys. USP11 deubiquitinated KLF4. Knockout of Usp11 or pretreatment with the USP11 inhibitor mitoxantrone (3 mg/kg, i.p., twice a week for two weeks before UUO surgery) significantly alleviated the increases in KLF4 expression, pyroptosis and renal fibrosis. These results demonstrated that the increased expression of USP11 in renal tubular cells prevents the ubiquitin degradation of KLF4 and that elevated KLF4 promotes inflammation and renal fibrosis by initiating tubular cell pyroptosis.

Magnetoencephalogram-based brain-computer interface for hand-gesture decoding using deep learning.

Advancements in deep learning algorithms over the past decade have led to extensive developments in brain-computer interfaces (BCI). A promising imaging modality for BCI is magnetoencephalography (MEG), which is a non-invasive functional imaging technique. The present study developed a MEG sensor-based BCI neural network to decode Rock-Paper-scissors gestures (MEG-RPSnet). Unique preprocessing pipelines in tandem with convolutional neural network deep-learning models accurately classified gestures. On a single-trial basis, we found an average of 85.56% classification accuracy in 12 subjects. Our MEG-RPSnet model outperformed two state-of-the-art neural network architectures for electroencephalogram-based BCI as well as a traditional machine learning method, and demonstrated equivalent and/or better performance than machine learning methods that have employed invasive, electrocorticography-based BCI using the same task. In addition, MEG-RPSnet classification performance using an intra-subject approach outperformed a model that used a cross-subject approach. Remarkably, we also found that when using only central-parietal-occipital regional sensors or occipitotemporal regional sensors, the deep learning model achieved classification performances that were similar to the whole-brain sensor model. The MEG-RSPnet model also distinguished neuronal features of individual hand gestures with very good accuracy. Altogether, these results show that noninvasive MEG-based BCI applications hold promise for future BCI developments in hand-gesture decoding.

Effect of Low-Frequency Pulsed Electrotherapy Combined with Acupoint Nursing on Postpartum Urinary Retention in Patients with Vaginal Delivery.

INTRODUCTION AND HYPOTHESIS: This study was carried out to investigate the effect of low-frequency pulsed electrotherapy combined with acupoint massage on postpartum urinary retention (PUR). METHODS: The patients were divided into control group, intervention group 1, and intervention group 2 according to the nursing method. The control group received conventional postpartum care, intervention group 1 received conventional postpartum care and low frequency pulsed electrotherapy, and intervention group 2 received conventional postpartum care, low-frequency pulsed electrotherapy, and Shuidao point massage. The bladder function, comfort score, and quality of life score before and after intervention were compared among the three groups. RESULTS: The bladder function, comfort level, and quality of life of intervention group 1 and intervention group 2 after nursing were significantly better than those of the control group. In addition, intervention group 2 had better bladder function than intervention group 1, with lower residual urine volume and higher bladder compliance. In the Kolcaba score, the mental dimension of intervention group 2 was significantly higher than that of intervention group 1. In terms of QOL scores, the social function, physical function, and state of material life scores of intervention group 2 were significantly higher than those of intervention group 1. CONCLUSIONS: Low-frequency pulsed electrotherapy combined with acupoint massage can significantly improve the bladder function, comfort, and quality of life of patients with PUR.

High-performance reconstruction method combining total variation with a video denoiser for compressed ultrafast imaging.

Compressed ultrafast photography (CUP) is a novel two-dimensional (2D) imaging technique to capture ultrafast dynamic scenes. Effective image reconstruction is essential in CUP systems. However, existing reconstruction algorithms mostly rely on image priors and complex parameter spaces. Therefore, in general, they are time-consuming and result in poor imaging quality, which limits their practical applications. In this paper, we propose a novel reconstruction algorithm, to the best of our knowledge, named plug-in-plug-fast deep video denoising net-total variation (PnP-TV-FastDVDnet), which exploits an image's spatial features and correlation features in the temporal dimension. Therefore, it offers higher-quality images than those in previously reported methods. First, we built a forward mathematical model of the CUP, and the closed-form solution of the three suboptimization problems was derived according to plug-in and plug-out frames. Secondly, we used an advanced video denoising algorithm based on a neural network named FastDVDnet to solve the denoising problem. The peak signal-to-noise ratio (PSNR) and structural similarity index measure (SSIM) are improved on actual CUP data compared with traditional algorithms. On benchmark and real CUP datasets, the proposed method shows the comparable visual results while reducing the running time by 96% over state-of-the-art algorithms.

In Utero and Childhood/Adolescence Exposure to Tobacco Smoke, Genetic Risk, and Lung Cancer Incidence and Mortality in Adulthood.

Rationale: The individual effects of early-life tobacco smoke exposure and its interactions with genetic factors on lung cancer in adulthood remain unclear. Objectives: To investigate the associations of early-life tobacco exposures as well as their interactions with polygenic risk scores (PRSs) with lung cancer incidence and mortality. Methods: A total of 432,831 participants from the UK Biobank study were included. We estimated the associations of in utero exposure to tobacco smoke, the age of smoking initiation and their interactions with PRSs with lung cancer incidence and mortality in adulthood using Cox proportional hazard models. Measurements and Main Results: Lung cancer incidence (hazard ratio [HR]: 1.59, 95% confidence interval [CI], 1.44-1.76) increased among participants with in utero tobacco exposure. Multivariable-adjusted HRs (with 95% CIs) of lung cancer incidence for smoking initiation in adulthood, adolescence, and childhood (versus never-smokers) were 6.10 (5.25-7.09), 9.56 (8.31-11.00), and 15.15 (12.90-17.79) (Ptrend < 0.001). Similar findings were observed in lung cancer mortality. Participants with high PRSs and in utero tobacco exposure (versus low PRSs participants without in utero exposure) had an HR of 2.35 for lung cancer incidence (95% CI, 1.97-2.80, Pinteraction = 0.089) and 2.43 for mortality (95% CI, 2.05-2.88, Pinteraction = 0.032). High PRSs with smoking initiation in childhood (versus never-smokers with low PRSs) had HRs of 18.71 for incidence (95% CI, 14.21-24.63, Pinteraction = 0.004) and 19.74 for mortality (95% CI, 14.98-26.01, Pinteraction = 0.033). Conclusions: In utero and childhood/adolescence exposure to tobacco smoke and its interaction with genetic factors may substantially increase the risks of lung cancer incidence and mortality in adulthood.

The relationship between psoriasis and vitiligo: From a comprehensive study.

BACKGROUND: Both psoriasis and vitiligo are autoimmune skin diseases. Previous observational studies have indicated a relationship between the two conditions, and simultaneous onset of both diseases poses increased health risks to patients. However, limited research has explored the causal relationship between psoriasis and vitiligo. OBJECTIVES: To investigate whether a causal association exists between psoriasis and vitiligo. METHODS: A case of Chinese patients diagnosed with psoriasis and vitiligo has been reported. Transcriptome sequencing was performed on normal, psoriasis, vitiligo, and co-morbid skin tissues of the patients, and single-cell transcriptome sequencing was conducted on the co-morbid skin tissues. A comprehensive Mendelian randomization analysis of Genome-wide association studies (GWAS) was performed on a cohort of 261 018 European individuals with psoriasis from the IEU Open GWAS Project and vitiligo from the National Institutes of Health (NIH) Database of Genotypes and Phenotypes. RESULTS: Case report and transcriptome results showed that skin tissue with vitiligo combined with psoriasis exhibited both vitiligo and psoriasis. Single-cell transcriptome sequencing results showed that in comparison to normal skin and psoriatic skin, the proportions of CD8+ T cells, natural killer cells, naive T cells, T helper cells 17, regulatory T cells, conventional type 1 dendritic cells, Conventional type 2 dendritic cells, and plasmacytoid dendritic cells were all increased in skin tissue with vitiligo combined with psoriasis. Mendelian randomization analysis included 4510 patients with psoriasis and 4680 patients with vitiligo. The results showed no causal relationship between vitiligo and psoriasis in the forward direction (p = 0.192; odds ratio [OR], 1.059; 95% confidence interval [CI], 0.971-1.155) or in the reverse direction (p = 0.459; OR, 0.927; 95% CI, 0.757-1.134). CONCLUSIONS: This study suggests that the association between psoriasis and vitiligo may be closely related to immunity, however, Mendelian randomization studies do not support a causal relationship. These findings hold significant implications for clinicians aiming to enhance their understanding and treatment approaches for psoriasis and vitiligo.