Personalizing age of gastric cancer screening based on comorbidity in China: Model estimates of benefits, affordability and cost-effectiveness optimization.

The benefits of gastric cancer screening are related to age and comorbidity status, but reliable estimates are lacking in China. This study aimed to estimate the benefits and affordability of the gastric cancer screening strategy by level of comorbidity to inform decisions to screening age. We assessed six current gastric cancer screening strategies in China using a microsimulation model with different starting and stopping ages and comorbidity profiles, for a total of 378 strategies. 1,000,000 individuals were simulated in the model and followed the alternative strategies. Primary outcomes included gastric cancer incidence, the number of endoscopy and complications, life-years, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. Future costs and QALYs are discounted by 5% per year. Sensitivity analyses were used to evaluate model uncertainty. Strategies with longer screening durations were associated with higher benefits of life-year gained and gastric cancer deaths averted, but were also accompanied by a large number of endoscopy screening, and complication events. Using the threshold of US$18,575 per QALY gained, at the no, moderate, and severe comorbidity level, the leading cost-effectiveness strategies were the new gastric cancer screening scoring system strategy (NGCS) screening from age 40 years to 60 years (40-60), 40-55-NGCS, and 40-55-NGCS strategy, respectively. The results are robust in sensitivity analyses. Our study illustrates the importance of considering comorbidity conditions and age when determining the starting and stopping screening age for gastric cancer and informs the discussion on personalizing decisions. The trade-off between benefits and harms can also be referenced when necessary.

Human-multimodal deep learning collaboration in 'precise' diagnosis of lupus erythematosus subtypes and similar skin diseases.

BACKGROUND: Lupus erythematosus (LE) is a spectrum of autoimmune diseases. Due to the complexity of cutaneous LE (CLE), clinical skin image-based artificial intelligence is still experiencing difficulties in distinguishing subtypes of LE. OBJECTIVES: We aim to develop a multimodal deep learning system (MMDLS) for human-AI collaboration in diagnosis of LE subtypes. METHODS: This is a multi-centre study based on 25 institutions across China to assist in diagnosis of LE subtypes, other eight similar skin diseases and healthy subjects. In total, 446 cases with 800 clinical skin images, 3786 multicolor-immunohistochemistry (multi-IHC) images and clinical data were collected, and EfficientNet-B3 and ResNet-18 were utilized in this study. RESULTS: In the multi-classification task, the overall performance of MMDLS on 13 skin conditions is much higher than single or dual modals (Sen = 0.8288, Spe = 0.9852, Pre = 0.8518, AUC = 0.9844). Further, the MMDLS-based diagnostic-support help improves the accuracy of dermatologists from 66.88% ± 6.94% to 81.25% ± 4.23% (p = 0.0004). CONCLUSIONS: These results highlight the benefit of human-MMDLS collaborated framework in telemedicine by assisting dermatologists and rheumatologists in the differential diagnosis of LE subtypes and similar skin diseases.

Systemic lupus erythematosus patients contain B-cell receptor repertoires sensitive to immunosuppressive drugs.

Immune repertoire (IR) during treatment may be a surrogate biomarker for disease response. Changes of the IR in systemic lupus erythematosus patients in response to immunosuppressive drugs were identified in ten SLE patients. Patients provided peripheral blood mononuclear cells at two time points for sequencing. They were divided into sensitive and nonsensitive groups by their clinical responses to immunosuppressive drugs. After treatment, the BCR expression significantly decreased in patients from the sensitive group while there was no change in patients from the nonsensitive group. IgM comprised a dominant portion of the BCR repertoire and increased slightly in all patients in the sensitive group but decreased in the nonsensitive group. IgA also exhibited opposing changes between the two groups. Shorter CDR3 of TRB and TRG chains occurred in the sensitive group. CDR3 length of IGK decreased significantly in the sensitive group. CDR3 of TCR δ/γ changed distinctly between time points in the sensitive group. Six immune-related genes showed differential expression levels in sensitive and nonsensitive groups. Our study shows that it is BCR repertoire sensitivity to immunosuppressive drugs in SLE patients and sheds light on personalized therapy for SLE.

Estimated projection of incidence and mortality of alcohol-related liver disease in China from 2022 to 2040: a modeling study.

BACKGROUND: China has one of the highest numbers of liver disease cases in the world, including 6.4 million cirrhosis associated with alcohol-related liver disease (ALD) cases. However, there is still a lack of urgent awareness about the growth of alcohol consumption and the increased burden of ALD in China. Therefore, we aimed to project the potential impact of changes in alcohol consumption on the burden of ALD in China up to 2040 under different scenarios. METHODS: We developed a Markov model to simulate the natural history of ALD until 2040 in China. We estimated the incidence and mortality of alcohol-related cirrhosis and hepatocellular carcinoma between 2022 and 2040 under four projected scenarios: status quo scenario and scenarios with a 2%, 4%, and 8% annual decrease in excessive alcohol consumption, respectively. RESULTS: Under the status quo scenario, the cumulative new cases of cirrhosis from 2022 to 2040 was projected to be 3.61 million (95% UI 3.03-4.44 million), resulting in a cumulative 1.96 million (1.66-2.32 million) deaths from alcohol-related cirrhosis and hepatocellular carcinoma. However, a 2% annual reduction in excessive alcohol consumption was expected to avert 0.3 million deaths associated with ALD, and a 4% annual reduction was projected to prevent about 1.36 million new cases of cirrhosis and prevent 0.5 million ALD-related deaths. Moreover, an 8% annual reduction would prevent about 2 million new cases of cirrhosis and 0.82 million deaths. CONCLUSIONS: Without any substantial change in alcohol attitudes and policies to regulate excessive drinking, the disease burden of ALD in China will increase enormously. Strengthening the implementation of alcohol restriction interventions is critical and urgent to reduce the impact of ALD on the Chinese population.

Trametinib for patients with recurrent low-grade serous ovarian cancer: A cost-effectiveness analysis.

OBJECTIVE: The GOG 281/LOGS trial found that trametinib prolonged progression-free survival (PFS) in patients with recurrent low-grade serous ovarian cancer (LGSOC), compared with standard of care (SOC). The current study aimed to evaluate the cost-effectiveness of trametinib versus standard of care for recurrent LGSOC from the US payer perspective. METHODS: A Markov model was adopted to compare the cost and effectiveness of trametinib and standard of care group in patients with recurrent LGSOC. Life years (LYs), quality-adjusted LYs (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs) were calculated. One-way, and probabilistic sensitivity analyses were performed to explore the model robustness. RESULT: Trametinib group provided an additional 0.58 QALYs (1.14 LYs) and an incremental cost of $248,214 compared with the SOC group. The incremental cost-effectiveness ratio was $424,097 per QALY. The results of one-way sensitivity analyses suggested that our model was sensitive to the hazard ratio of OS and PFS between trametinib and SOC group, utility of PFS and the cycle cost of trametinib. Probabilistic sensitivity analyses revealed that there was 6% probability of the trametinib group being cost-effective at a willingness-to-pay (WTP) threshold of $150,000 per QALY. CONCLUSIONS: From the US payer perspective, trametinib is not cost-effective for patients with recurrent LGSOC at the assumed WTP threshold of $150,000 per QALY. Based on the value standpoint, price reduction of trametinib is expected to improve the cost-effectiveness of trametinib in patients with recurrent LGSOC.

P25 Gene Knockout Contributes to Human Epidermal Growth Factor Production in Transgenic Silkworms.

Transgenic silkworm expression systems have been applied for producing various recombinant proteins. Knocking out or downregulating an endogenous silk protein is considered a viable strategy for improving the ability of transgenic expression systems to produce exogenous proteins. Here, we report the expression of human epidermal growth factor (hEGF) in a P25 gene knockout silkworm. The hEGF gene regulated by the P25 gene promoter was integrated into a silkworm's genome. Five transgenic positive silkworm lineages were generated with different insertion sites on silkworm chromosomes and the ability to synthesize and secrete proteins into cocoons. Then, a cross-strategy was used to produce transgenic silkworms with a P25 gene knockout background. The results of the protein analysis showed that the loss of an endogenous P25 protein can increase the hEGF production to about 2.2-fold more than normal silkworms. Compared to those of transgenic silkworms with wild type (non-knockout) background, the morphology and secondary structure of cocoon silks were barely changed in transgenic silkworms with a P25 gene knockout background, indicating their similar physical properties of cocoon silks. In conclusion, P25 gene knockout silkworms may become an efficient bioreactor for the production of exogenous proteins and a promising tool for producing various protein-containing silk biomaterials.

Recombinant Silk Proteins with Additional Polyalanine Have Excellent Mechanical Properties.

This paper explores the structures of exogenous protein molecules that can effectively improve the mechanical properties of silkworm silk. Several transgenic vectors fused with the silkworm fibroin light chain and type 3 repeats in different multiples of the ampullate dragline silk protein 1 (MaSp1) from black widow spider with different lengths of the polyalanine motifs were constructed for this study. Transgenic silkworms were successfully obtained by piggyBac-mediated microinjection. Molecular detection showed that foreign proteins were successfully secreted and contained within the cocoon shells. According to the prediction of PONDR® VSL2 and PONDR® VL-XT, the type 3 repeats and the polyalanine motif of the MaSp1 protein were amorphous. The results of FTIR analysis showed that the content of ß-sheets in the silk of transgenic silkworms engineered with transgenic vectors with additional polyalanine was significantly higher than that of wild-type silkworm silk. Additionally, silk with a higher ß-sheet content had better fracture strength and Young's modulus. The mechanical properties of silk with longer chains of exogenous proteins were improved. In general, our results provide theoretical guidance and technical support for the large-scale production of excellent bionic silk.

Knockdown of IL-32 protects PC12 cells against oxygen-glucose deprivation/reoxygenation-induced injury via activation of Nrf2/NF-κB pathway.

Cerebral ischemia/reperfusion injury (IRI) is one of major causes of ischemic organ damage. It is well established that inflammatory cytokines serve as regulatory factors in cerebral oxygen glucose deprivation/reoxygenation (OGD/R). However, the involving mechanism is not clear enough. OGD/R PC12 cells were used as a hypoxia/reoxygenation model. IL-32 expression and cell viability were detected by qRT-PCR and CCK-8 assay, respectively. Cell apoptosis were determined by flow cytometry and western blotting. Protein levels of inflammatory factors, and the activity of MPO, MDA and SOD were analyzed. Furthermore, western blot assay was carried out to assess protein levels of Nrf2, keap1, NQO-1, p-p65, p-IκBα, p65 and IκBα. The results revealed that IL-32 expression was significantly upregulated in PC12 cells induced by OGD/R. Nrf2, keap1 and NQO-1 level was reduced while phosphorylation level of p65 and IκBα was up-regulated in OGD/R-induced PC12 cells. Mechanism investigations found that IL-32 silence elevated the level of Nrf2, Keap1 and NQO-1, reduced p-p65 and p-IκBα level, and regulated the contents of TNF-a, IL-1ß, IL-6 and MCP-1 in OGD/R PC12 cells. In addition, knockdown of IL-32 suppressed production of intracellular ROS, elevated SOD activity, reduced MPO and MDA content, and enhanced cell viability. Furthermore, cell apoptosis was induced in OGD/R PC12 cells with IL-32 silence. However, Nrf2 inhibitor reversed the effects of IL-32 knockdown on OGD/R PC12 cells. This research suggests that IL-32 silence may alleviate OGD/R and Nrf2 plays an important role in the protection by IL-32 silence on PC12 cells induced by OGD/R.

Improving Silkworm Genome Annotation Using a Proteogenomics Approach.

The silkworm genome has been deeply sequenced and assembled, but accurate genome annotation, which is important for modern biological research, remains far from complete. To improve silkworm genome annotation, we carried out a proteogenomics analysis using 9.8 million mass spectra collected from different tissues and developmental stages of the silkworm. The results confirmed the translational products of 4307 existing gene models and identified 1701 novel genome search-specific peptides (GSSPs). Using these GSSPs, 74 novel gene-coding sequences were identified, and 121 existing gene models were corrected. We also identified 1182 novel junction peptides based on an exon-skipping database that resulted in the identification of 973 alternative splicing sites. Furthermore, we performed RNA-seq analysis to improve silkworm genome annotation at the transcriptional level. A total of 1704 new transcripts and 1136 new exons were identified, 2581 untranslated regions (UTRs) were revised, and 1301 alternative splicing (AS) genes were identified. The transcriptomics results were integrated with the proteomics data to further complement and verify the new annotations. In addition, 14 incorrect genes and 10 skipped exons were verified using the two analysis methods. Altogether, we identified 1838 new transcripts and 1593 AS genes and revised 5074 existing genes using proteogenomics and transcriptome analyses. Data are available via ProteomeXchange with identifier PXD009672. The large-scale proteogenomics and transcriptome analyses in this study will greatly improve silkworm genome annotation and contribute to future studies.

Comparative Proteomic Analysis of Posterior Silk Glands of Wild and Domesticated Silkworms Reveals Functional Evolution during Domestication.

The wild silkworm Bombyx mandarina was domesticated to produce silk in China approximately 5000 years ago. Silk production is greatly improved in the domesticated silkworm B. mori, but the molecular basis of the functional evolution of silk gland remains elusive. We performed shotgun proteomics with label-free quantification analysis and identified 1012 and 822 proteins from the posterior silk glands (PSGs) of wild silkworms on the third and fifth days of the fifth instar, respectively, with 128 of these differentially expressed. Bioinformatics analysis revealed that, with the development of the PSG, the up-regulated proteins were mainly involved in the ribosome pathway, similar to what we previously reported for B. mori. Additionally, we screened 50 proteins with differential expression between wild and domesticated silkworms that might be involved in domestication at the two stages. Interestingly, the up-regulated proteins in domesticated compared to wild silkworms were enriched in the ribosome pathway, which is closely related to cell size and translation capacity. Together, these results suggest that functional evolution of the PSG during domestication was driven by reinforcing the advantageous pathways to increase the synthesis efficiency of silk proteins in each cell and thereby improve silk yield.

Expression of functional recombinant human fibroblast growth factor 8b and its protective effects on MPP⁺-lesioned PC12 cells.

Human fibroblast growth factor 8b (FGF8b) was expressed based on a baculovirus expression vector system (BEVS) and identified as having a protective effect on Parkinson's disease. Immunoblotting demonstrated that rhFGF8b proteins were recognized by a human anti-FGF8b antibody. The multiplicity of infection and timing of harvest had a significant effect on protein yield and protein quality. Our results indicated that the rhFGF8b was first detectable at 36 h postinfection and reached a maximum at 60 h. A multiplicity of infection (MOI) of 8 pfu/mL was suitable for harvest. The target protein was purified by heparin-affinity chromatography. In vitro methylthiazol tetrazolium (MTT) assays demonstrated that the purified rhFGF8b could significantly stimulate proliferation of NIH3T3 cells. Furthermore, to elucidate the effect of rhFGF8b on Parkinson's disease, we used FGF8b pretreatment on a cell model of Parkinson's disease. The results indicated that rhFGF8b prevented necrosis and apoptosis of 1-METHYL-4-phenyl pyridine (MPP(+)) treated PC12 cells. Moreover, the effect of FGF8b on messenger RNA (mRNA) levels of apoptosis and ERS genes was investigated to clarify the molecular mechanisms of FGF8b. The results suggest that FGF8b exerts neuroprotective effects by alleviating endoplasmic reticulum (ER) stress during PD. These results suggest that FGF8b may be a promising candidate therapeutic drug for neurodegenerative diseases related to ER stress.

High production in E. coli of biologically active recombinant human fibroblast growth factor 20 and its neuroprotective effects.

Fibroblast growth factor 20 (FGF20) has a wide range of biological activities; its expression is most pronounced in neural tissues where it has functions in development and neuroprotection. Given these activities, interest in the clinical applications of FGF20 is rising, which will lead to increasing demand for active recombinant human FGF20 (rhFGF20). To improve the production of rhFGF20, an artificial gene encoding fgf20 was cloned into pET3a and expressed in E. coli BL21(DE3)pLysS. By optimizing induction conditions, we successfully induced large amounts of insoluble rhFGF20. Following solubilization and refolding of the rhFGF20 from inclusion bodies, it was purified by HiTrap heparin affinity chromatography to a purity of over 96% with a yield of 218 mg rhFGF20/100 g wet cells. The purified rhFGF20 could stimulate proliferation of both NIH 3T3 cells and PC-12 cells, measured by the MTT assay. In a model of Aß25-35-induced apoptosis on PC-12 cells, rhFGF20 had a clear protective effect. RT-PCR and Western blot analysis of apoptosis-related genes and proteins revealed that the FGF20-derived protective mechanism was likely due to the relief of endoplasmic reticulum stress (ER stress). In conclusion, the approach described here may be a better means to produce active rhFGF20 in good quantity, thereby allowing for its future pharmacological and clinical use.

Cost-effectiveness analysis of first-line serplulimab plus chemotherapy for advanced squamous non-small-cell lung cancer in China: based on the ASTRUM-004 trial.

OBJECTIVE: In the ASTRUM-004 trial, serplulimab plus chemotherapy demonstrated significantly improved survival and controllable safety. This study assessed the cost-effectiveness of serplulimab plus chemotherapy in advanced squamous non-small cell lung cancer (sqNSCLC), considering the perspective of the Chinese healthcare system. METHODS: A decision tree and a Markov model were constructed to simulate the treatment. The interesting results included total cost, life-years (LYs), quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs). Scenario, one-way and probabilistic sensitivity analyses were used to examine model instability. RESULTS: Compared with placebo plus chemotherapy, serplulimab plus chemotherapy had an ICER of $55,539.46/QALY ($47,278.84/LY). The ICERs were estimated to be $58,706.03/QALY, $48,978.34/QALY and $59,709.54/QALY inpatients with programmed death-ligand 1 expression level of tumor proportion score (TPS) < 1%, 1% ≤ TPS < 50%, and TPS ≥ 50%. The cost-effective prices of serplulimab were $168.276/100 mg, $349.157/100 mg, and $530.039/100 mg at the willingness-to-pay threshold of $12,574.30/QALY, $25,148.60/QALY, and $37,722.90/QALY. Patient weight and price of serplulimab created the most significant impact. Presently, the probability of serplulimab plus chemotherapy being cost-effective was 14.15%. CONCLUSION: Compared with placebo plus chemotherapy, serplulimab plus chemotherapy might not be cost-effective in the first-line treatment for advanced sqNSCLC.

Cost-effectiveness of atezolizumab plus bevacizumab as first-line therapy for metastatic renal cell carcinoma.

OBJECTIVES: Recently, the IMmotion151 trial evaluated the safety and efficacy of atezolizumab plus bevacizumab in metastatic renal cell carcinoma (mRCC) and found that this combination led to longer progression-free survival. However, no studies have evaluated the cost-effectiveness of atezolizumab plus bevacizumab. METHODS: We constructed a Markov model to evaluate the cost-effectiveness of atezolizumab plus bevacizumab, using costs and utilities from the published studies. We set the willingness-to-pay (WTP) threshold at $150,000. One-way and probabilistic sensitivity analyses were performed to ensure that our results were robust. We performed a threshold analysis to explore a more appropriate price for atezolizumab. RESULTS: Our results found that although atezolizumab plus bevacizumab provided more quality-adjusted life years (QALYs), its incremental cost-effectiveness ratio (ICER) was $1,640,532/QALY, well above the WTP threshold. One-way and probabilistic sensitivity analysis results confirmed the robust of this conclusion. Based on the threshold analysis, for atezolizumab plus bevacizumab to be cost-effective, the price of them would need to be reduced by 46.3% or more. CONCLUSIONS: From the perspective of US payers, atezolizumab plus bevacizumab is not cost-effective for mRCC patients. To make this combination cost-effective in the future, the price of atezolizumab and bevacizumab needs to be reduced.

Cost-effectiveness of first-line enfortumab vedotin in addition to pembrolizumab for metastatic urothelial carcinoma in the United States.

Background and objective: The EV-302 trial found that the combination of enfortumab vedotin (EV) with pembrolizumab significantly improved survival for patients with metastatic urothelial carcinoma (mUC). However, given the high cost of the drugs, there is a need to assess its value by considering both efficacy and cost. This study assessed the cost-effectiveness of EV plus pembrolizumab as a first-line treatment for patients with mUC from the perspective of U.S. payers. Methods: A Markov model was developed to compare the lifetime costs and effectiveness of EV in combination with pembrolizumab with chemotherapy in the treatment of mUC patients from U.S. payer perspective. Life-years (LYs), quality-adjusted LYs (QALYs), and lifetime costs were estimated. One-way, two-way and probabilistic sensitivity analyses were conducted to evaluate model uncertainty. Additionally, subgroup analyses were performed. Results: Compared to chemotherapy, the combination of EV and pembrolizumab provided an additional 2.10 LYs and 1.72 QALYs, at an incremental cost of $962,240.8 per patient. The incremental cost-effectiveness ratio (ICER) is $558,973 per QALY. Subgroup analysis indicated that patients ineligible for cisplatin treatment had a lower ICER compared to those who were eligible for cisplatin. Conclusions: From the perspective of US payers, at a willingness-to-pay threshold of $150,000 per QALY, the combination of EV and pembrolizumab is estimated to not be cost-effective compared to traditional chemotherapy in the first-line treatment of mUC patients.

Effects and Costs of Hepatitis C Virus Elimination for the Whole Population in China: A Modelling Study.

BACKGROUND AND OBJECTIVE: China has the highest number of hepatitis C virus (HCV) infections in the world. However, it is unclear what levels of screening and treatment are needed to achieve the WHO 2030 hepatitis C elimination targets. We aimed to evaluate the impact of scaling up interventions on the hepatitis C epidemic and determine how and at what cost these elimination targets could be achieved for the whole population in China. METHODS: We developed a compartmental model incorporating HCV transmission, disease progression, and care cascade for the whole population in China, calibrated with data on demographics, injecting drug use, HCV prevalence, and treatments. Five different scenarios were evaluated for effects and costs for 2022-2030. All costs were converted to 2021 US dollar (USD) and discounted at an annual rate of 5%. One-way sensitivity analyses were conducted to assess the robustness of the model. RESULTS: Under the status quo scenario, the incidence of hepatitis C is projected to increase from 60.39 (57.60-63.45) per 100,000 person-years in 2022 to 68.72 (65.3-73.97) per 100,000 person-years in 2030, and 2.52 million (1.94-3.07 million) infected patients are projected to die between 2022 and 2030, of which 0.76 (0.61-1.08) million will die due to hepatitis C. By increasing primary screening to 10%, conducting regular rescreening (annually for PWID and every 5 years for the general population) and treating 90% of patients diagnosed, the incidence would be reduced by 88.15% (86.61-89.45%) and hepatitis C-related mortality by 60.5% (52.62-65.54%) by 2030, compared with 2015 levels. This strategy would cost USD 52.78 (USD 43.93-58.53) billion. CONCLUSIONS: Without changes in HCV prevention and control policy, the disease burden of HCV in China will increase dramatically. To achieve the hepatitis C elimination targets, China needs to sufficiently scale up screening and treatment.

Sex separation by body color via a W-chromosome-linked transgene.

Sex separation processes are important for commercial insect production and sterile insect techniques. Here, we describe the transgenic insertion of a DsRed expression cassette driven by the enhancer HR3 and strong promoter IE1 into the silkworm W chromosome as a dominant visible marker of sex separation. The obtained transgenic lines showed female-specific body color visible to the naked eye at the second- to fifth-instar larval, pupal and adult stages, and their performance traits were comparable to those of a nontransgenic practical silkworm variety. This strategy can greatly facilitate the sex separation of silkworms for male-only rearing and to obtain hybrids while avoiding sibling mating, and it can also be applied to the sex separation of other light-colored insects.

Leptin deficiency in CD8+ T cells ameliorates non-segmental vitiligo by reducing interferon-γ and Granzyme B.

Background: Vitiligo is an autoimmune skin disease mainly mediated by CD8+ T cells, which affects about 0.1%-2% population of the world. Leptin plays a critical role in regulating the activation of CD8+ T cells. However, the effect of Leptin on vitiligo remains unclear. Objectives: To explore the effect of leptin on CD8+ T cells and its influence on vitiligo. Methods: RNA sequencing and Quantitative Real-time PCR (RT-qPCR) were used to explore the differentially expressed genes. Immunofluorescence staining was performed on skin lesions. Leptin in serum was detected by enzyme linked immunosorbent assay (ELISA). The peripheral blood mononuclear cells were detected by flow cytometry after leptin stimulation for 72 hours. A vitiligo model was established by monobenzone on Leptin KO mice. Results: 557 differentially expressed genes were found, including 154 up-regulated and 403 down-regulated genes. Lipid metabolism pathways showed a close relationship to the pathogenesis of vitiligo, especially the PPAR signaling pathway. RT-qPCR (p = 0.013) and immunofluorescence staining (p = 0.0053) verified that LEPR expressed significantly higher in vitiligo. The serum leptin level of vitiligo patients was significantly lower than that of healthy controls (p = 0.0245). The interferon-γ subset of CD8+LEPR+ T cells from vitiligo patients was significantly higher (p = 0.0189). The protein level of interferon-γ was significantly increased after leptin stimulation in vitro (p = 0.0217). In mice, Leptin deficiency resulted in less severe hair depigmentation. Leptin deficiency also resulted in significantly lower expressed vitiligo-related genes, such as Cxcl9 (p = 0.0497), Gzmb (p < 0.001), Ifng (p = 0.0159), and Mx1 (p < 0.001) after modeling. Conclusion: Leptin could promote the progression of vitiligo by enhancing the cytotoxic function of CD8+ T cells. Leptin may become a new target for vitiligo treatment.

A Multilayered Magnetoelectric Transmitter with Suppressed Nonlinearity for Portable VLF Communication.

Acoustically actuated magnetoelectric (ME) antenna based on the efficient oscillation of magnetic dipoles has recently been considered as a promising solution for portable very-low-frequency communications. However, the severe nonlinear dynamic behavior in the case of strong-field excitation results in insufficient radiation capability and poor communication performance for a conventional ME antenna. In this work, we propose to suppress the nonlinearity of an ME antenna by neutralizing the spring-hardening effect in amorphous Metglas and the spring-softening effect in piezoelectric ceramics through an ME multilayered transmitter (ME-MLTx) design. With a driving voltage of 50 Vpp at the resonance frequency of 21.2 kHz, a magnetic flux density as high as 108 fT at a distance of 100 m is produced from a single ME-MLTx. In addition, ME-MLTx performs a decreased mechanical quality factor (Q m) less than 40.65, and, thus, a broadened bandwidth of 500 Hz is generated. Finally, a communication link transmitting binary American Standard Code for Information Interchange-coded message is built, which allows for an error-free communication with a distance of 18 m and a data rate of 300 bit/s in the presence of heavy environment noise. The communication distance can be further estimated over 100 m when using a femtotesla-class-inductive magnetic field receiver. The obtained results are believed to bring ME antennas one step closer to being applicable in very-low-frequency communications.

Mechanism of silk secretion revealed by proteomic analysis of silkworm cocoons with fibroin light chain mutations.

Silkworm is an economically important insect due to its efficient production of silk proteins. Silk itself and the silk trade have enriched human civilization through art and culture and contributed to early globalization in the Silk Road era for nearly two thousand years. Although a large number of studies on silk have been carried out, the mechanism of silk secretion in silkworms has not been thoroughly studied thus far. As the main component of fibroin, fibroin light chain (Fib-L) plays a key role in the secretion of silk. In this study, we constructed a homozygous Fib-L gene mutant population of a nonpractical variety using the CRISPR/Cas9 system. The homozygous mutants displayed a thin cocoon layer, but their viability was not affected by the Fib-L mutation. Furthermore, a comparative proteomic analysis of homozygous mutant cocoons and wild-type cocoons was performed. Strikingly, fibrohexamerin (P25) was secreted almost normally in the homozygous mutant. Further analysis of cocoon proteins revealed that the mutant responded to greater environmental stress caused by a dramatic decrease in fibroin by significantly increasing the secretion of protease inhibitors. These results will further help explain the silk secretion mechanism of silkworm. SIGNIFICANCE: This study generated a homozygous Fib-L gene mutant population of a nonpractical variety using the CRISPR/Cas9 system. The homozygous mutants displayed a thin cocoon layer, but their viability was not affected by the Fib-L mutation. Furthermore, a comparative proteomic analysis of homozygous mutant cocoons and wild-type cocoons was performed. The analysis of the abundance of silk proteins in the cocoons revealed that P25 could be secreted almost normally. The analysis of the abundance of cocoon proteins other than silk proteins showed that the homozygous mutants responded to greater environmental stress by increasing the secretion of defense-related proteins, such as protease inhibitors. These results will further help explain the silk secretion mechanism of silkworm.