The association of GNB5 with Alzheimer disease revealed by genomic analysis restricted to variants impacting gene function.

Disease-associated variants identified from genome-wide association studies (GWASs) frequently map to non-coding areas of the genome such as introns and intergenic regions. An exclusive reliance on gene-agnostic methods of genomic investigation could limit the identification of relevant genes associated with polygenic diseases such as Alzheimer disease (AD). To overcome such potential restriction, we developed a gene-constrained analytical method that considers only moderate- and high-risk variants that affect gene coding sequences. We report here the application of this approach to publicly available datasets containing 181,388 individuals without and with AD and the resulting identification of 660 genes potentially linked to the higher AD prevalence among Africans/African Americans. By integration with transcriptome analysis of 23 brain regions from 2,728 AD case-control samples, we concentrated on nine genes that potentially enhance the risk of AD: AACS, GNB5, GNS, HIPK3, MED13, SHC2, SLC22A5, VPS35, and ZNF398. GNB5, the fifth member of the heterotrimeric G protein beta family encoding Gß5, is primarily expressed in neurons and is essential for normal neuronal development in mouse brain. Homozygous or compound heterozygous loss of function of GNB5 in humans has previously been associated with a syndrome of developmental delay, cognitive impairment, and cardiac arrhythmia. In validation experiments, we confirmed that Gnb5 heterozygosity enhanced the formation of both amyloid plaques and neurofibrillary tangles in the brains of AD model mice. These results suggest that gene-constrained analysis can complement the power of GWASs in the identification of AD-associated genes and may be more broadly applicable to other polygenic diseases.

Rapid detection of IDH mutations in gliomas by intraoperative mass spectrometry.

The development and performance of two mass spectrometry (MS) workflows for the intraoperative diagnosis of isocitrate dehydrogenase (IDH) mutations in glioma is implemented by independent teams at Mayo Clinic, Jacksonville, and Huashan Hospital, Shanghai. The infiltrative nature of gliomas makes rapid diagnosis necessary to guide the extent of surgical resection of central nervous system (CNS) tumors. The combination of tissue biopsy and MS analysis used here satisfies this requirement. The key feature of both described methods is the use of tandem MS to measure the oncometabolite 2-hydroxyglutarate (2HG) relative to endogenous glutamate (Glu) to characterize the presence of mutant tumor. The experiments i) provide IDH mutation status for individual patients and ii) demonstrate a strong correlation of 2HG signals with tumor infiltration. The measured ratio of 2HG to Glu correlates with IDH-mutant (IDH-mut) glioma (P < 0.0001) in the tumor core data of both teams. Despite using different ionization methods and different mass spectrometers, comparable performance in determining IDH mutations from core tumor biopsies was achieved with sensitivities, specificities, and accuracies all at 100%. None of the 31 patients at Mayo Clinic or the 74 patients at Huashan Hospital were misclassified when analyzing tumor core biopsies. Robustness of the methodology was evaluated by postoperative re-examination of samples. Both teams noted the presence of high concentrations of 2HG at surgical margins, supporting future use of intraoperative MS to monitor for clean surgical margins. The power of MS diagnostics is shown in resolving contradictory clinical features, e.g., in distinguishing gliosis from IDH-mut glioma.

Transcription factor OsNF-YC1 regulates grain size by coordinating the transcriptional activation of OsMADS1 in Oryza sativa L.

Grain weight, grain number per panicle, and the number of panicles are the three factors that determine rice (Oryza sativa L.) yield. Of these, grain weight, which not only directly determines rice yield but also influences appearance and quality, is often considered the most important for rice production. Here, we describe OsNF-YC1, a member of the NF-Y transcription factor family that regulates rice grain size. OsNF-YC1 knockout plants (osnf-yc1), obtained using CRISPR-Cas9 technology, showed reduced grain weight due to reduced width and thickness, with no change in grain length, leading to a slenderer grain shape. Downregulation of OsNF-YC1 using RNA interference resulted in similar grain phenotypes as osnf-yc1. OsNF-YC1 affects grain formation by regulating both cell proliferation and cell expansion. OsNF-YC1 localizes in both the nucleus and cytoplasm, has transcriptional activation activity at both the N-terminus and C-terminus, and is highly expressed in young panicles. OsNF-YC1 interacts with OsMADS1 both in vivo and in vitro. Further analysis showed that the histone-like structural CBFD-NFYB-HMF domain of OsNF-YC1 conserved in the OsNF-YC transcription factor family can directly interact with the MADS-box domain of OsMADS1 to enhance its transcriptional activation activity. This interaction positively regulates the expression of OsMADS55, the direct downstream target of OsMADS1. Therefore, this paper reveals a potential grain size regulation pathway controlled by an OsNF-YC1-OsMADS1-OsMADS55 module in rice.

DNA Cryogels with Anisotropic Mechanical and Responsive Properties for Specific Cell Capture and Release.

Due to their programmable stimuli-responsiveness, excellent biocompatibility, and water-rich and soft structures similar to biological tissues, smart DNA hydrogels hold great promise for biosensing and biomedical applications. However, most DNA hydrogels developed to date are composed of randomly oriented and isotropic polymer networks, and the resulting slow response to biotargets and lack of anisotropic properties similar to those of biological tissues have limited their extensive applications. Herein, anisotropic DNA hydrogels consisting of unidirectional void channels internally oriented up to macroscopic length scales were constructed by a directional cryopolymerization method, as exemplified by a DNA-incorporated covalently cross-linked DNA cryogel and a DNA duplex structure noncovalently cross-linked DNA cryogel. Results showed that the formation of unidirectional channels significantly improved the responsiveness of the gel matrix to biomacromolecular substances and further endowed the DNA cryogels with anisotropic properties, including anisotropic mechanical properties, anisotropic swelling/shrinking behaviors, and anisotropic responsiveness to specific biotargets. Moreover, the abundant oriented and long macroporous channels in the gel matrix facilitated the migration of cells, and through the introduction of aptamer structures and thermosensitive polymers, an anisotropic DNA cryogel-based platform was further constructed to achieve the highly efficient capture and release of specific cells. These anisotropic DNA hydrogels may provide new opportunities for the development of anisotropic separation and biosensing systems.

Inherited CARD9 Deficiency Due to a Founder Effect in East Asia.

Autosomal recessive CARD9 deficiency can underly deep and superficial fungal diseases. We identified two Japanese patients, suffering from superficial and invasive Candida albicans diseases, carrying biallelic variants of CARD9. Both patients, in addition to another Japanese and two Korean patients who were previously reported, carried the c.820dup CARD9 variant, either in the homozygous (two patients) or heterozygous (three patients) state. The other CARD9 alleles were c.104G > A, c.1534C > T and c.1558del. The c.820dup CARD9 variant has thus been reported, in the homozygous or heterozygous state, in patients originating from China, Japan, or South Korea. The Japanese, Korean, and Chinese patients share a 10 Kb haplotype encompassing the c.820dup CARD9 variant. This variant thus originates from a common ancestor, estimated to have lived less than 4,000 years ago. While phaeohyphomycosis caused by Phialophora spp. was common in the Chinese patients, none of the five patients in our study displayed Phialophora spp.-induced disease. This difference between Chinese and our patients probably results from environmental factors. (161/250).

Transcription factor OsSHR2 regulates rice architecture and yield per plant in response to nitrogen.

MAIN CONCLUSION: Mutation of OsSHR2 adversely impacted root and shoot growth and impaired plant response to N conditions, further reducing the yield per plant. Nitrogen (N) is a crucial factor that regulates the plant architecture. There is still a lack of research on it. In our study, it was observed that the knockout of the SHORTROOT 2 (OsSHR2) which was induced by N deficiency, can significantly affect the regulation of plant architecture response to N in rice. Under N deficiency, the mutation of OsSHR2 significantly reduced root growth, and impaired the sensitivity of the root meristem length to N deficiency. The mutants were found to have approximately a 15% reduction in plant height compared to wild type. But mutants showed a significant increase in tillering at post-heading stage, approximately 26% more than the wild type, particularly in high N conditions. In addition, due to reduced seed setting rate and 1000-grain weight, mutant yield was significantly decreased by approximately 33% under low N fertilizer supply. The mutation also changed the distribution of N between the vegetative and reproductive organs. Our findings suggest that the transcription factor OsSHR2 plays a regulatory role in the response of plant architecture and yield per plant to N in rice.

Pretreatment multiparametric MRI radiomics-integrated clinical hematological biomarkers can predict early rapid metastasis in patients with nasopharyngeal carcinoma.

BACKGROUND: To establish and validate a predictive model combining pretreatment multiparametric MRI-based radiomic signatures and clinical characteristics for the risk evaluation of early rapid metastasis in nasopharyngeal carcinoma (NPC) patients. METHODS: The cutoff time was used to randomly assign 219 consecutive patients who underwent chemoradiation treatment to the training group (n = 154) or the validation group (n = 65). Pretreatment multiparametric magnetic resonance (MR) images of individuals with NPC were employed to extract 428 radiomic features. LASSO regression analysis was used to select radiomic features related to early rapid metastasis and develop the Rad-score. Blood indicators were collected within 1 week of pretreatment. To identify independent risk variables for early rapid metastasis, univariate and multivariate logistic regression analyses were employed. Finally, multivariate logistic regression analysis was applied to construct a radiomics and clinical prediction nomogram that integrated radiomic features and clinical and blood inflammatory predictors. RESULTS: The NLR, T classification and N classification were found to be independent risk indicators for early rapid metastasis by multivariate logistic regression analysis. Twelve features associated with early rapid metastasis were selected by LASSO regression analysis, and the Rad-score was calculated. The AUC of the Rad-score was 0.773. Finally, we constructed and validated a prediction model in combination with the NLR, T classification, N classification and Rad-score. The area under the curve (AUC) was 0.936 (95% confidence interval (95% CI): 0.901-0.971), and in the validation cohort, the AUC was 0.796 (95% CI: 0.686-0.905). CONCLUSIONS: A predictive model that integrates the NLR, T classification, N classification and MR-based radiomics for distinguishing early rapid metastasis may serve as a clinical risk stratification tool for effectively guiding individual management.

What Determines the Low-Friction Mechanism of the Silicon-Doped Diamond-like Carbon Film in a Water Environment: An Atomic-Level Understanding.

It is widely acknowledged that doping silicon can significantly enhance the friction performance of diamond-like carbon (DLC) films in a water environment. However, the mechanism of low friction caused by doped silicon is still highly controversial. Therefore, this article compares the interface interaction between DLC and Si-DLC films in a water environment through first-principles calculations of physisorption and chemisorption effects. The results indicate that water molecules are predominantly chemically adsorbed rather than physically adsorbed on the Si-DLC surface. Further study reveals that when OH-termination is formed on the Si-DLC surface, water molecules are predominantly physically adsorbed rather than chemically adsorbed on the Si-DLC hydroxylation surface. Consequently, a more stable hydration layer is formed on the surface through the hydrogen bond network formed by Si-OH groups, ultimately leading to lower friction. Moreover, molecular dynamics simulations further suggest that the lower friction coefficient of Si-DLC films in a water environment may be due to more water molecules at the friction interface and fewer interface covalent bonds. In short, the low-friction coefficient of the Si-DLC film in a water environment may be caused not only by the chemisorption of water molecules on its surface but also by the physisorption of water molecules on the Si-DLC film after surface hydroxylation.

Transcriptomic analysis reveals molecular characterization and immune landscape of PANoptosis-related genes in atherosclerosis.

BACKGROUND: Atherosclerosis is a chronic inflammatory disease characterized by abnormal lipid deposition in the arteries. Programmed cell death is involved in the inflammatory response of atherosclerosis, but PANoptosis, as a new form of programmed cell death, is still unclear in atherosclerosis. This study explored the key PANoptosis-related genes involved in atherosclerosis and their potential mechanisms through bioinformatics analysis. METHODS: We evaluated differentially expressed genes (DEGs) and immune infiltration landscape in atherosclerosis using microarray datasets and bioinformatics analysis. By intersecting PANoptosis-related genes from the GeneCards database with DEGs, we obtained a set of PANoptosis-related genes in atherosclerosis (PANoDEGs). Functional enrichment analysis of PANoDEGs was performed and protein-protein interaction (PPI) network of PANoDEGs was established. The machine learning algorithms were used to identify the key PANoDEGs closely linked to atherosclerosis. Receiver operating characteristic (ROC) analysis was used to assess the diagnostic potency of key PANoDEGs. CIBERSORT was used to analyze the immune infiltration patterns in atherosclerosis, and the Spearman method was used to study the relationship between key PANoDEGs and immune infiltration abundance. The single gene enrichment analysis of key PANoDEGs was investigated by GSEA. The transcription factors and target miRNAs of key PANoDEGs were predicted by Cytoscape and online database, respectively. The expression of key PANoDEGs was validated through animal and cell experiments. RESULTS: PANoDEGs in atherosclerosis were significantly enriched in apoptotic process, pyroptosis, necroptosis, cytosolic DNA-sensing pathway, NOD-like receptor signaling pathway, lipid and atherosclerosis. Four key PANoDEGs (ZBP1, SNHG6, DNM1L, and AIM2) were found to be closely related to atherosclerosis. The ROC curve analysis demonstrated that the key PANoDEGs had a strong diagnostic potential in distinguishing atherosclerotic samples from control samples. Immune cell infiltration analysis revealed that the proportion of initial B cells, plasma cells, CD4 memory resting T cells, and M1 macrophages was significantly higher in atherosclerotic tissues compared to normal tissues. Spearman analysis showed that key PANoDEGs showed strong correlations with immune cells such as T cells, macrophages, plasma cells, and mast cells. The regulatory networks of the four key PANoDEGs were established. The expression of key PANoDEGs was verified in further cell and animal experiments. CONCLUSIONS: This study evaluated the expression changes of PANoptosis-related genes in atherosclerosis, providing a reference direction for the study of PANoptosis in atherosclerosis and offering potential new avenues for further understanding the pathogenesis and treatment strategies of atherosclerosis.

Dual stimuli-responsive upconversion nanoparticle-poly-N-isopropylacrylamide/DNA core-shell microgels.

Stimuli-responsive upconversion nanoparticle (UCNP)-poly-N-isopropylacrylamide (pNIPAM)/DNA core-shell microgels with tunable sizes and programmable functions have been prepared. Thanks to the near-infrared (NIR)-responsive UCNP cores and thermosensitive polymeric shells, functional DNA-incorporated microgels with high DNA activity and loading efficiency are obtained, and the activity of the loaded DNA structures can be smartly regulated by NIR illumination and temperature simultaneously.

Risk factors for Pneumocystis jirovecii pneumonia after kidney transplantation: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Pneumocystis jirovecii pneumonia (PJP), an opportunistic infection, often leads to an increase in hospitalization time and mortality rates in kidney transplant (KT) recipients. However, the risk factors associated with PJP in KT recipients remain debatable. Therefore, we conducted this meta-analysis to identify risk factors for PJP, which could potentially help to reduce PJP incidence and improve outcome of KT recipients. METHODS: We systematically retrieved relevant studies in PubMed, EMBASE, and the Cochrane Library up to November 2023. Pooled odds ratios (ORs) or mean differences (MDs) and the corresponding 95% confidence intervals (CIs) were calculated to assess the impact of potential risk factors on the occurrence of PJP. RESULTS: 27 studies including 42383 KT recipients were included. In this meta-analysis, age at transplantation (MD = 3.48; 95% CI = .56-6.41; p = .02), cytomegalovirus (CMV) infection (OR = 4.00; 95% CI = 2.53-6.32; p = .001), BK viremia (OR = 3.38; 95% CI = 1.70-6.71; p = .001), acute rejection (OR = 3.66; 95% CI = 2.44-5.49; p = .001), ABO-incompatibility (OR = 2.51; 95% CI = 1.57-4.01; p = .001), estimated glomerular filtration rate (eGFR) (MD = -14.52; 95% CI = -25.37- (-3.67); p = .009), lymphocyte count (MD = -.54; 95% CI = -.92- (-.16); p = .006) and anti-PJP prophylaxis (OR = .53; 95% CI = .28-.98; p = .04) were significantly associated with PJP occurrence. CONCLUSION: Our findings suggest that transplantation age greater than 50 years old, CMV infection, BK viremia, acute rejection, ABO-incompatibility, decreased eGFR and lymphopenia were risk factors for PJP.

Expression analysis and antiviral activity of koi carp (Cyprinus carpio) viperin against carp edema virus (CEV).

Viperin, also known as radical S-Adenosyl methionine domain containing 2 (RSAD2), is an IFN stimulated protein that plays crucial roles in innate immunity. Here, we identified a viperin gene from the koi carp (Cyprinus carpio) (kVip). The ORF of kVip is 1047 bp in length, encoding a polypeptide of 348 amino acids with neither signal peptide nor transmembrane protein. The predicted molecular weight is 40.37 kDa and the isoelectric point is 7.7. Multiple sequence alignment indicated that putative kVip contains a radical SAM superfamily domain and a conserved C-terminal region. kVip was highly expressed in the skin and spleen of healthy koi carps, and significantly stimulated in both natural and artificial CEV-infected koi carps. In vitro immune stimulation analysis showed that both extracellular and intracellular poly (I: C) or poly (dA: dT) caused a significant increase in kVip expression of spleen cells. Furthermore, intraperitoneal injection of recombinant kVip (rkVip) not only reduced the CEV load in the gills, but also improved the survival of koi carps following CEV challenge. Additionally, rkVip administration effectively regulated inflammatory and anti-inflammatory cytokines (IL-6, IL-1ß, TNF-α, IL-10) and interferon-related molecules (cGAS, STING, MyD88, IFN-γ, IFN-α, IRF3 and IRF9). Collectively, kVip effectively responded to CEV infection and exerted antiviral function against CEV partially by regulation of inflammatory and interferon responses.

Bottom-Up Construction of Rhombic Lamellar CoNi-MOFs for the Electrochemical Sensing of H2S.

Lamellar metal-organic frameworks (MOFs) have attracted significant attention in the field of electrochemical sensing due to their abundant open active sites and specific electron conductivity. Herein, by employing a bottom-up synthesis strategy, rhombic lamellar heterometallic CoNi-MOFs with varying thicknesses are constructed. This is achieved by using 4-methylpyridine as a capping agent based on the (4,6)-linked Co2(azpy)2(bptc) (azpy = 4,4'-azopyridine, bptc = 3,3',5,5'-biphenyltetracarboxylic acid) structure with a fsc topology and by introducing Ni species simultaneously. To mitigate sulfur deposition on electrodes, the triple pulse amperometry (TPA) method is employed. Among the synthesized lamellar CoNi-MOFs, lamellar CoNi-MOF-3 with the minimum thickness exhibits an optimal electrochemical sensing performance toward hydrogen sulfide, with a sensitivity of 119.3 µA·mM-1·cm-2 in the linear range of 2-2000 µM. This study pioneers a new approach to the controlled construction and electrochemical activity modification of lamellar MOF materials.

Longitudinal measurement invariance and psychometric properties of the Patient Health Questionnaire-Four in China.

BACKGROUND: Depression and anxiety symptoms among medical students are often a concern. The Patient Health Questionnaire-Four (PHQ-4), an important tool for depression and anxiety screening, is commonly used and easy to administer. This study aimed to assess and update the longitudinal measurement invariance and psychometric properties of the simplified Chinese version. METHODS: A three-wave longitudinal survey was conducted among healthcare students using the PHQ-4. Structural validity was based on one-factor, two-factor, and second-order factor models, construct validity was based on the Self-Rated Health Questionnaire (SRHQ), Sleep Quality Questionnaire (SQQ), and Rosenberg Self-Esteem Scale (RSES), and longitudinal measurement invariance (LMI), internal consistency, and test-retest reliability were based on structural consistency across three time points. RESULTS: The results of the confirmatory factor analysis indicated that two-factor model was the best fit, and LMI was supported at three time points. Inter-factor, factor-total, and construct validity correlations of the PHQ-4 were acceptable. Additionally, Cronbach's alpha, McDonald's omega, and the intraclass correlation coefficient demonstrated acceptable/moderate to excellent reliability of the PHQ-4. CONCLUSIONS: This study adds new longitudinal evidence that the Chinese version of the PHQ-4 has promising LMI and psychometric properties. Such data lends confidence to the routine and the expanded use of the PHQ-4 for routine screening of depression and anxiety in Chinese healthcare students.

Meta-analysis and systematic review of the relationship between sex and the risk or incidence of poststroke aphasia and its types.

OBJECTIVE: To analyse and discuss the association of gender differences with the risk and incidence of poststroke aphasia (PSA) and its types, and to provide evidence-based guidance for the prevention and treatment of poststroke aphasia in clinical practice. DATA SOURCES: Embase, PubMed, Cochrane Library and Web of Science were searched from January 1, 2002, to December 1, 2023. STUDY SELECTION: Including the total number of strokes, aphasia, the number of different sexes or the number of PSA corresponding to different sex. DATA EXTRACTION: Studies with missing data, aphasia caused by nonstroke and noncompliance with the requirements of literature types were excluded. DATA SYNTHESIS: 36 papers were included, from 19 countries. The analysis of 168,259 patients with stroke and 31,058 patients with PSA showed that the risk of PSA was 1.23 times higher in female than in male (OR = 1.23, 95% CI = 1.19-1.29, P < 0.001), with a prevalence of PSA of 31% in men and 36% in women, and an overall prevalence of 34% (P < 0.001). Analysis of the risk of the different types of aphasia in 1,048 patients with PSA showed a high risk in females for global, broca and Wenicke aphasia, and a high risk in males for anomic, conductive and transcortical aphasia, which was not statistically significant by meta-analysis. The incidence of global aphasia (males vs. females, 29% vs. 32%) and broca aphasia (17% vs 19%) were higher in females, and anomic aphasia (19% vs 14%) was higher in males, which was statistically significant (P < 0.05). CONCLUSIONS: There are gender differences in the incidence and types of PSA. The risk of PSA in female is higher than that in male.

Epidemiologic features and therapeutic strategies of kerion: A nationwide multicentre study.

BACKGROUND: Kerion is a severe type of tinea capitis that is difficult to treat and remains a public health problem. OBJECTIVES: To evaluate the epidemiologic features and efficacy of different treatment schemes from real-world experience. METHODS: From 2019 to 2021, 316 patients diagnosed with kerion at 32 tertiary Chinese hospitals were enrolled. We analysed the data of each patient, including clinical characteristics, causative pathogens, treatments and outcomes. RESULTS: Preschool children were predominantly affected and were more likely to have zoophilic infection. The most common pathogen in China was Microsporum canis. Atopic dermatitis (AD), animal contact, endothrix infection and geophilic pathogens were linked with kerion occurrence. In terms of treatment, itraconazole was the most applied antifungal agent and reduced the time to mycological cure. A total of 22.5% of patients received systemic glucocorticoids simultaneously, which reduced the time to complete symptom relief. Furthermore, glucocorticoids combined with itraconazole had better treatment efficacy, with a higher rate and shorter time to achieving mycological cure. CONCLUSIONS: Kerion often affects preschoolers and leads to serious sequelae, with AD, animal contact, and endothrix infection as potential risk factors. Glucocorticoids, especially those combined with itraconazole, had better treatment efficacy.

Correlation of skin color and plasma carotenoid-related metabolites of ornamental koi carp under temperature fluctuations.

The skin color of koi carp (Cyprinus carpio L.) is one of the traits that most influence their ornamental and economic values. The present study suggested the effects of temperature fluctuation on koi carp in terms of skin color and plasma carotenoids and related-metabolites. The main results were as follows. (1) The vulnerability of koi skin color to acute temperature stress was in the order of white koi> black koi> yellow koi. Both high- (25°C-30°C-25°C) and low-temperature (25°C-20°C-25°C) fluctuations tended to decrease the saturation of white koi. The temperature fluctuation had little effects on the skin color of black and yellow koi. (2) Targeted metabolomics analysis indicated that the effects of cooling stress on oxycarotenoids of all five koi varieties were reversible. The plasma oxycarotenoids in mirror koi with all colors were insensitive to acute heat stress. However, the cooling process from a high temperature (30°C-25°C) still made contributions to the increase of oxycarotenoids. (3) The principal component analysis confirmed the deviation of carotenoid-related metabolites after high temperature fluctuation and the reversibility after low temperature fluctuation. Finally, the correlation analysis revealed that koi skin brightness was negatively correlated with the plasma guanine content and that temperature fluctuations might change koi skin brightness via the L(-)-epinephrine-guanine pathway. The red hue and yellow hue were negatively correlated with the oxycarotenoids in plasma, suggesting that oxycarotenoids were favorable for enhancing koi skin color saturation. Overall, this study revealed the direct action of temperature fluctuations on the skin color and carotenoid-related metabolites of koi.

Targeted metabolomics revealed the seasonal plasticity of skin color and pigment metabolites in ornamental koi carp.

The koi carp is an ornamental fish that was obtained through artificial selection from the common carp (Cyprinus carpio L.). The most economically important traits of koi are their beautiful skin patterns in bright colors. As seasonality is an important factor in the biology and ecology of fish, we thus assumed that seasonal changes are involved in regulating the formation of skin color and patterns of koi carp. The white, red, cyan, and black skin colors from four varieties of scaleless koi carp (Doitsu Shiromuji (W), Doitsu Kohaku (WR), Doitsu Showa Sanke (WRI), and Kumonryu (WI)) were evaluated using the CIELab color space (lightness, redness, and yellowness) in different seasons. Compared to winter, the yellowness of the white color in all koi varieties decreased in summer and autumn. The black skin color areas in WRI and WI koi increased in summer and autumn compared to winter. The yellowness of the red color decreased only in WRI koi, while no changes were observed in WR koi. Targeted metabolomics analysis revealed that the levels of the structural pigment guanine of all koi varieties showed significant seasonal variation. Of seven detected carotenoids, the zeaxanthin and tunaxanthin contents in W, WI, and WRI koi changed with the seasons, while none of the carotenoids in WR koi were altered. Of the seven potential regulatory metabolites, epinephrine, melatonin, and cyclic adenosine monophosphate (cAMP) in all four koi varieties showed the highest levels in winter. A correlation analysis suggested that the seasonal changes in white skin color occurred through the epinephrine-cAMP pathway; melanin-dependent and carotenoid-dependent skin color changes occurred through melatonin in koi carp. This study demonstrated the seasonal plasticity of skin color in koi carp regulated by melatonin and epinephrine, associating with variety and color specificity.

Targeted degradation of KRAS protein in non-small cell lung cancer: Therapeutic strategies using liposomal PROTACs with enhanced cellular uptake and pharmacokinetic profiles.

The role of KRAS mutation in non-small cell lung cancer (NSCLC) initiation and progression is well-established. However, "undruggable" KRAS protein poses the research of small molecule inhibitors a significant challenge. Addressing this, proteolysis-targeting chimeras (PROTACs) have become a cutting-edge treatment method, emphasizing protein degradation. A modified ethanol injection method was employed in this study to formulate liposomes encapsulating PROTAC drug LC-2 (LC-2 LPs). Precise surface modifications using cell-penetrating peptide R8 yielded R8-LC-2 liposomes (R8-LC-2 LPs). Comprehensive cellular uptake and cytotoxicity studies unveiled that R8-LC-2 LPs depended on concentration and time, showcasing the superior performance of R8-LC-2 LPs compared to normal liposomes. In vivo pharmacokinetic profiles demonstrated the capacity of DSPE-PEG2000 to prolong the circulation time of LC-2, leading to higher plasma concentrations compared to free LC-2. In vivo antitumor efficacy research underscored the remarkable ability of R8-LC-2 LPs to effectively suppress tumor growth. This study contributed to the exploration of enhanced therapeutic strategies for NSCLC, specifically focusing on the development of liposomal PROTACs targeting the "undruggable" KRAS protein. The findings provide valuable insights into the potential of this innovative approach, offering prospects for improved drug delivery and heightened antitumor efficacy.

Isolation, Purification of Phenolic Glycoside 1 from Moringa oleifera Seeds and Formulation of Its Liposome Delivery System.

In this study, N, N '-bis {4- [(α-L- rhamnosyloxy) benzyl]} thiourea (PG-1), a phenolic glycoside compound was purified from Moringa seed. The PG-1 has attracted extensive attention due to its anti-cancer, antioxidant, anti-inflammatory and hypoglycemic properties. However, some of its physicochemical properties such as oral bioavailability has not been studied. Herein, a highly purified PG-1 was extracted and incorporated in multiple layered liposomes (PG-1-L) to avoid its burst release and enhance oral bioavailability. After appropriate characterization, it was discovered that the obtained PG-1-L was stable, homogeneous and well dispersed with the average particle size being 89.26 ± 0.23 nm. Importantly, the in vitro release and in vivo oral bioavailability of PG-1-L were significantly improved compared with PG-1. In addition, MTT results showed that compared with the free PG-1, PG-1-L displayed obvious inhibitory effect on the HepG2 cells, while the inhibitory effect on healthy non-malignant 3T6 and LO-2 cells was not significant, indicating that PG-1-L had high safety. In conclusion, PG-1-L can be used as a promising delivery system and an ideal novel approach to improve the oral bioavailability and anticancer activity of PG-1.