Identification of EGFR R776H germline mutations in a patient with multifocal lung adenocarcinoma: A case report and literature review.

The advancement of molecular pathology techniques has led to the discovery of rare EGFR mutations for targeted therapy in lung cancer. Additionally, a substantial body of evidence indicates a connection between the development of lung cancer and genetic variations in the EGFR gene. Here, we present a case report of a patient with multifocal lung adenocarcinoma who possessed a rare germline mutation, EGFR R776H. An investigation into the family history of the patient exposed the notable incidence of lung adenocarcinoma, indicating a plausible genetic vulnerability to the ailment. To be specific, the patient's older brother and sister both suffered from lung cancer, which underlines the hereditary predisposition. Furthermore, it should be noted that the patient's daughter has inherited the germline mutation and also presented with multiple lung ground-glass nodules, emphasizing the clinical importance of this genetic variation. Following the lobectomy, the patient received treatment with almonertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), and at the latest follow-up, the patient has achieved partial remission. This case highlights the significance of taking into account germline possibilities when multiple lesions carry the same mutation. It stresses the importance of acquiring a comprehensive family history and performing genetic testing on leukocytes. Moreover, for the infrequent EGFR R776H mutation, third generation EGFR-TKIs may be a viable option.

UGEE-Net: Uncertainty-guided and edge-enhanced network for image splicing localization.

Image splicing, a prevalent method for image tampering, has significantly undermined image authenticity. Existing methods for Image Splicing Localization (ISL) struggle with challenges like limited accuracy and subpar performance when dealing with imperceptible tampering and multiple tampered regions. We introduce an Uncertainty-Guided and Edge-Enhanced Network (UGEE-Net) for ISL to tackle these issues. UGEE-Net consists of two core tasks: uncertainty guidance and edge enhancement. We employ Bayesian learning to model uncertainty maps of tampered regions, directing the model's focus to challenging pixels. Simultaneously, we employ a frequency domain-auxiliary edge enhancement strategy to imbue localization features with global contour information and fine-grained local details. These mechanisms work in parallel, synergistically boosting performance. Additionally, we introduce a cross-level fusion and propagation mechanism that effectively utilizes contextual information for cross-layer feature integration and leverages channel-level correlations for cross-layer feature propagation, gradually enhancing the localization feature's details. Experiment results affirm UGEE-Net's superiority in terms of detection accuracy, robustness, and generalization capabilities. Furthermore, to meet the growing demand for high-quality datasets in image forensics, we present the HTSI12K dataset, which includes 12,000 spliced images with imperceptible tampering traces and diverse categories, rendering it suitable for real-world auxiliary model training.

Accelerated Fibrosis Progression of Diabetic Nephropathy From High Uric Acid's Activation of the ROS/NLRP3/SHP2 Pathway in Renal Tubular Epithelial Cells Under High Glucose Conditions.

Context: Elevated uric-acid levels in the blood are closely associated with hypertension, metabolic syndrome, diabetic nephropathy, cardiovascular diseases, and chronic kidney disease (CKD). A high-glucose diet promotes the accumulation of uric acid. Fibrosis commonly occurs in patients with late-stage type 1 or 2 diabetes and can lead to organ dysfunction. Objective: The study intended to investigate whether high uric acid under high glucose conditions can promote the fibrotic progression of diabetic nephropathy by activating the reactive oxygen species (ROS)/ "nod-like receptor (NLR) family pyrin domain containing 3" (NLRP3)/ "Src homology 2 (SH2) domain-containing protein tyrosine phosphatase-2" (SHP2) pathway, which can promote epithelial-mesenchymal transition (EMT) in renal tubular epithelial cells. Design: The research team conducted an animal study. Setting: The study took place at the Affiliated Hospital of Hebei University in Baoding, Hebei Province, China. Animals: The animals were 14 healthy, male, C57BL/6J mice. Outcome Measures: The research team: (1) using Masson's trichrome staining, examined the fibrosis of renal, tubular epithelial cells in the streptozotocin (STZ) modeling and the STZ modeling + uric-acid groups; (2) used Western Blot analysis to detect the protein expression of NLRP3, "nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase 2" (NOX2), NOX4, alpha-smooth muscle actin (α-SMA), fibronectin 1 (FN-1), collagen-I, and mothers against decapentaplegic homolog 2/3 (SMAD2/3); (3) conducted in-vitro experiments by dividing transformed C3H mouse kidney-1 (TCMK-1) cells into different groups: STZ modeling group, STZ modeling + high-glucose group, STZ modeling + high-glucose + advanced glycation end (AGE) product group, STZ modeling+ high-glucose + AGE + uric-acid group, STZ modeling+ high glucose + SHP2 small interfering RNA (SiRNA) group, STZ modeling + high glucose + SHP2 SiRNA + AGE group, and STZ modeling+ high-glucose + SHP2 SiRNA + AGE + uric-acid group for Western Blot experiments; and (4) performed immunofluorescence, CCK-8, and transwell experiments on the seven groups of TCMK-1 cells with different treatments. Results: The STZ modeling + uric acid group's levels of fibrosis was significantly higher than that of the STZ modeling group (P < .01). Additionally, the STZ modeling + uric acid groups' expression of α-SMA, FN-1, collagen-I, P-SMAD2, P-SMAD3, NLRP3, and reactive oxygen species (ROS), EMT, and SMAD-related proteins were significantly higher than those of the STZ modeling group (P < .01). The protein expression of SHP2, P-SMAD2, α-SMA, and FN-1 for the STZ modeling + high glucose + SHP2 SiRNA, the STZ modeling + high glucose + SHP2 SiRNA + AGE, and the STZ modeling + high glucose + SHP2 SiRNA + AGE + uric acid groups were significantly lower than those of the STZ modeling + high glucose, STZ modeling + high glucose + AGE, and the STZ modeling + high glucose + AGE + uric acid groups, respectively. Immunofluorescence indicated that the STZ modeling+ high glucose + AGE + uric acid group had the highest relative fluorescence intensity, while the three groups treated with SHP2 SiRNA showed the least expression. The cell counting kit-8 (CCK-8) assay showed that STZ modeling group had less cell proliferation, STZ modeling + high sugar group had less cell proliferation than STZ modeling + high sugar +AGE group, STZ modeling + high sugar +AGE+ uric acid group had the highest cell proliferation, STZ modeling + high sugar +SHP2 SiRNA group and STZ modeling + high sugar +SHP2 SiRNA+AGE group and STZ modeling + high sugar +SHP2 SiRNA+AGE+ uric acid group showed the least number of cell proliferation. The results of the transwell cell migration assay were consistent with the CCK-8 assay. Conclusions: In a high-glucose environment, high uric acid can promote the fibrotic progression of diabetic nephropathy by activating the ROS/NLRP3/SHP2 pathway, leading to mesenchymal transition between renal tubular epithelial cells.

Clinical characteristics of patients with autoimmune nodopathy with anti-neurofascin155 antibodies.

Background: According to the latest guidelines on chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), patients with CIDP with anti-neurofascin 155 (NF155) antibodies are referred to as autoimmune nodopathy (AN), an autoimmune disorder distinct from CIDP. We aimed to compare the clinical data of patients with AN with anti-NF155 antibodies with those of anti-NF155 antibodies-negative patients with CIDP, and to summarize the clinical characteristics of patients with AN with anti-NF155 antibodies. Methods: Nine patients with AN with anti-NF155 antibodies and 28 serologically negative patients with CIDP were included in this study. Diagnosis was made according to the diagnostic criteria in the European Academy of Neurology (EAN)/Peripheral Nerve Society (PNS) guidelines on CIDP published in 2021. Demographics, clinical manifestations, electrophysiological examination, cerebrospinal fluid (CSF) tests, and response to treatment were retrospectively analyzed. Results: Compared with serologically negative patients with CIDP, those patients with AN with anti-NF155 antibodies were younger (p=0.007), had a younger onset age (p=0.009), more frequent ataxia (p=0.019), higher CSF protein levels (p=0.001), and more frequent axon damage in electrophysiology (p=0.025). The main characteristics of patients with AN with anti-NF155 antibodies include younger age and onset age, limb weakness, sensory disturbance, ataxia, multiple motor-sensory peripheral neuropathies with demyelination and axonal damage on electrophysiological examination, markedly elevated CSF protein levels, and varying degrees of response to immunotherapy. Conclusions: Patients with AN with anti-NF155 antibodies differed from serologically negative patients with CIDP in terms of clinical characteristics. When AN is suspected, testing for antibodies associated with the nodes of Ranvier is essential for early diagnosis and to guide treatment.

Optimizing Large-Scale Educational Assessment with a "Divide-and-Conquer" Strategy: Fast and Efficient Distributed Bayesian Inference in IRT Models.

With the growing attention on large-scale educational testing and assessment, the ability to process substantial volumes of response data becomes crucial. Current estimation methods within item response theory (IRT), despite their high precision, often pose considerable computational burdens with large-scale data, leading to reduced computational speed. This study introduces a novel "divide- and-conquer" parallel algorithm built on the Wasserstein posterior approximation concept, aiming to enhance computational speed while maintaining accurate parameter estimation. This algorithm enables drawing parameters from segmented data subsets in parallel, followed by an amalgamation of these parameters via Wasserstein posterior approximation. Theoretical support for the algorithm is established through asymptotic optimality under certain regularity assumptions. Practical validation is demonstrated using real-world data from the Programme for International Student Assessment. Ultimately, this research proposes a transformative approach to managing educational big data, offering a scalable, efficient, and precise alternative that promises to redefine traditional practices in educational assessments.

Unlocking the distinctive enzymatic functions of the early plant biomass deconstructive genes in a brown rot fungus by cell-free protein expression.

Saprotrophic fungi that cause brown rot of woody biomass evolved a distinctive mechanism that relies on reactive oxygen species (ROS) to kick-start lignocellulosic polymers' deconstruction. These ROS agents are generated at incipient decay stages through a series of redox relays that shuttle electrons from fungus's central metabolism to extracellular Fenton chemistry. A list of genes has been suggested encoding the enzyme catalysts of the redox processes involved in ROS's function. However, navigating the functions of the encoded enzymes has been challenging due to the lack of a rapid method for protein synthesis. Here, we employed cell-free expression system to synthesize four redox or degradative enzymes, which were identified, by transcriptomic data, as conserved players of the ROS oxidation phase across brown rot fungal species. All four enzymes were successfully expressed and showed activities that enable confident assignment of function, namely, benzoquinone reductase (BQR), ferric reductase, α-L-arabinofuranosidase (ABF), and heme-thiolate peroxidase (HTP). Detailed analysis of their catalytic features within the context of brown rot environments allowed us to interpret their roles during ROS-driven wood decomposition. Specifically, we validated the functions of BQR as the driver redox enzyme of Fenton cycles and reconstructed its interactions with the co-occurring HTP or laccase and ABF. Taken together, this research demonstrated that the cell-free expression platform is adequate for synthesizing functional fungal enzymes and provided an alternative route for the rapid characterization of fungal proteins, escalating our understanding of the distinctive biocatalyst system for plant biomass conversion.IMPORTANCEBrown rot fungi are efficient wood decomposers in nature, and their unique degradative systems harbor untapped catalysts pursued by the biorefinery and bioremediation industries. While the use of "omics" platforms has recently uncovered the key "oxidative-hydrolytic" mechanisms that allow these fungi to attack lignocellulose, individual protein characterization is lagging behind due to the lack of a robust method for rapid synthesis of crucial fungal enzymes. This work delves into the studies of biochemical functions of brown rot enzymes using a rapid, cell-free expression platform, which allowed the successful depictions of enzymes' catalytic features, their interactions with Fenton chemistry, and their roles played during the incipient stage of brown rot when fungus sets off the reactive oxygen species for oxidative degradation. We expect this research could illuminate cell-free protein expression system's use to fulfill the increasing need for functional studies of fungal enzymes, advancing the discoveries of novel biomass-converting catalysts.

Exceptional Long-Term Survival of a Patient With Hepatoid Adenocarcinoma of the Colon and the Treatment Strategy: A Case Report.

Hepatoid adenocarcinoma (HAC) of the colon is a rare type of tumor with hepatocellular differentiation. HAC often produces alpha-fetoprotein (AFP) and metastasizes to lymph nodes and the liver. HAC is usually aggressive with a poor prognosis and has a propensity for intravascular growth and frequent distant metastasis. Because the biology of HAC is not fully understood, there are very limited therapeutic options known to reduce recurrence and improve survival. In addition, because HAC is so rare, it is difficult to acquire data from large randomized clinical trials to guide practice; therefore, case reports can provide valuable information for the treatment of HAC. In this report, we present a case of a 30-year-old male patient with HAC with high AFP levels and liver metastases. The patient underwent hepatic arterial infusion chemotherapy (HAIC) with doxorubicin/oxaliplatin to treat the liver metastasis, and three weeks later, he received radical sigmoid and rectal resection, left liver resection, and ileostomy. Then, the patient received eight cycles of chemotherapy with epirubicin plus folinic acid, fluorouracil, and oxaliplatin (FOLFOX) every three weeks, followed by maintained therapy with capecitabine for 2.5 years without relapse. This case report indicates that, although HAC is usually an aggressive disease with frequent distant metastasis, patients with HAC may still have a good prognosis if treated with appropriate strategy.

NFKB2 mediates colorectal cancer cell immune escape and metastasis in a STAT2/PD­L1­dependent manner.

This study systematically analyzed the molecular mechanism and function of nuclear factor kappa B subunit 2 (NFKB2) in colorectal cancer (CRC) to investigate the potential of NFKB2 as a therapeutic target for CRC. Various experimental techniques, including RNA sequencing, proteome chip assays, and small molecule analysis, were used to obtain a deeper understanding of the regulation of NFKB2 in CRC. The results revealed that NFKB2 was upregulated in a significant proportion of patients with advanced hepatic metastasis of CRC. NFKB2 played an important role in promoting tumor growth through CD8+ T-cell exhaustion. Moreover, NFKB2 directly interacted with signal transducer and activator of transcription 2 (STAT2), leading to increased phosphorylation of STAT2 and the upregulation of programmed death ligand 1 (PD-L1). Applying a small molecule inhibitor of NFKB2 (Rg5) led to a reduction in PD-L1 expression and improved response to programmed death-1 blockade-based immunotherapy. In conclusion, the facilitated NFKB2-STAT2/PD-L1 axis may suppress immune surveillance in CRC and targeting NFKB2 may enhance the efficacy of immunotherapeutic strategies. Our results provide novel insights into the molecular mechanisms underlying the contribution of NFKB2 in CRC immune escape.

Notoginsenoside Ft1 inhibits colorectal cancer growth by increasing CD8+ T cell proportion in tumor-bearing mice through the USP9X signaling pathway.

The management of colorectal cancer (CRC) poses a significant challenge, necessitating the development of innovative and effective therapeutics. Our research has shown that notoginsenoside Ft1 (Ng-Ft1), a small molecule, markedly inhibits subcutaneous tumor formation in CRC and enhances the proportion of CD8+ T cells in tumor-bearing mice, thus restraining tumor growth. Investigation into the mechanism revealed that Ng-Ft1 selectively targets the deubiquitination enzyme USP9X, undermining its role in shielding ß-catenin. This leads to a reduction in the expression of downstream effectors in the Wnt signaling pathway. These findings indicate that Ng-Ft1 could be a promising small-molecule treatment for CRC, working by blocking tumor progression via the Wnt signaling pathway and augmenting CD8+ T cell prevalence within the tumor environment.

Guided wave resonance-based digital holographic microscopy for high-sensitivity monitoring of the refractive index.

Surface plasmon resonance holographic microscopy (SPRHM) has been employed to measure the refractive index but whose performance is generally limited by the metallic intrinsic loss. Herein we first, to our knowledge, utilize guided wave resonance (GWR) with low loss to realize the monitoring of the refractive index by integrating with digital holographic microscopy (DHM). By depositing a dielectric layer on a silver film, we observe a typical GWR in the dielectric layer with stronger field enhancement and higher sensitivity to the surrounding refractive index compared to the silver film-supported SPR, which agrees well with calculations. The innovative combination of the GWR and DHM contributes to the highly sensitive dynamic monitoring of the surrounding refractive index variation. Through the measurement with DHM, we found that the GWR presents an excellent sensitivity, which is 2.6 times higher than that of the SPR on the silver film. The results will pave a new pathway for digital holographic interferometry and its applications in environmental and biological detections.

Essential tremor is associated with reduced serum ceruloplasmin levels.

BACKGROUND: Essential tremor (ET), a prevalent movement disorder, has an elusive pathogenesis. A reduction in ceruloplasmin (Cp) levels can be found in some patients with ET. In addition, some studies have suggested an association between ET and neurodegeneration. As a ferroxidase, Cp is critical for iron metabolism, protecting against oxidative stress and neurodegeneration. Iron metabolism dysregulation, linked to ferroptosis, has implications in neurodegenerative diseases. Yet, research on Cp and ET remains limited. OBJECTIVES: This study aims to elucidate the relationship between ET and serum Cp levels. METHODS: We collected demographic and clinical data from 62 patients with ET satisfying the diagnostic criteria and compared these to data from 100 healthy controls. RESULTS: The median Cp levels in ET patients were 21.5 (18.8, 23.9) mg/dL, significantly lower than those in controls (23.1 [(20.7, 25.7) mg/dL; P = 0.006]). A reduction in Cp levels emerged as a risk factor for ET incidence (odds ratio (OR) = 0.873, 95% confidence interval (CI), 0.795, 0.959; P = 0.005). The area under the receiver operating characteristic (ROC) curve for serum Cp levels to predict the onset of ET was 0.629 (95% CI, 0.537-0.720; P = 0.006), and the optimal cut-off value for Cp levels was 19.5 mg/dL with a sensitivity of 91% and a specificity of 33.9%. CONCLUSION: Our analysis suggests that reduced Cp levels are associated with ET. We speculate that reduced Cp levels may be involved in the pathogenesis of ET, which requires further studies.

Loss of functional cryptochrome 1 reduces robustness of 24-hour behavioral rhythms in monarch butterflies.

Light is one of the strongest cues for entrainment of circadian clocks. While some insect species rely only on visual input, others like Drosophila melanogaster use both the visual system and the deep-brain blue-light photoreceptor cryptochrome for entraining circadian rhythms. Here, we used the monarch butterfly Danaus plexippus (dp), which possesses a light-sensitive cryptochrome 1 (dpCry1), to test the conservation of mechanisms of clock entrainment. We showed that loss of functional dpCry1 reduced the amplitude and altered the phase of adult eclosion rhythms, and disrupted brain molecular circadian rhythms. Robust rhythms could be restored by entrainment to temperature cycles, indicating a likely functional core circadian clock in dpCry1 mutants. We also showed that rhythmic flight activity was less robust in dpCry1 mutants, and that visual impairment in dpNinaB1 mutants impacted flight suppression at night. Our data suggest that dpCRY1 is a major photoreceptor for light-entrainment of the monarch circadian clock.

Increased Siglec-9/Siglec-9L interactions on NK cells predict poor HCC prognosis and present a targetable checkpoint for immunotherapy.

BACKGROUND & AIMS: Natural killer (NK) cell-based anti-hepatocellular carcinoma (HCC) therapy is an increasingly attractive approach that warrants further study. Siglec-9 interacts with its ligand (Siglec-9L) and restrains NK cell functions, suggesting it is a potential therapeutic target. However, in situ Siglec-9/Siglec-9L interactions in HCC have not been reported, and a relevant interventional strategy is lacking. Herein, we aim to illustrate Siglec-9/Siglec-9L-mediated cell sociology and identify small-molecule inhibitors targeting Siglec-9 that could improve the efficacy of NK cell-based immunotherapy for HCC. METHODS: Multiplexed immunofluorescence staining was performed to analyze the expression pattern of Siglec-7, -9 and their ligands in HCC tissues. Then we conducted docking-based virtual screening combined with bio-layer interferometry assays to identify a potent small-molecule Siglec-9 inhibitor. The therapeutic potential was further evaluated in vitro and in hepatoma-bearing NCG mice. RESULTS: Siglec-9 expression, rather than Siglec-7, was markedly upregulated on tumor-infiltrating NK cells, which correlated significantly with reduced survival of patients with HCC. Moreover, the number of Siglec-9L+ cells neighboring Siglec-9+ NK cells was increased in HCC tissues and was also associated with tumor recurrence and reduced survival, further suggesting that Siglec-9/Siglec-9L interactions are a potential therapeutic target in HCC. In addition, we identified a small-molecule Siglec-9 inhibitor MTX-3937 which inhibited phosphorylation of Siglec-9 and downstream SHP1 and SHP2. Accordingly, MTX-3937 led to considerable improvement in NK cell function. Notably, MTX-3937 enhanced cytotoxicity of both human peripheral and tumor-infiltrating NK cells. Furthermore, transfer of MTX-3937-treated NK92 cells greatly suppressed the growth of hepatoma xenografts in NCG mice. CONCLUSIONS: Our study provides the rationale for HCC treatment by targeting Siglec-9 on NK cells and identifies a promising small-molecule inhibitor against Siglec-9 that enhances NK cell-mediated HCC surveillance. IMPACT AND IMPLICATIONS: Herein, we found that Siglec-9 expression is markedly upregulated on tumor-infiltrating natural killer (TINK) cells and correlates with reduced survival in patients with hepatocellular carcinoma (HCC). Moreover, the number of Siglec-9L+ cells neighboring Siglec-9+ NK cells was increased in HCC tissues and was also associated with tumor recurrence and reduced survival. More importantly, we identified a small-molecule inhibitor targeting Siglec-9 that augments NK cell functions, revealing a novel immunotherapy strategy for liver cancer that warrants further clinical investigation.

Rice false smut virulence protein subverts host chitin perception and signaling at lemma and palea for floral infection.

The flower-infecting fungus Ustilaginoidea virens causes rice false smut, which is a severe emerging disease threatening rice (Oryza sativa) production worldwide. False smut not only reduces yield, but more importantly produces toxins on grains, posing a great threat to food safety. U. virens invades spikelets via the gap between the 2 bracts (lemma and palea) enclosing the floret and specifically infects the stamen and pistil. Molecular mechanisms for the U. virens-rice interaction are largely unknown. Here, we demonstrate that rice flowers predominantly employ chitin-triggered immunity against U. virens in the lemma and palea, rather than in the stamen and pistil. We identify a crucial U. virens virulence factor, named UvGH18.1, which carries glycoside hydrolase activity. Mechanistically, UvGH18.1 functions by binding to and hydrolyzing immune elicitor chitin and interacting with the chitin receptor CHITIN ELICITOR BINDING PROTEIN (OsCEBiP) and co-receptor CHITIN ELICITOR RECEPTOR KINASE1 (OsCERK1) to impair their chitin-induced dimerization, suppressing host immunity exerted at the lemma and palea for gaining access to the stamen and pistil. Conversely, pretreatment on spikelets with chitin induces a defense response in the lemma and palea, promoting resistance against U. virens. Collectively, our data uncover a mechanism for a U. virens virulence factor and the critical location of the host-pathogen interaction in flowers and provide a potential strategy to control rice false smut disease.

Single-cell profiling of the microenvironment in human bone metastatic renal cell carcinoma.

Bone metastasis is of common occurrence in renal cell carcinoma with poor prognosis, but no optimal treatment approach has been established for bone metastatic renal cell carcinoma. To explore the potential therapeutic targets for bone metastatic renal cell carcinoma, we profile single cell transcriptomes of 6 primary renal cell carcinoma and 9 bone metastatic renal cell carcinoma. We also include scRNA-seq data of early-stage renal cell carcinoma, late-stage renal cell carcinoma, normal kidneys and healthy bone marrow samples in the study to better understand the bone metastasis niche. The molecular properties and dynamic changes of major cell lineages in bone metastatic environment of renal cell carcinoma are characterized. Bone metastatic renal cell carcinoma is associated with multifaceted immune deficiency together with cancer-associated fibroblasts, specifically appearance of macrophages exhibiting malignant and pro-angiogenic features. We also reveal the dominance of immune inhibitory T cells in the bone metastatic renal cell carcinoma which can be partially restored by the treatment. Trajectory analysis showes that myeloid-derived suppressor cells are progenitors of macrophages in the bone metastatic renal cell carcinoma while monocytes are their progenitors in primary tumors and healthy bone marrows. Additionally, the infiltration of immune inhibitory CD47+ T cells is observed in bone metastatic tumors, which may be a result of reduced phagocytosis by SIRPA-expressing macrophages in the bone microenvironment. Together, our results provide a systematic view of various cell types in bone metastatic renal cell carcinoma and suggest avenues for therapeutic solutions.

Recent advances of phenotypic screening strategies in the application of anti-influenza virus drug discovery.

Seasonal and pandemic influenza virus infections not only pose a serious threat to human health but also cause tremendous economic losses and social burdens. However, due to the inherent high variability of influenza virus RNA genomes, the existing anti-influenza virus drugs have been frequently faced with the clinical issue of emerging drug-resistant mutants. Therefore, there is an urgent need to develop efficient and broad-spectrum antiviral agents against wild-type and drug-resistant mutant strains. Phenotypic screening has been widely employed as a reliable strategy to evaluate antiviral efficacy of novel agents independent of their modes of action, either directly targeting viral proteins or regulating cellular factors involved in the virus life cycle. Here, from the point of view of medicinal chemistry, we review the research progress of phenotypic screening strategies by focusing direct acting antivirals against influenza virus. It could provide scientific insights into discovery of a distinctive class of therapeutic candidates that ensure high efficiency but low cytotoxicity, and address issues from circulation of drug-resistant influenza viruses in the future.

Identification of NADPH Oxidase Genes Crucial for Rice Multiple Disease Resistance and Yield Traits.

Reactive oxygen species (ROS) act as a group of signaling molecules in rice functioning in regulation of development and stress responses. Respiratory burst oxidase homologues (Rbohs) are key enzymes in generation of ROS. However, the role of the nine Rboh family members was not fully understood in rice multiple disease resistance and yield traits. In this study, we constructed mutants of each Rboh genes and detected their requirement in rice multiple disease resistance and yield traits. Our results revealed that mutations of five Rboh genes (RbohA, RbohB, RbohE, RbohH, and RbohI) lead to compromised rice blast disease resistance in a disease nursery and lab conditions; mutations of five Rbohs (RbohA, RbohB, RbohC, RbohE, and RbohH) result in suppressed rice sheath blight resistance in a disease nursery and lab conditions; mutations of six Rbohs (RbohA, RbohB, RbohC, RbohE, RbohH and RbohI) lead to decreased rice leaf blight resistance in a paddy yard and ROS production induced by PAMPs and pathogen. Moreover, all Rboh genes participate in the regulation of rice yield traits, for all rboh mutants display one or more compromised yield traits, such as panicle number, grain number per panicle, seed setting rate, and grain weight, resulting in reduced yield per plant except rbohb and rbohf. Our results identified the Rboh family members involved in the regulation of rice resistance against multiple pathogens that caused the most serious diseases worldwide and provide theoretical supporting for breeding application of these Rbohs to coordinate rice disease resistance and yield traits.

Calcium sensing receptor: A promising therapeutic target in pulmonary hypertension.

Pulmonary hypertension (PH) is characterized by elevation of pulmonary arterial pressure and pulmonary vascular resistance. The increased pulmonary arterial pressure and pulmonary vascular resistance due to sustained pulmonary vasoconstriction and pulmonary vascular remodeling can lead to right heart failure and eventual death. A rise in intracellular Ca2+ concentration ([Ca2+]i) and enhanced pulmonary arterial smooth muscle cells (PASMCs) proliferation contribute to pulmonary vasoconstriction and pulmonary vascular remodeling. Recent studies demonstrated that extracellular calcium sensing receptor (CaSR) as a G-protein coupled receptor participates in [Ca2+]i increase induced by hypoxia in the experimental animals of PH and in PH patients. Pharmacological blockade or gene knockout of CaSR significantly attenuates the development of PH. This review will aim to discuss and update the pathogenicity of CaSR attributed to onset and progression in PH.

A sequential Bayesian changepoint detection procedure for aberrant behaviours in computerized testing.

Changepoints are abrupt variations in a sequence of data in statistical inference. In educational and psychological assessments, it is essential to properly differentiate examinees' aberrant behaviours from solution behaviour to ensure test reliability and validity. In this paper, we propose a sequential Bayesian changepoint detection algorithm to monitor the locations of changepoints for response times in real time and, subsequently, further identify types of aberrant behaviours in conjunction with response patterns. Two simulation studies were conducted to investigate the efficiency and accuracy of the proposed detection procedure in terms of identifying one or multiple changepoints at different locations. In addition to manipulating the number and locations of changepoints, two types of aberrant behaviours were also considered: rapid guessing behaviour and cheating behaviour. Simulation results indicate that ability estimates could be improved after removing responses from aberrant behaviours identified by our approach. Two empirical examples were analysed to illustrate the application of the proposed sequential Bayesian changepoint detection procedure.

Prevalence of self-reported thyroid disease among adults with depression.

BACKGROUND: Thyroid disorders are a common comorbidity in patients with depression, yet there is limited information available about the clinical epidemiology of thyroid diseases in this specific population. This study aims to describe the prevalence of thyroid disease among US adults with depression from 2007 to 2018. METHODS: This cross-sectional study used nationally representative data collected through the National Health and Nutrition Examination Survey (NHANES) between January 1, 2007, to December 31, 2018. Age-standardized prevalence of thyroid disease among depressed patients was calculated within 4-year survey periods (2007-2010, 2011-2014, and 2015-2018), and adjusted to the 2000 U.S. standard population. RESULTS: In our weighed sample, 6.1% of depressed individuals and 4.3% of non-depressed individuals reported thyroid disease between 2007 and 2018 (P < 0.0001). The age-standardized prevalence of thyroid disease in patients with depression increased over time, from 5.4% (95%CI, 4.6%-6.2%) in 2007-2010 to 6.8% (95%CI, 5.8%-8.0%) in 2015-2018 (P for trend = 0.0270). Furthermore, thyroid disease prevalence was highest in non-Hispanic white individuals, increased with age, and tended to be higher in women. Mean depression scores in patients with thyroid disease (9.1; 95%CI, 8.7-9.5) did not significantly different from those without thyroid disease (9.1; 95%CI, 9.0-9.3) (P = 0.96). CONCLUSION: The age-standardized prevalence of thyroid disease among US adults with depression exhibited a consistent increase from 2007 to 2018, with the highest rate occurring in older, non-Hispanic white individuals, and women.