Physiological and transcriptomic analysis provides new insights into osmoregulation mechanism of Ruditapes philippinarum under low and high salinity stress.

The Manila clam (Ruditapes philippinarum) is a commercially important marine bivalve, which inhabits the estuarine and mudflat areas. The osmoregulation is of great significance for molluscs adaptation to salinity fluctuations. In this study, we investigated the effects of low salinity (10 psu) and high salinity (40 psu) stress on survival and osmoregulation of the R. philippinarum. The results of physiological parameters showed that the ion (Na+, K+, Cl-) concentrations and Na+/K+-ATPase (NKA) activity of R. philippinarum decreased significantly under low salinity stress, but increased significantly under high salinity stress, indicating that there are differences in physiological adaptation of osmoregulation of R. philippinarum. In addition, we conducted the transcriptome analysis in the gills of R. philippinarum exposed to low (10 psu) and high (40 psu) salinity challenge for 48 h using RNA-seq technology. A total of 153 and 640 differentially expressed genes (DEGs) were identified in the low salinity (LS) group and high salinity (HS) group, respectively. The immune (IAP, TLR6, C1QL4, Ank3), ion transport (Slc34a2, SLC39A14), energy metabolism (PCK1, LDLRA, ACOX1) and DNA damage repair-related genes (Gadd45g, HSP70B2, GATA4) as well as FoxO, protein processing in endoplasmic reticulum and endocytosis pathways were involved in osmoregulation under low salinity stress of R. philippinarum. Conversely, the ion transport (SLC6A7, SLC6A9, SLC6A14, TRPM2), amino acid metabolism (GS, TauD, ABAT, ALDH4A1) and immune-related genes (MAP2K6, BIRC7A, CTSK, GVIN1), and amino acid metabolism pathways (beta-Alanine, Alanine, aspartate and glutamate, Glutathione) were involved in the process of osmoregulation under high salinity stress. The results obtained here revealed the difference of osmoregulation mechanism of R. philippinarum under low and high salinity stress through physiological and molecular levels. This study contributes to the assessment of salinity adaptation of bivalves in the context of climate change and provides useful information for marine resource conservation and aquaculture.

[Clinical value of high frequency ultrasound in the diagnosis of hip joint involvement in patients with ankylosing spondylitis].

OBJECTIVE: To analyze the correlation between hip joint musculoskeletal ultrasound score and ankylosing spondylitis (AS) disease activity, as well as to investigate the value of high frequency ultrasound in the assessment of hip joint involvement in AS. METHODS: The clinical data of 244 patients with AS who were treated in the rheumatology department of from March 2019 to March 2022 were retrospectively analyzed. Among them, there 174 males and 70 females, aged from 19 to 58 years old with an average of (34.22±9.49) years old;the disease duration of AS patients ranged from 8 months to 26 years, with an average of (13.68±4.04) years.The 244 patients were divided into disease group (83 cases) and control group (161 cases) based in the presence of hip joint involuement. According to the the disease activity, patients in the disease group were further categorezed into active phase (45 cases) and stable phase (38 cases). The ultrasound scores of patients in the active and stable phases of the disease group and the control group were compared. Relevant factors of hip joint involvement in AS patients were analyzed, and analyze the correlation between ultrasound score and Bath ankylosing spondylitis disease activity score index(BASDAI), Bath ankylosing spondylitis functional index(BASFI), visual analogue score of pain (VAS), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and the correlation between hip joint capsule score and tendon attachment end score and BASDAI, BASFI, VAS, CRP and ESR. RESULTS: The hip joint capsule score(3.06±1.12), femoral head score(1.45±0.43), tendon attachment end score(3.28±1.30) and total ultrasound score(6.65±2.31) of the disease group were higher than those of the control group(1.51±0.48)、(0.66±0.27)、(1.61±0.53)、(3.81±1.44)scores (P<0.05). Multifactor Logstic regression analysis showed that the course of disease, hip joint capsule score and total ultrasound score were independent risk factors for hip involvement in AS patients.The hip capsule score (3.65±1.22)and total ultrasound score(8.28±2.33) in the active phase of the disease group were higher than those in the stable phase (2.48±1.04)、( 6.82±1.96)scores(P<0.05). The hip joint capsule score and total ultrasonic score of AS patients were positively correlated with BASDAI, BASFI, VAS, CRP, and ESR (P<0.05, P<0.01).The score of tendon attachment end was positively correlated with CRP (P<0.05). The score of joint capsule effusion in AS patients was positively correlated with BASDAI, BASFI and VAS (P<0.05, P<0.01). The synovial blood flow score was positively correlated with BASDAI, VAS, CRP and ESR (P<0.05, P<0.01). The synovial thickening score was positively correlated with BASDAI, BASFI, VAS, CRP and ESR (P<0.05, P<0.01). There was no correlation between the score of tendon attachment end and BASDAI, BASFI, VAS, CRP and ESR. CONCLUSION: There is a correlation between hip joint ultrasonic score of hip joint and clinical indexes in AS patients.Hip joint capsule score and total ultrasonic score were independent risk factors for hip involvement in AS patients. High frequency ultrasound exhibits clinical value in the diagnosis of hip joint involvement in AS patients.

Assessment and solutions for vulnerability of urban rail transit network based on complex network theory: A case study of Chongqing.

As a typical complex network system, the operating environment of rail transit network (RTN) is complex and demanding. This study aims to accurate assess the weaknesses and vulnerability of RTN, which is crucial for ensuring its smooth operation. Taking Chongqing Rail Transit (CRT) as an example, this study developed a network topology model using the spatial L method and analyzed the network structure characteristics, along with the importance of key nodes under different indicators, based on complex network theory. Additionally, this study analyzed the geographical spatial distribution characteristics of nodes based on the topography and urban spatial structure of Chongqing. Then, this study classified the nodes in the RTN according to basic topological indicators, namely degree, betweenness centrality, network efficiency, and passenger flow volume (PFV). The results indicated six cluster of nodes, reflecting the variability in node vulnerability concerning overall influence (providing alternative paths, reducing path length), regional aggregation capacity, and transportation capacity. Finally, this study proposed targeted management strategies for different clusters of nodes and their respective geographical locations, providing necessary references for rational planning, safety protection, and sustainable construction of RTN.

Neuromuscular ultrasound in combination with nerve conduction studies helps identify inflammatory motor neuropathies from lower motor neuron syndromes.

BACKGROUND AND PURPOSE: Identifying patients with inflammatory motor neuropathies (IMNs) is warranted since effective treatments are available and the prognosis of these patients differs from that of amyotrophic lateral sclerosis patients. METHODS: Between January 2019 and May 2022, 102 consecutive treatment-naïve lower motor neuron syndrome (LMNS) patients were recruited; these patients were suspected of having multifocal motor neuropathy, pure motor chronic inflammatory demyelinating polyneuropathy or amyotrophic lateral sclerosis with initial lower motor neuron presentation. Neuromuscular ultrasound (US) and nerve conduction studies (NCSs) were conducted at baseline. Relevant diagnostic investigations were performed if clinically warranted. The proposed US evidence of IMN was as follows: (i) nerve enlargement at ≥1 of the predetermined sites or (ii) absence of high intensity fasciculations in predefined muscle groups. Final diagnoses were made by experienced physicians after a prolonged follow-up period (≥12 months). IMN patients were defined as LMNS patients who experienced convincing improvements in response to immunotherapies. IMN patients without electrodiagnostic demyelinating features were diagnosed with treatment-responsive LMNS (TR-LMNS). RESULTS: In total, 16 patients were classified as IMN, including nine chronic inflammatory demyelinating polyneuropathy/multifocal motor neuropathy patients and seven TR-LMNS patients. Six TR-LMNS patients were identified by neuromuscular US. The sensitivity and specificity of NCSs, nerve US and muscle US were 56.3% and 100%, 43.8% and 90.7% and 68.8% and 97.7%, respectively. When these three modalities were combined, the sensitivity and specificity were 93.8% and 88.4%, respectively. CONCLUSION: Neuromuscular US studies are supplementary modalities to NCSs, and the combined use of these techniques might improve the identification of IMNs in LMNS patients.

A trispecific antibody induces potent tumor-directed T-cell activation and antitumor activity by CD3/CD28 co-engagement.

Aim: A novel CD19xCD3xCD28 trispecific antibody with a tandem single-chain variable fragments (scFv) structure was developed for the treatment of B-cell malignancies. Methods: The trispecific antibody in inducing tumor-directed T-cell activation and cytotoxicity was evaluated in vitro and in vivo and compared with its bispecific counterpart BiTE-CD19xCD3 lacking a CD28-targeting domain. Results: The trispecific antibody with a co-stimulatory domain exhibited augmented T-cell activation and memory T-cell differentiation capability and it induced faster tumor cell lysis than the bispecific antibody. RNAseq analysis revealed that the trispecific antibody modulates CD3/TCR complex-derived signal and upregulates antiapoptotic factors to influence the survival of T cells. Conclusion: By CD3/CD28 co-engagement, the trispecific antibody demonstrated its advantages in T-cell immunity and potential use as a more powerful and long-lasting T-cell engager.

T-cell based immunotherapies are a type of treatment that stimulates the body's own immune system to fight cancer. They have grown in popularity in recent years and have had impressive results in cancer treatment. One type of T-cell immunotherapy is a T-cell engager antibody. This is a type of molecule that redirects the body's immune cells to recognise and kill cancer cells. In this study, we developed a new type of T-cell engager antibody to treat two types of blood and bone marrow cancer. The antibody works by joining immune cells and cancer cells close together, to help activate the immune cells for cancer killing. This new type of T-cell engager antibody worked better than previous versions. It helped the immune cells survive longer and kill cancer more effectively. This means the new antibody might be better at treating people who have these types of cancers, but more testing in humans needs to be done.

Quantification of the apical palatal bone index for maxillary incisor immediate implant assessment: A retrospective cross-sectional study.

BACKGROUND: Apical palatal bone is important in immediate implant evaluation. Current consensus gives qualitative suggestions regarding it, limiting its clinical decision-making value. OBJECTIVES: To quantify the apical palatal bone dimension in maxillary incisors and reveal its quantitative correlation with other implant-related hard tissue indices to give practical advice for pre-immediate implant evaluation and design. MATERIAL AND METHODS: A retrospective analysis of immediate implant-related hard tissue indices in maxillary incisors obtained by cone beam computed tomography (CBCT) was conducted. Palatal bone thickness at the apex level (Apical-P) on the sagittal section was selected as a parameter reflecting the apical palatal bone. Its quantitative correlation with other immediate implant-related hard tissue indices was revealed. Clinical advice of pre-immediate implant assessment was given based on the quantitative classification of Apical-P and its other correlated immediate implant-related hard tissue indices. RESULTS: Apical-P positively correlated with cervical palatal bone, whole cervical buccal-palatal bone, sagittal root angle, and basal bone width indices. while negatively correlated with apical buccal bone, cervical buccal bone, and basal bone length indices. Six quantitative categories of Apical-P are proposed. Cases with Apical-P below 4 mm had an insufficient apical bone thickness to accommodate the implant placement, while Apical-P beyond 12 mm should be cautious about the severe implant inclination. Cases with Apical-P of 4-12 mm can generally achieve satisfying immediate implant outcomes via regulating the implant inclination. CONCLUSIONS: Quantification of the apical palatal bone index for maxillary incisor immediate implant assessment can be achieved, providing a quantitative guide for immediate implant placement in the maxillary incisor zone.

Development and Validation of a Pyroptosis-Related Signature for Predicting Prognosis in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) has emerged as a primary health problem and threat to global mortality, especially in China. Since pyroptosis as a new field for HCC prognosis is not well studied, it is important to open a specific prognostic model. In this study, consensus clustering method for 42 pyroptosis-related genes to classify 374 HCC patients in the TCGA database. After cox regression analysis of the differentially expressed genes between the two clusters, LASSO-Cox analysis was then performed to construct a pyroptosis-related prognostic model with 11 genes including MMP1, KPNA2, LPCAT1, NEIL3, CDCA8, SLC2A1, PSRC1, CBX2, HAVCR1, G6PD, MEX3A. The ICGC dataset was served as the validation cohort. Patients in the high-risk group had significantly lower overall survival (OS) rates than those in the low-risk group (p < 0.05). COX regression analysis showed that our model could be used as an independent prognostic factor to predict prognosis of patients and was significantly correlated with clinicopathological characteristics. Nomogram showing the stability of the model predicting the 1, 3, 5 year survival probability of patients. In addition, based on the risk model, ssGSEA analysis revealed significant differences in the level of immune cell infiltration and activation of immune-related functional pathways between high and low-risk groups, and patients with the high-risk score may benefit more from treatment with immune checkpoint inhibitors. Furthermore, patients in the high-risk group were more tend to develop chemoresistance. Overall, we identified a novel pyroptosis-related risk signature for prognosis prediction in HCC patients and revealed the overall immune response intensity of the tumor microenvironment. All these findings make the pyroptosis signature shed light upon a latent therapeutic strategy aimed at the treatment and prevention of cancers.

Hyperglycemia induces miR-26-5p down-regulation to overexpress PFKFB3 and accelerate epithelial-mesenchymal transition in gastric cancer.

Gastric cancer (GC) is one of the most deadly malignancies with high morbidity worldwide. Cancer cells exhibited higher level of glucose catabolism than normal cells to meet the needs for rapid growth. Emerging evidences indicated that hyperglycemia has positive effects on the progression of tumor. As a vital regulator of glycolysis, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) was confirmed to have a higher expression level in tumor tissue and correlated with the prognosis of GC patients. However, the role of PFKFB3 in GC patients with hyperglycemia remains unclear. The data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were utilized to analyze the expression level of PFKFB3 and conducted survival analysis of GC patients. Western blot assay was used to detect gene expression at the protein level. Small interfering RNA (siRNA) transfection assay was conducted to down-regulate the expression of PFKFB3. Cell functional assays were carried out to reflect the ability of cell proliferation and migration. The results indicated that PFKFB3 was significantly upregulated and its overexpression was associated with poor prognosis of GC patients. Besides, hyperglycemia stimulated the higher expression of PFKFB3 along with the enhanced proliferation, migration and epithelial-mesenchymal transition (EMT) in GC cells. Knocking down of PFKFB3 effectively reversed the effects of high glucose concentration on GC malignant phenotype and the opposite results were gained when miR-26-5p was inhibited. Therefore, PFKFB3 down-regulated by miR-26-5p inhibited the malignant phenotype of GC with hyperglycemia.

Hypoxia-Related Gene-Based Signature Can Evaluate the Tumor Immune Microenvironment and Predict the Prognosis of Colon Adenocarcinoma Patients.

BACKGROUND: Colon adenocarcinoma (COAD) is a common gastrointestinal tumor and often occurs in the left colon with a poor prognosis. The progression of COAD is closely related to the tumor microenvironment, especially the hypoxia. Currently, few studies have reported the correlation between hypoxia-related genes and the prognosis of COAD patients. Furthermore, we constructed a prognostic model using four hypoxia-related genes to predict the prognosis of COAD patients. METHODS: The mRNA expression profiles and corresponding clinicopathological data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The string online analysis tool was used to construct a protein-protein interaction network (PPI) of hypoxia-related genes. Kaplan-Meier curve was used to analyze the relationship of hypoxia risk score and the overall survival of COAD patients, and the receiver operating characteristic (ROC) curve was used to assess the reliability. RESULTS: We screened out four hypoxia genes, including TKTL1 (transketolase like 1), SLC2A3 (solute carrier family 2 member 3), ALDOB (aldolase, fructose-bisphosphate B) and ENO3 (enolase 3), which were used to construct a hypoxia risk model to predict the overall survival of COAD patients. Besides, we also found that the hypoxia risk score was correlated with the immunosuppression of tumor microenvironment. CONCLUSION: The model we constructed with four survival-related hypoxia genes, including TKTL1, SLC2A3, ALDOB and ENO3, could be used to predict the overall survival of COAD patients with high stability.

Integrative analysis of prognostic value and immune infiltration of spindle and kinetochore-associated family members in breast cancer.

Spindle and kinetochore associated (SKA) complex subunit, which maintains the stability of mitotic metaphase, with emerging research implying its effect as a carcinogenic regulator in cancer. However, its potential role in BC has not been fully elucidated. ONCOMINE, UALCAN, GEPIA, Kaplan-Meier Plotter, cBioPortal and TIMER databases were performed to analyze the expression, prognosis, mutation, immune infiltration and potential biological mechanisms of SKA1/2/3 in BC. Our results showed that SKA1/2/3 expression was upregulated in BC. Survival analysis reveals that SKA3 overexpression was associated with poor overall survival (OS), relapse-free survival (RFS), post-progression survival (PPS) and distant metastasis-free survival (DMFS). SKA1 overexpression was associated with poor OS, RFS and DMFS while SKA2 overexpression was only associated with RFS and DMFS. Notably, the results implied that SKA1 has a good prognostic value in HER2-positive BC. Besides, the genetic alterations of SKA were investigated and the altered group correlated with shorter progress-free survival (PFS) and disease-specific survival (DSS). GO and KEGG analysis showed that SKA1/2/3 were implicated in regulating cell cycle, p53 signaling pathway and DNA replication. The 10 Hub genes in the protein network were upregulated in BC and related to poorer prognosis. Additionally, SKA1/2/3 expression was negatively correlated with infiltration of various immune cells with antitumor effects, whereas positively correlated with the expression of immune checkpoints molecules. Further experiments revealed that SKA1/2/3 silencing markedly impeded the proliferation and migration of BC cells. Herein, our study firmly shows that SKA genes may serve as a promising therapeutic target for patients with BC.

The association of OPG polymorphisms with risk of osteoporotic fractures: A systematic review and meta-analysis.

BACKGROUND: Subjects with low bone mineral density and osteoporosis are more likely to suffer osteoporotic fractures during their lifetime. Polymorphisms in osteoprotegerin (OPG) gene are found to be associated with low bone mineral density and osteoporosis risk but their association with fracture risk is inconclusive. Here, we performed a meta-analysis to investigate the relationship between OPG polymorphisms with susceptibility to osteoporotic fractures. METHODS: Eligible studies investigating the association between common OPG polymorphisms (A164G, T245G, T950C, and G1181C) and risk of osteoporotic fracture were retrieved from PubMed, EMBASE, Web of Science, and the Cochrane Library. Odds ratio (OR) and the 95% confidence interval (CI) were calculated in the allelic, dominant, recessive, and homozygous model. Subgroup analyses of vertebral fractures, Caucasians, and postmenopausal women were also performed. RESULTS: A total of 14 studies comprising 5459 fracture cases and 9860 non-fracture controls were included. A163G was associated with fracture risk in dominant (OR = 1.29, 95%CI 1.11-1.50), recessive (OR = 1.64, 95%CI 1.10-2.44), and homozygous model (OR = 1.73, 95%CI 1.16-2.59). T245G was significantly correlated with susceptibility to fractures in all genetic models. Subjects with CC genotype of T950C had a reduced risk of fracture compared to those with CT or TT genotypes (OR = 0.81, 95%CI 0.70-0.94, P = .004). Subgroup analysis showed that A163G and T245G but not T950C and G1181C were associated with vertebral fracture risk. CONCLUSION: OPG A163G and T245G polymorphisms were risk factors of osteoporotic fractures while T950C had a protective role. These polymorphisms can be used as predictive markers of fractures.

A 4-gene-based hypoxia signature is associated with tumor immune microenvironment and predicts the prognosis of pancreatic cancer patients.

BACKGROUND: Pancreatic cancer (PAC) is one of the most devastating cancer types with an extremely poor prognosis, characterized by a hypoxic microenvironment and resistance to most therapeutic drugs. Hypoxia has been found to be one of the factors contributing to chemoresistance in PAC, but also a major driver of the formation of the tumor immunosuppressive microenvironment. However, the method to identify the degree of hypoxia in the tumor microenvironment (TME) is incompletely understood. METHODS: The mRNA expression profiles and corresponding clinicopathological information of PAC patients were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, respectively. To further explore the effect of hypoxia on the prognosis of patients with PAC as well as the tumor immune microenvironment, we established a hypoxia risk model and divided it into high- and low-risk groups in line with the hypoxia risk score. RESULTS: We established a hypoxia risk model according to four hypoxia-related genes, which could be used to demonstrate the immune microenvironment in PAC and predict prognosis. Moreover, the hypoxia risk score can act as an independent prognostic factor in PAC, and a higher hypoxia risk score was correlated with poorer prognosis in patients as well as the immunosuppressive microenvironment of the tumor. CONCLUSIONS: In summary, we established and validated a hypoxia risk model that can be considered as an independent prognostic indicator and reflected the immune microenvironment of PAC, suggesting the feasibility of hypoxia-targeted therapy for PAC patients.

Identification of shell-color-related microRNAs in the Manila clam Ruditapes philippinarum using high-throughput sequencing of small RNA transcriptomes.

Shell-color polymorphism is a common phenomenon in several mollusk species and has been associated with thermal capacity, developmental stability, shell strength, and immunity. Shell-color polymorphism has been related to the differential expression of genes in several signal transduction pathways; however, the functions of micro-RNAs (miRNAs) in shell-color formation remain unclear. In the present study, we compared high-quality, small-RNA transcriptomes in three strains of the Manila clam Ruditapes philippinarum with specific shell-color patterns, artificially selected for six generations. Totals of 114 known and 208 novel miRNAs were identified by high-throughput sequencing, of which nine known and one novel miRNA were verified by stem-loop quantitative real time-polymerase chain reaction. Predicted miRNA targets were subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. miR-137 and miR-216b and the Hedgehog signaling pathway and Wnt signaling pathway were identified as being potentially involved in pigment formation and regulation in R. philippinarum. These results may help to clarify the role of miRNAs in shell coloration and shed light on the mechanisms regulating color formation in bivalve shells.

Transcriptome analysis reveals the pigmentation related genes in four different shell color strains of the Manila clam Ruditapes philippinarum.

Ruditapes philippinarum is an important marine bivalve species. In this study, we conducted the RNA-seq of four different shell color strains of the R. philippinarum and investigated the analysis of the differential expression patterns of specific genes associated with pigmentation. The maximum different genes was 13 between WZ vs O, WZ vs W and WZ vs O have same numbers of different genes, was 5, Z vs W has 4 genes of 18 DEGs, W vs O just have two DEGs, while there is no DEGs between WZ vs Z. The synthesis of melanin plays important roles in the pigmentation of the shell and is closely related to the formation of the surface pattern. We speculate the possible involvement of porphyrin and chlorophyll metabolism combined with calcium signaling pathway in shell color determination. This study sheds light on the pigmentation and coloration mechanism of the Manila clam.

Clam Genome Sequence Clarifies the Molecular Basis of Its Benthic Adaptation and Extraordinary Shell Color Diversity.

Ruditapes philippinarum is an economically important bivalve with remarkable diversity in its shell coloration patterns. In this study, we sequenced the whole genome of the Manila clam and investigated the molecular basis of its adaptation to hypoxia, acidification, and parasite stress with transcriptome sequencing and an RNA sequence analysis of different tissues and developmental stages to clarify these major issues. A number of immune-related gene families are expanded in the R. philippinarum genome, such as TEP, C3, C1qDC, Hsp70, SABL, and lysozyme, which are potentially important for its stress resistance and adaptation to a coastal benthic life. The transcriptome analyses demonstrated the dynamic and orchestrated specific expression of numerous innate immune-related genes in response to experimental challenge with pathogens. These findings suggest that the expansion of immune- and stress-related genes may play vital roles in resistance to adverse environments and has a profound effect on the clam's adaptation to benthic life.

Ultrafast physical random bit generation from a chaotic oscillator with a silicon modulator.

We demonstrate physical random bit (PRB) generation from two chaotic optoelectronic oscillators (OEOs) with silicon Mach-Zehnder and microring resonator modulators. The carrier-injection modulation and the beam interference provide the nonlinearity for the OEO. We digitalize the chaotic waveforms from the two OEOs at 40 GS/s with 8-bit resolution and use self-delay bitwise exclusive-or operation as a post-processing method. The randomness of the resulting 320 Gbps PRB sequences is verified by the National Institute of Standards and Technology Special Publication 800-22 statistical tests. With the progress of silicon photonic circuits, there is a potential to fabricate a monolithic chaotic OEO chip for compact PRB generation.

Understanding the influence of individual variables contributing to multivariate outliers in assessments of data quality.

Mahalanobis distance is often recommended to identify patients or clinical sites that are considered unusual in clinical trials. Patients extreme in one or more covariates may be considered outliers in that they reside some distance from the multivariate mean, which can be thought of as the center of the data cloud. Less often discussed, patients whose data are believed to be "too good to be true" are located near the centroid as inliers. In order to efficiently investigate these anomalies for potential lapses in data quality, it is important to understand how the individual variables contribute to each multivariate outlier. There is a lack of literature describing a reasonable workflow for identification of outliers and their subsequent investigation to understand how each variable contributes to an observation being considered extreme. We describe how to identify multivariate inliers and outliers, classify outliers according to varying levels of severity, and summarize the contributions of variables using principal components in a manner that is accessible to a wide audience with straightforward interpretation. We illustrate how numerous data visualizations, including Pareto plots, can facilitate further review even in studies containing numerous observations and variables. We illustrate these methodologies using data from a multicenter clinical trial.

Publisher Correction: Construction of a High-Density Genetic Map and Quantitative Trait Locus Mapping in the Manila clam Ruditapes philippinarum.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

On-chip broadband silicon thermo-optic 2☓2 four-mode optical switch for optical space and local mode switching.

We present a silicon thermo-optic 2☓2 four-mode optical switch optimized for optical space switching plus local optical mode switching. Four asymmetric directional couplers are utilized for mode multiplexing and de-multiplexing. Sixteen 2☓2 single-mode optical switches based on balanced thermally tunable Mach-Zehnder interferometers are exploited for switching function. The measured insertion losses are 8.0~12.2 dB and the optical signal-to-noise ratios are larger than 11.2 dB in the wavelength range of 1525~1565 nm. The optical links in "all-bar" and "all-cross" states exhibit less than 2.0 dB and 1.4 dB power penalties respectively below 10-9 bit error rates for 40 Gbps data transmission.

Four-port mode-selective silicon optical router for on-chip optical interconnect.

We propose and demonstrate a four-port mode-selective optical router on a silicon-on-insulator platform. The passive routing property ensures that the router consumes no power to establish the optical links. For each port, input signals with different modes are selectively routed to the target ports through the pre-designed architecture. In general, the device intrinsically supports broadcasting of multiplexed signals from one port to the other three ports through mode division multiplexing. In some applications, the input signal from one port would only be sent to another port as in reconfigurable optical routers. The prototype is constructed by mode multiplexers/de-multiplexers and single-mode interconnect waveguides between them. The insertion losses for all optical links are lower than 8.0 dB, and the largest optical crosstalk values are lower than -18.7 dB and -22.0 dB for the broadcasting and port-to-port routing modes, respectively, at the wavelength range of 1525-1565 nm. In order to verify the routing functionality, a 40-Gbps bidirectional data transmission experiment is performed. The device offers a promising building block for passive routing by utilizing the dimension of the modes.