Hybrid minigene splicing assay verifies the pathogenicity of a novel splice site variant in the COL1A1 gene of a chinese patient with osteogenesis imperfecta type I

Abstract(#br)Background(#br)Osteogenesis imperfecta (OI) is a rare genetic bone disease associated with brittle bones and fractures. Among all known types, OI type I is the most common type and characterized by increased bone fragility, low bone mass, distinctly blue-gray sclera, and susceptibility to conductive hearing loss beginning in adolescence. Mutations in genes encoding type I collagen ( COL1A1 and COL1A2 ) contribute to the main pathogenic mechanism of OI.(#br)Methods(#br)Subtle mutation of the COL1A1 gene in the proband was detected by targeted next-generation sequencing (NGS) and confirmed by Sanger sequencing. We then assessed the effect of the mutation on the splicing of the COL1A1 gene by bioinformatics prediction and hybrid minigene splicing assay (HMSA).(#br)Results(#br)A novel splice site mutation c.1821+1 G > C was discovered in the proband by NGS and further confirmed by Sanger sequencing, which was also simultaneously identified from the proband’s mother and elder sister. Bioinformatics predicted that this mutation would result in a disappearance of the 5′ donor splice site in intron 26, thereby leading to abnormal splicing and generation of premature stop codon. The follow-up experimental data generated by HMSA was consistent with this prediction.(#br)Conclusion(#br)Our study identified a novel splice site mutation that caused OI type I in the proband by abnormal splicing and demonstrated that combined applications of NGS, bioinformatics and HMSA are comprehensive and effective methods for diagnosis and aberrant splicing study of OI

Human Metapneumovirus Glycoprotein G Inhibits Innate Immune Responses

Human metapneumovirus (hMPV) is a leading cause of acute respiratory tract infection in infants, as well as in the elderly and immunocompromised patients. No effective treatment or vaccine for hMPV is currently available. A recombinant hMPV lacking the G protein (rhMPV-ΔG) was recently developed as a potential vaccine candidate and shown to be attenuated in the respiratory tract of a rodent model of infection. The mechanism of its attenuation, as well as the role of G protein in modulation of hMPV-induced cellular responses in vitro, as well as in vivo, is currently unknown. In this study, we found that rhMPV-ΔG-infected airway epithelial cells produced higher levels of chemokines and type I interferon (IFN) compared to cells infected with rhMPV-WT. Infection of airway epithelial cells with rhMPV-ΔG enhanced activation of transcription factors belonging to the nuclear factor (NF)-κB and interferon regulatory factor (IRF) families, as revealed by increased nuclear translocation and/or phosphorylation of these transcription factors. Compared to rhMPV-WT, rhMPV-ΔG also increased IRF- and NF-κB-dependent gene transcription, which was reversely inhibited by G protein expression. Since RNA helicases have been shown to play a fundamental role in initiating viral-induced cellular signaling, we investigated whether retinoic induced gene (RIG)-I was the target of G protein inhibitory activity. We found that indeed G protein associated with RIG-I and inhibited RIG-I-dependent gene transcription, identifying an important mechanism by which hMPV affects innate immune responses. This is the first study investigating the role of hMPV G protein in cellular signaling and identifies G as an important virulence factor, as it inhibits the production of important immune and antiviral mediators by targeting RIG-I, a major intracellular viral RNA sensor

Attentive Part-Based Alignment Network for Vehicle Re-Identification

Vehicle Re-identification (Re-ID) has become a research hotspot along with the rapid development of video surveillance. Attention mechanisms are utilized in vehicle Re-ID networks but often miss the attention alignment across views. In this paper, we propose a novel Attentive Part-based Alignment Network (APANet) to learn robust, diverse, and discriminative features for vehicle Re-ID. To be specific, in order to enhance the discrimination of part features, two part-level alignment mechanisms are proposed in APANet, consisting of Part-level Orthogonality Loss (POL) and Part-level Attention Alignment Loss (PAAL). Furthermore, POL aims to maximize the diversity of part features via an orthogonal penalty among parts whilst PAAL learns view-invariant features by means of realizing attention alignment in a part-level fashion. Moreover, we propose a Multi-receptive-field Attention (MA) module to adopt an efficient and cost-effective pyramid structure. The pyramid structure is capable of employing more fine-grained and heterogeneous-scale spatial attention information through multi-receptive-field streams. In addition, the improved TriHard loss and Inter-group Feature Centroid Loss (IFCL) function are utilized to optimize both the inter-group and intra-group distance. Extensive experiments demonstrate the superiority of our model over multiple existing state-of-the-art approaches on two popular vehicle Re-ID benchmarks

Quality Of Life Among Patients With Alopecia Areata And The Impact On Family Members

Alopecia areata (AA) negatively impacts health-related quality of life (HRQoL) among adults. The effect of AA on HRQoL among children and family members of affected individuals has not been well described. This study aims to explore the impact of AA on adults and children and their families. A prospective questionnaire assessing HRQoL among AA patients and family members was distributed at a National Alopecia Areata Foundation conference and to their listserv. Outcome measures included Dermatology Life Quality Index (DLQI), Children’s DLQI (CDLQI), Family DLQI (FDLQI), and screens for depression. Overall, 292 adults and 91 children with AA and 229 family members were included. AA negatively impacted both affected adults and children (mean DLQI 7.7, CDLQI 6.3). 77.1% of adults and 78.1% of children reported impaired HRQoL. Increasing age in adults (p=0.0148) and a history of being seen by a mental health provider in children (p=0.00757) were associated with poor HRQoL. For parents of children with AA, spending \u3e$5000 on treatments was associated with poor HRQoL (p=0.00128). Limitations include missing data and lack of a control group. In conclusion, children and adults with AA experience poor HRQoL. The negative effects of AA reach beyond those with AA, and family members also experience poor HRQoL

Attentive Part-Based Alignment Network for Vehicle Re-Identification

Vehicle Re-identification (Re-ID) has become a research hotspot along with the rapid development of video surveillance. Attention mechanisms are utilized in vehicle Re-ID networks but often miss the attention alignment across views. In this paper, we propose a novel Attentive Part-based Alignment Network (APANet) to learn robust, diverse, and discriminative features for vehicle Re-ID. To be specific, in order to enhance the discrimination of part features, two part-level alignment mechanisms are proposed in APANet, consisting of Part-level Orthogonality Loss (POL) and Part-level Attention Alignment Loss (PAAL). Furthermore, POL aims to maximize the diversity of part features via an orthogonal penalty among parts whilst PAAL learns view-invariant features by means of realizing attention alignment in a part-level fashion. Moreover, we propose a Multi-receptive-field Attention (MA) module to adopt an efficient and cost-effective pyramid structure. The pyramid structure is capable of employing more fine-grained and heterogeneous-scale spatial attention information through multi-receptive-field streams. In addition, the improved TriHard loss and Inter-group Feature Centroid Loss (IFCL) function are utilized to optimize both the inter-group and intra-group distance. Extensive experiments demonstrate the superiority of our model over multiple existing state-of-the-art approaches on two popular vehicle Re-ID benchmarks

Structural Characteristics of Endorheic Rivers in the Tarim Basin

Endorheic rivers as landlocked systems with no hydrological connections to marine environments are suffering from water and ecosystem crisis worldwide, yet little is known about their structural characteristics with complex geomorphic and climatic dependence. Based on the river networks identified from 30 m resolution digital elevation models and surface water dynamic information derived from Landsat images, we investigate the hierarchical characteristics of 60 sub-basins in the Tarim Basin, the largest endorheic river basin in China. In the Tarim River basin, endorheic rivers exhibit a self-similarity only in the range of stream-orders 1–4, compared to the range of stream-orders 1–5 observed in exorheic rivers, owning to the limited stream power to maintain the similar aggregation of rivers in the arid regions. Moreover, the Tarim River networks demonstrate lower bifurcation ratio (2.48), length ratio (2.03), fractal dimension (1.38), and drainage density (0.24 km−1) in representative sub-basins, with a significant decay in median values compared with those derived from exohreic rivers at similar scales, suggesting sparser and imperfect developed branching river networks in endorheic basins. Further analysis on the Tarim reveals that endorheic river structure is more related to glacier extent (r = 0.67~0.84), potential evapotranspiration (r = 0.63~0.81), and groundwater type index (r = 0.64~0.73), which is essentially different from the structure of exorheic river represented by the Yellow River largely controlled by surface runoff, precipitation, and vegetation coverage. This study stresses the differences in intrinsic structural characteristics and extrinsic drivers of endorheic and exorheic rivers and highlights the necessity of differentiated strategies for endorheic river management in fragile ecosystems

Structural Characteristics of Endorheic Rivers in the Tarim Basin

Endorheic rivers as landlocked systems with no hydrological connections to marine environments are suffering from water and ecosystem crisis worldwide, yet little is known about their structural characteristics with complex geomorphic and climatic dependence. Based on the river networks identified from 30 m resolution digital elevation models and surface water dynamic information derived from Landsat images, we investigate the hierarchical characteristics of 60 sub-basins in the Tarim Basin, the largest endorheic river basin in China. In the Tarim River basin, endorheic rivers exhibit a self-similarity only in the range of stream-orders 1–4, compared to the range of stream-orders 1–5 observed in exorheic rivers, owning to the limited stream power to maintain the similar aggregation of rivers in the arid regions. Moreover, the Tarim River networks demonstrate lower bifurcation ratio (2.48), length ratio (2.03), fractal dimension (1.38), and drainage density (0.24 km−1) in representative sub-basins, with a significant decay in median values compared with those derived from exohreic rivers at similar scales, suggesting sparser and imperfect developed branching river networks in endorheic basins. Further analysis on the Tarim reveals that endorheic river structure is more related to glacier extent (r = 0.67~0.84), potential evapotranspiration (r = 0.63~0.81), and groundwater type index (r = 0.64~0.73), which is essentially different from the structure of exorheic river represented by the Yellow River largely controlled by surface runoff, precipitation, and vegetation coverage. This study stresses the differences in intrinsic structural characteristics and extrinsic drivers of endorheic and exorheic rivers and highlights the necessity of differentiated strategies for endorheic river management in fragile ecosystems

Credit market development and corporate earnings management: Evidence from banking and branching deregulations

We investigate how external credit market development affects corporate earnings management, by studying the impact of the U.S. interstate banking and branching deregulations on the intensity of accruals-based and real earnings management. We find that the banking and branching deregulations significantly decrease both accruals-based and real earnings-management intensity among firms in deregulated states. The effect is stronger for those deregulated states that have lower bank branch density before deregulation and states that have greater out-of-state bank entry after deregulation. The impact on corporate earnings management is channelled through increased banking competition and credit supply providing firms with easier access to external financing. The findings are robust to various endogeneity concerns. We further document that interstate banking and branching deregulations reduce the instances of financial results being subsequently affected by accounting restatements and improve firms’ information environment.</p

Bank intervention and firms’ earnings management: evidence from debt covenant violations

Earnings management has long been one of the main concerns in accounting and management literature, and the extent to which corporate governance mechanisms can discipline management behaviour and prevent earnings management has attracted increasing interest among policy makers and academic researchers. Differing from previous corporate governance literature that focuses mainly on the board and auditors, we explore the role of creditors in corporate governance. In particular, we examine the effect of bank intervention on earnings management via the lens of debt covenant violations, where control rights are transferred to creditors (banks). Using a Difference-in-Difference approach, we find that firms reduce both their accruals-based and real earnings management following debt covenant violations. The negative effect on earnings management is more prominent when banks possess greater bargaining and monitoring power and when firms are more financially constrained. By identifying a specific channel through which debt providers influence corporate financial reporting, our findings suggest that creditors can play an important role in governing organisations and disciplining management behaviour.</p

Watch out for bailout: TARP and bank earnings management

We study the impact of the recent government bailout, called Trouble Asset Relief Program (TARP), on bank accounting quality. By adopting a difference-in-difference (DID) method, we find a significantly positive impact of TARP on earnings management of recipient banks, compared with their non-recipient peers. Further, we observe that TARP-recipient banks engage more in earnings-decreasing manipulation rather than earnings-increasing manipulation. This behavior is more obvious for those banks that voluntarily request for TARP funds. Also, participant banks change their accounting strategy to manipulate earnings upwards after TARP funds are paid back. Our findings confirm our hypothesis that TARP-recipient banks are motivated to manipulate downwards (or hide some earnings) to obtain further favorable treatment by the program administrators