Spread of Mutant Middle East Respiratory Syndrome Coronavirus with Reduced Affinity to Human CD26 during the South Korean Outbreak

The newly emerging Middle East respiratory syndrome coronavirus (MERS-CoV) causes a severe respiratory infection with a high mortality rate (similar to 35%). MERS-CoV has been a global threat due to continuous outbreaks in the Arabian peninsula and international spread by infected travelers since 2012. From May to July 2015, a large outbreak initiated by an infected traveler from the Arabian peninsula swept South Korea and resulted in 186 confirmed cases with 38 deaths (case fatality rate, 20.4%). Here, we show the rapid emergence and spread of a mutant MERS-CoV with reduced affinity to the human CD26 receptor during the South Korean outbreak. We isolated 13 new viral genomes from 14 infected patients treated at a hospital and found that 12 of these genomes possess a point mutation in the receptor-binding domain (RBD) of viral spike (S) protein. Specifically, 11 of these genomes have an I529T mutation in RBD, and 1 has a D510G mutation. Strikingly, both mutations result in reduced affinity of RBD to human CD26 compared to wild-type RBD, as measured by surface plasmon resonance analysis and cellular binding assay. Additionally, pseudotyped virus bearing an I529T mutation in S protein showed reduced entry into host cells compared to virus with wild-type S protein. These unexpected findings suggest that MERS-CoV adaptation during human-to-human spread may be driven by host immunological pressure such as neutralizing antibodies, resulting in reduced affinity to host receptor, and thereby impairs viral fitness and virulence, rather than positive selection for a better affinity to CD26. IMPORTANCE Recently, a large outbreak initiated by an MERS-CoV-infected traveler from the Middle East swept South Korea and resulted in 186 confirmed cases with 38 deaths. This is the largest outbreak outside the Middle East, and it raised strong concerns about the possible emergence of MERS-CoV mutations. Here, we isolated 13 new viral genomes and found that 12 of them possess a point mutation in the receptor-binding domain of viral spike protein, resulting in reduced affinity to the human cognate receptor, CD26, compared to the wild-type virus. These unexpected findings suggest that MERS-CoV adaptation in humans may be driven by host immunological pressure.111819Ysciescopu

Physical constraints on a class of two-Higgs doublet models with FCNC at tree level

We analyse the constraints and some of the phenomenological implications of a class of two Higgs doublet models where there are flavour-changing neutral currents (FCNC) at tree level but the potentially dangerous FCNC couplings are suppressed by small entries of the CKM matrix V. This class of models have the remarkable feature that, as a result of a discrete symmetry of the Lagrangian, the FCNC couplings are entirely fixed in the quark sector by V and the ratio v(2)/v(1) of the vevs of the neutral Higgs. The discrete symmetry is extended to the leptonic sector, so that there are FCNC in the leptonic sector with their flavour structure fixed by the leptonic mixing matrix. We analyse a large number of processes, including decays mediated by charged Higgs at tree level, processes involving FCNC at tree level, as well as loop induced processes. We show that in this class of models one has new physical scalars beyond the standard Higgs boson, with masses reachable at the next round of experiments

Similar clinical characteristics of familial and sporadic inflammatory bowel disease in South Korea.

AIM: To investigate differences of clinical characteristics and disease courses between familial and sporadic inflammatory bowel disease (IBD) patients. METHODS: We obtained clinical data on Crohn's disease (CD) (n = 691) and ulcerative colitis (n = 1113) from a tertiary referral medical center between 2005 and 2012. Seventeen patients (2.5%) with CD and 27 patients (2.4%) with ulcerative colitis (UC) were identified as having a familial history of IBD, including the first and second degree relatives. For each control case, three times the number of age-, sex-, and diagnosis year-matched CD and UC patients, without a family history of IBD, were randomly selected in this case control study. RESULTS: There were no significant differences in age or main symptom at diagnosis, extraintestinal manifestation, location/extent, behavior of disease activity, number of hospitalizations, number of operations, operation type, number of relapses, or oral medical treatment between familial and sporadic CD and UC patients. Median (min-max) follow-up periods after diagnosis of familial CD and sporadic CD patients were 84 (24-312) and 36 (8-240) mo, respectively (P = 0.008). Familial CD patients more frequently used anti-tumor necrosis factor (TNF) antibodies compared to sporadic CD patients (17.6% vs 0%, P = 0.014). CONCLUSION: In conclusion, a family history of IBD does not seem to be an important predictive factor affecting clinical characteristics or disease course even if there is a more frequent use of anti-TNF antibodies in familial CD patients compared to sporadic CD patients

Toward highly efficient deep-blue OLEDs: tailoring the multiresonance-induced TADF molecules for suppressed excimer formation and near-unity horizontal dipole ratio

Boron-based compounds exhibiting a multiresonance thermally activated delayed fluorescence are regarded promising as a narrowband blue emitter desired for efficient displays with wide color gamut. However, their planar nature makes them prone to concentration-induced excimer formation that broadens the emission spectrum, making it hard to increase the emitter concentration without raising CIE y coordinate. To overcome this bottleneck, we here propose o-Tol-ν-DABNA-Me, wherein sterically hindered peripheral phenyl groups are introduced to reduce intermolecular interactions, leading to excimer formation and thus making the pure narrowband emission character far less sensitive to concentration. With this approach, we demonstrate deep-blue OLEDs with y of 0.12 and full width at half maximum of 18 nm, with maximum external quantum efficiency (EQE) of ca. 33%. Adopting a hyperfluorescent architecture, the OLED performance is further enhanced to EQE of 35.4%, with mitigated efficiency roll-off, illustrating the immense potential of the proposed method for energy-efficient deep-blue OLEDs

Type-1 Collagen differentially alters β-catenin accumulation in primary Dupuytren's Disease cord and adjacent palmar fascia cells

<p>Abstract</p> <p>Background</p> <p>Dupuytren's Disease (DD) is a debilitating contractile fibrosis of the palmar fascia characterised by excess collagen deposition, contractile myofibroblast development, increased Transforming Growth Factor-β levels and β-catenin accumulation. The aim of this study was to determine if a collagen-enriched environment, similar to <it>in vivo </it>conditions, altered β-catenin accumulation by primary DD cells in the presence or absence of Transforming Growth Factor-β.</p> <p>Methods</p> <p>Primary DD and patient matched, phenotypically normal palmar fascia (PF) cells were cultured in the presence or absence of type-1 collagen and Transforming Growth Factor-β1. β-catenin and α-smooth muscle actin levels were assessed by western immunoblotting and immunofluorescence microscopy.</p> <p>Results</p> <p>DD cells display a rapid depletion of cellular β-catenin not evident in patient-matched PF cells. This effect was not evident in either cell type when cultured in the absence of type-1 collagen. Exogenous addition of Transforming Growth Factor-β1 to DD cells in collagen culture negates the loss of β-catenin accumulation. Transforming Growth Factor-β1-induced α-smooth muscle actin, a marker of myofibroblast differentiation, is attenuated by the inclusion of type-1 collagen in cultures of DD and PF cells.</p> <p>Conclusion</p> <p>Our findings implicate type-1 collagen as a previously unrecognized regulator of β-catenin accumulation and a modifier of TGF-β1 signaling specifically in primary DD cells. These data have implications for current treatment modalities as well as the design of <it>in vitro </it>models for research into the molecular mechanisms of DD.</p

Diagnostic Yield and Clinical Impact of Video Capsule Endoscopy in Patients with Chronic Diarrhea: A Korean Multicenter CAPENTRY Study

Background/Aims: In some cases, chronic diarrhea is unexplained, and small bowel disorders may be one of the causes. The aim of this study was to assess the diagnostic yield and clinical impact of video capsule endoscopy (VCE) in patients with chronic diarrhea. Methods: We retrospectively analyzed records from October 2002 to August 2013 in the VCE nationwide database registry (n=2,964). Ninety-one patients from 15 medical centers (60 males and 31 females: mean age, 47+/-19 years) were evaluated for VCE as a result of chronic diarrhea. Results: The duration of chronic diarrhea was 8.3+/-14.7 months. The positive diagnostic yield of VCE was 42.9% (39/91). However, 15.4% (14/91) exhibited an inconsistent result, and 41.8% (38/91) were negative. Abnormal findings consistent with chronic diarrhea included erosions/aphthous ulcers (19.8%), ulcers (17.6%), mucosal erythema (3.3%), edema (1.1%), and luminal narrowing (1.1%). The most common diagnoses were functional diarrhea associated with irritable bowel syndrome in 37 patients (40.7%) and Crohn's disease in 18 patients (19.8%). After VCE examination, the diagnosis was changed in 34.1% of the patients (31/91). Hematochezia (odds ratio [OR], 8.802: 95% confidence interval [CI], 2.126 to 36.441) and hypoalbuminemia (OR, 4.811: 95% CI, 1.241 to 18.655) are predictive factors of a positive diagnostic yield. Conclusions: VCE had a favorable diagnostic yield and clinical impact on the management of patients with chronic diarrhea

Clinical Features and Long-term Prognosis of Crohn's Disease in Korea: Results from the Prospective CONNECT Study

BACKGROUND/AIMS: The prospective Crohn's Disease Clinical Network and Cohort Study is a nationwide multicenter cohort study of patients with Crohn's disease (CD) in Korea, aiming to prospectively investigate the clinical features and long-term prognosis associated with CD. METHODS: Patients diagnosed with CD between January 2009 and September 2019 were prospectively enrolled. They were divided into two cohorts according to the year of diagnosis: cohort 1 (diagnosed between 2009 and 2011) versus cohort 2 (between 2012 and 2019). RESULTS: A total of 1,175 patients were included, and the median follow-up duration was 68 months (interquartile range, 39.0 to 91.0 months). The treatment-free durations for thiopurines (p&lt;0.001) and anti-tumor necrosis factor agents (p=0.018) of cohort 2 were shorter than those of cohort 1. Among 887 patients with B1 behavior at diagnosis, 149 patients (16.8%) progressed to either B2 or B3 behavior during follow-up. Early use of thiopurine was associated with a reduced risk of behavioral progression (adjusted hazard ratio [aHR], 0.69; 95% confidence interval [CI], 0.50 to 0.90), and family history of inflammatory bowel disease was associated with an increased risk of behavioral progression (aHR, 2.29; 95% CI, 1.16 to 4.50). One hundred forty-one patients (12.0%) underwent intestinal resection, and the intestinal resection-free survival time was significantly longer in cohort 2 than in cohort 1 (p=0.003). The early use of thiopurines (aHR, 0.35; 95% CI, 0.23 to 0.51) was independently associated with a reduced risk of intestinal resection. CONCLUSIONS: The prognosis of CD in Korea appears to have improved over time, as evidenced by the decreasing intestinal resection rate. Early use of thiopurines was associated with an improved prognosis represented by a reduced risk of intestinal resection

European clinical guidelines for Tourette syndrome and other tic disorders. Part II: pharmacological treatment

To develop a European guideline on pharmacologic treatment of Tourette syndrome (TS) the available literature was thoroughly screened and extensively discussed by a working group of the European Society for the Study of Tourette syndrome (ESSTS). Although there are many more studies on pharmacotherapy of TS than on behavioral treatment options, only a limited number of studies meets rigorous quality criteria. Therefore, we have devised a two-stage approach. First, we present the highest level of evidence by reporting the findings of existing Cochrane reviews in this field. Subsequently, we provide the first comprehensive overview of all reports on pharmacological treatment options for TS through a MEDLINE, PubMed, and EMBASE search for all studies that document the effect of pharmacological treatment of TS and other tic disorders between 1970 and November 2010. We present a summary of the current consensus on pharmacological treatment options for TS in Europe to guide the clinician in daily practice. This summary is, however, rather a status quo of a clinically helpful but merely low evidence guideline, mainly driven by expert experience and opinion, since rigorous experimental studies are scarce

Exclusive J/ψ detection and physics with ECCE

The file available on this institutional repository is an arXiv preprint which may not have been certified by peer review. The definitive version of record published by Elsevier is available at https://doi.org/10.48550/arXiv.2207.10356.Copyright © The Authors 2023. The EIC Comprehensive Chromodynamics Experiment (ECCE) detector has been recommended as a reference design for the proposed Electron-Ion Collider (EIC) program. This paper presents simulation studies of exclusive J/ψ detection and selected physics impact results in EIC using the projected ECCE detector concept. Exclusive quarkonium photoproduction is one of the most popular processes in EIC, which has a large cross section and a simple final state. Due to the gluonic nature of the exchange Pomeron, this process can be related to the gluon distributions in the nucleus. Preliminary results estimate the excellent statistics benefited from the large cross section of J/ψ photoproduction and superior performance of ECCE detector concept. The precise measurement of exclusive J/ψ photoproduction at EIC will help us to more deeply understand nuclear gluon distributions, near threshold production mechanism and nucleon mass structure.X. Li and W. Zha are supported by the National Natural Science Foundation of China (12005220, 12175223) and MOST (2018YFE0104900). The authors would like to thank the ECCE Consortium for performing a full simulation of their detector design, for providing up-to-date information on EIC run conditions, and for suggestions and comments on the manuscript. X. Li and W. Zha would like to thank Y. Zhou for useful suggestions and discussions related to this analysis. W. Zha is supported by Anhui Provincial Natural Science Foundation No. 2208085J23 and Youth Innovation Promotion Association of Chinese Academy of Sciences. AANL group are supported by the Science Committee of RA , in the frames of the research project 21AG-1C028