The coronavirus disease 2019 (COVID-19) pandemic has led to accelerated efforts to develop therapeutics and vaccines. A key target of these efforts is the spike (S) protein, which is metastable and ...difficult to produce recombinantly. We characterized 100 structure-guided spike designs and identified 26 individual substitutions that increased protein yields and stability. Testing combinations of beneficial substitutions resulted in the identification of HexaPro, a variant with six beneficial proline substitutions exhibiting higher expression than its parental construct (by a factor of 10) as well as the ability to withstand heat stress, storage at room temperature, and three freeze-thaw cycles. A cryo-electron microscopy structure of HexaPro at a resolution of 3.2 angstroms confirmed that it retains the prefusion spike conformation. High-yield production of a stabilized prefusion spike protein will accelerate the development of vaccines and serological diagnostics for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
The human metapneumovirus (hMPV) fusion (F) protein is essential for viral entry and is a key target of neutralizing antibodies and vaccine development. The prefusion conformation is thought to be ...the optimal vaccine antigen, but previously described prefusion F proteins expressed poorly and were not well stabilized. Here, we use structures of hMPV F to guide the design of 42 variants containing stabilizing substitutions. Through combinatorial addition of disulfide bonds, cavity-filling substitutions, and improved electrostatic interactions, we describe a prefusion-stabilized F protein (DS-CavEs2) that expresses at 15 mg/L and has a melting temperature of 71.9 °C. Crystal structures of two prefusion-stabilized hMPV F variants reveal that antigenic surfaces are largely unperturbed. Importantly, immunization of mice with DS-CavEs2 elicits significantly higher neutralizing antibody titers against hMPV A1 and B1 viruses than postfusion F. The improved properties of DS-CavEs2 will advance the development of hMPV vaccines and the isolation of therapeutic antibodies.
Current COVID-19 vaccines and many clinical diagnostics are based on the structure and function of the SARS-CoV-2 spike ectodomain. Using hydrogen-deuterium exchange monitored by mass spectrometry, ...we have uncovered that, in addition to the prefusion structure determined by cryo-electron microscopy, this protein adopts an alternative conformation that interconverts slowly with the canonical prefusion structure. This new conformation-an open trimer-contains easily accessible receptor-binding domains. It exposes the conserved trimer interface buried in the prefusion conformation, thus exposing potential epitopes for pan-coronavirus antibody and ligand recognition. The population of this state and kinetics of interconversion are modulated by temperature, receptor binding, antibody binding, and sequence variants observed in the natural population. Knowledge of the structure and populations of this conformation will help improve existing diagnostics, therapeutics, and vaccines.
To investigate the risk of immune-mediated inflammatory diseases (IMIDs) in patients with ankylosing spondylitis (AS).
Using 2003-2012 claims data from the Taiwanese National Health Insurance ...Research Database, we identified 30,911 newly diagnosed AS patients requiring medical therapy from 2006 to 2012. In addition, we randomly selected 309,110 non-AS individuals matching (1:10) the AS patients with regard to age, sex and the year of the index date. After excluding subjects with the corresponding prior IMIDs, we calculated the incidence rates (IRs) of various IMIDs in the AS and non-AS cohorts and estimated the hazard ratios (HRs) with 95% confidence intervals after adjusting for age, sex, the Charlson comorbidity index, the frequency of ambulatory visits during the follow-up period and medications. We conducted sensitivity analyses by excluding those who developed IMIDs within 3 months after the index date.
In the follow-up period, we found that newly diagnosed AS patients had significantly increased risks of acute anterior uveitis, psoriasis, Sjögren's syndrome, thromboangiitis obliterans, Behcet's disease and sarcoidosis. However, the risk of Sjögren's syndrome did not increase in AS patients in the sensitivity analysis. In the same period, this study found no significant differences in the risks of Crohn's disease, ulcerative colitis, systemic lupus erythematosus, systemic sclerosis, dermatomyositis, polymyositis, pemphigus and vitiligo between newly diagnosed AS patients and non-AS individuals. AS patients had a significantly reduced risk of rheumatoid arthritis.
Newly diagnosed Taiwanese AS patients had increased risks of acute anterior uveitis, psoriasis, thromboangiitis obliterans, Behcet's disease and sarcoidosis, but a reduced risk of rheumatoid arthritis.
The purpose of this study was to construct a computerized adaptive test (CAT) for measuring self-care performance (the CAT-SC) in children with developmental disabilities (DD) aged from 6 months to ...12 years in a content-inclusive, precise, and efficient fashion.
The study was divided into 3 phases: (1) item bank development, (2) item testing, and (3) a simulation study to determine the stopping rules for the administration of the CAT-SC. A total of 215 caregivers of children with DD were interviewed with the 73-item CAT-SC item bank. An item response theory model was adopted for examining the construct validity to estimate item parameters after investigation of the unidimensionality, equality of slope parameters, item fitness, and differential item functioning (DIF). In the last phase, the reliability and concurrent validity of the CAT-SC were evaluated.
The final CAT-SC item bank contained 56 items. The stopping rules suggested were (a) reliability coefficient greater than 0.9 or (b) 14 items administered. The results of simulation also showed that 85% of the estimated self-care performance scores would reach a reliability higher than 0.9 with a mean test length of 8.5 items, and the mean reliability for the rest was 0.86. Administering the CAT-SC could reduce the number of items administered by 75% to 84%. In addition, self-care performances estimated by the CAT-SC and the full item bank were very similar to each other (Pearson r = 0.98).
The newly developed CAT-SC can efficiently measure self-care performance in children with DD whose performances are comparable to those of TD children aged from 6 months to 12 years as precisely as the whole item bank. The item bank of the CAT-SC has good reliability and a unidimensional self-care construct, and the CAT can estimate self-care performance with less than 25% of the items in the item bank. Therefore, the CAT-SC could be useful for measuring self-care performance in children with DD in clinical and research settings.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this article, we disclose a 3‐inch 250ppi active matrix field sequential color (FSC) display based on electrically suppressed ferroelectric liquid crystal (ESHFLC). ESHFLC's ultra‐fast response ...time (~10 μs at 6.67 V/μm) enables the display resolution to be tripled via FSC technique. The photo‐alignment technology provides ESHFLC with optimal anchoring energy that contributes to a high contrast ratio over 10 K:1 on single pixel level measurement. A specific 3T1C pixel circuit is designed to generate continuous gray scale from FLC binary switching by utilizing the pulse width modulation concept. The low temperature poly silicon thin‐film transistor array has been used to fabricate the FSC ESHFLC display panel. We achieved an 8‐bit gray level for each color subframe, that is, R, G, and B colors that results in 24‐bit color images. We believe, because of the good optical quality and cost‐effective fabrication, this display may replace in‐plane switching or fringe‐field switching in the near future for the portable device market. Moreover, high resolution FSC ESHFLCs can find applications in the emerging virtual reality displays.
An active matrix 3‐inch field sequential color electrically suppressed helix ferroelectric liquid crystal display prototype is demonstrated via low temperature poly silicon thin‐film transistor array. 3T1C pixel circuit is designed to generate analogy gray scale by utilizing pulse width modulation method. The electrically suppressed ferroelectric liquid crystal's microsecond fast switching enables the system with 8‐bit color level for each primary color.
Phase 3 studies suggest that induction chemotherapy (ICT) of cisplatin and 5-fluorouracil plus docetaxel (TPF) is effective but toxic for patients with squamous-cell carcinoma of the head and neck ...(SCCHN). Dose-dense chemotherapy may yield favorable outcomes compared with standard-dose chemotherapy, yet the optimal induction regimen remains undefined. We assessed the efficacy and tolerability of biweekly dose-dense TPF ICT in patients with SCCHN.
In this prospective phase II study, We enrolled patients with stage III/IV (AJCC 7th edition) unresectable squamous cell carcinoma of head and neck cancer. Patients received dose-dense TPF (ddTPF) with cisplatin and docetaxel 50 mg/m2 on day 1, leucovorin 250 mg/m2 on day1, followed by 48-h continuous infusion of 2500 mg/m2 of 5-fluorouracil on day 1 and 2, every 2 weeks for 6 cycles followed by radiotherapy. The primary endpoint was the response rate (RR) after ICT.
Fifty-eight patients were enrolled from June 2014 to September 2015. Overall RR after ICT was 89.6% complete response (CR), 31%; partial response (PR), 58.6%. Grade 3/4 neutropenia, mucositis, and diarrhea incidences were 25.9, 1.7, and 1.7%, respectively. 94.8% of patients completed all treatment courses of ICT without dose reduction. The 3-year overall survival (OS) was 54.3% (95%CI: 39.7 to 66.8%) and progression-free survival (PFS) was 34.3% (95%CI: 22.0 to 46.9%). Multivariate analysis showed that CR after ICT is an independent prognostic factor for OS and PFS.
Six cycles of ddTPF is an active, well-tolerated induction regimen for patients with SCCHN. The presence of CR after ICT predicted long-term survival.
ClinicalTrials.gov Identifier: NCT04397341 , May 21, 2020, retrospectively registered.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Peripheral innate immune response may induce sickness behavior through activating microglia, excessive cytokines production, and neuroinflammation. Dexmedetomidine (Dex) has anti-inflammatory effect. ...We investigated the effects of Dex on lipopolysaccharide (LPS)-induced neuroinflammation and sickness behavior in mice.
BALB/c mice were intraperitoneally (i.p.) injected with Dex (50 ug/kg) or vehicle. One hour later, the mice were injected (i.p.) with Escherichia coli LPS (0.33 mg/kg) or saline (n = 6 in each group). We analyzed the food and water intake, body weight loss, and sucrose preference of the mice for 24h. We also determined microglia activation and cytokines expression in the brains of the mice. In vitro, we determine cytokines expression in LPS-treated BV-2 microglial cells with or without Dex treatment.
In the Dex-pretreated mice, LPS-induced sickness behavior (anorexia, weight loss, and social withdrawal) were attenuated and microglial activation was lower than vehicle control. The mRNA expression of TNF-α, MCP-1, indoleamine 2, 3 dioxygenase (IDO), caspase-3, and iNOS were increased in the brain of LPS-challenged mice, which were reduced by Dex but not vehicle.
Dexmedetomidine diminished LPS-induced neuroinflammation in the mouse brain and modulated the cytokine-associated changes in sickness behavior.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Beck Depression Inventory II (BDI-II) and the Taiwan Geriatric Depression Scale (TGDS) are self-report scales used for assessing depression in patients with Parkinson's disease (PD) and geriatric ...people. The minimal detectable change (MDC) represents the least amount of change that indicates real difference (i.e., beyond random measurement error) for a single subject. Our aim was to investigate the test-retest reliability and MDC of the BDI-II and the TGDS in people with PD.
Seventy patients were recruited from special clinics for movement disorders at a medical center. The patients' mean age was 67.7 years, and 63.0% of the patients were male. All patients were assessed with the BDI-II and the TGDS twice, 2 weeks apart. We used the intraclass correlation coefficient (ICC) to determine the reliability between test and retest. We calculated the MDC based on standard error of measurement. The MDC% was calculated (i.e., by dividing the MDC by the possible maximal score of the measure).
The test-retest reliabilities of the BDI-II/TGDS were high (ICC = 0.86/0.89). The MDCs (MDC%s) of the BDI-II and TGDS were 8.7 (13.8%) and 5.4 points (18.0%), respectively. Both measures had acceptable to nearly excellent random measurement errors.
The test-retest reliabilities of the BDI-II and the TGDS are high. The MDCs of both measures are acceptable to nearly excellent in people with PD. These findings imply that the BDI-II and the TGDS are suitable for use in a research context and in clinical settings to detect real change in a single subject.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The minimal detectable change (MDC) is the smallest amount of difference in individual scores that represents true change (beyond random measurement error). The MDCs of the Timed "Up & Go" Test (TUG) ...and the Dynamic Gait Index (DGI) in people with Parkinson disease (PD) are largely unknown, limiting the interpretability of the change scores of both measures.
The purpose of this study was to estimate the MDCs of the TUG and the DGI in people with PD.
This investigation was a prospective cohort study.
Seventy-two participants were recruited from special clinics for movement disorders at a university hospital. Their mean age was 67.5 years, and 61% were men. All participants completed the TUG and the DGI assessments twice, about 14 days apart. The MDC was calculated from the standard error of measurement. The percentage MDC (MDC%) was calculated as the MDC divided by the mean of all scores for the sample. Furthermore, the intraclass correlation coefficient was used to examine the reproducibility between testing sessions (test-retest reliability).
The respective MDC and MDC% of the TUG were 3.5 seconds and 29.8, and those of the DGI were 2.9 points and 13.3. The test-retest reliability values for the TUG and the DGI were high; the intraclass correlation coefficients were .80 and .84, respectively.
The study sample was a convenience sample, and the participants had mild to moderately severe PD.
The results showed that the TUG and the DGI have generally acceptable random measurement error and test-retest reliability. These findings should help clinicians and researchers determine whether a change in an individual patient with PD is a true change.
Celotno besedilo
Dostopno za:
DOBA, FSPLJ, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
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