The variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) harbor diverse spike (S) protein sequences, which can greatly influence the efficacies of therapeutics. Therefore, it ...would be of great value to develop neutralizing monoclonal antibodies (mAbs) that can broadly recognize multiple variants.
Using an mRNA-LNP immunization strategy, we generated several mAbs that specifically target the conserved S2 subunit of SARS-CoV-2 (B-S2-mAbs). These mAbs were assessed for their neutralizing activity with pseudotyped viruses and binding ability for SARS-CoV-2 variants.
Among these mAbs, five exhibited strong neutralizing ability toward the Gamma variant and also recognized viral S proteins from the Wuhan, Alpha, Beta, Gamma, Delta and Omicron (BA.1, BA.2 and BA.5) variants. Furthermore, we demonstrated the broad reactivities of these B-S2-mAbs in several different applications, including immunosorbent, immunofluorescence and immunoblotting assays. In particular, B-S2-mAb-2 exhibited potent neutralization of Gamma variant (IC
= 0.048 µg/ml) in a pseudovirus neutralization assay. The neutralizing epitope of B-S2-mAb-2 was identified by phage display as amino acid residues 1146-1152 (DSFKEEL) in the S2 subunit HR2 domain of SARS-CoV-2.
Since there are not many mAbs that can bind the S2 subunit of SARS-CoV-2 variants, our set of B-S2-mAbs may provide important materials for basic research and potential clinical applications. Importantly, our study results demonstrate that the viral S2 subunit can be targeted for the production of cross-reactive antibodies, which may be used for coronavirus detection and neutralization.
Objective: To develop and verify a CMOS bone-guided cochlear implant (BGCI) microsystem with electrodes placed on the bone surface of the cochlea and the outside of round window for treating ...high-frequency hearing loss. Methods: The BGCI microsystem consists of an external unit and an implanted unit. The external system-on-chip is designed to process acoustic signals through an acquisition circuit and an acoustic DSP processor to generate stimulation patterns and commands that are transmitted to the implanted unit through a 13.56 MHz wireless power and bidirectional data telemetry. In the wireless power telemetry, a voltage doubler/tripler (2X/3X) active rectifier is used to enhance the power conversion efficiency and generate 2 and 3 V output voltages. In the wireless data telemetry, phase-locked loop based binary phase-shift keying and load-shift keying modulators/demodulators are adopted for the downlink and uplink data through high-Q coils, respectively. The implanted chip with four-channel high-voltage-tolerant stimulator generates biphasic stimulation currents up to 800 μA. Results: Electrical tests on the fabricated BGCI microsystem have been performed to verify the chip functions. The in vivo animal tests in guinea pigs have shown the evoked third wave of electrically evoked auditory brainstem response waveforms. It is verified that auditory nerves can be successfully stimulated and acoustic hearing can be partially preserved. Conclusion and Significance: Different from traditional cochlear implants, the proposed BGCI microsystem is less invasive, preserves partially acoustic hearing, and provides an effective alternative for treating high-frequency hearing loss.
Parkinson's disease (PD) is the second most common degenerative disorder of the central nervous system that impairs motor skills and cognitive function. To date, the disease has no effective ...therapies. The identification of new drugs that provide benefit in arresting the decline seen in PD patients is the focus of much recent study. However, the lengthy time frame for the progression of neurodegeneration in PD increases both the time and cost of examining potential therapeutic compounds in mammalian models. An alternative is to first evaluate the efficacy of compounds in Caenorhabditis elegans models, which reduces examination time from months to days. n-Butylidenephthalide is the naturally-occurring component derived from the chloroform extract of Angelica sinensis. It has been shown to have anti-tumor and anti-inflammatory properties, but no reports have yet described the effects of n-butylidenephthalide on PD. The aim of this study was to assess the potential for n-butylidenephthalide to improve PD in C. elegans models.
In the current study, we employed a pharmacological strain that expresses green fluorescent protein specifically in dopaminergic neurons (BZ555) and a transgenic strain that expresses human α-synuclein in muscle cells (OW13) to investigate the antiparkinsonian activities of n-butylidenephthalide. Our results demonstrate that in PD animal models, n-butylidenephthalide significantly attenuates dopaminergic neuron degeneration induced by 6-hydroxydopamine; reduces α-synuclein accumulation; recovers lipid content, food-sensing behavior, and dopamine levels; and prolongs life-span of 6-hydroxydopamine treatment, thus revealing its potential as a possible antiparkinsonian drug. n-Butylidenephthalide may exert its effects by blocking egl-1 expression to inhibit apoptosis pathways and by raising rpn-6 expression to enhance the activity of proteasomes.
n-Butylidenephthalide may be one of the effective neuroprotective agents for PD.
In sweet potato (Ipomoea batatas cv Tainung 57), MAPK cascades are involved in the regulation of Ipomoelin (IPO) expression upon wounding. p38 MAPK plays an important role in plant's responses to ...various environmental stresses. However, the role of p38-like MAPK in wounding response is still unknown. In this study, the levels of phosphorylated-p38-like MAPK (pp38-like MAPK) in sweet potato were noticeably reduced after wounding. In addition, SB203580 (SB), a specific inhibitor blocking p38 MAPK phosphorylation, considerably decreased the accumulation of pp38-like MAPK. Expression of a wound-inducible gene IPO was elevated by SB. Moreover, it stimulated hydrogen peroxide (H
O
) production rather than cytosolic Ca
elevation in sweet potato leaves. However, NADPH oxidase (NOX) inhibitor diphenyleneiodonium could not inhibit IPO induction stimulated by SB. These results indicated a p38-like MAPK mechanism was involved in the regulation of IPO expression through NOX-independent H
O
generation. In addition, the presence of the protein phosphatase inhibitor okadaic acid or the MEK1/ERK inhibitor PD98059 repressed the H
O
- or SB-induced IPO expression, demonstrating phosphatase(s) and MEK1/ERK functioning in the downstream of H
O
and pp38-like MAPK in the signal transduction pathway stimulating IPO. Conclusively, wounding decreased the amount of pp38-like MAPK, stimulated H
O
production, and then induced IPO expression.
This study investigates the flying sidekick traveling salesman problem (FSTSP), in which a truck and an unmanned aerial vehicle work together to make deliveries. This study develops a revised ...mixed-integer linear programming (MILP) model for the FSTSP. The revised MILP model performs better than the existing model. Due to the FSTSP’s high complexity, we propose an effective heuristic based on simulated annealing (SA) to solve the problem. The novelty of the proposed SA heuristic lies in the new solution representation, which not only determines the visiting sequence of customers but also the service type of customers and rendezvous positions. Another feature of the proposed SA is a new operator specifically designed for the FSTSP. To evaluate the performance of the proposed SA heuristic, we conduct a comprehensive computational study where we fine-tune the parameters of the SA heuristic and compare the performance of the SA heuristic with several state-of-the-art algorithms including hybrid genetic algorithm (HGA) and iterated local search (ILS) in solving existing FSTSP benchmark instances. The results indicate that the proposed SA heuristic outperforms ILS and is statistically competitive with HGA. It obtains best-known solutions for all small FSTSP instances and 29 best-known solutions for the 60 large FSTSP instances, including 20 new best-known solutions.
To counteract heat stress in dairy cows, a more reliable and efficient method for monitoring the activity of dairy cows and ambient environmental conditions should be developed. This research ...presents a cost-effective embedded imaging system that is capable of monitoring the drinking behaviour of dairy cows, while ambient temperature and humidity are simultaneously and continuously recorded with the integrated sensor modules. The embedded imaging system was implemented and tested on an experimental dairy farm, with imaging modules installed above the drinking troughs to collect video streams. To estimate the drinking time and frequency of dairy cows, detections of the dairy cow's head over the drinking troughs was performed on video stream using a deep learning convolutional neural network (CNN) model. The F1 score and true positive rate of the cow head detection were 0.987 and 0.983, respectively. The drinking behaviour data and environmental conditions were recorded and analysed to further assess the effects of heat stress on the drinking behaviour of dairy cows. The experimental results show that the daily total length and frequency of drinking bouts of the dairy cows were highly related to the temperature and humidity index (THI). Data from long-term monitoring using the automated imaging system clearly demonstrated that drinking behaviour reflects the effects of heat stress on dairy cows. The proposed monitoring system offers a novel approach for automatic and quantitative assessment of the drinking behaviours of dairy cows.
A brain-computer interface (BCI) is a communication system that can help users interact with the outside environment by translating brain signals into machine commands. The use of ...electroencephalographic (EEG) signals has become the most common approach for a BCI because of their usability and strong reliability. Many EEG-based BCI devices have been developed with traditional wet- or micro-electro-mechanical-system (MEMS)-type EEG sensors. However, those traditional sensors have uncomfortable disadvantage and require conductive gel and skin preparation on the part of the user. Therefore, acquiring the EEG signals in a comfortable and convenient manner is an important factor that should be incorporated into a novel BCI device. In the present study, a wearable, wireless and portable EEG-based BCI device with dry foam-based EEG sensors was developed and was demonstrated using a gaming control application. The dry EEG sensors operated without conductive gel; however, they were able to provide good conductivity and were able to acquire EEG signals effectively by adapting to irregular skin surfaces and by maintaining proper skin-sensor impedance on the forehead site. We have also demonstrated a real-time cognitive stage detection application of gaming control using the proposed portable device. The results of the present study indicate that using this portable EEG-based BCI device to conveniently and effectively control the outside world provides an approach for researching rehabilitation engineering.
PurposeA good customer experience means meeting the customer expectation. Thus, unexpected customer experience is usually a good point to initiate improvement or innovation for product or service ...design. Attempting to enhance the customer experience in the customer journey, this study aims to demonstrate a customer journey centred service design approach to receive the design requirements based on customers' needs and to use a systematic approach to generate solutions.Design/methodology/approachA holistic service design method named 3E model was proposed. It integrates customer experience journey map (CXJM), the theory of inventive problem solving (TRIZ) and service assembly and service replacement mechanism into three design stages. In stage 1, CXJM is enhanced with emotional range analysis to identify the customer pain points as well as customers' requirements (CRs) in exhibition, tourism and hotel sectors for initializing service design. Stage 2 investigates the specific design requirements (DRs) of the smart exhibition system and the contradictions. Then, the innovative principles were analyzed. In Stage 3, expected exhibition service system was designed.FindingsThe new service system which named the smart expo system based on information and communication technology (ICT) is proposed. It consists of “Tourism Link assists”, “i-Kaohsiung hotel service center”, “Smart AEC” and “O2O e-tickets”.Originality/valueThe proposed 3E model builds a systematic and coherent design method for the smart exhibition service area. It provides the linkage and action-oriented guidance from customer pain points, service parameters, innovative principles to solutions.
Background
The link between elevated serum uric acid (SUA) levels and cardiovascular disease (CVD)–related mortality in the elderly population remains inconclusive. Nutritional status influences both ...SUA and CVD outcomes. Therefore, we investigated whether SUA‐predicted mortality and the effect‐modifying roles of malnourishment in older people.
Methods and Results
A longitudinal Taiwanese cohort including 127 771 adults 65 years and older participating in the Taipei City Elderly Health Examination Program from 2001 to 2010 were stratified by 1‐mg/dL increment of SUA. Low SUA (<4 mg/dL) strata was categorized by malnourishment status defined as Geriatric Nutritional Risk Index <98, serum albumin <38 g/L, or body mass index <22 kg/m2. Study outcomes were all‐cause and CVD‐related mortality. Cox models were used to estimate hazard ratios (HRs) of mortality, after adjusting for 20 demographic and comorbid covariates. Over a median follow‐up of 5.8 years, there were 16 439 all‐cause and 3877 CVD‐related deaths. Compared with the reference SUA strata of 4 to <5 mg/dL, all‐cause mortality was significantly higher at SUA <4 mg/dL (HR, 1.16; 95% confidence interval, 1.07–1.25) and ≥8 mg/dL (HR, 1.13; confidence interval, 1.06–1.21), with progressively elevated risks at both extremes. Similarly, increasingly higher CVD‐related mortality was found at the SUA level <4 mg/dL (HR, 1.19; confidence interval, 1.00–1.40) and ≥7 mg/dL (HR, 1.17; confidence interval, 1.04–1.32). Remarkably, among the low SUA (<4 mg/dL) strata, only malnourished participants had greater all‐cause and CVD‐related mortality. This modifying effect of malnourishment remained consistent across subgroups.
Conclusions
SUA ≥8 or <4 mg/dL independently predicts higher all‐cause and CVD‐related mortality in the elderly, particularly in those with malnourishment.
Dengue virus (DENV) infection is the most prevalent mosquito-borne viral disease. Stroke is a severe manifestation of dengue. However, few large-scale studies have investigated post-dengue risk of ...stroke.
This population-based cohort study included 57,934 newly diagnosed, laboratory-confirmed dengue patients in Taiwan from 2002 to 2015; patients were matched to nondengue individuals by age, sex, and area of residence at a ratio of 1:4 (n = 231,736). We used subdistribution hazard regression to evaluate short-term (≤ 30 days), medium-term (31–365 days), and long-term (1–3 years) risk of stroke after DENV infection. The robustness of the results to unmeasured confounding was assessed with E-values.
DENV infection was associated with a significantly increased risk of overall stroke (aSHR 4.51; 95% CI: 3.23–6.32; P < 0.0001; E-value = 8.49), hemorrhagic stroke (aSHR 4.13; 95% CI: 2.20–7.76; P < 0.0001; E-value =7.73), and ischemic stroke (aSHR 3.80; 95% CI: 2.37–6.11; P < 0.0001; E-value = 7.06) within 30 days. Stratified analysis by age showed that the aSHRs for overall stroke, hemorrhagic stroke, and ischemic stroke were larger among dengue patients aged ≥ 65 during the first 30 days. The 30-day risks of overall stroke, hemorrhagic stroke, and ischemic stroke among elderly dengue patients were 6.71, 1.29, and 3.49 per 1000, respectively. No increased risk was observed after 30 days.
DENV infection was associated with a significant short-term increased risk of stroke. Clinical practitioners should remain alert to patients with stroke-associated symptoms during epidemic seasons, especially elderly patients.
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