SlGAD2 is the target of SlTHM27, positively regulates cold tolerance by mediating anthocyanin biosynthesis in tomato.

Cold stress significantly limits the yield and quality of tomato. Deciphering the key genes related to cold tolerance is important for selecting and breeding superior cold-tolerant varieties. γ-aminobutyric acid (GABA) responds to various types of stress by rapidly accumulating in plant. In this study, glutamic acid decarboxylase (GAD2) was a positive regulator to enhance cold stress tolerance of tomato. Overexpression of SlGAD2 decreased the extent of cytoplasmic membrane damage and increased the endogenous GABA content, antioxidant enzyme activities, and reactive oxygen species (ROS) scavenging capacity in response to cold stress, whereas Slgad2 mutant plants showed the opposite trend. In addition, SlGAD2 induced anthocyanin biosynthesis in response to cold stress by increasing the content of endogenous GABA. Further study revealed that SlGAD2 expression was negatively regulated by the transcription factor SlTHM27. However, the transcript levels of SlTHM27 were repressed under cold stress. Antioxidant enzyme activities, SlGAD2 transcript levels, GABA and anthocyanin contents were significantly increased in Slthm27 mutant plants. Further, our study demonstrated that SlTHM27 decreases SlGAD2-promoted cold resistance in tomato by repressing SlGAD2 transcription. Overall, our results showed that the SlTHM27-SlGAD2 model regulates the cold tolerance in tomato by regulating GABA and anthocyanin.

Preparation of a Porous Protein-Based Composite Material by In Situ Polymerization of Pickering High Internal Phase Emulsion for Adsorption of Lead Ions.

The preparation of complex porous materials using a small molecular surfactant as the stabilizer of a high internal phase emulsion can result in harm to the environment. In this study, porous composites based on soy protein isolate with poly(acrylic acid) were prepared by in situ polymerization of a high internal phase monomer emulsion with an internal phase volume fraction of 80%. The material was prepared from acrylic acid and an N,N-methyl diacrylic acid monomer solution as the continuous phase, peanut oil as the dispersed phase, and soy protein isolate as the composite stabilizer. Scanning electron microscopy showed that porous composites exhibited a concave/convex three-dimensional interpenetrating pore structure. Fourier-transform infrared spectra revealed the existence of many active groups such as carboxyl, amino, hydroxyl, and sulfhydryl. The composite had a high adsorption capacity for lead ions, even at low concentration, with a removal rate of up to 95.7%. The adsorption process conformed to a two-stage model involving internal diffusion and Langmuir isothermal adsorption. The maximum saturated adsorption capacity was 36.71 mg/g when the initial solution concentration was 150 mg/L, the adsorbent concentration was 7.0 g/L, and the adsorption mechanism involved chemical interactions between the lead ions and the composite groups -COOH, -OH, and -SH.

Neural network-based finite-time command-filtered adaptive backstepping control of electro-hydraulic servo system with a three-stage valve.

This paper aims to improve the tracking control performance of the three-stage valve (TSV) controlled electro-hydraulic servo system (EHSS) with parameter uncertainties and other lumped unknown nonlinearities, including unknown dynamics and disturbances. A more accurate nonlinear model of the TSV-controlled EHSS is established and a neural network-based finite-time command-filtered adaptive backstepping control (NNFCABC) method is proposed for the EHSS. Adaptive control is used to deal with the system parameter uncertainties, and the radial basis function neural network (RBFNN) algorithm is introduced to approximate the lumped unknown nonlinearities. The prediction errors of serial-parallel estimation models (SPEMs) and the tracking errors are utilized together to design adaptive laws to estimate the system parameters and the weights of the RBFNNs. The entire control framework utilizes command-filtered control and backstepping techniques. By applying Levant differentiators as command filters and introducing fractional power terms into the virtual control laws and the SPEMs, the proposed NNFCABC theoretically guarantees the tracking performance of the closed-loop control system with finite-time convergence. Comparative simulations and experiments verify the feasibility and superiority of the proposed control scheme.

A dual-attention based coupling network for diabetes classification with heterogeneous data.

Diabetes Mellitus (DM) is a group of metabolic disorders characterized by hyperglycaemia in the absence of treatment. Classification of DM is essential as it corresponds to the respective diagnosis and treatment. In this paper, we propose a new coupling network with hierarchical dual-attention that utilizes heterogeneous data, including Flash Glucose Monitoring (FGM) data and biomarkers in electronic medical records. The long short-term memory-based FGM sub-network extracts the time-dependent features of dynamic FGM sequences, while the biomarkers sub-network learns the features of static biomarkers. The convolutional block attention module (CBAM) for dispersing the feature weights of the spatial and channel dimensions is implemented into the FGM sub-network to endure the variability of FGM and allows us to extract high-level discriminative features more accurately. To better adjust the importance weights of the characteristics of the two sub-networks, self-attention is introduced to integrate the characteristics of heterogeneous data. Based on the dataset provided by Peking University People's Hospital, the proposed method is evaluated through factorial experiments of multi-source heterogeneous data, ablation studies of various attention strategies, time consumption evaluation and quantitative evaluation. The benchmark tests reveal the proposed network achieves a type 1 and 2 diabetes classification accuracy of 95.835% and the comprehensive performance metrics, including Matthews correlation coefficient, F1-score and G-mean, are 91.333%, 94.939% and 94.937% respectively. In the factorial experiments, the proposed method reaches the maximum area under the receiver operating characteristic curve of 0.9428, which indicates the effectiveness of the coupling between the nominated sub-networks. The coupling network with a dual-attention strategy performs better than the one without or only with a single-attention strategy in the ablation study as well. In addition, the model is also tested on another data set, and the accuracy of the test reaches 94.286%, reflecting that the model is robust when it is transferred to untrained diabetes data. The experimental results show that the proposed method is feasible in the classification of diabetes types. The code is available at https://github.com/bitDalei/Diabetes-Classification-with-Heterogeneous-Data.

Estimated minimum prices and lowest available national prices for antiobesity medications: Improving affordability and access to treatment.

OBJECTIVE: Novel antiobesity treatments are highly effective in recent clinical trials. Access to these medications is needed to supplement lifestyle and surgical interventions for millions living with obesity worldwide, but high prices are limiting. This study aimed to review current treatment costs and calculate potential estimated minimum prices (EMPs). METHODS: The authors searched national drug price databases across various countries for orlistat, naltrexone-bupropion, topiramate-phentermine, liraglutide, semaglutide, and tirzepatide. EMPs for antiobesity medications were calculated using established methodology, using active pharmaceutical ingredients (API) from the Panjiva database. EMPs were calculated per 30-day course and include costs of active pharmaceutical ingredients, excipients, formulation, taxation, and 10% profit margin. RESULTS: National prices of antiobesity medications were significantly higher than calculated EMPs. Semaglutide 30-day course prices ranged from $804 (United States) to $95 (Turkey) while the EMP was $40. Liraglutide prices ranged from $1418 (United States) to $252 (Norway) while the EMP was $50. Some oral treatments could be generically manufactured at very low costs per course ($7 for orlistat; $5 for phentermine/topiramate combination tablets), while naltrexone/bupropion was more expensive ($54). CONCLUSIONS: This study shows that certain weight loss treatments can be manufactured and sold profitably at low costs, but prices currently range widely between countries, limiting access for those in need.

Tobacco smoking and risks of more than 470 diseases in China: a prospective cohort study.

BACKGROUND: Tobacco smoking is estimated to account for more than 1 million annual deaths in China, and the epidemic continues to increase in men. Large nationwide prospective studies linked to different health records can help to periodically assess disease burden attributed to smoking. We aimed to examine associations of smoking with incidence of and mortality from an extensive range of diseases in China. METHODS: We analysed data from the prospective China Kadoorie Biobank, which recruited 512 726 adults aged 30-79 years, of whom 210 201 were men and 302 525 were women. Participants who had no major disabilities were identified through local residential records in 100-150 administrative units, which were randomly selected by use of multistage cluster sampling, from each of the ten diverse study areas of China. They were invited and recruited between June 25, 2004, and July 15, 2008. Upon study entry, trained health workers administered a questionnaire assessing detailed smoking behaviours and other key characteristics (eg, sociodemographics, lifestyle, and medical history). Participants were followed up via electronic record linkages to death and disease registries and health insurance databases, from baseline to Jan 1, 2018. During a median 11-year follow-up (IQR 10-12), 285 542 (55·7%) participants were ever hospitalised, 48 869 (9·5%) died, and 5252 (1·0%) were lost to follow-up during the age-at-risk of 35-84 years. Cox regression yielded hazard ratios (HRs) associating smoking with disease incidence and mortality, adjusting for multiple testing. FINDINGS: At baseline, 74·3% of men and 3·2% of women (overall 32·4%) ever smoked regularly. During follow-up, 1 137 603 International Classification of Diseases, 10th revision (ICD-10)-coded incident events occurred, involving 476 distinct conditions and 85 causes of death, each with at least 100 cases. Compared with never-regular smokers, ever-regular smokers had significantly higher risks for nine of 18 ICD-10 chapters examined at age-at-risk of 35-84 years. For individual conditions, smokers had significantly higher risks of 56 diseases (50 for men and 24 for women) and 22 causes of death (17 for men and nine for women). Among men, ever-regular smokers had an HR of 1·09 (95% CI 1·08-1·11) for any disease incidence when compared with never-regular smokers, and significantly more episodes and longer duration of hospitalisation, particularly those due to cancer and respiratory diseases. For overall mortality, the HRs were greater in men from urban areas than in men from rural areas (1·50 [1·42-1·58] vs 1·25 [1·20-1·30]). Among men from urban areas who began smoking at younger than 18 years, the HRs were 2·06 (1·89-2·24) for overall mortality and 1·32 (1·27-1·37) for any disease incidence. In this population, 19·6% of male (24·3% of men residing in urban settings and 16·2% of men residing in rural settings) and 2·8% of female deaths were attributed to ever-regular smoking. INTERPRETATION: Among Chinese adults, smoking was associated with higher risks of morbidity and mortality from a wide range of diseases. Among men, the future smoking-attributed disease burden will increase further, highlighting a pressing need for reducing consumption through widespread cessation and uptake prevention. FUNDING: British Heart Foundation, Cancer Research UK, Chinese Ministry of Science and Technology, Kadoorie Charitable Foundation, UK Medical Research Council, National Natural Science Foundation of China, Wellcome Trust.

Barriers to Worldwide Access for Paxlovid, a New Treatment for COVID-19.

Pfizer and the Medicines Patent Pool (MPP) have reached a voluntary licensing agreement for Paxlovid (nirmatrelvir+ritonavir), a novel antiviral for coronavirus disease 2019 (COVID-19) taken orally in the first 5 days from symptom onset. The Pfizer-MPP deal enables 95 low- and middle-income countries (L/MICs) to access affordable biosimilars. Generics are delayed awaiting bioequivalence testing and may be ineffective in L/MICs with reduced testing capacity, which comprise only 10% of global diagnoses. Thirty-nine percent of diagnoses originate in MICs forced to pay high prices due to exclusion from the Pfizer-MPP deal. The cost-effectiveness of Paxlovid could be limited compared with the creation of sustainable vaccine infrastructure in these nations, delaying socioeconomic pandemic recovery. Furthermore, Paxlovid may not be cost-effective in vaccinated populations, and concerns remain over ritonavir drug interactions with COVID-19 comorbidity medications. We call for expanded coverage by the Paxlovid-MPP deal and greater access to testing.

Active suspension control with consensus strategy for dynamic posture tracking of wheel-legged robotic systems on uneven surfaces.

This work presents a dynamic posture tracking control strategy for wheel-legged systems on uneven surfaces. Based on the kinematic model of a wheel-legged robotic system, the expected positions for the end-effectors of wheel-legs are calculated according to posture references and sensor feedback. The position control problem for a general wheel-leg is investigated for the active mechanism to imitate a passive suspension and respond to the external contact forces. The position tracking accuracy of the wheel-leg is sacrificed to enhance the compliance performance under rough terrain. Because of the unique contact state with the uneven ground for each wheel-leg, the position responses are different. As a result, the forces from the wheel-legs to the fuselage are inconsistent, which leads to the risk of posture oscillations. Equipping the wheel-legs with an undirected communication network, a consensus scheme for the robotic system is developed with proven global asymptotic stability to improve the posture tracking property. A novel robotic system is established with Stewart-structured wheel-legs, which are connected by a user datagram protocol network. Comparative experimental results are carried out on the physical prototype to validate the effectiveness of the proposed approach.

Current prices versus minimum costs of production for CFTR modulators.

BACKGROUND: While the clinical benefits of CFTR modulators are clear, their high prices render them inaccessible outside of the world's richest countries. Despite this, there is currently limited evidence regarding global access to these transformative therapies. Therefore, this study aims to estimate the minimum costs of production of CFTR modulators, assuming robust generic competition, and to compare them with current list prices to evaluate the feasibility of increased global access to treatment. METHODS: Minimum costs of production for CFTR modulators were estimated via an algorithm validated in previous literature and identification of cost-limiting key starting materials from published routes of chemical synthesis. This algorithm utilised per kilogram active pharmaceutical ingredient costs obtained from global import/export data. Estimated production costs were compared with published list prices in a range of countries. RESULTS: Costs of production for elexacaftor/tezacaftor/ivacaftor are estimated at $5,676 [$4,628-6,723] per year, over 90% lower than the US list price. Analysis of chemical structure and published synthetic pathways for elexacaftor/tezacaftor/ivacaftor revealed relatively straightforward routes of synthesis related to currently available products. Total cost of triple therapy for all eligible diagnosed CF patients worldwide would be $489 million per year. Comparatively, the annual cost at US list price would be $31.2 billion. CONCLUSIONS: Elexacaftor/tezacaftor/ivacaftor could be produced via generic companies for a fraction of the list price. The current pricing model restricts access to the best available therapy, thereby exacerbating existing inequalities in CF care. Urgent action is needed to increase the availability of triple combination treatment worldwide. One strategy based on previous success is originator-issued voluntary licenses.

Retraction to: Meta-analysis of Randomized Trials of Ivermectin to Treat SARS-CoV-2 Infection.

[This retracts the article DOI: 10.1093/ofid/ofab358.]

A ratiometric fluorescent probe for selective detection of thiophenol derivatives.

Though a number of on-off or off-on fluorescent probes have been developed for the detection of thiophenol by using its unique recognition groups, such as 2, 4-dinitrophenyl ether, 2, 4-dinitrophenyl sulfonamide, and 2, 4-dinitrophenyl sulfonate, up to now, there are few probes that can detect thiophenol by the proportional fluorescence signal. We developed a ratiometric fluorescent probe with coumarin pyridine derivative as fluorophore and 2, 4-dinitrophenyl ether moiety as the sensing unit which could be used to detect thiophenol derivatives by the aromatic nucleophilic substitution reaction. This probe (CPBPN) displayed significant change in fluorescence ratio (256 fold) to result in a more reliable analysis by self-calibration and a relatively low detection limit of 24 nM toward 4-methylthiophenol (MTP) within 30 min to achieve more sensitivity. Besides, the probe was also applied to detect the presence of thiophenol derivatives in actual water samples and fluorescence imaging in living cells. The present work is of great importance for monitoring environmental pollutants and studying their biological function.

Minimum Manufacturing Costs, National Prices, and Estimated Global Availability of New Repurposed Therapies for Coronavirus Disease 2019.

BACKGROUND: Currently, only dexamethasone, tocilizumab, and sarilumab have conclusively been shown to reduce mortality of coronavirus disease 2019 (COVID-19). Safe and effective treatments will need to be both affordable and widely available globally to be used alongside vaccination programs. This analysis will estimate and compare potential generic minimum costs of a selection of approved COVID-19 drug candidates with available international list prices. METHODS: We searched for repurposed drugs that have been approved by at least one of the World Health Organization, US Food and Drug Administration, or the United Kingdom National Institute of Health and Care Excellence organizations or at least given emergency use authorization or recommended for off-label prescription. Drug prices were searched for dexamethasone, budesonide, baricitinib, tocilizumab, casirivimab, and imdevimab, and sarilumab, using active pharmaceutical ingredients (APIs) data extracted from global shipping records. This was compared with national pricing data from a range of low-, medium-, and high-income countries. Annual API export volumes from India were used to estimate the current availability of each drug. RESULTS: Repurposed therapies can be generically manufactured for some treatments at very low per-course costs, ranging from US $2.58 for intravenous (IV) dexamethasone (or US $0.19 orally) and US $4.34 for inhaled budesonide. No export price data were available for baricitinib, tocilizumab, casirivimab, and imdevimab, or sarilumab, but courses of these treatments have higher prices, ranging from US $6.67 for baricitinib to US $875.5 for sarilumab. When comparing international list prices, we found wide variations between countries. CONCLUSIONS: Successful management of COVID-19 will require equitable access to treatment for all populations, not just those able to pay high prices. Dexamethasone and budesonide are widely available and affordable, whereas monoclonal antibodies and IV treatment courses are more expensive.

Speed consensus control for a parallel six-wheel-legged robot on uneven terrain.

Wheel-legged robots suffer from the disturbances arising from the inconsistent of the wheel's speed and the external environments while driving over the uneven terrain, which may impair the smoothness of driving, or even fail in moving over the terrain. In this study, a speed consensus control (SCC) method that combines the distributed consensus algorithm (DCA) with the linear active disturbance rejection control (LADRC) is proposed to enhance the smoothness of the wheel-legged robot while traversing the uneven terrain. Firstly, the DCA is employed to reach a consensus amongst the speeds of the robot's body and each wheel which are regarded as a multi-agent system. Furthermore, the LADRC is applied to attenuate the disturbances arising from the model uncertainty and the unknown environments and to precisely track each wheel's desired speed obtained by the DCA. Finally, a series of simulations and experiments are conducted on a parallel six-wheel-legged robot (i.e., BIT-NAZAII) to validate the proposed method.

Meta-analysis of Randomized Trials of Ivermectin to Treat SARS-CoV-2 Infection.

Ivermectin is an antiparasitic drug being investigated for repurposing against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Ivermectin showed in vitro activity against SARS-COV-2, but only at high concentrations. This meta-analysis investigated ivermectin in 23 randomized clinical trials (3349 patients) identified through systematic searches of PUBMED, EMBASE, MedRxiv, and trial registries. The primary meta-analysis was carried out by excluding studies at a high risk of bias. Ivermectin did not show a statistically significant effect on survival (risk ratio [RR], 0.90; 95% CI, 0.57 to 1.42; P = .66) or hospitalizations (RR, 0.63; 95% CI, 0.36 to 1.11; P = .11). Ivermectin displayed a borderline significant effect on duration of hospitalization in comparison with standard of care (mean difference, -1.14 days; 95% CI, -2.27 to -0.00; P = .05). There was no significant effect of ivermectin on time to clinical recovery (mean difference, -0.57 days; 95% CI, -1.31 to 0.17; P = .13) or binary clinical recovery (RR, 1.19; 95% CI, 0.94 to 1.50; P = .15). Currently, the World Health Organization recommends the use of ivermectin only inside clinical trials. A network of large clinical trials is in progress to validate the results seen to date.

Human-robot skill transmission for mobile robot via learning by demonstration.

This paper proposed a skill transmission technique for the mobile robot via learning by demonstration. When the material is transported to the designated location, the robot can show the human-like capabilities: autonomous tracking target. In this case, a skill transmission framework is designed, which the Kinect sensor is utilized to distinguish human activity recognition to create a planned path. Moreover, the dynamic movement primitive method is implemented to represent the teaching data, and the Gaussian mixture regression is utilized to encode the learning trajectory. Furthermore, in order to realize the accurate position control of trajectory tracking, a model predictive tracking control is investigated, where the recurrent neural network is used to eliminate the uncertain interaction. Finally, some experimental tasks using the mobile robot (BIT-6NAZA) are carried out to demonstrate the effectiveness of the developed techniques in real-world scenarios.

Icariin, Formononetin and Caffeic Acid Phenethyl Ester Inhibit Feline Calicivirus Replication In Vitro.

Cats infected with feline calicivirus (FCV) often display oral ulcers and inflammation of the upper respiratory tract, which can lead to death in severe cases. Antiviral therapy is one of the most effective ways to control FCV infection. Natural compounds in Chinese herbal medicines and medicinal plants provide abundant resources for research on antiviral drugs. In this study, we found that icariin (ICA), formononetin (FMN) and caffeic acid phenethyl ester (CPAE) show low cytotoxicity towards F81 cells, that the three natural compounds have apparent antiviral effects on FCV in vitro, and that they can inhibit different FCV strains. Then, we found that ICA and FMN mainly function in the early stage of FCV infection, while CAPE can function in both the early and late stages of FCV infection. Finally, we found that ICA has an antagonistic effect on FMN and CAPE in FCV infection, and FMN has a synergistic effect with CAPE against FCV infection. Our results showed that ICA, FMN and CAPE may be potential drug candidates for FCV-induced diseases.

A new turn-on fluorescent probe for sensing 4-methylbenzenethiol in real water samples.

A new fluorescent probe (MBT) for the detection of 4-methylbenzenethiol (p-MePhSH) was developed by using 4-(benzo[d]thiazol-2-yl)-3-methoxyphenol as the fluorophore and 2,4-dinitrophenyl ether as the sensing moiety. Probe MBT displayed good selectivity toward p-MePhSH in DMSO/PBS buffer (5/5, v/v) solution and anti-interference over other competitive species via nucleophilic aromatic substitution. The fluorescence intensities of the probe responded p-MePhSH showed a 22-fold enhancement and good linearity with p-MePhSH concentration collected in the range of 0-15 µM. Moreover, the probe is sensitive to p-MePhSH and the limit of detection is 45 nM. The sensing mechanism of probe MBT was verified by high-resolution mass spectrometry and fluorescence lifetime. Furthermore, the probe was used to the detection of p-MePhSH in real water samples.

Value of [68Ga]Ga-FAPI-04 imaging in the diagnosis of renal fibrosis.

PURPOSE: Renal fibrosis is a pathological state in the progression of chronic kidney disease. Early detection and treatment are vital to prolonging patient survival. Renal puncture examination is the gold standard for renal fibrosis, but it has several limitations. This study aims to evaluate the diagnostic performance of a novel PET radiotracer, [68Ga]Ga-fibroblast activation protein inhibitor (FAPI)-04, which specifically images fibroblast activation protein (FAP) expression for renal fibrosis. METHODS: All patients underwent renal puncture before receiving [68Ga]Ga-FAPI-04 PET/CT imaging. They then underwent [68Ga]Ga-FAPI-04 PET/CT and immunochemistry examinations. The data obtained were analyzed. RESULTS: The [68Ga]Ga-FAPI-04 PET/CT examination results demonstrated that almost all patients (12/13) exhibited increased radiotracer uptake. The maximum standardized uptake value (SUVmax) in patients with mild, moderate, and severe fibrosis was 3.92 ± 1.50, 5.98 ± 1.6, and 7.67 ± 2.23, respectively. CONCLUSION: Compared with renal puncture examination, non-invasive imaging of FAP expression through [68Ga]Ga-FAPI-04 PET/CT quickly demonstrates bilateral kidney conditions with high sensitivity. [68Ga]Ga-FAPI-04 PET/CT can facilitate the evaluation of disease progression, diagnosis, and the development of a treatment plan.

Control strategy of stable walking for a hexapod wheel-legged robot.

This paper provides a legged stable walking control strategy based on multi-sensor information feedback about BIT-NAZA-II, a large load parallel hexapod wheel-legged robot developing for the problem of vertical contact impact and horizontal sliding of heavy leg robot in complex terrain environments. The BIT-NAZA-II robot has six legs and six wheels, and the wheels are installed on the foot-end. The wheels of each foot-end for the legs of the robot are locked when walking with legs. In order to realize the smooth transition between swing phase and stance phase, the leg motion is divided into different stages for control by state machine switching controller based on event (SMSCE). In the Z-direction, in order to avoid the shaking of the body caused by the contact impact at the moment of contact between the foot-end and the ground during the walking of the robot, an active compliance controller (ACC) based on impedance control (IC) is applied to solve the problem of contact impact. Moreover, in the X-direction, the swing leg retraction (SLR) based on Bezier curve (BC) is introduced to generate the foot-end trajectory of the robot, which solves the slip problem of the heavy leg robot and improves the horizontal stability. Finally, the control strategy of stable walking is respectively verified by the simulations and experiments. The results show that the ACC based on IC can effectively reduce the contact impact between the foot-end and the ground in the Z-direction and improve the stability of body. Besides, the anti-sliding ability is realized after introducing SLR based on BC in the X-direction, and we also verify that stable walking control strategy is effective, which provides a reference value for the stable walking of heavy leg robot in complex terrain.