TRPC4 aggravates hypoxic pulmonary hypertension by promoting pulmonary endothelial cell apoptosis.

Pulmonary hypertension (PH) is a devastating disease that lacks effective treatment options and is characterized by severe pulmonary vascular remodeling. Pulmonary arterial endothelial cell (PAEC) dysfunction drives the initiation and pathogenesis of pulmonary arterial hypertension. Canonical transient receptor potential (TRPC) channels, a family of Ca2+-permeable channels, play an important role in various diseases. However, the effect and mechanism of TRPCs on PH development have not been fully elucidated. Among the TRPC family members, TRPC4 expression was markedly upregulated in PAECs from hypoxia combined with SU5416 (HySu)-induced PH mice and monocrotaline (MCT)-treated PH rats, as well as in hypoxia-exposed PAECs, suggesting that TRPC4 in PAECs may participate in the occurrence and development of PH. In this study, we aimed to investigate whether TRPC4 in PAECs has an aggravating effect on PH and elucidate the molecular mechanisms. We observed that hypoxia treatment promoted PAEC apoptosis through a caspase-12/endoplasmic reticulum stress (ERS)-dependent pathway. Knockdown of TRPC4 attenuated hypoxia-induced apoptosis and caspase-3/caspase-12 activity in PAECs. Accordingly, adeno-associated virus (AAV) serotype 6-mediated pulmonary endothelial TRPC4 silencing (AAV6-Tie-shRNA-TRPC4) or TRPC4 antagonist suppressed PH progression as evidenced by reduced right ventricular systolic pressure (RVSP), pulmonary vascular remodeling, PAEC apoptosis and reactive oxygen species (ROS) production. Mechanistically, unbiased RNA sequencing (RNA-seq) suggested that TRPC4 deficiency suppressed the expression of the proapoptotic protein sushi domain containing 2 (Susd2) in hypoxia-exposed mouse PAECs. Moreover, TRPC4 activated hypoxia-induced PAEC apoptosis by promoting Susd2 expression. Therefore, inhibiting TRPC4 ameliorated PAEC apoptosis and hypoxic PH in animals by repressing Susd2 signaling, which may serve as a therapeutic target for the management of PH.

Gubi Zhitong formula alleviates osteoarthritis in vitro and in vivo via regulating BNIP3L-mediated mitophagy.

BACKGROUND: Osteoarthritis (OA) is characterized by degeneration of articular cartilage, leading to joint pain and dysfunction. Gubi Zhitong formula (GBZTF), a traditional Chinese medicine formula, has been used in the clinical treatment of OA for decades, demonstrating definite efficacy. However, its mechanism of action remains unclear, hindering its further application. METHODS: The ingredients of GBZTF were analyzed and performed with liquid chromatography-mass spectrometry (LC-MS). 6 weeks old SD rats were underwent running exercise (25 m/min, 80 min, 0°) to construct OA model with cartilage wear and tear. It was estimated by Micro-CT, Gait Analysis, Histological Stain. RNA-seq technology was performed with OA Rats' cartilage, and primary chondrocytes induced by IL-1ß (mimics OA chondrocytes) were utilized to evaluated and investigated the mechanism of how GBZTF protected OA cartilage from being damaged with some functional experiments. RESULTS: A total of 1006 compounds were identified under positive and negative ion modes by LC-MS. Then, we assessed the function of GBZTF through in vitro and vivo. It was found GBZTF could significantly up-regulate OA rats' limb coordination and weight-bearing capacity, and reduce the surface and sub-chondral bone erosions of OA joints, and protect cartilage from being destroyed by inflammatory factors (iNOS, IL-6, IL-1ß, TNF- α, MMP13, ADAMTS5), and promote OA chondrocytes proliferation and increase the S phage of cell cycle. In terms of mechanism, RNA-seq analysis of cartilage tissues revealed 1,778 and 3,824 differentially expressed genes (DEGs) in model vs control group and GBZTF vs model group, respectively. The mitophagy pathway was most significantly enriched in these DEGs. Further results of subunits of OA chondrocytes confirmed that GBZTF could alleviate OA-associated inflammation and cartilage damage through modulation BCL2 interacting protein 3-like (BNIP3L)-mediated mitophagy. CONCLUSION: The therapeutic effectiveness of GBZTF on OA were first time verified in vivo and vitro through functional experiments and RNA-seq, which provides convincing evidence to support the molecular mechanisms of GBZTF as a promising therapeutic decoction for OA.

Self-attention CNN for retinal layer segmentation in OCT.

The structure of the retinal layers provides valuable diagnostic information for many ophthalmic diseases. Optical coherence tomography (OCT) obtains cross-sectional images of the retina, which reveals information about the retinal layers. The U-net based approaches are prominent in retinal layering methods, which are usually beneficial to local characteristics but not good at obtaining long-distance dependence for contextual information. Furthermore, the morphology of retinal layers with the disease is more complex, which brings more significant challenges to the task of retinal layer segmentation. We propose a U-shaped network combining an encoder-decoder architecture and self-attention mechanisms. In response to the characteristics of retinal OCT cross-sectional images, a self-attentive module in the vertical direction is added to the bottom of the U-shaped network, and an attention mechanism is also added in skip connection and up-sampling to enhance essential features. In this method, the transformer's self-attentive mechanism obtains the global field of perception, thus providing the missing context information for convolutions, and the convolutional neural network also efficiently extracts local features, compensating the local details the transformer ignores. The experiment results showed that our method is accurate and better than other methods for segmentation of the retinal layers, with the average Dice scores of 0.871 and 0.820, respectively, on two public retinal OCT image datasets. To perform the layer segmentation of retinal OCT image better, the proposed method incorporates the transformer's self-attention mechanism in a U-shaped network, which is helpful for ophthalmic disease diagnosis.

The properties of the rice resistant starch processing and its application in skimmed yogurt.

Extrusion is typically employed to prepare resistant starch (RS). However, the process is complicated. In this study, the effects of twin-screw extrusion on the crystallinity, thermal properties, and functional properties of starch formed in different extrusion zones were investigated. The effects of this process on the rheological properties and microstructure of RS-added skimmed yogurt were also studied. According to the results, the RS content increased from 7.40 % in the raw material to 33.79 % in the extrudate. The A-type crystal structure of the starch was not observed. The dissociation temperature of the extruded starch ranged from 87.76 °C to 100.94 °C. The glycemic index (GI) of skimmed yogurt fortified with 0.4 % RS was 48.7, and the viscosity was also improved. The microstructure exhibited a uniform network of the starch-protein structure. The findings may serve as a theoretical basis for the application of RS in the food industry.

Exploring Aeromonas dhakensis in Aldabra giant tortoises: a debut report and genetic characterization.

Aeromonas dhakensis (A. dhakensis) is becoming an emerging pathogen worldwide, with an increasingly significant role in animals and human health. It is a ubiquitous bacteria found in terrestrial and aquatic milieus. However, there have been few reports of reptile infections. In this study, a bacterial strain isolated from a dead Aldabra giant tortoise was identified as A. dhakensis HN-1 through clinical observation, matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF/MS), and gene sequencing analysis. Subsequently, to evaluate its pathogenicity, the detection of virulence genes and mice infection experiments were performed. A. dhakensis HN-1 was found to contain seven virulence genes, including alt, ela, lip, act, aerA, fla, and hlyA. Mice infected with A. dhakensis HN-1 exhibited hemorrhage of varying degrees in multiple organs. The half-maximal lethal dose (LD50) value of A. dhakensis HN-1 for mice was estimated to be 2.05 × 107 colony forming units (CFU)/mL. The antimicrobial susceptibility test revealed that A. dhakensis HN-1 was resistant to amoxicillin, penicillin, ampicillin and erythromycin. This is the first report of A. dhakensis in Aldabra giant tortoises, expanding the currently known host spectrum. Our findings emphasize the need for One Health surveillance and extensive research to reduce the spread of A. dhakensis across the environment, humans, and animals.

Disappearing Cerebral Communicating Vessels in Embryonic Development-With a Case of Carotid-Vertebrobasilar Artery Anastomosis.

In early embryonic development, anastomoses between carotid and basilar arteries occur in the primitive trigeminal, primitive otic, primitive hypoglossal, and primitive proatlantal arteries, and these anastomoses gradually disappear as the embryo continues to develop. This article reported a case of vascular anastomosis occurring between the external carotid artery and vertebral artery.

pH-induced physiochemical and structural changes of milk proteins mixtures and its effect on foaming behavior.

Milk proteins are well known to produce aerated food due to the amphiphilicity. However, milk proteins are commonly added in blends for the desirable properties in food industry. In this study, the foaming properties of milk protein mixtures (MPM), a mixtures of whey protein isolated (WPI) and milk protein concentrate (MPC), was studied through foaming capacity (FC), foam stability (FS), and foam morphology at pH 3.0-9.0. Physiochemical, structural, surface properties, and Pearson correlation analysis were measured to gain insight into foaming behavior. Results indicated that MPM showed excellent FC (113.0-114.3 %) and FS (90.7-93.0 %) at pH 6.0-9.0, and foam displayed a smaller size and uniform distribution. MPM solutions showed smaller particles, higher solubility, and lower apparent viscosity at pH 6.0-9.0, which resulted in an increase in surface pressure and adsorption rate (Kdiff), facilitating more protein absorbed to interface. To further investigate structural changes, various spectral methods were used, in which the structure of MPM was changed with pH. Correlation analysis further suggests that Kdiff and solubility positively affect the formation of foam, while free sulfhydryl and ß-sheet contributed to stabilizing foams. These findings provide valuable information on MPM as ingredients for aerated foods under acidic, neutral, and alkaline conditions.

The influence of arm positions on mechanical dyssynchrony measured by gated myocardial perfusion imaging.

Background: In routine procedures, patient's arms are positioned above their heads to avoid potential attenuation artifacts and reduced image quality during gated myocardial perfusion imaging (G-MPI). However, it is difficult to achieve this action in the acute period following pacemaker implantation. This study aimed to explore the influence of arm positioning on myocardial perfusion imaging (MPI) in different types of heart disease. Methods: This study was conducted retrospectively. A total of 123 patients were enrolled and underwent resting G-MPI using a standard protocol with arms positioned above their heads and again with their arms at their sides. All individuals were divided into 3 groups: the normal group, the obstructive coronary artery disease (O-CAD) group, and the dilated cardiomyopathy (DCM) group. The G-MPI data were measured by QGS software and Emory Reconstruction Toolbox, including left ventricular ejection fraction (LVEF), end-diastolic volume (EDV), end-systolic volume (ESV), extent, total perfusion deficit (TPD), summed rest score (SRS), scar burden, phase standard deviation (SD), and phase histogram bandwidth (BW). Results: In total, extent, TPD, EDV, ESV, LVEF, systolic SD, systolic BW, diastolic SD, and diastolic BW were all significantly different between the 2 arm positions (all P<0.01). On the Bland-Altman analysis, both EDV and ESV with the arm-down position were significantly underestimated (P<0.001). Meanwhile, TPD, extent, and LVEF with the arm-down position were significantly overestimated (P<0.05). Systolic SD, systolic BW, diastolic SD, and diastolic BW were systematically overestimated (P<0.001). In the DCM group (n=52), EDV, ESV, systolic SD, systolic BW, diastolic SD, and diastolic BW were identified as significantly different by the paired t-test between the 2 arm positions (P<0.05). In the O-CAD group (n=32), scar burden, ESV, LVEF, and diastolic BW were significantly different between the 2 arm positions (P<0.05). Conclusions: Systolic and diastolic dyssynchrony parameters and most left ventricular (LV) functional parameters were significantly influenced by arm position in both normal individuals and patients with heart failure (HF) with different pathophysiologies. More attention should be given to LV dyssynchrony data during clinical evaluation of cardiac resynchronization therapy (CRT) implantation procedure.

Misdiagnosis of Chronic Subdural Hematoma in Children.

Chronic subdural hematoma is a common intracranial disease in elderly individuals, but in very rare cases, it can also develop in children. Some subdural hematomas are prone to misdiagnosis as epidural hematomas, which can affect the surgical approach and patient prognosis. We report a case of a 12-year-old male child with a misdiagnosed subdural hematoma as an epidural hematoma. We reviewed the data of this misdiagnosed patient with chronic subdural hematoma, analyzed relevant imaging information, identified the reasons for misdiagnosis, and summarized our experience to enhance our understanding of this condition.

Comparison of proanthocyanidins A2 and B2 on IgE-reactivity and epitopes in Gly m 6 using multispectral, LC/MS-MS and molecular docking.

This study comparatively analyzed the changes in IgE-reactivity and epitopes in proanthocyanidins A2- (PA-Gly m 6) and B2-Gly m 6 (PB-Gly m 6) conjugates prepared by alkali treatment at 80 °C for 20 min. Similar to the western blot, ELISA also showed a higher reduced IgE-reactivity in PA-Gly m 6 (70.12 %) than PB-Gly m 6 (63.17 %). SDS-PAGE demonstrated that proanthocyanidins A2 caused more formation of >180 kDa polymers than proanthocyanidins B2. Multispectral analyses revealed that PA-Gly m 6 exhibited more structural alteration (e.g., a decrease of α-helical content and ANS fluorescence intensity) to unfold protein structure than proanthocyanidins B2, improving the accessibility to modify Gly m 6 for shielding or destroying conformational epitopes. LC/MS-MS revealed that PA-Gly m 6 conjugates had a lower abundance of allergens, peptides and linear epitopes than PB-Gly m 6 conjugates. Molecular docking showed that proanthocyanidins A2 and B2 reacted with Gln-317 and Asn-94 of epitopes, respectively. Overall, proanthocyanidins A2 is more effective than proanthocyanidins B2 to decrease the IgE-reactivity of Gly m 6 due to more shielding or destruction of conformational epitopes and lower content allergens and linear epitopes, which was attributed to more protein-crosslinks formation and structural changes in PA-Gly m 6 conjugates.

Development and validation of an intensive care unit acquired weakness prediction model: A cohort study.

Background: At present, intensive care unit acquired weakness (ICU-AW) has become an important health care issue. The aim of this study was to develop and validate an ICU-AW prediction model for adult patients in intensive care unit (ICU) to provide a practical tool for early clinical diagnosis. Methods: An observational cohort study was conducted including 400 adult patients admitted from September 2021 to June 2022 at an ICU with four ward at a medical university affiliated hospital in China. The Medical Research Council (MRC) scale was used to assess bedside muscle strength in ICU patients as a diagnostic basis for ICUAW. Patients were divided into the ICU-AW group and the no ICU-AW group and the clinical data of the two groups were statistically analyzed. A risk prediction model was then developed using binary logistic regression. Sensitivity, specificity, and the area under the curve (AUC) were used to evaluate the predictive ability of the model. The Hosmer-Lemeshow test was used to assess the model fit. The bootstrap method was used for internal verification of the model. In addition, the data of 120 patients in the validation group were selected for external validation of the model. Results: The prediction model contained five risk factors: gender (OR: 4.31, 95% CI: 1.682-11.042), shock (OR: 3.473, 95% CI: 1.191-10.122), mechanical ventilation time (OR: 1.592, 95% CI: 1.317-1.925), length of ICU stay (OR: 1.085, 95% CI: 1.018-1.156) and age (OR: 1.075, 95% CI: 1.036-1.115). The AUC of this model was 0.904 (95% CI: 0.847-0.961), with sensitivity of 87.5%, specificity of 85.8%, and Youden index of 0.733. The AUC of the model after resampling is 0.889. The model verification results showed that the sensitivity, specificity and accuracy were 71.4, 92.9, and 92.9%, respectively. Conclusion: An accurate, and readily implementable, risk prediction model for ICU-AW has been developed. This model uses readily obtained variables to predict patient ICU-AW risk. This model provides a tool for early clinical screening for ICU-AW.

The alteration of composition, conformation, IgE-reactivity and functional attributes in proanthocyanidins-soy protein 7S conjugates formed by alkali-heating treatment: Multi-spectroscopic and proteomic analyses.

This study assessed the alteration of IgE-reactivity and functional attribute in soy protein 7S-proanthocyanidins conjugates (7S-80PC) formed by alkali-heating treatment (pH 9.0, 80 °C, 20 min). SDS-PAGE demonstrated that 7S-80PC exhibited the formation of >180 kDa polymers, although the heated 7S (7S-80) had no changes. Multispectral experiments revealed more protein unfolding in 7S-80PC than in 7S-80. Heatmap analysis showed that 7S-80PC showed more alteration of protein, peptide and epitope profiles than 7S-80. LC/MS-MS demonstrated that the content of total dominant linear epitopes was increased by 11.4 % in 7S-80, but decreased by 47.4 % in 7S-80PC. As a result, Western-blot and ELISA showed that 7S-80PC exhibited lower IgE-reactivity than 7S-80, probably because 7S-80PC exhibited more protein-unfolding to increase the accessibility of proanthocyanidins to mask and destroy the exposed conformational epitopes and dominant linear epitopes induced by heating treatment. Furthermore, the successful attachment of PC to soy 7S protein significantly increased antioxidant activity in 7S-80PC. 7S-80PC also showed higher emulsion activity than 7S-80 owing to its high protein flexibility and protein unfolding. However, 7S-80PC exhibited lower foaming properties than 7S-80. Therefore, the addition of proanthocyanidins could decrease IgE-reactivity and alter the functional attribute of the heated soy 7S protein.

Improved FAST algorithm for non-uniform rotational distortion correction in OCT endoscopic imaging.

Optical Coherence Tomography (OCT) is widely used for endoscopic imaging in endoluminal organs because of its high imaging accuracy and resolution. However, OCT endoscopic imaging suffers from Non-Uniform Rotational Distortion (NURD), which can be caused by many factors, such as irregular motor rotation and changes in friction between the probe and the sheath. Correcting this distortion is essential to obtaining high-quality Optical Coherence Tomography Angiography (OCTA) images. There are two main approaches for correcting NURD: hardware-based methods and algorithm-based methods. Hardware-based methods can be costly, challenging to implement, and may not eliminate NURD. Algorithm-based methods, such as image registration, can be effective for correcting NURD but can also be prone to the problem of NURD propagation. To address this issue, we process frames by coarse and fine registration, respectively. The new reference frame is generated by filtering out the A-scan that may have the NURD problem by coarse registration. And the fine registration uses this frame to achieve the final NURD correction. In addition, we have improved the Features from Accelerated Segment Test (FAST) algorithm and put it into coarse and fine registration process. Four evaluation functions were used for the experimental results, including signal-to-noise ratio (SNR), peak signal-to-noise ratio (PSNR), mean squared error (MSE), and structural similarity index measure (SSIM). By comparing with Scale-invariant feature transform (SIFT), Speeded up robust features (SURF), Oriented FAST and Rotated BRIEF (ORB), intensity-based (Cross-correlation), and Optical Flow algorithms, our algorithm has a higher similarity between the corrected frames. Moreover, the noise in the OCTA data is better suppressed, and the vascular information is well preserved. Our image registration-based algorithm reduces the problem of NURD propagation between B-scan frames and improves the imaging quality of OCT endoscopic images.

Multi-spectral and proteomic insights into the impact of proanthocyanidins on IgE binding capacity and functionality in soy 11S protein during alkali-heating treatment.

This study evaluated the impact of proanthocyanidins on immunoglobulin E (IgE) binding capacity, antioxidant, foaming and emulsifying properties in soy 11S protein following alkali treatment at 80 °C for 20 min. The formation of >180 kDa polymer was observed in the combined heating and proanthocyanidins-conjugation treatment sample (11S-80PC) rather than in the heating treated sample (11S-80) using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The structural analyzes demonstrated that 11S-80PC exhibited more protein unfolding than 11S-80. Heatmap analysis revealed that 11S-80PC had more alteration of peptide and epitope profiles in 11S than in 11S-80. Molecular docking showed that PC could well react with soy protein 11S. Liquid chromatography tandem MS analysis (LC/MS-MS) demonstrated that there was a 35.6 % increase in 11S-80, but a 14.5 % decrease in 11S-80PC for the abundance of total linear epitopes. As a result, 11S-80PC exhibited more reduction in IgE binding capacities than 11S-80 owing to more obscuring and disruption of linear and conformational epitopes induced by structural changes. Moreover, 11S-80PC exhibited higher antioxidant capacities, foaming properties and emulsifying activity than 11S-80. Therefore, the addition of proanthocyanidins could decrease allergenic activity and enhance the functional properties of the heated soy 11S protein.

Understanding the influence of fluctuated low-temperature combined with high-humidity thawing on gelling properties of pork myofibrillar proteins.

The present study further investigated the effects of fluctuated low-temperature combined with high-humidity thawing (FLHT) on the gelling properties of pork myofibrillar proteins (MPs). Results showed that compared with refrigerator thawing (RT) and low-temperature combined with high-humidity thawing (LHT), FLHT effectively reduced the protein aggregation and maintained the relative stability by decreasing the variation in the turbidity and absolute ζ-potential value. The rheological results confirmed its improved elastic gel network. Meanwhile, FLHT samples exhibited markedly higher WHC with lower cooking loss (P < 0.05). The whiteness and strength of MPs gel were significantly higher in the FLHT group (P < 0.05). Moreover, there was no difference in textural properties between FLHT samples and fresh meat (FS) (P > 0.05), due to its homogeneous and compact microstructure. Therefore, FLHT plays an essential role in holding a superior gel quality and a compact structure, thereby evidencing its potential application in meat thawing.

Design and fabrication of diffraction grating with optimized efficiency for transient grating spectroscopy.

Transient grating spectroscopy (TGS) based on diffraction gratings is a powerful optical method for studying the transport of energy carriers such as phonons and electrons. The diffraction grating in a TGS system is a key component to form a large-area interference pattern, i.e., transient grating, and to study the mean free path distribution of energy carriers. In this work, a design method for polarization-insensitive diffraction gratings with periods in the range 2-50 µm for TGS by a combination of rigorous coupled wave analysis and genetic algorithm was discussed. The method was tested for pump/probe wavelength of 515/532 or 1030/808 nm. Each ±1st diffraction order carries 35%-40% of the incident energy and the diffraction efficiencies of the other orders are lower than 10%. The optimized diffraction gratings were fabricated by a combination of photolithography and inductively coupled plasma etching, with the processing parameters introduced in detail, and their optical characteristics were evaluated. Finally, as a demonstration, the diffraction gratings for 1030/808 nm were applied to TGS to study the thermal transport properties of Ge. This work provides a useful guide for future applications and the development of TGS.

A systematic review and meta-analysis of risk factors for intensive care unit acquired weakness.

BACKGROUND: The aim of this meta-analysis is to systematically evaluate and summarize the risk factors of intensive care unit acquired weakness (ICU-AW), to provide evidence-based evidence for the formulation of prevention strategies for ICU-AW. METHODS: PubMed, EMBASE, Web of Science, CBM (China Biology Medicine, China), Chinese National Knowledge Infrastructure, Chinese WANFANG, and VIP will be searched to define relevant risk factors for ICU-AW. The databases search period is from January 1, 2005 to August 13, 2021. The Newcastle Ottawa Scale (NOS) is used to evaluate the quality of the included studies. RevMan 5.3 analysis software will be used for meta-analysis. RESULTS: This systematic review and meta-analysis included a total of 12 cohort studies, including 9 international journals and 3 Chinese journals, with a total of 1950 patients, of which 856 had ICU-AW. The results showed that the significant risk factors for ICU-AW included female (odds ratio [OR] = 1.34, 95% confidence interval [CI]: 1.06-1.71; P = .02), mechanical ventilation days (OR = 3.04, 95% CI: 1.82-4.26; P < .00001), age (OR = 6.33, 95% CI: 5.05-7.61; P < .00001), length of intensive care unit (ICU) stay (OR = 3.78, 95% CI: 2.06-5.51; P < .0001), infectious disease (OR = 1.67, 95% CI: 1.20-2.33; P = .002), renal replacement therapy (OR = 1.59, 95% CI: 1.11-2.28; P = .01), use of aminoglucoside drugs (OR = 2.51, 95% CI: 1.54-4.08; P = .0002), sepsis related organ failure assessment (SOFA) score (OR = 1.07, 95% CI: 0.24-1.90; P = .01), hyperglycemia (OR = 2.95, 95% CI: 1.70-5.11; P = .0001). CONCLUSION: This meta-analysis provides comprehensive evidence-based on the assessment of the risk factors for ICU-AW, their multifactorial etiology was confirmed. This study indicated that female, mechanical ventilation days, age, length of ICU stay, infectious disease, renal replacement therapy, use of aminoglucoside drugs, SOFA score, and hyperglycemia are independent risk factors for ICU-AW. We have not found consistent evidence that corticosteroids, neuromuscular blockers, sepsis have any effect on ICU-AW risk.

A Multi-Specific DARPin Potently Neutralizes Shiga Toxin 2 via Simultaneous Modulation of Both Toxin Subunits.

Shiga toxin-producing E. coli (STEC) is a common cause of bloody diarrhea. The pathology of STEC infection derives from two exotoxins-Shiga toxin 1 (Stx1) and Shiga toxin 2 (Stx2)-that are secreted by STEC in the gut, from where they are systemically absorbed, causing severe kidney damage leading to hemolytic uremic syndrome (HUS). Currently, there is no effective treatment for HUS, and only supportive care is recommended. We report the engineering of a panel of designed ankyrin repeat proteins (DARPin) with potent neutralization activity against Stx2a, the major subtype associated with HUS. The best dimeric DARPin, SD5, created via a combination of directed evolution and rational design, neutralizes Stx2a with a half maximal effective concentration (EC50) of 0.61 nM in vitro. The two monomeric DARPin constituents of SD5 exhibit complementary functions-SHT targets the enzymatic A subunit of Stx2a and inhibits the toxin's catalytic activity, while DARPin #3 binds the B subunit, based on the cryo-EM study, and induces a novel conformational change in the B subunit that distorts its five-fold symmetry and presumably interferes with toxin attachment to target cells. SD5 was fused to an albumin-binding DARPin, and the resulting trimeric DARPin DA1-SD5 efficiently protects mice in a toxin challenge model, pointing to a high potential of this DARPin as a therapeutic for STEC infection. Finally, the unprecedented toxin conformational change induced by DARPin #3 represents a novel mode of action for neutralizing Stx2 toxicity and reveals new targets for future drug development.

Sesame allergy: mechanisms, prevalence, allergens, residue detection, effects of processing and cross-reactivity.

Sesame allergy is a serious public health problem and is mainly induced by IgE-mediated reactions, whose prevalence is distributed all over the world. Sesame has been included on the priority allergic food list in many countries. This review summarizes the mechanism and prevalence of sesame allergy. The characteristics, structures and epitopes of sesame allergens (Ses i 1 to Ses i 7) are included. Moreover, the detection methods for sesame allergens are evaluated, including nucleic-acid, immunoassays, mass spectrometry, and biosensors. Various processing techniques for reducing sesame allergenicity are discussed. Additionally, the potential cross-reactivity of sesame with other plant foods is assessed. It is found that the allergenicity of sesame is related to the structures and epitopes of sesame allergens. Immunoassays and mass spectrometry are the major analytical tools for detecting and quantifying sesame allergens in food. Limited technologies have been successfully used to reduce the antigenicity of sesame, involving microwave heating, high hydrostatic pressure, salt and pH treatment. More technologies for reducing the allergenicity of sesame should be widely investigated in future studies. The reduction of allergenicity in processed sesames should be ultimately confirmed by clinical studies. What's more, sesame may exhibit cross-reactivity with peanut and tree nuts.

Understanding the Antecedents of the Routine Use of Mobile Health Services: A Person-Technology-Health Framework.

Although numerous studies have been conducted to understand the antecedents of usage of mobile health (mHealth) services, most of them solely focus on characteristics of mHealth services themselves but neglect taking users' psychological and health-related factors into consideration. Besides, the comprehensive understanding of what influences users' routine use intentions regarding mHealth services is lacking. Therefore, this study proposes a person-technology-health framework that underlines how personal factors (e.g., personal innovativeness in IT), technological factors (e.g., trust), and health factors (e.g., perceived health severity) jointly influence individuals' routine use intentions regarding mHealth services. The proposed research model and related hypotheses were tested based on survey data from 270 respondents. The results indicate that personal innovativeness in IT, trust, and perceived health severity are important for enhancing routine use intention of mHealth services. Specifically, in situations of high perceived health severity, trust relates less positively to routine use intention than personal innovativeness in IT. In contrast, in situations of low perceived health severity, trust relates more positively to routine use intention than personal innovativeness in IT. The research findings extend the existing literature on routine use intention related to mHealth services and provide significant implications for practitioners.