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The Fused Filament Fabrication is an economic 3D printing process to produce lightweight polymers-based structures. Therefore, it is drawing a consistently increasing interest from industry and researchers. Flexural and impact properties are two of the critical performance measures for gauging the integrity of the printed structures. Since 2014, numerous studies have been carried out on this topic, however, their holistic overview with a focus on the flexural and impact properties has been barely presented in the literature. The current article reviews the relationship between the process parameters, both operating and geometrical, and these properties in detail. The cause-effect relationship is thoroughly examined considering material effect. This allows the identification of the complex interactive effects and conducive ranges of the important parameters to effectively control the process for achieving the desired mechanical properties. The review establishes that the crystallinity of post-printed polymers is a crucial factor in controlling the mechanical properties, and filled polymers generally offer better properties than unfilled ones if the right filler given the desired properties is chosen. Topology optimization, recyclability of polymers through FFF, and retention of polymer properties after printing are also discussed as innovative trends. Finally, limitations and research gaps are identified, and the latest ideas are proposed as a way forward for further development of the FFF technology.

To develop high activity Auricularia auricula polysaccharide yogurt, Auricularia cornea var. Li. polysaccharides was used as the material to determine its basic components and rheological properties, and the production process of ACP yogurt was optimized by one-way comparative experiments and orthogonal experiments. Moreover, the effect of ACP on the quality of yogurt was investigated in order to develop high-activity Auricularia cornea polysaccharides yogurt. The results showed that: The total sugar, glucuronic acid and protein contents of ACP were 82.21%±2.40%, 11.95%±1.28% and 2.36%±0.10%, respectively. The rheological properties showed that the polysaccharides solution exhibited both liquid and solid characteristics, with good viscoelasticity and potential application as a thickener and gelling agent. What's more, ACP could promote the fermentation of yogurt, increase the number of viable lactic acid bacteria, increase the acidity, and reduce the pH. Low-concentration ACP (0.02%~0.08%) could increase the water-holding capacity of yogurt, improve the tissue condition and stability of yogurt, and reduce whey precipitation. With the amount of ACP added was 0.04%, the yogurt showed the greatest water-holding capacity, hardness, consistency, cohesiveness and viscosity, and the best sensory quality. With the ACP addition amount was 0.06%, the number of viable lactic acid bacteria in yogurt was the largest and the acidity was the highest. The optimal production process of ACP yogurt was to add 0.04% ACP, 6% sucrose, and 0.1% starter culture of fresh milk, ferment at 42 ℃ for 7 hours, and refrigerate at 4 ℃ for 24 hours. The yogurt produced had higher viable bacterial count, better sensory quality and textural properties than ordinary yogurt. This research explored the effect of ACP on lactic acid bacteria fermentation and yogurt quality, in order to provide a scientific theoretical basis for improving the health care performance and quality of yogurt and broadening the application scope of Auricularia cornea var. Li..

Abstract Microengineering the dielectric layers with three-dimensional microstructures has proven effective in enhancing the sensitivity of flexible pressure sensors. However, the widely employed geometrical designs of solid microstructures exhibit limited sensitivity over a wide range of pressures due to their inherent but undesired structural compressibility. Here, a Marangoni-driven deterministic formation approach is proposed for fabricating hollow microstructures, allowing for greater deformation while retarding structural stiffening during compression. Fluid convective deposition enables solute particles to reassemble in template microstructures, controlling the interior cavity with a void ratio exceeding 90%. The hollow micro-pyramid sensor exhibits a 10-fold sensitivity improvement across wider pressure ranges over the pressure sensor utilizing solid micro-pyramids, and an ultra-low detect limit of 0.21 Pa. With the advantages of facilitation, scalability, and large-area compatibility, such an approach for hollow microstructures can be expanded to other sensor types for superior performance and has considerable potential in robotic tactile and epidermal devices.

Abstract Background Cancer cells frequently evolve necroptotic resistance to overcome various survival stress during tumorigenesis. However, we have previously showed that necroptosis is widespread in head and neck squamous cell carcinoma (HNSCC) and contributes to tumor progression and poor survival via DAMPs-induced migration and invasiveness in peri-necroptotic tumor cells. This implicated an alternative strategy that cancers cope with necroptotic stress by reprogramming a pro-invasive necroptotic microenvironment (NME). Here, we aim to decipher how necroptotic cells shape the NME and affect HNSCC progression. Methods Both our pre-established cellular necroptotic model and newly established Dox-induce intratumoral necroptosis model were used to investigate how necroptosis affect HNSCC progression. Transcriptomic alterations in peri-necroptotic tumor cells were analyzed by RNA-seq and validated in the NME in mice and patients’ samples. The differential DAMPs compositon among apopotosis. Necrosis, and necroptosis were analyzed by label-free proteomic technique, and the necroptosis-specific DAMPs were then identified and validated. The potential receptor for ISG15 were simulated using molecular docking and further validated by in vitro assays. Then the ISG15-RAGE axis was blocked by either knockdown of necroptotic-ISG15 release and RAGE inhibitor FPS-ZM1, and the impact on tumor progression were tested. Last, we further tested our findings in a HNSCC-patients cohort. Results Necroptosis played a crucial role in driving tumor-cell invasiveness and lymphatic metastasis via tumor-type dependent DAMPs-releasing. Mechanistically, necroptotic DAMPs induced peri-necroptotic EMT via NF-κB and STAT3 signaling. Furthermore, intrinsic orchestration between necroptotic and cGAS-STING signaling resulted in producing a group of interferon stimulated genes (ISGs) as HNSCC-dependent necroptotic DAMPs. Among them, ISG15 played an essential role in reprogramming the NME. We then identified RAGE as a novel receptor for extracellular ISG15. Either blockage of ISG15 release or ISG15-RAGE interaction dramatically impeded necroptosis-driven EMT and lymphatic metastasis in HNSCC. Lastly, clinicopathological analysis showed high ISG15 expression in NME. Extensive necroptosis and high tumor-cell RAGE expression correlated with tumor progression and poor survival of HNSCC patients. Conclusions Our data revealed a previously unknown cGAS-ISG15-RAGE dependent reprogramming of the necroptotic microenvironment which converts the necroptotic stress into invasive force to foster HNSCC-cell dissemination. By demonstrating the programmatic production of ISG15 via necroptosis-cGAS orchestration and its downstream signaling through RAGE, we shed light on the unique role of ISG15 in HNSCC progression. Targeting such machineries may hold therapeutic potential for restoring intratumoral survival stress and preventing lymphatic metastasis in HNSCC. Graphical Abstract

Abstract To overcome the disadvantages of premature convergence and easy trapping into local optimum solutions, this paper proposes an improved particle swarm optimization algorithm (named NDWPSO algorithm) based on multiple hybrid strategies. Firstly, the elite opposition-based learning method is utilized to initialize the particle position matrix. Secondly, the dynamic inertial weight parameters are given to improve the global search speed in the early iterative phase. Thirdly, a new local optimal jump-out strategy is proposed to overcome the "premature" problem. Finally, the algorithm applies the spiral shrinkage search strategy from the whale optimization algorithm (WOA) and the Differential Evolution (DE) mutation strategy in the later iteration to accelerate the convergence speed. The NDWPSO is further compared with other 8 well-known nature-inspired algorithms (3 PSO variants and 5 other intelligent algorithms) on 23 benchmark test functions and three practical engineering problems. Simulation results prove that the NDWPSO algorithm obtains better results for all 49 sets of data than the other 3 PSO variants. Compared with 5 other intelligent algorithms, the NDWPSO obtains 69.2%, 84.6%, and 84.6% of the best results for the benchmark function ( $${f}_{1}-{f}_{13}$$ f 1 - f 13 ) with 3 kinds of dimensional spaces (Dim = 30,50,100) and 80% of the best optimal solutions for 10 fixed-multimodal benchmark functions. Also, the best design solutions are obtained by NDWPSO for all 3 classical practical engineering problems.

Summary: Background: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with traditional endocrine therapy (ET) are now the recommended first-line treatment for hormone receptor (HR)-positive and HER2-negative metastatic breast cancer (MBC). However, the benefits of adding CDK4/6 inhibitors to ET in HER2-low-positive and HER2-0 subgroups remain unclear. We aimed to assess the effectiveness of CDK4/6 inhibitors in combination with ET in patients with HR-positive, HER2-low-positive and HER2-0 MBC. Methods: This secondary analysis assessed progression-free survival (PFS) among HER2-low-positive and HER2-0 patients enrolled in the double-blind, placebo-controlled randomised clinical trials PALOMA-2 and PALOMA-3. The study included 1186 HER2-negative, HR-positive female patients, with available immunohistochemistry (IHC) and/or in situ hybridization (ISH) results, across 17 countries enrolled between February 2013 and August 2014. HER2-low-positive status was defined by IHC 1+ or 2+ with negative ISH, and HER2-zero by IHC 0. Data analyses were conducted between March and May 2023. In the PALOMA-2 trial, patients were randomly assigned to receive either palbociclib or placebo, in combination with letrozole in the first-line treatment for HR-positive MBC. Patients in the PALOMA-3 study, who had progression or relapse during previous ET, were randomly allocated to receive either palbociclib plus fulvestrant or placebo plus fulvestrant. The primary endpoint was investigator-assessed PFS. Kaplan–Meier approach and Cox proportional hazards model were applied to estimate the association of treatment strategies with PFS among HER2-0 and HER2-low-positive populations. The two trials are registered with ClinicalTrials.gov, number NCT01740427 and NCT01942135. Findings: Of the 666 patients with MBC from the PALOMA-2 study, there were 153 HER2-0 and 513 HER2-low-positive patients. In the HER2-0 population, no significant difference in PFS was observed between the palbociclib-letrozole and placebo-letrozole groups (hazard ratio = 0.79, 95% confidence interval [CI] 0.48–1.30, p = 0.34). In the HER2-low-positive population, palbociclib-letrozole demonstrated a significantly lower risk of PFS than placebo-letrozole group (hazard ratio = 0.52, 95% CI 0.41–0.66, p

Label-free techniques including Surface Plasmon Resonance (SPR) and Biolayer Interferometry (BLI) are biophysical tools widely used to collect binding kinetics data of bimolecular interactions. To efficiently analyze SPR and BLI binding kinetics data, we have built a new high throughput analysis tool named the TitrationAnalysis. It can be used as a package in the Mathematica scripting environment and ultilize the non-linear curve-fitting module of Mathematica for its core function. This tool can fit the binding time course data and estimate association and dissociation rate constants (ka and kd respectively) for determining apparent dissociation constant (KD ) values. The high throughput fitting process is automatic, requires minimal knowledge on Mathematica scripting and can be applied to data from multiple label-free platforms. We demonstrate that the TitrationAnalysis is optimal to analyze antibody-antigen binding data acquired on Biacore T200 (SPR), Carterra LSA (SPR imaging) and ForteBio Octet Red384 (BLI) platforms. The ka , kd and KD values derived using TitrationAnalysis very closely matched the results from the commercial analysis software provided specifically for these instruments. Additionally, the TitrationAnalysis tool generates user-directed customizable results output that can be readily used in downstream Data Quality Control associated with Good Clinical Laboratory Practice operations. With the versatility in source of data input source and options of analysis result output, the TitrationAnalysis high throughput analysis tool offers investigators a powerful alternative in biomolecular interaction characterization.

ABSTRACT: Meat production performance is the most important economic trait in broilers, and skeletal muscle, as the largest organ in animals, is directly related to meat production during embryonic and postnatal growth and development. N6-Methyladenosine (m6A) is a chemical modification occurs on RNA adenosine that has been reported to participate in a variety of biological processes in all species. However, there are still few reports on the regulatory role of muscle growth and development in poultry after birth. This study aims to reveal the distribution of m6A modification sites in chicken pectoralis major muscle after birth and find out the regulatory relationship between m6A and muscle development. As representatives of leaner (Xinghua chicken [XH]) and hypertrophic (White Recessive Rock chicken [WRR]) broilers, there are significant differences in body weight, muscle fiber diameter, and muscle fiber cross-sectional area between XH and WRR chickens. RNA sequencing detected a total of 397 differentially expressed genes (DEG) in the pectoralis major muscle of XH and WRR chicken, and these DEGs were mainly enriched in catalytic activity and metabolic pathways. MeRIP sequencing results showed that among all 6,476 differentially modified m6A peaks, about 90% peaks (5,823) were differentially down regulated in XH chickens. The joint analysis of the mRNA and MeRIP sequencing data found 145 DEGs with differential m6A peak, ALKBH5 as a m6A demethylase, was also included. The highly expression of ALKBH5 in the muscle tissue of poultry and differential expression between XH and WRR chickens suggest that ALKBH5 may play a crucial role in regulating muscle development. Our results revealed that there were significant differences in growth rate, body weight, muscle fiber diameter, and fiber cross-section area between WRR and XH chicken, as well as significant differences in m6A methylation level and muscle metabolism level.

Abstract Purpose Previous randomized studies have shown a survival benefit of using regorafenib but a high rate of adverse events in unresectable colorectal cancer patients. To reduce these adverse events and improve the tolerability, we examined the appropriate dose of regorafenib based on body weight. Methods We used a nationwide claims database in Japan and examined the efficacy and safety of regorafenib for patients with metastatic colorectal cancer between groups divided by body weight (60 kg) and median average dose (120 mg) between 2013 and 2018. We also assessed overall survival (OS) and adverse events between these groups. Results We identified 2530 Japanese patients (heavy weight/high dose: 513, light weight/low dose: 921, heavy weight/low dose: 452, and light weight/high dose: 644). There was no significant difference in the adverse events and OS after inverse probability treatment weighting (IPTW) adjustment between heavy weight/high dose group and light weight/low dose group (hazard ratio, HR=0.97). Among the light-weight patients, higher average dose was associated with shorter OS (IPTW adjusted HR=1.21, 95% CI 1.05 – 1.39, Table 3) while among the heavy-weight patients, there was no significant difference in OS between high and low dose groups (IPTW adjusted HR=1.14, 95% CI 0.95 – 1.37). Conclusion The findings suggest that a low dose of regorafenib for light-weight patients may be as safe and effective as high doses for heavy-weight patients. Further studies should be conducted to identify an appropriate dose based on each patient's physique and condition.

Optically pumped magnetometers can provide functionality for bio-magnetic field detection and mapping. This has attracted widespread attention from researchers in the biomedical science field. Magnetocardiography has been proven to be an effective method for examining heart disease. Notably, vector magnetocardiography obtains more spatial information than the conventional method by only taking a component that is perpendicular to the chest surface. In this work, a spin-exchange-relaxation-free (SERF) magnetometer with a compact size of 14 mm × 25 mm × 90 mm was developed. The device has a high sensitivity of 25 fT/ Hz. Meanwhile, in the multichannel working mode, synchronous sensor manipulation and data acquisition can be achieved through our control software without additional data acquisition boards. Since a typical SERF magnetometer only responds to dual-axis magnetic fields, two sensors are orthogonally arranged to form a vector detection channel. Our system consists of seven channels and allows 7 × 9 vector MCG mapping by scanning. High-quality heart vector signals are measured, and P peak, QRS peak, and T peak can be distinguished clearly. To better demonstrate the vectorial information, a vector scatter plot form is also provided. Through a basic bio-electric current model, it demonstrates that triaxial MCG measurements capture a richer spatial current information than traditional uniaxial MCG, offering substantial diagnostic potential for heart diseases and shedding more light on the inversion of cardiac issues.

Chip-scale devices harnessing the interaction between hot atomic ensembles and light are pushing the boundaries of precision measurement techniques into unprecedented territory. These advancements enable the realization of super-sensitive, miniaturized sensing instruments for measuring various physical parameters. The evolution of this field is propelled by a suite of sophisticated components, including miniaturized single-mode lasers, microfabricated alkali atom vapor cells, compact coil systems, scaled-down heating systems, and the application of cutting-edge micro-electro-mechanical system (MEMS) technologies. This review delves into the essential technologies needed to develop chip-scale hot atomic devices for quantum metrology, providing a comparative analysis of each technology’s features. Concluding with a forward-looking perspective, this review discusses the future potential of chip-scale hot atomic devices and the critical technologies that will drive their advancement.

The speed and accuracy of navigation road extraction and driving stability affect the inspection accuracy of cage chicken coop inspection robots. In this paper, a new grayscale factor (4B-3R-2G) was proposed to achieve fast and accurate road extraction, and a navigation line fitting algorithm based on the road boundary features was proposed to improve the stability of the algorithm. The proposed grayscale factor achieved 92.918% segmentation accuracy, and the speed was six times faster than the deep learning model. The experimental results showed that at the speed of 0.348 m/s, the maximum deviation of the visual navigation was 4 cm, the average deviation was 1.561 cm, the maximum acceleration was 1.122 m/s2, and the average acceleration was 0.292 m/s2, with the detection number and accuracy increased by 21.125% and 1.228%, respectively. Compared with inertial navigation, visual navigation can significantly improve the navigation accuracy and stability of the inspection robot and lead to better inspection effects. The visual navigation system proposed in this paper has better driving stability, higher inspection efficiency, better inspection effect, and lower operating costs, which is of great significance to promote the automation process of large-scale cage chicken breeding and realize rapid and accurate monitoring.

Facile fabrication of highly conductive and self-encapsulated graphene electronics is in urgent demand for carbon-based integrated circuits, field effect transistors, optoelectronic devices, and flexible sensors. The current fabrication of these electronic devices is mainly based on layer-by-layer techniques (separate circuit preparation and encapsulation procedures), which show multistep fabrication procedures, complicated renovation/repair procedures, and poor electrical property due to graphene oxidation and exfoliation. Here, we propose a laser-guided interfacial writing (LaserIW) technique based on self-confined, nickel-catalyzed graphitization to directly fabricate highly conductive, embedded graphene electronics inside multilayer structures. The doped nickel is used to induce chain carbonization, which firstly enhances the photothermal effect to increase the confined temperature for initial carbonization, and the generated carbon further increases the light-absorption capacity to fabricate high-quality graphene. Meanwhile, the nickel atoms contribute to the accelerated connection of carbon atoms. This interfacial carbonization inherently avoids the exfoliation and oxidation of the as-formed graphene, resulting in an 8-fold improvement in electrical conductivity (~20,000 S/m at 7,958 W/cm2 and 2 mm/s for 20% nickel content). The LaserIW technique shows excellent stability and reproducibility, with ±2.5% variations in the same batch and ±2% variations in different batches. Component-level wireless light sensors and flexible strain sensors exhibit excellent sensitivity (665 kHz/(W/cm2) for passive wireless light sensors) and self-encapsulation (

Adding TiB2 particle to SiC particle reinforced Al composite to form TiB2-SiCp/Al composite can increase the tensile properties and lower the thermal expansion coefficient and friction coefficient of the material. The microstructures, mechanical properties, thermal expansion coefficient, and wear behavior of TiB2–SiC particles reinforced AlSi10Mg composites formed by laser powder bed fusion (L-PBF) were investigated in this study. The ultimate tensile strength, thermal expansion coefficient, and the friction coefficient of LPBF-formed 1 vol% TiB2-SiCp/AlSi10Mg composite are 477.6 MPa, 19.91 × 10−6 °C−1, and 0.38, respectively. The results show that the addition of 1 vol% TiB2 weakens the orientation of SiCp/AlSi10Mg composite in the (001) direction. The orientation tends to be random, and the coarse cellular grain with the best orientation in the (001) direction transforms into fine grains in the (111) and (101) directions gradually. This makes the microstructure of the composite be more refined and uniform, eradicating the anisotropy of the temperature gradient, and eliminating the internal stress concentration in the composite. The average grain size of the composite decreases from 3.68 to 1.52 μm. The primary strengthening mechanism of TiB2-SiCp/AlSi10Mg composites is dispersion strengthening. Theoretically, the ultimate tensile strength of the 1 vol% TiB2-SiCp/AlSi10Mg composite is expected to achieve 540.26 MPa.

The determination of illegal drugs and psychoactive substances in wastewater is increasingly being used to monitor the use of both by populations in specific areas. This article describes a method for the simultaneous determination of 78 illegal drugs and psychoactive substances in wastewater using direct-injection ultra-high-performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS). This method includes the analysis of stimulants, opioids, antidepressants, antipsychotic drugs, anti-anxiety drugs, and hallucinogens. The method was validated in terms of the selectivity, calibration range, recovery, matrix effects, accuracy, precision, limit of detection (LOD), and limit of quantification (LOQ). The correlation coefficients were higher than 0.99 for all analytes, and the calibration range was from 0.2 to 500 ng/L. The LOD and LOQ of this method were 0.1–1 ng/L and 0.2–5 ng/L, respectively. The intra- and inter-day precisions were

Seed coating is the most important type of pretreatment. Since cotton is an important economic crop, the cost of its cultivation and the resulting economic benefits are undoubtedly important aspects to be considered. In recent years, the high cost of coating materials and complex production processes have prevented the widespread application of cotton seed coating. Moreover, cotton plants emerge from cotyledons, and the coating material on the seed coat does not play a role after the seed emerges. Given the above shortcomings, to adapt to the mechanized direct seeding method and to include a large number of fertilizers and fungicides, insecticides can be used together with the seed direct seeding into the soil; at the same time, this will improve the cotton seedling emergence rate, the physiological qualities of cotton seedlings after the emergence of cotton seedlings, and the resilience of cotton seedlings in the early stage of resistance ability. In this study, we devised a technique for balling cotton seeds employing components such as cassava starch, bentonite, diatomite, attapulgite, and seedling substrate. The compositional ratios of the method were determined via a growth chamber trial, and we evaluated its effect throughout the cotton reproductive period using field trials. The results showed that the emergence and emergence hole rates of the balled cotton seeds increased by 34.42% and 28.84%, respectively, compared with the uncoated control. In terms of cotton yield, the seed balling treatment increased the number of bolls per plant and the overall cotton yield. Seed balling technology is different from traditional seed pelleting or seed coating techniques. It gathers one or more seeds in seed balls, enabling the simultaneous sowing of multiple seeds of the same variety or different varieties in the same crop. Additionally, seed balls can encourage seeds to carry fertilizer and pesticides into the soil, further weakening soil-borne diseases and abiotic stresses, form a relatively stable internal environment in the soil, and ensure the germination of cotton seeds. Our findings provide a reference point to improve cotton seedling emergence through the utilization of this novel technology.

Background: Almost one-third of patients with major depressive disorder (MDD) do not respond to conventional antidepressants, and new treatments for MDD are urgently needed. Objectives: This phase IIb clinical trial was designed to evaluate the efficacy and safety of Anyu Peibo capsules in the treatment of adults with MDD. Design: A multicenter, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study. Methods: A total of 172 patients with MDD from nine study centers were randomized (1:1) to receive placebo ( n = 86) or oral Anyu Peibo capsules (0.8 g) twice per day ( n = 86) for 6 weeks. The primary endpoint was the change in the Montgomery Åsberg Depression Rating Scale (MADRS) total score from baseline to week 6, analyzed using an analysis of covariance (ANCOVA) approach with the baseline MADRS score, center effect and center by group interaction as the covariates. Other efficacy endpoints and variables included clinical response and remission rates according to the MADRS and the 17-item Hamilton Depression Rating Scale (HAMD-17) scores, the change in the HAMD-17, Clinical Global Impression – Severity scale and Clinical Global Impression – Improvement scale scores and the reduction in the Hamilton Anxiety Scale from baseline to week 6. Results: The mean baseline MADRS total scores were 29.20 and 29.72 in the Anyu Peibo ( n = 82) and placebo groups ( n = 81), respectively. The least squares mean change in the MADRS score from baseline to week 6 was 16.59 points in the Anyu Peibo group and 14.51 points in the placebo group. Although there were greater reductions in the MADRS score from baseline to week 6 in the Anyu Peibo capsule group compared to the placebo group, the difference did not reach statistical significance (least-squares mean difference, 2.07 points; 95% confidence interval, −0.27 to 4.41; p = 0.0819). The results of sensitivity analyses by ANCOVA with the last observation carried forward method for missing data indicated that the administration of Anyu Peibo capsules may lead to a significant reduction in depressive symptoms compared to the placebo (least-squares mean difference: 3.29 points; 95% confidence interval: 0.64–5.93; p = 0.0152). Furthermore, Anyu Peibo capsules showed significant benefits over placebo when the change in the HAMD-17 score from baseline to week 6 was evaluated as the secondary analysis ( t = 2.01; 95% confidence interval, 0.03–4.23; p = 0.0464). Conclusion: Anyu Peibo capsules may have an effective and safe antidepressant effect, which warrants further research.

Summary: IGHV3-33-encoded antibodies are prevalent in the human humoral response against the Plasmodium falciparum circumsporozoite protein (PfCSP). Among VH3-33 antibodies, cross-reactivity between PfCSP major repeat (NANP), minor (NVDP), and junctional (NPDP) motifs is associated with high affinity and potent parasite inhibition. However, the molecular basis of antibody cross-reactivity and the relationship with efficacy remain unresolved. Here, we perform an extensive structure-function characterization of 12 VH3-33 anti-PfCSP monoclonal antibodies (mAbs) with varying degrees of cross-reactivity induced by immunization of mice expressing a human immunoglobulin gene repertoire. We identify residues in the antibody paratope that mediate cross-reactive binding and delineate four distinct epitope conformations induced by antibody binding, with one consistently associated with high protective efficacy and another that confers comparably potent inhibition of parasite liver invasion. Our data show a link between molecular features of cross-reactive VH3-33 mAb binding to PfCSP and mAb potency, relevant for the development of antibody-based interventions against malaria.

Trimethyltin chloride (TMT) is a highly toxic organotin compound often used in plastic heat stabilizers, chemical pesticides, and wood preservatives. TMT accumulates mainly through the environment and food chain. Exposure to organotin compounds is associated with disorders of glucolipid metabolism and obesity. The mechanism by which TMT damages pancreatic tissue is unclear. For this purpose, a subacute exposure model of TMT was designed for this experiment to study the mechanism of damage by TMT on islet. The fasting blood glucose and blood lipid content of mice exposed to TMT were significantly increased. Histopathological and ultrastructural observation and analysis showed that the TMT-exposed group had inflammatory cell infiltration and necrosis. Then, mouse pancreatic islet tumour cells (MIN-6) were treated with TMT. Autophagy levels were detected by fluorescence microscopy. Real-time quantitative polymerase chain reaction and Western blotting were used for verification. A large amount of autophagy occurred at a low concentration of TMT but stagnated at a high concentration. Excessive autophagy activates apoptosis when exposed to low levels of TMT. With the increase in TMT concentration, the expression of necrosis-related genes increased. Taken together, different concentrations of TMT induced apoptosis and necrosis through autophagy disturbance. TMT impairs pancreatic (islet β cell) function.

ABSTRACT The host–bacterial interactions play the key role in inflammatory bowel disease (IBD). Dysbiosis of the intestinal flora can lead to pathological changes in the intestine. Rosmarinic acid (RA) is a natural phenolic acid compound with antioxidant, anti-cancer, anti-inflammatory, anti-apoptotic, anti-fibrotic, and anti-bacterial activities that has a palliative effect on acute IBD. We have established an in vivo model for mice. Histological staining was performed to directly observe RA alterations in the intestinal tract. The alteration of RA on mouse intestinal flora was observed by 16S rRNA high-throughput sequencing, and the effect of RA on intestinal mechanism of action was detected by qPCR and western blot. The results showed that RA had a significant protective effect on the intestine. RA upregulated the abundance of Lactobacillus johnsonii and Candidatus Arthromitus sp SFB-mouse-NL and downregulated the abundance of Bifidobacterium pseudolongum, Escherichia coli, and Romboutsia ilealis. RA downregulated the expressions of ROCK, RhoA, CaM, MLC, MLCK, ZEB1, ZO-1, ZO-2, occludin, E-cadherin, IL-1β, IL-6, TNF-α, GRP78, PERK, IRE1, ATF6, CHOP, Caspase12, Caspase9, Caspase3, Bax, Cytc, RIPK1, RIPK3, MLKL, and upregulated the expression of IL-10 and Bcl-2. These results displayed that RA inhibited the inflammation, which is caused by tight junction damage, by repairing intestinal flora dysbiosis, relieved endoplasmic reticulum stress, inhibited cell death, and corrected smooth muscle contractile dysregulation. The results of this study revealed RA could have a protective effect on the small intestine of mice by regulating intestinal flora. IMPORTANCE Inflammatory bowel disease (IBD) is a chronic, relapsing, remitting disorder of the gastrointestinal system. In this study, we investigated the protective effects of rosmarinic acid on the intestinal tract. The results showed that RA was effective in reducing inflammatory damage, endoplasmic reticulum stress, smooth muscle contraction abnormalities, and regulating intestinal flora disorders.

Tetrabromobisphenol A (TBBPA) is a common brominated flame retardant that has a wide range of toxic effects on organisms. However, the mechanism of the toxic effects of TBBPA on the digestive system has rarely been studied. The purpose of this study was to investigate the mechanism of TBBPA toxicity on the gastric mucosa. In this study, TBBPA (mixed with corn oil) was administered by gavage at doses of 0 mg/kg (CG), 10 mg/kg and 20 mg/kg. The results showed that the levels of ROS, MDA and LPO were increased, and the activities of antioxidant enzymes were decreased. Large amounts of ROS activated the NF-κB pathway, leading to the development of an inflammatory response. The expression of BCL family and Caspase (Cas) family genes was increased, inducing apoptosis. The RIP3/MLKL pathway was activated, leading to cell necrosis. In summary, TBBPA can cause damage to the gastric mucosa through oxidative stress, leading to increased ROS activation of the NF-κB pathway. Treatment with the antioxidant NAC alleviated the damage to the gastric mucosa caused by TBBPA.

A novel method for simultaneous separation and detection of the racemates and the enantiomers of common chiral antidepressants in wastewater matrix was developed by online heart-cutting two-dimensional liquid chromatography (2D-LC) coupled to solid-phase extraction (SPE). Screening of chiral stationary phases (CSPs) and chromatographic conditions was investigated for complete enantioseparation to be compatible with RP-HPLC in 1st D-LC. Using methanol-0.1 % (v/v) ammonia solution as mobile phase, a 2D-LC system was configured by reversed mode with a combination of C18 column and the serially CPS columns as 2D-LC stationary phases respectively. The target analytes could achieve satisfactory transformation between 2D-LCs with transfer rate of 90.57–98.58 %. By means of freeze-drying and SPE, three antidepressants in wastewater were greatly preconcentrated under the optimized conditions, improving the method performance. The racemates and the enantiomers of mirtazapine, bupropion and fluoxetine exhibited good linearity in the range of 0.10–30.00 ng/mL (R2≥0.9986), and LODs and LOQs ranged in 0.0183–0.0549 ng/mL and 0.0661–0.1831 ng/mL, respectively. By this way, the method was successfully applied to simultaneous determination of the racemates and the enantiomers of mirtazapine, bupropion and fluoxetine in wastewater samples. Among them, three samples contained bupropion at level of 0.401–0.822 ng/mL, and mirtazapine at level of 0.328 and fluoxetine at level of 0.381 ng/mL were detected respectively in the other two samples. The enantiomers were at level of 0.140–0.189 ng/mL for mirtazapine, 0.182–0.419 ng/mL for bupropion and 0.179–0.204 ng/mL for fluoxetine, respectively. The proposed method providing an efficient approach to monitoring chiral drugs and their enantiomers in wastewater, facilitating to pollution assessment of chiral drugs in the environment and regional survey of illicit abuse in drug control.

This study aimed to describe the pathogen spectrum of bacteria and viruses of RTIs in hospitalized children during the Coronavirus disease 2019 (COVID-19) epidemic in Shenzhen.

Keyhole plasma arc welding (PAW) of the super duplex stainless steel (SDSS) is expected to achieve full-penetration joints of medium-thickness plates in a single pass with higher efficiency. However, the unique key-holing processes due to the special constricted arc behaviors cause much different thermal cycles of the liquid metals as well as changed microstructures. SDSS 2507 with a thickness of 10 mm was joined by PAW to investigate the joints' microstructure and properties. Microstructure characterization reveals substantial differences in the content of austenite, ranging from 68.9% in weld metal (WM) to 32.1% in the heat-affected zone (HAZ). The oxide inclusions in the WM enhance the hardness of the welded joints, but provide the path for crack propagation to decrease its impact toughness. While complicated microstructure is found in HAZ forming ferrite and diverse austenite, such as grain boundary austenite (GBA), intragrain austenite (IGA), and Widmanstätten austenites (WA). A small amount of secondary austenite (γ2) and chromium nitride are also found in HAZ, and they significantly deteriorate its corrosion resistance. The grain boundary misorientation angle distribution of the austenite in WM is found to be dominated by the low angle boundaries (LABs). However, its content decreases from the WM to base metal (BM). Selective corrosion occurs in all samples, where ferrite is preferentially dissolved when the extrinsic voltage is low (0.5 V), indicating the different electrochemical activity of the two phases.

The present study aims to reveal the deterioration law and service life of concrete durability in the saline soil area of western China. For this purpose, the indoor accelerated tests with multiple damage factors including compound salt erosion, dry-wet cycle, freeze-thaw damage, and solar radiation were designed. The deterioration mechanisms of concrete durability were analysed from both macroscopic and microscopic aspects. The Birnbaum-Saunders (B-S) model was selected for modeling, and parameters were estimated by various methods such as moment estimation method (MEM), inverse estimation method (IMEM), quantile estimation Method (QEM), regression estimation method (REM), and maximum likelihood method (MIM). The results showed that under the action of multiple damage factors, the surface of the concrete gradually becomes rough and pitted from the initial smooth and flat surface. As the concrete’s interior gel is not dense, rod-shaped, and needle-shaped corrosion products were formed. For the two-parameter model, the reliability curve, density curve, and failure rate curve obtained by the QEM differ the most from the other 5 types of parameter estimation methods. When the MEM is used for parameter estimation, the difference between the two-parameter model and the three-parameter model under the same reliability level is relatively small.

Abstract Background N6-methyladenosine (m6A) is an abundant post-transcriptional RNA modification that affects various biological processes. The fat mass and obesity-associated (FTO) protein, a demethylase encoded by the FTO gene, has been found to regulate adipocyte development in an m6A-dependent manner in multiple species. However, the effects of the m6A methylation and FTO demethylation functions on chicken adipogenesis remain unclear. This study aims to explore the association between m6A modification and chicken adipogenesis and the underlying mechanism by which FTO affects chicken preadipocyte development. Results The association between m6A modification and chicken lipogenesis was assessed by treating chicken preadipocytes with different doses of methyl donor betaine and methylation inhibitor cycloleucine. The results showed that betaine significantly increased methylation levels and inhibited lipogenesis, and the inverse effect was found in preadipocytes after cycloleucine treatment. Overexpression of FTO significantly inhibited m6A levels and promoted proliferation and differentiation of chicken preadipocytes. Silencing FTO showed opposite results. Mechanistically, FTO overexpression increased the expression of catenin beta 1 (CTNNB1) by improving RNA stability in an m6A-dependent manner, and we proved that FTO could directly target CTNNB1. Furthermore, CTNNB1 may be a positive regulator of adipogenesis in chicken preadipocytes. Conclusions m6A methylation of RNA was negatively associated with adipogenesis of chicken preadipocytes. FTO could regulate CTNNB1 expression in a demethylation manner to promote lipogenesis.

Abstract Aim Our study aimed to evaluate the sleep status of psychiatric nurses in Chinese population and analyse the influencing factors. Design Cross‐sectional, correlation design with logistic regression analysis. Methods We investigated 1,044 psychiatric nurses from seven psychiatric hospitals in China. Pittsburgh Sleep Quality Index and Maslach Burnout Inventory General Survey were used as main measures. Results The average Pittsburgh Sleep Quality Index score of 1,044 psychiatric nurses was 7.00 ± 3.59, and 38.63% of nurses had a total Pittsburgh Sleep Quality Index score >7. Our study found that middle‐night shift nurses had poor sleep quality and sleep disorders are positively correlated with emotional exhaustion and cynical disregard for job burnout. Middle‐night shift nurses showed 1.586 times more likely to suffer from sleep disorders than those non‐middle‐night shift. The higher the score of emotional exhaustion, the greater the risk of sleep disorders.

Abstract Owing to excellent performance and a simple mechanism, stretchable piezoresistive strain sensors have been applied to human skin for monitoring physical activities, physiological activities, etc. However, it is still a challenge to simultaneously realize highly sensitive and stretchable piezoresistive strain sensors with high optical transparency. This study reports a transparent and stretchable piezoresistive strain sensor with 2D surface buckling by fabricating ultrathin indium tin oxide (ITO) film on the biaxially pre‐stretched polyacrylate (VHB) elastomer followed by pre‐stretch releasing. To the authors' knowledge, semiconductors are applied for a stretchable piezoresistive strain sensor for the first time. Furthermore, this strain sensor exhibits a high sensitivity of 569, a high transparency of 88% and a high biaxial stretchability of 110% at the same time. This device demonstrates the good long‐term stability over 500 stretching–relaxing cycles. The high sensitivity can be mainly attributed to the piezoresistive effect of the semiconductor where carrier mobility and the resulting resistivity can be significantly changed by the strain. The strain sensors attached to human skin are used to monitor many human motions such as chewing, swallowing, breathing, and walking. ITO‐based strain sensors pave the way toward the development of highly stretchable and sensitive wearable electronics.

Label-free techniques including Surface Plasmon Resonance (SPR) and Biolayer Interferometry (BLI) are biophysical tools widely used to collect binding kinetics data of bimolecular interactions. To efficiently analyze SPR and BLI binding kinetics data, we have built a new high throughput analysis tool named the TitrationAnalysis. It can be used as a package in the Mathematica scripting environment and ultilize the non-linear curve-fitting module of Mathematica for its core function. This tool can fit the binding time course data and estimate association and dissociation rate constants (ka and kd respectively) for determining apparent dissociation constant (KD) values. The high throughput fitting process is automatic, requires minimal knowledge on Mathematica scripting and can be applied to data from multiple label-free platforms. We demonstrate that the TitrationAnalysis is optimal to analyze antibody-antigen binding data acquired on Biacore T200 (SPR), Carterra LSA (SPR imaging) and ForteBio Octet Red384 (BLI) platforms. The ka, kd and KD values derived using TitrationAnalysis very closely matched the results from the commercial analysis software provided specifically for these instruments. Additionally, the TitrationAnalysis tool generates user-directed customizable results output that can be readily used in downstream Data Quality Control associated with Good Clinical Laboratory Practice operations. With the versatility in source of data input source and options of analysis result output, the TitrationAnalysis high throughput analysis tool offers investigators a powerful alternative in biomolecular interaction characterization.

Abstract Immunotherapy has been recognized as one of the most promising treatment strategies for head and neck squamous cell carcinoma (HNSCC). As a pioneering trend of immunotherapy, dendritic cell (DC) vaccines have displayed the ability to prime an immune response, while the insufficient immunogenicity and low lymph node (LN) targeting efficiency, resulted in an unsubstantiated therapeutic efficacy in clinical trials. Herein, a hybrid nanovaccine (Hy‐M‐Exo) is developed via fusing tumor‐derived exosome (TEX) and dendritic cell membrane vesicle (DCMV). The hybrid nanovaccine inherited the key protein for lymphatic homing, CCR7, from DCMV and demonstrated an enhanced efficiency of LN targeting. Meanwhile, the reserved tumor antigens and endogenous danger signals in the hybrid nanovaccine activated antigen presenting cells (APCs) elicited a robust T‐cell response. Moreover, the nanovaccine Hy‐M‐Exo displayed good therapeutic efficacy in a mouse model of HNSCC. These results indicated that Hy‐M‐Exo is of high clinical value to serve as a feasible strategy for antitumor immunotherapy.

Transformer-based models for action segmentation have achieved high frame-wise accuracy against challenging benchmarks. However, they rely on multiple decoders and self-attention blocks for informative representations, whose huge computing and memory costs remain an obstacle to handling long video sequences and practical deployment. To address these issues, we design a light transformer model for the action segmentation task, named LASFormer, with a novel encoder–decoder structure based on three key designs. First, we propose a receptive field-guided distillation to realize mode reduction, which can overcome more generally the gap in semantic feature structure between the intermediate features by aggregated temporal dilation convolution (ATDC). Second, we propose a simplified implicit attention to replace self-attention to avoid its quadratic complexity. Third, we design an efficient action relation encoding module embedded after the decoder, where the temporal graph reasoning introduces an inductive bias that adjacent frames are more likely to belong to the same class of model global temporal relations, and the cross-model fusion structure integrates frame-level and segment-level temporal clues, which can avoid over-segmentation independent of multiple decoders, thus reducing further computational complexity. Extensive experiments have verified the effectiveness and efficiency of the framework. Against the challenging 50Salads, GTEA, and Breakfast benchmarks, LASFormer significantly outperforms the current state-of-the-art methods in accuracy, edit score, and F1 score.

Abstract Road geometry perception indicates road direction and drivable area for Lane Keeping System and Lane Departure Warning System in Advanced Driver Assistance Systems or routing and decision‐making in Autonomous Driving. High‐definition map with accurate positioning or lane information is generally required. However, these two types of information are not always available because of positioning failure or lane mark degradation. In this paper, a road geometry estimation method is proposed without requirement of accurate positioning and lane information. Due to the fact the lane guides the front vehicle, the potential correlation between the relative azimuth of front vehicle and the direction of road is explored. The stable and observable information of front vehicles are exploited, such as the license plate location. A radar‐camera fusion system using image processing, and a nonlinear system is then built with Unscented Kalman Filter to estimate the road curvature. Simulation results with Carla demonstrate that the method enhances the road geometry perception by 77.1%, compared with the baseline method. The proposed method can provide reliable road geometry information for autonomous driving when accurate positioning and lane information are unavailable, so that it renders more robust and safer perception for future autonomous driving.

Tetrabromobisphenol A (TBBPA), a non-degradable environmental pollutant, was discharge into the air during the manufacture, use and recycling of plastic products. Respiratory exposure is the main way to inhalation of TBBPA. However, the research on the damage of TBBPA to the respiratory system is still extremely few. The aim of this experiment was to explore the mechanism of TBBPA toxicity to the lungs. Forty C57BL/6 J mice randomly divided into 4 groups, and the experimental groups with TBBPA at 10 n M/kg, 20 n M/kg and 40 n M/kg for 14 consecutive days. Histopathological and ultrastructural analysis showed that the inflammatory cells infiltrated and tissue structure damaged in the lung of mice with exposing to TBBPA. The ROS and MDA levels increase and the T-AOC, GSH-Px, CAT, SOD activities inhibition was found in lung tissue with TBBPA exposure. The expression of autophagy-related factors Beclin-1, P62, LC3-II, ATG5, and ATG7 decreased. The activation of NF-κB/TNF-α pathway indicates the occurrence of inflammation. The expression of Bax, caspase3, caspase7, caspase 9 increase, the expression of Bcl-2 decreased, and the apoptosis pathway activated. The autophagy inducer rapamycin can reverse the adverse effects of inflammation and apoptosis. Taken together, TBBPA inhibits autophagy-induced pneumonia and apoptosis by overproduction ROS.

Introduction: Phosphoinositide 3-kinase gamma (PI3Kγ) has been regarded as a promising drug target for the treatment of various diseases, and the diverse physiological roles of class I PI3K isoforms (α, β, δ, and γ) highlight the importance of isoform selectivity in the development of PI3Kγ inhibitors. However, the high structural conservation among the PI3K family makes it a big challenge to develop selective PI3Kγ inhibitors. Objectives: A novel machine learning-based virtual screening with multiple PI3Kγ protein structures was developed to discover novel PI3Kγ inhibitors. Methods: A large chemical database was screened using the virtual screening model, the top-ranked compounds were then subjected to a series of bio-evaluations, which led to the discovery of JN-KI3. The selective inhibition mechanism of JN-KI3 against PI3Kγ was uncovered by a theoretical study. Results: 49 hits were identified through virtual screening, and the cell-free enzymatic studies found that JN-KI3 selectively inhibited PI3Kγ at a concentration as low as 3,873 nM but had no inhibitory effect on Class IA PI3Ks, leading to the selective cytotoxicity on hematologic cancer cells. Meanwhile, JN-KI3 potently blocked the PI3K signaling, finally led to distinct apoptosis of hematologic cell lines at a low concentration. Lastly, the key residues of PI3Kγ and the structural characteristics of JN-KI3, which both would influence γ isoform-selective inhibition, were highlighted by systematic theoretical studies. Conclusion: The developed virtual screening model strongly manifests the robustness to find novel PI3Kγ inhibitors. JN-KI3 displays a specific cytotoxicity on hematologic tumor cells, and significantly promotes apoptosis associated with the inhibition of the PI3K signaling, which depicts PI3Kγ as a potential target for the hematologic tumor therapy. The theoretical results reveal that those key residues interacting with JN-KI3 are less common compared to most of the reported PI3Kγ inhibitors, indicating that JN-KI3 has novel structural characteristics as a selective PIK3γ inhibitor.

A novel drug monitoring method is experimentally demonstrated by optically pumped atomic magnetometer. An elliptically polarized single-beam spin-exchange-relaxation-free atomic magnetometer (SERF AM) is used to realize magnetorelaxometry (MRX) measurement and thereby quantify concentrations of superparamagnetic nanoparticles in solutions. Moreover, drug-conjugated magnetic nanoparticles are monitored in mice for twelve hours to study the drug sustained-release mechanism. Our results show the great potential of optically pumped atomic magnetometer for application in biophysical, pharmaceutical and medical areas, and may promote fields such as drug delivery research, virus detection, and molecule quantification.

Diversity in specificity of polyclonal antibody (pAb) responses is extensively investigated in vaccine efficacy or immunological evaluations, but the heterogeneity in antibody avidity is rarely probed as convenient tools are lacking. Here we have developed a polyclonal antibodies avidity resolution tool (PAART) for use with label-free techniques, such as surface plasmon resonance and biolayer interferometry, that can monitor pAb-antigen interactions in real time to measure dissociation rate constant (kd) for defining avidity. PAART utilizes a sum of exponentials model to fit the dissociation time-courses of pAb-antigens interactions and resolve multiple kd contributing to the overall dissociation. Each kd value of pAb dissociation resolved by PAART corresponds to a group of antibodies with similar avidity. PAART is designed to identify the minimum number of exponentials required to explain the dissociation course and guards against overfitting of data by parsimony selection of best model using Akaike information criterion. Validation of PAART was performed using binary mixtures of monoclonal antibodies of same specificity but differing in kd of the interaction with their epitope. We applied PAART to examine the heterogeneity in avidities of pAb from malaria and typhoid vaccinees, and individuals living with HIV-1 that naturally control the viral load. In many cases, two to three kd were dissected indicating the heterogeneity of pAb avidities. We showcase examples of affinity maturation of vaccine induced pAb responses at component level and enhanced resolution of heterogeneity in avidity when antigen-binding fragments (Fab) are used instead of polyclonal IgG antibodies. The utility of PAART can be manifold in examining circulating pAb characteristics and could inform vaccine strategies aimed to guide the host humoral immune response.

Summary: The SARS-CoV-2 Omicron variant of concern (VoC) and its sublineages contain 31–36 mutations in spike and escape neutralization by most therapeutic antibodies. In a pseudovirus neutralization assay, 66 of the nearly 400 candidate therapeutics in the Coronavirus Immunotherapeutic Consortium (CoVIC) panel neutralize Omicron and multiple Omicron sublineages. Among natural immunoglobulin Gs (IgGs), especially those in the receptor-binding domain (RBD)-2 epitope community, nearly all Omicron neutralizers recognize spike bivalently, with both antigen-binding fragments (Fabs) simultaneously engaging adjacent RBDs on the same spike. Most IgGs that do not neutralize Omicron bind either entirely monovalently or have some (22%–50%) monovalent occupancy. Cleavage of bivalent-binding IgGs to Fabs abolishes neutralization and binding affinity, with disproportionate loss of activity against Omicron pseudovirus and spike. These results suggest that VoC-resistant antibodies overcome mutagenic substitution via avidity. Hence, vaccine strategies targeting future SARS-CoV-2 variants should consider epitope display with spacing and organization identical to trimeric spike.

Many slabbing rock masses have emerged in hydropower slopes and underground engineering, with the construction of basic engineering and resource development projects along the zone of the Belt and Road. The anti-dip slabbing rock mass is prone to toppling and the degree of slabbing controls the development of toppling deformation. There are a few reports on the mechanical mechanism of rock mass toppling deformation after slabbing. Based on the analysis of the genetic conditions of rock mass slabbing, the influence of rock mass after slabbing on toppling deformation was explored by means of the mechanics method. The toppling bending deflection (TBD) and the toppling fracture depth (TFD) were selected as the analysis indexes, and the response regularity of slabbing on toppling rock mass was analyzed with examples. The results show that the width and thickness of the slabbing rock mass become narrower and thinner, the toppling bending deflection (TBD) increases, the toppling fracture depth (TFD) decreases, and the toppling deformation and failure intensify. The TBD is independent of the width of rock mass slabbing under self-weight, and the change of TBD is slow when the slab beam slabbing number (n) of thickness is

ABSTRACT Intestinal microbiota dysbiosis is a well established characteristic of ulcerative colitis (UC). Regulating the gut microbiota is an effective UC treatment strategy. Berberine (BBR), an alkaloid extracted from several Chinese herbs, is a common traditional Chinese medicine. To establish the efficacy and mechanism of action of BBR, we constructed a UC model using healthy adult shorthair cats to conduct a systematic study of colonic tissue pathology, inflammatory factor expression, and gut microbiota structure. We investigated the therapeutic capacity of BBR for regulating the gut microbiota and thus work against UC in cats using 16S rRNA genes amplicon sequencing technology. Our results revealed that dextran sulfate sodium (DSS)-induced cat models of UC showed weight loss, diarrhea accompanied by mucous and blood, histological abnormalities, and shortening of the colon, all of which were significantly alleviated by supplementation with BBR. A 16S rRNA gene-based microbiota analysis demonstrated that BBR could significantly benefit gut microbiota. Western blot, quantitative PCR, and enzyme-linked immunosorbent assays (ELISAs) showed that in DSS-induced cat models, the expression of the inflammatory factors was increased, activating the JAK2/STAT3 signaling pathway, and treatment with BBR reversed this effect. The myosin light chain (MLC) phosphorylation in the smooth muscle of the intestines is associated with motility of inflammation-related diarrhea in cats. This study used gut flora analyses to demonstrate the anti-UC effects of BBR and its potential therapeutic mechanisms and offers novel insights into the prevention of inflammatory diseases using natural products. IMPORTANCE Ulcerative colitis (UC) is common in clinics. Intestinal microbiota disorder is correlated with ulcerative colitis. Although there are many studies on ulcerative colitis in rats, there are few studies on colitis in cats. Therefore, this study explored the possibility of the use of BBR as a safe and efficient treatment for colitis in cats. The results demonstrated the therapeutic effects of BBR on UC based on the state of the intestinal flora. The study found BBR supplementation to be effective against dextran sulfate sodium (DSS)-induced colitis, smooth muscle damage, and gut microbiota dysbiosis.

ABSTRACT: Prior studies on transcriptomes of hypothalamus and ovary revealed that AKT3 is one of the candidate genes that might affect egg production in White Muscovy ducks. The role of AKT3 in the uterus during reproductive processes cannot be overemphasized. However, functional role of this gene in the tissues and on egg production traits of Muscovy ducks remains unknown. To identify the relationship between AKT3 and egg production traits in ducks, relative expression profile was first examined prior to identifying the variants within AKT3 that may underscore egg production traits [age at first egg (AFE), number of eggs at 300 d (N300D), and number of eggs at 59 wk (N59W)] in 549 ducks. The mRNA expression of AKT3 gene in high producing (HP) ducks was significantly higher than low producing (LP) ducks in the ovary, oviduct, and hypothalamus (P < 0.05 or 0.001). Three variants in AKT3 (C-3631A, C-3766T, and C-3953T) and high linkage block between C-3766T and C-3953T which are significantly (P < 0.05) associated with N300D and N59W were discovered. This study elucidates novel knowledge on the molecular mechanism of AKT3 that might be regulating egg production traits in Muscovy ducks.

N6-Methyladenosine (m6A) has been reported to involve and play an important role in various biological activities but seldom in poultry myogenesis. Cycloleucine usually functions as a nucleic acid methylation inhibitor, the inhibition efficiency of cycloleucine at the m6A level and corresponding dynamic changes of poultry muscle cells remain unknown. In this study, we aim to find out the effect of cycloleucine on the total N6-Methyladenosine level and its molecular mechanism for regulating myogenesis. A total of 745 differentially expressed genes (DEGs) were obtained by 10 mM, 20 mM, and 30 mM of cycloleucine treatment compared with 0 mM treatment. DEGs in 10 mM cycloleucine were significantly enriched in the biological process of skeletal muscle and satellite cell proliferation and differentiation, DEGs in 20 and 30 mM cycloleucine were enriched in some metabolic and biosynthetic processes. The trend analysis showed that 85% of all DEGs were significantly clustered into 4 files, among them 59% DEGs were dose-dependent and 26% were dose-independent, 52% DEGs were in downtrend and 33% DEGs were in uptrend. Also, the cycloleucine treatment could trigger cell cycle arrest in the G1 phase and depress myoblast cell proliferation and inhibit myotube formation. In conclusion, cycloleucine could continuously reduce the m6A level of myoblast cells, depress myoblast cell proliferation and inhibit myotube formation.

Antibodies targeting the human malaria parasite Plasmodium falciparum circumsporozoite protein (PfCSP) can prevent infection and disease. PfCSP contains multiple central repeating NANP motifs; some of the most potent anti-infective antibodies against malaria bind to these repeats. Multiple antibodies can bind the repeating epitopes concurrently by engaging into homotypic Fab-Fab interactions, which results in the ordering of the otherwise largely disordered central repeat into a spiral. Here, we characterize IGHV3-33/IGKV1-5-encoded monoclonal antibody (mAb) 850 elicited by immunization of transgenic mice with human immunoglobulin loci. mAb 850 binds repeating NANP motifs with picomolar affinity, potently inhibits Plasmodium falciparum (Pf) in vitro and, when passively administered in a mouse challenge model, reduces liver burden to a similar extent as some of the most potent anti-PfCSP mAbs yet described. Like other IGHV3-33/IGKV1-5-encoded anti-NANP antibodies, mAb 850 primarily utilizes its HCDR3 and germline-encoded aromatic residues to recognize its core NANP motif. Biophysical and cryo-electron microscopy analyses reveal that up to 19 copies of Fab 850 can bind the PfCSP repeat simultaneously, and extensive homotypic interactions are observed between densely-packed PfCSP-bound Fabs to indirectly improve affinity to the antigen. Together, our study expands on the molecular understanding of repeat-induced homotypic interactions in the B cell response against PfCSP for potently protective mAbs against Pf infection.

Abstract With exceptional performance, flexible sensors have found broad applications, including human health monitoring, motion detection, human–machine interaction, smart wearable technology, and robot control. Crack‐sensitive structures based on animal bionics have also caught increasing attention because of their extraordinary sensitivity. Crack‐based flexible sensors, which combine the flexibility of the flexible sensors and the high sensitivity of the crack sensing structures, have seen rapid development in recent years. In this review, we summarize the sensing mechanisms of the flexible sensors based on the crack disconnection–reconnection process. The effects of crack type, depth, and density on sensor performance are explored in detail. We also discuss the performance characteristics and applications of the crack‐based flexible sensors with various materials, design structures, and crack generation procedures. Finally, the main challenges of the crack‐based flexible sensors are also reviewed, and several research directions are proposed.

With the structure of biprism, polarization beam splitting in a Glan-Taylor polarizer was explored based on the birefringence and Goos-Hanchen shift. Due to the birefringence of the light in calcite crystal, the extraordinary light worked as the position calibration. As for the ordinary light, the propagated direction tilted noticeably due to the refraction as well as Goos-Hanchen effect at the prism-air interface of in the air gap. The Snell's law and stationary-phase approach were utilized for the calculation of the beam splitting between the two orthogonal polarization elements. By choosing appropriate incident angle and initial polarization, remarkable beam splitting was realized. With this configuration, the resolution with a magnitude of 10−5° and 10−3° was achieved for the response of the incident angle and polarization detection respectively.

Additive 3D printing has been one of the most powerful and effective techniques to realize 3D intricate structures. However, its limitations including a high threshold for high-precision preparation and poor surface roughness in metalworking impede further development, such as metallic pentamode metamaterials (PMs) due to the special structural regimes and extremely strict size requirement at the intersection nodes. Herein, a novel electropolishing-enhanced 3D printing method is proposed to fabricate high-precision metallic PMs with improved precision and surface smoothness. Experimental results evince that this hybrid additive-subtractive method can fabricate PMs with much smaller critical size and smoother surface, which cannot be achieved by the same-level 3D printing methods. The minimum processable size can reach ∼ 100 μm that greatly breaks through the limitation of initial additive manufacturing (EOS M280 SLM, ∼ 200 ± 50 μm). A ∼ 100 μm intersection can support 107 times its own weight. Moreover, the D/d of elementary biconical rods can be refined from an initial 6 to an astounding 52, which is beyond the scope of conventional 3D printing. This proposed hybrid additive-subtractive method, namely electropolishing-enhanced 3D printing, breaks the limits of conventional 3D printing by significantly improving the precision and shows great potential in low-cost but high-precision manufacturing.

Multiple primary cancers (MPCs) refer to cancers that occur simultaneously or metachronously in the same individual. The incidence of MPC has increased recently, as the survival time of malignant tumor patients has been greatly prolonged. It is difficult to differentiate MPC from primary cancers (PCs) in the same anatomical region from the clinical manifestation alone. However, their biological behaviors appear to be distinct. In this study, we show that the prognosis of multiple primary oral cancers (MP-OCs) is worse than primary oral cancers (P-OCs). To better understand the molecular mechanisms of MP-OC, we used whole exome sequencing (WES) to analyze samples from 9 patients with MP-OC and 21 patients with P-OC. We found more somatic mutations in MP-OC than in P-OC. MP-OC had more complicated mutation signatures, which were associated with age-related and Apolipoprotein B mRNA Editing Catalytic Polypeptide-like (APOBEC) activity-related signatures. Tumor mutational burden (TMB) and mutant-allele tumor heterogeneity (MATH) of MP-OC trended higher compared to P-OC. KEGG and GO analysis showed the differential pathways of MP-OC versus P-OC. In addition, MP-OC took amplification, not loss, as the main pattern of copy number variation (CNV), while P-OC took both. Lastly, we did not find significantly different mutant germline genes, but MSH-6 mutation may be a potential MP-OC driver. In short, our preliminary results show that MP-OC and P-OC have different molecular characteristics.