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Recently, the construction of the trisubstituted olefin-type probe molecules has elicited the attention of many researchers. However, the synthesis of the trisubstituted olefin-type probes containing two N-heterocycles simultaneously has been rarely reported. In this study, starting from the inexpensive mucobromic acid 1 and N-heterocyclic compound 2, we first utilized a simple one-step reaction to synthesize a series of trisubstituted olefin-type compounds 3 simultaneously bearing with the structure of two N-heterocyclic rings in the absence of transition metal catalysts with a yield of 62–86%. The optimal reaction conditions were systematically explored, and the structure of the obtained compounds 3 were well characterized with 1H NMR, 13C NMR, X-ray single-crystal and HR-MS. The preliminary observation showed that, in the presence of base, mucobromic acid 1 reacts as its ring-opening structure, and the successive nucleophilic substitution reaction and Michael addition reaction can generate the target product 3. Considering that the aldehyde group in the molecular structure of the trisubstituted olefin-type compounds 3 may react with malononitrile, we carried out some relevant investigations so as to realize the visual detection of malononitrile. Interestingly, among the products, compounds 3a–3c can be prepared in portable test strips through a simple process and used to achieve the naked-eye detection of malononitrile in environmental systems as designed. [ABSTRACT FROM AUTHOR]

Retinal ischemia plays a vital role in vision-threatening retinal ischemic disorders, such as diabetic retinopathy, age-related macular degeneration, glaucoma, etc. The aim of this study was to investigate the effects of S-allyl L-cysteine (SAC) and its associated therapeutic mechanism. Oxidative stress was induced by administration of 500 μM H2O2 for 24 h; SAC demonstrated a dose-dependent neuroprotective effect with significant cell viability effects at 100 μM, and it concurrently downregulated angiogenesis factor PKM2 and inflammatory biomarker MCP-1. In a Wistar rat model of high intraocular pressure (HIOP)-induced retinal ischemia and reperfusion (I/R), post-administration of 100 μM SAC counteracted the ischemic-associated reduction of ERG b-wave amplitude and fluorogold-labeled RGC reduction. This study supports that SAC could protect against retinal ischemia through its anti-oxidative, anti-angiogenic, anti-inflammatory, and neuroprotective properties. [ABSTRACT FROM AUTHOR]

As virtual reality and 3D-modeling technology continue to advance, the amount of digital geometric media data is growing at an explosive rate. For example, 3D meshes, an important type of digital geometric media, can precisely record geometric information on a model's surface. However, as the complexity and precision of 3D meshes increase, it becomes more challenging to store and transmit them. The traditional method of compressing non-isomorphic 3D-mesh sequences through frame-by-frame compression is inefficient and destroys the inter-frame correlations of the sequences. To tackle these issues, this study investigates the generation of time-dependent geometric image sequences for compressing non-isomorphic 3D-mesh sequences. Two methods are proposed for generating such sequences: one through image registration and the other through parametrization-geometry cooperative registration. Based on the experimental compression results of the video-coding algorithms, it was observed that the proposed geometric image-sequence-generation method offers superior objective and subjective qualities, as compared to the traditional method. [ABSTRACT FROM AUTHOR]

Atezolizumab is an immune checkpoint inhibitor (ICI) targeting PD-L1 for treatment of solid malignancies. Immune checkpoints control the immune tolerance, and the adverse events such as hepatotoxicity induced by ICIs are often considered as an immune-related adverse event (irAE). However, PD-L1 is also highly expressed in normal tissues, e.g., hepatocytes. It is still not clear whether, targeting PD-L1 on hepatocytes, the atezolizumab may cause damage to liver cells contributing to hepatotoxicity. Here, we reveal a novel mechanism by which the atezolizumab induces hepatotoxicity in human hepatocytes. We find that the atezolizumab treatment increases a release of LDH in the cell culture medium of human hepatocytes (human primary hepatocytes and THLE-2 cells), decreases cell viability, and inhibits the THLE-2 and THLE-3 cell growth. We demonstrate that both the atezolizumab and the conditioned medium (T-CM) derived from activated T cells can induce necroptosis of the THLE-2 cells, which is underscored by the fact that the atezolizumab and T-CM enhance the phosphorylation of RIP3 and MLKL proteins. Furthermore, we also show that necrostatin-1, a necrosome inhibitor, decreases the amount of phosphorylated RIP3 induced by the atezolizumab, resulting in a reduced LDH release in the culture media of the THLE-2 cells. This finding is further supported by the data that GSK872 (a RIP3 inhibitor) significantly reduced the atezolizumab-induced LDH release. Taken together, our data indicate that the atezolizumab induces PD-L1-mediated necrosome formation, contributing to hepatotoxicity in PD-L1+-human hepatocytes. This study provides the molecular basis of the atezolizumab-induced hepatotoxicity and opens a new avenue for developing a novel therapeutic approach to reducing hepatotoxicity induced by ICIs. [ABSTRACT FROM AUTHOR]

Relative energy deficiency in sport (RED-S), which underpins the concept of low energy availability (LEA), can negatively affect athletes' health and performance. This study aims to investigate the prevalence of RED-S among national athletes in Malaysia. A total of 192 national athletes (97 males, 18–39 years old) responded to an online survey regarding the RED-S risk. Most athletes (67.2%) were classified as having a medium/high RED-S risk. Female (41.2%), weight-class (23.9%), and intermittent sports (20.3%) had the highest prevalence of medium/high RED-S risk. Overall, most athletes spent 2–5 h daily (55.2%) and 6–7 days weekly (53.6%) practicing or playing their sport, and 47.9% reported feeling tired recently. The athletes were also terrified of being overweight (61.5%), worried about what they eat (64.7%), concerned about having fat on their bodies (62.6%), and thinking about burning calories while exercising (69.3%). Only 16.7% of the athletes had a prior history of stress fractures, and 40.6% continued to participate in activities 6–7 days per week while injured. The majority of female athletes (88.3%) had regular menstrual cycles. These findings support the notion that RED-S screening should be addressed in the athletic community. Future research is needed to clinically assess these athletes and investigate the impacts of RED-S on their health and sports performance. [ABSTRACT FROM AUTHOR]

Dental pulp and periapical diseases make patients suffer from acute pain and economic loss. Although root canal therapies, as demonstrated through evidence-based medicine, can relieve symptoms and are commonly employed by dentists, it is still difficult to fully restore a dental pulp's nutrition, sensory, and immune-regulation functions. In recent years, researchers have made significant progress in tissue engineering to regenerate dental pulp in a desired microenvironment. With breakthroughs in regenerative medicine and material science, bioactive scaffolds play a pivotal role in creating a suitable microenvironment for cell survival, proliferation, and differentiation, following dental restoration and regeneration. This article focuses on current challenges and novel perspectives about bioactive scaffolds in creating a microenvironment to promote dental pulp regeneration. We hope our readers will gain a deeper understanding and new inspiration of dental pulp regeneration through our summary. [ABSTRACT FROM AUTHOR]

We generated two IgG1-like bispecific antibodies (BsAbs) with different molecular formats, symmetrical DVD-Ig and asymmetrical knob-in-hole (KIH), targeting the same antigens, EGFR and PD-L1 (designated as anti-EGFR/PD-L1). We performed the physiochemical and biological characterization of these two formats of anti-EGFR/PD-L1 BsAbs and compared some key quality attributes and biological activities of these two formats of BsAbs. Physiochemical binding characterization data demonstrated that both formats bound EGFR and PD-L1. However, the binding affinity of the KIH format was weaker than the DVD-Ig format in Biacore binding assays. In contrast, both DVD-Ig and KIH BsAbs had similar ELISA and cell surface binding activities, comparable to mAbs. Triple-negative breast cancer (TNBC) cells and a xenograft model were used to test the potency of BsAbs and other biological activities. Results showed that anti-EGFR/PD-L1 BsAbs exhibited in vitro and in vivo antitumor proliferation activity, but there was a difference in the potencies of the respective BsAb formats (DVD-Ig and KIH) when different cells or assays were used. This study provides evidence that the potency of the BsAbs targeting the same antigens can be affected by the respective molecular features, and selection of appropriate cell lines and assays is critically important for the assay development and potency testing of BsAbs. [ABSTRACT FROM AUTHOR]

Molecular motors convert light and thermal energies into mechanical work, offering good opportunities to design novel molecular devices. Among them, molecular motors alternate a photoisomerization and a thermal helix inversion to achieve unidirectional rotation. The rotational speed is limited by the helix inversion step, which in turn is governed by a barrier in the electronic ground state. In this work, we systematically study the solvation effect on the thermal process of selected molecular motors, comparing reaction barriers obtained from both density functional theory (DFT) in the isolated system and umbrella sampling within a hybrid quantum mechanics/molecular mechanics (QM/MM) model in solution. We find more prominent solvation effects on those molecular motors with larger dipole moments. The results could provide insight into how to functionalize molecular motors to speed up their rotation. [ABSTRACT FROM AUTHOR]

Excitatory-inhibitory imbalance (E/I) is a fundamental mechanism underlying autism spectrum disorders (ASD). TRIM32 is a risk gene genetically associated with ASD. The absence of TRIM32 causes impaired generation of inhibitory GABAergic interneurons, neural network hyperexcitability, and autism-like behavior in mice, emphasizing the role of TRIM32 in maintaining E/I balance, but despite the description of TRIM32 in regulating proliferation and differentiation of cultured mouse neural progenitor cells (NPCs), the role of TRIM32 in cerebral cortical development, particularly in the production of excitatory pyramidal neurons, remains unknown. The present study observed that TRIM32 deficiency resulted in decreased numbers of distinct layer-specific cortical neurons and decreased radial glial cell (RGC) and intermediate progenitor cell (IPC) pool size. We further demonstrated that TRIM32 deficiency impairs self-renewal of RGCs and IPCs as indicated by decreased proliferation and mitosis. A TRIM32 deficiency also affects or influences the formation of cortical neurons. As a result, TRIM32-deficient mice showed smaller brain size. At the molecular level, RNAseq analysis indicated reduced Notch signalling in TRIM32-deficient mice. Therefore, the present study indicates a role for TRIM32 in pyramidal neuron generation. Impaired generation of excitatory pyramidal neurons may explain the hyperexcitability observed in TRIM32-deficient mice. [ABSTRACT FROM AUTHOR]

Buildings are subject to many uncertainties ranging from thermophysical performance to user activity. Climate change is an additional source of uncertainty that complicates building performance evaluation. This study aims to quantify the share of uncertainties stemming from building factors, user behavior, and climate uncertainty from boilers, chillers, fans, pumps, total HVAC systems, and total site energy use. A novel method combining Monte Carlo analysis and ANOVA is proposed to partition uncertainties from building energy simulation results under different climate change scenarios. The Monte Carlo method is used to generate distributions of building and user factors as building simulation inputs. Then, simulation results under current and future climate conditions are post-processed using a three-way ANOVA technique to discretize the uncertainties for a reference office building in Philadelphia, PA. The proposed method shows the share in percentages of each input factor (building, user, and climate) in the total uncertainty of building energy simulation output results. Our results indicate that the contribution of climate uncertainty increases from current conditions to future climate scenarios for chillers, boilers, fans, and pumps' electricity use. User parameters are the dominant uncertainty factor for total site energy use and fans' electricity use. Moreover, boiler and HVAC energy use are highly sensitive to the shape and range of user and building input factor distributions. We underline the importance of selecting the appropriate distribution for input factors when partitioning the uncertainties of building performance modeling. [ABSTRACT FROM AUTHOR]

Background: Intradialytic hypotension (IDH) is a frequent and grave complication of hemodialysis (HD). However, the dynamic hemodynamic changes and cardiac performances during each dialytic session have been rarely explored in patients having IDH. Methods: Seventy-six HD patients (IDH = 40, controls = 36) were enrolled. Echocardiography examinations were performed in all patients at the pre-HD, during-HD and post-HD phases of a single HD session. A two-way analysis of variance was applied to compare differences of echocardiographic parameters between IDH and controls over time. The risk association was estimated by using a logistic regression analysis. Results: The IDH patients had a higher ejection fraction during HD followed by a greater reduction at the post-HD phase than the controls. Significant decreases in septal ratios of transmitral flow velocity to annular velocity (E/e') over times were detected between IDH patients and controls after adjusting for gender, age and ultrafiltration (p = 0.016). A lower septal E/e' ratio was independently associated with IDH (OR = 0.040; 95% CI = 0.003–0.606; p = 0.02). In contrast, significant systolic and diastolic dysfunctions over time were found in diabetic IDH compared to non-diabetic counterparts. Conclusion: The septal E/e' ratio was a significant predictor for IDH. [ABSTRACT FROM AUTHOR]

To study the dynamic plastic properties of high-purity molybdenum materials at high temperature and high strain rate, we designed tests to compare the mechanical behaviour of two high-purity molybdenum materials with different purities and two with different processing deformation conditions under dynamic impact compression in the temperature range of 297–1273 K. We analysed the molybdenum materials' sensitivities to the strain-hardening effect, strain rate-strengthening effect, and temperature-softening effect as well as the comprehensive response to the combined effect of the strain rate and temperature, the adiabatic impact process, and the microstructure at high temperature and high strain rate. Furthermore, based on a modified Johnson–Cook constitutive model, we quantitatively analysed the flow stresses in these materials. The calculation results strongly agree with the test results. Our findings indicate that the high-purity molybdenum materials show consistent sensitivity to the combined effect of strain rate and temperature regarding the dynamic plastic properties. The materials with higher purity are less sensitive to the combined effect of the strain rate and temperature, and those with less processing deformation experience more pronounced strain-hardening effects. Under high strain rate at room temperature, these materials are highly susceptible to impact embrittlement and decreases in dynamic plastic properties due to intergranular fracture in the internal microstructure. However, increasing the impact environment temperature can significantly improve their plastic properties. The higher the temperature, the better the plastic properties and the higher the impact toughness. [ABSTRACT FROM AUTHOR]

The mechanisms of mAb-induced ADCC have been well established. However, the ADCC bioassays used to quantify mAb-induced ADCC require continued development/refinement to properly assess and compare the potency of newly developed therapeutic mAbs and biosimilars to meet regulatory requirements. We used trastuzumab and a lactate dehydrogenase (LDH)-based ADCC bioassay as a model to define critical parameters of the ADCC bioassay, describing how several bioassay parameters, including preparation of effector cells, E/T ratio, target cell selection, bioassay media components, and treatment time can influence the data quality of the ADCC activity. We confirm that a 4 to 24 h recovery cultivation is required to restore peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cell activity toward ADCC when using cryopreserved PBMCs. Furthermore, we delineated the cellular mechanisms underlying the restored ADCC activity following the recovery cultivation. We observed that CD69, an early marker of NK cell activation, was upregulated and a new subset CD56 dim /CD16 dim population was dramatically increased in the recovered NK cells, which led to an increase in expression and secretion of perforin, granzyme B, and cytokine production. This study provides comprehensive technical insights into ADCC bioassay optimization to inform trastuzumab biosimilar development. The knowledge gained from this study can also be leveraged to guide bioassay development for therapeutic mAbs with ADCC as the primary mechanism of action.