[Effect of Chlorambucil Combined with Ibrutinib on Mantle Cell Lymphoma Cell Line Jeko-1 and Its Related Mechanism].

OBJECTIVE: To investigate the toxic effect of chlorambucil combined with ibrutinib on mantle cell lymphoma (MCL) cell line Jeko-1 and its related mechanism. METHODS: The MCL cell line Jeko-1 was incubated with different concentrations of chlorambucil or ibrutinib or the combination of the two drugs, respectively. CCK-8 assay was used to detect the proliferation of the cells, and Western blot was used to measure the protein expression levels of BCL-2, caspase-3, PI3K, AKT and P-AKT. RESULTS: After Jeko-1 cells were treated with chlorambucil (3.125, 6.25, 12.5, 25, 50 µmol/L) and ibrutinib (3.125, 6.25, 12.5, 25, 50 µmol /L) alone for 24, 48, 72h respectively, the cell proliferation was inhibited in a time- and dose-dependent manner. Moreover, the two drugs were applied in combination at low doses (single drug inhibition rate<50%), and the results showed that the combination of two drugs had a more significant inhibitory effect (all P < 0.05). Compared with the control group, the apoptosis rate of the single drug group of chlorambucil (3.125, 6.25, 12.5, 25, 50 µmol/L) and ibutinib (3.125, 6.25, 12.5, 25, 50 µmol/L) was increased in a dose-dependent manner. The combination of the two drugs at low concentrations (3.125, 6.25, 12.5 µmol/L) could significantly increase the apoptosis rate compared with the corresponding concentration of single drug groups (all P < 0.05). Compared with control group, the protein expression levels of caspase-3 in Jeko-1 cells were upregulated, while the protein expression levels of BCL-2, PI3K, and p-AKT/AKT were downregulated after treatment with chlorambucil or ibrutinib alone. The combination of the two drugs could produce a synergistic effect on the expressions of the above-mentioned proteins, and the differences between the combination group and the single drug groups were statistically significant (all P < 0.05). CONCLUSION: Chlorambucil and ibrutinib can promote the apoptosis of MCL cell line Jeko-1, and combined application of the two drugs shows a synergistic effect, the mechanism may be associated with the AKT-related signaling pathways.

Effect of L-cysteine on the physicochemical properties of heat-induced sheep plasma protein gels.

The effects of different l-Cysteine additions (0-2 %) on the gel properties, microstructure and physicochemical stability of sheep plasma protein gels were studied. The introduction of l-Cys significantly improved the water retention capacity and whiteness of the plasma protein gel (p < 0.05). The addition of 0.2 %-0.4 % l-Cys increased gel strength, but l-Cys had no significant effect on gel elasticity (p < 0.05). Scanning electron microscopy confirmed that the addition of l-Cys also promoted the formation of a porous three-dimensional network structure in the gel. Raman spectroscopy and SDS-PAGE revealed that the addition of l-Cys generally reduced α-helix structures in protein gels and promoted the formation of ß-folds. Addition of 0.2 % l-Cys treatment leading to the greatest increase in disulfide bonds, and its surface hydrophobicity and endogenous fluorescence intensity were the largest. At this time, the comprehensive performance of sheep plasma protein gel is the best performance.

Surplus fatty acid synthesis increases oxidative stress in adipocytes and lnduces lipodystrophy.

Adipocytes are the primary sites for fatty acid storage, but the synthesis rate of fatty acids is very low. The physiological significance of this phenomenon remains unclear. Here, we show that surplus fatty acid synthesis in adipocytes induces necroptosis and lipodystrophy. Transcriptional activation of FASN elevates fatty acid synthesis, but decreases NADPH level and increases ROS production, which ultimately leads to adipocyte necroptosis. We identify MED20, a subunit of the Mediator complex, as a negative regulator of FASN transcription. Adipocyte-specific male Med20 knockout mice progressively develop lipodystrophy, which is reversed by scavenging ROS. Further, in a murine model of HIV-associated lipodystrophy and a human patient with acquired lipodystrophy, ROS neutralization significantly improves metabolic disorders, indicating a causal role of ROS in disease onset. Our study well explains the low fatty acid synthesis rate in adipocytes, and sheds light on the management of acquired lipodystrophy.

Psychological stress induces hair regenerative disorders through corticotropin-releasing hormone-mediated autophagy inhibition.

Psychosocial stress is increasing, causing a growing number of people to suffer from hair loss. Stress-related corticotropin-releasing hormone (CRH) is associated with hair loss, but the mechanism by which hair follicles respond to stress and CRH remain poorly understood. The aim of the study is to elucidate the association between CRH and stress-related hair regenerative disorders, and reveal the potential pathological mechanisms. A chronic unpredictable stress mouse model and a chronic social defeat stress mouse model were used to examine the role of CRH and stress-related hair regrowth. Chronic unpredictable stress and chronic social defeat stress increased the expression of CRH and CRH receptors (CRHRs), and contributed to the onset of hair-cycle abnormalities. Psychoemotional stress and stress-related CRH blocked hair follicle regrowth, which could be restored by astressin, a CRHR antagonist. Long-term exposure to either chronic unpredictable stress or CRH induced a decrease in autophagy, which could be partially rescued by astressin. Activating CRHR, by stress or CRH administration, decreased autophagy via the mTOR-ULK1 signaling pathway to mediate hair regenerative disorders, which could be partially reversed through enhancing autophagy by administration of brefeldin A. These findings indicate that CRH-mediated autophagy inhibition play an important role in stress-induced hair regenerative disorders. CRH regulates the local hypothalamic-pituitary-adrenal axis of hair follicles, but also plays an independent pathogenic role in stress-related hair regenerative disorders through CRH-mediated autophagy inhibition. This work contributes to the present understanding of hair loss and suggests that enhancing autophagy may have a therapeutic effect on stress-induced hair loss.

A deep learning fusion network trained with clinical and high-frequency ultrasound images in the multi-classification of skin diseases in comparison with dermatologists: a prospective and multicenter study.

Background: Clinical appearance and high-frequency ultrasound (HFUS) are indispensable for diagnosing skin diseases by providing internal and external information. However, their complex combination brings challenges for primary care physicians and dermatologists. Thus, we developed a deep multimodal fusion network (DMFN) model combining analysis of clinical close-up and HFUS images for binary and multiclass classification in skin diseases. Methods: Between Jan 10, 2017, and Dec 31, 2020, the DMFN model was trained and validated using 1269 close-ups and 11,852 HFUS images from 1351 skin lesions. The monomodal convolutional neural network (CNN) model was trained and validated with the same close-up images for comparison. Subsequently, we did a prospective and multicenter study in China. Both CNN models were tested prospectively on 422 cases from 4 hospitals and compared with the results from human raters (general practitioners, general dermatologists, and dermatologists specialized in HFUS). The performance of binary classification (benign vs. malignant) and multiclass classification (the specific diagnoses of 17 types of skin diseases) measured by the area under the receiver operating characteristic curve (AUC) were evaluated. This study is registered with www.chictr.org.cn (ChiCTR2300074765). Findings: The performance of the DMFN model (AUC, 0.876) was superior to that of the monomodal CNN model (AUC, 0.697) in the binary classification (P = 0.0063), which was also better than that of the general practitioner (AUC, 0.651, P = 0.0025) and general dermatologists (AUC, 0.838; P = 0.0038). By integrating close-up and HFUS images, the DMFN model attained an almost identical performance in comparison to dermatologists (AUC, 0.876 vs. AUC, 0.891; P = 0.0080). For the multiclass classification, the DMFN model (AUC, 0.707) exhibited superior prediction performance compared with general dermatologists (AUC, 0.514; P = 0.0043) and dermatologists specialized in HFUS (AUC, 0.640; P = 0.0083), respectively. Compared to dermatologists specialized in HFUS, the DMFN model showed better or comparable performance in diagnosing 9 of the 17 skin diseases. Interpretation: The DMFN model combining analysis of clinical close-up and HFUS images exhibited satisfactory performance in the binary and multiclass classification compared with the dermatologists. It may be a valuable tool for general dermatologists and primary care providers. Funding: This work was supported in part by the National Natural Science Foundation of China and the Clinical research project of Shanghai Skin Disease Hospital.

Protein-guided biomimetic nanomaterials: a versatile theranostic nanoplatform for biomedical applications.

Over the years, bioinspired mineralization-based approaches have been applied to synthesize multifunctional organic-inorganic nanocomposites. These nanocomposites can address the growing demands of modern biomedical applications. Proteins, serving as vital biological templates, play a pivotal role in the nucleation and growth processes of various organic-inorganic nanocomposites. Protein-mineralized nanomaterials (PMNMs) have attracted significant interest from researchers due to their facile and convenient preparation, strong physiological activity, stability, impressive biocompatibility, and biodegradability. Nevertheless, few comprehensive reviews have expounded on the progress of these nanomaterials in biomedicine. This article systematically reviews the principles and strategies for constructing nanomaterials using protein-directed biomineralization and biomimetic mineralization techniques. Subsequently, we focus on their recent applications in the biomedical field, encompassing areas such as bioimaging, as well as anti-tumor, anti-bacterial, and anti-inflammatory therapies. Furthermore, we discuss the challenges encountered in practical applications of these materials and explore their potential in future applications. This review aspired to catalyze the continued development of these bioinspired nanomaterials in drug development and clinical diagnosis, ultimately contributing to the fields of precision medicine and translational medicine.

Measurement of enzyme activity of insoluble substrates based on ordered porous layer interferometry and the application in evaluation of thrombolytic drugs.

The development of innovative methods for real-time surveillance of enzymatic activity determination processes is essential, particularly for insoluble substrate enzymatic assessments. In this work, a novel method for enzymatic activity determination was devised by assembling a 190 nm silica colloidal crystal (SCC) film onto a glass slide, coupled with Ordered Porous Layer Interferometry (OPLI) technology. By fixing the substrate of the enzyme on the surface of the silica sphere, a solid-liquid interface can be formed for monitoring enzymatic activity. The enzymatic activity is gauged by the change in the SCC film's thickness caused by the digestion of the loaded substrate. The procedure of chymotrypsin-mediated casein digestion was documented in real time, facilitating the examination of chymotrypsin's activity and kinetics. The newly-developed enzymatic activity determination method demonstrated exceptional sensitivity towards chymotrypsin activity, with a linear range spanning 0.0505-2.02 units per mg. Additionally, the method was extended to the assessment of fibrinolysis enzyme activity and kinetic analysis, yielding promising results. Therefore, this technique can serve as a real-time, user-friendly, cost-effective novel approach for enzymatic activity determination, providing fresh perspectives for enzymatic activity determination studies.

Modeling of human muscle and its deformation.

There is a lack of volume preserving and reasonable deformation of human muscles during bones and joints movement in the field of digital orthopedics. A novel approach for modeling of human muscle and its deformation was put forward to effectively assist doctors in guiding patients to carry out rehabilitation exercises. Firstly, based on Magnetic Resonance Imaging (MRI) data, the generated slice images were used to extract the outer contour lines and then the corresponding contour lines and optimal matching points of the adjacent layer images were connected to construct the three-dimensional (3D) geometric models of the muscles; Secondly, the mapping relationship between parameters can be established through hierarchical definition of the muscle characteristics to realize the volume-preserving deformation of muscle; Finally, the movement of human joints can be realized based on the constraint range of joint movement, and the vector-valued dynamic fourth-order differential equation was proposed to make the characteristic curve dynamically simulate the process of muscle deformation, thereby forming the corresponding relationship between bone movement and muscle deformation. The effectiveness and feasibility of this method have been verified in our experiments with biceps brachii and triceps brachii as examples. The maximum volume errors of biceps brachii and triceps brachii during the deformation process were less than 0.6%, which can be ignored within a certain allowable error range, reflecting that the parametric method was used to realize the reasonable volume-preserving deformation of human muscle.

Assessment of the Diagnostic Performance of Clinical Examinations and High-Frequency Ultrasound in Patients With Pigmented Skin Tumors.

OBJECTIVES: To investigate whether the integration of high-frequency ultrasound (HFUS) to routine clinical examinations could improve diagnostic performance and management decision for pigmented skin tumors. METHODS: Three general practitioners trained previously and a dermatologist independently assessed pigmented skin tumors and rendered management decision based on clinical examinations alone or clinical examinations integrating HFUS. RESULTS: After integrating HFUS, the diagnostic area under the curve (AUC) (0.658-0.693 versus 0.848, all P < .05) and specificity (46.6-58.6% versus 89.7%, all P < .05) for pigmented skin malignancies were improved for general practitioners, meanwhile unnecessary biopsy rate reduced (42.9-53.6% versus 10.7%, P < .001). To the dermatologist, the diagnostic AUC (0.822 versus 0.949, P < .001), sensitivity (81.7% versus 96.7%, P = .012) and specificity (0.828 versus 0.931, P = .031) improved significantly, meanwhile both missed biopsy rate (14.5% versus 4.8%, P = .031) and unnecessary biopsy rate (19.6% versus 7.1%, P = .016) decreased. Additionally, the diagnostic performance of the general practitioner with integrating HFUS could be comparable with the dermatologist based on clinical examinations alone (all P > .05). CONCLUSIONS: As a complementary tool of clinical examinations, HFUS could help physicians differentiate pigmented skin malignancies and manage decision.

Deep Learning-Based Quantitative Blastocyst Assessment.

Selecting the single best blastocyst based on morphological appearance for implantation is a crucial part of in vitro fertilization (IVF). Various deep learning and computer vision-based methods have recently been applied for assessing blastocyst quality. However, to the best of our knowledge, most previous works utilize classification networks to give a qualitative evaluation. It would be challenging to rank blastocyst quality with the same qualitative result. Thus, this paper proposes a regression network combined with a soft attention mechanism for quantitatively evaluating blastocyst quality. The network outputs a continuous score to represent blastocyst quality precisely rather than some categories. As to the soft attention mechanism, the attention module in the network outputs an activation map (attention map) localizing the regions of interest (ROI, i.e., inner cell mass (ICM)) of microscopic blastocyst images. The generated activation map guides the entire network to predict ICM quality more accurately. The experimental results demonstrate that the proposed method is superior to traditional classification-based networks. Moreover, the visualized activation map makes the proposed network decision more reliable.

SlMYB7, an AtMYB4-Like R2R3-MYB Transcription Factor, Inhibits Anthocyanin Accumulation in Solanum lycopersicum Fruits.

Tomato is a horticultural crop with an incomplete flavonoid metabolic pathway that does not typically accumulate anthocyanins in the fruit. In recent years, intensive studies of the loci Anthocyanin fruit (Aft) and atroviolacium (atv) have clarified the functions of positive regulators (R2R3-MYBs) and a negative regulator (CPC-MYB) in anthocyanin biosynthesis in the fruits. However, little is known about the R2R3-MYB repressors. Here, we used transient overexpression analysis to show that SlMYB7, a subgroup 4 AtMYB4-like R2R3-MYB, inhibited anthocyanin accumulation and reduced expression of anthocyanin synthase genes in the 'black pearl' tomato fruits, which usually accumulate high concentrations of anthocyanins. These findings revealed that SlMYB7 served as a repressor of anthocyanin production. Furthermore, SlMYB7 actively repressed SlANS expression by binding its promoter and passively inhibited anthocyanin synthesis by interacting with the basic helix-loop-helix (bHLH) proteins SlJAF13 and SlAN1, which are involved in the formation of MBW complexes. Thus, SlMYB7 and the MBW complex may coregulate the anthocyanin content of 'black pearl' tomato fruits via a negative feedback loop. These findings provide a theoretical basis for the future enhancement of tomato anthocyanin contents through genetic manipulation of the biosynthetic regulatory network.

Sympathetic Reinnervation of Intact and Upper Follicle Xenografts into BALB/c-nu/nu Mice.

Increasing concerns about hair loss affect people's quality of life. Recent studies have found that sympathetic nerves play a positive role in regulating hair follicle stem cell activity to promote hair growth. However, no study has investigated sympathetic innervation of transplanted follicles. Rat vibrissa follicles were extracted and implanted under the dorsal skin of BALB/c-nu/nu mice using one of two types of follicles: (1) intact follicles, where transplants included bulbs, and (2) upper follicles, where transplants excluded bulbs. Follicular samples were collected for hematoxylin and eosin staining, immunofluorescence staining for tyrosine hydroxylase (TH, a sympathetic marker) and enzyme-linked immunosorbent assays. At 37 days after implantation in both groups, follicles had entered anagen, with the growth of long hair shafts; tyrosine-hydroxylase-positive nerves were innervating follicles (1.45-fold); and norepinephrine concentrations (2.03-fold) were significantly increased compared to 5 days, but did not return to normal. We demonstrate the survival of intact and upper follicle xenografts and the partial restoration of sympathetic reinnervations of both transplanted follicles.

LncRNA MIR31HG fosters stemness malignant features of non-small cell lung cancer via H3K4me1- and H3K27Ace-mediated GLI2 expression.

Non-coding RNAs are responsible for oncogenesis and the development of stemness features, including multidrug resistance and metastasis, in various cancers. Expression of lncRNA MIR31HG in lung cancer tissues and peripheral sera of lung cancer patients were remarkably higher than that of healthy individuals and indicated a poor prognosis. Functional analysis showed that MIR31HG fosters stemness-associated malignant features of non-small cell lung cancer cells. Further mechanistic investigation revealed that MIR31HG modulated GLI2 expression via WDR5/MLL3/P300 complex-mediated H3K4me and H3K27Ace modification. In vivo MIR31HG repression with an antisense oligonucleotide attenuated tumor growth and distal organ metastasis, whereas MIR31HG promotion remarkably encouraged cellular invasion in lung and liver tissues. Our data suggested that MIR31HG is a potential diagnostic indicator and druggable therapeutic target to facilitate multiple strategic treatments for lung cancer patients.

An Advanced Review: Polyurethane-Related Dressings for Skin Wound Repair.

The inability of wounds to heal effectively through normal repair has become a burden that seriously affects socio-economic development and human health. The therapy of acute and chronic skin wounds still poses great clinical difficulty due to the lack of suitable functional wound dressings. It has been found that dressings made of polyurethane exhibit excellent and diverse biological properties, but lack the functionality of clinical needs, and most dressings are unable to dynamically adapt to microenvironmental changes during the healing process at different stages of chronic wounds. Therefore, the development of multifunctional polyurethane composite materials has become a hot topic of research. This review describes the changes in physicochemical and biological properties caused by the incorporation of different polymers and fillers into polyurethane dressings and describes their applications in wound repair and regeneration. We listed several polymers, mainly including natural-based polymers (e.g., collagen, chitosan, and hyaluronic acid), synthetic-based polymers (e.g., polyethylene glycol, polyvinyl alcohol, and polyacrylamide), and some other active ingredients (e.g., LL37 peptide, platelet lysate, and exosomes). In addition to an introduction to the design and application of polyurethane-related dressings, we discuss the conversion and use of advanced functional dressings for applications, as well as future directions for development, providing reference for the development and new applications of novel polyurethane dressings.

Leopard predation on wild Sichuan snub-nosed monkeys.

Predation is widely recognized as a powerful selective pressure on primate behavior and ecology, although knowledge of predator-prey relationships remains limited partly due to the rarity of directly observed attacks on primates. Here, we describe four confirmed or suspected instances of leopard (Panthera pardus) predation on free-ranging Sichuan (golden) snub-nosed monkeys (Rhinopithecus roxellana), a highly endangered colobine species endemic to China. We recorded predation events and the reactions of monkey group members. We suggest that the evolution of a multilevel society may be an adaptive response by Sichuan snub-nosed monkeys to the risk from leopards as well as other potential predators, one that balances the pressures of predation and intra-species competition and conflict.

Channeling and dampening: The role of political ties in information disclosure and concealment.

Non-profit organizations (NPOs) help the state achieve its social objectives. At the same time, they often depend on the private-sector actors for donations. The different beliefs of public- and private-sector actors regarding which practices are desirable for NPOs can affect the transparency of these organizations. We propose that political ties influence NPOs to comply with state-mandated disclosure requirements, while simultaneously dampening their willingness to voluntarily disclose sensitive information that may jeopardize their legitimacy in the eyes of private-sector stakeholders. The impact of political ties on disclosure is contingent upon two factors. First, market institutions moderate such effects because expectations of public- and private-sector actors may diverge more in freer markets than where the state has inordinate power. Second, financial dependence on the state amplifies both effects as dependence on the state exerts more pressure for compliance whilst making politically connected organizations appear even more questionable in the eyes of the private-sector stakeholders. Leveraging a policy shock that weakened political ties, we found that following the policy shock, charities in China reduced their compliance to state-mandated information disclosure, but increased their voluntary disclosure. The opposing roles of political ties in mandatory versus voluntary disclosure is further supported by a policy capturing study involving private donors in China. This study has important implications for research on political ties and information disclosure.

Air Pollution and Prosocial Behavior in Chinese Adolescents: The Role of Resilience and Interpersonal Relations.

Purpose: Past studies have indicated that air pollution is a major environmental factor that negatively affects prosocial behavior in adolescents. However, the mechanism underlying this negative relationship has not been fully explored. This study postulated that this impact may occur through individual resilience, a major psychological capital for adolescents. In addition, we studied interpersonal relations, namely, adolescents' perceived family and teacher support, which may moderate the proposed relationship. Methods: This study combined the three-year tracking survey data of 11-to-15 old adolescents (N=1301; approximately 48% female) in China with objective data from the air quality index (AQI) to measure the level of air pollution. Results: Findings from ordinary least squares analysis indicated that air pollution negatively influences adolescents' prosocial behavior, and their resilience mediates this negative relationship. In addition, the results showed that the negative effect of air pollution on adolescent resilience is attenuated by higher family income, whereas it is accentuated by the absence of teacher support. Conclusion: Our study provides insight into how the negative effect of air pollution on adolescents' prosocial behavior is mediated by their psychological resilience, and highlights the moderating role of adolescents' interpersonal relations in the association between air pollution and their psychological resilience. Our research also provides practical advice on how families, teachers, and psychologists can mitigate this negative impact.

Randomized, Placebo-Controlled, Multicenter Clinical Study on the Efficacy and Safety of Lidocaine Patches in Chinese Patients with Postherpetic Neuralgia.

INTRODUCTION: To evaluate the efficacy and safety of lidocaine patches in Chinese patients with postherpetic neuralgia (PHN). METHODS: Patients were randomized to receive lidocaine patches or placebo every day for 4 weeks. Efficacy endpoints included the decrease of analogue scale score (VAS) value at week 4, 2 and 1 and the percentage of patients that achieved a 30% decrease of VAS value. Safety analyses were conducted as well. RESULTS: Two hundred forty Chinese patients were randomized. At week 1, lidocaine patch-treated patients had a higher clinical response versus placebo, and at week 4, the mean (SD) decreases of VAS value compared to the baseline were 14.01 (14.35) in the treatment group and 9.36 (12.03) in the placebo group (p = 0.0088). Overall, the safety profile in the treatment group was consistent with that observed in the placebo group [adverse event (AE) incidence rate: 33.33% versus 37.29%, p = 0.5857]. CONCLUSIONS: Lidocaine patches resulted in improved clinical response versus placebo in the treatment of PHN patients and were well tolerated.

Chromatin reprogramming and bone regeneration in vitro and in vivo via the microtopography-induced constriction of cell nuclei.

Topographical cues on cells can, through contact guidance, alter cellular plasticity and accelerate the regeneration of cultured tissue. Here we show how changes in the nuclear and cellular morphologies of human mesenchymal stromal cells induced by micropillar patterns via contact guidance influence the conformation of the cells' chromatin and their osteogenic differentiation in vitro and in vivo. The micropillars impacted nuclear architecture, lamin A/C multimerization and 3D chromatin conformation, and the ensuing transcriptional reprogramming enhanced the cells' responsiveness to osteogenic differentiation factors and decreased their plasticity and off-target differentiation. In mice with critical-size cranial defects, implants with micropillar patterns inducing nuclear constriction altered the cells' chromatin conformation and enhanced bone regeneration without the need for exogenous signalling molecules. Our findings suggest that medical device topographies could be designed to facilitate bone regeneration via chromatin reprogramming.