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PROteolysis-TArgeting Chimeras (PROTACs) have emerged as an innovative drug development platform. However, most PROTACs have been generated empirically because many determinants of PROTAC specificity and activity remain elusive. Through computational modelling of the entire NEDD8-VHL Cullin RING E3 ubiquitin ligase (CRL VHL )/PROTAC/BCL-xL/UbcH5B(E2)-Ub/RBX1 complex, we find that this complex can only ubiquitinate the lysines in a defined band region on BCL-xL. Using this approach to guide our development of a series of ABT263-derived and VHL-recruiting PROTACs, we generate a potent BCL-xL and BCL-2 (BCL-xL/2) dual degrader with significantly improved antitumor activity against BCL-xL/2-dependent leukemia cells. Our results provide experimental evidence that the accessibility of lysines on a target protein plays an important role in determining the selectivity and potency of a PROTAC in inducing protein degradation, which may serve as a conceptual framework to guide the future development of PROTACs. Simultaneous targeting of BCL-xL and BCL-2 is an attractive approach for cancer treatment. Based on information gained by computational structure modelling, the authors develop a PROTAC that induces degradation of both BCL-xL and BCL-2 and effectively targets BCL-xL/2-dependent leukaemia cells.

Internet gaming disorder among university students has become a great concern for university counsellors worldwide since the COVID-19 pandemic. The factors influencing the development of internet gaming disorder in students during the COVID-19 pandemic could be different from those before the pandemic. This study aims to explore the associations among social isolation, self-control, and internet gaming disorder in Chinese university students and to examine whether self-control mediates the positive effects of social isolation on internet gaming disorder. A cross-sectional survey was employed to collect data from university students in Shandong province of China from April to September 2022. The Isolation subscale of the Self-Compassion Scale, Self-Control Scale, and Internet Gaming Disorder Scale were used to assess the social isolation, self-control, and internet gaming disorder among university students, respectively. Models 4 and 5 of PROCESS software were used to analyze the mediating role of self-control and the moderating role of gender on the association between social isolation and internet gaming disorder. A total of 479 students were recruited from 6 universities located in 3 different regions of Shandong, China. Students had low levels of internet gaming disorder and moderate levels of social isolation and self-control, with mean scores of 8.94 (SD 9.06), 12.04 (SD 3.53), and 57.15 (SD 8.44), respectively. Social isolation was positively correlated with internet gaming disorder (r=0.217; P<.001), and self-control was negatively correlated with social isolation (r=-0.355; P<.001) and internet gaming disorder (r=-0.260; P<.001). Self-control played a mediating role in the association between social isolation and internet gaming disorder (β=-.185, 95% CI -.295 to -.087). The effects of social isolation on internet gaming disorder among female students were lower than those among male students. Self-control was a mediator in the association between social isolation and internet gaming disorder. Moreover, gender played a moderating role in the association between social isolation and internet gaming disorder. This study highlights the need to alleviate the development of internet gaming disorder among students during a pandemic, especially that of male students. Effective interventions that lessen social isolation and promote self-control should be developed.

This paper presents a new model for multi-object tracking (MOT) with a transformer. MOT is a spatiotemporal correlation task among interest objects and one of the crucial technologies of multi-unmanned aerial vehicles (Multi-UAV). The transformer is a self-attentional codec architecture that has been successfully used in natural language processing and is emerging in computer vision. This study proposes the Vision Transformer Tracker (ViTT), which uses a transformer encoder as the backbone and takes images directly as input. Compared with convolution networks, it can model global context at every encoder layer from the beginning, which addresses the challenges of occlusion and complex scenarios. The model simultaneously outputs object locations and corresponding appearance embeddings in a shared network through multi-task learning. Our work demonstrates the superiority and effectiveness of transformer-based networks in complex computer vision tasks and paves the way for applying the pure transformer in MOT. We evaluated the proposed model on the MOT16 dataset, achieving 65.7% MOTA, and obtained a competitive result compared with other typical multi-object trackers.

The natural frequency of coal is one of the important technical parameters for the application of the permeability enhancement technology of coal and rock forced vibration. Aiming at exploring the dominant frequency of the permeability enhancement technology of coal vibration excited by vibration wave, the model of coal vibration excited by simple harmonic wave (SHW) was constructed. Furthermore, considering the three main control parameters, i.e., excitation force, coal sample size and mechanical parameters, the response characteristics of coal vibration excited by SHW were simulated and calculated. The calculation results demonstrate that when the frequency of excitation force equals the natural frequency of coal, the vibration occurs and the peak values of response parameters all increase significantly. The peak acceleration response of coal increases with the increase of excitation force, whereas it decreases with the increase of coal size. Under the same SHW excitation force, the mechanical parameters of coal determine the vibration response characteristics of coal, and the natural frequency of coal is proportional to the elastic modulus. Finally, the variation law of natural frequency response characteristics of coal vibration excited by SHW was verified by the response experiment on coal vibration under SHW excitation and related test results. The research results can serve as a theoretical basis for the application of the permeability enhancement technology of coal vibration excited by vibration wave.

Object detection is an essential task in computer vision. Many methods have made significant progress in ordinary object detection. Due to the particularity of remote sensing images, the detection target is tiny, the background is messy, dense, and has mutual occlusion, which makes the general detection method challenging to apply to remote sensing images. For these problems, we propose a new detection framework feature extraction and filtration method with a mask improvement network (EFM-Net) to enhance object detection ability. In EFM-Net, we designed a multi-branched feature extraction (MBFE) module to better capture the information in the feature graph. In order to suppress the background interference, we designed a background filtering module based on attention mechanisms to enhance the attention of objects. Finally, we proposed a mask generate the boundary improvement method to make the network more robust to occlusion detection. We tested the DOTA v1.0, NWPU VHR-10, and UCAS-AOD datasets, and the experimental results show that our method has excellent effects.

PurposeThe objective of the present study was to prepare stable and high bioavailability ocular atropine loaded films (ATR-films) as potential ocular drug delivery systems for the treatment of myopia.MethodsATR-films were prepared by the solvent casting method and the physical properties of films were evaluated including thickness, water content, light transparency, disintegration time, and mechanical properties. FT-IR, DSC, XRD, TGA, AFM, and Raman spectroscopy were performed to characterize the film. The stability test was conducted under different conditions, such as high humidity, high temperature, and strong light. The pharmacokinetic study and irritation assessment were conducted in rabbits. The efficacy of ATR-films was evaluated by refraction and ocular biometry in myopia guinea pigs.ResultAfter optimizing the formulation, the resulting ATR-film was flexible and transparent with lower water content (8.43% ± 1.25). As expected, the ATR-film was stable and hydrolysate was not detected, while the content of hydrolysate in ATR eye drops can reach up to 8.1867% (limit: < 0.2%) in the stability study. The safety assessment both in vitro and in vivo confirmed that the ATR-film was biocompatible. Moreover, the bioavailability (conjunctiva 3.21-fold, cornea 2.87-fold, retina 1.35-fold, sclera 2.05-fold) was greatly improved compared with the ATR eye drops in vivo pharmacokinetic study. The pharmacodynamic study results showed that the ATR-film can slow the progress of form-deprivation myopia (~ 100 ± 0.81D), indicating that it has a certain therapeutic effect on form-deprivation myopia.ConclusionThe ATR-film with good stability and high bioavailability will have great potential for the treatment of myopia.

Background Among all types of mental disorders, individuals with schizophrenia exhibit the highest frequency of aggressive behavior. This disrupts the healthcare environment and poses threats to family life and social harmony. Present approaches fail to identify individuals with schizophrenia who are predisposed to aggressive behavior. In this study, we aimed to construct a risk prediction model for aggressive behavior in stable patients with schizophrenia, which may facilitate early identification of patients who are predisposed to aggression by assessing relevant factors, enabling the management of high-risk groups to mitigate and prevent aggressive behavior. Methods A convenience sample of stable inpatients with schizophrenia were selected from Daqing Municipal Third Hospital and Chifeng Municipal Anding Hospital from March 2021 to July 2023. A total of 429 patients with stable schizophrenia who met the inclusion criteria were included. A survey was conducted with them using a questionnaire consisting of general information questionnaire, Positive and Negative Symptom Scale, Childhood Trauma Questionnaire-Short Form, Connor-Davidson Resilience Scale and Self-esteem Scale. Patients enrolled in this study were divided into aggressive and non-aggressive groups based on whether there was at least one obvious and recorded personal attack episode (including obvious wounding and self-injurious behavior) following diagnosis. Binary Logistic regression was used to determine the influencing factors, and R software was used to establish a nomogram model for predicting the risk of aggressive behavior. Bootstrap method was used for internal validation of the model, and the validation group was used for external validation. C statistic and calibration curve were used to evaluate the prediction performance of the model. Results The model variables included Age, Duration of disease, Positive symptom, Childhood Trauma, Self-esteem and Resilience. The AUROC of the model was 0.790 (95% CI:0.729–0.851), the best cutoff value was 0.308; the sensitivity was 70.0%; the specificity was 81.4%; The C statistics of internal and external validation were 0.759 (95%CI:0.725–0.814) and 0.819 (95%CI:0.733–0.904), respectively; calibration curve and Brier score showed good fit. Conclusions The prediction model has a good degree of discrimination and calibration, which can intuitively and easily screen the high risk of aggressive behavior in stable patients with schizophrenia, and provide references for early screening and intervention.

Background The diagnosis of mixed phenotype acute leukemia (MPAL) with T/megakaryocyte or T/myeloid lineages accompanied by t(3;3) is always a challenge. Therefore, multiple experimental methods are usually required to avoid misdiagnosis. In this report, we presented a rare case of MPAL with T/myeloid lineages accompanied by t(3;3) and discussed the experience of differential diagnosis and our appreciation of the MPAL with T/megakaryocyte and T/myeloid lineages accompanied by t(3;3). Case presentation: A 31-year-old woman was admitted to our hospital due to recurrent fever for 20 days. Two distinct blast populations were detected by flow cytometry analysis: one population fulfills the immunophenotypic criteria for T-lymphoblastic leukemia, while the other population is highly suggestive of megakaryoblasts. These immunophenotypic features support the diagnosis of MPAL (T/megakaryocyte), which is rarely reported​. Interestingly, a complex karyotype was detected afterward by cytogenetics with t(3;3)(q21;q26.2), indicating a diagnosis of AML with t(3;3), a subset of which is also characterized by megakaryocytic markers such as CD41 and CD61. It seems that the second blast population detected by flow cytometry could not be classified into either diagnosis based on the morphology, immunophenotyping, and even cytogenetic findings, posing a real diagnostic problem because of the lack of clear-cut cytogenetic morphological defined criteria to distinguish between acute megakaryocytic leukemia and AML with t(3;3). Combining all of the examination data, this case was ultimately diagnosed as MPAL (T + My)-NOS with t(3;3) through differential diagnosis. Before the cytogenetic results were available, the patient received an acute lymphoblastic leukemia (ALL) regimen for MPAL treatment, but the effect was unsatisfactory. After the diagnosis was clear, she received an AML-like regimen with azacitidine for 7 days and venetoclax for 14 days, and achieved complete morphological remission. Conclusion MPAL with either T/megakaryocyte or T/myeloid lineages accompanied by t(3;3) is rare, and it is difficult to make a clear diagnosis. Thus, comprehensive examinations, including bone marrow cell morphology, flow cytometry analysis, cytogenetics, and molecular analysis are recommended to avoid misdiagnosis. AML-like regimen including azacitidine and venetoclax may be effective for treating MPAL (T + My)-NOS with t(3;3).

Target-specific next-generation sequencing technology was used to analyze 112 genes in adult patients with acute lymphoblastic leukemia (ALL). This sequencing mainly focused on the specific mutational hotspots. Among the 121 patients, 93 patients were B-ALL (76.9%), and 28 patients (23.1%) were T-ALL. Of the 121 patients, 110 (90.9%) harbored at least one mutation. The five most frequently mutated genes in T-ALL are NOTCH1 , JAK3 , FBXW7 , FAT1 , and NRAS . In B-ALL, FAT1 , SF1 , CRLF2 , TET2 , and PTPN1 have higher incidence of mutations. Gene mutations are different between Ph + ALL and Ph − ALL patients. B-ALL patients with PTPN11 mutation and T-ALL patients with NOTCH1 and/or FBXW7 mutations showed better survival. But B-ALL with JAK1/JAK2 mutations showed worse survival. The results suggest that gene mutations exist in adult ALL patients universally, they are related with prognosis.

The optimal timing and type of hematopoietic stem cell transplantation (HSCT) for treating peripheral T-cell lymphoma (PTCL) remain controversial. This retrospective real-world study investigated the application pattern and outcomes of HSCT in China. The analysis encompassed 408 PTCL patients with a median age of 45.5 years, all of whom received initial adequate therapy at five hospitals. Among patients with nodal PTCL who responded effectively to first-line therapy (the “responders”, n  = 127) and subsequently underwent HSCT consolidation ( n  = 47, 37.0%), 93.6% received auto-HSCT, while 6.4% underwent allo-HSCT. Front-line auto-HSCT showed potential for long-term disease control in nodal PTCL responders. Among non-nodal PTCL responders ( n  = 80) with HSCT ( n  = 26, 32.5%), 46.2% underwent allo-HSCT and 53.8% received auto-HSCT. Upfront allo-HSCT provides longer progression-free survival (PFS) for non-nodal PTCL responders, with lower 3-year cumulative incidence of relapse (CIR) (16.7% vs. 56.0%) and comparable non-relapse mortality (NRM) (10.4% vs. 11.0%) compared to auto-HSCT. For patients who achieved remission with second-line salvage regimens, allo-HSCT was the primary choice (82.4%) for non-nodal PTCL, while auto-HSCT was more common (82.4%) in nodal PTCL. Nodal PTCL patients underwent auto-HSCT after ≥ 3 lines of treatment had a higher 3-year CIR (81.0%) compared to those treated in the first (26.0%) or second line (26.0%). Non-nodal PTCL patients underwent allo-HSCT after ≥ 3 lines had a higher 3-year NRM (37.5%) compared to after first (10.4%) or second line treatment (8.5%). These findings highlight distinct HSCT application patterns for PTCL in China, emphasizing the impact of early disease control and upfront consolidative HSCT.