Heterozygous variants in USP25 cause genetic generalized epilepsy.

USP25 encodes ubiquitin-specific proteases 25, a key member of deubiquitinating enzyme family and is involved in neural fate determination. Although abnormal expression in Down's syndrome was reported previously, the specific role of USP25 in human diseases has not been defined. In this study, we performed trio-based whole exome sequencing in a cohort of 319 cases (families) with generalized epilepsy of unknown etiology. Five heterozygous USP25 variants including two de novo and three co-segregated variants were determined in eight individuals affected by generalized seizures and/or febrile seizures from five unrelated families. The frequency of USP25 variants showed a significantly high aggregation in this cohort compared to the East Asian population and all populations in the gnomAD database. The mean onset ages of febrile and afebrile seizures were 10 months (infancy) and 11.8 years (juvenile), respectively. The patients achieved seizure freedom except one had occasional nocturnal seizures at the last follow-up. Two patients exhibited intellectual disability. Usp25 was ubiquitously expressed in mouse brain with two peaks on embryonic days (E14‒E16) and postnatal day 21, respectively. Similarly, USP25 expressed in fetus/early childhood stage with a second peak at approximately 12‒20 years old in human brain, consistent with the seizure onset age at infancy and juvenile in the patients. To investigate the functional impact of USP25 deficiency in vivo, we established Usp25 knock-out mice, which showed increased seizure susceptibility compared to wild-type mice in pentylenetetrazol-induced seizure test. To explore the impact of USP25 variants, we employed multiple functional detections. In HEK293T cells, the severe phenotype associated variant (p.Gln889Ter) led to a significant reduction of mRNA and protein expressions but formed a stable truncated dimers with increment of deubiquitinating enzyme activities and abnormal cellular aggregations, indicating a gain-of-function effect. The p.Gln889Ter and p.Leu1045del increased neuronal excitability in mice brain, with a higher firing ability in p.Gln889Ter. These functional impairments align with the severity of the observed phenotypes, suggesting a genotype-phenotype correlation. Hence, a moderate association between USP25 and epilepsy was noted, indicating USP25 is potentially a predisposing gene for epilepsy. Our results from Usp25 null mice and the patient-derived variants indicated that USP25 would play epileptogenic role via loss-of-function or gain-of-function effects. The truncated variant p.Gln889Ter would have profoundly different effect on epilepsy. Together, our results underscore the significance of USP25 heterozygous variants in epilepsy, thereby highlighting the critical role of USP25 in the brain.

IgG antibody response to SARS-CoV-2 infection and its influencing factors in lymphoma patients.

BACKGROUND: The ability of generating effective humoral immune responses to SARS-CoV-2 infection has not been clarified in lymphoma patients. The study aimed to investigate the antibody (Ab) production after SARS-Cov-2 infection and clarify the factors affecting the Ab generation in these patients. PATIENTS & METHODS: 80 lymphoma patients and 51 healthy controls were included in this prospective observational study. Clinical factors and treatment regimens affecting Ab positive rate (APR) and Ab levels were analyzed by univariate and multivariate methods. RESULTS: The anti-SARS-CoV-2 IgG APR and Ab levels in lymphoma patients were significantly lower than those in healthy controls. Lymphoma patients with COVID-19 vaccination had significantly higher APR and Ab levels compared with those without vaccination. Additionally, the use of dexamethasone for COVID-19 treatment had a negative impact on Ab levels. For the impact of treatment regimens on the APR and Ab levels, the results showed that patients treated with ≥ 6 times CD20 monoclonal Ab (mAb) and patients treated with autologous hematopoietic stem cell transplantation (ASCT) prior to infection produced a statistically lower APR and Ab levels compared with those treated with 1-5 times CD20 mAb and those treated without ASCT, respectively. Furthermore, multiple regression analysis indicated that the number of anti-CD20 treatment was an independent predictor for both APR and Ab levels. CONCLUSIONS: Humoral immune response to SARS-CoV-2 infection was impaired in lymphoma patients partly due to anti-CD20 and ASCT treatment. COVID-19 vaccination may be more needed for these patients.

An optimized short-term steroid therapy for chronic drug-induced liver injury: A prospective randomized clinical trial.

BACKGROUND AND AIMS: The use of corticosteroids in chronic drug-induced liver injury (DILI) is an important issue. Our previous randomized controlled trial showed that patients with chronic DILI benefited from a 48-week steroid stepwise reduction (SSR) regimen. However, it remains unclear whether a shorter course of therapy can achieve similar efficacy. In this study, we aimed to assess whether a 36-week SSR can achieve efficacy similar to that of 48-week SSR. METHODS: A randomized open-label trial was performed. Eligible patients were randomly assigned to the 36- or 48-week (1:1) SSR group. Liver biopsies were performed at baseline and at the end of treatment. The primary outcome was the proportion of patients with relapse rate (RR). The secondary outcomes were improvement in liver histology and safety. RESULTS: Of the 90 participants enrolled, 84 (87.5%) completed the trial, and 62 patients (68.9%) were women. Hepatocellular damage was observed in 53.4% of the cohort. The RR was 7.1% in the 36-week SSR group but 4.8% in the 48-week SSR group, as determined by per-protocol set analysis (p = 1.000). Significant histological improvements in histological activity (93.1% vs. 92.9%, p = 1.000) and fibrosis (41.4% vs. 46.4%, p = .701) were observed in both the groups. Biochemical normalization time did not differ between the two groups. No severe adverse events were observed. CONCLUSIONS: Both the 36- and 48-week SSR regimens demonstrated similar biochemical response and histological improvements with good safety, supporting 36-week SSR as a preferable therapeutic choice (ClinicalTrials.gov, NCT03266146).

Preoperative vascular heterogeneity based on dynamic susceptibility contrast MRI in predicting spatial pattern of locally recurrent high-grade gliomas.

OBJECTIVES: To investigate if spatial recurrence pattern is associated with patient prognosis, and whether MRI vascular habitats can predict spatial pattern. METHODS: In this retrospective study, 69 patients with locally recurrent high-grade gliomas (HGGs) were included. The cohort was divided into intra-resection cavity recurrence (ICR) and extra-resection cavity recurrence (ECR) patterns, according to the distance between the location of the recurrent tumor and the resection cavity or surgical region. Four vascular habitats, high angiogenic tumor, low angiogenic tumor, infiltrated peripheral edema, and vasogenic peripheral edema, were segmented and vascular heterogeneity parameters were analyzed. The survival and diagnostic performance under different spatial recurrence patterns were analyzed by Kaplan-Meier and ROC. A nomogram model was constructed by regression analysis and validated by bootstrapping technique. RESULTS: Progression-free survival (PFS) and overall survival (OS) were longer for ICR (n = 32) than those for ECR (n = 37) (median PFS: 8 vs. 5 months, median OS: 17 vs. 13 months, p < 0.05). MRI vascular habitat analyses showed ECR had higher median relative cerebral blood volume (rCBVmedian) at each habitat than ICR (all p < 0.01). The rCBVmedian at IPE had good diagnostic performance (AUC: 0.727, 95%CI: 0.607, 0.828). The AUC of the nomogram based on MRI vascular habitats and clinical factors was 0.834 (95%CI: 0.726, 0.913) and was confirmed as 0.833 (95%CI: 0.830, 0.836) by bootstrapping validation. CONCLUSIONS: The spatial pattern of locally recurrent HGGs is associated with prognosis. MRI vascular heterogeneity parameter could be used as a non-invasive imaging marker to predict spatial recurrence pattern. CLINICAL RELEVANCE STATEMENT: Vascular heterogeneity parameters based on MRI vascular habitat analyses can non-invasively predict the spatial patterns of locally recurrent high-grade gliomas, providing a new diagnostic basis for clinicians to develop the extent of surgical resection and postoperative radiotherapy planning. KEY POINTS: • Intra-resection cavity pattern was associated with longer progression-free survival and overall survival in locally recurrent high-grade gliomas. • Higher vascular heterogeneities in extra-resection cavity recurrence than in intra-resection cavity recurrence and the vascular heterogeneity parameters had good diagnostic performance in discriminating spatial recurrence pattern. • A nomogram model based on MRI vascular habitats and clinical factors had good performance in predicting spatial recurrence pattern.

Loss of sweet taste despite the conservation of sweet receptor genes in insectivorous bats.

The evolution of taste perception is usually associated with the ecology and dietary changes of organisms. However, the association between feeding ecology and taste receptor evolution is unclear in some lineages of vertebrate animals. One example is the sweet taste receptor gene Tas1r2 Previous analysis of partial sequences has revealed that Tas1r2 has undergone equally strong purifying selection between insectivorous and frugivorous bats. To test whether the sweet taste function is also important in bats with contrasting diets, we examined the complete coding sequences of both sweet taste receptor genes (Tas1r2 and Tas1r3) in 34 representative bat species. Although these two genes are highly conserved between frugivorous and insectivorous bats at the sequence level, our behavioral experiments revealed that an insectivorous bat (Myotis ricketti) showed no preference for natural sugars, whereas the frugivorous species (Rousettus leschenaultii) showed strong preferences for sucrose and fructose. Furthermore, while both sweet taste receptor genes are expressed in the taste tissue of insectivorous and frugivorous bats, our cell-based assays revealed striking functional divergence: the sweet taste receptors of frugivorous bats are able to respond to natural sugars whereas those of insectivorous bats are not, which is consistent with the behavioral preference tests, suggesting that functional evolution of sweet taste receptors is closely related to diet. This comprehensive study suggests that using sequence conservation alone could be misleading in inferring protein and physiological function and highlights the power of combining behavioral experiments, expression analysis, and functional assays in molecular evolutionary studies.

Characterization of VOC emissions and health risk assessment in the plastic manufacturing industry.

Volatile organic compounds (VOCs) significantly contribute to ozone pollution formation, and many VOCs are known to be harmful to human health. Plastic has become an indispensable material in various industries and daily use scenarios, yet the VOC emissions and associated health risks in the plastic manufacturing industry have received limited attention. In this study, we conducted sampling in three typical plastic manufacturing factories to analyze the emission characteristics of VOCs, ozone formation potential (OFP), and health risks for workers. Isopropanol was detected at relatively high concentrations in all three factories, with concentrations in organized emissions reaching 322.3 µg/m3, 344.8 µg/m3, and 22.6 µg/m3, respectively. Alkanes are the most emitted category of VOCs in plastic factories. However, alkenes and oxygenated volatile organic compounds (OVOCs) exhibit higher OFP. In organized emissions of different types of VOCs in the three factories, alkenes and OVOCs contributed 22.8%, 67%, and 37.8% to the OFP, respectively, highlighting the necessity of controlling them. The hazard index (HI) for all three factories was less than 1, indicating a low non-carcinogenic toxic risk; however, there is still a possibility of non-cancerous health risks in two of the factories, and a potential lifetime cancer risk in all of the three factories. For workers with job tenures exceeding 5 years, there may be potential health risks, hence wearing masks with protective capabilities is necessary. This study provides evidence for reducing VOC emissions and improving management measures to ensure the health protection of workers in the plastic manufacturing industry.

Value of preoperative controlling nutritional status score in prognosis of patients with high-risk factors for early-stage cervical cancer.

Objective: To investigate whether the preoperative controlling nutritional status (COUNT) score is a prognostic factor of patients with high-risk factors for early-stage cervical cancer after surgery and concurrent chemoradiotherapy (CCRT). Methods: This was a retrospective study. From July 2017 to March 2021, a total of 354 patients with histologically confirmed FIGO stage IB-IIA cervical cancer undergoing surgery and postoperative CCRT were included at Hunan University of Medicine General Hospital, China. According to receiver operating characteristic (ROC) curve analysis, the patients were divided into a low CONUT score (< 3) group and a high CONUT score (≥ 3) group. Overall survival (OS) was used as the primary outcome measure and disease-free survival (DFS) as the secondary outcome measure. Results: Among the 354 patients, 239(67.5%) were included in the low CONUT score group and 115 (32.5%) in the high CONUT score group. The 3, 5 and 10-year OS rates in the low CONUT score group and high CONUT score group were respectively presenting statistically significant differences (p<0.001). The 3, 5 and 10-year DFS rates in the low CONUT score group and in the high CONUT score group were respectively with statistically significant differences (p<0.001). Multivariate Cox regression analysis showed that CONUT score, histological type, PNI and lymph node metastasis were all independent predictors for OS and DFS (all p<0.05). Conclusion: High preoperative CONUT score indicates poor prognosis of patients with high-risk factors for early-stage cervical cancer after surgery and postoperative CCRT. In clinical practice, consolidation chemotherapy is recommended for patients with high CONUT scores.

Nanostructure Engineering of Sn-Based Catalysts for Efficient Electrochemical CO2 Reduction.

Excessive anthropogenic CO2 emission has caused a series of ecological and environmental issues, which threatens mankind's sustainable development. Mimicking the natural photosynthesis process (i.e., artificial photosynthesis) by electrochemically converting CO2 into value-added products is a promising way to alleviate CO2 emission and relieve the dependence on fossil fuels. Recently, Sn-based catalysts have attracted increasing research attentions due to the merits of low price, abundance, non-toxicity, and environmental benignancy. In this review, the paradigm of nanostructure engineering for efficient electrochemical CO2 reduction (ECO2 R) on Sn-based catalysts is systematically summarized. First, the nanostructure engineering of size, composition, atomic structure, morphology, defect, surficial modification, catalyst/substrate interface, and single-atom structure, are systematically discussed. The influence of nanostructure engineering on the electronic structure and adsorption property of intermediates, as well as the performance of Sn-based catalysts for ECO2 R are highlighted. Second, the potential chemical state changes and the role of surface hydroxides on Sn-based catalysts during ECO2 R are introduced. Third, the challenges and opportunities of Sn-based catalysts for ECO2 R are proposed. It is expected that this review inspires the further development of highly efficient Sn-based catalysts, meanwhile offer protocols for the investigation of Sn-based catalysts.

Inhibition of Amyloid ß Aggregation and Cytotoxicity by Berbamine Hydrochloride.

Alzheimer's disease (AD) continues to be a major global health challenge, and the recent approval of Aduhelm and Leqembi has opened new avenues for its treatment. Small-molecule inhibitors targeting Aß aggregation hold promise as an alternative to monoclonal antibodies. In this study, we evaluated the ability of berbamine hydrochloride (BBMH), a member of the bisbenzylisoquinoline alkaloids, to reduce Aß aggregation and cytotoxicity. Thioflavin T kinetics, circular dichroism spectroscopy, and atomic force microscopy results indicated that BBMH effectively inhibited Aß aggregation. Surface plasmon resonance and molecular docking results further revealed that BBMH could bind to Aß fibrils, thereby hindering the aggregation process. This physical picture has been confirmed in a quantitative way by chemical kinetics analysis, which showed BBMH tends to bind with the fibril ends and thus prevents the transition from protofibrils to mature fibrils as well as the elongation process. Additionally, our MTT results showed that BBMH was able to reduce the cytotoxicity of Aß40 on N2a cells. Our results demonstrate, for the first time, the potential of BBMH to inhibit Aß aggregation and cytotoxicity, offering a promising direction for further research and drug development efforts in the fight against Alzheimer's disease.

The Value of Sports and Functional Exercise on Preventing Falls in Elderly Patients with Cognitive Impairment: A Systematic Review and Meta-Analysis.

Objective: To explore the value of sports and functional exercises in preventing falls in elderly patients with cognitive impairment. Methods: PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure, VIP, Wanfang Database, and China Biomedical Literature Database (CBM), from inception to January 2023, were used to search the randomized controlled trials (RCTs) of sports and functional exercises in elderly patients with cognitive impairment. Two independent researchers extracted the data and evaluated the quality of the included literature. RevMan5.4 software was adopted for data analysis. Results: The results indicated that exercise combined with functional exercise could noticeably enhance the fall effect score and shorten the Timed Up and Go Test (TUGT) time of elderly patients with cognitive impairment compared to simple drug treatment (P < .05). Our results showed that the exercise combined with functional exercise can noticeably prolong the standing time of elderly patients with cognitive impairment upon monocular eye closure. Our results also showed that exercise combined with functional exercise can noticeably improve the fear of falls in elderly patients with cognitive impairment. Conclusion: Sports and functional exercise intervention can promote the balance ability and fall self-efficacy of elderly patients with cognitive impairment and have a positive effect on enhancing patients' fear of falls. The findings need to be further verified and methodological quality needs to be improved. In addition, longer intervention times are required to verify the findings.

Study of Resource Allocation for 5G URLLC/eMBB-Oriented Power Hybrid Service.

With the rapid development of the 5G power Internet of Things (IoT), new power systems have higher requirements for data transmission rates, latency, reliability, and energy efficiency. Specifically, the hybrid service of enhanced mobile broadband (eMBB) and ultra-reliable low-latency communication (URLLC) has brought new challenges to the differentiated service of the 5G power IoT. To solve the above problems, this paper first constructs a power IoT model based on NOMA for the mixed service of URLLC and eMBB. Considering the shortage of resource utilization in eMBB and URLLC hybrid power service scenarios, the problem of maximizing system throughput through joint channel selection and power allocation is proposed. The channel selection algorithm based on matching as well as the power allocation algorithm based on water injection are developed to tackle the problem. Both theoretical analysis and experimental simulation verify that our method has superior performance in system throughput and spectrum efficiency.

Designing a Mucoadhesive ChemoPatch to Ablate Oral Dysplasia for Cancer Prevention.

Oral cancer has a high mortality rate, and its treatment often causes debilitating complications. More than 90% of oral cancers are oral squamous cell carcinomas (OSCCs) that may develop from clinically recognizable oral premalignant lesions (OPLs). To eradicate OPLs before they turn into cancers, a non-invasive topical formulation is developed based on a novel combination of synergistically acting oxaliplatin (OXP) and mycophenolate (MPS) embedded in a controlled-release mucoadhesive patch fabricated by computer-aided 3D printing. After multiple rounds of testing and optimization, a v6.4 ChemoPatch is designed, which shows sustained release of OXP and MPS in vitro, minimal side leakage of drugs, an average elastic modulus of 2.38 MPa, and suitable drug stability at 4 °C or below for up to 12 months. In vivo analyses show almost all patches adhere to the dorsal tongue surface for 4 hours, and display a sustained release of OXP and MPS to tongue tissue for 3-4 hours. When applied in the 4-nitroquinoline-1-oxide-induced OPL rat model, the OXP-MPS patch significantly ablates dysplastic lesions with no damage to normal epithelial cells and minimal systemic absorption and side effects. This study reports the design of a novel mucoadhesive ChemoPatch as a noninvasive therapy to treat OPLs.

MicroRNA-320a-containing exosomes from human umbilical cord mesenchymal stem cells curtail proliferation and metastasis in lung cancer by binding to SOX4.

Exosomes from human umbilical cord mesenchymal stem cells (HUCMSCs) containing microRNAs (miRNAs) have been underscored as possible therapeutic options for cancers. Hence, our goal here was to investigate the relevance of miR-320a-containing exosomes from HUCMSCs to lung cancer. First, H1299 and H460 cells were co-cultured with the exosomes overexpressing miR-320a from HUCMSCs. The data displayed that HUCMSCs-secreted exosomes expressing miR-320a exerted anti-tumor effects in vitro and in vivo. Online analysis available at TargetScan database revealed that miR-320a bound to sex-determining region Y-box 4 (SOX4), and the luciferase reporter gene assay clarified this targeting relationship. Next, a ß-catenin-specific agonist WAY-262611 was delivered into the H1299 and H460 cells to assess the effects of the Wnt/ß-catenin pathway on lung cancer cellular processes. The results demonstrated that WAY-262611 potentiated lung cancer cell viability, invasion, and migration, but inhibited cell apoptosis. Altogether, exosomes carrying miR-320a from HUCMSCs might suppress lung cancer cell growth via the SOX4/Wnt/ß-catenin axis, which highpoints the potency of exosomes expressing miR-320a as a possible therapeutic option for lung cancer treatment.

Low carbon footprint preparation of MXene incorporated lignocellulosic fibers for high thermal conductivity applications.

New wood-based composite materials with thermal conductivity are greatly desired in the fields of packaging materials for electronic components. In this study, a new multifunctional composite material (M@FC) is prepared by simply blending clay-like Ti3C2Tx MXene and delignified wood fibers together, and then followed by an infusing epoxy resin with environmentally friendly vacuum assisted resin transfer molding (VARTM) process. The resulting M@FC (0.92 W m-1 K-1) possesses superior thermal conductivity as compared to natural wood (0.099 W m-1 K-1) and most polymers. Furthermore, after the VARTM process, the structure of the M@FC is tighter, and thus showing excellent mechanical properties (tensile strength of 93.0 MPa and flexural strength of 172.7 MPa). In addition, good water resistance and excellent flame retardant property are observed for M@FC. The improvement of thermal conductivity provides the possibility for its application for packaging materials in electronic components. This study using waste wood as the important component provides a new idea for carbon cycling and recycling of natural resources.

Dynamic PSF-based jitter compensation and quality improvement for push-broom optical images considering terrain relief and the TDI effect.

Platform attitude jitter is inevitable during a satellite flight. The jitter reduces the quality of push-broom optical images, resulting in geometric deformation and image blur. This paper proposes an approach that offers jitter effect compensation and quality improvement for push-broom optical images based on dynamic point spread function (PSF) estimation and iterative image restoration considering the effect of terrain relief and time delay integration (TDI). First, the attitude jitter is precisely detected and estimated by considering the terrain relief. The jitter information is then used to establish the dynamic PSF of each image line considering the changing jitter values and TDI effect. Finally, based on the constructed PSF, the image is improved by iterative restoration using the optimal-window Richardson-Lucy algorithm. The method is validated by both simulation and real data experiments. In the simulation experiment, we apply jitter with different amplitudes and frequencies to generate the degraded images and then restore the image using the proposed restoration method. The results show that the proposed method can effectively restore images affected by jitter. In addition, real data experiments are carried out with multispectral remote sensing images from the ZY-3 satellite. The results show that in addition to the improvement of the radiometric quality, the geometric quality is also significantly improved in both the across-track and the along-track directions. The experimental results validated that the proposed method outperformed other methods without considering the terrain and TDI effect.

Metabolite Identification of a Novel Anti-Leishmanial Agent OJT007 in Rat Liver Microsomes Using LC-MS/MS.

The purpose of this study was to identify potential metabolic pathways and metabolites of OJT007, a methionine aminopeptidase 1 (MetAP1) inhibitor. OJT007 is a novel drug with potent antiproliferative effects against Leishmania Major. We conducted in vitro Phase I oxidation and Phase II glucuronidation assays on OJT007 using rat liver microsomes. Four unknown metabolites were initially identified using a UPLC-UV system from microsomal incubated samples. LC-MS/MS analysis was then used to identify the structural characteristics of these metabolites via precursor ion scan, neutral loss scan, and product ion scan. A glucuronide metabolite was further confirmed by ß-glucuronidase hydrolysis. The kinetic parameters of OJT007 glucuronidation demonstrated that OJT007 undergoes rapid metabolism. These results demonstrate the liver's microsomal ability to mediate three mono-oxidated metabolites and one mono-glucuronide metabolite. This suggests hepatic glucuronidation metabolism of OJT007 may be the cause of its poor oral bioavailability.

[Suitable harvest period of Aurantii Fructus based on UPLC-Q-TOF-MS metabolomics].

The types of secondary metabolites of Aurantii Fructus samples from GAP base in different harvest periods were detected by UPLC-Q-TOF-MS metabolomics, and the differential metabolites were screened out by multivariate statistical analysis. The variation of the content of differential metabolites with different harvest periods was analyzed, and the correlation analysis was carried out on the differential metabolites to determine the suitable harvest period for different components. Sixteen differential metabolites were obtained. With the delay of harvest time, the content of flavonoid glycosides, including naringin, neohesperidin, poncirin, narirutin, and hesperidin, gradually decreased. It is suggested that the suitable harvest period for raw materials of Aurantii Fructus with flavonoids as active components is from July 18 to July 25(within one week before and after the Great heat). The content of nobiletin, tangeretin, natsudaidain, 7-hydroxyl-4',3,5,6,8-pentamethoxyflavone, sinensetin, isosinensetin, 5,6,7,4'-tetramethoxyflavone, and isomeranzin decreased first, then increased, and finally decreased. It is suggested that the suitable harvest time for raw materials of Aurantii Fructus with these components as the active components is July 18. The content changes of meranzin, limonin, and 3,5,6,7,8,3',4'-heptamethoxyflavone have their characteristics. According to the conditions of actual production, it is suggested that the suitable harvest time is June 27, July 11, and July 25, respectively. The results showed that there were differences in the content of chemical components of Aurantii Fructus in different harvest periods, and the suitable harvest period should be determined according to the differences in chemical component content. This study is expected to provide a scientific basis for the purchase of raw materials of Aurantii Fructus for Chinese patent medicines with different effects.

Discovery of novel tubulin inhibitors targeting taxanes site by virtual screening, molecular dynamic simulation, and biological evaluation.

Microtubules play crucial role in process of mitosis and cell proliferation, which have been considered as attractive drug targets for anticancer therapy. The aim of this study was to discover novel and chemically diverse tubulin inhibitors for treatment of cancer. In this investigation, the multilayer virtual screening methods, including common feature pharmacophore model, structure-based pharmacophore model and molecular docking, were developed to screen BioDiversity database with 30,000 compounds. A total of 102 compounds were obtained by the virtual screening, and further filtered by diverse chemical clusters with desired properties and PAINS analysis. Finally, 50 compounds were selected and submitted to the biological evaluation. Among these hits, hits 8 and 30 with novel scaffolds displayed stronger antiproliferative activity on four human tumor cells including Hela, A549, MCF-7, and HepG2. Moreover, the two hits were subsequently submitted to molecular dynamic simulations of 90 ns with the aim of exploring the stability of ligand-protein interactions into the binding pocket, and further probing the mechanism of the interaction between tubulin and hits. The molecular dynamic simulation results revealed there had stronger interactions between tubulin and hits in equilibrium state. Therefore, the hits 8 and 30 have been well characterized as lead compounds for developing new tubulin inhibitors with potential anticancer activity.

Geometric modeling of attitude jitter for three-line-array imaging satellites.

Attitude jitter causes image motion and degrades geometric accuracy of high-resolution satellite images. This work studies the mechanism of the attitude jitter effect on the imaging geometry of three-line-array push-broom sensors onboard satellites, which is a typical configuration used for topographic mapping. Based on a rigorous physical imaging model, we derived quantitative models of the geometric effect of attitude jitter in the roll, pitch, and yaw angles on the image distortions of the forward, nadir, and backward view sensors, and the accuracy of the derived models is validated through comprehensive experiments and analyses. The experimental results reveal the following. First, the attitude jitter in the roll angle dominates the cross-track image deviation; it does not affect the along-track geometry of the nadir-view sensor but marginally affects the off-nadir-view sensors, and the image distortions share a linear relationship with the image column coordinates. Second, the attitude jitter in the pitch angle dominates the along-track image deviation, and the image distortions in the off-nadir-view images are relatively larger than those in the nadir-view images. The attitude jitter in the pitch angle does not affect the cross-track geometry of the nadir-view sensor but marginally affects the off-nadir-view sensors, and the image distortions share a linear relationship with the image column coordinates. Finally, the attitude jitter in the yaw angle mainly causes the cross-track image deviation in the off-nadir-view sensors, and the along-track image geometries of all the three view sensors are marginally affected to the same extent by the yaw angle variation.

The impact of primary human papillomavirus screening on negative loop excision histology following biopsy-proven high-grade cervical intra-epithelial lesions: A review from a large tertiary colposcopy unit.

BACKGROUND: The renewed National Cervical Screening Program incorporating primary human papillomavirus (HPV) screening was implemented in Australia in December 2017. In a previous study conducted in the UK, primary HPV screening was found to be associated with a 25% reduction in the incidence of negative histology following loop electrosurgery excision procedure (LEEP). AIM: To examine the change in incidence and associated risk factors for a negative LEEP with introduction of primary HPV screening. MATERIALS AND METHODS: A retrospective review of the records of all patients undergoing a LEEP excision for biopsy-proven high-grade cervical intra-epithelial lesions between 1 January 2014 and 30 June 2019 in a specialised centre. RESULTS: There were 1123 patients who underwent a LEEP included in the analysis. The incidence of a negative LEEP specimen was 7.5% (59/784) and 5.3% (18/339) in the pre- and post-HPV screening cohort. More patients in the post-HPV screening group had low-grade cytology on referral (P < 0.001), smaller cervical lesions on colposcopy (P = 0.012) and longer biopsy to treatment interval (P = 0.020). Primary HPV screening was associated with a significant reduction in the incidence of a negative LEEP specimen in a propensity matched cohort (11.2% to 5.1%, P = 0.006) and a 41% (P = 0.045) decreased relative risk of a negative LEEP on multivariate analysis. CONCLUSIONS: Primary HPV screening results in a lower incidence of negative LEEP histology, despite a longer biopsy to treatment wait time and higher proportion of low-grade cytology at triage.