Design and Synthesis of Benzimidazoles as CDK5 Inhibitors and Progress toward the Total Synthesis of Tubulysin D

This thesis describes the design and synthesis of 1,4,6-trisubstituted benzimidazoles as CDK5 inhibitors and the progress toward the total synthesis of tubulysin D. Tubulysin is a natural product with potential anti-cancer activity. The two gamma-amino acids in the Tuv and Tup fragments of tubulysin were synthesized. Evans\u27 oxazolidinone chemistry was employed for the stereoselective synthesis of Cbz-beta-homovaline in Tuv fragment. A crystal structure of the Tup fragment was obtained. Cyclin dependent kinase 5 (CDK5) is one of the kinases that can hyperphosphorylate tau. Selective inhibition of the CDK5/p25 complex may be a useful component for Alzheimer\u27s disease therapy. Benzimidazole based analogs of the known non-selective CDK5 inhibitor (R)-Roscovitine were designed. Synthesis of 6-benzyl substituted benzimidazole analogs was developed and two compounds were synthesized in this series. Two methods of the synthesis of 6-(2-hydroxy-1-alkyl)amino substituted benzimidazole analogs were developed

Use of Structural Equation Modelling and Neural Network to Analyse Shared Parking Choice Behaviour

The shared parking mode represents a feasible solution to the persistent problem of parking scarcity in urban areas. This paper aims to examine the shared parking choice behaviours using a combination of structural equation modelling (SEM) and neural network, taking into account both the parking location characteristics and the travellers’ characteristics. Data were collected from a commercial district in Nanjing, China, through an online questionnaire survey covering 11 factors affecting shared parking choice. The method involved two steps: firstly, SEM was applied to examine the influence of these factors on shared parking choice. Following this, the seven factors with the strongest correlation to shared parking choice were used to train a neural network model for shared parking prediction. This SEM-informed model was found to outperform a neural network model trained on all eleven factors across precision, recall, accuracy, F1 and AUC metrics. The research concluded that the selected factors significantly influence shared parking choice, reinforcing the hypothesis regarding the importance of parking location and traveller characteristics. These findings provide valuable insights to support the effective implementation and promotion of shared parking

O-GlcNAcylation of MITF regulates its activity and CDK4/6 inhibitor resistance in breast cancer

Cyclin-dependent kinases 4 and 6 (CDK4/6) play a pivotal role in cell cycle and cancer development. Targeting CDK4/6 has demonstrated promising effects against breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i), such as palbociclib, remains a substantial challenge in clinical settings. Using high-throughput combinatorial drug screening and genomic sequencing, we find that the microphthalmia-associated transcription factor (MITF) is activated via O-GlcNAcylation by O-GlcNAc transferase (OGT) in palbociclib-resistant breast cancer cells and tumors. Mechanistically, O-GlcNAcylation of MITF at Serine 49 enhances its interaction with importin α/β, thus promoting its translocation to nuclei, where it suppresses palbociclib-induced senescence. Inhibition of MITF or its O-GlcNAcylation re-sensitizes resistant cells to palbociclib. Moreover, clinical studies confirm the activation of MITF in tumors from patients who are palbociclib-resistant or undergoing palbociclib treatment. Collectively, our studies shed light on the mechanism regulating palbociclib resistance and present clinical evidence for developing therapeutic approaches to treat CDK4/6i-resistant breast cancer patients

Incidence and spontaneous clearance of gonorrhea and chlamydia infections among men who have sex with men: a prospective cohort study in Zhuhai, China

BackgroundMen who have sex with men (MSM) face significant risks of Chlamydia trachomatis (CT) and/or Neisseria gonorrhoeae (NG) infection. Nevertheless, only limited studies have looked into the site-specific infection and clearance of CT/NG. In order to prevent transmission, it is essential to understand the underlying factors that drive infection and spontaneous clearance.MethodsA 12-week cohort study examined the association between CT/NG infection, self-clearance, and sexual behaviors among MSM. The Willingness Service recruited participants who completed weekly questionnaires and provided urine, throat, and rectal swab samples.ResultsThe study involved 151 men, in which 51 (33.8%) were diagnosed with CT/NG infection during the study period. HIV (OR = 11.31), kissing (OR = 1.59), receptive oral sex (OR = 36.64), and insertive anal sex (OR = 19.73) constituted significant risk factors. 100% condom use (OR = 5.78) and antibiotic (OR = 7.53) were more likely to cause spontaneous clearance.DiscussionMSM may engage in riskier sexual behaviors due to insufficient knowledge and awareness of STI prevention, leading to increased susceptibility to NG/CT. It is crucial to concentrate on enhancing health education for MSM.ConclusionThis study found that the rectum was the most prevalent site of CT/NG and sexual behavior can influence the infection. Additionally, the appropriate use of antibiotics and consistent condom use may contribute to clear spontaneously

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

On the Quality Control of HY-2 Scatterometer High Winds

The operational wind processor for the Ku-band scatterometers onboard HY-2 satellite series uses a quality control (QC) scheme based on the maximum likelihood estimator (MLE). Since it is difficult to discriminate rain contamination from “true” high winds, the MLE-based wind QC is set in a conservative way, which rejects up to ~35% of high winds (w ≥ 20 m/s) in HY-2 scatterometers (HSCATs). In this paper, the sensitivity of MLE and its spatially averaged value (i.e., MLEm) to wind quality and rain is reconsidered by analyzing the collocated HSCAT observations and buoy data, as well as rain data from the global precipitation measurement satellite’s microwave imagers. It shows that MLEm is more effective than MLE in terms of flagging rain data. More interestingly, the HSCAT high winds are much less strongly affected by rain, compared to the prior Ku-band pencil-beam scatterometers (e.g., RapidScat). Consequently, a MLEm-based approach is proposed to improve the HSCAT wind QC, particularly for high winds. The new QC method results in ~8% rejections at 20 m/s and above. Compared to the collocated buoy winds, the HSCAT high winds preserved by the new QC (but rejected by the operational QC) are of fairly good quality

Expandable versus static cages in unilateral biportal endoscopy lumbar interbody fusion (ULIF) for treating degenerative lumbar spondylolisthesis (DLS): comparison of clinical and radiological results

Abstract Background In recent years, early rehabilitation after spinal fusion and the recovery of physiological curvature have attracted much attention. Therefore, expandable cages have entered the field of vision of scientists. The goal of the current study was to compare the clinical and radiological results of unilateral portal endoscopic lumbar interbody fusion (ULIF) in the treatment of degenerative lumbar spondylolisthesis (DLS) with expandable versus static cages. Methods We retrospectively analysed patients who received ULIF treatment for DLS from May 2019 to February 2021. Patients were categorized by cage type (static vs. expandable), and the main study was the preop and postop clinical and radiological index changes of the patients. Results Eighty-four patients were included (38 in the static cages group; 46 in the expandable cages group). There was no difference in the preop results between the two groups. The VAS scores for low back and leg pain and ODI scores in the expandable cages group 7 d postop were significantly superior to those in the static cages group (P < 0.05), and the segmental angle and PDH in the expandable cages group postop were significantly higher than those in the static cages group (P < 0.05). The fusions at 6 m postop in the expandable cages group were superior to those in the Static Cages group (P < 0.05). Conclusions The results of this study showed that compared with the stable cage group, the expandable cage group had unique advantages in restoring the physiological curvature of the lumbar spine, increasing the fusion rate, and relieving pain in the early postoperative period. ULIF can be used to treat single-segment, mild lumbar spondylolisthesis patients using expandable cages instead of static cages

Oblique lateral interbody fusion (OLIF) compared with unilateral biportal endoscopic lumbar interbody fusion (ULIF) for degenerative lumbar spondylolisthesis: a 2-year follow-up study

Abstract Background Oblique lumbar interbody fusion (OLIF) has been proven to be an effective method of indirect decompression for the treatment of Degenerative Lumbar Spondylolisthesis (DLS). However, its superiority over Unilateral biportal endoscopic Lumbar Interbody Fusion (ULIF) has not been reported yet. The current study aimed to compare the clinical and radiological outcomes of OLIF and ULIF in patients with DLS. Methods A total of 107 patients were included in this study, divided into two groups according to the surgical methods with 45 patients treated by OLIF combined with anterolateral single screwrod fixation, and 62 patients treated by ULIF. To compare the perioperative parameters (blood loss, operation time, and postop hospitalization) and clinical (the Visual Analog Scale (VAS) scores of the low back pain and leg pain and the Oswestry Disability Index (ODI)) and radiological (disk height (DH), lumbar lordosis (LL), segmental lordosis (SL), the cross-sectional area (CSA) of the spinal canal) results of the two surgical approaches to evaluate their efficacy. Results Compared with the ULIF group, the blood loss and operation time in the OLIF-AF group were significantly reduced, and the Postop hospitalization was comparable. The VAS scores in both groups were significantly improved compared to preop; however, the VAS score of low back pain in the OLIF-AF group was superior to that in ULIF group throughout the follow-up period (P < 0.05). The improvements in DH, LL, and Segmental angle were significantly lower in the ULIF group, and the expansion rate of CSA in the OLIF-AF group was superior to that in the ULIF group, but the difference was not statistically significant. The fusion rate in OLIF-AF group was significantly higher than that in ULIF group within 6 mo postop, and there was no significant difference at the last follow-up. The incidence of complications was comparable between the two groups, and there was no statistical difference. Conclusions Both OLIF-AF and ULIF achieved good short-term results in the treatment of DLS, and both surgical approaches are desirable. However, OLIF-AF has advantages over ULIF in terms of postoperative restoration of lumbar sagittal parameters and earlier intervertebral fusion. Long-term follow-up and larger clinical studies are needed to confirm this result

Identifying Potentially Risky Intersections for Heavy-Duty Truck Drivers Based on Individual Driving Styles

In developing countries, heavy-duty trucks play an important role in transportation for infrastructure construction. However, frequent truck accidents cause great losses. Previous studies have mainly focused on passenger drivers; to date, little has been done to assess the driving behavior of heavy truck drivers. The overall objective of this study is to classify driving styles at intersections, analyze the impacts of differing types of traffic control at intersections on driving styles, and identify potentially risky intersections. We selected 11 heavy-duty truck drivers and collected kinematic driving parameters (including driving speed and both lateral and longitudinal acceleration) from field experiments in Nanjing for our study. Our study on driving styles followed the following steps. First, we reduced data size and extracted data features on the basis of time windows in Python. Second, driving styles were classified into three driving styles: cautious, normal, and aggressive, based on the K-means clustering method, and the corresponding thresholds for each category were obtained. Kinematic driving parameters were used as driving style measurements. Third, according to classifications of driving style, the impacts of four different intersection traffic control types: two-phase signalized, multiphase signalized, stop, and yield intersections, on driving styles have been analyzed using the multinomial logit model. Moreover, based on the above analysis, potentially risky intersections were identified. The results suggest that different types of traffic control at intersections lead to variations in driving styles and have different influences on driving styles. In terms of accuracy, our method, which uses driving speed, both lateral and longitudinal acceleration, and jerk as features, performs better than traditional methods which only use speed and acceleration. The results of the study allow us to analyze the driving data of heavy-duty trucks and identify drivers who drive more aggressively during a trip. In addition, the results show that aggressive driving styles mostly occur at stop intersections and in the dilemma zones of signalized intersections. Therefore, early-warning interventions can be provided during a driver’s trip by analyzing the different types of traffic control at intersections on the route in advance. Finally, the cumulative analysis of driving styles at intersections over multiple trips can be used to identify potentially high-risk intersections. It is possible to eliminate potential risks in these areas through measures such as early warnings and by improving traffic management control methods

Effects of Plant-Derived Glycerol Monolaurate (GML) Additive on the Antioxidant Capacity, Anti-Inflammatory Ability, Muscle Nutritional Value, and Intestinal Flora of Hybrid Grouper (Epinephelus fuscoguttatus&#9792; &times; Epinephelus lanceolatus&#9794;)

In a context where the search for plant-derived additives is a hot topic, glycerol monolaurate (GML) was chosen as our subject to study its effect on grouper (Epinephelus fuscoguttatus&#9792; &times; Epinephelus lanceolatus&#9794;). Seven gradient levels of GML (0, 600, 1200, 1800, 2400, 3000, and 3600 mg/kg) were used for the experiment. Based on our experiments, 1800 mg/kg GML significantly increased the final body weight (FBW) and weight gain rate (WGR). GML increased the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and decreased malondialdehyde (MDA). Adding 1800 mg/kg GML also significantly increased the levels of lauric acid (C12:0) (LA), n-3 polyunsaturated fatty acids (PFA), and the n-6 PFA-to-n-3/n-6 ratio, while significantly decreasing the levels of saturated fatty acids (SFA). Dietary supplementation with GML significantly inhibited the expression of pro-inflammatory factors and reduced the occurrence of inflammation. GML improved intestinal flora and the abundance of beneficial bacteria (Bacillus, Psychrobacter, Acinetobacter, Acinetobacter, Stenotrophomonas, and Glutamicibacter). It provides a theoretical basis for the application of GML in aquafeed and greatly enhances the possibility of using GML in aquafeed. Based on the above experimental results, the optimum level of GML in grouper feed is 1800 mg/kg