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Selective serotonin reuptake inhibitors (SSRIs) are characterized by delayed therapeutic onset largely due to their reliance on the desensitization of 5-HT1A autoreceptors (5-HT1ARautos) within the dorsal raphe nucleus (DRN). It has been shown that dissociation of serotonin transporter (SERT) and neuronal nitric oxide synthase (nNOS) interaction selectively modulates 5-HT1ARautos, thereby facilitating fast-onset antidepressant responses. Targeting the atypical disk large/ZO-1 (PDZ) domain has been implicated in the SERT-nNOS interaction. In this study, we established a drug screening system based on mBRET combined with biological tests to find SERT-nNOS interaction blockers (SNIBs). During screening the compound libraries, 9 top candidates were found to be capable of binding to the PDZ domain of nNOS. We then identified esflurbiprofen as a promising fast-onset antidepressant candidate. Pharmacodynamic studies revealed that esflurbiprofen effectively penetrated the DRN following systemic administration. Esflurbiprofen (10, 20, 40 mg/kg, i.p., once every 4 days) dose-dependently ameliorated depressive-like behaviors in mice subjected to chronic social defeat stress (CSDS) and chronic restraint stress (CRS). In rs-fMRI analysis, we found that esflurbiprofen enhanced the functional connectivity of emotion-related neural networks in CSDS mice. We further demonstrated that esflurbiprofen disrupted the SERT-nNOS complex in the DRN, augmented membrane-associated SERT, and reduced the concentration of 5-HT in the extracellular space of the DRN. This cascade subsequently enhanced serotonergic neuronal firing through the inhibition of negative feedback mediated by 5-HT1ARautos, culminating in an augmented release of 5-HT from serotonergic neurons projecting to the prefrontal cortex and hippocampus. These results highlight the potential of esflurbiprofen to induce rapid antidepressant effects by targeting the SERT-nNOS interaction within the DRN.

This study explores the association of individual cognition and social environment of smoking with autonomy over tobacco, providing evidence and insights to help smokers effectively prevent and reduce tobacco dependence. Data were collected from 1389 participants, aged &#x2265;15 years, by face-to-face interviews from June 2018 to November 2019 in central China. We assessed autonomy over tobacco using the Autonomy Over Smoking Scale (AUTOS), including Withdrawal Symptoms (WS), Psychological Dependence (PD) and Cue-induced Cravings (CC), and examined factors of individual cognition and social environment, as well as covariates, including demographic characteristics, health status, and smoking behavior. AUTOS total score was 16.92 &#xb1; 9.05, WS score was the lowest (4.40 &#xb1; 3.36) in the three subscales, and CC score was the highest (6.88 &#xb1; 3.2). After adjustment, WS score of having a greater awareness of smoking hazards to one's own health was lower than those who had no awareness (&#x3b2;=0.14; 95% CI: -0.31-0.00), and the total score of AUTOS, the score of PD and CC for those who thought smoking was 'more helpful (high)' to interpersonal communication were higher than 'not helpful (not at all)' (&#x3b2;=0.14; 95% CI: 0.01-0.28 with &#x3b2;=0.16; 95% CI: 0.02-0.29; and &#x3b2;=0.14; 95% CI: 0.00-0.28; respectively). Having a greater difficulty in smoking cessation was associated with higher AUTOS total and subscale scores (p<0.001). Notably, none of the social-environmental factors included had a significant association with AUTOS scores. Interventions targeting individual cognitive factors of tobacco dependence seem to be more effective in smoking cessation. Future research may explore the influence of family and workplace among social environmental factors, which may reveal the effect of a binding force.

Best Practice Advisories (BPAs) are clinical decision support tools integrated into the patient's electronic health record to assist registered nurses. They provide reminders and highlight patterns based on clinical assessment findings. To analyze their use at a hospital in Southern Arizona, the AUTOS (Artifact, User, Task, Organization, and Situation) framework was used, which follows a human-centered design approach. Although BPAs offer significant support, they can disrupt critical care nurses' workflows. In 2023, this Southern Arizona hospital reported more than 36 unique BPAs, resulting in an average of 783 alerts for critical care nurses in the intensive care unit each month.

This paper examines the household commuting problem in a bi-modal transportation that includes both autos and school buses. Traditional studies of household commuting have assumed that adults first drop off their children at school before driving to work. However, with the increasing use of school buses in metropolitan areas, household commuting patterns have changed. This paper investigates the impact of school buses on household travel behavior during morning peak hours. Simultaneously, this paper also takes into account the positive utilities of household commuters' activities at home, school and workplace, as well as the negative utilities of travel time and schedule delay. In this paper, based on activity approach, first, a net utility function is developed using these factors. Then, based on the net utility function, the occurrence conditions of all the possible equilibrium travel patterns are analytically solved and the properties of the user equilibrium are researched. Specifically, this paper examines how equilibrium travel patterns are affected by school bus fares and school-work start time difference, and at equilibrium travel patterns, the net utilities of household commuters are also analyzed. Finally, a first-best time-varying toll model is suggested to alleviate traffic congestion caused by household commuting.

Joint communication and sensing (JCS) is becoming an important trend in 6G, owing to its efficient utilization of spectrums and hardware resources. Utilizing echoes of the same signal can achieve the object location sensing function, in addition to the V2X communication function. There is application potential for JCS systems in the fields of ADAS and unmanned autos. Currently, the NR-V2X sidelink has been standardized by 3GPP to support low-latency high-reliability direct communication. In order to combine the benefits of both direct communication and JCS, it is promising to extend existing NR-V2X sidelink communication toward sidelink JCS. However, conflicting performance requirements arise between radar sensing accuracy and communication reliability with the limited sidelink spectrum. In order to overcome the challenges in the distributed resource allocation of sidelink JCS with a full-duplex, this paper has proposed a novel consecutive-collision mitigation semi-persistent scheduling (CCM-SPS) scheme, including the collision detection and Q-learning training stages to suppress collision probabilities. Theoretical performance analyses on Cram&#xe9;r-Rao Lower Bounds (CRLBs) have been made for the sensing of sidelink JCS. Key performance metrics such as CRLB, PRR and UD have been evaluated. Simulation results show the superior performance of CCM-SPS compared to similar solutions, with promising application prospects.

Temporal networks, whose network topology changes over time, are used to represent, e.g., opportunistic mobile networks, vehicle networks, and social contact networks, where two mobile devices (autos or individuals) are connected only when they are close to (interact with) each other. Such networks facilitate the transfer of information. In this paper, we address the problem of navigation on temporal networks: how to route a traffic demand from a source s to a destination d at time t s , based on the network observed before t s ? Whenever the node hosting the information has a contact or interacts with another node, the routing method has to decide whether the information should be forwarded to the contacted node or not. Once the information is forwarded, the contacted node becomes the only node hosting the information. Firstly, we introduce a framework of designing navigation algorithms, in which a distance metric is defined and computed between any node to the target d based on the network observed before t s . Whenever a hosting node has a contact, it forwards the information to the contacted node if the contacted node is closer to the target than the hosting node according to the distance metric. Secondly, we propose systematically distance metrics of a node pair in the temporal network observed, that capture different network properties of a node pair. Thirdly, these metrics or routing strategies are evaluated in empirical contact networks, from the perspective of the time duration of the routing and the probability that the destination can be reached. Their performance is further explained via the correlation between distance metrics and the stability of each metric in ranking nodes' distance to a target node. This work may serve as inspiration for evaluating and redesigning these strategies in other types of networks beyond physical contact networks.

The autonomy over tobacco scale (AUTOS) is a 12-item theory-based instrument used to measure tobacco dependence in smokers. It provides separate measures of three factors that make smoking cessation more difficult: withdrawal symptoms, psychological dependence, and cue-induced urges to use tobacco. We compared the internal reliability and concurrent validity of the AUTOS to those of the Fagerstr&#xf6;m test for nicotine dependence (FTND). Adult current smokers (n=422; 62% female; 86.8% white; mean age 33.3 years, SD=13.7; 57% daily smokers) completed an anonymous web-based survey that included the AUTOS, the FTND and 11 smoking-related behavioral measures. Cronbach's &#x3b1; was .94 for the AUTOS and &#x3b1;>.75 for each of the 3 subscales; &#x3b1;=.73 for the FTND. The AUTOS and its subscales correlated with all measures of concurrent validity (r=.70 between AUTOS & FTND). The AUTOS correlated better than the FTND with the Hooked on Nicotine Checklist, the longest period of abstinence, latency to wanting, percentage of time a person smokes because of momentary need, pleasure from smoking, days smoked per month, and concern about deprivation. The measures showed similar correlations with the latencies to craving and needing. The FTND correlated better with the duration of smoking and cigarettes smoked per day. Based on these results and those from prior studies, we conclude that the AUTOS offers researchers a valid and highly reliable, theory-based measure that is more versatile in its applications than the FTND.

At least 10% of proteins constituting the human proteome are subject to S-acylation by a long-chain fatty acid, thioesterified to a Cys thiol side chain. Fatty S-acylation (prototypically, S-palmitoylation) operates across eukaryotic phylogeny and cell type. S-palmitoylation is carried out in mammalian cells by a family of 23-24 dedicated zDHHC palmitoyl transferase enzymes, and mutation of zDHHCs is associated with a number of human pathophysiologies. Activation of the zDHHCs by auto-S-palmitoylation, the transthioesterification of the active site Cys by fatty acyl coenzyme A, is the necessary first step in zDHHC-mediated protein S-palmitoylation. Most prior in&#xa0;vitro assessments of zDHHC activation have utilized purified zDHHCs, a time- and effort-intensive approach, which removes zDHHCs from their native membrane environment. We describe here a facile assay for zDHHC activation in native membranes. We overexpressed hemagglutinin-tagged wild-type or mutant zDHHCs in cultured HEK293&#xa0;cells and prepared a whole membrane fraction, which was incubated with fluorescent palmitoyl CoA (NBD-palmitoyl-CoA) followed by SDS-PAGE, fluorescence imaging, and Western blotting for hemagglutinin. We show by mutational analysis that, as assayed, zDHHC auto-S-palmitoylation by NBD-palmitoyl-CoA is limited to the active site Cys. Application of the assay revealed differential effects on zDHHC activation of posttranslational zDHHC modification and of zDHHC mutations associated with human disease, in particular cancer. Our assay provides a facile means of assessing zDHHC activation, and thus of differentiating the effects of zDHHC mutation and posttranslational modification on zDHHC activation versus secondary effects on zDHHC functionality including altered zDHHC interaction with substrate palmitoyl-proteins.

Protein S-acyl transferases (PATs) are a family of enzymes that catalyze protein S-acylation, a post-translational lipid modification involved in protein membrane targeting, trafficking, stability, and protein-protein interaction. S-acylation plays important roles in plant growth, development, and stress responses. Here, we report the genome-wide analysis of the PAT family genes in the woodland strawberry (Fragaria vesca), a model plant for studying the economically important Rosaceae family. In total, 21 'Asp-His-His-Cys' Cys Rich Domain (DHHC-CRD)-containing sequences were identified, named here as FvPAT1-21. Expression profiling by reverse transcription quantitative PCR (RT-qPCR) showed that all the 21 FvPATs were expressed ubiquitously in seedlings and different tissues from adult plants, with notably high levels present in vegetative tissues and young fruits. Treating seedlings with hormones indole-3-acetic acid (IAA), abscisic acid (ABA), and salicylic acid (SA) rapidly increased the transcription of most FvPATs. A complementation assay in yeast PAT mutant akr1 and auto-S-acylation assay of one FvPAT (FvPAT19) confirmed its enzyme activity where the Cys in the DHHC motif was required. An AlphaFold prediction of the DHHC and the mutated DHHC155S of FvPAT19 provided further proof of the importance of C155 in fatty acid binding. Together, our data clearly demonstrated that S-acylation catalyzed by FvPATs plays important roles in growth, development, and stress signaling in strawberries. These preliminary results could contribute to further research to understand S-acylation in strawberries and plants in general.

Conflict-based road safety assessments may provide a deeper insight into the processes leading to crashes compared to assessments solely based on field crash data. The evaluation of road safety is conducted on specific road segments using different surrogate measure of safety indicators, such as temporal, spatial, and kinematic proximity measures, depending on the relevant context and applicability of these measures. Therefore, this study endeavored to develop a methodology by adopting safety measures such as post encroachment time (PET) and conflicting speeds of through vehicles for crossing maneuvers and time to collision (TTC) for rear-end collisions at five unsignalized intersections in urban mixed traffic conditions. Critical conflicts are calculated by calculating a speed variable known as the critical speed, which is based on the braking distance. A study found that the motorized two wheeler (MTW) categories involve the highest proportion of critical conflict with right-turning vehicles, followed by cars, autos, and light commercial vehicle (LCVs). Furthermore, crossing conflicts were modeled as a function using the generalized linear regression approach. The findings revealed that the most significant factors were traffic volume and vehicular composition in a conflicting stream. The unsupervised classification technique k-mean clustering was used to determine the defined severity level threshold for rear-end maneuvers. The result observed was that a TTC threshold of less than 1.15&#xa0;s was identified as high-risk vehicular interaction. Additional investigation indicated that presence of certain moving vehicle categories, including MTWs and cars, led to a higher proportion of critical crossing conflicts. The conceptualized safety framework can be applied to evaluate safety at unsignalized intersections in the mixed traffic scenarios.

We investigated the psychometric properties of a German translation of the 12-item Autonomy over Tobacco Scale (AUTOS) among 1,195 eighth-grade students. Data for this study were collected as part of the fourth wave of data collection of the Smokefree Class Competition intervention in the Saxony-Anhalt region of Germany. Students from the control arm of the Smokefree Class Competition study who indicated that they had ever smoked 'at least a few puffs' on a cigarette were classified as ever-smokers. They self-completed questionnaires distributed by teachers. AUTOS scores ranged from 0 to 36 with a distribution highly skewed toward lower-response categories. Inter-item correlations ranged from 0.65 to 0.89 (mean = 0.79, SD = 0.06). Composite reliability for the AUTOS was high (&#x3a9; = 0.96) and 3 lower-order factors were also reliable (withdrawal: 0.89, psychological dependence: 0.91, cue-induced cravings: 0.87). Concurrent validity was supported by strong relationships between the AUTOS and both lifetime cigarette consumption and current smoking frequency. Youths were 18 times more likely to be current smokers (95% CI = 11.9-27.2, p < 0.001) if they endorsed any AUTOS item. The German AUTOS is reliable and valid, and the results are consistent with the English AUTOS for use with adolescents.

There are guidelines recommending the use of Indwelling pleural catheter (IPC), but there is no established consensus or guidelines regarding the modality of drainage post-IPC insertion. We have devised a novel drainage technique that combines the advantages of both aggressive and symptom-guided drainage. This was a prospective intervention trial in which patients with malignant pleural effusion, drained with IPC, were initially given one week of 'high-intensity' drainage on an outpatient basis using a low-pressure suction pump, followed by symptom-based home drainage using vacuum bottles. Patients were assessed for improvement in breathlessness, the number of autos pleurodesis, and the number of vacuum bottles consumed. A total of 25 patients with malignant pleural effusion who satisfied the inclusion criteria were selected. The mean breathlessness as per the visual analogue scale (VAS) was 87 before the insertion of IPC, which decreased to 48.2 immediately after IPC insertion and drainage. The 'high-intensity' drainage was able to maintain this fall in VAS. Thirteen patients (52%) achieved pleurodesis, of which 10 achieved pleurodesis after 5 weeks of IPC insertion, and 3 achieved pleurodesis after 7 weeks of IPC insertion. Eleven patients (44%) had the IPC in situ until death. One patient had the IPC removed due to empyema. None of the 10 patients who achieved pleurodesis within 5 weeks of IPC insertion had to use vacuum bottles at home for 'symptom-guided' fluid drainage. This novel method of draining malignant pleural effusion brought about symptomatic improvement, increase auto-pleurodesis, and thereby reduce the number of vacuum bottles consumed in the study population.