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In this work, three dimensional (3D) self-supported Ni-FeOH@Ni-FeP needle arrays with core-shell heterojunction structure are fabricated via in situ hydroxide growth over Ni-FeP surface. The as-prepared electrodes show an outstanding oxygen evolution reaction (OER) performance, only requiring the low overpotential of 232 mV to reach 200 mA cm -2 with the Tafel slop of 40 mV dec -1 . For overall water splitting, an alkaline electrolyzer with these electrodes only requires a cell voltage of 2.14 V to reach 1 A cm -2 . Mechanistic investigations for such excellent electrocatalytic performances are utilized by in situ Raman spectroscopy in conjunction with density functional theory (DFT) calculations. The computation results present that Ni-FeOH@Ni-FeP attains better intrinsic conductivity and the D-band center (close to that of the ideal catalyst), thus giving superior excellent catalytic performances. Likewise, the surface Ni-FeOH layer can improve the structural stability of Ni-FeP cores and attenuate the eventual formation of irreversible FeOOH products. More importantly, the appearance of FeOOH intermediates can effectively decrease the energy barrier of NiOOH intermediates, and then rapidly accelerate the sluggish reaction dynamics, as well as further enhance the electrocatalytic activities, reversibility and cycling stability., (© 2024 Wiley‐VCH GmbH.)

Background/objectives: Sunflower receptacles are the main by-product of the processing of Helianthus annuus L., Methods: In this study, several extraction methods of soluble dietary fiber (SDF) from sunflower receptacles were evaluated, and then, the physicochemical structure and functional properties of these SDFs were examined. Finally, a mouse constipation model was established to explore its therapeutic potential for constipation., Results: The results showed that the SDF yield of citric acid extraction and enzyme extraction was better than that of hot-water extraction. Structural characterization showed that the three SDF functional groups were similar and amorphous, while the surface distribution of the SDF obtained by the citric acid extraction method (ASDF) had more fine pores. Physicochemical analysis showed that ASDF had the best water-holding capacity, oil-holding capacity, and expansion force. Animal experiments showed that the first black stool defecation time of the model group changed significantly ( p < 0.001), indicating that the model was successful. Compared with the model group, the middle- and high-dose groups reduced the first black stool defecation time ( p < 0.05 or p < 0.01) and increased the fecal water content ( p < 0.05). The high-dose group significantly promoted the intestinal peristalsis of mice ( p < 0.05). From hematoxylin-eosin (H&E) staining, it can be seen that the three dose groups of ASDF can improve the damage of mouse colon tissue induced by loperamide hydrochloride to a certain extent., Conclusions: Our results show that ASDF has good physical and chemical properties and laxative properties and has broad development space in the field of health food.

Rechargeable aqueous Zn-ion batteries (AZIBs) have been recognized as competitive devices for large-scale energy storage due to their characteristics of low cost, safe operation, and environmental friendliness. Nevertheless, their practical applications are greatly limited by zinc dendrite growth and side reactions occurring at the anode/electrolyte interface. Herein, we propose an effective and simple electrolyte engineering strategy, which is the introduction of l-lysine additive containing two amino groups and one carboxyl group into a ZnSO 4 electrolyte to achieve stable and reversible Zn depositions. Theoretical calculations and experimental results reveal that the l-lysine can adsorb on the Zn anode surface due to the strong coordination effects between amino groups and Zn metal (Zn-N binding) and induce the reduction of ZnSO 4 into inorganic ZnS, which can not only prevent interfacial side reactions but also regulate interfacial electric field on the zinc electrode surface to guide uniform Zn 2+ electrodeposition to inhibit zinc dendrites. Consequently, the l-lysine additive in the electrolyte enables Zn||Zn symmetric cells to achieve an ultralong stable cycling up to 2400 h at 1 mA cm -2 with a low polarization of only about 16 mV and Zn||Cu asymmetric cells to obtain a high average Coulombic efficiency of 99.80% after stably cycling for more than 2000 h at 2 mA cm -2 (1 mAh cm -2 ). In addition, the Zn||MnO 2 @CNT full cell in an l-lysine-containing electrolyte also exhibits good cycling performance. This study offers a new perspective on multifunctional electrolyte additive for achieving highly reversible Zn metal anodes in AZIBs.

The escalating costs and high failure rates have decelerated the pace of drug development, which amplifies the research interests in developing combinatorial/repurposed drugs and understanding off-target adverse drug reaction (ADR). In other words, it is demanded to delineate the molecular atlas and pharma-information for the combinatorial/repurposed drugs and off-target interactions. However, such invaluable data were inadequately covered by existing databases. In this study, a major update was thus conducted to the DrugMAP, which accumulated (a) 20831 combinatorial drugs and their interacting atlas involving 1583 pharmacologically important molecules; (b) 842 repurposed drugs and their interacting atlas with 795 molecules; (c) 3260 off-targets relevant to the ADRs of 2731 drugs and (d) various types of pharmaceutical information, including diverse ADMET properties, versatile diseases, and various ADRs/off-targets. With the growing demands for discovering combinatorial/repurposed therapies and the rapidly emerging interest in AI-based drug discovery, DrugMAP was highly expected to act as an indispensable supplement to existing databases facilitating drug discovery, which was accessible at: https://idrblab.org/drugmap/., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: In recent years, the traditional simulation-based medical teaching approach has faced challenges in meeting the requirements of practical emergency medicine education. This study utilized open-source tools and software to develop immersive panoramic videos using virtual reality technology for emergency medical teaching. It aims to investigate the efficacy of this novel teaching methodology. This transformation shifted the focus from physical simulation to virtual simulation in medical education, establishing a metaverse for emergency medical teaching., Methods: In accordance with the curriculum guidelines, the instructors produced panoramic videos demonstrating procedures such as spinal injury management, humeral fracture with abdominal wall intestinal tube prolapse, head and chest composite injuries, cardiopulmonary resuscitation, and tracheal intubation. Using Unity software, a virtual training application for bronchoscopy was developed and integrated into the PICO4 VR all-in-one device to create a metaverse teaching environment. Fourth-year medical undergraduate students were allocated into either an experimental group (n = 26) or a control group (n = 30) based on student IDs. The experimental group received instruction through the metaverse immersive teaching method, while the control group followed the traditional simulation-based medical teaching approach. Both groups participated in theoretical and practical lessons as usual. Subsequently, all students underwent a four-station Objective Structured Clinical Examination (OSCE) to assess the effectiveness of the teaching methods based on their performance. Additionally, students in the experimental group provided subjective evaluations to assess their acceptance of the new teaching approach., Results: Before the training commenced, there were no significant statistical differences in the first aid test scores between the experimental and control groups. Following the training, the experimental group outperformed the control group in the four-station OSCE examination, with all P-values being less than 0.05. The satisfaction rate among the experimental group regarding the new teaching method reached 88.46%, reflecting levels of satisfaction and extreme satisfaction., Conclusion: The open-source metaverse immersive teaching method has demonstrated a positive impact on enhancing the emergency skills of medical undergraduate students, with a high level of acceptance among students. In comparison to traditional simulated medical teaching methods, this approach requires less time and space, incurring lower costs, and is deemed worthy of wider adoption., (© 2024. The Author(s).)

Structured passivation layers and hydrated Zn 2+ solvation structure strongly influence Zn depositions on Zn electrodes and then the cycle life and electrochemical performance of aqueous zinc ion batteries. To achieve these, the electrolyte additive of sodium L-ascorbate (Ass) is introduced into aqueous zinc sulfate (ZnSO 4 , ZS) electrolyte solutions. Combined experimental characterizations with theoretical calculations, the unique passivation layers with vertical arrayed micro-nano structure are clearly observed, as well as the hydrated Zn 2+ solvation structure is changed by replacing two ligand water molecules with As - , thus regulating the wettability and interfacial electric field intensity of Zn surfaces, facilitating rapid ionic diffusions within electrolytes and electrodes together with the inhibited side reactions and uniform depositions of Zn 2+ . When tested in Zn||Zn symmetric cell, the electrolyte containing Ass is extraordinarily stably operated for the long time ≈3700 h at both 1 mA cm -2 and 1 mAh cm -2 . In Zn||MnO 2 full coin cells, the energy density can still maintain as high as ≈184 Wh kg -1 at the power density high up to 2 kW kg -1 , as well as the capacity retention can reach up to 80.5% even after 1000 cycles at 2 A g -1 , which are substantially superior to the control cells., (© 2024 Wiley‐VCH GmbH.)

Objective: This study sought to evaluate a modified palatoplasty technique (MPT) concerning the postoperative outcomes and associated influencing factors., Design: A retrospective cohort study., Participants and Setting: One hundred forty-three consecutive patients with non-syndromic cleft palate, who received MPT before one year of age within an oral and maxillofacial surgery department of a university-affiliated tertiary hospital between 2011-2017, were reviewed., Main Measures: The postoperative wound healing and velopharyngeal function (VPF) were the primary outcome measures. The sex, age at surgery, cleft type, cleft width, palatal width, soft palate length, pharyngeal cavity depth, and operation duration were preselected as influencing factors. Univariate and multivariate analyses were conducted., Results: The mean age at surgery was 9 ± 1.31 months (5-11), and the average cleft width was 9.03 ± 2.41 mm (4-15). The rate of incomplete cleft palate was 84.6% while the complete cleft palate was 15.4%. Complete wound healing was reported in 96.5% while the others (3.5%) had persistent oronasal fistula. About 90.2% of cases have shown normal velopharyngeal function whereas the others (9.8%) had sustained velopharyngeal insufficiency. The wound healing appeared to be significantly impacted by cleft width and pharyngeal cavity depth ( P  = .015 and 0.049, respectively). However, none of the factors had a significant association with VPF., Conclusions: The present modified palatoplasty technique has obtained a low fistula rate and appropriate speech outcome. Therefore, this MPT could be promoted for early repairing cleft palate of different severities., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ferroptosis is a non-apoptotic, iron-dependent regulatory form of cell death characterized by the accumulation of intracellular reactive oxygen species. In recent years, a large and growing body of literature has investigated ferroptosis. Since ferroptosis is associated with various physiological activities and regulated by a variety of cellular metabolism and mitochondrial activity, ferroptosis has been closely related to the occurrence and development of many diseases, including cancer, aging, neurodegenerative diseases, ischemia-reperfusion injury and other pathological cell death. The regulation of ferroptosis mainly focuses on three pathways: system Xc-/GPX4 axis, lipid peroxidation and iron metabolism. The genes involved in these processes were divided into driver, suppressor and marker. Importantly, small molecules or drugs that mediate the expression of these genes are often good treatments in the clinic. Herein, a newly developed database, named 'FERREG', is documented to (i) providing the data of ferroptosis-related regulation of diseases occurrence, progression and drug response; (ii) explicitly describing the molecular mechanisms underlying each regulation; and (iii) fully referencing the collected data by cross-linking them to available databases. Collectively, FERREG contains 51 targets, 718 regulators, 445 ferroptosis-related drugs and 158 ferroptosis-related disease responses. FERREG can be accessed at https://idrblab.org/ferreg/., (© The Author(s) 2024. Published by Oxford University Press.)

The metabolic roadmap of drugs (MRD) is a comprehensive atlas for understanding the stepwise and sequential metabolism of certain drug in living organisms. It plays a vital role in lead optimization, personalized medication, and ADMET research. The MRD consists of three main components: (i) the sequential catalyses of drug and its metabolites by different drug-metabolizing enzymes (DMEs), (ii) a comprehensive collection of metabolic reactions along the entire MRD and (iii) a systematic description on efficacy & toxicity for all metabolites of a studied drug. However, there is no database available for describing the comprehensive metabolic roadmaps of drugs. Therefore, in this study, a major update of INTEDE was conducted, which provided the stepwise & sequential metabolic roadmaps for a total of 4701 drugs, and a total of 22 165 metabolic reactions containing 1088 DMEs and 18 882 drug metabolites. Additionally, the INTEDE 2.0 labeled the pharmacological properties (pharmacological activity or toxicity) of metabolites and provided their structural information. Furthermore, 3717 drug metabolism relationships were supplemented (from 7338 to 11 055). All in all, INTEDE 2.0 is highly expected to attract broad interests from related research community and serve as an essential supplement to existing pharmaceutical/biological/chemical databases. INTEDE 2.0 can now be accessible freely without any login requirement at: http://idrblab.org/intede/., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The phenotypic and regulatory variability of drug transporter (DT) are vital for the understanding of drug responses, drug-drug interactions, multidrug resistances, and so on. The ADME property of a drug is collectively determined by multiple types of variability, such as: microbiota influence (MBI), transcriptional regulation (TSR), epigenetics regulation (EGR), exogenous modulation (EGM) and post-translational modification (PTM). However, no database has yet been available to comprehensively describe these valuable variabilities of DTs. In this study, a major update of VARIDT was therefore conducted, which gave 2072 MBIs, 10 610 TSRs, 46 748 EGRs, 12 209 EGMs and 10 255 PTMs. These variability data were closely related to the transportation of 585 approved and 301 clinical trial drugs for treating 572 diseases. Moreover, the majority of the DTs in this database were found with multiple variabilities, which allowed a collective consideration in determining the ADME properties of a drug. All in all, VARIDT 3.0 is expected to be a popular data repository that could become an essential complement to existing pharmaceutical databases, and is freely accessible without any login requirement at: https://idrblab.org/varidt/., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

A thorough understanding of cell-line drug response mechanisms is crucial for drug development, repurposing, and resistance reversal. While targeted anticancer therapies have shown promise, not all cancers have well-established biomarkers to stratify drug response. Single-gene associations only explain a small fraction of the observed drug sensitivity, so a more comprehensive method is needed. However, while deep learning models have shown promise in predicting drug response in cell lines, they still face significant challenges when it comes to their application in clinical applications. Therefore, this study proposed a new strategy called DD-Response for cell-line drug response prediction. First, a limitation of narrow modeling horizons was overcome to expand the model training domain by integrating multiple datasets through source-specific label binarization. Second, a modified representation based on a two-dimensional structurized gridding map (SGM) was developed for cell lines & drugs, avoiding feature correlation neglect and potential information loss. Third, a dual-branch, multi-channel convolutional neural network-based model for pairwise response prediction was constructed, enabling accurate outcomes and improved exploration of underlying mechanisms. As a result, the DD-Response demonstrated superior performance, captured cell-line characteristic variations, and provided insights into key factors impacting cell-line drug response. In addition, DD-Response exhibited scalability in predicting clinical patient responses to drug therapy. Overall, because of DD-response's excellent ability to predict drug response and capture key molecules behind them, DD-response is expected to greatly facilitate drug discovery, repurposing, resistance reversal, and therapeutic optimization.

Objective: To assess the maxillofacial growth of patients with isolated cleft palate following the Sommerlad-Furlow modified technique and compare it with the effect of the Sommerlad technique., Study Design: A Retrospective Cohort Study., Methods: A total of 90 participants, 60 patients with non-syndromic isolated soft and hard cleft palate (ISHCP) underwent primary palatoplasty without relaxing incision (30 patients received the Sommerlad-Furlow modified (S-F) technique and 30 received Sommerlad (S) technique). While the other 30 were healthy noncleft participants with skeletal class I pattern (C group). All participants had lateral cephalometric radiographs at least 5 years old age. All the study variables were measured by using stable landmarks, including 11 linear and 9 angular variants., Results: The means age at collection of cephalograms were 6.03 ± 0.80 (5-7 yrs) in the S group, 5.96 ± 0.76 (5-7 yrs) in the S-F group, and 5.91 ± 0.87 (5-7 yrs) in the C group. Regarding cranial base, the results showed that there were no statistically significant differences between the three groups in S-N and S-N-Ba. The S group had a significantly shortest S-Ba than the S-F & C groups (P = 0.01), but there was no statistically significant difference between S-F and C groups (P = 0.80). Regarding skeletal maxillary growth, the S group had significantly shorter Co-A, S- PM and significantly less SNA angle than the C group (P =  < 0.01). While there was no significant difference between S-F & C groups (P = 0.42). The S group had significantly more MP-SN inclination than the C group (P =  < 0.01). Regarding skeletal mandibular growth, there were no statistically significant differences in all linear and angular mandibular measurements between the three groups, except Co-Gn of the S group had a significantly shorter length than the C group (P = 0.05). Regarding intermaxillary relation, the S-F group had no significant differences in Co-Gn-Co-A and ANB as compared with the C group. The S group had significantly less ANB angle than S-F & C groups (P = 0.01 & P =  < 0.01). In addition, there were no significant differences in all angular occlusal measurements between the three groups., Conclusion: As a preliminary report, Sommerlad-Furlow modified technique showed that maxillary positioning in the face tended to be better, and the intermaxillary relationship was more satisfactory than that in Sommerlad technique when compared them in healthy noncleft participants., (© 2023. The Author(s).)

Objective: To estimate the impact of relaxing incisions on maxillofacial growth following Sommerlad-Furlow modified technique in patients with isolated cleft palate., Study Design: A Retrospective Cohort Study., Methods: A total of 90 participants, 60 patients with non-syndromic isolated soft and hard cleft palate underwent primary palatoplasty (30 patients received the Sommerlad-Furlow modified technique without relaxing incision (S.F -RI group), and 30 received Sommerlad-Furlow modified technique with relaxing (S.F +RI group) with no significant difference found between them regarding the cleft type, cleft width, and age at repair. While the other 30 were healthy noncleft participants with skeletal class I pattern as a Control group. The control group (C group) was matched with the patient groups in number, age, and sex. All participants had lateral cephalometric radiographs at least 5 years old age. The lateral cephalometric radiographs were taken with the same equipment by the same experienced radiologist while the participants were in centric occlusion and a standardized upright position, with the transporionic axis and Frankfort horizontal plane parallel to the surface of the floor. A well-trained assessor (S. Elayah) used DOLPHIN Imaging Software to trace twice to eliminate measurement errors. All the study variables were measured using stable landmarks, including 12 linear and 10 angular variants., Results: The mean age at collection of cephalograms was 6.03 ± 0.80 in the S.F +RI group, 5.96 ± 0.76 in the S.F -RI group, and 5.91 ± 0.87 in the C group. Regarding cranial base, the results showed no statistically significant differences between the three groups in S-N and S-N-Ba. While the S.F +R.I group had a significantly shortest S-Ba than the S.F -R.I & C groups (P = 0.01 & P < 0.01), but there was no statistically significant difference between S.F -R.I & C groups (P = 0.71). Regarding the skeletal maxilla, there was no significant difference between the S.F +R.I and S.F -R.I groups in all linear measurements (N-ANS and S-PM) except Co-A, the S.F +R.I group had significantly shorter Co-A than the S.F -R.I & C groups (P =  < 0.01). While the angular measurement, S.F +R.I group had significantly less SNA angle than the S.F -R.I & C groups (P =  < 0.01). Regarding mandibular bone, there were no statistically significant differences in all linear and angular mandibular measurements between the S.F +R.I and S.F -R.I. groups. Regarding intermaxillary relation, the S.F +R.I group had significant differences in Co-Gn-Co-A and ANB compared to the S.F -R.I & C groups (P =  < 0.01). While there was no statistically significant difference in PP-MP between the three groups., Conclusion: As a preliminary report, the Sommerlad-Furlow modified technique without relaxing incisions was found to have a good maxillary positioning in the face and a satisfactory intermaxillary relationship compared to the Sommerlad-Furlow modified technique with relaxing incisions., (© 2023. The Author(s).)

Epidemiological investigations show that noise exposure in early life is associated with health and cognitive impairment. The gut microbiome established in early life plays a crucial role in modulating developmental processes that subsequently affect brain function and behavior. Here, we examined the impact of early-life exposure to noise on cognitive function in adolescent rats by analyzing the gut microbiome and metabolome to elucidate the underlying mechanisms. Chronic noise exposure during early life led to cognitive deficits, hippocampal injury, and neuroinflammation. Early-life noise exposure showed significant difference on the composition and function of the gut microbiome throughout adolescence, subsequently causing axis-series changes in fecal short-chain fatty acid (SCFA) metabolism and serum metabolome profiles, as well as dysregulation of endothelial tight junction proteins, in both intestine and brain. We also observed sex-dependent effects of microbiota depletion on SCFA-related beneficial bacteria in adolescence. Experiments on microbiota transplantation and SCFA supplementation further confirmed the role of intestinal bacteria and related SCFAs in early-life noise-exposure-induced impairments in cognition, epithelial integrity, and neuroinflammation. Overall, these results highlight the homeostatic imbalance of microbiota-gut-brain axis as an important physiological response toward environmental noise during early life and reveals subtle differences in molecular signaling processes between male and female rats., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Human UDP-glucuronosyltransferases (UGTs) play a pivotal role as prominent phase II metabolic enzymes, mediating the glucuronidation of both endobiotics and xenobiotics. Dimerization greatly modulates the enzymatic activities of UGTs. In this study, we examined the influence of three mutations (H35A, H268Y, and N68A/N315A) and four truncations (signal peptide, single transmembrane helix, cytosolic tail, and di-lysine motif) in UGT2B7 on its heterodimerization with wild-type UGT1A9, using a Bac-to-Bac expression system. We employed quantitative fluorescence resonance energy transfer (FRET) techniques and co-immunoprecipitation assays to evaluate the formation of heterodimers between UGT1A9 and UGT2B7 allozymes. Furthermore, we evaluated the glucuronidation activities of the heterodimers using zidovudine and propofol as substrates for UGT2B7 and UGT1A9, respectively. Our findings revealed that the histidine residue at codon 35 was involved in the dimeric interaction, as evidenced by the FRET efficiencies and catalytic activities. Interestingly, the signal peptide and single transmembrane helix domain of UGT2B7 had no impact on the protein-protein interaction. These results provide valuable insights for a comprehensive understanding of UGT1A9/UGT2B7 heterodimer formation and its association with glucuronidation activity. SIGNIFICANCE STATEMENT: Our findings revealed that the H35A mutation in UGT2B7 affected the affinity of protein-protein interaction, leading to discernable variations in fluorescence resonance energy transfer efficiencies and catalytic activity. Furthermore, the signal peptide and single transmembrane helix domain of UGT2B7 did not influence heterodimer formation. These results provide valuable insights into the combined effects of polymorphisms and protein-protein interactions on the catalytic activity of UGT1A9 and UGT2B7, enhancing our understanding of UGT dimerization and its impact on metabolite formation., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

Poor palatal wound healing after cleft palate repair could lead to unfavorable prognosis such as oronasal fistula (ONF), which might affect the patient's velopharyngeal function as well as their quality of life. Thus, restoring poor palatal wound healing for avoiding the occurrence of ONF should be considered the key to postoperative care after cleft palate repair. This review provided current insights in the preclinical study of poor palatal wound healing after cleft palate repair. This review comprehensively introduced the animal model establishment for palatal wound healing and related ONF, including the models by mice, rats, piglets, and dogs, and then demonstrated the aspects for investigating poor palatal wound healing and related treatments, including possible signaling pathways that could be involved in the formation of poor palatal wound healing, the related microbiota changes because of the deformity of palatal structure, and the studies for potential therapeutic strategies for palatal wound healing and ONF. The purpose of this review was to show the state of the art in preclinical studies about palatal wound healing after cleft palate repair and to show the promising aspects for better management of palatal wound healing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Yang, Yin, Shi and Huang.)

This study presents a method utilizing heated ophthalmologic cautery to develop a viable model for investigating oronasal fistulas. C57BL/6 mice were used to establish the oronasal fistula (ONF) model. To create the ONF, the mice were anesthetized, immobilized, and their hard palates were exposed. During the surgical procedure, a 2.0 x 1.5 mm full-thickness mucosal injury was induced in the midline of the hard palate using ophthalmologic cautery. It was crucial to control the size of the ONF and minimize bleeding in order to ensure the success of the experiment. Verification of the ONF model's effectiveness was conducted on the 7th-day post-operation, encompassing both anatomical and functional assessments. The presence of the nasal septum within the oral cavity and the outflow of sterile water from the nostrils upon injection into the oral cavity confirmed the successful establishment of the ONF model. The model demonstrated a practical and successful oronasal fistula, characterized by a low mortality rate, significant weight changes, and minimal variation in ONF size. Future studies may consider adopting this methodology to elucidate the mechanisms of palate wound healing and explore novel treatments for oronasal fistulas.

Endoplasmic reticulum stress is implicated in the etiopathogenesis of Parkinson disease (PD). Our previous study has revealed that thioredoxin-1 (Trx-1) attenuated IRE1 activation in 1-methyl-4-phenylpyridinium ion (MPP + )/1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD models. However, its exact mechanism has been largely unclear. In this research, it was reported for the first time that the protein levels of heat shock protein 90 (Hsp90) and phosphorylated cell division cycle 37 (p-Cdc37) were significantly decreased and the interaction of Hsp90/p-Cdc37 complex with IRE1 was disturbed in MPP + /MPTP-induced PD models. Trx-1 overexpression reversed the expression of Hsp90 and p-Cdc37 in cultured cells and the substantia nigra pars compacta of mice. More importantly, Trx-1 overexpression enhanced the interaction of Hsp90/p-Cdc37 complex with IRE1. In conclusion, our data demonstrated that Trx-1 inhibited IRE1 activation in PD by elevating the expression of Hsp90 and p-Cdc37 and strengthening the interaction of Hsp90/p-Cdc37 complex and IRE1., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to report., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: To evaluate the postoperative outcomes together with analyzing the associated influencing factors following a late cleft palate repair by the Sommerlad-Furlow modified technique (S-F)., Materials and Methods: In a retrospective cohort, 320 consecutive patients with cleft palate, who received S-F technique between 2011 and 2017, were reviewed. The patients were divided into three age groups, less than one year (143), one to two years (113), and greater than 2 years (64). The postoperative outcomes included wound healing (complete/fistula) and velopharyngeal function (VPF)., Results: The overall cleft width was 10 ± 3.07 mm. The overall rates of complete wound healing and proper velopharyngeal function were 96.6% and 81.56%, respectively. No significant difference was found between the age groups regarding wound healing, with an overall fistula rate of 3.4%. The VPF was significantly varied among the age groups (P<0.001). In context, the rates of velopharyngeal insufficiency (VPI) were 9.8%, 14.2%, and 45.4% among patients repaired at ˂1, 1-2, and >2 years old, respectively. The cleft type was the most potential factor associated with fistula. The age at repair was identified as the most implicating factor for VPI., Conclusions: The S-F technique had achieved low fistula rate and satisfactory speech outcome, especially in early repair group and even in the wide cleft palate. The older age at repair and severe cleft type had a major impact on the postoperative outcomes., Competing Interests: Declaration of Competing Interest The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Objective: Patients with a cleft palate often experience a velopharyngeal dysfunction known as velopharyngeal insufficiency (VPI). The purpose of this study was to examine the development of velopharyngeal function (VPF) following primary palatoplasty and the factors that are linked to it., Methods: A retrospective study was conducted to examine the medical records of patients who had cleft palate, with or without cleft lip (CP ± L) and underwent palatoplasty at a Tertiary Affiliated Hospital between 2004 and 2017. Postoperative evaluation of VPF was conducted at two follow-up times (T1, T2) and was classified as either normal VPF, mild VPI, or moderate/severe VPI. The consistency of VPF evaluations between the two time points was then assessed, and patients were categorized into either the consistent or inconsistent group. The study collected and analyzed data on gender, cleft type, age at operation, follow-up duration, and speech records., Results: The study included 188 patients with CP ± L. Out of these, 138 patients (73.4%) showed consistent VPF evaluations, while 50 patients (26.6%) showed inconsistent VPF evaluations. Among those with VPI at T1 (91 patients), 36 patients (39.6%) had normal VPF at T2. The rate of VPI decreased from 48.40% at T1 to 27.13% at T2, whereas the rate of normal VPF increased from 44.68% at T1 to 68.09% at T2. The consistent group had a significantly younger age at operation (2.90 ± 3.82 vs 3.68 ± 4.02), a longer duration of T1 (1.67 ± 0.97 vs 1.04 ± 0.59), and a lower comprehensive score of speech performance (1.86 ± 1.27 vs 2.60 ± 1.07) than the inconsistent group., Conclusions: It has been verified that there are changes in the development of VPF over time. Patients who underwent palatoplasty at a younger age were more likely to have confirmed VPF diagnosis at the first evaluation. The duration of follow-up was identified as a critical factor that affects the confirmation of VPF diagnosis., Competing Interests: Declaration of competing interest All authors whose names are listed immediately below certify that they have no affiliations with or involvement in any organization or entity with any financial (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in the current manuscript. The ethical approval for our project was obtained from the Institutional Ethics Committee of the school of stomatology, Sichuan University., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The ChatGPT, a lite and conversational variant of Generative Pretrained Transformer 4 (GPT-4) developed by OpenAI, is one of the milestone Large Language Models (LLMs) with billions of parameters. LLMs have stirred up much interest among researchers and practitioners in their impressive skills in natural language processing tasks, which profoundly impact various fields. This paper mainly discusses the future applications of LLMs in dentistry. We introduce two primary LLM deployment methods in dentistry, including automated dental diagnosis and cross-modal dental diagnosis, and examine their potential applications. Especially, equipped with a cross-modal encoder, a single LLM can manage multi-source data and conduct advanced natural language reasoning to perform complex clinical operations. We also present cases to demonstrate the potential of a fully automatic Multi-Modal LLM AI system for dentistry clinical application. While LLMs offer significant potential benefits, the challenges, such as data privacy, data quality, and model bias, need further study. Overall, LLMs have the potential to revolutionize dental diagnosis and treatment, which indicates a promising avenue for clinical application and research in dentistry., (© 2023. The Author(s).)

Background: This study aims to investigate the necessity of nostril retention after secondary unilateral cleft rhinoplasty., Methods: Seventy four patients who underwent secondary unilateral cleft rhinoplasty were categorized into control group, nasal retainer group, and nasal clip group. A nasal retainer or nasal clip was applied 7 days after secondary correction and retained in the nostrils of the patients for 6 to 12 months. Measurements from pre- and post-operative photos and patient-reported outcomes were used in this study., Results: After 6 to 12 months, although relapse still occurred in three groups, the nasal retainer group showed a better effect in the ratio of nostril height, whereas the nasal clip group showed a significant improvement in the ratio of nasal base. And both the two groups also showed significant improvement in the ratio of nasal columella. Patients from the control group generally had lower Derriford Appearance Scale (DAS) scores than the nasal retainer group and nasal clip group. Wearing a nasal retainer may negatively influence self-concept, facial self-consciousness of appearance and physical state, and significant differences in mean scores were also found in 9 items., Conclusions: The nostril retention after secondary unilateral cleft rhinoplasty could help preserve nasal morphology and reduce postoperative relapse but worsen the patients' quality of life. The necessity of applying the nostril retention should consider the forms of nasal deformity and the potential influence on the quality of life., Level of Evidence: 3 Laryngoscope, 133:1618-1623, 2023., (© 2022 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: This study aimed to investigate the outcomes of using a novel nasal clip designed for nostril retention after primary unilateral cleft rhinoplasty., Design: This is a retrospective study., Setting: Department of Cleft Lip and Palate in a stomatological hospital., Patients: A retrospective study was conducted on 57 patients who had a unilateral complete cleft lip without cleft palate and underwent primary surgical repair., Interventions: The patients were categorized into 3 groups: the group in which the conventional nasal retainer was used, that in which the nasal clip was used, and the control group in which no postoperative nasal retainer was used. The nasal retainer or our nasal clip was applied 7 days after primary surgical repair and kept in the nostrils of children from 6 to 12 months., Main Outcome Measures: Noses underwent photogrammetry preoperatively, postoperatively, and at follow-up. The nose was also subjectively scored at the follow-up., Results: The nasal retainer and the nasal clip significantly minimized relapse as determined by nasal tip deviation. The nasal clip sustained nasal symmetry, as determined by the postoperative nostril width ratio, better than did the conventional retainer. After 6 to 12 months, the nasal clip achieved better columellar morphology and a more symmetric nasal base than did the conventional nasal retainer. Statistical differences in subjective scores between the control and nostril retention groups were noted., Conclusion: The application of the novel nasal clip after primary unilateral cleft rhinoplasty preserves nasal morphology and reduces postoperative relapse without the need for adhesive tape.

Background: Environmental noise exposure is linked to neuroinflammation and imbalance of the gut microbiota. Promoting gut microbiota homeostasis may be a key factor in relieving the deleterious non-auditory effects of noise. This study aimed to investigate the effect of Lactobacillus rhamnosus GG (LGG) intervention on noise-induced cognitive deficits and systemic inflammation in rats., Methods: Learning and memory were assessed using the Morris water maze, while 16S rRNA sequencing and gas chromatography-mass spectrometry were used to analyze the gut microbiota and short-chain fatty acid (SCFA) content. Endothelial tight junction proteins and serum inflammatory mediators were assessed to explore the underlying pathological mechanisms., Results: The results indicated that Lactobacillus rhamnosus GG intervention ameliorated noise-induced memory deterioration, promoted the proliferation of beneficial bacteria, inhibited the growth of harmful bacteria, improved dysregulation of SCFA-producing bacteria, and regulated SCFA levels. Mechanistically, noise exposure led to a decrease in tight junction proteins in the gut and hippocampus and an increase in serum inflammatory mediators, which were significantly alleviated by Lactobacillus rhamnosus GG intervention., Conclusion: Taken together, Lactobacillus rhamnosus GG intervention reduced gut bacterial translocation, restored gut and blood-brain barrier functions, and improved gut bacterial balance in rats exposed to chronic noise, thereby protecting against cognitive deficits and systemic inflammation by modulating the gut-brain axis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Zheng, Cao, Cao, She, Yang, Ma, Wu, Gao, Fu, Yin, Wei, Jiang and Cui.)

Graphdiyne and its analogs are a series of artificial two-dimensional nanomaterials with sp hybridized carbon atoms, which can be viewed as the insertion of two acetylenic units between adjacent aromatic rings, evenly expanded on a flat surface. Although developed in recent years, new synthetic strategies for graphdiyne analogs are still required. This work proposed a new method to prepare hydrogen-substituted graphdiyne powder via a dehalogenative homocoupling reaction. The polymerization was unanticipated while the initial goal was to synthesize a γ-graphyne analog via Sonogashira cross-coupling reaction. Compared with previous synthetic strategies, the reaction time was conspicuously shortened and the Pd catalyst was inessential. The powder obtained exhibited a porous structure and high electrocatalytic activity in the hydrogen/oxygen evolution reaction, which has the potential for application in electrochemical catalysis. The reported methodology provides an efficient synthetic strategy for large-scale preparation.

Awareness of COVID-19 infection risk and oscillation patterns ('waves') may affect older people's mental health. Empirical data from populations experiencing multiple waves of community outbreaks can inform guidance for maintaining mental health. This study aims to investigate the effects of COVID-19 infection risk and oscillations on depression among community-dwelling older people in Hong Kong., A rolling cross-sectional telephone survey method was used. Screening for depression risk was conducted among 8,163 older people (age ≥ 60) using the Patient Health Questionnaire-2 (PHQ-2) from February to August 2020. The relationships between PHQ-2, COVID-19 infection risk proxies - change in newly infected cases and effective reproductive number (R t ), and oscillations - stage of a 'wave' reported in the media, were analysed using correlation and regression., 8.4% of survey respondents screened positive for depression risk. Being female ( β = .08), having a pre-existing mental health issue ( β = .21), change in newly infected cases ( β = .05), and screening during the latency period before the media called out new waves ( β = .03), contributed to higher depression risk ( R 2 = .06, all p <.01)., While depression risk does not appear alarming in this sample, our results highlight that older people are sensitive to reporting of infection, particularly among those with existing mental health needs. Future public health communication should balance awareness of infection risks with mental health protection.

The efficacy and safety of drugs are widely known to be determined by their interactions with multiple molecules of pharmacological importance, and it is therefore essential to systematically depict the molecular atlas and pharma-information of studied drugs. However, our understanding of such information is neither comprehensive nor precise, which necessitates the construction of a new database providing a network containing a large number of drugs and their interacting molecules. Here, a new database describing the molecular atlas and pharma-information of drugs (DrugMAP) was therefore constructed. It provides a comprehensive list of interacting molecules for >30 000 drugs/drug candidates, gives the differential expression patterns for >5000 interacting molecules among different disease sites, ADME (absorption, distribution, metabolism and excretion)-relevant organs and physiological tissues, and weaves a comprehensive and precise network containing >200 000 interactions among drugs and molecules. With the great efforts made to clarify the complex mechanism underlying drug pharmacokinetics and pharmacodynamics and rapidly emerging interests in artificial intelligence (AI)-based network analyses, DrugMAP is expected to become an indispensable supplement to existing databases to facilitate drug discovery. It is now fully and freely accessible at: https://idrblab.org/drugmap/., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Coronavirus has brought about three massive outbreaks in the past two decades. Each step of its life cycle invariably depends on the interactions among virus and host molecules. The interaction between virus RNA and host protein (IVRHP) is unique compared to other virus-host molecular interactions and represents not only an attempt by viruses to promote their translation/replication, but also the host's endeavor to combat viral pathogenicity. In other words, there is an urgent need to develop a database for providing such IVRHP data. In this study, a new database was therefore constructed to describe the interactions between coronavirus RNAs and host proteins (CovInter). This database is unique in (a) unambiguously characterizing the interactions between virus RNA and host protein, (b) comprehensively providing experimentally validated biological function for hundreds of host proteins key in viral infection and (c) systematically quantifying the differential expression patterns (before and after infection) of these key proteins. Given the devastating and persistent threat of coronaviruses, CovInter is highly expected to fill the gap in the whole process of the 'molecular arms race' between viruses and their hosts, which will then aid in the discovery of new antiviral therapies. It's now free and publicly accessible at: https://idrblab.org/covinter/., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Widespread drug resistance has become the key issue in global healthcare. Extensive efforts have been made to reveal not only diverse diseases experiencing drug resistance, but also the six distinct types of molecular mechanisms underlying this resistance. A database that describes a comprehensive list of diseases with drug resistance (not just cancers/infections) and all types of resistance mechanisms is now urgently needed. However, no such database has been available to date. In this study, a comprehensive database describing drug resistance information named 'DRESIS' was therefore developed. It was introduced to (i) systematically provide, for the first time, all existing types of molecular mechanisms underlying drug resistance, (ii) extensively cover the widest range of diseases among all existing databases and (iii) explicitly describe the clinically/experimentally verified resistance data for the largest number of drugs. Since drug resistance has become an ever-increasing clinical issue, DRESIS is expected to have great implications for future new drug discovery and clinical treatment optimization. It is now publicly accessible without any login requirement at: https://idrblab.org/dresis/., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Alzheimer's disease (AD) is the most common neurodegenerative disease. Increasing studies suggest that mitochondrial dysfunction is closely related to the pathogenesis of AD. Thioredoxin-1 (Trx-1), one of the major redox proteins in mammalian cells, plays neuroprotection in AD. However, whether Trx-1 could regulate the mitochondrial biogenesis in AD is largely unknown. In the present study, we found that Aβ 25-35 treatment not only markedly induced excessive production of reactive oxygen species and apoptosis, but also significantly decreased the number of mitochondria with biological activity and the adenosine triphosphate content in mitochondria, suggesting mitochondrial biogenesis was impaired in AD cells. These changes were reversed by Lentivirus-mediated stable overexpression of Trx-1 or exogenous administration of recombinant human Trx-1. What's more, adeno-associated virus-mediated specific overexpression of Trx-1 in the hippocampus of β-amyloid precursor protein/presenilin 1 (APP/PS1) mice ameliorated the learning and memory and attenuated hippocampal Aβ deposition. Importantly, overexpression of Trx-1 in APP/PS1 mice restored the decrease in mitochondrial biogenesis-associated proteins, including adenosine monophosphate -activated protein kinase (AMPK), silent information regulator factor 2-related enzyme 1 (Sirt1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). In addition, Lentivirus-mediated overexpression of Trx-1 in rat adrenal pheochromocytoma (PC12) cells also restored the decrease of AMPK, Sirt1, and PGC1α by Aβ 25-35 treatment. Pharmacological inhibition of AMPK activity significantly abolished the effect of Trx-1 on mitochondrial biogenesis. Taken together, our data provide evidence that Trx-1 promoted mitochondrial biogenesis via restoring AMPK/Sirt1/PGC1α pathway in AD.

Protein transporters not only have essential functions in regulating the transport of endogenous substrates and remote communication between organs and organisms, but they also play a vital role in drug absorption, distribution, and excretion and are recognized as major determinants of drug safety and efficacy. Understanding transporter function is important for drug development and clarifying disease mechanisms. However, the experimental-based functional research on transporters has been challenged and hinged by the expensive cost of time and resources. With the increasing volume of relevant omics datasets and the rapid evolution of artificial intelligence (AI) techniques, next-generation AI is becoming increasingly prevalent in the functional and pharmaceutical research of transporters. Thus, a comprehensive discussion on the state-of-the-art application of AI in three cutting-edge directions was provided in this review, which included (a) transporter classification and function annotation, (b) structure discovery of membrane transporters, and (c) drug-transporter interaction prediction. This study provides a panoramic view of AI algorithms and tools applied to the field of transporters. It is expected to guide a better understanding and utilization of AI techniques for in-depth studies of transporter-centered functional and pharmaceutical research., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: This brief research report aimed to evaluate the short-term efficacy of presurgical nasoalveolar molding (PNAM) therapy on the nasolabial morphology three dimensionally in patients with non-syndromic complete unilateral cleft lip and palate (UCLP)., Methods: Thirty-six patients with non-syndromic complete unilateral complete cleft lip and palate were enrolled retrospectively and categorized into 2 groups: 18 patients who had received PNAM treatment (PNAM group) and 18 age-matched patients who have not receive PNAM treatment (no PNAM group) from 2017 to 2021. The average starting age for PNAM therapy was 18.33 days, and the average PNAM treatment duration was 99.08 days. Twelve nasolabial parameters were measured to compare the postsurgical outcomes of two groups., Results: In PNAM groups, cleft width, vertical distance between double Crista philtri and columellar deviation were reduced compared to that in no PNAM group. And nostril height was larger than that in no PNAM group. The differences between two groups were statistically significant ( p  < .05). There were no statistical differences in columellar length, nostril width and bi-alar width between two groups. However, the nostril width on cleft side in PNAM group was decreased by an average of 1.1 mm., Conclusion: Our result indicated that PNAM therapy decreased cleft width and vertical distance between Crista philtri. It also increased nasal symmetry by decreasing columellar deviation, increasing nostril height., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Yin, Zhang, Huang, Shi, Zheng and Yang.)

Single-stranded DNA-binding proteins (SSBs) interact with single-stranded DNA (ssDNA) to form filamentous structures with various degrees of cooperativity, as a result of intermolecular interactions between neighboring SSB subunits on ssDNA. However, it is still challenging to perform structural studies on SSB-ssDNA filaments at high resolution using the most studied SSB models, largely due to the intrinsic flexibility of these nucleoprotein complexes. In this study, HaLEF-3, an SSB protein from Helicoverpa armigera nucleopolyhedrovirus, was used for in vitro assembly of SSB-ssDNA filaments, which were structurally studied at atomic resolution using cryo-electron microscopy. Combined with the crystal structure of ssDNA-free HaLEF-3 octamers, our results revealed that the three-dimensional rearrangement of HaLEF-3 induced by an internal hinge-bending movement is essential for the formation of helical SSB-ssDNA complexes, while the contacting interface between adjacent HaLEF-3 subunits remains basically intact. We proposed a local cooperative SSB-ssDNA binding model, in which, triggered by exposure to oligonucleotides, HaLEF-3 molecules undergo ring-to-helix transition to initiate continuous SSB-SSB interactions along ssDNA. Unique structural features revealed by the assembly of HaLEF-3 on ssDNA suggest that HaLEF-3 may represent a new class of SSB., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Hypertrophic scarring (HTS) is a major source of morbidity after cutaneous injury. Recent studies indicate that mechanical force significantly impacts wound healing and skin regeneration which opens up a new direction to combat scarring. Hence, a thorough understanding of the underlying mechanisms is essential in the development of efficacious scar therapeutics. This review provides an overview of the current understanding of the mechanotransduction signaling pathways in scar formation and some strategies that offload mechanical forces in the wounded region for scar prevention and treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yin, Zhang, Yang, Wang, Shi, Zheng, Zeng and Huang.)

The accidental injury or surgery on soft and hard palatal tissue has an adverse impact on normal maxillary morphology. To design a single-factor experiment that excludes other interfering factors on maxillary growth, a young rat model was established to simulate the various degrees of palatal trauma. Eight maxillary parameters were measured to evaluate the impact of palatal trauma on maxillary growth. Furthermore, the acellular dermal matrix (ADM) was applied to cure the palatal trauma and alleviate the adverse impact of bone denudation on the maxillary growth. Micro-CT scanning and histology analyses were used. One-way ANOVA with least significant difference (LSD) post-test was used to evaluate the statistical significance. The palatal trauma mainly disturbed the transverse development of the maxilla. ADM promotes mucosa healing, but there is still an inhibitory effect on maxillofacial growth.

The discovery of proper molecular signature from OMIC data is indispensable for determining biological state, physiological condition, disease etiology, and therapeutic response. However, the identified signature is reported to be highly inconsistent, and there is little overlap among the signatures identified from different biological datasets. Such inconsistency raises doubts about the reliability of reported signatures and significantly hampers its biological and clinical applications. Herein, an online tool, ConSIG, was constructed to realize consistent discovery of gene/protein signature from any uploaded transcriptomic/proteomic data. This tool is unique in a) integrating a novel strategy capable of significantly enhancing the consistency of signature discovery, b) determining the optimal signature by collective assessment, and c) confirming the biological relevance by enriching the disease/gene ontology. With the increasingly accumulated concerns about signature consistency and biological relevance, this online tool is expected to be used as an essential complement to other existing tools for OMIC-based signature discovery. ConSIG is freely accessible to all users without login requirement at https://idrblab.org/consig/., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Panax ginseng and Panax notoginseng, two well-known herbs with enormous medical value in Asian countries, have a long usage history in China for the therapy of some diseases, such as stroke. Ginsenoside Rb1 is one of most important active ingredients in Panax ginseng and Panax notoginseng. In the last two decades, more attention has focused on ginsenoside Rb1 as an antioxidative, anti-apoptotic and anti-inflammatory agent that can protect the nervous system. In the review, we summarize the neuroprotective roles of ginsenoside Rb1 and its potential mechanisms in central nervous system diseases (CNSDs), including neurodegenerative diseases, cerebral ischemia injury, depression and spinal cord injury. In conclusion, ginsenoside Rb1 has a potential neuroprotection due to its inhibition of oxidative stress, apoptosis, neuroinflammation and autophagy in CNSDs and may be a promising candidate agent for clinical therapy of CNSDs in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gong, Yin, Zhang, Huang, Lou, Jiang, Sun, Jia and Zeng.)

Mass spectrometry-based proteomic technique has become indispensable in current exploration of complex and dynamic biological processes. Instrument development has largely ensured the effective production of proteomic data, which necessitates commensurate advances in statistical framework to discover the optimal proteomic signature. Current framework mainly emphasizes the generalizability of the identified signature in predicting the independent data but neglects the reproducibility among signatures identified from independently repeated trials on different sub-dataset. These problems seriously restricted the wide application of the proteomic technique in molecular biology and other related directions. Thus, it is crucial to enable the generalizable and reproducible discovery of the proteomic signature with the subsequent indication of phenotype association. However, no such tool has been developed and available yet. Herein, an online tool, POSREG, was therefore constructed to identify the optimal signature for a set of proteomic data. It works by (i) identifying the proteomic signature of good reproducibility and aggregating them to ensemble feature ranking by ensemble learning, (ii) assessing the generalizability of ensemble feature ranking to acquire the optimal signature and (iii) indicating the phenotype association of discovered signature. POSREG is unique in its capacity of discovering the proteomic signature by simultaneously optimizing its reproducibility and generalizability. It is now accessible free of charge without any registration or login requirement at https://idrblab.org/posreg/., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Crimean-Congo hemorrhagic fever virus (CCHFV) is a causative agent of serious hemorrhagic diseases in humans with high mortality rates. CCHFV glycoprotein Gc plays critical roles in mediating virus-host membrane fusion and has been studied extensively as an immunogen. However, the molecular mechanisms involved in membrane fusion and Gc-specific antibody-antigen interactions remain unresolved largely because structural information of this glycoprotein is missing. We designed a trimeric protein including most of the ectodomain region of Gc from the prototype CCHFV strain, IbAr10200, which enabled the cryo-electron microscopy structure to be solved at a resolution of 2.8 ​Å. The structure confirms that CCHFV Gc is a class II fusion protein. Unexpectedly, structural comparisons with other solved Gc trimers in the postfusion conformation revealed that CCHFV Gc adopted hybrid architectural features of the fusion loops from hantaviruses and domain III from phenuiviruses, suggesting a complex evolutionary pathway among these bunyaviruses. Antigenic sites on CCHFV Gc that protective neutralizing antibodies target were mapped onto the CCHFV Gc structure, providing valuable information that improved our understanding of potential neutralization mechanisms of various antibodies., (Copyright © 2022 The Authors. Publishing services by Elsevier B.V. All rights reserved.)

The structural variability data of drug transporter (DT) are key for research on precision medicine and rational drug use. However, these valuable data are not sufficiently covered by the available databases. In this study, a major update of VARIDT (a database previously constructed to provide DTs' variability data) was thus described. First, the experimentally resolved structures of all DTs reported in the original VARIDT were discovered from PubMed and Protein Data Bank. Second, the structural variability data of each DT were collected by literature review, which included: (a) mutation-induced spatial variations in folded state, (b) difference among DT structures of human and model organisms, (c) outward/inward-facing DT conformations and (d) xenobiotics-driven alterations in the 3D complexes. Third, for those DTs without experimentally resolved structural variabilities, homology modeling was further applied as well-established protocol to enrich such valuable data. As a result, 145 mutation-induced spatial variations of 42 DTs, 1622 inter-species structures originating from 292 DTs, 118 outward/inward-facing conformations belonging to 59 DTs, and 822 xenobiotics-regulated structures in complex with 57 DTs were updated to VARIDT (https://idrblab.org/varidt/ and http://varidt.idrblab.net/). All in all, the newly collected structural variabilities will be indispensable for explaining drug sensitivity/selectivity, bridging preclinical research with clinical trial, revealing the mechanism underlying drug-drug interaction, and so on., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

With the rapid progress in pharmaceutical experiments and clinical investigations, extensive knowledge of drug transporters (DTs) has accumulated, which is valuable data for the understanding of drug metabolism and disposition. However, such data are largely dispersed in the literature, which hampers its utility and significantly limits its possibility for comprehensive analysis. A variety of databases have, therefore, been constructed to provide DT-related data, and they were reviewed in this study. First, several knowledge bases providing data regarding clinically important drugs and their corresponding transporters were discussed, which constituted the most important resources of DT-centered data. Second, some databases describing the general transporters and their functional families were reviewed. Third, various databases offering transporter information as part of their entire data collection were described. Finally, customized database functions that are available to facilitate DT-related research were discussed. This review provided an overview of the whole collection of DT-related databases, which might facilitate research on precision medicine and rational drug use. SIGNIFICANCE STATEMENT: A collection of well established databases related to drug transporters were comprehensively reviewed, which were organized according to their importance in drug absorption, distribution, metabolism, and excretion research. These databases could collectively contribute to the research on rational drug use., Competing Interests: No author has an actual or perceived conflict of interest with the contents of this article., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

An appropriate therapeutic index is crucial for drug discovery and development since narrow therapeutic index (NTI) drugs with slight dosage variation may induce severe adverse drug reactions or potential treatment failure. To date, the shared characteristics underlying the targets of NTI drugs have been explored by several studies, which have been applied to identify potential drug targets. However, the association between the drug therapeutic index and the related disease has not been dissected, which is important for revealing the NTI drug mechanism and optimizing drug design. Therefore, in this study, two classes of disease (cancers and cardiovascular disorders) with the largest number of NTI drugs were selected, and the target property of the corresponding NTI drugs was analyzed. By calculating the biological system profiles and human protein-protein interaction (PPI) network properties of drug targets and adopting an AI-based algorithm, differentiated features between two diseases were discovered to reveal the distinct underlying mechanisms of NTI drugs in different diseases. Consequently, ten shared features and four unique features were identified for both diseases to distinguish NTI from NNTI drug targets. These computational discoveries, as well as the newly found features, suggest that in the clinical study of avoiding narrow therapeutic index in those diseases, the ability of target to be a hub and the efficiency of target signaling in the human PPI network should be considered, and it could thus provide novel guidance in the drug discovery and clinical research process and help to estimate the drug safety of cancer and cardiovascular disease., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Besides the environmental factors having tremendous impacts on the composition of microbial community, the host factors have recently gained extensive attentions on their roles in shaping human microbiota. There are two major types of host factors: host genetic factors (HGFs) and host immune factors (HIFs). These factors of each type are essential for defining the chemical and physical landscapes inhabited by microbiota, and the collective consideration of both types have great implication to serve comprehensive health management. However, no database was available to provide the comprehensive factors of both types. Herein, a database entitled 'Host Genetic and Immune Factors Shaping Human Microbiota (GIMICA)' was constructed. Based on the 4257 microbes confirmed to inhabit nine sites of human body, 2851 HGFs (1368 single nucleotide polymorphisms (SNPs), 186 copy number variations (CNVs), and 1297 non-coding ribonucleic acids (RNAs)) modulating the expression of 370 microbes were collected, and 549 HIFs (126 lymphocytes and phagocytes, 387 immune proteins, and 36 immune pathways) regulating the abundance of 455 microbes were also provided. All in all, GIMICA enabled the collective consideration not only between different types of host factor but also between the host and environmental ones, which is freely accessible without login requirement at: https://idrblab.org/gimica/., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Drug-metabolizing enzymes (DMEs) are critical determinant of drug safety and efficacy, and the interactome of DMEs has attracted extensive attention. There are 3 major interaction types in an interactome: microbiome-DME interaction (MICBIO), xenobiotics-DME interaction (XEOTIC) and host protein-DME interaction (HOSPPI). The interaction data of each type are essential for drug metabolism, and the collective consideration of multiple types has implication for the future practice of precision medicine. However, no database was designed to systematically provide the data of all types of DME interactions. Here, a database of the Interactome of Drug-Metabolizing Enzymes (INTEDE) was therefore constructed to offer these interaction data. First, 1047 unique DMEs (448 host and 599 microbial) were confirmed, for the first time, using their metabolizing drugs. Second, for these newly confirmed DMEs, all types of their interactions (3359 MICBIOs between 225 microbial species and 185 DMEs; 47 778 XEOTICs between 4150 xenobiotics and 501 DMEs; 7849 HOSPPIs between 565 human proteins and 566 DMEs) were comprehensively collected and then provided, which enabled the crosstalk analysis among multiple types. Because of the huge amount of accumulated data, the INTEDE made it possible to generalize key features for revealing disease etiology and optimizing clinical treatment. INTEDE is freely accessible at: https://idrblab.org/intede/., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Our study aims to solve the problems caused by the large numbers of prescriptions and insufficient pharmacists in the hospital by using a prescription review model based on data mining., Methods: A hospital pharmacy management analysis and decision system was established based on the data of the hospital information system, requirement of pharmacy management and data mining technology. Based on application of this information system, a four-step data mining prescription review model was created and put into practice, which included presentation of model for prescription evaluation, instance problem model, full-scale extraction of problem prescriptions tracking correction and dynamic monitoring of changes in drug dosage distribution for proposing new problem model., Results: Through the application of this model, the problems caused by overdosage, over-treatment, the combined use of drugs with the same curative effect, and non-indication use of antibacterial drugs in our hospital's prescription reviews were almost solved. The unreasonable rate of prescriptions has remained below 0.05% since 2015, and the unreasonable rate of doctor's orders has been controlled below 0.24%. The proportion of medicines dropped from 45.4% to 28.2%. The proportion of adjuvant drugs used decreased from 21% to 1.6%., Conclusions: This data mining prescription evaluation model is an efficient prescription quality management tool suitable for implementation in the digital, big data era., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-3933). The authors have no conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)

The absorption, distribution and excretion of drugs are largely determined by their transporters (DTs), the variability of which has thus attracted considerable attention. There are three aspects of variability: epigenetic regulation and genetic polymorphism, species/tissue/disease-specific DT abundances, and exogenous factors modulating DT activity. The variability data of each aspect are essential for clinical study, and a collective consideration among multiple aspects becomes crucial in precision medicine. However, no database is constructed to provide the comprehensive data of all aspects of DT variability. Herein, the Variability of Drug Transporter Database (VARIDT) was introduced to provide such data. First, 177 and 146 DTs were confirmed, for the first time, by the transporting drugs approved and in clinical/preclinical, respectively. Second, for the confirmed DTs, VARIDT comprehensively collected all aspects of their variability (23 947 DNA methylations, 7317 noncoding RNA/histone regulations, 1278 genetic polymorphisms, differential abundance profiles of 257 DTs in 21 781 patients/healthy individuals, expression of 245 DTs in 67 tissues of human/model organism, 1225 exogenous factors altering the activity of 148 DTs), which allowed mutual connection between any aspects. Due to huge amount of accumulated data, VARIDT made it possible to generalize characteristics to reveal disease etiology and optimize clinical treatment, and is freely accessible at: https://db.idrblab.org/varidt/ and http://varidt.idrblab.net/., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Motivation: Numerous experimental and computational studies in the biomedical literature have provided considerable amounts of data on diverse RNA-RNA interactions (RRIs). However, few text mining systems for RRIs information extraction are available., Results: RNA Interactome Scoper (RIscoper) represents the first tool for full-scale RNA interactome scanning and was developed for extracting RRIs from the literature based on the N-gram model. Notably, a reliable RRI corpus was integrated in RIscoper, and more than 13 300 manually curated sentences with RRI information were recruited. RIscoper allows users to upload full texts or abstracts, and provides an online search tool that is connected with PubMed (PMID and keyword input), and these capabilities are useful for biologists. RIscoper has a strong performance (90.4% precision and 93.9% recall), integrates natural language processing techniques and has a reliable RRI corpus., Availability and Implementation: The standalone software and web server of RIscoper are freely available at www.rna-society.org/riscoper/., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Pituitary adenoma (PA) is prevalent in the general population. Due to its severe complications and aggressive infiltration into the surrounding brain structure, the effective management of PA is required. Till now, no drug has been approved for treating non-functional PA, and the removal of cancerous cells from the pituitary is still under experimental investigation. Due to its superior specificity and safety profile, immunotherapy stands as one of the most promising strategies for dealing with PA refractory to the standard treatment, and various studies have been carried out to discover immune-related gene markers as target candidates. However, the lists of gene markers identified among different studies are reported to be highly inconsistent because of the greatly limited number of samples analyzed in each study. It is thus essential to substantially enlarge the sample size and comprehensively assess the robustness of the identified immune-related gene markers. Herein, a novel strategy of direct data integration (DDI) was proposed to combine available PA microarray datasets, which significantly enlarged the sample size. First, the robustness of the gene markers identified by DDI strategy was found to be substantially enhanced compared with that of previous studies. Then, the DDI of all reported PA-related microarray datasets were conducted to achieve a comprehensive identification of PA gene markers, and 66 immune-related genes were discovered as target candidates for PA immunotherapy. Finally, based on the analysis of human protein⁻protein interaction network, some promising target candidates ( GAL , LMO4 , STAT3 , PD-L1 , TGFB and TGFBR3 ) were proposed for PA immunotherapy. The strategy proposed together with the immune-related markers identified in this study provided a useful guidance for the development of novel immunotherapy for PA.

One of the most challenging puzzles in drug discovery is the identification and characterization of candidate drug of well-balanced profile between efficacy and safety. So far, extensive efforts have been made to evaluate this balance by estimating the quantitative structure-therapeutic relationship and exploring target profile of adverse drug reaction. Particularly, the therapeutic index (TI) has emerged as a key indicator illustrating this delicate balance, and a clinically successful agent requires a sufficient TI suitable for it corresponding indication. However, the TI information are largely unknown for most drugs, and the mechanism underlying the drugs with narrow TI (NTI drugs) is still elusive. In this study, the collective effects of human protein-protein interaction (PPI) network and biological system profile on the drugs' efficacy-safety balance were systematically evaluated. First, a comprehensive literature review of the FDA approved drugs confirmed their NTI status. Second, a popular feature selection algorithm based on artificial intelligence (AI) was adopted to identify key factors differencing the target mechanism between NTI and non-NTI drugs. Finally, this work revealed that the targets of NTI drugs were highly centralized and connected in human PPI network, and the number of similarity proteins and affiliated signaling pathways of the corresponding targets was much higher than those of non-NTI drugs. These findings together with the newly discovered features or feature groups clarified the key factors indicating drug's narrow TI, and could thus provide a novel direction for determining the delicate drug efficacy-safety balance.