Novel Acyl Thiourea-Based Hydrophobic Tagging Degraders Exert Potent Anti-Influenza Activity through Two Distinct Endonuclease Polymerase Acidic-Targeted Degradation Pathways.

The spread of the influenza virus has caused devastating pandemics and huge economic losses worldwide. Antiviral drugs with diverse action modes are urgently required to overcome the challenges of viral mutation and drug resistance, and targeted protein degradation strategies constitute excellent candidates for this purpose. Herein, the first degradation of the influenza virus polymerase acidic (PA) protein using small-molecule degraders developed by hydrophobic tagging (HyT) technology to effectively combat the influenza virus was reported. The SAR results revealed that compound 19b with Boc2-(L)-Lys demonstrated excellent inhibitory activity against A/WSN/33/H1N1 (EC50 = 0.015 µM) and amantadine-resistant strain (A/PR/8/H1N1), low cytotoxicity, high selectivity, substantial degradation ability, and good drug-like properties. Mechanistic studies demonstrated that the proteasome system and autophagic lysosome pathway were the potential drivers of these HyT degraders. Thus, this study provides a powerful tool for investigating the targeted degradation of influenza virus proteins and for antiviral drug development.

Flexible and Free-Standing Metal-Organic Framework Nanowire Paper.

Beyond traditional paper, multifunctional nanopaper has received much attention in recent years. Currently, many nanomaterials have been successfully used as building units of nanopaper. However, it remains a great challenge to prepare flexible and freestanding metal-organic framework (MOF) nanopaper owing to the low aspect ratio and brittleness of MOF nanocrystals. Herein, this work develops a flexible and free-standing MOF nanopaper with MOF nanowires as building units. The manganese-based MOF (Mn-MOF) nanowires with lengths up to 100 µm are synthesized by a facile solvothermal method. Through a paper-making technique, the Mn-MOF nanowires interweave with each other to form a three-dimensional architecture, thus creating a flexible and free-standing Mn-MOF nanowire paper. Furthermore, the surface properties can be engineered to obtain high hydrophobicity by modifying polydimethylsiloxane (PDMS) on the surfaces of the Mn-MOF nanowire paper. The water contact angle reaches 130°. As a proof of concept, this work presents two potential applications of the Mn-MOF/PDMS nanowire paper: (i) The as-prepared Mn-MOF/PDMS nanowire paper is compatible with a commercial printer. The as-printed colorful patterns are of high quality, and (ii) benefiting from the highly hydrophobic surfaces, the Mn-MOF/PDMS nanowire paper is able to efficiently separate oil from water.

Correlation among post-surgery recurrence of CRSwNP and TCM syndromes and tissue inflammatory cell infiltration type: a study protocol.

BACKGROUND: Functional endoscopic sinus surgery is a principal option for treating chronic rhinosinusitis with nasal polyps (CRSwNP) after medication failures. Unfortunately, some patients still have unsatisfactory postoperative recovery. The type of inflammatory cell infiltration in nasal polyp tissue has been reported available for recurrence prediction. As it is invasive and time-consuming, this technique is hard to promote clinically under the existing technical conditions. And during the course of clinical treatment, we have noted that differences in the postoperative recurrence rate of patients present among different traditional Chinese medicine syndrome types. METHODS AND ANALYSIS: This is a non-randomized, single-center, and prospective cohort study started in Chengdu Sichuan Province, People's Republic of China, in January 2021. A total of 200 participants will be recruited from patients who are diagnosed with CRSwNP and prepared for functional endoscopic sinus surgery. We collect preoperative data which includes general information, medical history, TCM syndromes, visual analogue scale (VAS) of subjective symptoms, Lund-Kennedy endoscopic score, and Lund-Mackay score of computed tomography (CT) scanning of sinuses. We acquire the VAS score and Lund-Kennedy score of subjective symptoms through multiple planned follow-up after surgery. After 1 year of follow-up, the recurrence rate will be calculated, and the curative effect will be assessed. Meanwhile, the patients' pathological sections will be sorted out, and inflammatory cell infiltration will be analyzed. Statistical analysis will be carried out to evaluate the correlation among CRSwNP recurrence and TCM syndrome types and tissue inflammatory cell infiltration types. Then we will establish a predictive model for CRSwNP recurrence. Analyses of survey data include descriptive and inferential statistical approaches. DISCUSSION: This is the first prospective cohort study on investigating the correlation of CRSwNP recurrence with TCM syndrome types and tissue inflammatory cell infiltration types. Through this study, we hope to discover a new and simple, effective, and noninvasive way to predict the recurrence rate rapidly after CRSwNP and provide reference for the intervention timing of traditional Chinese medicine application, thereby achieving customized diagnosis and treatment, minimizing risks of surgical events, and delaying postoperative recurrence of CRSwNP. SYSTEMATIC REVIEW REGISTRATION: PROSPERO ChiCTR2100041646.

Short-term dietary teprenone improved thermal tolerance and mitigated liver damage caused by heat stress in juvenile largemouth bass (Micropterus salmoides).

Heat stress seriously threatens fish survival and health, demanding immediate attention. Teprenone is a gastric mucosal protective agent that can induce heat shock protein expression. This research investigated the effects of teprenone on largemouth bass (Micropterus salmoides) subjected to heat stress. Juvenile fish were assigned to different groups: group C (control group, 0 mg teprenone/kg diet), T0, T200, T400, and T800 (0, 200, 400, and 800 mg teprenone/kg diet, respectively), which were fed for 3 days, followed by a day without the diet. All groups except group C were subjected to acute heat stress (from 24 °C to 35 °C at 1 °C per hour and then maintained at 35 °C for 3 h). The results were as follows: The critical thermal maxima were significantly higher in the T200, T400, and T800 groups compared with the T0 group (P < 0.05). Heat stress caused severe damage to the tissue morphology of the liver, while teprenone significantly reduced this injury (P < 0.05). Serum cortisol concentration decreased gradually as teprenone concentration increased, and the lowest concentration was observed in the T800 group (P < 0.05). Compared with the T0 group, the serum activities of aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase were significantly lower in the T200, T400, and T800 groups (P < 0.05). The liver activities of catalase, total superoxide dismutase, and peroxidase were significantly higher in the T200 group than in the T0 group (P < 0.05). Transcript levels of the heat shock proteins (hsp90, hsp70, hspa5, and hsf1) and caspase family (caspase3 and caspase9) in the liver of the T200 group were significantly higher than those of the T0 group (P < 0.05). Western blot results showed that HSP70 and HSPA5 in the liver were significantly upregulated in the T200 group compared with the T0 group (P < 0.05). In summary, dietary teprenone improved thermal tolerance, alleviated heat stress damage in the liver, enhanced antioxidant capacity, and upregulated heat shock proteins in juvenile largemouth bass. This study offers theoretical support for applying teprenone in aquaculture to reduce financial losses caused by abiotic factors.

The complete chloroplast genome sequence of Calystegia hederacea Wall. in Roxb. 1824 (Convolvulaceae) in Enshi, Hubei.

Calystegia hederacea Wall. in Roxb. 1824 is a perennial herbaceous vine in the family Convolvulaceae and has several biological effects. Herein, we reported the first complete chloroplast genome of C. hederacea. The chloroplast genome sequence was 152,057 bp in length, comparing a large single-copy (LSC) region of 87,891 bp, a small single-copy (SSC) region of 19,866 bp, and a pair of inverted repeat (IR) regions of 22,150 bp. This sequenced chloroplast genome contained 126 predicted genes, including 81 protein-coding genes, 37 tRNA genes, and eight rRNA genes, and the total GC content of the chloroplast genome was 37.79%. Phylogenetic analysis revealed that C. hederacea was closely related to C. soldanella. The chloroplast genome presented in this study will enrich the genome information of the genus Calystegia and provide deeper insights into the evolution study of the family Convolvulaceae.

Ganoderma lucidum spores-derived particulate ß-glucan treatment improves antitumor response by regulating myeloid-derived suppressor cells in triple-negative breast cancer.

Granular ß-1,3-glucan extracted from the wall of Ganoderma lucidum spores, named GPG, is a bioregulator. In this study, we investigated the structural, thermal, and other physical properties of GPG. We determined whether GPG ameliorated immunosuppression caused by Gemcitabine (GEM) chemotherapy. Triple-negative breast cancer mice with GPG combined with GEM treatment had reduced tumor burdens. In addition, GEM treatment alone altered the tumor microenvironment(TME), including a reduction in antitumor T cells and a rise in myeloid-derived suppressor cells (MDSC) and regulatory T cells (Tregs). However, combined GPG treatment reversed the tumor immunosuppressive microenvironment induced by GEM. GPG inhibited bone marrow (BM)-derived MDSC differentiation and reversed MDSC expansion induced by conditioned medium (CM) in GEM-treated E0771 cells through a Dectin-1 pathway. In addition, GPG downgraded PD-L1 and IDO1 expression on MDSC while boosting MHC-II, CD86, TNF-α, and IL-6 expression. In conclusion, this study demonstrated that GPG could alleviate the adverse effects induced by GEM chemotherapy by regulating TME.

Circ_100549 promotes tumor progression in lung adenocarcinoma through upregulation of BIRC6.

Lung adenocarcinoma (LUAD) is a subtype of lung cancer with high incidence and mortality globally. Emerging evidence suggests that circular RNAs (circRNAs) exert critical functions in human cancers, including LUAD. CircRNA_100549 (circ_100549) has been reported to be significantly upregulated in non-small cell lung cancer (NSCLC) samples, while its role in modulating LUAD progression remains to be explored. The current study aims at investigating the functional roles of circ_100549 in LUAD and its downstream molecular mechanism. First, we found that the expression of circ_100549 was higher in LUAD cell lines. Loss-of-function assays verified that depletion of circ_100549 repressed LUAD cell proliferation but accelerated cell apoptosis. Furthermore, in vivo experiments demonstrated that silencing of circ_100549 suppressed tumor growth. Subsequently, based on database analysis, we carried out a series of experiments to explore the mechanisms and effects of circ_100549 underlying LUAD progression, including RNA-binding protein immunoprecipitation (RIP), RNA/DNA pull-down, luciferase reporter, and chromatin immunoprecipitation (ChIP) assays. The results indicated that circ_100549 serves as a ceRNA by sponging miR-95-5p to upregulate BPTF expression, thus upregulating BIRC6 expression at a transcriptional level in LUAD. In summary, our study demonstrated that circ_100549 facilitates LUAD progression by upregulating BIRC6 expression.

Genome-wide characterization of post-transcriptional processes related to wood formation in Dalbergia odorifera.

BACKGROUND: Alternative polyadenylation (APA), alternative splicing (AS), and long non-coding RNAs (lncRNAs) play regulatory roles in post-transcriptional processes in plants. However, little is known about their involvement in xylem development in Dalbergia odorifera, a valuable rosewood species with medicinal and commercial significance. We addressed this by conducting Isoform Sequencing (Iso-Seq) using PacBio's SMRT technology and combined it with RNA-seq analysis (RNA sequencing on Illumina platform) after collecting xylem samples from the transition zone and the sapwood of D. odorifera. RESULTS: We identified 14,938 full-length transcripts, including 9,830 novel isoforms, which has updated the D. odorifera genome annotation. Our analysis has revealed that 4,164 genes undergo APA, whereas 3,084 genes encounter AS. We have also annotated 118 lncRNAs. Furthermore, RNA-seq analysis identified 170 differential alternative splicing (DAS) events, 344 genes with differential APA site usage (DE-APA), and 6 differentially expressed lncRNAs in the transition zone when compared to the sapwood. AS, APA, and lncRNAs are differentially regulated during xylem development. Differentially expressed APA genes were enriched for terpenoid and flavonoid metabolism, indicating their role in the heartwood formation. Additionally, DE-APA genes were associated with cell wall biosynthesis and terpenoid metabolism, implying an APA's role in wood formation. A DAS gene (involved in chalcone accumulation) with a significantly greater inclusion of the last exon in the transition zone than in the sapwood was identified. We also found that differentially expressed lncRNAs targeted the genes related to terpene synthesis. CONCLUSIONS: This study enhances our understanding of the molecular regulatory mechanisms underlying wood formation in D. odorifera, and provides valuable genetic resources and insights for its molecular-assisted breeding.

Deciphering the Roles of Extracellular Polymeric Substances (EPS) in Shaping Disinfection Kinetics through Permanent Removal via Genetic Disruption.

Extracellular polymeric substances (EPS) ubiquitously encapsulate microbes and play crucial roles in various environmental processes. However, understanding their complex interactions with dynamic bacterial behaviors, especially during the disinfection process, remains very limited. In this work, we investigated the impact of EPS on bacterial disinfection kinetics by developing a permanent EPS removal strategy. We genetically disrupted the synthesis of exopolysaccharides, the structural components of EPS, in Pseudomonas aeruginosa, a well-known EPS-producing opportunistic pathogen found in diverse environments, creating an EPS-deficient strain. This method ensured a lasting absence of EPS while maintaining bacterial integrity and viability, allowing for real-time in situ investigations of the roles of EPS in disinfection. Our findings indicate that removing EPS from bacteria substantially lowered their susceptibility threshold to disinfectants such as ozone, chloramine B, and free chlorine. This removal also substantially accelerated disinfection kinetics, shortened the resistance time, and increased disinfection efficiency, thereby enhancing the overall bactericidal effect. The absence of EPS was found to enhance bacterial motility and increase bacterial cell vulnerability to disinfectants, resulting in greater membrane damage and intensified reactive oxygen species (ROS) production upon exposure to disinfectants. These insights highlight the central role of EPS in bacterial defenses and offer promising implications for developing more effective disinfection strategies.

Heterozygous mutations in factor H aggravate pathological damage in a stable IgA deposition model induced by Lactobacillus casei cell wall extract.

Introduction: Activation of complement through the alternative pathway (AP) has a key role in the pathogenesis of IgA nephropathy (IgAN). We previously showed, by intraperitoneal injection of Lactobacillus casei cell wall extract (LCWE), C57BL/6 mice develop mild kidney damage in association with glomerular IgA deposition. To further address complement activity in causing glomerular histological alterations as suggested in the pathogenesis of IgAN, here we used mice with factor H mutation (FHW/R) to render AP overactivation in conjunction with LCWE injection to stimulate intestinal production of IgA. Methods: Dose response to LCWE were examined between two groups of FHW/R mice. Wild type (FHW/W) mice stimulated with LCWE were used as model control. Results: The FHW/R mice primed with high dose LCWE showed elevated IgA and IgA-IgG complex levels in serum. In addition to 100% positive rate of IgA and C3, they display elevated biomarkers of kidney dysfunction, coincided with severe pathological lesions, resembling those of IgAN. As compared to wild type controls stimulated by the same high dose LCWE, these FHW/R mice exhibited stronger complement activation in the kidney and in circulation. Discussion: The new mouse model shares many disease features with IgAN. The severity of glomerular lesions and the decline of kidney functions are further aggravated through complement overactivation. The model may be a useful tool for preclinical evaluation of treatment response to complement-inhibitors.

Enhancing thermostability of tryptophan hydroxylase via protein engineering and its application in 5-hydroxytryptophan production.

5-Hydroxytryptophan (5-HTP), as the precursor of serotonin and melatonin in animals, can regulate mood, sleep, and behavior, which is widely used in pharmaceutical and health products industry. The enzymatic production of 5-hydroxytryptophan (5-HTP) from L-tryptophan (L-Trp) using tryptophan hydroxylase (TPH) show huge potential in application due to its advantages, such as mild reaction conditions, avoidance of protection/deprotection processes, excellent regioselectivity and considerable catalytic efficiency, compared with chemical synthesis and natural extraction. However, the low thermostability of TPH restricted its hydroxylation efficiency toward L-Trp. In this study, we aimed to improve the thermostability of TPH via semi-rational design guided by (folding free energy) ΔΔG fold calculation. After two rounds of evolution, two beneficial mutants M1 (S422V) and M30 (V275L/I412K) were obtained. Thermostability evaluation showed that M1 and M30 possessed 5.66-fold and 6.32-fold half-lives (t1/2) at 37 °C, and 4.2 °C and 6.0 °C higher melting temperature (Tm) than the WT, respectively. The mechanism behind thermostability improvement was elucidated with molecular dynamics simulation. Furthermore, biotransformation of 5-HTP from L-Trp was performed, M1 and M30 displayed 1.80-fold and 2.30-fold than that of WT, respectively. This work provides important insights into the thermostability enhancement of TPH and generate key mutants that could be robust candidates for practical production of 5-HTP.

Network analysis of maternal parenting practices and adolescent mental health problems: a longitudinal study.

BACKGROUND: An extensive literature has shown a strong connection between maternal parenting practices and adolescent mental health problems. However, it has been difficult for previous research to map a dynamic concurrent and prospective relationships within and between types of parenting practices and adolescent mental health problems. The present study addressed these issues using a network analysis approach and a longitudinal design. METHODS: This study involved 591 Chinese adolescents (249 males; mean age at T1 = 13.53) and their mothers (mean age at T1 = 39.71) at two time points (T1 and T2) with eighteen months apart. Mothers reported their parenting practices including warmth, monitoring, inductive reasoning, hostility, and harshness, while adolescents reported their mental health problems including anxiety, depression, aggression, and conduct problems. Network analysis was conducted for contemporaneous networks at T1 and T2 and temporal networks from T1 to T2. RESULTS: The contemporaneous networks revealed the negative association between monitoring and conduct problems served as the main pathway through which parenting practices and adolescent mental health mutually influenced each other, and further, warmth was the most influential parenting practice on adolescent mental health. The temporal network revealed that maternal hostility exerted the most influence on adolescent mental health problems, whereas adolescents' depression was most influenced by maternal parenting practices. Moreover, maternal hostility was most predicted by maternal harshness. CONCLUSIONS: This study presents a novel perspective to gain a better understanding of the dynamics between and within maternal parenting practices and adolescent mental health problems. Findings highlight maternal harshness and warmth as potential prevention and intervention targets for adolescent mental health problems.

Timely use of Bakri intrauterine balloon tamponade contributes to the effectiveness in controlling severe postpartum hemorrhage.

The aim of the present study was to explore the effectiveness of Bakri intrauterine balloon tamponade (IUBT) in treating severe postpartum hemorrhage (SPPH). A cohort of 198 women with SPPH using IUBT were retrospectively selected. The baseline and maternal outcome characteristics were examined. The results demonstrated that women with SPPH had a high proportion of placenta accrete (53.0%). Bakri IUBT demonstrated a global effectiveness of 84.5% in SPPH treatment, accounting for 82.9% in women with placenta accrete. Compared with women with Bakri failure, women who experienced Bakri success had reduced rates of less use of pre-/post-IUBT intervention, blood transfusion, lower genital tract trauma, estimated blood loss (EBL), and a longer indwelling duration (P<0.05). Logistic regression revealed that the pre-IUBT intervention (OR=3.910; 95% CI: 1.684-9.079; P=0.002) was positively associated with hemostasis success, while lower genital tract trauma was negatively associated with Bakri success (OR=0.091; 95% CI: 0.009-0.894; P=0.040). Moreover, women diagnosed with placenta accrete underwent a greater number of transabdominal placed Bakri IUBT and pre-IUBT interventions than those without placenta accrete (P<0.05). No significant differences were observed in Bakri success, total EBL, pre-/post-IUBT EBL, infused volume of IUBT, IUBT indwelling duration, even the rate of hemostasis, lower genital tract trauma, blood transfusion, post-IUBT intervention, and puerperal fever between women with and without placenta accrete (P>0.05). In conclusion, placenta accrete may be the leading cause of SPPH. Bakri IUBT is an effective and safe measure for SPPH. Pre-IUBT intervention may be predictive of Bakri's success. The timely use of IUBT during labor may mitigate the impact of risk factors identified on PPH.

Combining Spleen Diameter and the Baveno VI Criteria Assessed by 2-Dimensional Shear Wave Elastography to Rule Out High-Risk Varices.

ABSTRACT: Patients with compensated advanced chronic liver disease (cACLD) can safely spared screening esophagogastroduodenoscopy (EGD) when they meet the Baveno VI criteria as assessed by transient elastography. Recently, the cutoff values of the Baveno VI criteria assessed by 2-dimensional shear wave elastography (2D-SWE) were proposed. We aimed to validate it to rule out high-risk varices (HRVs) in cACLD patients; combine spleen diameter (SPD) with the Baveno VI criteria and assess whether it can spare more screening EGD. A total of 173 cACLD patients with successful liver stiffness (LS) measurements and EGD examinations were included. We analyzed the risk factors that predicted HRVs and compared the performances of different models for ruling out HRVs. The platelet count, LS, and SPD were independent predictors of HRVs. The AUCs of platelet count, LS, spleen stiffness and SPD for diagnosing HRVs were 0.797, 0.757, 0.834, and 0.804, respectively. The Baveno VI criteria assessed by 2D-SWE spared 25.4% of EGD screenings and missed 2.4% of the HRV patients. Combining SPD ≤11.1 cm with the Baveno VI criteria could spare more EGD screenings than just applying the Baveno VI criteria (45.1% vs 25.4%, P < 0.001), and missed 4.9% of the HRV patients. The Baveno VI criteria assessed by 2D-SWE could be safely applied in cACLD patients to rule out HRV patients. The combined model Baveno VI/SPD could safely and significantly increase the rate of spared EGD.

A Vancomycin-Templated DNA-Encoded Library for Combating Drug-Resistant Bacteria.

It is an urgent need to tackle the global crisis of multidrug-resistant bacterial infections. We report here an innovative strategy for large-scale screening of new antibacterial agents using a whole bacteria-based DNA-encoded library (DEL) of vancomycin derivatives via peripheral modifications. A bacterial binding affinity assay was established to select the modification fragments in high-affinity compounds. The optimal resynthesized derivatives demonstrated excellently enhanced activity against various resistant bacterial strains and provided useful structures for vancomycin derivatization. This work presents the new concept in a natural product-templated DEL and in antibiotic discovery through bacterial affinity screening, which promotes the fight against drug-resistant bacteria.

Efficacy of Bakri Intrauterine Balloon in Managing Postpartum Hemorrhage: A Comparative Analysis of Vaginal and Cesarean Deliveries with Placenta Accreta Spectrum Disorders.

BACKGROUND The incidence of placenta accreta spectrum disorder (PAS) has been increasing in past decades, and women with PAS are a high-risk maternal population. This study aimed to explore the performance of Bakri intrauterine balloon tamponade (IUBT) in the treatment of postpartum hemorrhage (PPH), among those with and without PAS. MATERIAL AND METHODS The outcomes of 198 women who underwent treatment for PPH using IUBT were retrospectively analyzed. The demographics and maternal outcomes were analyzed for vaginal and cesarean births, with PAS and without PAS. RESULTS Compared to women with vaginal births (n=130), women who underwent cesarean births (n=68) showed a higher proportion of age ≥35 years (χ²=6.85, P=0.013), multiple births (χ²=13.60, P<0.001), preeclampsia (χ²=9.81, P=0.002), use of transabdominal IUBT (χ²=84.12, P<0.001) and pre-IUBT interventions (χ²=41.61, P<0.001), but had less infused volume of physiological saline (t=6.41, P<0.001). Women with PAS (n=105) showed a higher rate of pre-IUBT intervention (χ²=4.96, P=0.029) and transabdominal IUBT placement (χ²=9.37, P=0.002) than non-PAS women (n=93). The 36 women with PAS (n=36) showed a higher rate of preeclampsia (χ²=4.80, P=0.029), pre-IUBT intervention (χ²=5.90, P=0.015), and transabdominal IUBT placement (χ²=14.94, P<0.001) and a shorter duration from delivery to Bakri insertion (χ²=3.31, P=0.002), than non-PAS women (n=32). CONCLUSIONS PAS was a major cause of PPH at 198 vaginal and cesarean births. An accurate and timely pre-IUBT intervention and Bakri IUBT placement was critical for controlling PPH in cesarean births, especially in women with PAS.

Scientific mapping of research on English as a foreign language (EFL) reading instruction: A thirty-year perspective.

In recent years, English as a foreign language (EFL) reading instruction has emerged as a prominent and recurring research theme in the realm of education. Despite this growing interest, prior studies have not outlined the research status of EFL reading instruction from a bibliometric lens. Addressing this gap, the present study aims to provide valuable insights into the research landscape of EFL reading instruction by using scientific mapping analysis on documents sourced from the Web of Science Database between 1994 and 2023. The study found that: 1) The analysis of publication trends suggests that the field of EFL reading instruction continues to evolve, with a foreseeable ongoing increase in research output. 2) Asian countries, specifically Iran, China, and Saudi Arabia emerge as leading contributors and collaborators in terms of research on EFL reading instruction. 3) Authors mainly from Asian countries demonstrate the highest levels of productivity and citation impact. 4) The most productive and cited journals primarily originate from developed countries, notably the United Kingdom and the United States. 5) The research foci identified cover various aspects such as "technology-based instruction," "critical thinking," and "literacy skills." However, there is an emerging shift in research focus towards themes "English proficiency," "Covid-19," "technology," "blended learning" and "mobile-assisted language learning (MALL)." By shedding light on the significant concepts and trends of the research field, this study adds to the burgeoning body of literature and provides valuable guidance to new scholars seeking to enrich their knowledge and perspectives on this particular topic.

Design, synthesis and biological evaluation of thiazolyl-halogenated pyrroles or pyrazoles as novel antibacterial and antibiofilm agents.

The formation of biofilm is one of the important factors for bacteria to develop drug-resistant. A series of halogenated-pyrroles or pyrazoles containing thiazole groups as antibacterial agents were designed and synthesized to target biofilms. Among them, compound 8c showed antibacterial activity against various Gram-positive bacteria, particularly against vancomycin-resistant Enterococcus faecalis (MIC ≤0.125 µg/mL). Additionally, this compound significantly inhibited biofilm formation of Staphylococcus aureus and Pseudomonas aeruginosa at sub-MIC doses. Furthermore, compound 8c exhibited significantly lower mammalian cell toxicity compared to pyrrolomycin C and its hepatic microsomal metabolic stability in various species was also evaluated. Further experiment on the infection model of Galleria mellonella proved that the compound was effective in vivo.

Structure Guided Discovery of Novel Pan Metallo-ß-Lactamase Inhibitors with Improved Gram-Negative Bacterial Cell Penetration.

The use of ß-lactam (BL) and ß-lactamase inhibitor combination to overcome BL antibiotic resistance has been validated through clinically approved drug products. However, unmet medical needs still exist for the treatment of infections caused by Gram-negative (GN) bacteria expressing metallo-ß-lactamases. Previously, we reported our effort to discover pan inhibitors of three main families in this class: IMP, VIM, and NDM. Herein, we describe our work to improve the GN coverage spectrum in combination with imipenem and relebactam. This was achieved through structure- and property-based optimization to tackle the GN cell penetration and efflux challenges. A significant discovery was made that inhibition of both VIM alleles, VIM-1 and VIM-2, is essential for broad GN coverage, especially against VIM-producing P. aeruginosa. In addition, pharmacokinetics and nonclinical safety profiles were investigated for select compounds. Key findings from this drug discovery campaign laid the foundation for further lead optimization toward identification of preclinical candidates.