CXCL9/CXCL10 as biomarkers the monitoring of treatment responses in Pulmonary TB patients: a systematic review and meta-analysis.

BACKGROUND: Tuberculosis (TB) remains a persistent threat to global public health and traditional treatment monitoring approaches are limited by their potential for contamination and need for timely evaluation. Therefore, new biomarkers are urgently required for monitoring the treatment efficacy of TB. METHODS: This study aimed to elucidate the levels of CXCL10 and CXCL9 in pulmonary TB patients who underwent anti-TB treatment. The data was acquired from five databases, including PubMed, Ovid, Web of Science, Embase, and the Cochrane Library. A meta-analysis of CXCL10 data from all time points was conducted. Furthermore, a trend meta-analysis of temporal data of CXCL10 and CXCL9 from multiple time points was also performed. RESULTS: It was revealed that patients who responded poorly to anti-TB treatment had higher serum levels relative to those who responded well (SMD: 1.23, 95% CI: -0.37-2.84) at the end of intensive treatment (2 months). Furthermore, heterogeneity was observed in these results, which might be because patients with a prior history of TB and different treatment monitoring methods than those selected in this study were also included. The analysis of alterations in CXCL10 and CXCL9 levels since the last collection time points indicated that their levels reduced with time. CONCLUSION: In summary, the study revealed that reductions in CXCL10 levels during the first two months of anti-TB treatment are correlated with treatment responses. Furthermore, decreasing levels of CXCL9 during the treatment suggest that it may also serve as a biomarker with a similar value to CXCL10. Future in-depth studies are thus warranted to further probe the relevance of CXCL10 and CXCL9 in monitoring the treatment efficacy of TB.

Dermal fibroblasts retain site-specific transcriptomic identity in keloids.

BACKGROUND: Human skin displays extensive spatial heterogeneity and maintains distinct positional identity. However, the impact of disease processes on these site-specific differences remains poorly understood, especially in keloid, a skin disorder characterized by pronounced spatial heterogeneity. OBJECTIVE: This study aimed to assess whether the spatial heterogeneity and positional identity observed in different anatomic sites persist in keloids. METHODS: Transcriptome sequencing was conducted on 139 keloid dermal tissues and 19 keloid fibroblast samples spanning seven distinct anatomic sites to identify the spatial transcriptomic heterogeneity. In addition, single-cell RNA sequencing data were utilized to elucidate the contributions of various cell types to the maintenance of positional identity. RESULTS: Keloid dermal tissues from diverse sites were categorized into three anatomic groupings: trunk and extremity, ear, and mandible regions. Enrichment analysis of differentially expressed genes unveiled that keloids across distinct regions retained unique anatomically-related gene expression profiles, reminiscent of those observed in normal skin. Notably, regional disparities consistently prevailed and surpassed inter-donor variations. Single-cell RNA sequencing further revealed that mesenchymal cells, particularly fibroblasts, made major contributions to positional identity in keloids. Moreover, gene expression profiles in primary keloid fibroblasts demonstrated a remarkable persistence of positional identity, enduring even after prolonged in vitro propagation. CONCLUSION: Taken together, these findings imply that keloids remain positional identity and developmental imprinting characteristic of normal skin. Fibroblasts predominantly contribute to the spatial heterogeneity observed in keloids.

Development and Validation of a Diagnostic Model for Enhancing Lesions on Breast MRI: Based on Kaiser Score.

RATIONALE AND OBJECTIVES: This study aims to develop and validate a new diagnostic model based on the Kaiser score for preoperative diagnosis of the malignancy probability of enhancing lesions on breast MRI. MATERIALS AND METHODS: This study collected consecutive inpatient data (including imaging data, clinical data, and pathological data) from two different institutions. All patients underwent preoperative breast Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) examinations and were found to have enhancing lesions. These lesions were confirmed as benign or malignant by surgical resection or biopsy pathology (all carcinomas in situ were confirmed by pathology after surgical resection). Data from one institution were used as the training set(284 cases), and data from the other institution were used as the validation set(107 cases). The Kaiser score was directly incorporated into the diagnostic model as a single predictive variable. Other predictive variables were screened using Least Absolute Shrinkage and Selection Operator (LASSO) regression. Multivariate logistic regression was employed to integrate the Kaiser score and other selected predictive variables to construct a new diagnostic model, presented in the form of a nomogram. Receiver operating characteristic (ROC) curve, DeLong test, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were adopted to evaluate and compare the discrimination of the diagnostic model for breast enhancing lesions based on Kaiser score (hereinafter referred to as the "breast lesion diagnostic model") and the Kaiser score alone. Calibration curves were used to assess the calibration of the breast lesion diagnostic model, and decision curve analysis (DCA) was used to evaluate the clinical efficacy of the diagnostic model and the Kaiser score. RESULTS: LASSO regression indicated that, besides the indicators already included in the Kaiser score system, "age", "MIP sign", "associated imaging features", and "clinical breast examination (CBE) results" were other valuable diagnostic parameters for breast enhancing lesions. In the training set, the AUCs of the breast lesion diagnostic model and the Kaiser score were 0.948 and 0.869, respectively, with a statistically significant difference (p < 0.05). In the validation set, the AUCs of the breast lesion diagnostic model and the Kaiser score were 0.956 and 0.879, respectively, with a statistically significant difference (p < 0.05). The DeLong test, NRI, and IDI showed that the breast lesion diagnostic model had a higher discrimination ability for breast enhancing lesions compared to the Kaiser score alone, with statistically significant differences (p < 0.05). The calibration curves indicated good calibration of the breast lesion diagnostic model. DCA demonstrated that the breast lesion diagnostic model had higher clinical application value, with greater net clinical benefit over a wide range of diagnostic thresholds compared to the Kaiser score. CONCLUSION: The Kaiser score-based breast lesion diagnostic model, which integrates "age," "MIP sign", "associated imaging features", and "CBE results", can be used for the preoperative diagnosis of the malignancy probability of breast enhancing lesions, and it outperforms the classic Kaiser score in terms of diagnostic performance for such lesions.

Vaccine optimization for highly pathogenic avian influenza: Assessment of antibody responses and protection for virus-like particle vaccines in chickens.

Background: Recent outbreaks of clade 2.3.4.4b highly pathogenic avian influenza (HPAI) H5N1 viruses in regions previously less affected since 2020 have raised global concerns. Implementing mass immunization or ring vaccination in poultry should be a countermeasure ready to contain disease outbreaks. This study focuses on developing a recombinant H5N2 vaccine based on virus-like particles (VLPs) against clade 2.3.4.4c, the predominant HPAI subclade in Taiwan since its emergence, leading to a large outbreak in 2015. Methods: The study aimed to confirm the effectiveness of clade 2.3.4.4c H5N2 VLPs in protecting chickens and identify the best adjuvants for the VLP vaccine. We used Montanide 71VG-adjuvanted inactivated RG6 to establish the immunization protocol, followed by prime-boost H5N2-VLP immunizations. We compared adjuvants: 71VG, 71VG with VP3, and Alum with VP3. Serum samples were tested for antibodies against homologous vaccine antigens and cross-clade antigens by hemagglutination inhibition (HI) assays. Finally, we evaluated the protective efficacy by lethally challenging immunized chickens with H5 viruses from clade 1 or 2.3.4.4c. Results: Poultry adjuvant 71VG significantly enhanced antibody responses in chickens with inactivated RG6 compared to unadjuvanted inactivated virus. While increasing antigen dosage enhanced 71VG adjuvanted RG6-induced antibody titers, the vaccine displayed minimal cross-reactivity against locally circulating HPAI H5N2. In contrast, H5N2-VLP containing the HA protein of clade 2.3.4.4c, adjuvanted with (FMDV) VP3 in 71VG, significantly promoted HI antibody responses. All H5N2-VLP immunized chickens survived lethal challenges with the local clade 2.3.4.4c H5 strain. Conclusion: The study demonstrated the immunogenic potential of the VLP vaccine in chickens. Our findings offer insights for optimizing VLP vaccines, allowing the incorporation of the HA of currently circulating H5 viruses to effectively mitigate the impact of the rapidly evolving clade 2.3.4.4 H5 outbreaks.

Effectiveness of combination therapy with intrathecal or intraventricular administration of polymyxin B for hospital-acquired central nervous system infections caused by carbapenem-resistant Acinetobacter baumannii: a retrospective study.

OBJECTIVES: To evaluate the therapeutic regimen, efficacy and safety of intrathecal or intraventricular (ITH/IVT) administration of polymyxin B for hospital-acquired central nervous system (CNS) infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB). METHODS: A retrospective study was performed on patients with CNS infections caused by CRAB treated with ITH/IVT combination therapy. The primary study outcome was the clinical efficacy after treatment. Secondary outcomes were bacterial clearance rate and safety of therapy. RESULTS: In total, 35 patients who received ITH (13[37.1%]) or IVT (22[62.9%]) polymyxin B as combination therapy were included. The median duration of ITH/IVT polymyxin B therapy was 9 days (interquartile ranges, 7-11). The overall clinical cure and bacterial clearance rate was 77.1% and 85.7%, respectively. No adverse effects deemed related with ITH/IVT polymyxin B were recorded. Clinical failure was independently associated with the initial Acute Physiology and Chronic Health Evaluation II (≥ 15) (odds ratio [OR], 1.24; 95% confidence interval [CI]: 1.05-1.42; P = 0.038) and Glasgow Coma Scale scores (≤ 8) (OR, 0.69; 95% CI: 0.49-0.88; P = 0.029). Early administration (within 4 days) of ITH/IVT polymyxin B therapy can support significantly higher clinical cure rate (OR, 0.65; 95% CI: 0.49-1.12; P < 0.001), and potentially reduce the length of treatment and the adverse effects. CONCLUSIONS: ITH/IVT administration of polymyxin B is a valid alternative for the treatment of CNS infections caused by CRAB. Early use of ITH/IVT polymyxin B can lead to higher clinical success.

Rational Design of Live Biotherapeutic Products for the Prevention of Clostridioides difficile Infection.

Clostridioides difficile infection (CDI) is a major cause of healthcare- and antibiotic-associated diarrhea. While fecal microbiota transplantation (FMT) shows promise for recurrent CDI, its mechanisms and long-term safety are not fully understood. Live biotherapeutic products (LBPs) using pre-defined bacterial consortia offer an alternative option, but the rational designing LBPs remains challenging. Here, we employ a computational pipeline and three metagenomic datasets to identify microbial strains for LBPs targeting CDI. We constructed the CDI-related microbial genome catalog, comprising 3,741 non-redundant metagenome-assembled genomes (nrMAGs) and identified multiple potential protective nrMAGs, including strains from Dorea formicigenerans, Oscillibacter welbionis, and Faecalibacterium prausnitzii. Importantly, some of these protective nrMAGs were found to play an important role in FMT success, and most top protective nrMAGs can be validated by various previous findings. Our results demonstrate a framework for selecting microbial strains targeting CDI, paving the way for the computational design of LBPs against other enteric infections.

An improved tetracycline-inducible expression system for fission yeast.

The ability to manipulate gene expression is valuable for elucidating gene function. In the fission yeast Schizosaccharomyces pombe, the most widely used regulatable expression system is the nmt1 promoter and its two attenuated variants. However, these promoters have limitations, including a long lag, incompatibility with rich media, and unsuitability for non-dividing cells. Here, we present a tetracycline-inducible system free of these shortcomings. Our system features the enotetS promoter, which achieves a similar induced level and a higher induction ratio compared to the nmt1 promoter, without exhibiting a lag. Additionally, our system includes four weakened enotetS variants, offering an expression range similar to the nmt1 series promoters but with more intermediate levels. To enhance usability, each promoter is combined with a Tet-repressor-expressing cassette in an integration plasmid. Importantly, our system can be used in non-dividing cells, enabling the development of a synchronous meiosis induction method with high spore viability. Moreover, our system allows for the shutdown of gene expression and the generation of conditional loss-of-function mutants. This system provides a versatile and powerful tool for manipulating gene expression in fission yeast.

Self-management experiences in fall prevention among community-dwelling older adults in China: a descriptive qualitative study.

BACKGROUND: Falls are the most common injuries in older adults, and fall prevention is one of the primary measures to achieve healthy aging. Self-management refers to the measures taken by individuals to avoid various adverse factors and health damage to protect and promote their health. This study aimed to explore the factors and measures of self-managed fall prevention among community-dwelling older adults. METHODS: A qualitative study based in two communities under the jurisdiction of Ninghua Street and Shanghai Street was conducted in Fuzhou, China. Semi-structured and face-to-face individual interviews were conducted with 15 community-dwelling older adults. Interviews were conducted by the first and second authors who had participated in qualitative training and were audio-recorded and transcribed. The data were analysed deductively with content analysis. RESULTS: The research revealed two themes with associated sub-themes: 1) influencing factors of self-managed fall prevention, and 2) promoting self-managed measures to prevent falls. CONCLUSIONS: Individual, social support, community advocacy, and road condition influenced self-managed fall prevention. Active exercise, adjusting home environment and clothing, and multi-channel acquisition of self-managed fall prevention knowledge can reduce the incidence of falls among older adults. Identifying these experiences will help older adults improve their awareness of preventing falls, take responsibility for themselves, and reduce the incidence of falls. TRIAL REGISTRATION: Chinese Clinical Trial Register: ChiCTR2200060705; reg. date: June 8, 2022.

Characterization of a ß-carotene isomerase from the cyanobacterium Cyanobacteria aponinum.

Carotenoids are essential components of the photosynthetic apparatus and precursors of plant hormones, such as strigolactones (SLs). SLs are involved in various aspects of plant development and stress-response processes, including the establishment of root and shoot architecture. SL biosynthesis begins with the reversible isomerization of all-trans-carotene into 9-cis-ß-carotene, catalysed by DWARF27 ß-carotene isomerase (D27). Sequence comparisons have revealed the presence of D27-related proteins in photosynthetic eukaryotes and cyanobacteria lacking SLs. To gain insight into the evolution of SL biosynthesis, we characterized the activity of a cyanobacterial D27 protein (CaD27) from Cyanobacterim aponinum, using carotenoid-accumulating Escherichia coli cells and in vitro enzymatic assays. Our results demonstrate that CaD27 is an all-trans/cis and cis/cis-ß-carotene isomerase, with a cis/cis conversion preference. CaD27 catalysed 13-cis/15-cis-, all-trans/9-cis-ß-carotene, and neurosporene isomerization. Compared with plant enzymes, it exhibited a lower 9-cis-/all-trans-ß-carotene conversion ratio. A comprehensive genome survey revealed the presence of D27 as a single-copy gene in the genomes of 20 out of 200 cyanobacteria species analysed. Phylogenetic and enzymatic analysis of CaD27 indicated that cyanobacterial D27 genes form a single orthologous group, which is considered an ancestral type of those found in photosynthetic eukaryotes. This article is part of the theme issue 'The evolution of plant meta|bolism'.

Navigating the Global Landscape of Exercise Interventions for Knee Osteoarthritis: Exploring Evolving Trends and Emerging Frontiers From a Bibliometric and Visualization Analysis Perspective (2011-2022).

OBJECTIVES: This study utilizes visual analysis methods to retrospectively examine the evolution and trends in exercise interventions for knee osteoarthritis (KOA) research from 2011 to 2022. DESIGN: Bibliometric and visualization analysis review. SETTING AND PARTICIPANTS: Using the Web of Science database, the literature search range is from January 1, 2011, to December 31, 2022, with the language specified as English and document type set to Article. METHODS: Visual analysis was used to analyze literature in the field of exercise interventions for KOA, with KOA and exercise interventions as the key search terms. Visualization maps for countries/regions were created using Tableau and Scimago Graphica software. Institutional, author, and keyword visualization maps were drawn using CiteSpace and VOSviewer software. RESULTS: In total, 3137 articles were included in the visual analysis. The United States emerged as the leading country in terms of publication volume and contribution. Moreover, developed countries such as the United States, Australia, United Kingdom, and Canada have established close and stable cooperative relationships. The University of Melbourne stood out as the institution with both the highest publication volume and centrality. At the forefront of research output in this field was Bennell K.L. from the University of Melbourne. The journal with the highest co-citation frequency was Osteoarthritis and Cartilage. The keyword clustering map highlighted an evolution in the field of exercise interventions for KOA, emphasizing 8 key research themes spanning knee osteoarthritis, serum cartilage, osteoarthritis initiative, patellofemoral pain, total knee arthroplasty, exercise-induced hypoalgesia, isometric exercise, and anterior cruciate ligament reconstruction. Burst analysis revealed that older adult was the earliest and most prominent keyword, with contemporary topics such as patellofemoral pain, safety, musculoskeletal disorder, and neuromuscular exercise considered as research hotspots and future directions in this field. CONCLUSIONS AND IMPLICATIONS: The global attention on exercise interventions for KOA research is expanding, emphasizing the importance of strengthened connections among developing countries and collaborative author groups. Recent trends have shifted toward topics such as neuromuscular training, treatment safety, and musculoskeletal disorders, whereas research interest in patellofemoral pain remains unabated. Neuromuscular training for KOA represents the current frontier in this field. Future research should delve into the effects of diverse types of exercise interventions for KOA on neuromuscular injury and recovery, exploring feasibility and safety to formulate personalized exercise plans for patients with KOA.

Anti-flammable, anti-fouling, anti-bacterial treatment of cotton fabrics with MOF-based hybrid coatings for highly efficient oil-water separation.

A flame-retardant and hydrophobic coating was deposited on the surface of the cotton fabric via a two-step spray deposition technique. Specifically, the coating was composed of flame-retardant component (guanidine phosphate) and hydrophobic components (Ti-MOF and bis(3-aminopropyl)-terminated poly(dimethylsiloxane) (PDMS)) and crosslinked with glutaraldehyde. The limiting oxygen index (LOI) of the coated cotton fabrics increased from 18.0 % to 32.0 % (15#) and 26.5 % (15#-Ti-PDMS) relative to that of the original cotton fabric, and the coated cotton fabrics also self-extinguished in the UL-94 flammability test. Compared with that of the original cotton fabric, the PHRR of the coated fabrics was significantly lower, reaching 80 %. The coated cotton fabrics (15# and 15#-Ti-PDMS) had good antibacterial properties against Staphylococcus aureus (S. aureus). In addition, 15#-Ti-PDMS had high hydrophobicity, good washing and abrasion resistance and good water-oil separation performance. Its water contact angle was 146°. The water contact angle remained above 130° after 10 laundering cycles and 50 scratch cycles. Even under strongly acidic and strongly basic conditions, the water-oil separation efficiency of 15#-Ti-PDMS was greater than 99 %, and it was still greater than 90 % after 10 cycles. Therefore, a simple and effective method for preparing flame-retardant, hydrophobic and antibacterial cotton fabric was developed.

Tactile Mechanisms and Afferents Underlying the Rat Pup Transport Response.

Juvenile rodents and other altricial mammals react with calming, immobility and folding up of feet to parental pickup, a set of behaviors referred to as transport response. Here we investigate sensory mechanisms underlying the rat transport response. Grasping rat pups in anterior neck positions evokes strong immobility and folding up of feet, whereas more posterior grasping positions have lesser effects on immobility and foot position. Transport responses are enhanced by slow (1Hz) and even more so by fast (4Hz) gentle shaking and translation of the pup, features consistent with parental transport. In response to lateral grasping, the forepaw below the grasping position points downwards and the forepaw lateral to the grasping position points upwards and medially. Such forepaw adjustments put the pup's center of gravity below the grasping point, optimizing pup transportability along with folding up of feet and tail lifting. Tactile stimuli on the back, belly, tail, whisker, dorsal forepaws and dorsal hind-paws do not significantly affect the behaviour of anterior-neck-held pups. Instead, ground contact or paw stimulation consistent with ground contact disrupts transport responses. We identify afferents mediating the transport response by examining membrane labelling with FM1-43 following anterior neck grasping. We observe a dense innervation of the anterior neck skin region (~30 terminals/ mm2). We also observed an age-related decrease of cytochrome oxidase reactivity in the rat somatosensory cortical neck representation, a possible correlate to the developmental decrease in the pup transport response. We conclude anterior neck grasping and loss of ground contact trigger calming and postural adjustments for parental transport in rat pups, responses putatively driven from the densely innervated anterior neck skin.

Anxiety disorders: Treatments, models, and circuitry mechanisms.

Anxiety disorders are one of the most prevalent mental health conditions worldwide, imposing a significant burden on individuals affected by them and society in general. Current research endeavors aim to enhance the effectiveness of existing anxiolytic drugs and reduce their side effects through optimization or the development of new treatments. Several anxiolytic novel drugs have been produced as a result of discovery-focused research. However, many drug candidates that show promise in preclinical rodent model studies fail to offer any substantive clinical benefits to patients. This review provides an overview of the diagnosis and classification of anxiety disorders together with a systematic review of anxiolytic drugs with a focus on their targets, therapeutic applications, and side effects. It also provides a concise overview of the constraints and disadvantages associated with frequently administered anxiolytic drugs. Additionally, the study comprehensively reviews animal models used in anxiety studies and their associated molecular mechanisms, while also summarizing the brain circuitry related to anxiety. In conclusion, this article provides a valuable foundation for future anxiolytic drug discovery efforts.

GLP-1 Receptor Agonists and Risk for Cirrhosis and Related Complications in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease.

Importance: Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasing cause of cirrhosis. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are effective in improving liver inflammation in patients with MASLD. Objective: To determine whether use of GLP-1 RAs is associated with lower risk of developing cirrhosis and its complications, including decompensation and hepatocellular cancer (HCC), among patients with MASLD. Design, Setting, and Participants: This retrospective cohort study with an active comparator, new-user design used data from the national Veterans Health Administration Corporate Data Warehouse and Central Cancer Registry. Patients with MASLD and diabetes who were seen at 130 Veterans Health Administration hospitals and associated ambulatory clinics and who initiated either a GLP-1 RA or dipeptidyl peptidase 4 inhibitor (DPP-4i) between January 1, 2006, and June 30, 2022, were included. Patients were followed up from baseline until one of the study outcomes or the end of the study period (December 31, 2022), whichever came first. Exposures: Each GLP-1 RA new user was propensity score matched in 1:1 ratio to a patient who initiated a DPP-4i during the same month. Separate analyses were conducted among patients without and with cirrhosis at baseline. Main Outcomes and Measures: For patients without cirrhosis, the primary outcome was progression to cirrhosis defined by validated diagnoses codes or a noninvasive marker of liver fibrosis, and secondary outcomes were cirrhosis complications defined both as a composite and individual complications, including decompensation, HCC, or liver transplant, and all-cause mortality. For patients with cirrhosis, the primary outcome was a composite outcome of cirrhosis complications, and secondary outcomes were decompensation, HCC, and all-cause mortality. Results: Of 16 058 patients who initiated GLP-1 RAs, 14 606 did not have cirrhosis (mean [SD] age, 60.56 [10.31] years; 13 015 [89.1%] male), and 1452 had cirrhosis (mean [SD] age, 66.99 [7.09] years; 1360 [93.7%] male) at baseline. These patients were matched to an equal number of patients who initiated a DPP-4i. In patients without cirrhosis, GLP-1 RA use, compared with DPP-4i use, was associated with a lower risk of cirrhosis (9.98 vs 11.10 events per 1000 person-years; hazard ratio [HR], 0.86; 95% CI, 0.75-0.98). Similar results were seen for the secondary outcomes. GLP-1 RA use, compared with DPP-4i use, was associated with a lower risk of the composite outcome of cirrhosis complications (1.89 vs 2.55 events per 1000 person-years; HR, 0.78; 95% CI, 0.59-1.04) and mortality (21.77 vs 24.43 events per 1000 person-years; HR, 0.89; 95% CI, 0.81-0.98). There were no associations between GLP-1 RA use and outcomes in patients with cirrhosis. Conclusions and Relevance: In this cohort study, GLP-1 RA use was associated with a lower risk of progression to cirrhosis and mortality among patients with MASLD and diabetes. The protective association was not seen in patients with existing cirrhosis, underscoring the importance of treatment earlier in the disease course.

Re-Evaluating PIN1 as a Therapeutic Target in Oncology Using Neutral Inhibitors and PROTACs.

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) has emerged as a promising therapeutic target for cancer treatment. However, the current PIN1 inhibitors have shown limited efficacy in animal models, leaving the question of whether PIN1 is a proper oncologic target still unanswered. By screening a 1 trillion DNA-encoded library (DEL), we identified novel nonacidic compounds. Among resynthesized DEL compounds, DEL1067-56-469 (A0) is the most potent one (KD = 430 nM, IC50 = 420 nM). Further optimization of A0 resulted in compound C10 with much improved potency (KD = 25 nM, IC50 = 150 nM). As an alternative approach, C10 was then converted into proteolysis targeting chimeras (PROTACs) in order to achieve deeper downregulation of the PIN1 protein in cancer cell lines. Unfortunately, neither PIN1 inhibitors nor PIN1 PROTACs demonstrated meaningful antiproliferation activity. In addition, siRNA knock-down experiments provided unfavorable evidence of PIN1 as an oncologic target. Our findings highlight the complexity of targeting PIN1 for cancer therapy.

Camera-based 3D Semantic Scene Completion with Sparse Guidance Network.

Semantic scene completion (SSC) aims to predict the semantic occupancy of each voxel in the entire 3D scene from limited observations, which is an emerging and critical task for autonomous driving. Recently, many studies have turned to camera-based SSC solutions due to the richer visual cues and cost-effectiveness of cameras. However, existing methods usually rely on sophisticated and heavy 3D models to process the lifted 3D features directly, which are not discriminative enough for clear segmentation boundaries. In this paper, we adopt the dense-sparse-dense design and propose a one-stage camera-based SSC framework, termed SGN, to propagate semantics from the semantic-aware seed voxels to the whole scene based on spatial geometry cues. Firstly, to exploit depth-aware context and dynamically select sparse seed voxels, we redesign the sparse voxel proposal network to process points generated by depth prediction directly with the coarse-to-fine paradigm. Furthermore, by designing hybrid guidance (sparse semantic and geometry guidance) and effective voxel aggregation for spatial geometry cues, we enhance the feature separation between different categories and expedite the convergence of semantic propagation. Finally, we devise the multi-scale semantic propagation module for flexible receptive fields while reducing the computation resources. Extensive experimental results on the SemanticKITTI and SSCBench-KITTI-360 datasets demonstrate the superiority of our SGN over existing state-of-the-art methods. And even our lightweight version SGN-L achieves notable scores of 14.80% mIoU and 45.45% IoU on SeamnticKITTI validation with only 12.5 M parameters and 7.16 G training memory. Code is available at https://github.com/Jieqianyu/SGN.

Noninvasive high-intensity focused ultrasound for skin brightening efficacy using a topical agent containing glutathione and hyaluronic acid.

BACKGROUND: High-intensity focused ultrasound (HIFU) is well-documented for skin rejuvenation, lifting, and tightening. However, its synergistic effects with topical agents, enhanced by HIFU-induced vibration and heat, remain underexplored. OBJECTIVE: To evaluate clinical and photographic outcomes of HIFU combined with a topical agent versus the topical agent alone. METHOD: This non-randomized controlled trial involved 20 female volunteers (ages 30-55) divided into two groups. Group A (n = 10) received two HIFU sessions combined with a topical agent containing glutathione and hyaluronic acid. Group B (n = 10) received the topical agent alone. Outcomes were assessed using digital photography, patient satisfaction surveys, and the A-One Smart™ system for fine wrinkles, hyperpigmentation, and hydration. Skin brightening was evaluated with the Global Esthetic Improvement Scale (GAIS). RESULTS: Group A showed significant reductions in fine wrinkles (6.25 ± 2.00 mm to 3.10 ± 1.62 mm), improved hyperpigmentation (3.50 ± 0.80 to 2.10 ± 1.05), and increased hydration (28 ± 10 to 55 ± 11) (all p < 0.05). Over two-thirds of Group A reported significant improvements, with no complications. Group B showed minimal, non-significant changes (p > 0.05), with only 30% reporting noticeable improvements. CONCLUSION: Combining HIFU with a topical agent significantly enhances skin quality and brightness without adverse effects.