Correcting for library size is an essential step in bulk RNA-seq analyses, as differences in sequencing depth across samples can obscure biological signal with technical noise. While numerous normalization methods and model-based strategies have been proposed, we demonstrate here that library size-normalized counts and differential expression results obtained from such widely adopted approaches often remain strongly correlated with library size in large-scale RNA-seq experiments. Through a systematic analysis of over 100 publicly available GEO and TCGA RNA-seq datasets with raw count data, we show that library size association is observed for a substantial proportion of genes even after state-of-the-art library size correction approaches recommended by leading normalization tools. To address this issue, we propose gecco , a gene-specific exponent-corrected normalization method for RNA-seq counts that incorporates library size directly into the statistical framework via a gene-specific correction term, rather than applying a uniform adjustment factor across all genes. This formulation generalizes existing normalization approaches and yields normalized counts that are free of residual library size effects. Using both simulation studies and real large-scale RNA-seq datasets, we show that our method mitigates library size bias while preserving biological signal across a range of parameter settings. We further demonstrate that our approach leads to higher detection accuracy and more biologically meaningful pathway enrichment results in downstream differential expression and rhythmicity analyses without compromising false discovery rate control. Our method is implemented in R and is fully compatible with the widely used differential expression analysis methods DESeq2 and edgeR .
The History of Medicine Library at the Royal Australasian College of Physicians is now one of the leading comprehensive research collections on the history of medicine of Australasia. This is a far cry from the founding fellows' original proposition in 1938, when they felt the need for a 'scientific library' to ensure the academic standards of their fledgling college. The present library has been made possible by donations from many personal and corporate collections. The first was a gift from the Royal College of Physicians of London in 1954, which redirected the focus to the history of medicine, followed in 1978 by the first munificent gift from Sir Edward Ford of his personal collection of Australiana. In the concluding decades of the 20th century, the value of all traditional history of medicine libraries worldwide was brought into question. Our library has survived the threat of dispersal on several occasions. The library and the extensive heritage collection of archives, artefacts, artwork and an image library have adapted to the challenges of the digital age, with greater visibility and accessibility through digital platforms. Our library, with its own unique history, has never looked so vibrant.
Y. Wei, Y. Bai, X. Cheng, B. Zhu, R. J. Reiter, and H. Shi, "The Dual Roles of Melatonin Biosynthesis Enzymes in the Coordination of Melatonin Biosynthesis and Autophagy in Cassava," Journal of Pineal Research 69, no. 1 (2020): e12652, https://doi.org/10.1111/jpi.12652. The above article, published online on 23 March 2020 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Gianluca Tosini; and John Wiley & Sons Ltd. A report on PubPeer [1] indicated that the pTRV and pTRV-MeASMT3 images in Figure 3D had been duplicated and presented as different samples in Figure 7B following rotation and further alteration. Additionally, several samples presented in Figure 4 contained overlapping or duplicated images. These concerns were confirmed by the publisher. The authors responded to an inquiry by the publisher and reported that an additional image duplication had occurred in between Figures 6C and 7C, in addition to the other errors. They reported that the duplications were due to mistakes during manuscript preparation. While the authors presented original as well as repeat data with the intention of correcting these errors, the authors did not provide a satisfactory explanation for the evidence of image rotation and alteration of images between Figures 3 and 7. Therefore, the publisher and the editor have lost confidence in the results and the conclusions, and the article must be retracted. The authors agree with the retraction.
X. Liu, Y. Ma, X. Wei, and T. Fan, "Neuroprotective Effect of Licochalcone a Against Oxygen-glucose Deprivation/Reperfusion in Rat Primary Cortical Neurons by Attenuating Oxidative Stress Injury and Inflammatory Response via the SIRT1/Nrf2 Pathway," Journal of Cellular Biochemistry 119, no. 4 (2018): 3210-3219, https://doi.org/10.1002/jcb.26477. The above article, published online on 6 November 2017 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Lucie Kalvodova; and Wiley Periodicals LLC. The retraction has been agreed due to concerns raised by third parties. Specifically, multiple image elements in Figure 1 were found to have been previously published in several articles from different author groups and presented in different scientific contexts. The authors did not respond to our requests for clarification. Accordingly, the article has been retracted as the editors consider its conclusions to be invalid. The authors have been informed of the retraction decision but were not available for final confirmation.
T. Fan, H. Pi, M. Li, Z. Ren, Z. He, F. Zhu, L. Tian, M. Tu, J. Xie, M. Liu, Y. Li, M. Tan, G. Li, W. Qing, R. J. Reiter, Z. Yu, H. Wu, and Z. Zhou, "Inhibiting MT2-TFE3-Dependent Autophagy Enhances Melatonin-Induced Apoptosis in Tongue Squamous Cell Carcinoma," Journal of Pineal Research 64, no. 2 (2018): e12457, https://doi.org/10.1111/jpi.12457. The above article, published online on 08 May 2017 in Wiley Online Library (wileyonlinelibrary.com) and its corrigendum (https://doi.org/10.1111/jpi.12645), has been retracted by agreement between the journal Editor-in-Chief, Gianluca Tosini; and John Wiley & Sons Ltd. A third party brought the publisher's attention to a report on PubPeer [1] which suggested that the row of BAX bands in Figure 7E had been duplicated in Figure 8E and represented as CL-PARP following a vertical flip, while the row of GAPDH bands in Figure 7E had also likely been duplicated with further brightness changes and vertical resizing. Additionally, the row of CL-PARP bands in Figure 1B had been duplicated in Figure 2B and represented as SQSTM1 following a horizontal flip, while the row of GAPDH bands had also been duplicated between those same figures. While the corrigendum published online on 28 March 2020 corrected the duplication in Figure 2B, the corrigendum did not address how the mistake was made and did not address the duplications between Figure 7E and 8E. Further investigation by the publisher also found that most of the row of p-TFE3 bands in Figure 6A had been potentially duplicated from another article which shares one of the same authors [Chen et al. 2016 (https://doi.org/10.18632/oncotarget.12894)]. Both articles represented the data as being from different samples. Additionally, one further potential duplication between the c-TFEB and Histone H3 bands in Figure 4B was also detected. The authors responded to an inquiry by the publisher and presented original data as well as original experimental documentation. A review of these data by the publisher found that, while some of the bands in question were not duplicated, there were further discrepancies between the labeling of the original data and the data presented in the article. There were also further discrepancies between the presentation of the original data and the data included in the corrigendum. Following contact with the authors, an additional round of checks found further evidence of image duplication in the supplementary data. Part of the MT2 band in Figure S2A was potentially shared with the p-P70S6K band in Supplementary Figure S4B. Part of the GAPDH band in Figure S3A was shared with the GAPDH band in Figure S3B. A portion of the GAPDH band in Figure S4A was duplicated and represented as P70S6K in Figure S4C. Lastly, a portion of the row of GAPDH bands in Figure S3A was duplicated in Figure 6B in the main article text and represented as Histone H3 while the BAX band in Figure S5 was duplicated in Figure 4B in the main article text and represented as Histone H3. The Retraction has been agreed to because the evidence of image duplication of different samples within this work fundamentally compromises the editors' confidence in the results presented in this article. The authors were informed of the retraction. Reference 1. Phytotoma raimondii. Comments on "Inhibiting MT2-TFE3-Dependent Autophagy Enhances Melatonin-Induced Apoptosis in Tongue Squamous Cell Carcinoma," PubPeer, February 2020. https://pubpeer.com/publications/982C03B89308C90F5E87B7A19843AC.
Dimethyl sulfate (DMS) chemical mapping probes RNA structure, where low reactivity is generally interpreted as Watson-Crick (WC) base pairs and high reactivity as unpaired nucleotides. Studies examining DMS reactivity of RNAs with known 3D structures have identified nucleotides that deviate from this interpretation with distinct solvent accessibility and hydrogen bonding patterns. Understanding the frequency of these outliers and their recurring 3D structural features remains incomplete. To address this, we systematically analyzed DMS reactivity across a library of 7500 RNA constructs containing two-way junctions with known 3D structures. DMS reactivity exists on a continuum over four orders of magnitude, with ∼10% overlap between WC and non-WC nucleotides. Non-WC bases with WC-like protection exhibit increased hydrogen bonding and decreased solvent accessibility, whereas reactive WC pairs tend to flank junctions, correlating with weaker base stacking and greater junction dynamics. Reactivity in noncanonical pairs correlates with specific atomic distances, allowing discrimination among base-pair conformations. These underlying reactivity-distance correlations are independently reproduced under in vivo-like probing conditions (37°C, 2 min). Using a single reactivity-derived distance constraint in Rosetta Full-Atom Refinement (FARFAR) recovers native A-G base-pair conformations and lowers root-mean-square deviation to high-resolution structures. These results establish that DMS reactivity provides predictive geometric information for RNA 3D modeling.
Enterovirus D68 (EV-D68) is a non-polio picornavirus that has caused increasing rates of severe respiratory illness and acute flaccid myelitis in children worldwide this century. There are no approved vaccines or antivirals for EV-D68. Thus, we conducted a crystallographic fragment screening (CFS) and a high-throughput screening (HTS) biochemical assay against the EV-D68 RNA-dependent RNA polymerase 3D (3D pol ) to identify ligandable sites and non-nucleoside compounds that can spearhead anti-enteroviral drug discovery. The CFS, involving 650 fragments, identified 68 hit compounds (~10% hit rate) distributed across 3D pol , including the functionally relevant sites RNA template channel, Active site, and RNA primer channel, and the previously unknown "Thumb site II" and "Index-middle finger pocket". Inhibition assays confirmed that compounds binding to each site can inhibit EV-D68 3D pol activity. The HTS, a fluorescence-based PicoGreen biochemical assay, permitted screening 50,000 compounds of the ChemBridge Premium Library (0.77% hit rate). After a second-round dose-response screening, we identified 5-aminoindazole as a promising scaffold that inhibits EV-D68 3D pol , including hit-to-lead compound 727590, which displayed an IC 50 value of 25 μM and preliminary structure-activity relationships. These hits offer amenable starting points for discovery and development of non-nucleoside inhibitors and provide opportunities for structure-based drug design against enteroviruses.
Adults are at heightened risk of anxiety, stress, and depression; animal-assisted therapy (AAT) may serve as an effective approach to promote psychological well-being. In this study, we compared the effectiveness of AAT in improving depression, anxiety, stress, pain, and gait among adults with or without illness. We systematically searched six electronic databases (PubMed, CINAHL, Embase, Web of Science, the Cochrane Library, and Scopus) and included all studies published up to August 2024. We used comprehensive meta-analysis software to complete the quantitative synthesis. We reported pooled effect sizes as Hedges' g with corresponding 95% confidence intervals (CIs), after applying a random-effects model. Furthermore, we assessed heterogeneity using Cochran's Q test and the I2 statistic. We applied the Cochrane Risk of Bias 2.0 tool to appraise the methodological quality of the included studies. The synthesis process followed PRISMA guidelines. From the 13,345 studies identified, 35 randomised controlled trials involving 2391 adults were included. Across diverse populations, AAT was associated with reductions in depression (Hedges' g = -0.403; 95% CI = -0.536, -0.271), anxiety (Hedges' g = -0.661; 95% CI = -1.069, -0.253), and stress (Hedges' g = -1.062; 95% CI = -1.849, -0.275) at post-intervention, although substantial between-study variability was observed. We demonstrated that AAT significantly improves anxiety, depression and stress in adults, but has no meaningful effect on pain or gait. Subgroup and meta-regression analyses indicate that psychological benefits depend on population and intervention characteristics, and are not moderated by age or gender. PROSPERO: CRD42024570108.
Short linear motifs (SLiMs) within intrinsically disordered protein regions mediate transient interactions crucial for cell physiology 1 . However, the global interaction landscape of human SLiMs remains largely uncharted. Here we present the Atlas of SLiM-mediated Human protein-protein Interactions (ASHI), which maps more than 20,000 interactions by screening over 800 human protein domains against a library of one million peptides tiling the human disordered proteome. ASHI expands the SLiM interactome, uncovers novel binding modes for known peptide-binding domains, and reveals unexpected peptide-binding activities in enzymes, chaperones, RNA-binding proteins, and modification-reader domains. Furthermore, intrinsically disordered regions emerge as densely encoded interaction platforms where interaction specificity is governed by diverse mechanisms, including key motif determinants, flanking residues, competition, and multivalency. These data provide an unprecedented foundation for modeling dynamic interaction networks, interpreting disease-associated variants, and decoding the dark proteome.
Biosimilar adalimumab agents have been introduced as cost-effective alternatives to reference adalimumab for inflammatory bowel disease (IBD); however, uncertainties remain regarding the outcomes of switching between reference and biosimilars in routine practice. Therefore, this systematic review was conducted to assess outcomes following switching between reference adalimumab and biosimilars in adult patients with IBD. A systematic search was undertaken in PubMed/MEDLINE, the Cochrane Library, and Google Scholar to identify relevant studies. Eligible studies included randomized controlled trials, cohort studies, registry-based analyses, and real-world evidence evaluating adult IBD patients (≥18 years) who switched between reference and biosimilar adalimumab. A total of seven studies comprising 5721 patients were included. Among these, three were prospective studies, three were retrospective studies, and one was a cross-sectional study. Follow-up ranged from six months to 26 months. Across studies, remission and response rates after switching were comparable to continuation on reference adalimumab, with most cohorts reporting remission in 74-90% of patients. Biomarkers generally remained stable or improved. Persistence outcomes were heterogeneous, with specialized centers reporting high multi-year persistence (>80%). Safety profiles were similar across products, with injection-site reactions being the most frequent adverse events (AEs) and a common cause of discontinuation. Serious AEs were rare. Immunogenicity data were limited but did not indicate clinically meaningful differences between reference and biosimilars.
Fear is a multifaceted and pervasive phenomenon among people with Parkinson's disease. Although some qualitative studies have explored fear-related psychological experiences in this population, there remains a lack of comprehensive integration of these insights. This study aimed to synthesize existing qualitative research on fear-related emotional experiences in people with Parkinson's disease, and to provide a theoretical basis for developing effective psychological interventions in clinical practice. A comprehensive computer-based search was conducted across 11 databases, including PubMed, Web of Science, Cochrane Library, CINAHL, PsycINFO, Embase, Scopus, CNKI, Wanfang, VIP, and SinoMed, to identify relevant qualitative studies. The methodological quality of the included studies was appraised using the 2020 Joanna Briggs Institute Critical Appraisal Checklist for Qualitative Research. A thematic synthesis approach was then employed to synthesize the findings. A total of 17 studies were included in the systematic review. Three themes related to fear-related psychological experiences in people with Parkinson's disease were identified: (1) multidimensional manifestations, (2) triggering contexts, and (3) coping strategies, comprising 12 categories in total. Fear in people with Parkinson's disease is a multifaceted phenomenon that spans physical, psychological, and social domains. These fear experiences arise from the interaction of multiple factors, and individuals show marked differences in their responses and coping strategies, resulting in diverse patterns of psychological adaptation. The findings underscore the need for healthcare providers to recognize fear as a central element of the Parkinson's disease experience and to deliver personalized support. The study protocol was registered in PROSPERO (Registration No. CRD420251246323).
Emergency laparotomies carry profound physiological morbidity, yet the adoption of minimally invasive surgery (MIS) in acute care remains hindered by laparoscopic limitations. While robotic platforms offer 3D visualization and wristed articulation to overcome these barriers, their application in emergency general surgery (EGS) and visceral trauma remains controversial. This systematic review aims to define the clinical and physiological boundaries of robotic surgery in the acute care setting. A PRISMA-compliant systematic review was conducted using PubMed/MEDLINE, Embase, Scopus, the Cochrane Library, and Web of Science from database inception through March 2026. Eligible studies included adult patients undergoing robotic surgery for EGS or visceral trauma. To minimize analytical confounding, studies were synthesized within two predefined cohorts: EGS and visceral trauma. Primary outcomes included conversion to open surgery, technical success, and timing of intervention. Secondary outcomes included operative time, length of hospital stay, postoperative morbidity, and cost-related outcomes. Thirty-six primary studies met the inclusion criteria, comprising 22 EGS studies and 14 visceral trauma studies. Within the EGS cohort, several comparative studies reported lower conversion-to-open rates with robotic surgery (0.0%-11.5%) compared with conventional laparoscopy (0.0%-28.7%), particularly in acute cholecystitis and complex hernia repair. Operative times were generally longer in robotic procedures, reflecting platform setup and docking requirements, whereas some studies reported shorter postoperative hospital stays. The visceral trauma literature consisted predominantly of case reports, case series, and observational studies. Robotic intervention was almost exclusively performed in hemodynamically stable patients during a delayed or semi-acute phase of care, with a median reported intervention interval of approximately 76 hours in the largest registry analysis. Reported applications were concentrated in complex diaphragmatic, thoracic, pancreatic, and pelvic reconstructions, with high rates of successful completion via minimally invasive techniques. Current evidence suggests that robotic surgery is a feasible minimally invasive option in selected acute care scenarios. In EGS, robotic platforms may facilitate completion of complex procedures while maintaining low conversion rates in appropriately selected patients. In visceral trauma, robotic surgery appears most applicable during delayed or semi-acute reconstruction following physiological stabilization rather than during damage-control interventions. Further prospective studies are required to define patient selection criteria, clinical effectiveness, and cost-effectiveness in acute care surgery.
Use of effective contraceptive methods (ECMs) reduces maternal mortality. Person-centered counseling increases uptake, but barriers to high-quality counseling persist. Telehealth may improve access to comprehensive contraceptive care, but its effectiveness remains unclear. This study assesses the effectiveness and acceptability of tailored, interactive telehealth contraceptive counseling (TECC) compared with in-person counseling. We conducted a systematic review and meta-analysis of English-language randomized controlled trials (RCTs) comparing TECC with in-person counseling for women and girls of any age and setting. We searched MEDLINE, Embase, Web of Science, and the Cochrane Library from inception through October 15, 2025. Outcomes were use of ECM less than 6 months from intervention (primary outcome); use of ECM at 6-12 months; use of long-acting reversible contraception (LARC); choice of ECM; choice of LARC; satisfaction with counseling; and method switching. Two researchers assessed risk of bias (RoB) using Cochrane RoB 2, certainty of evidence using GRADE (Grading of Recommendations Assessment, Development, and Evaluation), and performed meta-analysis using a random-effects model. The protocol was registered with PROSPERO (International Prospective Register of Systematic Reviews) a priori (CRD42023404402). No specific funding was received. Eight RCTs (RoB: low, n=4; moderate, n=2; and high, n=2) and 1 cluster RCT (moderate-to-high RoB) were included in the review, with 5353 participants across all included studies. Eight studies evaluated TECC as an adjunct to in-person care (hybrid model) and 1 as a standalone model, of which 7 and 1, respectively, contributed outcome data for the meta-analyses. Certainty of evidence was low to very low. The pooled effect of 4 studies of TECC on ECM use less than 6 months showed no clear evidence of an effect (relative risk [RR] 1.10; 95% CI 0.95-1.29). The pooled effect of 4 studies of TECC on choice of ECM (RR 1.07; 95% CI 0.96-1.18) likewise showed no clear effect. The pooled effect of 4 studies of TECC on ECM use at 6-12 months showed a small but statistically significant (P=.04) effect in favor of TECC, narrowly excluding the null (RR 1.07; 95% CI 1.002-1.130). Because of high statistical and clinical heterogeneity (I2=87%-96%), results for LARC choice (2 studies) and LARC use at 0-6 months (2 studies) and 6-12 months (2 studies) were narratively described. The evidence for these outcomes was very uncertain. Narrative analysis of satisfaction across 2 studies showed no difference in effect. There were no data on method switching to support the analysis. Current evidence suggests, with low certainty, that adjunct TECC, when delivered alongside in-person care, shows little to no effect on contraceptive use compared with in-person care. For use at 12 months, method choice, LARC use, and satisfaction compared with in-person care, the evidence is very uncertain. Future research should prioritize adequately powered evaluations of standalone models and assess how tailoring, timing, and delivery influence effectiveness, including long-term use and method switching.
Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection (LRTI) in infants and young children, which may progress to bronchiolitis, pneumonia, and other severe respiratory complications. This study aimed to evaluate the efficacy and safety of monoclonal antibodies (mAbs) against the RSV disease in premature infants. A comprehensive literature search was conducted across the PubMed, Cochrane Library, and Embase databases from inception through December 2025. Statistical analyses were performed using STATA software (version 15.0). Effect estimates were expressed as relative risk (RR) with corresponding 95% confidence intervals, and treatment rankings were evaluated using the surface under the cumulative ranking curve (SUCRA) probability. This Network Meta-analysis (NMA) included 7 randomized controlled trials involving 4 drugs and 11319 infants. Compared with the placebo, nirsevimab, motavizumab, and palivizumab have shown beneficial effects at reducing RSV-related hospitalization rates (RR, nirsevimab: 0.20, 95% CI: 0.09-0.45; motavizumab: 0.32 95% CI: 0.19-0.53; palivizumab: 0.43; 95% CI: 0.30-0.61) and Intensive Care Unit (ICU) admissions due to RSV infections (nirsevimab: 0.09, 95% CI: 0.01-0.87; motavizumab: 0.23, 95% CI: 0.08-0.65; palivizumab: 0.43, 95% CI: 0.21-0.90) in preterm infants. Nirsevimab was most likely to exert the best therapeutic effects, with the highest (SUCRA) values of 94.4% for RSV-related hospitalization rates and 89.1% for ICU admissions. No significant differences were found in mechanical ventilation use, deaths related to RSV Infections and drug-related adverse events. Nirsevimab, motavizumab, and palivizumab all reduced RSV-related hospitalizations and ICU admissions in preterm infants, with nirsevimab showing the greatest effect. However, further studies are needed to confirm these findings. https://www.crd.york.ac.uk/PROSPERO/view/CRD42024583222, identifier CRD42024583222.
To synthesise nursing students' experiences of peer support during clinical practice. A qualitative meta-synthesis. We searched the Cochrane Library, Embase, PubMed, Web of Science, CNKI, Wanfang and VIP databases for qualitative studies exploring nursing students' experiences of peer support, up to 11 September 2024. The Joanna Briggs Institute Qualitative Appraisal and Review Instrument was used to assess methodological quality, and findings were synthesised using a thematic synthesis approach. Ten studies were included. From 35 extracted findings, eight categories were developed and further synthesised into two overarching themes: (1) benefits of peer support for nursing students, and (2) challenges associated with peer support experiences. Peer support in clinical practice offers meaningful benefits-including enhanced confidence, emotional support and skill development-but also presents challenges related to mentor competence, interpersonal dynamics and reduced hands-on practice. Structured programme design and mentor preparation are essential to maximise benefits while mitigating risks. The findings suggest that peer support should be formally integrated into clinical placement designs to enhance student learning and well-being. In nursing education, structured peer mentoring programmes with clear role definitions and preparatory training for mentors are recommended to improve support quality. For clinical practice settings, regular supervision and monitoring are needed to safeguard students from over-dependence on peers and to ensure that peer support complements, rather than replaces, hands-on clinical learning opportunities. No patient or public contribution.
We evaluated the antiviral activity of a library of 36 urea-based small-molecule cyclophilin inhibitors (SMCypIs) against human respiratory syncytial virus (hRSV) and human metapneumovirus (hMPV). Structure-spectrum analysis revealed virus-specific structural requirements for antiviral efficacy. By combining the key determinants identified for each virus, we rationally designed optimized dual-acting derivatives. Among these, the optimized compound F832/33 emerged as a potent, broad-spectrum antiviral agent with nanomolar activity against both hRSV and hMPV, submicromolar inhibition of cyclophilin (Cyp) peptidyl-prolyl isomerase (PPIase) activity, and no detectable cytotoxicity. Interestingly, no direct correlation was observed between Cyp PPIase inhibition and antiviral potency, suggesting that Cyp engagement rather than enzymatic inhibition per se is required for antiviral activity. Competition assays with alisporivir confirmed that the antiviral effects of SMCypIs depend on their specific interaction with Cyp. Beyond its dual efficacy, F832/33 displayed strong antiviral activity against additional clinically relevant respiratory pathogens, including parainfluenza virus type 3, enterovirus D68, and both ancestral and Omicron severe acute respiratory syndrome coronavirus 2 strains, in immortalized cell lines and fully differentiated human nasal epithelial cells, a physiologically relevant model of respiratory infection. Collectively, our results demonstrate that structure-activity relationship-guided optimization can be successfully applied to expand the antiviral spectrum of SMCypIs, positioning F832/33 as a promising host-targeted broad-spectrum antiviral candidate. Further in vivo studies are warranted to evaluate its therapeutic potential and clarify its precise mechanism of action.
rAAV2.5T was identified through directed evolution of an AAV capsid library in polarized human airway epithelium (HAE) cultured at an air-liquid interface (ALI). The capsid gene of rAAV2.5T is a chimera of the N-terminal unique region of AAV2 VP1 (VP1u) and the VP2 and VP3 regions of AAV5 with a single A581T substitution at the variable region (VR) VIII of the capsids. GPR108, a G protein-coupled receptor, is known as an essential host factor for the transduction of rAAV2 but not of rAAV5. Both AAV2 and AAV5 VP1u colocalized well with GPR108 and, to a lesser extent, with the trans -Golgi network (TGN). GPR108 knockout (KO) abolished rAAV2.5T transduction in both HeLa cells and HAE-ALI cultures. Remarkably, short-term treatment with doxorubicin (DOX) at 2 µM completely restored transduction, indicating that DOX can compensate for the loss of GPR108 function. DOX enhanced rAAV2.5T transduction by 50-100-fold in wild-type HAE-ALI cultures and by over 300-fold in the GPR108-deficient cultures. Mechanistic studies demonstrated that this enhancement resulted from altered intracellular trafficking that promoted efficient vector nuclear import, rather than increased vector internalization, proteasome inhibition, or activation of the DNA damage response. Importantly, we identified that the N-terminal 15 amino acids of AAV2 VP1u as the primary determinant of rAAV2.5T dependence on GPR108 for transduction. Collectively, these findings demonstrate that productive transduction of rAAV2.5T in polarized HAE cultures depends on GPR108-mediated intracellular trafficking that limits efficient nuclear entry, and that DOX can relieve this constraint by promoting efficient vector import. AAV2.5T is an airway-tropic vector with considerable promise for pulmonary gene therapy. We found that host factor GPR108 is required for rAAV2.5T trafficking from the TGN to the nucleus and that this step constitutes a major bottleneck to productive transduction in polarized HAE. In contrast, KIAA0319L (AAVR) plays a key role in AAV intracellular trafficking from the endosome to the TGN but not in internalization into polarized HAE during apical transduction. Transient treatment with low-dose doxorubicin (DOX, 2 µM) enhanced rAAV2.5T transduction in HAE by 50-100-fold through a significant increase in vector nuclear import. Notably, DOX can overcome the transduction deficit caused by GPR108 deficiency, but not that caused by AAVR deficiency. Mechanistically, the N-terminal 15 amino acids of the VP1u confer GPR108 dependence during rAAV2.5T apical transduction of polarized HAE. DOX bypasses this requirement by promoting efficient nuclear import without affecting vector internalization, inhibiting proteasomes, or inducing DNA damage response.
Polar faculae are footprints of the polar magnetic field that are visible as bright spots along intergranular lanes. Unlike equatorial faculae and sunspots, which are found at low to moderate solar latitudes and peak in number at solar maximum, polar faculae are found at latitudes greater than 70 ∘ and peak in number around solar minimum. Polar faculae tend to have the same magnetic polarity as the general polar magnetic field, and their number has been shown to correlate with the strength of that magnetic field. This makes them good candidates for studying the evolution of polar conditions throughout the solar cycle from the ecliptic. We present a new automated method for counting and studying polar faculae in Helioseismic and Magnetic Imager (HMI) Ic_720s data using a source detection function from the Python library Photutils. We applied this method to both polar regions, using data averaged over each hour throughout the day between 2010 and 2022, the period for which HMI data is available in HelioCloud. Our results show a variation that is similar to that of the faculae count data from the Debrecen Heliophysical Observatory when they overlap, and extend that time series to December 2022. We also found that the magnetic field of the polar faculae averaged over the polar cap has the same polarity as the polar magnetic field from other measurements. However, we show that faculae with both polarities are present throughout the sunspot cycle. This indicates that some polar faculae may be generated by a local dynamo.
This study systematically evaluated the effects of Tai Chi on pain, functional disability, and sleep quality in patients with chronic non-specific low back pain (CNLBP). We searched CNKI, WanFang, VIP, China Biology Medicine Database, PubMed, Web of Science, Embase, and the Cochrane Library for randomized controlled trials (RCTs) of Tai Chi for CNLBP. Study quality was assessed using the Cochrane RoB 2 tool and the PEDro scale. Meta-analysis was used to pool the data. Eight RCTs involving 526 patients with CNLBP were included. Meta-analysis showed that Tai Chi significantly reduced pain, improving VAS scores (MD = -1.40, 95% CI: -2.41 to -0.40) and NRS scores. Tai Chi also significantly improved RMDQ scores (MD = -1.67, 95% CI: -2.75 to -0.59) and overall functional disability (SMD = -0.51, 95% CI: -0.90 to -0.12), but did not significantly affect ODI scores (MD = -0.62, 95% CI: -2.53 to 1.29). Moreover, improvements in PSQI scores were not statistically significant (MD = -0.18, 95% CI: -1.82 to 1.45). Tai Chi can effectively relieve pain and improve functional disability in patients with CNLBP. It is a safe and feasible non-pharmacological rehabilitation approach. However, current evidence is insufficient to confirm its effect on sleep quality. Further high-quality RCTs are needed. PROSPERO CRD420261361228.
Sleep disturbances frequently affect patients undergoing spinal surgery, impairing recovery, reducing quality of life, increasing postoperative complications, and impairing physical function improvements. However, the prevalence and associated risk factors of these disturbances remain poorly understood. This systematic review and meta-analysis aims to bridge this gap. The review protocol was prospectively registered on PROSPERO (CRD42024599851). A comprehensive search of PubMed, Embase, Cochrane Library, and Web of Science was conducted on November 14th, 2025. Studies evaluating sleep disturbances in adults undergoing spinal surgery were included. Proportional meta-analysis was conducted using a generalized linear mixed model. Studies utilizing sleep questionnaires and studies using spinal disability outcome measures with a sleep component were meta-analyzed separately. Heterogeneity was investigated via meta-regressions. Risk of bias was assessed using the Newcastle-Ottawa scale (NOS). Twenty studies were included. Preoperative sleep disturbance prevalence varied substantially by assessment instrument, ranging from 44.7% (95% CI: 28.6% to 61.7%) using PIRS-20 and 54.3% (95% CI: 47.7% to 60.8%) using PROMIS-SD to 91.2% (95% CI: 70.5% to 97.8%) using the PSQI. Younger age explained part of the between-study heterogeneity. Postoperative sleep disturbance prevalence was 35.3% (95% CI: 14.3% to 64.0%) using the PSQI and 29.7% (95% CI: 24.4% to 35.6%) using PROMIS-SD, while male sex was associated with a higher postoperative prevalence. Spinal disability outcome measures reported preoperative and postoperative sleep disturbance prevalences ranging from 79.7% to 84.2% and 27.2% to 52.0%, respectively. Consistent preoperative risk factors included younger age, female sex, greater pain severity, disability, and lower educational attainment. Greater pain, pre-existing sleep problems, and increased intraoperative bleeding volume were the most consistent postoperative risk factors. Sleep disturbances are highly prevalent before spinal surgery and remain common after surgery, although prevalence estimates vary substantially according to the assessment instrument used. Pain and disability appear to be important determinants of perioperative sleep disturbance. Routine screening and targeted perioperative interventions may improve patient outcomes.