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Androgenic alopecia (AGA) is the most common type of hair loss that occurs due to androgens, specially, dihydrotestosterone (DHT), and the 5-alpha reductase is the key enzyme to control AGA, as it is responsible for the conversion of testosterone to DHT, the more potent form of testosterone involved in the pathogenesis of AGA. Blockers of this enzyme suppress the conversion of androgens to DHT. Dutasteride is one of the 5-alpha reductase inhibitors and is frequently used as an anti-hair loss treatment. Gamma-oryzanol (GO) is an anti-oxidant and anti-5-alpha reductase, which has been introduced as an anti-hair loss treatment by some studies. The nanostructured lipid carriers (NLCs) were developed for targeting the dutasteride and GO in hair follicles. The NLCs were prepared from herbal oils pumpkin seed oil (PSO) and saw palmetto (SP), which also have a 5-alpha reductase inhibitory effect, contributing to the therapeutic effect. NLCs in follicular targeting enable to accumulation of the drugs in the target area (hair follicle cells), reduce the absorption of dutasteride in other organs and tissues, and reduce the side effects. NLCs were prepared by adopting a hot homogenization method and were characterized by particle size analyzer, scanning electron microscope, and X-ray diffraction. An in-vivo study was conducted using C57BL/6 mice to assess NLCs ability in drug delivery and accumulation in hair follicles. NLCs had great potentials for reducing the dutasteride daily dose. Moreover, the accumulation of NLCs was confirmed by histopathological images even after two weeks of the discontinued treatment. NLCs may have facilitated the follicular delivery of the anti-hair loss drugs. Since the NLCs have potential for accumulation in the hair follicles, the interval of formulation usage may have been increased to more than once a week which was of great interest to the practitioners aiming at developing more efficient formulations for androgenetic alopecia.

The Antarctic ozone hole was first reported in 1985, and small ozone losses at the global scale were also observed in the late 1980s. The combination of field and laboratory measurements, together with modeling, quickly established anthropogenic chlorofluorocarbons (CFCs) as the cause of both the Antarctic and global ozone depletion. However, when, where, and why the earliest ozone depletion could have been detected has not been determined. Here, we conduct a thought experiment to investigate when human-induced ozone depletion could have first been detectable, assuming the availability of accurate stratospheric ozone observations from 1950 onward. We find that human-caused ozone depletion was likely identifiable as early as 1957 in the tropical upper stratosphere. This region's low internal variability enables the earliest detection of the anthropogenic signal, even though tropical ozone losses in the upper stratosphere were smaller than those in higher-latitude regions. Our results highlight the key role of considering both internal variability ("noise") and the forced response ("signal") in detection studies. Further, while CFCs are widely recognized as the primary drivers of current ozone depletion, we find that early ozone loss was primarily caused by human-made carbon tetrachloride (CCl4), used mainly as a solvent. These findings suggest that a clear human influence on the stratospheric ozone layer began nearly 70 y ago, even before substantial emissions of CFCs from spray cans or air conditioning.

The complement system is a key driver of geographic atrophy (GA), a disease that leads to progressive, irreversible vision loss. Pharmacological preclinical studies characterizing an antibody fragment, which is a novel complement C3 inhibitor under investigation for GA treatment, are presented. Kinetic parameters were determined for the antibody fragment binding to C3, C3b, and C3 variants associated with GA. Inhibition of membrane attack complex (MAC) formation after classical (CP), alternative (AP), and lectin (LP) pathway activation was determined. Comparisons with the second-generation compstatin derivative (APL-1) were made because of the expected similarity of binding behavior and in vitro potency with pegcetacoplan (which could not be sourced at the time of the study). Diffusion through Bruch's membrane (BrM) was investigated for the antibody fragment and a pegcetacoplan-similar (PEG-s) molecule using enriched porcine BrM in Ussing chamber devices. The antibody fragment showed high (picomolar) affinity for all tested C3 ligands. APL-1 showed lower (single-digit nanomolar) affinity than the antibody fragment, comparable with published values. The antibody fragment exhibited dose-dependent inhibition of MAC formation via CP (half-maximal inhibitory concentration [IC50] 79 nM), AP (344 nM), and LP (67 nM), with enhanced potency for inhibiting CP- and LP-mediated complement activation vs. APL-1. More efficient permeation of the BrM was observed with the antibody fragment than with the PEG-s molecule. The antibody fragment is a potent and specific C3 inhibitor that displays dose-dependent inhibition of MAC formation across all three complement pathways and effectively crosses the BrM. In line with these results, the antibody fragment is being investigated in patients with GA. Graphical abstract available for this article. Geographic atrophy is the late stage of age-related macular degeneration. Geographic atrophy is a disease that causes damage to the retina in the eye and can cause loss of vision and reduce a person’s quality of life. There are currently only a few medicines approved to treat geographic atrophy. The development and progression of geographic atrophy is linked to the components of the immune system that are responsible for inflammation and the formation of destructive protein complexes. This preclinical study used laboratory experiments to investigate how a potential new therapy called an antibody fragment affects these immune system components and to see if it is suitable for the treatment for geographic atrophy. The study found that the antibody fragment bound strongly to its target immune components, and it may prevent the formation of destructive protein complexes. The antibody fragment was also able to readily pass through the membrane found in the eye where the immune components need to be targeted. These promising preclinical results support further investigation of the antibody fragment in people with geographic atrophy.

Spiking Neural Networks (SNNs) have emerged as a promising paradigm for brain-inspired edge computing. Leveraging binary spikes and local learning rules, SNNs enable energy-efficient on-chip learning and rapid adaptation to changing environments, which is crucial for edge AI that needs to learn continuously from new data. However, many SNN processors enabling on-chip learning for edge computing confront a trade-off: small-scale task-specific designs offer low power but poor multi-task inference accuracy, while large-scale general-purpose designs achieve high multi-task accuracy at the cost of large memory and poor energy efficiency. To overcome this challenge, this paper presents ANP-R, a 22nm asynchronous SNN-based edge AI processor with coarse-grained reconfigurable architecture enabling one-shot, few-shot, batch and incremental on-chip learning. The processor integrates 64 cores containing 4096 neurons and 0.262 million synapses. Two key features are proposed: 1) An asynchronous coarse-grained reconfigurable architecture that supports various STDP-based SNN topologies. These topologies enable over 95% average accuracy across four sensory tasks; 2) an energy-efficient asynchronous training method incorporating a self-adaptive synaptic weight update mechanism reducing up to 65% redundant updates without accuracy loss, and a trained weights low-bit width coding method reducing up to 50% storage cost with 0.3% accuracy loss. Measurement results demonstrate 92.1% accuracy for hand gesture classification, 93.9% for keyword spotting, 98.6% for object recognition and 99.2% for gas identification. Compared with state-of-the-art SNN-based chips, this work achieves up to 6.02x, 8.61x and 7.1% improvement in energy efficiency, energy per step, and accuracy, respectively.

Dielectric capacitors offering ultrafast charge-discharge capability and superior reliability are essential for advanced electronic systems, but achieving both high energy density and efficiency within simple and eco-friendly compositions remains a great challenge. Here, guided by machine learning, we achieve high-efficiency and thermally stable capacitive energy storage in strontium titanate-based ceramics. Through synergistic local structural engineering and optimized fabrication process, the materials exhibit enhanced polarization, reduced hysteresis loss, and improved breakdown strength. The designed materials deliver an ultrahigh energy density of 10.69 J cm-3 with a near-ideal efficiency of ∼97% and a record high figure of merit of 392 J cm-3 at room temperature, and retains high performance at 150°C with a figure of merit of 152 J cm-3 and an efficiency of ∼94%. This remarkable performance arises from the incorporation of Bi3+ ions with high polarizability at the A-sites of strontium titanate quantum paraelectrics, which breaks structural symmetry and induces lattice and octahedral distortions, leading to the formation of nanoscale polar clusters with highly dynamic fluctuations. These findings establish a compositionally simple, environmentally benign pathway for developing dielectrics with superior energy storage capability and thermal stability, offering new opportunities for high-performance capacitive energy storage systems.

Nutrient and water supply are decisive limiting factors for trees and their productivity. Yet, the consequences of fertilization for drought responses, especially during the sensitive nursery stage, remain poorly understood. In this study, we exposed potted saplings of Pinus sylvestris, Fagus sylvatica, and Quercus robur to two levels of fertilization and three water regimes. The effects of fertilization, drought, and their interaction on gas exchange, hydraulic traits, and growth were examined. Fertilization generally promoted gas exchange, hydraulic conductance, and biomass accumulation but responses were species-specific and did not always persist under and after drought. While fertilized Q. robur maintained or even increased its biomass and physiological performance under drought, the benefits of fertilization for P. sylvestris and F. sylvatica diminished under increasing drought intensity. No consistent changes in drought resistance traits (e.g., turgor loss point, embolism resistance) were observed across species in response to fertilization, which may indicate limited plasticity or acclimation potential of saplings. Our findings highlight the species-specific fertilization effects on drought responses and post-drought performance of saplings, emphasizing the need to consider both factors in silvicultural practices under future climate scenarios.

This preliminary prospective study aimed to evaluate the effectiveness of antimicrobial photodynamic therapy (aPDT) as an adjunct treatment for angular cheilitis (AC) in critically ill patients and to investigate its feasibility in a high-complexity hospital setting. The study included 13 patients admitted to the intensive care unit (ICU) of a referral infectious disease hospital in Northeastern Brazil. The aPDT protocol consisted of 0.1% methylene blue (10-minute pre-irradiation) followed by low-level laser therapy (660 nm, 4 J/point, 40 s) applied to three points per affected commissure. Clinical evolution was monitored at T1 (72 h), T2 (7 days), and T3 (follow-up), with lesions classified according to severity. Most patients presented severe systemic compromise, predominantly related to HIV infection and diabetes mellitus. In addition, 76.9% of patients exhibited concomitant oral candidiasis, and 92.3% were receiving systemic antifungal therapy. Complete lesion regression was observed in 40% of patients within 72 h (T1). By the final follow-up (T3), the overall clinical cure rate reached 61.5% (8/13), including cases of delayed resolution confirmed up to day 15. Although a 30.8% loss to follow-up occurred due to the inherent challenges of the intensive care setting, no adverse effects or complications were reported. Within the limitations of this preliminary study, aPDT demonstrated promising clinical applicability as an adjunctive approach for managing angular cheilitis in critically ill patients.

Obesity is a recognized risk factor for postoperative complications after spine surgery, but body mass index (BMI) does not capture regional fat distribution. The visceral-to-subcutaneous fat area (VFA/SFA) ratio measured on CT reflects an unfavorable fat distribution pattern, yet its role in wound healing after posterior lumbar fusion (PLF) is unclear. We retrospectively analyzed 526 adults who underwent instrumented PLF for degenerative lumbar pathology and had preoperative non-contrast abdominal CT including the L4-L5 level. On a single axial slice at L4-L5, visceral fat area (VFA) and subcutaneous fat area (SFA) were segmented using a semi-automated protocol and the VFA/SFA ratio was calculated and grouped into quartiles. The primary outcome was impaired wound healing within 30 days, defined as persistent erythema or swelling, fat liquefaction, prolonged serous/serosanguinous exudation, partial wound edge necrosis or superficial dehiscence, or the need for negative-pressure therapy, delayed suture removal, additional antibiotics, or surgical debridement. Group comparisons used t tests and &#x3c7; 2 tests. Univariable and multivariable logistic regression were performed, and discrimination of BMI, VFA, SFA, VFA/SFA, and clinical prediction models was assessed using receiver operating characteristic curves. Impaired wound healing occurred in 59 patients (11.2%). Compared with patients with good healing, those with impaired wound healing had higher BMI (25.4&#x2009;&#xb1;&#x2009;4.0 vs. 23.1&#x2009;&#xb1;&#x2009;3.8&#x2005;kg/m2, p&#x2009;<&#x2009;0.001) and higher VFA/SFA ratio (1.063&#x2009;&#xb1;&#x2009;0.246 vs 0.895&#x2009;&#xb1;&#x2009;0.259, p&#x2009;<&#x2009;0.001), whereas SFA did not differ. Each 0.1 increase in VFA/SFA ratio was associated with an adjusted odds ratio of 1.32 (95% CI 1.16-1.50; p&#x2009;<&#x2009;0.001) for impaired wound healing, independent of age, sex, BMI, diabetes, ASA class, albumin, multilevel fusion, operative time, and blood loss. The AUC was 0.66 for BMI and 0.70 for VFA/SFA; adding VFA/SFA to a clinical model increased the AUC from 0.70 to 0.77. The preoperative VFA/SFA ratio at L4-L5 is an independent predictor of impaired wound healing after PLF and provides incremental discriminative value beyond BMI and conventional clinical risk factors.

This case report describes a 71-year-old woman presenting with altered speech, gait difficulties, and hearing loss diagnosed with infratentorial superficial siderosis and a thoracic spinal cord cleft.

Desert Hedgehog (Dhh) mutations cause Leydig cell dysfunction, yet the mechanisms governing Leydig lineage commitment through Dhh-mediated receptor selectivity, transcriptional effector specificity, and steroidogenic coupling remain elusive. In this study, using CRISPR/Cas9-mediated gene knockout and stem Leydig cells (SLCs) transplantation, we identified a critical Dhh/Patched 2 (Ptch2)/Glioma-associated oncogene homolog 1 (Gli1)/steroidogenic factor 1 (Sf1) signaling axis essential for SLC differentiation in Nile tilapia (Oreochromis niloticus). Dhh deficiency resulted in defective adult Leydig cells and androgen insufficiency. Rescue experiments involving 11-ketotestosterone administration and a Dhh agonist treatment, combined with SLCs transplantation, demonstrated that Dhh regulates SLC differentiation, not survival. In vitro knockout of ptch1 and ptch2 in SLCs revealed that Ptch2 likely acts as the functional receptor for Dhh. This was further supported by in vivo genetic rescue experiments, where ptch2 mutation did not impair testicular development, yet completely rescued the testicular defects in dhh mutants-consistent with Ptch2 acting as an inhibitory receptor whose loss alleviates Dhh pathway suppression. Luciferase assays in Gli-knockout SLCs demonstrated that Gli1 acts as the primary transcriptional effector and transactivates sf1 expression. Additionally, functional transplantation assays confirmed that Sf1 is indispensable for SLC differentiation, as Sf1-overexpressing SLCs rescued differentiation, whereas sf1-mutant SLCs failed. Overall, our work delineates the Dhh-Ptch2-Gli1-Sf1 axis and provides fundamental insights into the endocrine regulation of Leydig cell lineage development.

Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is featured by oxidative stress and impaired bone regeneration. Alpha-2-Macroglobulin (&#x3b1;-2&#xa0;M) was reported to possess cytoprotective and anti-inflammatory properties, and have shown its role in alleviating GIONFH. nuclear factor erythroid 2-related factor 2 (Nrf2) was proved to mediate oxidative stress in GIONFH. We aimed to investigate whether &#x3b1;-2&#xa0;M attenuates GIONFH by exerting a dual osteogenic and antioxidant effect through the Akt/Nrf2 signaling pathway. We induced GIONFH model in rats and injected &#x3b1;-2&#xa0;M and Nrf2 inhibitor subsequently. Micro-CT and histology revealed that &#x3b1;-2&#xa0;M treatment prevented methylprednisolone (MPS)-induced bone loss, preserving trabecular structure and reducing empty lacunae. &#x3b1;-2&#xa0;M reversed the MPS-mediated suppression of Akt-Nrf2 pathway, upregulating the expression of heme oxygenase-1 (HO-1) and osteogenic markers. The Nrf2 inhibitor ML385 negated these benefits, confirming that &#x3b1;-2&#xa0;M mitigates GIONFH by upregulating osteogenesis and reducing oxidative stress through the Akt/Nrf2 axis. The results demonstrated that &#x3b1;-2&#xa0;M is a promising target for managing GIONFH.

Aspartame (APM), a widely used sweetener, has been linked to cancers, yet its molecular impact on metabolic dysfunction-associated steatotic liver disease (MASLD) and subsequent hepatocellular carcinoma (HCC) remains undefined. We integrated network toxicology, bulk RNA-seq and docking to map the mechanism. APM targets were retrieved from ChEMBL, STITCH and SwissTargetPrediction. MASLD and HCC RNA-seq data from GEO were used to call differentially expressed genes(DEGs). WGCNA identified disease modules and hub genes. Intersection of APM targets, DEGs and hubs defined core genes for GO/KEGG and PPI analyses. CytoHubba (DMNC, EPC, Degree, MCC), LASSO, RF and SVM-RFE shortlisted key genes, and docking verified APM binding. Twelve genes intersected across APM, MASLD and HCC datasets. Enrichment supports a "dual-track" mechanism: APM-MASLD targets suppress bile-acid export, impair lipid clearance and fuel steatosis; MASLD-HCC targets jointly activate TNF/IL-17 and chemical-carcinogenesis pathways, indicating chronic inflammation bridges steatosis to cancer; APM-HCC targets map to p53, nuclear-receptor and xenobiotic-response networks, revealing APM hijacks receptor signalling to impose proliferative stress that, coupled with p53 loss, drives clonal selection. Machine-learning nominated EGR1 and PTGS2 as top diagnostic genes (AUC&#x2009;>&#x2009;0.7); docking showed high-affinity APM binding (-7.1 and-7.9&#xa0;kcal mol&#x207b;&#xb9;, respectively), identifying them as key relays in APM-induced HCC. EGR1 and PTGS2 are central nodes through which APM precipitates MASLD and accelerates progression to HCC. We propose a "dual-track" oncogenic paradigm: Track A follows the canonical MASLD-HCC axis (bile-acid retention - lipid deposition - TNF/IL-17-driven ROS-mutational amplification), whereas Track B allows APM, via PTGS2/EGR1, to usurp gate-keeper proteins governing proliferation and apoptosis, initiating malignant programming before overt steatosis develops. These findings provide mechanistic insight into APM-related hepatocarcinogenesis, nominate tractable diagnostic biomarkers and therapeutic targets, and inform future re-evaluation of APM carcinogenicity classifications.

Iron deficiency is a highly prevalent nutrient deficiency and the most common cause of anemia. Although iron deficiency exacerbates cardiovascular disease, the direct impact of iron deficiency on the vasculature remains unstudied. We assessed iron levels across the vascular endothelium in mouse and human endothelial cells and found resistance artery endothelial cells have the lowest iron stores, suggesting they may be especially impacted by iron deficiency. Anemia has previously been shown to increase arterial NO signaling in patients, and we have previously shown endothelial a-globin scavenges nitric oxide (NO) in the resistance artery endothelium. We hypothesized iron regulates vascular function through regulation of endothelial a-globin. To test this, we used a mouse model of iron deficiency anemia (IDA). In female mice, IDA increased NO signaling, which was rescued to control levels by repletion of vascular iron with iron dextran. Despite being similarly anemic and having a similar reduction in a-globin protein, there were no changes in NO signaling across groups in male mice. We further measured whether a-globin was in its heme-bound (holo a-globin) or heme-free (apo a-globin) state and found males did not fully lose its functional, heme-bound a-globin. Using endothelial specific a-globin knockout mice, we show loss of endothelial a-globin is necessary for increased NO signaling in IDA and for the rescue of NO signaling by iron dextran in female mice. Altogether, the data presented here demonstrate iron is a determinant of endothelial identity and modulates endothelial NO signaling through the regulation of a-globin.

The fine balance between cellular homeostasis and stress response is crucial for cell survival under conditions of genotoxic stress. Here, we identify a regulatory role for the translation repressor Sbp1 in modulating autophagy during hydroxyurea (HU)-induced replication stress. We observe that Sbp1 localizes to reversible, mRNA-containing cytoplasmic granules specifically upon HU treatment in an RGG motif-dependent manner. Loss of Sbp1 leads to selective translational upregulation of key autophagy genes ATG1, ATG2, and ATG9. Consistent with these translational changes, sbp1&#x2206; cells exhibit increased selective macroautophagy/autophagy and enhanced bulk autophagy, whereas Sbp1 overexpression suppresses both processes. Interestingly, overexpression of Sbp1 shifts DNA repair toward non-homologous end joining (NHEJ) repair, linking altered autophagy to genome maintenance. Together, these findings identify Sbp1 as a negative regulator of autophagy during replication stress and suggest a regulatory axis linking granule-mediated mRNA sequestration, translational control of autophagy factors, and the cellular response to genotoxic stress.Abbreviations: CHX: cycloheximide; CPT: camptothecin; DDR: DNA damage response; GTA: genotoxin-associated targeted autophagy; HR: homologous recombination; HU: hydroxyurea; MMS: methyl methanesulfonate; mRNPs: mRNA-protein complexes; NHEJ: non-homologous end joining; P-bodies: processing bodies; RBPs: RNA binding proteins.

Resistance to 5-fluorouracil (5-FU) remains a major clinical challenge in colorectal cancer (CRC) treatment. This study investigates the non-canonical role of ribonucleotide reductase subunit M1 (RRM1) in regulating autophagy-mediated chemoresistance. A comprehensive multi-omics strategy, including metabolomics, transcriptomics and proteomics analyses, was employed to study 5-fluorouracil-resistant colorectal cancer tissues from patients and matched drug-resistant cell models. Protein-protein interactions, ubiquitination events and functional consequences were validated via complementary assays including Co-IP, GST pull-down, in vivo ubiquitination, structure-guided molecular docking, site-directed mutagenesis, and subcutaneous xenograft mouse models. Structure-based virtual screening was conducted to identify candidate compounds targeting the RRM1-USP19 interaction, with in vivo anti-tumor activity verified in 5-FU-resistant CRC xenografts. RRM1 is significantly downregulated in 5-FU-resistant CRC tissues, and low RRM1 expression correlates with poor clinical prognosis. Mechanistically, RRM1 directly binds USP19 via conserved E647/R648 residues, competitively blocking NEDD4-mediated USP19 K387 ubiquitination and subsequent proteasomal degradation. Loss of RRM1 destabilizes USP19, impairs autophagic substrate deubiquitination, hyperactivates autophagic flux and thereby induces 5-FU resistance. Restoration of RRM1 or expression of the ubiquitination-defective USP19-K387R mutant re-sensitizes resistant CRC cells to 5-FU. The peptide GAGGVGKSAL, identified via virtual screening, specifically disrupts the RRM1-USP19 interface, inhibits excessive autophagy and potently suppresses tumor progression in 5-FU-resistant CRC xenograft models. This study identifies the novel RRM1-USP19-NEDD4 regulatory axis as a core mediator of autophagy-driven 5-FU resistance in CRC, uncovers a non-canonical, metabolism-independent role of RRM1 as a USP19 stabilizer via competitive inhibition of NEDD4-mediated ubiquitination, and validates GAGGVGKSAL as a promising lead compound targeting this axis to reverse 5-FU resistance. The RRM1-USP19-NEDD4 axis represents a novel therapeutic target for overcoming chemoresistance in CRC.