Search Results (1,178)

Background: There is growing interest in the potential role of manganese (Mn) in the development of Alzheimer’s Disease and related dementias (ADRD). Methods: In this nested pilot study of a ferroalloy worker cohort, we investigated the impact of chronic occupational Mn exposure on cognitive function through β-amyloid (Aβ) deposition and multi-omics profiling. We evaluated six male Mn-exposed workers (median age 63, exposure duration 31 years) and five historical controls (median age: 60 years), all of whom had undergone brain PET scans. Exposed individuals showed significantly higher Aβ deposition in exposed individuals (p < 0.05). The average annual cumulative respirable Mn was 329.23 ± 516.39 µg/m³ (geometric mean 118.59), and plasma Mn levels were significantly elevated in the exposed group (0.704 ± 0.2 ng/mL) compared to controls (0.397 ± 0.18 in controls). Results: LC-MS/MS-based pathway analyses revealed disruptions in olfactory signaling, mitochondrial fatty acid β-oxidation, biogenic amine synthesis, transmembrane transport, and choline metabolism. Simoa analysis showed notable alterations in ADRD-related plasma biomarkers. Protein microarray revealed significant differences (p < 0.05) in antibodies targeting neuronal and autoimmune proteins, including Aβ (25–35), GFAP, serotonin, NOVA1, and Siglec-1/CD169. Conclusion: These findings suggest Mn exposure is associated with neurodegenerative biomarker alterations and disrupted biological pathways relevant to cognitive decline. Full article

Background/Objectives: Gastrin-releasing peptide receptor (GRPR) is overexpressed in breast cancer and might be used as a theranostics target. The expression of GRPR strongly correlates with estrogen receptor (ER) expression. Visualization of GRPR-expressing breast tumors might help to select the optimal treatment. Developing GRPR-specific probes for SPECT would permit imaging-guided therapy in regions with restricted access to PET facilities. In this first-in-human study, we evaluated the safety, biodistribution, and dosimetry of the [^99mTc]Tc-DB8 GRPR-antagonistic peptide. We also addressed the important issue of finding the optimal injected peptide mass. Methods: Fifteen female patients with ER-positive primary breast cancer were enrolled and divided into three cohorts receiving [^99mTc]Tc-DB8 (corresponding to three distinct doses of 40, 80, or 120 µg DB8) comprising five patients each. Additionally, four patients with ER-negative primary tumors were injected with 80 µg [^99mTc]Tc-DB8. The injected activity was 360 ± 70 MBq. Planar scintigraphy was performed after 2, 4, 6, and 24 h, and SPECT/CT scans followed planar imaging 2, 4, and 6 h after injection. Results: No adverse events were associated with [^99mTc]Tc-DB8 injections. The effective dose was 0.009–0.014 mSv/MBq. Primary tumors and all known lymph node metastases were visualized irrespective of injected peptide mass. The highest uptake in the ER-positive tumors was 2 h after injection of [^99mTc]Tc-DB8 at a 80 µg DB8 dose (SUV_max 5.3 ± 1.2). Injection of [^99mTc]Tc-DB8 with 80 µg DB8 provided significantly (p < 0.01) higher uptake in primary ER-positive breast cancer lesions than injection with 40 µg DB8 (SUV_max 2.0 ± 0.3) or 120 µg (SUV_max 3.2 ± 1.4). Tumor-to-contralateral breast ratio after injection of 80 μg was also significantly (p < 0.01, ANOVA test) higher than ratios after injection of other peptide masses. The uptake in ER-negative lesions was significantly lower (SUV_max 2.0 ± 0.3) than in ER-positive tumors. Conclusions: Imaging using [^99mTc]Tc-DB8 is safe, tolerable, and associated with low absorbed doses. The tumor uptake is dependent on the injected peptide mass. The injection of an optimal mass (80 µg) provides the highest uptake in ER-positive tumors. At optimal dosing, the uptake was significantly higher in ER-positive than in ER-negative lesions. Full article

Fe³⁺-incorporated hydrogels are particularly valuable for wearable devices due to their tunable mechanical properties and ionic conductivity. However, conventional immersion-based fabrication fundamentally limits hydrogel performance because of heterogeneous ion distribution, ionic leaching, and scalability limitations. To overcome these challenges, we report a novel one-pot strategy where controlled amounts of Fe³⁺ are directly added to polyacrylamide-sodium acrylate (PAM-SA) precursor solutions, ensuring homogeneous ion distribution. Combining this with Photoinduced Electron/Energy Transfer Reversible Addition–Fragmentation Chain Transfer (PET-RAFT) polymerization enables efficient hydrogel fabrication under open-vessel conditions, improving its scalability. Fe³⁺ concentration achieves unprecedented modulation of mechanical properties: Young’s modulus (10 to 150 kPa), toughness (0.26 to 2.3 MJ/m³), and strain at break (800% to 2500%). The hydrogels also exhibit excellent compressibility (90% strain recovery), energy dissipation (>90% dissipation efficiency at optimal Fe³⁺ levels), and universal adhesion to diverse surfaces (plastic, metal, PTFE, and cardboard). Finally, these Fe³⁺-incorporated hydrogels demonstrated high effectiveness as strain sensors for monitoring finger/elbow movements, with gauge factors dependent on composition. This work provides a scalable, oxygen-tolerant route to tunable hydrogels for advanced wearable devices. Full article

Research on human–animal relationships suggests that close bonds with animals can enhance empathy, reduce speciesism, and improve human physical and psychological health. This study investigated whether pet ownership—particularly attachment to a companion animal during childhood—is associated with differences in moral concerns toward all animals in adulthood. It also aimed to explore the potential effects of empathy and speciesism on overall moral concerns toward animals. Using self-report questionnaires among 72 participants recruited online, the analyses revealed a significant effect of animal categories on moral concerns, F(1, 1.98) = 59.37, p < 0.001. Mean moral concern scores were significantly higher for companion animals (M = 6.04, SD = 1.15) than for food animals (M = 4.90, SD = 1.44), unappealing wild animals (M = 4.20, SD = 1.87), and appealing wild animals (M = 5.73, SD = 1.32), p < 0.05. Additionally, childhood pet owners reported greater moral concerns for all animals, F(1, 1.98) = 4.87, η² = 0.065, p < 0.05. Attachment to a companion animal in childhood was positively correlated with moral concerns for all animal categories. Finally, although attachment and empathy were both positively related to moral concern, only attachment was a significant predictor (p < 0.05). Further research is needed to understand the psychological mechanisms influencing views on animal rights and welfare. Full article

Porcine Rotavirus (PoRV), a predominant causative agent of neonatal diarrhea in piglets, shares substantial genetic homology with human rotavirus and represents a considerable threat to both public health and the global swine industry in the absence of specific antiviral interventions. The VP6 protein, an internal capsid component, is characterized by exceptional sequence conservation and robust immunogenicity, rendering it an ideal candidate for viral genotyping and vaccine development. In the present study, the recombinant plasmid pET28a(+)-VP6 was engineered to facilitate the high-yield expression and purification of the VP6 antigen. BALB/c mice were immunized to generate monoclonal antibodies (mAbs) through hybridoma technology, and the antigenic specificity of the resulting mAbs was stringently validated. Subsequently, a panel of truncated protein constructs was designed to precisely map linear B-cell epitopes, followed by comparative conservation analysis across diverse PoRV strains. Functional validation demonstrated that all three mAbs exhibited high-affinity binding to VP6, with a peak detection titer of 1:3,000,000 and exclusive specificity toward PoRVA. These antibodies effectively recognized representative genotypes such as G3 and X1, while exhibiting no cross-reactivity with unrelated viral pathogens; however, their reactivity against other PoRV serogroups (e.g., types B and C) remains to be further elucidated. Epitope mapping identified two novel linear B-cell epitopes, ¹²⁸YIKNWNLQNR¹³⁷ and ¹³⁸RQRTGFVFHK¹⁴⁷, both displaying strong sequence conservation among circulating PoRV strains. Collectively, these findings provide a rigorous experimental framework for the functional dissection of VP6 and reinforce its potential as a valuable diagnostic and immunoprophylactic target in PoRV control strategies. Full article

The intranasal delivery of exogenous mitochondria is a potential therapy for Parkinson’s disease (PD). The regulatory mechanisms and effectiveness in genetic models remains uncertain, as well as the impact of modulating the mitochondrial permeability transition pore (mPTP) in grafts. Utilizing UQCRC1 (p.Tyr314Ser) knock-in mice, and a cellular model, this study validated the transplantation of mitochondria with or without cyclosporin A (CsA) preloading as a method to treat mitochondrial dysfunction and improve disease progression through intranasal delivery. Liver-derived mitochondria were labeled with bromodeoxyuridine (BrdU), incubated with CsA to inhibit mPTP opening, and were administered weekly via the nasal route to 6-month-old mice for six months. Both treatment groups showed significant locomotor improvements in open-field tests. PET imaging showed increased striatal tracer uptake, indicating enhanced dopamine synthesis capacity. The immunohistochemical analysis revealed increased neuron survival in the dentate gyrus, a higher number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) and striatum (ST), and a thicker granule cell layer. In SN neurons, the function of mitochondrial complex III was reinstated. Additionally, the CsA-accumulated mitochondria reduced more proinflammatory cytokine levels, yet their therapeutic effectiveness was similar to that of unmodified mitochondria. External mitochondria were detected in multiple brain areas through BrdU tracking, showing a 3.6-fold increase in the ST compared to the SN. In the ST, about 47% of TH-positive neurons incorporated exogenous mitochondria compared to 8% in the SN. Notably, GFAP-labeled striatal astrocytes (ASTs) also displayed external mitochondria, while MBP-labeled striatal oligodendrocytes (OLs) did not. On the other hand, fewer ASTs and increased OLs were noted, along with lower S100β levels, indicating reduced reactive gliosis and a more supportive environment for OLs. Intranasally, mitochondrial transplantation showed neuroprotective effects in genetic PD, validating a noninvasive therapeutic approach. This supports mitochondrial recovery and is linked to anti-inflammatory responses and glial modulation. Full article

Background: Rosa L. is an economically significant genus with species that are notable for their rich content of phenolic compounds. Despite its importance, the taxonomy of Rosa remains complex and unresolved. Methods: We sequenced, assembled, and performed comparative analyses of the complete plastomes of four Rosa species: R. acicularis, R. iliensis, R. laxa, and R. spinosissima. In addition to the plastome, we sequenced the nuclear ribosomal internal transcribed spacer (ITS). Results: Plastomes ranged in size from 157,148 bp (R. iliensis) to 157,346 bp (R. laxa). In each plastome, 136 genes were annotated, comprising 90 protein-coding, 38 tRNA, and eight rRNA genes. A total of 905 SSRs were identified, ranging from 224 (R. acicularis) to 229 in R. spinosissima. Nine highly variable regions were detected, including two coding genes (rps16 and ycf1) and seven intergenic spacers (ycf3-trnS(GGA), trnT(UGU)-trnL(UAA), rpl14-rpl16, trnR(UCU)-atpA, trnD(GUC), trnG(UCC)-trnfM(CAU), and psbE-petL). Maximum Likelihood (ML) phylogenetic analyses based on the complete plastome and ycf1 gene datasets consistently resolved the Rosa species into three major clades, with strong bootstrap support. In contrast, the ML tree based on ITS resolved species into four clades but showed lower bootstrap values, indicating reduced resolution compared to plastid datasets. Conclusions: Our findings underscore the value of plastome data in resolving phylogenetic relationships within the genus Rosa. Full article

The fibrillary aggregation of α-synuclein is a hallmark of Parkinson’s disease (PD) and a potential target for diagnostics and therapeutics. Although substantial effort has been devoted to the development of positron emission tomography (PET) probes for detecting α-synuclein aggregates, no clinically suitable tracer has been reported. The design and synthesis of 43 new N-(6-methoxypyridin-3-yl)quinolin-2-amine derivatives and an evaluation of their α-synuclein binding affinity is reported here. Compounds 7f, 7j, and 8i exhibited high affinity for α-synuclein and were selected for ¹¹C, ¹⁸F, ¹²⁵I, or ³H radiolabeling. A photoaffinity variant, TZ-CLX, structurally related to 7j and 8i, demonstrated preferential binding to the C-terminal region of α-synuclein fibrils. PET brain imaging studies using [¹¹C]7f, [¹⁸F]7j, and [¹¹C]8i in non-human primates indicated that these three α-synuclein PET tracers penetrated the blood–brain barrier. Both [¹¹C]7f and [¹⁸F]7j showed more favorable brain washout pharmacokinetics than [¹¹C]8i. In vitro binding assays showed that [¹²⁵I]8i is a very potent α-synuclein radioligand, with K_d values of 5 nM for both PD brain tissues and LBD-amplified fibrils; it is also selective for PD tissues versus AD or control tissues. These results strongly suggest that the PET probes based on the N-(6-methoxypyridin-3-yl)quinoline-2-amine scaffold have potential utility in detecting α-synuclein aggregates in vivo. Full article

Infections caused by oxacillin-resistant Staphylococcus pseudintermedius are increasingly common in veterinary medicine. The indiscriminate use of antibiotics by pet owners worsens this problem, reducing treatment efficacy and creating the need for alternative therapies. This study aimed to evaluate the inhibitory effect of clove essential oil (Syzygium aromaticum) on both oxacillin-resistant and susceptible S. pseudintermedius. Thirty-five isolates from dogs with otitis externa were analyzed. The bacteria were identified by phenotypic tests and tested for susceptibility to 22 antibiotics using disk diffusion. Resistance genes (mecA and blaZ) were detected using conventional PCR. Among the isolates, 34.28% (12/35) were positive for mecA, and 97.14% (34/35) for blaZ. The essential oil’s efficacy was assessed using broth microdilution to determine its minimum inhibitory concentration (MIC). Clove oil showed an average MIC and minimum bactericidal concentration (MBC) of 6.4 mg/mL, inhibiting both resistant and susceptible isolates. In conclusion, clove essential oil demonstrated in vitro antimicrobial activity against S. pseudintermedius. Full article

Background/Objective: Programmed cell death ligand-1 (PD-L1), which is overexpressed in certain tumors, inhibits the body’s natural immune response by providing an “off” signal that enables cancer cells to evade the immune system. It has been demonstrated that [¹⁷⁷Lu]Lu-DOTA-iPD-L1 (PD-L1 inhibitor cyclic peptide) promotes immune responses. This study aimed to synthesize and evaluate [¹⁸F]AlF-NOTA-iPD-L1 as a novel radiotracer for PD-L1 positron emission tomography (PET) imaging and as a potential theranostic pair for [¹⁷⁷Lu]Lu-DOTA-iPD-L1. Methods: The NOTA-iPD-L1 peptide conjugate was synthesized and characterized by U.V.-vis, I.R.-FT, and UPLC-mass spectroscopies. Radiolabeling was performed using [¹⁸F]AlF as the precursor, and the radiochemical purity (HPLC), partition coefficient, and serum stability were assessed. Cellular uptake and internalization (in 4T1 triple-negative breast cancer cells), binding competition, immunofluorescence, and Western blot assays were applied for the radiotracer in vitro characterization. Biodistribution in mice bearing 4T1 tumors was performed, and molecular imaging (Cerenkov images) of [¹⁸F]AlF-NOTA-iPD-L1 and [¹⁷⁷Lu]Lu-DOTA-iPD-L1 in the same mouse was obtained. Results: [¹⁸F]AlF-NOTA-iPD-L1 was prepared with a radiochemical purity greater than 97%, and it demonstrated high in vitro and in vivo stability, as well as specific recognition by the PD-L1 protein (IC₅₀ = 9.27 ± 2.69 nM). Biodistribution studies indicated a tumor uptake of 6.4% ± 0.9% ID/g at 1-hour post-administration, and Cerenkov images showed a high tumor uptake of both [¹⁸F]AlF-NOTA-iPD-L1 and ¹⁷⁷Lu-iPD-L1 in the same mouse. Conclusions: These results warrant further studies to evaluate the clinical usefulness of [¹⁸F]AlF-NOTA-iPD-L1/[¹⁷⁷Lu]Lu-DOTA-iPD-L1 as a radiotheranostic pair in combination with anti-PD-L1/PD1 immunotherapy. Full article

Background: This Phase 2 trial evaluated the efficacy, tolerability, and safety of [¹⁷⁷Lu]Lu-PSMA-617 (¹⁷⁷Lu-PSMA-617) in patients with ≥1 measurable lesion and progressive prostate-specific membrane antigen-positive (PSMA+) metastatic castration-resistant prostate cancer (mCRPC) in Japan. Methods: This study comprises four parts; data from three parts are presented here. Part 1 evaluated safety and tolerability; Parts 2 (post-taxane) and 3 (pre-taxane/taxane-naive) assessed the overall response rate (ORR; primary endpoint), overall survival (OS), radiographic progression-free survival (rPFS), disease control rate (DCR), PFS, and safety; and Part 4 is the expansion part. Patients received 7.4 GBq (±10%) ¹⁷⁷Lu-PSMA-617 Q6W for up to six cycles. Results: Of the 35 patients who underwent a [⁶⁸Ga]Ga-PSMA-11 (⁶⁸Ga-PSMA-11) PET/CT scan, 30 received ¹⁷⁷Lu-PSMA-617 (post-taxane, n = 12; pre-taxane, n = 18). No dose-limiting toxicity was noted in Part 1 (n = 3). Post- and pre-taxane patients had a median of three and five cycles, respectively. The primary endpoint, ORR, met the pre-specified threshold, with the lower limit of the 90% confidence interval (CI) above the threshold of 5% for post-taxane and 12% for pre-taxane. Post- and pre-taxane patients had an ORR of 25.0% (90% CI: 7.2–52.7) and 33.3% (90% CI: 15.6–55.4), respectively. In post- and pre-taxane patients, the DCR was 91.7% and 83.3%, the median rPFS was 3.71 and 12.25 months, and the median PFS was 3.71 and 5.59 months, respectively. The median OS was 14.42 and 12.94 months in post- and pre-taxane patients, respectively. The most common adverse events were constipation, decreased appetite, decreased platelet count, anemia, and nausea. Conclusions: The primary endpoint (ORR) was met. The safety profile of ¹⁷⁷Lu-PSMA-617 was consistent with the VISION and PSMAfore studies, with no new safety signals in the Japanese patients with mCRPC. Full article

This study investigates the effects of substrate flexibility and metal deposition methods on piezoelectric-enhanced Surface-Enhanced Raman Scattering (SERS) in metal-deposited ZnO nanorod (NR) nanocomposites (NCPs). ZnO NRs were grown on both rigid (ITO–glass) and flexible (ITO-PET) substrates, followed by gold (Au) deposition by pulsed-laser-induced photolysis (PLIP) or silver (Ag) deposition by thermal evaporation. Structural analysis revealed that ZnO NRs on flexible substrates exhibited smaller diameters (60–80 nm vs. 80–100 nm on glass), a higher density, and diverse orientations that enhanced piezoelectric responsiveness. Optical characterization showed distinct localized surface plasmon resonance (LSPR) peaks at 420 nm for Ag and 525 nm for Au systems. SERS measurements demonstrated that Ag-ZnO NCPs achieved superior detection limits (10⁻⁹ M R6G) with enhancement factors of 10⁸–10⁹, while Au-ZnO NCPs reached 10⁻⁸ M detection limits. Mechanical bending of flexible substrates induced dramatic signal enhancement (50–100-fold for Au-ZnO/PET and 2–3-fold for Ag-ZnO/PET), directly confirming piezoelectric enhancement mechanisms. This work establishes quantitative structure–property relationships in piezoelectric-enhanced SERS and provides design principles for high-performance flexible sensors. Full article

Background/Objectives: Red bone marrow irradiation is a major concern for patients with advanced prostate cancer undergoing [¹⁷⁷Lu]Lu-PSMA therapy. However, low uptake in the red bone marrow and the presence of bone lesions complicate image-based red bone marrow dosimetry. This study aimed to investigate the general feasibility of image-based red bone marrow activity estimation for [¹⁷⁷Lu]Lu-PSMA treatment and to develop a fully automated workflow for clinical implementation. Methods: In the first part of the study, 175 virtual patient phantoms with realistic ¹⁷⁷Lu activity distributions were generated based on 639 pre-therapeutic [¹⁸F]F-PSMA-1007 PET/CT scans. The SIMIND Monte Carlo tool was used to simulate the ¹⁷⁷Lu SPECT acquisitions (24 h post-injection (p.i.)), which were used to assess the uncertainty of red bone marrow activity estimation. In the second part, red bone marrow self- and cross-absorbed doses were estimated for four therapy cycles of 20 patients. Results: The simulation study shows a significant overestimation of activity in skeletal sites with bone lesions, with median recovery coefficients (RCs) across all phantoms yielding a median of 225% (range: 106–1015%). In contrast, the median RCs were markedly lower in skeletal sites neighboring or distant to lesion-carrying sites (105% [72–163%] and 107% [77–130%], respectively). The median total absorbed dose to the red bone marrow was 20.8 mGy/GBq (range: 5.6–297.9 mGy/GBq). Median blood levels decreased with an increasing median cumulative total absorbed dose. Conclusions: Reliable estimation of activity concentration in skeletal sites without bone lesion infiltration has been shown to be feasible. Based on this finding, an automated workflow for routine image-based red bone marrow dosimetry was developed. Full article

(1) Background: Hemorrhagic fever with renal syndrome (HFRS) remains a prevalent zoonosis in Eurasia. Orthohantavirus puumalaense (PUUV), carried by bank voles (Myodes glareolus), is the principal zoonotic pathogen of HFRS in this region. Despite ongoing efforts to develop effective drugs and vaccines against PUUV, this challenge remains. (2) Aim: In this study, we aimed to express a large quantity of the PUUV recombinant N (rN) protein using E. coli. We also sought to develop a protocol for extracting the rN protein from pellets, solubilizing, and refolding it to restore its native form. This protocol is crucial for producing a large quantity of rN protein to develop vaccines and diagnostic tools for HFRS. (3) Methods; PUUV S segment open reading frame (ORF) coding for N protein was synthesized and cloned into the plasmid vector pET-28 (A+). The ORF was transformed, expressed and induced in BL21(DE3) pLysS E. coli strain. Subsequently, rN protein was purified using immobilized metal affinity and ion chromatography. Immune reactivity of rN protein was tested by employing in house and commercial VektoHanta-IgG kit ELISA methods (both in vitro and in vivo). (4) Results: The best conditions for scaling up the expression of the PUUV rN protein were an incubation temperature of 20 °C during a 20 h incubation period, followed by induction with 0.5 mM IPTG. The most significant protein yield was achieved when the pellets were incubated in denaturing buffer with 8M urea. The highest yield of refolded proteins was attained using non-denaturing buffer (50 mM Tris-HCl) supplemented with arginine. A final 50 μL of PUUV rN protein solution with a concentration of 7 mg/mL was recovered from 1 L of culture. The rN protein elicited an antibody response in vivo and reacted with serum taken from patients with HFRS by ELISA in vitro. (5) Conclusion: Therefore, the orthohantavirus N protein’s ability to elicit immune response in vivo suggests that it can be used to develop vaccines against PUUV after conducting in vitro and in vivo studies to ascertain neutralising antibodies. Full article

Antibiotic overuse has contributed to the emergence of multidrug-resistant (MDR) bacteria, posing a serious public health threat. Pets may act as reservoirs of MDR bacteria, with the potential to transmit these pathogens to humans. This study aimed to identify probiotic alternatives to antibiotics by isolating and evaluating lactic acid bacteria (LAB) from feline milk. In addition to conventional in vitro assessments such as growth kinetics, adhesion ability, safety, and antipathogenic activity, this study also evaluated the antioxidant capacity and production of beneficial metabolites. Three LAB strains were isolated from feline milk, including two strains of Lactobacillus plantarum (M2 and M3) and one strain of Weissella confusa (M1). Resistance assays revealed that strains M2 and M3 exhibited high survival rates under stress conditions, including exposure to bile salts, acidic environments, artificial intestinal and gastric juice. Notably, strain M3 demonstrated strong auto-aggregation ability (73.39%) and high hydrophobicity toward trichloromethane (62.16%). It was also nonhemolytic and susceptible to various β-lactam antibiotics. Furthermore, strain M3 exhibited potent antimicrobial activity in both co-aggregation and Oxford cup assays. Overall, L. plantarum M3 displayed superior probiotic properties, suggesting its potential as an adjunct or alternative to antibiotics in managing MDR bacterial infections in cats. Full article