Search Results (217)

Background: Bone and joint infections (BJIs) are a significant clinical challenge due to their tendency to recur, increased healthcare expenses, reduced quality of life, and mortality. Patients with BJIs are a heterogeneous group due to their different clinical presentations as well as patient-related risk factors. Empiric antibiotic regimens are commonly based on deductions from in vitro microbiologic findings, despite the fact that their relative efficacy and optimal antibiotic choices are underexplored. Methods: This retrospective cohort study included 521 patients surgically treated for BJIs at a specialized orthopedic infection unit between 2016 and 2023. Treatment strategies were guided by the Oral Versus Intravenous Antibiotics for Bone and Joint Infection (OVIVA) trial. All patients received a narrow-spectrum Gram-positive–targeted empiric systemic antibiotic regimen determined according to regional recommendations in collaboration with infectious disease specialists. The primary outcome was clinical failure within one year, with a minimum follow-up of 12 months. For the analyses, the patients were divided into three groups based on microbiological susceptibility: susceptible (SusEmp), non-susceptible (NonSus) and culture-negative (CulNeg) patients. Results: The three groups were found to differ significantly in seven patient-related factors: sex, age at primary operation (OP age), BMI, ASA group, diabetes status, peripheral arterial disease status (PAD), and endocrinopathy status (other than diabetes). In performing multivariate analyses, OP age was found to be independently associated with the overall failure rate (p = 0.04) and ASA group (p = 0.047), and PAD (p = 0.043) was independently associated with the secondary outcome of proximal amputation. Patients with non-susceptible pathogens (NonSus) had more than twice the odds of clinical failure (OR: 2.10; 95% CI: 1.12–3.95) and nearly fivefold higher odds of secondary proximal amputation (OR: 4.95; 95% CI: 1.41–23.2) compared with patients with susceptible pathogens (SusEmp). Conclusions: The current study demonstrates that a large group of patients can presumably be treated safely with a more restrictive narrow approach. More studies are needed to identify subgroups suited for the safe use of a narrow-spectrum empiric regimen, hereby reserving the broad-spectrum antibiotics for patients with the right indications and for whom it would have a positive effect on the clinical outcome. Such an approach would justify a more restrictive stewardship of broad-spectrum antibiotic use without negatively impacting patient outcomes. Full article

While the cerebellar dopaminergic system is suggested to be implicated in neurodevelopmental disorders, especially autism spectrum disorder (ASD), the details of its disturbances remain unclear. We performed a comparative analysis of human (GTEx) and mouse (GSE144046, GSE144277) transcriptomes, complemented by RT-qPCR in DAT-KO rats, to identify dopaminergic gene associations in the normal cerebellum and neurodevelopmental disorder models. Pairwise dopaminergic gene correlations were generally weak, with a slight increase in interaction complexity in ASD models. However, weighted gene co-expression network analysis identified a robust gene module involving Comt, which was consistently associated with synaptic translation across mouse datasets. These associations reflect regulatory processes in the whole cerebellum, which is commonly represented in rodent studies but absent in human data, which are acquired in studies of cerebellar subregions. ASD modeling exerted contrasting effects: Cul3 haploinsufficiency increased the number of genes involved in the module with a decrease in connectivity, while Mbd5 haploinsufficiency led to module collapse. These findings confirm neurodevelopmental disorders as a heterogeneous condition where divergent backgrounds uniquely rewire cerebellar dopaminergic networks. Considering the cerebellum’s role in ASD and that some ASD medications target the dopamine system, further investigation of these identified trends may support the development of more personalized therapeutic approaches. Full article

Nuclear factor erythroid 2-related factor 2 (NRF2) has traditionally been framed as a Kelch-like ECH-associated protein 1 (KEAP1)-regulated stress-response transcription factor, but three observations now require a broader framework: NRF2 turnover is controlled by parallel E3 ligase systems; transcriptional output can be limited by coactivator assembly despite unchanged NRF2 abundance; and NRF2 activation can be beneficial or harmful depending on disease context, as illustrated by lung cancer models in which NRF2 paradoxically promotes metastasis through BTB and CNC homology 1 (BACH1) stabilization. We synthesize these observations into an NRF2 partner-code framework in which NRF2 acts as a context-dependent transcriptional platform assembled through four partly independent modules: a degradation module (KEAP1; β-transducin repeat-containing protein, β-TrCP; HMG-CoA reductase degradation protein 1/synoviolin 1, Hrd1/SYVN1; WD repeat-containing protein 23/DDB1- and CUL4-associated factor 11, WDR23/DCAF11); a cytoplasmic scaffold module (p62/sequestosome 1, p62/SQSTM1; IQ motif-containing GTPase-activating protein 1, IQGAP1; type I phosphatidylinositol 4-phosphate 5-kinase γ/heat shock protein 27, PIPKIγ–HSP27; peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, PIN1; peptidyl-prolyl isomerase A/cyclophilin A, PPIA); a nuclear coactivator module at Neh4/5 (CREB-binding protein/p300, CBP/p300; receptor-associated coactivator 3/steroid receptor coactivator 3, RAC3/SRC-3; protein arginine methyltransferase 1/coactivator-associated arginine methyltransferase 1, PRMT1/CARM1; Mediator complex subunit 16, MED16); and a DNA/chromatin module at Neh1 (small musculoaponeurotic fibrosarcoma [Maf] proteins, BACH1, and chromodomain helicase DNA-binding protein 6, CHD6). Mapping 22 partners onto the Neh-domain architecture identifies approximately 25 pharmacologically addressable interfaces, stratified into four translational tiers. The framework reframes NRF2 pharmacology around one principle: the most actionable target is often a partner rather than NRF2 itself, with disease context dictating the direction of modulation. We close with five testable hypotheses and a partner-code decision matrix linking disease, biomarker, and candidate target. Full article

Biomolecular condensates in the cytoplasm and nucleus contribute to carcinogenesis through aberrant signaling by assorted transcription factors and fusion oncoproteins. Oral cancer, which is highly prevalent worldwide, frequently occurs in a U-shaped “high-risk” zone (floor of mouth, side of tongue, and anterior fauces) which forms the path of liquid transit through the mouth. We previously reported that environmental stresses of saliva-like hypotonicity and beverage-like temperature changes triggered cycles of disassembly/reassembly of biomolecular condensates of GFP-tagged human myxovirus resistance protein (MxA; alias Mx1) in oral cancer cells. In the present study, we identified some of the constituents of GFP-MxA cytoplasmic condensates in oral cells. These condensates were isolated from interferon (IFN)-λ1-treated GFP-MxA expressing OECM1 human oral cancer cells using magnetic bead-based immunoisolation. Unbiased peptide identification confirmed the presence of MxA/Mx1 peptides; however, the strongest intensity was for the BACH1 transcription factor family. Immunofluorescence analyses confirmed the association of BACH1 and the family member Nrf2 with cytoplasmic human GFP-MxA condensates. Moreover, GFP-BACH1 and GFP-Nrf2 colocalized with cytoplasmic human HA-MxA condensates in transiently transfected OECM1 cells. Western blot assays confirmed the presence of BACH1 and Nrf2 proteins in complexes isolated using anti-MxA pAb. As much as BACH1 and Nrf2 regulate oxidative stress response genes, it was remarkable that immunofluorescence assays revealed the presence of heme oxygenase 1 (HO1)—a downstream redox regulator—in GFP-MxA condensates. However, these condensates were devoid of p62, KEAP1 and Cul3. In terms of aberrant function, in live cells, the Nrf2 transcription factor underwent rapid disassembly and reassembly cycles driven by saliva-like hypotonicity, and was also disassembled by sulforaphane. The data highlight the unexpected intersections in oral cells between MxA condensates and BACH1, Nrf2 and HO1—proteins well known to be involved in pathways regulating cellular responses to environmental and oxidative stresses, antiviral defense, oral epithelial dysplasia, and cancer progression and metastases. Full article

Neurodevelopmental disorders (NDDs) are characterized by remarkable phenotypic heterogeneity, in which individuals harboring mutations in the same gene display divergent clinical manifestations, ranging from mild cognitive impairment to severe neurodevelopmental deficits. Advances in neurogenetics and neurogenomics have rapidly expanded the catalog of genes associated with NDDs and have provided unprecedented insight into the genetic architecture of these conditions. However, how identical or similar genetic variants give rise to such diverse phenotypic outcomes remains largely unknown. Ubiquitin-mediated protein regulation is a central mechanism controlling diverse processes essential for neural development, including chromatin regulation, transcriptional dynamics, protein turnover, and synaptic function. Importantly, ubiquitination is a multilayered regulatory process governed by multiple determinants, including the availability of ubiquitination sites on substrates, the activity of ubiquitin ligases, the opposing actions of deubiquitinases, and priming post-translational modifications such as phosphorylation or acetylation. These regulatory layers create a dynamic ubiquitination landscape that may vary across individuals, cell types, developmental stages, and environmental contexts. In this review, we discuss how insights from neurogenetics and neurogenomics can be integrated with knowledge of ubiquitin signaling to better understand the molecular basis of phenotypic heterogeneity in NDDs. We propose that differential ubiquitination represents an important mechanistic framework through which genetic variation is translated into diverse molecular and cellular outcomes. Understanding the interplay between neurogenetic variation and ubiquitin-dependent regulatory networks may provide new perspectives on disease mechanisms and inform future therapeutic strategies for neurodevelopmental disorders. Full article

As sessile organisms, plants must continuously perceive and integrate external environmental cues with internal developmental signals to optimize growth, reproduction, and survival. Central to this adaptive capacity is the ubiquitin-proteasome system (UPS), the primary pathway for selective protein degradation in eukaryotes. Within the UPS, BTB (Broad-Complex, Tramtrack, and Bric-à-brac) proteins serve as critical substrate adaptors for the Cullin3 (CUL3)-based E3 ubiquitin ligase complex. These proteins play indispensable roles in plant growth, development, hormone signaling, and responses to abiotic stresses. Recent advances have revealed the remarkable functional versatility of BTB proteins, implicating them in the regulation of photomorphogenesis, root architecture, flowering time, stress resilience, and yield-related traits. With 80 BTB-encoding genes in Arabidopsis thaliana and key orthologs identified in major crops—including of rice (Oryza sativa), soybean (Glycine max), and maize (Zea mays)—BTB proteins act as molecular “bridges” that integrate developmental programs with environmental stress signals. This review summarizes the structural features, classification, and multifaceted functions of plant BTB proteins, with an emphasis on their roles in growth regulation, abiotic stress tolerance, light signaling, and agricultural productivity. We further discuss their mechanisms in ubiquitin-dependent proteolysis, transcriptional regulation, and signal integration, offering insights into their potential as targets for engineering climate-resilient crops and advancing sustainable agriculture. Full article

Excessive accumulation of copper ions (Cu²⁺) in the environment and biological systems poses severe risks to ecological balance and human health, necessitating accurate detection and monitoring of Cu²⁺. Schiff base derivatives with favorable optical properties provide an efficient strategy for copper ion recognition. In this paper, fluorescent probe L (5-methyl-2-hydroxybenzaldehyde-(7-diethylaminocoumarin-3-formyl) hydrazone) was synthesized through a three-step reaction using 4-diethylaminosalicylaldehyde and diethyl malonate as starting materials. The structure of probe L was confirmed by melting point analysis, infrared spectroscopy, and nuclear magnetic resonance. Single-crystal X-ray analysis revealed that probe L crystallized into a triclinic lattice with space group $P_1^{-}$. Optical investigations, including UV–Vis spectroscopy, fluorescence spectroscopy, and aggregation-induced emission studies, demonstrated highly sensitive and selective fluorescence “turn-off” behavior of probe L towards Cu²⁺ ions in DMSO, with negligible interference from other metal ions. Job’s plot and crystallographic analysis revealed a 1:1 binding stoichiometry between probe L and Cu²⁺, forming the complex [Cu(L)]. Fluorescence titration experiments revealed a binding constant (K_b) of 5.2 × 10⁶ L/mol and a detection limit of 7.8 × 10⁻⁷ mol/L, indicating excellent sensitivity. These results suggest that probe L has considerable promise for Cu²⁺ detection in aqueous environments, with potential applications in environmental monitoring and public health protection. Full article

The transcription factor c-Myc is known to regulate DNA replication via a non-transcriptional mechanism by interacting with proteins of the pre-replicative complex. In addition, c-Myc localizes to DNA replication foci, similarly to Proliferating Cell Nuclear Antigen (PCNA); however, the significance of this localization remains unclear. Here, we investigated whether c-Myc interacts with PCNA and analyzed the possible function of this association. We found a conserved interaction motif, the PCNA-interacting protein (PIP) box, in the N-terminal region of c-Myc. Confocal microscopy analysis showed co-localization with PCNA in early S-phase, but not in late S-phase cells. Co-immunoprecipitation from cell extracts and pull-down of recombinant proteins indicated a direct physical association between c-Myc and PCNA, which was confirmed in situ by the Proximity Ligation Assay (PLA). Further experiments demonstrated that c-Myc interacts with CUL4A and DDB1, components of the Cullin Ring E3 ubiquitin ligase 4 (CRL4) complex, in which PCNA functions as a cofactor. Mutations in the PIP box of c-Myc, as well as depletion of CUL4A by RNA interference, resulted in an increased stability of c-Myc protein. These results suggest that the interaction with PCNA functionally contributes to the regulation of c-Myc stability in early S phase via the CRL4 complex. Full article

(1) Background: Hudson first described the procedure that includes en-block removal of an ovarian tumor fixed in the pelvis with the whole pelvic peritoneum and invaded surrounding structures. However, sometimes pelvic peritonectomy (PP) with or without shaving of the bowel serosa is not enough to achieve complete cytoreduction, and en-block rectosigmoid resection (RR) is necessary. This study aims to investigate the impact of bowel surgery on survival rates and morbidity of patients with advanced ovarian cancer. (2) Methods: We retrospectively analyzed patients with advanced ovarian cancer with cul-de-sac involvement that underwent debulking surgery at the 1st Department of Obstetrics—Gynecology of “Papageorgiou” General Hospital, from 2017–2022. The primary outcomes were the survival rates and morbidity between PP and RR. (3) Results: A total of 93 patients met the inclusion criteria. Patients were categorized into two groups: Group A (34 patients) with RR and Group B (59 patients) with PP. There was no statistically significant difference in the majority of patients’ characteristics and oncological outcomes. On the other hand, patients with RR had a significantly higher surgical complexity score (SCS), peritoneal cancer index (PCI), ICU admission, rate of postoperative complications, longer surgery duration and hospital stay. When comparing the duration of surgery, the RR group has significantly higher operation time during primary compared to interval debulking surgery. Concerning survival rates, there was no significant difference in progression-free (PFS) (p = 0.22) and overall survival (OS) (p = 0.85) between the two groups, while residual disease and postoperative complications were identified as independent prognostic factors for PFS and OS; (4) Conclusions: The modified Hudson procedure with RR is a safe and reproductible technique, but when complete gross resection can be achieved with PP, this technique is preferred in order to avoid increased patient’s morbidity. Full article

Street layout has a significant effect on accessibility and intelligibility, which ultimately affects navigation and movement efficiency. While previous research has examined planned and unplanned street patterns, most studies focus on single-scale analyses or isolated typologies, limiting understanding of how hybrid networks function across multiple spatial levels. Addressing this gap, this study investigates the effects of hybrid planned and organically evolved street layouts on spatial accessibility in Mandalay, Myanmar. The research employs space syntax analysis to assess the citywide, township-level, and micro-scale networks through measures of angular integration, choice, axial connectivity, and intelligibility. Using the Four-Point Star Model to identify Mandalay’s distinct spatial features, a global accessibility assessment compares it to 50 other cities. The results show that grid-based layouts with central townships exhibit the highest integration and connectivity, while organic and fragmented networks, particularly in Amarapura, reduce spatial coherence and accessibility. Micro-scale analysis indicates that hybrid layouts with cul-de-sacs and distorted grids can improve accessibility when they connect effectively with secondary roads. By analysing street networks across multiple spatial scales, this research presents significant implications for efficient accessibility and transport planning in mixed-pattern cities. Full article

CSN2, a highly conserved subunit of the COP9 signalosome (CSN), serves as the primary binding site for Cullin in the CSN complex. This interaction, dependent on lysine residues, positions CSN2 as a key player in approximately 20% of CRL-mediated ubiquitination reactions, a critical regulatory pathway for growth, development, and cellular processes in eukaryotes. While the role of CSN2 in human cells has been partially characterized, its function in rice (OsCSN2) remains poorly understood. Building on our previous findings regarding OsCSN2 function under natural light, this study investigates its regulatory mechanisms in rice seedlings under red and far-red light conditions. We demonstrate that under natural light, OsCSN2 mainly affects rice GA homeostasis by regulating the expression of SLR1 and influences rice photomorphogenesis by regulating the expression of the COP1-HY5 complex, thereby controlling rice growth through two pathways. Unlike under natural light, under red light, OsCSN2 promotes the expression of OsGID1, enhances the interaction between OsGID1 and OsSLR1, and promotes GA accumulation and OsPIL14 expression, leading to rice stem growth and inhibition of coleoptile elongation. Under far-red light, OsCSN2 mainly promotes the expression of OsCOP1, increasing the formation of the COP1-HY5 complex, which inhibits photomorphogenesis and coleoptile elongation. Lysine site mutations in OsCSN2 affect the interaction between the OsCSN complex and CRLs, regulating CRL-mediated ubiquitination reactions, promoting the ubiquitin-mediated degradation of OsSLR1 and OsCOP1, and thus promoting rice growth. These findings not only elucidate the functional roles of OsCSN2 in rice growth regulation but also provide valuable genetic resources for breeding rice varieties with enhanced agronomic traits. Full article

The dysregulation of CK1 isoforms is linked to various types of diseases, including neurodegeneration and different types of neoplasia such as colon, pancreatic, breast, and ovarian cancer. For CK1 isoforms, a plethora of effective small molecule inhibitors are available. However, only a few degraders of CK1α and, more recently, proteolysis targeting chimeras (PROTACs) for CK1δ/CK1ε have been reported. In this study, we applied the PROTAC concept by harnessing molecular modelling to design and synthesize a series of candidate CK1δ-targeting PROTACs based on a highly specific and potent benzothiazole-based CK1δ inhibitor that we previously developed in our lab. In the present study, we established a modular synthetic platform to systematically generate a set of PROTAC degrader candidates consisting of the CK1δ-specific inhibitor scaffold, alkyl and PEG linker motifs with various lengths, and Cereblon (CRBN)-engaging pomalidomide and thalidomide derivatives as E3 ligase binders. We demonstrate that several PROTACs degrade CK1δ/ε in various cells. The most potent PROTAC P1d inhibits the phosphorylation of downstream substrates through CK1δ/ε degradation. We establish the requirement of CUL4A^CRBN and the proteasome for the P1d-mediated degradation of CK1δ/ε. Full article

In Haiti, uncontrolled urbanization is increasing pressure on agricultural landscapes, compromising both their ecological integrity and productivity. This study examines spatio-temporal land-use changes across three agricultural plains, Cul-de-Sac, Maribahoux, and Léogâne, between 1997 and 2024, using Landsat imagery and landscape metrics of composition (percentage of landscape, PLAND) and configuration (largest patch index, LPI). The findings reveal a rapid expansion of built-up areas, primarily at the expense of farmland. In the Cul-de-Sac plain, built-up areas and bare soil grew by 152%, from 41.26 km² to 104.11 km², while agricultural land became highly fragmented (LPI dropping from 94.51% to 57.63%). In Maribahoux, urbanization was more moderate, partly offset by a temporary rise in woody vegetation that peaked at 20.04% in 2022 before declining. The Léogâne plain experienced a 17.38 km² increase in built-up areas and bare soil, alongside a slight decrease in woody vegetation. Population density showed limited differences in Maribahoux and Léogâne, but marked disparities in Cul-de-Sac, where landscape transformation was more pronounced. These findings highlight increasing fragmentation of agricultural landscapes, threatening ecological connectivity and functionality, and stress the urgent need for land-use planning that curbs urban growth, protects farmland, and safeguards biodiversity. Full article

This study reports the development of polyvinylidene fluoride (PVDF) membranes decorated with a copper(II) complex (CuL) for the removal of organic pollutants from wastewater. Using Drimaren Red X-6BN (DRX-6BN) as a probe, the PVDF membrane with the lowest CuL loading (PVDF/PDA/CuL-4) reached an adsorption capacity of 19.78 mg/g at 300 min, with removal of up to 50% DRX-6BN. Kinetic analysis favored Elovich (R² > 0.9928; RMSE < 0.4489) and the pseudo-second-order model (R² > 0.9540; RMSE < 1.1388), consistent with chemisorption. Intraparticle diffusion occurred in two steps. In the presence of 20 mg/L of hydrogen peroxide (H₂O₂), the removal was >80% within 180 min at higher CuL loadings (PVDF/PDA/CuL-40). In oily wastewater, PVDF/PDA/CuL-4 achieved ~100% COD removal in 120 min with H₂O₂, whereas pristine PVDF achieved 38.5%. Storage stability tests demonstrated the preservation of catalytic and separation performance for at least three months. All tests were conducted at pH ≈ 6.0 and a temperature of 25 °C. In contrast to many catalytic membranes, these membranes operate at near-neutral pH and ambient temperature in the absence of radiation. The results highlight PVDF membranes decorated with CuL as a robust and sustainable approach for the treatment of oily effluents, particularly by combining Fenton-like processes under mild conditions. Full article

Autism spectrum disorder (ASD) is a heritable neurodevelopmental condition with a complex genetic architecture. Dissecting the interplay between inherited variants and high-impact de novo variants is critical for understanding its etiology. We conducted a family-based study involving 42 families with ASD (139 individuals). Using a targeted next-generation sequencing (NGS) panel of 236 genes, we identified and characterized rare inherited and de novo variants in affected probands, parents, and unaffected siblings. Our analysis revealed a complex genetic landscape marked by diverse inheritance patterns. De novo variants were predominantly observed in individuals with atypical autism, while biparental (homozygous) inheritance was more common in Asperger syndrome. Maternally inherited variants showed significant enrichment in intronic regions, pointing to a potential regulatory role. We also detected variants in several high-confidence ASD risk genes, including SHANK3, MYT1L, MCPH1, NIPBL, and TSC2, converging on pathways central to synaptic function and neurogenesis. Across the cohort, five variants of uncertain significance (VUS) were identified, comprising two inherited variants in ABCC8 and additional variants in CUL23, TSC2, and MCPH1. Our findings underscore the profound genetic heterogeneity of ASD and suggest that distinct genetic mechanisms and inheritance patterns may contribute to different clinical presentations within the spectrum. This highlights the power of family-based genomic analyses in elucidating the complex interplay of inherited and de novo variants that underlies ASD. Full article