Search Results (776)

Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), remains one of the most devastating infectious diseases worldwide, with rising multidrug resistance limiting the effectiveness of conventional treatments. Novel therapeutic approaches are urgently needed to complement or replace existing regimens. Among emerging candidates, antimicrobial peptides (AMPs) stand out as versatile molecules capable of exerting direct antimycobacterial effects while also modulating the host immune response. This review explores peptide-based strategies against TB, with a focus on four major axes of innovation. First, we examine host-directed pathways, including the vitamin D–cathelicidin axis and other immunomodulatory mechanisms and their regulatory role in the induction of endogenous AMPs such as cathelicidin LL-37, which contributes to host-directed defense. Second, we discuss peptide-based vaccines designed to elicit robust and durable protective immunity, representing a complementary alternative to classical vaccine approaches. Third, we highlight the synergistic potential of AMPs in combination with first-line and second-line anti-TB drugs, aiming to restore or enhance bactericidal activity against resistant strains. Finally, we analyze technological platforms, including nanocarriers and inhalable formulations, that enable targeted pulmonary delivery, improve peptide stability, and enhance bioavailability. By integrating molecular design, immune modulation, and advanced delivery systems, peptide-based strategies provide a multifaceted approach to overcoming the limitations of current TB therapy. Collectively, these advances position AMPs not only as promising standalone agents but also as key components in combination and host-directed therapies, with strong potential to reshape the future clinical management of tuberculosis. Full article

Infectious diseases remain a global threat, with low- and middle-income countries disproportionately affected due to socio-economic and demographic vulnerabilities. Robust laboratory systems are critical for early detection, outbreak containment, and guiding effective interventions. This study aimed to map and evaluate Jordan’s laboratory diagnostic network for communicable diseases, identify gaps, and recommend strategies to strengthen capacity, harmonization, and alignment with international standards. A multi-method approach was employed in 2023 through collaboration between the Jordan Center for Disease Control and the Health Care Accreditation Council. Data were collected via (i) a desktop review of 226 national and international documents; (ii) 20 key informant interviews with stakeholders from the public, private, military, veterinary, and academic sectors; and (iii) 23 field visits across 27 laboratories in four Jordanian governorates. Data were analyzed thematically and synthesized using the LABNET framework, which outlined ten core laboratory capacities. Findings were validated through a multi-sectoral national workshop with 90 participants. The mapping revealed the absence of a unified national laboratory strategic plan, with governance dispersed across multiple authorities and limited inter-sectoral coordination. Standard operating protocols (SOPs) existed for high-priority diseases such as T.B, HIV, influenza, and COVID-19 but were lacking or outdated for other notifiable diseases, particularly zoonoses. Quality management was inconsistent, with limited participation in external quality assurance programs and minimal accreditation uptake. Biosafety and biosecurity frameworks were fragmented and insufficiently enforced, while workforce shortages, high turnover, and limited specialized training constrained laboratory performance. Despite these challenges, Jordan demonstrated strengths including skilled laboratory staff, established reference centers, and international collaborations, which provide a platform for improvement. Jordan’s laboratory network has foundational strengths but faces systemic challenges in policy coherence, standardization, quality assurance, and workforce capacity. Addressing these gaps requires the development of a national laboratory strategic plan, strengthened legal and regulatory frameworks, enhanced quality management and accreditation, and integrated One Health coordination across human, animal, and environmental health sectors. These measures will improve diagnostic reliability, preparedness, and alignment with the global health security agenda. Full article

The early secreted antigenic target of 6 kDa (ESAT-6), a main effector molecule of the ESX-1 secretion system, is identified as a virulence determinant and immunoregulatory protein of Mycobacterium tuberculosis (Mtb), affecting the interaction between host immune cells and pathogens. ESAT-6 facilitates the survival of mycobacteria and their cell-to-cell spreading through membrane-permeabilizing activity and the regulation of host immune cell functions. In this review, we first summarize the recent knowledge of the roles of ESAT-6 in the survival of bacteria, phagosomal escape, and pathogenicity during Mtb infection. Then, we focused on its complex immunomodulatory effects on different immune cells, such as macrophages, dendritic cells, neutrophils, and T cells, accentuating its capability to either facilitate or inhibit immune responses through different signaling pathways. While our review has summarized its main roles in immunopathology in the context of tuberculosis, we additionally search for emerging evidence indicating that ESAT-6 has anti-inflammatory and immunosuppressive properties. Particularly, we discuss recent preclinical studies showing its capability to suppress transplant rejection and alloimmunity, probably via the induction of regulatory T cells. Nevertheless, the potential clinical use of ESAT-6 remains uncertain and needs further verification by comprehensive preclinical and clinical studies. Thus, we propose that ESAT-6 may be exploited to ameliorate immunopathology in TB infection and to suppress immune-mediated inflammation or transplant rejection as well. Full article

Seasonal temperature variations significantly impact biological wastewater treatment performance, particularly affecting extracellular polymeric substance (EPS) composition and sludge settling characteristics in activated sludge systems. This study investigated the temperature-induced EPS response mechanisms and their effects on nitrogen removal efficiency in a full-scale modified Bardenpho wastewater treatment plant, combined with laboratory-scale evaluation of EPS-optimizing microbial agents for performance enhancement. Nine-month seasonal monitoring revealed that when the wastewater temperature dropped below 15 °C, the total nitrogen (TN) removal efficiency decreased from 86.5% to 80.6%, with a trend of significantly increasing polysaccharides (PS) in dissolved organic matter (DOM) and loosely-bound EPS (LB-EPS) and markedly decreasing tightly-bound EPS (TB-EPS). During the low-temperature periods, when the sludge volume index (SVI) exceeded 150 mL/g, deteriorated settling performance could primarily be attributed to the reduced TB-EPS content and increased LB-EPS accumulation. Microbial community analysis showed that EPS secretion-promoting genera of Trichococcus, Terrimonas, and Defluviimonas increased during the temperature recovery phase rather than initial temperature decline phase. Laboratory-scale experiments demonstrated that EPS-optimizing microbial agents dominated by Mesorhizobium (54.2%) effectively reduced protein (PN) and PS contents in LB-EPS by 70.2% and 54.5%, respectively, while maintaining stable nutrient removal efficiency. These findings provide mechanistic insights into temperature–EPS interactions and offer practical technology for improving winter operation of biological wastewater treatment systems. Full article

Neglected tropical diseases (NTDs) constitute a group of infectious diseases that severely affect the health of impoverished populations, and the health, economies, and health systems of affected countries. Leishmaniasis and human African trypanosomiasis (HAT) are particularly notable, and malaria, despite not being neglected, is part of the “big three” (HIV, tuberculosis, and malaria) with high incidence, increasing the probability of infection by NTDs. Therefore, efforts are ongoing in the search for new drugs targeting the enzyme N-myristoyltransferase (NMT), a potential drug target that has been explored. Thus, we provide a review here that highlights the epidemiological data for these diseases and the importance of discovering new drugs against these agents. Here, the importance of NMT and its inhibitors is clear, with this study highlighting thiochromene, pyrazole, thienopyridine, oxadiazole, benzothiophene, and quinoline scaffolds, identified by computational methods followed by biological assays to validate the findings; for example, this study shows the action of the aminoacylpyrrolidine derivative 13 against Leishmania donovani NMT (IC₅₀ of 1.6 nM) and the pyrazole analog 23 against Plasmodium vivax NMT (IC₅₀ of 9.48 nM), providing several insights that can be used in drug design in further work. Furthermore, the selectivity and improvement in activity are related to interactions with the residues Val⁸¹, Phe⁹⁰, Tyr²¹⁷, Tyr³²⁶, Tyr³⁴⁵, and Met⁴²⁰ for leishmaniasis (LmNMT); Tyr²¹¹, Leu⁴¹⁰, and Ser³¹⁹ for malaria (PvNMT); and Lys²⁵ and Lys³⁸⁹ for HAT (TbNMT). We hope our work provides valuable insights that research groups worldwide can use to search for innovative drugs to combat these diseases. Full article

Precise remote temperature sensing at the micro- and nanoscale is a growing necessity in modern science and technology. We report a series of luminescent tris-acetylacetonate lanthanide complexes, Ln(acac)₃(H₂O)₂ (Ln = Eu (1Eu), Tb (1Tb), Yb (1Yb)); acac⁻ = acetylacetonate), operating as self-referenced thermometers in the 290–350 K range, both in the solid state and when embedded in hybrid nanoparticles. Among the investigated systems, the Eu³⁺ complex exhibits excellent lifetime-based thermometric performance, achieving a maximum relative sensitivity (S_rmax) of 2.9%·K⁻¹ at 340 K with a temperature uncertainty (δT) as low as 0.02 K and an average temperature uncertainty ($\overline{\delta T}$) of 0.5 K, placing it among the most effective ratiometric lanthanide-based luminescent thermometers reported to date. The Yb³⁺ analog enables intensity-based thermometry in the near-infrared domain with a good sensitivity S_rmax = 0.5%·K⁻¹ at 293 K, δT = 0.5 K at 303 K, and $\overline{\delta T}$ = 1.6 K. These molecular thermometers were further incorporated into the shell of Prussian Blue@SiO₂ core–shell nanoparticles. Among the resulting hybrids, PB@SiO₂-acac/(1Tb/1Eu) (with a Tb/Eu ratio of 2/8) stood out by enabling ratiometric temperature sensing based on the Eu³⁺⁵D₀ → ⁷F₂ lifetime, with satisfactory parameters (S_rmax = 0.9%·K⁻¹, δT = 0.21 K at 303 K, and $\overline{\delta T}$ = 1.1 K). These results highlight the potential of simple coordination complexes and their nanohybrids for advanced luminescent thermometry applications. Full article

TB-840 is a novel RORα agonist being developed by Therasid Bioscience Inc. for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). This first-in-human study evaluated the safety, tolerability, pharmacokinetics, and food effect of single ascending doses of TB-840 in healthy adult volunteers. In the single ascending dose part, 64 participants were randomized to receive TB-840 (12.5–200 mg) or placebo. In the food effect part, 6 participants received a single 200 mg dose under fasted and fed conditions in a crossover design. TB-840 was rapidly absorbed (median T_max 1.7–2.5 h) with a mean half-life of 4.8–9.7 h. Systemic exposure increased dose-proportionally across the studied dose range. A high-fat meal delayed absorption and increased the systemic exposure. TB-840 was well-tolerated, with no serious adverse events reported. These results support the continued development of TB-840 as a potential treatment for MASH. Further studies are warranted to evaluate its efficacy and safety in the target patient population (ClinicalTrials.gov identifier: NCT05045534). Full article

The purpose of this in silico study was to evaluate the main difference of the adhesion strength of direct and semi-direct composite resin restorations in dentin using micro-tensile testing (μTBS) and finite element analysis (FEA). This in silico study employed cohesive zone traction and shear laws to investigate interfacial damage in both restoration groups. Tridimensional finite element models of both restoration specimens were created. A 20 μm thick resin cement layer was created for the semi-direct case. The Clearfil SE Bond 2 adhesive system and the restorative material, Ceram X Spectra ST HV composite resin, were used on both restorations. The numerical bond strength of both restoration techniques was evaluated using two different analysis assumptions. In the first assumption, the numerical analysis procedure included only the non-linear behavior of dentin and the von Mises damage criterion, whereas cohesive zone models were included in the second analysis assumption. The influence of dentin-adhesive cohesive mechanical properties was studied using values reported in the literature, and a sensitivity study helped improve the correlation between experimental and numerical results. The mechanical properties of the composite cohesive zone were defined assuming that the interface strength of dentin and composite follows the values reported by the manufacturer of Spectra ST. Damage initiation and progression were analyzed, and strains and stresses of the cohesive zone models (CZM) were compared with the corresponding perfect bonded models. The experimental µTBS results for the direct restoration strategy showed an adhesive strength of 38.156 ± 10.750 MPa, while the CZM predicted a slightly higher value of 40.4 ± 10.8 MPa. For the indirect restoration strategy, the experimental adhesive strength was 25.449 ± 10.193 MPa, compared to a numerically predicted strength of 28.1 ± 9.3 MPa. Overall, the CZM tends to overestimate the adhesive strength relative to experimental values. The statistical analysis of dentin extension strains for direct (DR) and semi-direct (SR) group models reveals that the SR configuration yields higher strain levels. Hence, these results suggest that, assuming identical dentin properties across both restoration groups, the material configuration in the direct restoration offers better mechanical protection to the dentin. These findings highlight the critical role of incorporating damage mechanics to more accurately characterize stress distribution during tooth rehabilitation. Full article

Objective: This systematic review and meta-analysis aimed to evaluate the effects of moisture control strategies (including wet-bonding techniques, universal adhesives, and etching type) on dentin bonding performance in restorative dentistry. Methods: A comprehensive literature search was conducted across PubMed, Scopus, and Google Scholar, following PRISMA guidelines. Only in vitro and ex vivo studies comparing wet- and dry-bonding protocols, using human dentin substrates, and reporting microtensile bond strength (μTBS) were included. The data were synthesized using a random-effects meta-analysis and the methodological quality was assessed using the MINORS tool. Certainty of evidence was evaluated using the GRADE framework. Results: Nine studies met the inclusion criteria, eight of which were included in this meta-analysis. The moisture control strategies significantly influenced the bonding outcomes, with ethanol and acetone wet bonding yielding higher μTBS and enhanced hybrid layer morphology. The universal adhesives performed effectively under both moist and dry conditions, although their performance varied by the adhesive composition and solvent system. The meta-analysis revealed a statistically significant advantage for hydrated dentin (SMD = +1.20; 95% CI: 0.52 to 1.86; p < 0.001), with the moist and ethanol-treated substrates outperforming the dry and over-wet surfaces. The long-term durability was better preserved with ethanol and acetone pretreatments and the adjunctive use of chlorhexidine. Conclusions: Moisture conditions influence dentin bond strength, but modern universal adhesives show consistent bonding performance across different moisture conditions. Solvent-wet-bonding protocols, particularly with ethanol or acetone, enhance the immediate and long-term performance. While the current evidence is limited by the in vitro designs and heterogeneity, the findings demonstrate protocol flexibility and highlight strategies to optimize adhesion in clinical practice. Future clinical trials are necessary to validate these approaches under real-world conditions. Full article

This study explores the visible-light-driven photolysis of Ferrioxalate complexes for the degradation of Toluidine Blue (TB), a persistent phenothiazine dye, using a 1 L recirculating batch-loop photoreactor. The reactor system incorporated two tubular photochemical units (35 cm × 3 cm each) in series: the first equipped with an immersed blue fluorescent lamp (12 W, 30 cm-tube), and the second with dual external blue LED lamps (18 W total, 30 cm) encasing a double-walled glass cell. Continuous flow between the units was maintained via a peristaltic pump. Experimental investigations were used to evaluate the effects of key parameters such as Fe(III) and oxalate concentrations, initial TB load, pH, light source, flow rate, ligand type, dissolved gas type, external H₂O₂ addition, and the presence of various inorganic ions. The results demonstrate efficient dye degradation, with ~75% TB removal within 1 h under combined fluorescent and LED irradiation, where each reactor contributing comparably. The optimal performance was achieved at pH 4, with a 10 oxalate-to-Fe(III) molar ratio (1 mM:0.1 mM) and a flow rate of 25 mL s⁻¹. Among various ligands tested (oxalate, acetate, citrate, EDTA), oxalate proved to be the most effective. The presence and type of anions significantly influenced degradation efficiency due to their potential scavenging effects. Although the process achieved high dye removal, TOC analysis indicated only moderate mineralization, suggesting the accumulation of non-colored intermediates. External H₂O₂ addition moderately improved TOC removal, likely due to enhanced hydroxyl radical generation via the Fenton mechanism. These findings highlight the promise of Ferrioxalate-based photochemical systems under visible light for dye removal, while also emphasizing the need for further research into by-product identification, mineralization enhancement, and toxicity reduction to ensure safe effluent discharge. Full article

Parasitic infections, such as those caused by the myxozoans Myxobolus cerebralis and Tetracapsuloides bryosalmonae, pose major threats to wild and farmed salmonids due to severe tissue damage and impairment of the host immune system. While individual infections have been studied, limited information is available on the host response during co-infection. This study investigated the transcriptomic immune response of rainbow trout (Oncorhynchus mykiss) during single and sequential co-infections with M. cerebralis and T. bryosalmonae using RNA-seq. Trout were exposed to single infections (Mc or Tb) followed by co-infections (Mc⁺ or Tb⁺). Fish were sampled at 31 days post-single infection (1 day post-co-infection). RNA from gill and caudal fin (portal of parasite entry) was sequenced, followed by differentially expressed genes (DEGs) identification and GO and KEGG enrichment. In the caudal fin, Mc⁺ (1 day after co-infection with T. bryosalomne) fish showed mild immune activation with C4B upregulation, while Tb⁺ fish exhibited a stronger response involving IFI44, ISG15, RSAD2, and TLR7 signaling. In gills, Mc⁺ fish showed moderate cytokine-related gene upregulation, while Tb⁺ (1 day after co-infection with M. cerebralis) fish displayed increased expression of humoral response genes (C3, immunoglobulin pathways) but suppression of genes involved in B cell development. These results indicate that the order of infection shapes the outcome of the host immune response, offering candidate targets at the host–pathogen interface. Full article

Osteoporosis compromises bone quality and impairs implant osseointegration. Since an adequate bone bed is essential for implant stability and success, this study evaluated the effects of implant surface functionalization with zoledronic acid (ZOL), alone or combined with ruterpy (TERPY), on peri-implant bone healing in healthy (SHAM) and osteoporotic (OVX) rats. ZOL has antiresorptive properties, while TERPY exhibits osteoinductive potential. The hypothesis was that ZOL + TERPY would act synergistically by inhibiting bone resorption and promoting new bone formation. Sixty-six female Wistar rats (3 months old) were divided into six groups (n = 11) according to systemic condition (SHAM or OVX) and implant type: conventional (CONV), ZOL, or ZOL + TERPY. Surgeries (sham or bilateral ovariectomy) were performed on day 0, and implants were placed in the tibial metaphysis on day 90. Fluorochromes were administered on days 104 (calcein) and 114 (alizarin), and euthanasia was performed on day 118. Samples were analyzed histologically via confocal microscopy and micro-computed tomography (Micro-CT). The ZOL + TERPY groups demonstrated significantly accelerated peri-implant bone repair, showing greater bone formation and organization; improved BV/TV, Tb.N, and I.S.; and reduced Tb.Sp and Po.Tot compared to CONV and ZOL-alone groups. In conclusion, ZOL + TERPY enhances and speeds bone healing, even under osteoporotic conditions. Full article

Current agentic AI frameworks such as LangGraph and AutoGen simulate autonomy via sequential prompt chaining but lack true multi-agent coordination architectures. These systems conflate semantic reasoning with orchestration, requiring LLMs at every coordination step and limiting scalability. By contrast, TB-CSPN (Topic-Based Communication Space Petri Net) is a hybrid formal architecture that fundamentally separates semantic processing from coordination logic. Unlike traditional Petri net applications, where the entire system state is encoded within the network structure, TB-CSPN uses Petri nets exclusively for coordination workflow modeling, letting communication and interaction between agents drive semantically rich, topic-based representations. At the same time, unlike first-generation agentic frameworks, here LLMs are confined to topic extraction, with business logic coordination implemented by structured token communication. This hybrid architectural separation preserves human strategic oversight (as supervisors) while delegating consultant and worker roles to LLMs and specialized AI agents, avoiding the state-space explosion typical of monolithic formal systems. Our empirical evaluation shows that TB-CSPN achieves 62.5% faster processing, 66.7% fewer LLM API calls, and 167% higher throughput compared to LangGraph-style orchestration, without sacrificing reliability. Scaling experiments with 10–100 agents reveal sub-linear memory growth (10× efficiency improvement), directly contradicting traditional Petri Net scalability concerns through our semantic-coordination-based architectural separation. These performance gains arise from the hybrid design, where coordination patterns remain constant while semantic spaces scale independently. TB-CSPN demonstrates that efficient agentic AI emerges not by over-relying on modern AI components but by embedding them strategically within a hybrid architecture that combines formal coordination guarantees with semantic flexibility. Our implementation and evaluation methodology are openly available, inviting community validation and extension of these principles. Full article

Modern cloud-based Internet of Things (IoT) infrastructures face increasingly sophisticated and diverse cyber threats that challenge traditional detection systems in terms of scalability, adaptability, and explainability. In this paper, we present (H-DIR)², a hybrid entropy-based framework designed to detect and mitigate anomalies in large-scale heterogeneous networks. The framework combines Shannon entropy analysis with Associated Random Neural Networks (ARNNs) and integrates semantic reasoning through RDF/SPARQL, all embedded within a distributed Apache Spark 3.5.0 pipeline. We validate (H-DIR)² across three critical attack scenarios—SYN Flood (TCP), DAO-DIO (RPL), and NTP amplification (UDP)—using real-world datasets. The system achieves a mean detection latency of 247 ms and an AUC of 0.978 for SYN floods. For DAO-DIO manipulations, it increases the packet delivery ratio from 81.2% to 96.4% (p < 0.01), and for NTP amplification, it reduces the peak load by 88%. The framework achieves vertical scalability across millions of endpoints and horizontal scalability on datasets exceeding 10 TB. All code, datasets, and Docker images are provided to ensure full reproducibility. By coupling adaptive neural inference with semantic explainability, (H-DIR)² offers a transparent and scalable solution for cloud–IoT cybersecurity, establishing a robust baseline for future developments in edge-aware and zero-day threat detection. Full article

Metal ions, including Mg(II), Ca(II), Sr(II), Co(II), Ni(II), Cu(II), Nd(III), Eu(III), and Tb(III), were investigated in binary systems alongside ampicillin at molar ratios of 1:1 and 1:2. These investigations were carried out in aqueous solutions, and the formation of complexes was verified through meticulous computational analysis. Detailed stability constants for the formed complexes and equilibrium constants for the involved reactions were meticulously determined. Furthermore, a comprehensive examination of the impact of ligand concentration on the configuration of the central metal atom’s coordination sphere was conducted. This investigation was complemented by spectroscopic measurements, which effectively confirmed the observed changes in the coordination sphere of the metal ions. Full article