Search Results (208)

Off-grid residential microgrids in tropical regions require storage architectures capable of maintaining renewable electricity supply under variable solar resources, evening demand peaks, and diverse household consumption levels. In PV–battery–hydrogen systems, however, economic indicators can be difficult to interpret when software-reported costs are compared directly with externally calculated LCOE values based on different accounting conventions. This study presents a metric-reconciled techno-economic reconstruction approach for retained PV–battery–hydrogen microgrid configurations serving off-grid residential demand in Chetumal, Mexico. The objective is not to introduce a new global optimization or to claim the universal superiority of a specific architecture, but to separate archived HOMER Pro benchmark outputs from an external techno-economic model (TEM). The TEM reconstructs net present cost, scheduled replacements, salvage treatment, discounted delivered electricity, HOMER-derived LCOE, TEM-derived LCOE, sensitivity indicators, and storage role metrics using declared accounting assumptions. The approach is applied to two representative residential demand scenarios of 16.67 and 53.42 kWh/day. Both retained configurations achieved a 100% renewable fraction with negligible unmet load. Battery discharge increased from 827.12 kWh/year in the low-demand case to 6125.52 kWh/year in the high-demand case, highlighting the increasing role of the battery in short-duration balancing. In contrast, the hydrogen pathway acted as a delayed-backup layer by converting surplus PV electricity into hydrogen and later recovering it through PEM fuel cell generation. The TEM closely matched the HOMER-derived LCOE benchmark, with deviations below 4%, yielding TEM-derived LCOE values of 0.3320 and 0.3571 USD/kWh for the low- and high-demand cases, respectively. Sensitivity analysis showed that delivered electricity, discount rate, PV cost, and battery cost were the main LCOE drivers, while deterministic multi-parameter scenarios confirmed the combined influence of financing, component costs, O&M, PV degradation, and electricity delivered. Overall, the proposed approach provides an auditable basis for metric reconciliation, early-stage technology assessment, and storage role interpretation in tropical off-grid microgrids. Future extensions should include architecture-level re-optimization, flexible loads, degradation-aware modeling, and part-load component behavior. Full article

Kienböck disease, osteonecrosis of the lunate of uncertain aetiology, presents with progressive pain, stiffness, and grip loss in dominant-hand-using adults during their most productive working years, yet its rehabilitation literature has lagged behind its surgical counterpart. This narrative review synthesises current rehabilitation evidence across conservative and post-operative pathways, mapping recommendations to disease stage and to surgical procedure. Following SANRA-aligned methods with selected PRISMA 2020 transparency elements, we appraise immobilisation and orthotic management, dart-throwing-motion-plane mobilisation, sensorimotor retraining, oedema and pain control, psychosocial screening, and procedure-specific protocols that span joint-levelling osteotomy, vascularised bone grafting (including medial femoral trochlea flap), limited intercarpal arthrodeses, proximal row carpectomy, wrist denervation, and salvage arthrodesis or arthroplasty. Patient-reported, performance-based, and occupational outcome instruments are reviewed, with explicit declaration that no Kienböck-validated MCIDs exist. We also set out an integrative reference frame that cross-walks osseous, articular, and tissue-healing axes, offered as clinical orientation rather than as a validated algorithm. The most pressing evidence gaps (Kienböck-specific functional movement screens, sustained return-to-work data, and procedure-specific rehabilitation cohorts) are translated into four registered, powered, COMET-aligned trial proposals. Full article

Pyridoxal 5′-phosphate (PLP), the catalytically active form of vitamin B6, is an enabling cofactor for synthetic biocatalysis, but PLP production remains difficult to compare across chemical, microbial, and cell-free routes. This review reframes PLP synthesis as a biocatalytic cascade-design problem. Chemical phosphorylation is used as a benchmark for selectivity, reagent burden, and purification, whereas de novo and salvage-pathway enzymes define the molecular constraints governing biological production. We focus on PdxK/PdxY, PdxH/PNPOx, PdxS/PdxT, engineered acid phosphatase, and polyphosphate kinase modules. Recent PPi-driven and PPK/polyP-supported cascades show that high PLP concentrations are attainable, but titer alone is not sufficient for route comparison: substrate identity, phosphate-donor equivalents, adenylate loading, whole-cell or cell-free format, oxygen and H₂O₂ management, catalyst reuse, salt burden, isolated recovery, and product purity must be evaluated separately. By distinguishing PN fermentation, intracellular cofactor supply, PNP intermediates, reaction-broth PLP concentration, and isolated PLP yield, this review proposes a route-readiness map for PLP-producing cascades. The most promising next-generation systems will couple product-tolerant phosphorylation, oxidase performance, cofactor regeneration, and downstream stabilization in a single process-aware design. Full article

Acute myeloid leukaemia (AML) exhibits profound metabolic plasticity that enables leukaemic cells to survive environmental stress, nutrient limitation, and therapeutic pressure, ultimately driving disease persistence and relapse. While genetic and epigenetic alterations have guided risk stratification and therapeutic development, accumulating evidence indicates that nutrient-dependent metabolic rewiring represents a critical and targetable vulnerability in AML. Nicotinamide adenine dinucleotide (NAD) is a central metabolic cofactor whose intracellular availability is tightly linked to dietary intake of its precursors, including tryptophan, niacin (vitamin B3), nicotinamide, and nicotinamide riboside. NAD supports redox balance, mitochondrial metabolism, DNA repair, and stress adaptation, processes that are particularly critical for leukaemic stem cell survival under therapeutic stress. Recent studies demonstrate that AML cells, including those resistant to venetoclax- and hypomethylating agent–based regimens, exhibit heightened dependence on the NAD salvage pathway mediated by nicotinamide phosphoribosyltransferase (NAMPT). Pharmacological inhibition of this pathway induces profound NAD depletion, mitochondrial dysfunction, and selective leukaemic cell death. In this review, we integrate nutritional biology with emerging translational evidence to examine NAD metabolism as a nutrient-regulated metabolic vulnerability in AML. We discuss dietary sources and systemic regulation of NAD, the role of NAD-dependent pathways in leukaemic persistence, the translational exploitation of NAD salvage dependency, and the emerging controversy surrounding NAD supplementation in cancer. Finally, we highlight key knowledge gaps and future directions at the interface of nutrition, metabolism, and therapy response in AML. Full article

Alterations in the ceramide (CER) profile have been associated with atopic dermatitis in dogs; however, the specific effects of CER subclasses on canine keratinocytes remain unclear. This study aimed to optimize a CER complex and evaluate its effects on cytokine expression, CER synthesis, and skin barrier formation using canine epidermal keratinocyte progenitor (CPEK) cells and a reconstructed canine epidermis (RCE) model. Among various CER combinations tested, only the mixture of CER [NS] and [EOP] significantly reduced proinflammatory cytokine mRNA levels in Staphylococcus pseudintermedius–stimulated CPEK cells. Further optimization revealed that a 4:1 ratio of CER [NS] to [EOP] (cCER complex) markedly decreased CCL17 and CCL22 mRNA expression while upregulating keratin 10, ceramide synthase 3 (CERS3), and ceramide synthase 4, as well as enzymes involved in both de novo and salvage CER biosynthesis pathways. In the RCE model, cCER administration improved stratum corneum organization and increased the expression of loricrin, CERS3, and CER. In vivo application of cCER in dogs accelerated skin barrier repair and improved hair condition. These findings suggest that a CER [NS]/[EOP] mixture represents a promising therapeutic option with anti-inflammatory and skin barrier-enhancing effects for canine atopic dermatitis. Full article

NAD⁺ depletion is a defining feature of the aging cell, driven by a progressive decline in nicotinamide phosphoribosyltransferase (NAMPT) activity, the rate-limiting enzyme of the NAD⁺ salvage pathway. Pyrroloquinoline quinone (PQQ), a plant-derived redox-active quinone cofactor, elevates intracellular NAD⁺ by a mechanism that remains incompletely understood. We employed an integrated in silico approach combining molecular docking, density functional theory (DFT), and 100 ns molecular dynamics (MD) simulation to evaluate whether PQQ directly targets NAMPT. Docking against the NAMPT crystal structure (PDB: 7ENQ) yielded a binding free energy of −9.4 kcal/mol, with PQQ positioned in the allosteric activation site and forming hydrogen bonds at His191, Asp219, and Val242 together with π–π stacking at Tyr188, extending a known synthetic activator pharmacophore to a dietary ligand class. MM-GBSA analysis yielded binding free energy = −31.2 kcal/mol, confirming dominant electrostatic and van der Waals stabilization. In silico alanine mutagenesis of Tyr188 and Val242 reduced binding affinity to −7.2 and −7.0 kcal/mol respectively, with complete loss of allosteric-site contacts, validating the proposed mechanism computationally. DFT analysis revealed a HOMO–LUMO gap of 3.20 eV and electrophilicity index ω = 8.91 eV, consistent with non-covalent binding to nucleophilic residues. MD simulation confirmed retention of PQQ within the allosteric site over 100 ns. These data provide a structural and electronic framework for the NAD⁺-boosting activity of PQQ and a rationale for experimental validation. Full article

Prostate-specific membrane antigen (PSMA) has become a central molecular target in prostate cancer because it enables both high-performance imaging and targeted radioligand therapy. PSMA positron emission tomography/computed tomography (PET/CT) is now used across several clinical settings, including primary staging of higher-risk localized disease, localization of biochemical recurrence, salvage radiotherapy planning, and assessment of oligometastatic disease. In metastatic castration-resistant prostate cancer, PSMA-targeted radioligand therapy (RLT), particularly lutetium-177-labeled PSMA-617, has established therapeutic value and is moving into earlier disease states. From an applied science perspective, the clinical performance of PSMA theranostics depends not only on target expression and trial efficacy, but also on radiopharmaceutical design, radionuclide selection, radiochemical quality, PET acquisition and reconstruction, standardized reporting, dosimetry, and quantitative response assessment. This narrative review summarizes the biological, radiochemical, and technical foundations of PSMA theranostics, the clinical evidence supporting PSMA PET/CT in key disease states, and the pivotal data for PSMA-targeted RLT. It also discusses imaging-based treatment eligibility, dosimetry, post-therapy imaging, Response Evaluation Criteria in PSMA Imaging, and next-generation beta- and alpha-emitting platforms. PSMA theranostics should be understood as an integrated clinical and technological platform that links molecular imaging, treatment selection, radionuclide delivery, and longitudinal response assessment across the prostate cancer care pathway. Full article

Myocardial ischemia–reperfusion injury (MIRI) represents a major contributor to morbidity and mortality in patients undergoing reperfusion therapy after acute myocardial infarction. Although timely restoration of coronary blood flow is essential for myocardial salvage, reperfusion paradoxically initiates a complex cascade of molecular and cellular events that may aggravate myocardial injury. Oxidative stress is considered one of the central mechanisms underlying MIRI, primarily through excessive production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), leading to mitochondrial dysfunction, calcium overload, endothelial injury, inflammatory activation, and cardiomyocyte death. This review summarizes the current understanding of the pathophysiological mechanisms involved in oxidative stress-mediated reperfusion injury, with emphasis on mitochondrial permeability transition pore opening, inflammasome activation, cytokine release, neutrophil extracellular trap formation, macrophage polarization, and interconnected cell death pathways including PANoptosis. Emerging evidence regarding immunometabolic regulation and epigenetic modulation in MIRI is also discussed. In addition, current pharmacological and non-pharmacological cardioprotective strategies targeting oxidative stress, mitochondrial dysfunction, and inflammatory signaling are reviewed, highlighting both promising experimental findings and the persistent challenges in clinical translation. A deeper understanding of the molecular interplay between oxidative stress and inflammatory pathways may facilitate the development of integrated therapeutic approaches aimed at improving myocardial recovery and long-term cardiovascular outcomes following reperfusion therapy. Full article

Nicotinamide (NAM), a precursor of nicotinamide adenine dinucleotide (NAD⁺), and NAD⁺ are integral to a variety of cellular processes. NAM supplementation has been shown to have benefits for cellular senescence. However, the mechanism by which NAM improves skin photoaging remains unclear. In this study, the multi-omics analysis revealed that insufficient nicotinamide metabolism may be associated with a decrease in NAD⁺ synthesis during skin aging. Importantly, we found that NAM has an ameliorating effect on the skin photoaging in mice. Supplementation with NAM restored the expression of the salvage-pathway enzymes and NAD⁺ consumers. In addition, the supplementation with NAM was shown to restore the expression of skin barrier-related proteins (ZO1 and E-cadherin) and collagen I, while reducing the expression of senescence markers (γ-H2AX, p53, and p21). Furthermore, we found that NAM effectively suppresses the senescence-associated secretory phenotype (SASP) factors’ expression in skin photoaging. Our research reveals the dual role of NAM in attenuating skin photoaging, acting not only to delay cellular senescence but also to suppress the SASP. Full article

Nicotinamide (NAM), the amide form of vitamin B3, has gained increasing attention in dermatology due to its potential role in both skin aging and non-melanoma skin cancer (NMSC) prevention. This review summarizes the biological rationale and current clinical evidence supporting the use of NAM and other NAD⁺ precursors in photoaging and cutaneous carcinogenesis. Chronic ultraviolet exposure induces DNA damage, oxidative stress, inflammation, immune dysregulation, and extracellular matrix remodeling, linking photoaged skin to increased susceptibility to actinic keratoses (AKs), squamous cell carcinoma (SCCs), and basal cell carcinoma (BCCs). Through the NAD⁺ salvage pathway, NAM contributes to the maintenance of intracellular NAD⁺ pools, thereby influencing energy metabolism, DNA repair, mitochondrial function, redox homeostasis, and the activity of NAD⁺-dependent enzymes. Preclinical studies indicate that NAM enhances DNA repair, reduces oxidative stress and inflammatory signaling, supports autophagy and mitophagy, and improves epidermal barrier function and extracellular matrix integrity. Clinically, the strongest evidence for anti-aging effects concerns topical NAM, which consistently improves wrinkles, texture irregularities, pigmentation, and barrier function. Oral NAM has demonstrated chemopreventive activity in high-risk patients with previous NMSC, particularly by reducing the incidence of new SCCs and AKs during active treatment. However, despite a strong mechanistic rationale, current evidence remains heterogeneous, and additional long-term, skin-focused clinical trials are needed to better define efficacy, safety, optimal dosing strategies, and patient selection. Full article

Background/Objectives: Chronic limb-threatening ischemia (CLTI) is the most advanced stage of peripheral arterial disease and is associated with high rates of major amputation and mortality. The angiosome concept has become an important tool for planning targeted revascularization. However, its clinical value may be limited in patients with complex arterial disease, impaired collateral circulation, and microvascular dysfunction. This review explores the relationship between angiosome-guided revascularization and the emerging woundosome concept, which focuses on functional wound perfusion. Methods: A narrative review with a structured literature search was performed using PubMed/MEDLINE, Scopus, and Web of Science. Studies evaluating angiosome-guided revascularization, direct versus indirect revascularization, collateral circulation, pedal arch integrity, and perfusion-related outcomes in CLTI and diabetic foot disease were included. Results: Most observational studies and meta-analyses suggest that direct angiosome-targeted revascularization may improve wound healing and limb salvage in selected patients. However, clinical outcomes are also influenced by collateral circulation, anatomical variability, infra-malleolar perfusion, pedal arch integrity, and microvascular function. The woundosome concept expands the traditional angiosome model by emphasizing effective perfusion of the wound bed through direct arterial inflow, collateral pathways, and functional perfusion assessment. Conclusions: Combining the angiosome and woundosome concepts may provide a more practical and individualized approach to revascularization planning in CLTI by integrating anatomical vascular mapping with functional wound perfusion assessment. Full article

Nicotinamide adenine dinucleotide (NAD⁺) and its reduced form, NADH, are essential coenzymes that play central roles in cellular redox homeostasis, energy metabolism, DNA repair, and signaling. Cellular NAD⁺ levels are maintained by a dynamic balance between the de novo Preiss–Handler, and salvage synthesis pathways, and consumption by enzymes like sirtuins, PARPs, and CD38. Among these, the nicotinamide Phosphoribosyltransferase (NAMPT)-driven salvage pathway represents the predominant route of NAD+ synthesis. The specific regulation of NAD (NAD⁺ and NADH) levels across distinct subcellular compartments has emerged as a critical determinant of cellular function but it remains poorly understood. Dysregulation of NAD metabolism is a hallmark of aging and various pathologies, including cancer, neurodegenerative disorders, and metabolic diseases, making strategies to modulate NAD levels a promising therapeutic frontier. This review provides the first integrated overview of NAD concentrations across cellular compartments (cytosol, mitochondria, nucleus, endoplasmic reticulum, Golgi, peroxisomes, and the extracellular space) together with measurement and modulation strategies. We summarize current knowledge on NAD distribution within organelles, address key challenges in accurate quantification, and highlight established and emerging approaches for both global and compartment-specific analysis. Finally, we discuss therapeutic strategies, from NAD⁺ precursor supplementation to enzyme modulators and gene therapy, highlighting both their translational potential and current limitations in treating diverse diseases and prolonging life and health span. Full article

Trimodality therapy (TMT)—maximal transurethral resection of bladder tumor (TURBT) followed by concurrent chemoradiotherapy—can offer oncologic outcomes comparable to radical cystectomy (RC) in carefully selected muscle-invasive bladder cancer (MIBC) patients while preserving the bladder and, possibly, the quality of life. Systematic reviews and long-term series support durable bladder-intact survival in responders, yet there is still a significant percentage of patients who exhibit incomplete response or invasive intravesical recurrence requiring salvage RC. This review covers computational genomics, transcriptomics, immune contexture, radiogenomics, and digital pathology approaches for predicting response in order to avoid preventable TMT failures. We discuss clinically relevant endpoints (complete response, invasive recurrence, bladder-intact survival, and salvage RC), patient selection (carcinoma in situ, hydronephrosis, debulking feasibility, and histology), and DNA damage response (DDR) biology—highlighting ERCC2 and related pathways as determinants of chemo-radiation sensitivity. We then review reproducible transcriptomic subtype classifiers and immune deconvolution methods, emphasizing translational constraints and reporting standards. Finally, we propose an integrated hypothetical modeling framework (calibration, external validation, and decision-curve thresholds) to guide recommendations for upfront RC versus bladder preservation with intensified surveillance and timely salvage RC. Full article

Heart failure is a leading cause of global morbidity and mortality, often developing as a consequence of acute myocardial infarction. Current management focuses on timely reperfusion via percutaneous coronary intervention. Yet, this approach fails to prevent the molecular cascades that drive the death of viable yet stressed cardiomyocytes within the infarct and peri-infarct zone. Effective antifibrotic therapies remain limited, highlighting a critical gap in current management strategies. This review aims to integrate current understanding of the molecular mechanisms underpinning post-infarct fibrosis and potential interventions for therapeutic development. This emphasis on molecular death signal activation and cell elimination highlights the redundancy of interconnecting fibrosis pathways. Anti-inflammatory and cell-targeted therapies focussing on oxidative stress and haemodynamic load have demonstrated strong preclinical promise. Yet, these approaches have largely failed to translate into clinical benefit. Overall, these limitations emphasise a narrow therapeutic window for intervention. As such, current therapies often fail to preserve metabolically vulnerable myocardium that remains potentially salvageable. Therefore, emerging approaches including RNA-based therapies, cardiac reprogramming, and targeted delivery systems offer new opportunities to improve therapeutic precision. Collectively, these findings support a shift toward early, cell-targeted intervention strategies. This approach aims to prevent progression to heart failure and increases patient quality of life. Full article

Polydeoxyribonucleotide (PDRN) activates the adenosine A2A receptor (A2AR), triggering anti-inflammatory signaling and providing essential nucleotides for the salvage pathway, thereby helping bypass metabolic bottlenecks and promoting tissue repair. Combining PDRN with biochemical agents and physical stimuli represents a significant shift in medical treatment, moving from monotherapy to an integrated, multi-target regenerative approach. These combinatorial strategies effectively address the limitations of PDRN, such as its rapid degradation and diffusion, by simultaneously meeting the structural, metabolic, and signaling needs of injured tissues. The mechanism of action for PDRN involves a synergistic effect with hyaluronic acid, amplification of growth factors (e.g., Platelet-Rich Plasma (PRP), Epidermal Growth Factor (EGF), Platelet-Derived Growth Factor (PDGF)), and enhancements from extracorporeal shockwave therapy (ESWT) and lasers. This results in a notable acceleration of the repair process for chronic wounds, musculoskeletal disorders, and neurological injuries. As intelligent delivery systems like responsive hydrogels and sustainable L-PDRN production continue to advance, these synergistic protocols are poised to redefine global standards of care in regenerative medicine and esthetic dermatology. Future clinical success will hinge on the standardization of sequence-specific protocols and large-scale validation to ensure long-term safety and efficacy. Full article