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While young muscle is capable of restoring the original architecture of damaged myofibers, aged muscle displays a markedly reduced regeneration. We show that expression of the “anti-aging” protein, α-Klotho, is up-regulated within young injured muscle as a result of transient Klotho promoter demethylation. However, epigenetic control of the Klotho promoter is lost with aging. Genetic inhibition of α-Klotho in vivo disrupted muscle progenitor cell (MPC) lineage progression and impaired myofiber regeneration, revealing a critical role for α-Klotho in the regenerative cascade. Genetic silencing of Klotho in young MPCs drove mitochondrial DNA (mtDNA) damage and decreased cellular bioenergetics. Conversely, supplementation with α-Klotho restored mtDNA integrity and bioenergetics of aged MPCs to youthful levels in vitro and enhanced functional regeneration of aged muscle in vivo in a temporally-dependent manner. These studies identify a role for α-Klotho in the regulation of MPC mitochondrial function and implicate α-Klotho declines as a driver of impaired muscle regeneration with age. While young muscle faithfully regenerates damaged myofibers, aged muscle is impaired. Here the authors show the “anti-aging” protein α-Klotho is upregulated in young muscle after damage via promoter demethylation and this regulation is lost in aging, resulting in mitochondrial damage and an impaired healing response.

Mitophagy is critical for cell homeostasis. Externalization of the inner mitochondrial membrane phospholipid, cardiolipin (CL), to the surface of the outer mitochondrial membrane (OMM) was identified as a mitophageal signal recognized by the microtubule-associated protein 1 light chain 3. However, the CL-translocating machinery remains unknown. Here we demonstrate that a hexameric intermembrane space protein, NDPK-D (or NM23-H4), binds CL and facilitates its redistribution to the OMM. We found that mitophagy induced by a protonophoric uncoupler, carbonyl cyanide m -chlorophenylhydrazone (CCCP), caused externalization of CL to the surface of mitochondria in murine lung epithelial MLE-12 cells and human cervical adenocarcinoma HeLa cells. RNAi knockdown of endogenous NDPK-D decreased CCCP-induced CL externalization and mitochondrial degradation. A R90D NDPK-D mutant that does not bind CL was inactive in promoting mitophagy. Similarly, rotenone and 6-hydroxydopamine triggered mitophagy in SH-SY5Y cells was also suppressed by knocking down of NDPK-D. In situ proximity ligation assay (PLA) showed that mitophagy-inducing CL-transfer activity of NDPK-D is closely associated with the dynamin-like GTPase OPA1, implicating fission–fusion dynamics in mitophagy regulation.

Background Canine vector-borne diseases (CVBDs) have significant clinical and public health implications. Methods This experimental study used a validated continuous-flow in vitro feeding system (CFIFS) to investigate the speed of transmission (SOT) of three tick-borne pathogens (TBPs): Ehrlichia canis by laboratory-infected Rhipicephalus sanguineus (18.3% infection rate), Anaplasma phagocytophilum by laboratory-infected Ixodes ricinus (56%), and Borrelia burgdorferi sensu stricto (s.s.) by laboratory-infected I. ricinus (76%). Three experiments were conducted, one per pathogen/tick model. A total of 58–60 ticks were used per feeding system. Four to six replicates were obtained per experiment. All ticks were laboratory-reared. The tick infections were performed by feeding the nymphal stages on infected hosts. Results All ticks began to attach and feed 3 h after being introduced to the feeding system. At the maximum attachment, 89.7% of R. sanguineus were attached at 57 h, with 4–30% attachment at 51 h for I. ricinus infected with A. phagocytophilum , and 6.3–47.9% at 48 h for I. ricinus infected with B. burgdorferi s.s. Polymerase chain reaction (PCR) tests were used to detect the presence of pathogens from blood samples collected every 3 h. Swab samples from the inner face of the feeding membrane were also collected and tested every 6 h during the B. burgdorferi s.s. study. In this experimental in vitro design, after the first tick attachments were observed, E. canis exhibited SOT of 3–6 h, A. phagocytophilum of 12–15 h, and B. burgdorferi of 42–45 h in blood but only 3–6 h on inner membrane swabs. Conclusions The findings of this in vitro study highlight the transmission time of some TBPs, confirming previous data obtained in vitro or in vivo, by using the same design for all tick/pathogen models. This is a way to estimate the possibility of using acaricidal drugs to block pathogen transmission based on the SOT and the speed of kill of these compounds. Graphical Abstract

Background Hookworms, specifically Ancylostoma caninum and Uncinaria stenocephala , have a clinical impact on the health of dogs, with A. caninum posing a zoonotic risk worldwide. The studies presented here were conducted to evaluate the efficacy of a novel, oral chewable tablet (Credelio Quattro) containing lotilaner, moxidectin, praziquantel, and pyrantel (as pamoate salt) against fourth-stage larvae (L 4 ), immature adult, and adult A. caninum , as well as adult U. stenocephala , infections in dogs. Methods Nine negatively controlled, masked, randomized laboratory studies evaluated the efficacy and non-interference of the drugs against various stages of A. caninum and U. stenocephala . In addition to one pilot study conducted against L 4 A .  caninum and one study that assessed efficacy in dogs with naturally acquired U. stenocephala , two experimental studies were conducted against each of the target hookworm species and stages. A total of 16–31 dogs comprised each study. With the exception of the study in dogs with naturally acquired U. stenocephala , dogs were experimentally infected with the target parasite and dosed on Day 0 or 4 with placebo tablets, Credelio Quattro tablets (or components of Credelio Quattro formulation for the pilot study), or individual actives, moxidectin or pyrantel, in the specific studies designed to assess interference. Efficacy was evaluated by comparing the number of worms recovered at necropsy 5–10 days post-treatment between the treated and control groups. Results All dogs tolerated Credelio Quattro well. Efficacy of Credelio Quattro was ≥ 99.0% against L 4 A. caninum , ≥ 99.8% against immature adult A. caninum , ≥ 99.9% against adult A. caninum , and ≥ 99.6% against adult U. stenocephala. Additionally, treatment with Credelio Quattro provided a ≥ 99.9% reduction in fecal egg counts 10 days post-treatment. Conclusions Credelio Quattro, a novel oral chewable tablet administered at the minimum effective dosages of 20 mg/kg lotilaner, 0.02 mg/kg moxidectin, 5.0 mg/kg praziquantel, and 5.0 mg/kg pyrantel (as pamoate salt), was safe and effective for the treatment and control of L 4 , immature adult, and adult stages of A. caninum and adult U. stenocephala in dogs. Graphical Abstract

Fibrosis is a chronic disease with heterogeneous clinical presentation, rate of progression, and occurrence of comorbidities. Systemic sclerosis (scleroderma, SSc) is a rare rheumatic autoimmune disease that encompasses several aspects of fibrosis, including highly variable fibrotic manifestation and rate of progression. The development of effective treatments is limited by these variabilities. The fibrotic response is characterized by both chronic inflammation and extracellular remodeling. Therefore, there is a need for improved understanding of which inflammation-related genes contribute to the ongoing turnover of extracellular matrix that accompanies disease. We have developed a multi-tiered method using Naïve Bayes modeling that is capable of predicting level of disease and clinical assessment of patients based on expression of a curated 60-gene panel that profiles inflammation and extracellular matrix production in the fibrotic disease state. Our novel modeling design, incorporating global and parametric-based methods, was highly accurate in distinguishing between severity groups, highlighting the importance of these genes in disease. We refined this gene set to a 12-gene index that can accurately identify SSc patient disease state subsets and informs knowledge of the central regulatory pathways in disease progression.

Recognition of injured mitochondria for degradation by macroautophagy is essential for cellular health, but the mechanisms remain poorly understood. Cardiolipin is an inner mitochondrial membrane phospholipid. We found that rotenone, staurosporine, 6-hydroxydopamine and other pro-mitophagy stimuli caused externalization of cardiolipin to the mitochondrial surface in primary cortical neurons and SH-SY5Y cells. RNAi knockdown of cardiolipin synthase or of phospholipid scramblase-3, which transports cardiolipin to the outer mitochondrial membrane, decreased the delivery of mitochondria to autophagosomes. Furthermore, we found that the autophagy protein microtubule-associated-protein-1 light chain 3 (LC3), which mediates both autophagosome formation and cargo recognition, contains cardiolipin-binding sites important for the engulfment of mitochondria by the autophagic system. Mutation of LC3 residues predicted as cardiolipin-interaction sites by computational modelling inhibited its participation in mitophagy. These data indicate that redistribution of cardiolipin serves as an ‘eat-me’ signal for the elimination of damaged mitochondria from neuronal cells. How injured mitochondria are targeted for autophagic degradation is not well understood. Chu and colleagues find that pro-mitophagy stimuli induce externalization of cardiolipin to the outer mitochondrial membrane of neuronal cells, and find that this is required for binding of the autophagy protein LC3 to mitochondria and mitophagy.

In canine leishmaniosis endemic areas, Leishmania infantum may occur in sympatry with the non-pathogenic Leishmania tarentolae , which is associated to reptiles. The potential infectivity of L . tarentolae for mammals raises questions about the interactions between the two Leishmania species, and the potential cross-immune protection in dogs. This study aimed to assess the outcome of experimental L . tarentolae infection in dogs, determining: i) the anti- L . tarentolae antibody production, ii) the duration of the immunity and cytokine expression, and iii) the possible pathogenic effect in the canine host. Twelve purpose-bred beagle dogs were randomly allocated to three groups (intravenous inoculation, G1; intradermal inoculation, G2; negative control, G3). G1 and G2 dogs were inoculated twice (day 0, day 28) with 10 8 promastigotes of L . tarentolae strain (RTAR/IT/21/RI-325) isolated from a Tarentola mauritanica gecko. The animals were followed until day 206. Blood, serum, conjunctival swabs and lymph node aspirate samples were collected monthly and bone marrow, liver and spleen biopsies on day 91. Hematological and biochemical parameters were assessed monthly, as well as serology (IFAT and ELISA) and molecular identification of L . tarentolae . Mononuclear cells (PBMC) were obtained to assess the cytokine expression through in vitro stimulation or (re-) infection. Data from this study demonstrated that DNA from L . tarentolae is detectable up to 3 months post-infection, with seroconversion after day 28. Moreover, the non-pathogenic nature of L . tarentolae was confirmed, with a neutral Th1/Th2 polarization, and a possible shift to Th1 phenotype after derived macrophages (re-) infection, as demonstrated by the expression of IFN-gamma. Therefore, L . tarentolae demonstrated a great potential as a surrogate pathogen and/or immune-prophylaxis/immune-therapy against Leishmania infections in dogs and humans.

Maintaining software once implemented on the end-user side is laborious and, over its lifetime, is most often considerably more expensive than the initial software development. The prediction of software maintainability has emerged as an important research topic to address industry expectations for reducing costs, in particular, maintenance costs. Researchers and practitioners have been working on proposing and identifying a variety of techniques ranging from statistical to machine learning (ML) for better prediction of software maintainability. This review has been carried out to analyze the empirical evidence on the accuracy of software product maintainability prediction (SPMP) using ML techniques. This paper analyzes and discusses the findings of 77 selected studies published from 2000 to 2018 according to the following criteria: maintainability prediction techniques, validation methods, accuracy criteria, overall accuracy of ML techniques, and the techniques offering the best performance. The review process followed the well-known systematic review process. The results show that ML techniques are frequently used in predicting maintainability. In particular, artificial neural network (ANN), support vector machine/regression (SVM/R), regression & decision trees (DT), and fuzzy & neuro fuzzy (FNF) techniques are more accurate in terms of PRED and MMRE. The N-fold and leave-one-out cross-validation methods, and the MMRE and PRED accuracy criteria are frequently used in empirical studies. In general, ML techniques outperformed non-machine learning techniques, e.g., regression analysis (RA) techniques, while FNF outperformed SVM/R, DT, and ANN in most experiments. However, while many techniques were reported superior, no specific one can be identified as the best.

In recent years, several researchers have investigated the challenges of accessibility in e-government portals and have contributed to many proposals for improvements. However, no comprehensive review has been conducted on this topic. This study aimed to survey and synthesize the published work on the accessibility of e-government portals for people with disabilities. We carried out a review using a systematic mapping study (SMS) to compile previous findings and provide comprehensive state-of-the-art. The SMS collected studies published between January 2000 and March 2025 were identified using an automated search in five known databases. In total, 112 primary studies were selected. The results showed a notable increase in interest and research activities related to accessibility in e-government portals. Journals are the most widely used publication channel; studies have mainly focused on evaluation research and show a commitment to inclusivity. “AChecker” and “Wave validator” are the most used accessibility evaluation tools. The findings also identified various accessibility guidelines, with the most frequently referenced being the web content accessibility guidelines (WCAG). Based on this study, several key implications emerge for researchers, and addressing them would be beneficial for researchers to advance e-government website accessibility in a meaningful way.

Background Roundworms such as Toxascaris leonina and Toxocara canis are routinely diagnosed in dogs globally, especially in dogs 6 months of age or younger. Toxocara canis is zoonotic, can cause significant disease in dogs, and is the causative agent of toxocariasis in humans. To protect both animal and human health, it is imperative that Toxocara canis  infections are effectively treated and controlled to minimize the risk of transmission. The following studies were performed to demonstrate the effectiveness and safety of a novel, combination chewable tablet (Credelio Quattro ™ ) containing the minimum effective dosages of lotilaner (20.0 mg/kg), moxidectin (0.02 mg/kg), praziquantel (5.0 mg/kg), and pyrantel (5.0 mg/kg) for the treatment and control of T. canis and T. leonina infections in dogs. Methods Six well-controlled studies were performed. Two studies each evaluated Credelio Quattro against immature adult T. canis , adult T. canis , and adult T. leonina infections. Post-treatment efficacy was calculated from necropsy worm counts, and fecal egg count reduction was determined 10 days post-treatment in studies evaluating experimentally induced or naturally acquired adult infections. Results Credelio Quattro was safe and ≥ 97.9% effective against immature adult stages and ≥ 97.0% effective against adult stages of induced and natural T. canis infections in dogs. After treatment with Credelio Quattro, fecal egg counts were reduced by ≥ 98.8% in T. canis -infected dogs. In both experimentally induced and naturally acquired adult T. leonina infections in dogs, Credelio Quattro was safe and 100% effective in eliminating adult worms and provided 100% reduction in fecal egg counts post-treatment. The most common adverse events reported included digestive tract disorders such as diarrhea, mucus and/or blood in feces, vomiting, and expelled ascarid worms, which occurred in both control- and treated-groups. Conclusions These laboratory studies confirm the effectiveness and safety of a single dose of Credelio Quattro, administered at the minimum dosages of 20 mg/kg lotilaner, 0.02 mg/kg moxidectin, 5 mg/kg praziquantel, and 5 mg/kg pyrantel, for the treatment and control of immature adult and adult T. canis and adult T. leonina in dogs. Graphical abstract