Protein Kinase A (PKA) neuronal function is controlled by the interaction of a regulatory (R) subunit dimer to two catalytic (C) subunits. Recently, the L50R variant in the gene encoding the RIβ subunit was identified in individuals with a novel neurodegenerative disease. However, the mechanisms driving the disease phenotype remained unknown. In this study, we generated a mouse model carrying the RIβ-L50R mutation to replicate the human disease phenotype and study its progression with age. We examined postmortem brains of affected individuals as well as live cell cultures. Employing biochemical assays, immunohistochemistry, and behavioral assessments, we investigated the impact of the mutation on PKA complex assembly, protein aggregation and neuronal degeneration. We reveal that RIβ is an aggregation-prone protein that progressively accumulates in wildtype and Alzheimer’s mouse models with age, while aggregation is accelerated in the RIβ-L50R mouse model. We define RIβ-L50R as a causal mutation driving an age-dependent behavioral and disease phenotype in human and mouse models. Mechanistically, this mutation disrupts RIβ dimerization, leading to aggregation of its monomers. Intriguingly, interaction with the C-subunit protects the RIβ-L50R from self-aggregating, in a dose-dependent manner. Furthermore, cAMP signaling induces RIβ-L50R aggregation. The pathophysiological mechanism elucidated here for a newly recognized neurodegenerative disease, in which protein aggregation is the result of disrupted homodimerization, sheds light on a remarkably under-appreciated but potentially common mechanism across several neurodegenerative diseases.

Hepatitis C virus (HCV) is one of the major etiologies of hepatocellular carcinoma with approximately 30% of HCC being due to HCV infection worldwide. HCV eradication by antivirals greatly reduces the risk of HCC; nevertheless, HCC remains to occur in CHC patients who have achieved a sustained virological response (SVR). The proportion of post-SVR HCC among newly diagnosed HCC patients is increasing in the DAA era and might be due to preexisting inflammatory and fibrotic liver background, immune dysregulation between host and virus interaction, as well as host epigenetic scar, genetic predispositions and alternations. By means of applying surrogate markers and adopting risk stratification, HCC surveillance should be consistently performed in high-risk populations. In this review, we discuss the possible molecular mechanism, risk factors and surveillance strategy for HCC development after HCV eradication.

Background A mother’s milk is considered the gold standard of nutrition in neonates and is a source of cytokines, immunoglobulins, growth factors, and other important components, yet little is known about the components of canine milk, specifically colostrum, and the knowledge related to its microbial and metabolic profiles is particularly underwhelming. In this study, we characterized canine colostrum and milk microbiota and metabolome for several breeds of dogs and examined profile shifts as milk matures in the first 8 days post-whelping. Results Through untargeted metabolomics, we identified 63 named metabolites that were significantly differentially abundant between days 1 and 8 of lactation. Surprisingly, the microbial compositions of the colostrum and milk, characterized using 16S rRNA gene sequencing, were largely similar, with only two differentiating genera. The shifts observed, mainly increases in several sugars and amino sugars over time and shifts in amino acid metabolites, align with shifts observed in human milk samples and track with puppy development. Conclusion Like human milk, canine milk composition is dynamic, and shifts are well correlated with developing puppies’ needs. Such a study of the metabolic profile of canine milk, and its relation to the microbial community, provides insights into the changing needs of the neonate, as well as the ideal nutrition profile for optimal functionality. This information will add to the existing knowledge base of canine milk composition with the prospect of creating a quality, tailored milk substitute or supplement for puppies.

Recent accounts of predictive processing in posttraumatic stress disorder (PTSD) suggest that trauma-exposed individuals struggle to update trauma-related hypotheses predicting danger, which may be involved in the etiology and maintenance of this disorder. Initial research supports this account, documenting an association between trauma-exposure, impaired expectation updating, and PTSD symptoms. Yet, no study to date has examined biased belief updating in PTSD using a scenario-based approach. Objective: Here, we examined the predictive processing account among trauma-exposed and non-trauma-exposed individuals using a modified Trauma-Related version of the Bias Against Disconfirmatory Evidence task. Method: The task presents both danger-and safety-related scenarios highly relevant for trauma-exposed individuals. For each scenario, participants viewed several explanations and rated their plausibility. Their ability to update their initial interpretation following new-contradictory information was assessed. Results: Preregistered analyses did not reveal any significant findings. Based on indications that our sample may not have been sufficiently powered, we conducted exploratory analyses in an extended sample of participants. These analyses yielded a significant association between reduced belief updating and PTSD symptoms which was evident for disconfirming both safety and danger scenarios. However, the effect sizes we found were in the small-to-medium range. Conclusion: Although preliminary, our current findings support initial evidence that individuals with higher PTSD symptoms show a higher resistance to update their beliefs upon new disconfirmatory evidence. Our results should be interpreted cautiously in light of the extended sample and the limitations of the current study.

Background: Colorectal cancer (CRC) is the second most widespread cancer among Palestinian patients. As cancer care improves in hospitals across the West Bank, services like palliative care, targeted therapy, bone marrow transplantation, and individualized therapy are still limited. This study aimed to assess the CRC stages, treatment protocols, and survival rates of patients in the West Bank. Methodology: This retrospective study collected data from the medical records of Al-Najah University Hospital (NUH), which specializes in the care of cancer patients. Patients with confirmed CRC (stages I–IV) undergoing surgical or medical treatment were included in the study. Data collection was standardized by using a data collection form to gather information from the medical records included in the study. All statistical analyses were performed using SPSS (version v27), and survival was assessed using a regression analysis of the number of days from the time of diagnosis to the most recent visit against the type of treatment (e.g., surgery, chemotherapy, radiotherapy). Results: A sample of 252 patients with CRC from NUH was collected, including 143 males and 109 females aged between 27 and 86 years, with the average age being 60.6 ± 11.4 years. The sample included 183 patients (72.6%) diagnosed with colon cancer only, 29 patients (11.5%) diagnosed with rectal cancer only, and 40 patients (15.9%) diagnosed with both. Diagnosis took place at CRC stage I for 3 patients (1.2%), stage II for 33 patients (13.1%), stage III for 57 patients (22.6%), and stage IV for 159 patients (63.1%). Surgery was the most prevailing mode of treatment for 230 patients (91.3%), while 227 patients (90.1%) received chemotherapy treatment, and 38 patients (15.1%) received radiotherapy. Of the 252 patients, 40 patients (15.8%) received FOLFOX (i.e., folinic acid, fluorouracil, oxaliplatin), and 25 patients (9.9%) received FOLFIRI (i.e., folinic acid, fluorouracil, irinotecan), while the 187 remaining patients (74.2%) were treated with capecitabine, oxaliplatin, bevacizumab, cetuximab, regorafenib, cisplatin, etoposide, gemcitabine, or a combination thereof. The sample was categorized into six outcomes: (1) death, (2) cure, (3) disease progression, (4) disease recurrence, (5) under-treatment, and (6) unknown. Mortality was high, with 104 patients (41.3%) dying within a short time after diagnosis, and may have been attributable to delayed diagnosis. Surgical treatment had a positive impact on increasing the survival years, and it was significant (p = 0.033). Conclusions: A high percentage of patients were diagnosed in advanced CRC stages. The treatment modes were adopted from general international guidelines; however, the cure rates were low, and mortality was high. More studies need to be undertaken to investigate the actual application of chemotherapy protocols, and survival would benefit from the involvement of clinical pharmacists in the chemotherapy protocol selection, dosing, frequency, and follow-up. The present study advocates for greater public awareness of CRC and attests to the merits of screening by primary care professionals, which can help to avoid this serious illness and to promote a better prognosis.

Complex lifeforms host microbiota, microbes that live synergistically with their host. Accordingly, hosts have mechanisms to defend against and tolerate the microbiota. The intestinal mucus, where these systems collide, plays a pivotal role in managing this relationship, yet lacks an integrative theoretical framework. We propose a minimal model to elucidate dynamics at this interface, focusing on the ileum's mucus defense. The model considers the effect of delay in host antimicrobial peptide secretion and how the host can use two different signals, from the bulk microbiota and from segmented filamentous bacteria (SFB), assuming that the SFB anticipate the bulk microbiota. We propose a theory whereby the host can optimize defense by minimizing antimicrobial peptide production and controlling bacterial exposure. Integrating two recent experiments, we show host dynamics are consistent with sensing both bulk and SFB, supporting our “optimal defense” hypothesis. Therefore, we propose that similar mechanisms could prove advantageous to other species and applicable beyond the ileum's mucus barrier.

Background

Hospital-acquired resistant infections (HARI) are infections, which develop 48 h or more after admission to a healthcare facility. HARI pose a considerably acute challenge, due to limited treatment options. These infections are associated bacterial biofilms, which act as a physical barrier to diverse external stresses, such as desiccation, antimicrobials and biocides. We assessed the influence of multiple factors on biofilm production by HARI -associated bacteria.

Methods

Bacteria were isolated from samples of patients with respiratory HARI who were hospitalized during 2020–2022 in north Israel. Following antibiotic susceptibility testing by disc diffusion or broth microdilution, biofilm formation capacities of resistant bacteria (methicillin-resistant staphylococcus aureus, extended spectrum beta-lactamase-producing Escherichia coli and Klebsiela pneumonia, and multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii) was assessed using the crystalline violet staining method. Data regarding season, time to infection, bacterial species, patient age and gender, year, and medical department were collected from the patient medical records.

Results

Among the 226 study isolates, K. pneumonia was the most prevalent (35.4%) bacteria, followed by P. aeruginosa (23.5%), and methicillin-resistant staphylococcus aureus (MRSA) (21.7%). A significantly higher rate of HARI was documented in 2022 compared to 2020–2021. The majority of isolates (63.3%) were strong biofilm producers, with K. pneumonia (50.3%) being most dominant, followed by P. aeruginosa (29.4%). Biofilm production strength was significantly affected by seasonality and hospitalization length, with strong biofilm production in autumn and in cases where hospitalization length exceeded 30 days.

Conclusion

Biofilm production by HARI bacteria is influenced by bacterial species, season and hospitalization length.

Systemic lupus erythematosus (SLE) poses formidable challenges due to its multifaceted etiology while impacting multiple tissues and organs and displaying diverse clinical manifestations. Genetic and environmental factors contribute to SLE complexity, with relatively limited approved therapeutic options. Murine models offer insights into SLE pathogenesis but do not always replicate the nuances of human disease. This review critically evaluates spontaneous and induced animal models, emphasizing their validity and relevance to neuropsychiatric SLE (NPSLE). While these models undoubtedly contribute to understanding disease pathophysiology, discrepancies persist in mimicking some NPSLE intricacies. The lack of literature addressing this issue impedes therapeutic progress. We underscore the urgent need for refining models that truly reflect NPSLE complexities to enhance translational fidelity. We encourage a comprehensive, creative translational approach for targeted SLE interventions, balancing scientific progress with ethical considerations to eventually improve the management of NPSLE patients. A thorough grasp of these issues informs researchers in designing experiments, interpreting results, and exploring alternatives to advance NPSLE research.

Musculoskeletal research should synergistically investigate bone and muscle to inform approaches for maintaining mobility and to avoid bone fractures. The relationship between sarcopenia and osteoporosis, integrated in the term ‘osteosarcopenia', is underscored by the close association shown between these two conditions in many studies, whereby one entity emerges as a predictor of the other. In a recent workshop of Working Group (WG) 2 of the EU Cooperation in Science and Technology (COST) Action ‘Genomics of MusculoSkeletal traits Translational Network' (GEMSTONE) consortium (CA18139), muscle characterization was highlighted as being important, but currently under-recognized in the musculoskeletal field. Here, we summarize the opinions of the Consortium and research questions around translational and clinical musculoskeletal research, discussing muscle phenotyping in human experimental research and in two animal models: zebrafish and mouse.

Background: Proton pump inhibitors (PPIs) are commonly prescribed long-acting drugs used to treat acid reflux, gastroesophageal reflux disease (GERD), and peptic ulcers. Recently, concerns have been raised about their safety, particularly due to the association between long-term PPI use and cancer development. Multiple comprehensive studies have consistently suggested a noteworthy link between prolonged PPI usage and an increased risk of developing gastric, esophageal, colorectal, and pancreatic cancers, yet the precise underlying mechanism remains elusive. Methods: First, we review the extensive body of research that investigates the intricate relationship between cancer and PPIs. Then, we predict PPI toxicity using the prodrug structures with the ProTox-II webserver. Finally, we predict the relative risk of cancer for each PPI, using PubMed citation counts of each drug and keywords related to cancer. Results: Our review indicates that prolonged PPI use (exceeding three months) is significantly associated with an elevated risk of cancer, while shorter-term usage (less than three months) appears to pose a comparatively lower risk. Our review encompasses various proposed mechanisms, such as pH and microbiome alterations, vitamin and mineral malabsorption, hypergastrinemia, and enterochromaffin-like cell proliferation, while ProTox-II also suggests aryl hydrocarbon receptor binding. Potentially, the PubMed citations count suggests that the PPIs omeprazole and lansoprazole are more associated with cancer than pantoprazole and esomeprazole. In comparison, the H2R blocker, famotidine, is potentially less associated with cancer than PPIs, and may serve as a safer alternative treatment for periods beyond 3 months. Conclusions: Despite the well-established cancer risk associated with PPIs, it is notable that these medications continue to be widely prescribed for periods longer than 3 months. Thus, it is of paramount importance for clinicians and patients to thoughtfully evaluate the potential risks and benefits of long-term PPI usage and explore alternative treatments before making informed decisions regarding their medical management.