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Humanity is facing an increasing health threat caused by a variety of multidrug resistant bacteria. Within this scenario, Staphylococcus aureus , in particular methicillin resistant S. aureus (MRSA), is responsible for a number of hospital-acquired bacterial infections. The emergence of microbial antibiotic resistance urgently requires the identification of new and innovative strategies to treat antibiotic resistant microorganisms. In this context, structure and function analysis of potential drug targets in metabolic pathways vital for bacteria endurance, such as the vitamin K 2 synthesis pathway, becomes interesting. We have solved and refined the crystal structure of the S. aureus DHNA thioesterase ( Sa DHNA), a key enzyme in the vitamin K 2 pathway. The crystallographic structure in combination with small angle X-ray solution scattering data revealed a functional tetramer of Sa DHNA. Complementary activity assays of Sa DHNA indicated a preference for hydrolysing long acyl chains. Site-directed mutagenesis of Sa DHNA confirmed the functional importance of Asp16 and Glu31 for thioesterase activity and substrate binding at the putative active site, respectively. Docking studies were performed and rational designed peptides were synthesized and tested for Sa DHNA inhibition activity. The high-resolution structure of Sa DHNA and complementary information about substrate binding will support future drug discovery and design investigations to inhibit the vitamin K 2 synthesis pathway.

Malaria is an infectious disease that results in serious health problems in the countries in which it is endemic. Annually this parasitic disease leads to more than half a million deaths; most of these are children in Africa. An effective vaccine is not available, and the treatment of the disease is solely dependent on chemotherapy. However, drug resistance is spreading, and the identification of new drug targets as well as the development of new antimalarials is urgently required. Attention has been drawn to a variety of essential plasmodial proteins, which are targeted to intra- or extracellular destinations, such as the digestive vacuole, the apicoplast, or into the host cell. Interfering with the action or the transport of these proteins will impede proliferation of the parasite. In this mini review, we will shed light on the present discovery of chemotherapeutics and potential drug targets involved in protein trafficking processes in the malaria parasite.

Malaria is a deadly infectious disease which affects millions of people each year in tropical regions. There is no effective vaccine available and the treatment is based on drugs which are currently facing an emergence of drug resistance and in this sense the search for new drug targets is indispensable. It is well established that vitamin biosynthetic pathways, such as the vitamin B6 de novo synthesis present in Plasmodium, are excellent drug targets. The active form of vitamin B6, pyridoxal 5-phosphate, is, besides its antioxidative properties, a cofactor for a variety of essential enzymes present in the malaria parasite which includes the ornithine decarboxylase (ODC, synthesis of polyamines), the aspartate aminotransferase (AspAT, involved in the protein biosynthesis), and the serine hydroxymethyltransferase (SHMT, a key enzyme within the folate metabolism).

Phishing attacks remain a persistent cybersecurity threat, and the widespread adoption of TLS certificates has unintentionally enabled malicious websites to appear trustworthy to users. This study examines whether certificate metadata and domain characteristics can help distinguish phishing domains from benign domains within the Danish .dk namespace. A dataset was constructed by combining registry information from Punktum dk with phishing reports and popularity rankings from external sources. TLS certificate attributes were collected using Netlas, while additional domain-based features were derived from DNS records and lexical analysis of domain names. The analysis compares phishing, popular, and less frequently visited domains across several feature categories, including Certificate Authorities (CAs), validity periods, missing certificate fields, SAN structure, registrant geography, hosting providers, and lexical properties of domain names. The results indicate that several features show observable differences between phishing and highly popular domains. However, phishing domains often resemble less popular domains, resulting in substantial overlap across many characteristics. Consequently, no individual feature provides a reliable standalone indicator of phishing activity within the Danish namespace. The findings suggest that certificate and domain attributes may still contribute to detection when combined, while also highlighting the limitations of relying on individual indicators in isolation. This work provides an empirical overview of phishing-related infrastructure patterns in the Danish .dk ecosystem and offers insights that may inform future phishing detection approaches.

Purpose The pyrimidine analogue gemcitabine (dFdC) is frequently used in the treatment of patients with solid tumors. However, after i.v. application dFdC is rapidly inactivated by metabolization. Here, the potential of thermosensitive liposomes based on 1,2-dipalmitoyl- sn -glycero-3-phosphodiglycerol (DPPG 2 -TSL) were investigated as carrier and targeting system for delivery of dFdC in combination with local hyperthermia (HT). Methods DPPG 2 -TSL were prepared by the lipid film hydration and extrusion method and characterized by dynamic light scattering, thin layer chromatography, phosphate assay and HPLC. In vivo experiments were performed in Brown Norway rats with a syngeneic soft tissue sarcoma. Local HT treatment was performed by light exposure. Results DPPG 2 -TSL were stable at 37°C in serum and showed a temperature dependent dFdC release >40°C. Plasma half-life of dFdC was strongly increased from 0.07 h (non-liposomal) to 0.53 h (liposomal, vesicle size 105 nm) or 2.59 h (liposomal, 129 nm). Therapy of BN175 tumors with dFdC encapsulated in DPPG 2 -TSL + HT showed significant improvement in tumor growth delay compared to non-liposomal dFdC without HT ( p  < 0.05), non-liposomal dFdC with HT ( p  < 0.01), and liposomal dFdC without HT ( p  < 0.05), respectively. Conclusions Gemcitabine encapsulated in DPPG 2 -TSL in combination with local HT is a promising tool for the treatment of solid tumors. Therefore, these encouraging results ask for further investigation and evaluation.

Castration of male pigs without anesthesia is a significant welfare issue. Improvac®, a GnRH vaccine induces an endogenous immune response leading to a decrease in testicular steroids. Consequences of different vaccination schemes on testicular function and carcass quality were evaluated in immunocastrated boars (IC), surgical castrates (SC), and entire males (EM). Therefore, 128 male piglets were assigned to five treatment-groups and a long term follow-up group. IC groups received two vaccinations (V1, V2) with Improvac® at 8 and 12, 12 and 16, or 12 and 18 weeks. Testosterone-concentrations decreased significantly two weeks after V2 in feces and dropped in serum from V2 to slaughter (S) except IC-8/12 without differing significantly. GnRH-binding results indicated the highest values for IC-12/18 animals. While IC-12/16 and IC-12/18 animals showed boar taint compounds below the threshold levels, two IC-8/12 animals had concentrations above the threshold level. Feed-efficiency was higher in EM than in SC with IC in between. In IC compared to EM, a decreasing amount of polyunsaturated-fatty-acids was obvious and GnRH-vaccination reduced penile injuries. The examined vaccination protocols reduce penile injuries, improve feed efficiency and carcass quality, and reliably prevents boar taint, if manufacturer’s recommendations concerning vaccination schedules are applied. Therefore immunocastration offers a reliable, animal friendly alternative to surgical castration.

Introduction: Neurofeedback (NF) or electroencephalogram (EEG)-Biofeedback is a drug-free form of brain training to directly alter the underlying neural mechanisms of cognition and behavior. It is a technique that measures a subject’s EEG signal, processes it in real time, with the goal to enable a behavioral modification by modulating brain activity. The most common application of the NF technology is in epilepsies, migraine, attention-deficit/hyperactivity disorder, autism spectrum disorder, affective disorders, and psychotic disorders. Few studies have investigated the use of NF in context of psychosomatic illnesses. Little is known about the use in cancer patients or postcancer survivors despite the high number of this patient group. Objectives: We here provide a systematic review of the use and effect of NF on symptoms and burden in cancer patients and long-term cancer survivors. Methods: In conducting this systematic review, we followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Statement. Results: Our search resulted in only 3 experimental studies, 1 observational study, and 2 case reports. Given the heterogeneity of the intervention systems and protocols, no meta-analysis was conducted. Conclusion: Altogether, there is initial evidence that NF is a complementary, drug-free, and noninvasive therapy that has the potential to ameliorate symptoms in this patient group, such as pain, fatigue, depression, and sleep. Further studies are highly needed.

Background We recently reported non-coding variants in a cis -regulatory element of the beta-cell disallowed gene hexokinase 1 ( HK1 ) as a novel cause of congenital hyperinsulinism. These variants lead to a loss of repression of HK1 in pancreatic beta-cells, causing insulin secretion during hypoglycaemia. In this study, we aimed to determine the prevalence, genetics, and phenotype of HK1 -hyperinsulinism by screening a large international cohort of patients living with the condition. Methods We screened the HK1 cis -regulatory region in 1761 probands with hyperinsulinism of unknown aetiology who had been referred to one of three large European genomics laboratories. Results We identified a HK1 variant in 89/1761 probands (5%) and 63 family members. Within the Exeter HI cohort, these variants accounted for 2.8% of all positive genetic diagnoses ( n  = 54/1913) establishing this as an important cause of HI. Individuals with a disease-causing variant were diagnosed with hyperinsulinism between birth and 26 years (median: 7 days) with variable response to treatment; 80% were medically managed and 20% underwent pancreatic surgery due to poor response to medical therapy. Glycaemic outcomes varied from spontaneous remission to hypoglycaemia persisting into adulthood. Eight probands had inherited the variant from a parent not reported to have hyperinsulinism (median current age: 39 years), confirming variable penetrance. Two of the 23 novel HK1 variants allowed us to extend the minimal cis -regulatory region from 42 to 46 bp. Conclusions Non-coding variants within the HK1 cis -regulatory region cause hyperinsulinism of variable severity ranging from neonatal-onset, treatment-resistant disease to being asymptomatic into adulthood. Discovering variants in 89 families confirms HK1 as a major cause of hyperinsulinism and highlights the important role of the non-coding genome in human monogenic disease.

With digital learning environments becoming more prevalent, the ease with which generative AI enables the scalable production of real-time, automated feedback holds the potential to reshape learning and teaching experiences. This meeting report synthesizes the interdisciplinary perspectives of 50 scholars from educational psychology, computer science, science education, and the learning sciences on the use of generative AI for feedback and its promises and risks in educational practice. We highlight points of convergence in the scholarship, identify areas of debate and unresolved challenges, and outline open questions and future directions for research and educational practice that emerged from structured small-group activities designed to bridge disciplinary barriers.