Search Results (15)

The recombinant vesicular stomatitis virus-Zaire Ebolavirus envelope glycoprotein vaccine (rVSVΔG-ZEBOV-GP) was highly effective against Ebola virus disease in a ring vaccination trial conducted during the 2014–2016 outbreak in Guinea and is licensed by regulatory agencies including US FDA, EMA, and prequalified by WHO. Vaccination studies in a nonhuman primate (NHP) model guided initial dose selection for clinical trial evaluation. We summarize two dose-ranging studies with the clinical-grade rVSVΔG-ZEBOV-GP vaccine candidate to assess the impact of dose level on immune responses and efficacy in an NHP Ebola virus (EBOV) challenge model. Forty-six cynomolgus macaques were vaccinated with a wide range of rVSVΔG-ZEBOV-GP doses and challenged 42 days later intramuscularly with 1000 pfu EBOV. Vaccination with rVSVΔG-ZEBOV-GP induced relatively high levels of EBOV-specific IgG and neutralizing antibodies, measured using the same validated assays as used in rVSVΔG-ZEBOV-GP clinical trials. Similar responses were observed across dose groups from 1 × 10⁸ to 1 × 10² pfu. A single vaccination conferred 98% protection from lethal intramuscular EBOV challenge across all dose groups. These results demonstrate that robust antibody titers are induced in NHPs across a wide range of rVSVΔG-ZEBOV-GP vaccine doses, correlating with high levels of protection against death from EBOV challenge. Full article

The rVSVΔG-ZEBOV-GP vaccine demonstrated efficacy in preventing Ebola virus (EBOV) disease in a ring vaccination clinical trial conducted during the 2014–2016 West Africa outbreak and is licensed by regulatory agencies, including the US FDA and the EMA. Here, we present two studies that evaluated the durability of immunogenicity and protection from an EBOV challenge up to ~12 months following vaccination with rVSVΔG-ZEBOV-GP in nonhuman primates (NHPs). Cynomolgus macaques were vaccinated with either one or two doses of rVSVΔG-ZEBOV-GP or a saline control and were challenged intramuscularly with EBOV at a target dose of 1000 pfu at ~4 months (Study 1) or ~8 or ~12 months (Study 2) after the last vaccination. All vaccinated animals developed robust ZEBOV-GP-specific IgG and neutralizing antibody titers, which were sustained until the last time point tested prior to the challenge. The majority of animals (88–93%) challenged with EBOV at ~4 or ~8 months post-vaccination survived, whereas the survival rate was lower (53%) in animals challenged ~12 months post-vaccination. These results demonstrate that both one-dose and two-dose regimens of the rVSVΔG-ZEBOV-GP vaccine induced durable ZEBOV-GP-specific antibody titers in NHPs and provided high levels of protection against a lethal EBOV challenge up to ~8 months post-vaccination. In this stringent challenge model, decreased protection was observed at ~12 months post-vaccination despite sustained antibody levels. Full article

“True” cobras (genus Naja) are among the venomous snakes most frequently involved in snakebite accidents in Africa and Asia. The Cape cobra (Naja nivea) is one of the African cobras of highest medical importance, but much remains to be learned about its venom. Here, we used a shotgun proteomics approach to better understand the qualitative composition of N. nivea venom and tested its cytotoxicity and protease activity as well as its effect on intracellular Ca²⁺ release and NO synthesis. We identified 156 venom components representing 17 protein families, with the dominant ones being three-finger toxins, mostly of the short-chain type. Two-thirds of the three-finger toxin entries identified were assigned as cytotoxins, while the remainder were categorized as neurotoxins, including short-chain, long-chain, and ancestral three-finger toxins. We also identified snake venom metalloproteinases and members of CRISP, l-amino acid oxidase, and other families. Protease activity and its effect on intracellular Ca²⁺ release and NO synthesis were low. Phospholipase A₂ activity was surprisingly high, despite this toxin family being marginally recovered in the analyzed venom. Cytotoxicity was relevant only at higher venom concentrations, with macrophage and neuroblastoma cell lines showing the lowest viability. These results are in line with the predominantly neurotoxic envenomation symptoms caused by Cape cobra bites. The present overview of the qualitatively complex and functionally intriguing venom of N. nivea may provide insights into the pathobiochemistry of this species’ venom. Full article

Facing rising financial pressure due to economic stagnation and lacklustre engagement from policy-makers, higher education institutions (HEIs) and local communities are placing increasing emphasis on cooperative efforts between universities and communities to co-create positive societal change in the face of the triple planetary crisis. Based on the PRISMA method, this systematic literature review seeks to contribute to the academic knowledge on Sustainable Development Goals (SDG) governance at the local level by unpacking the contribution of HEI-community cooperative approaches to transformative learning and action for sustainability. In order to successfully incorporate communities’ priorities in the local-level integration of the SDGs, it is crucial that these new collaborative initiatives foster transformative learning approaches to Education for Sustainable Development (ESD) in an equitable, intersubjective, and inductive manner. The findings present the various strategies used to build long-term, impactful, and resilient learning skills for sustainable development for all ESD stakeholders at the local level, including communities, HEIs, and city authorities. This review proposes these interventions as tools for better local governance towards the integration of the SDGs into HEIs and communities, specifically through SDG4 Quality Education. Full article

Brain tumor incidence is on the rise, and glioblastoma comprises the majority of primary tumors. Despite maximal safe resection and adjuvant chemoradiation, median survival for high-grade glioma remains poor. For this reason, it is important to develop and incorporate new treatment strategies. Oncolytic virotherapy has emerged as a viable new therapeutic entity to fill this gap. Preclinical research has shown oncolytic virotherapy to be a robust and effective treatment option for brain tumors, and clinical trials for both adult and pediatric high-grade glioma are underway. The unique and protected environment of the nervous system, in part due to the blood–brain barrier, prevents traditional systemic therapies from achieving adequate penetration. Brain tumors are also heterogenous in nature due to their diverse molecular profiles, further complicating systemic treatment efforts. Oncolytic viruses may serve to fill this gap in brain tumor treatment given their amenability to genetic modification and ability to target unique tumor epitopes. In addition, direct inoculation of the oncolytic virus agent to the tumor bed following surgical resection absolves risk of systemic side effects and ensures adequate delivery. As virotherapy transitions from bench to bedside, it is important to discuss factors to make this transition more seamless. In this article, we describe the current clinical evidence as it pertains to oncolytic virotherapy and the treatment of brain tumors as well as factors to consider for its incorporation into neurosurgical workflow. Full article

The venoms of spiders from the RTA (retro-lateral tibia apophysis) clade contain diverse short linear peptides (SLPs) that offer a rich source of therapeutic candidates. Many of these peptides have insecticidal, antimicrobial and/or cytolytic activities, but their biological functions are unclear. Here, we explore the bioactivity of all known members of the A-family of SLPs previously identified in the venom of the Chinese wolf spider (Lycosa shansia). Our broad approach included an in silico analysis of physicochemical properties and bioactivity profiling for cytotoxic, antiviral, insecticidal and antibacterial activities. We found that most members of the A-family can form α-helices and resemble the antibacterial peptides found in frog poison. The peptides we tested showed no cytotoxic, antiviral or insecticidal activities but were able to reduce the growth of bacteria, including clinically relevant strains of Staphylococcus epidermidis and Listeria monocytogenes. The absence of insecticidal activity may suggest that these peptides have no role in prey capture, but their antibacterial activity may help to defend the venom gland against infection. Full article

The venoms of ants (Formicidae) are a promising source of novel bioactive molecules with potential for clinical and agricultural applications. However, despite the rich diversity of ant species, only a fraction of this vast resource has been thoroughly examined in bioprospecting programs. Previous studies focusing on the venom of Central European ants (subfamily Myrmicinae) identified a number of short linear decapeptides and nonapeptides resembling antimicrobial peptides (AMPs). Here, we describe the in silico approach and bioactivity profiling of 10 novel AMP-like peptides from the fellow Central European myrmicine ants Myrmica rubra and Myrmica ruginodis. Using the sequences of known ant venom peptides as queries, we screened the venom gland transcriptomes of both species. We found transcripts of nine novel decapeptides and one novel nonapeptide. The corresponding peptides were synthesized for bioactivity profiling in a broad panel of assays consisting of tests for cytotoxicity as well as antiviral, insecticidal, and antimicrobial activity. U-MYRTX-Mrug5a showed moderately potent antimicrobial effects against several bacteria, including clinically relevant pathogens such as Listeria monocytogenes and Staphylococcus epidermidis, but high concentrations showed negligible cytotoxicity. U-MYRTX-Mrug5a is, therefore, a probable lead for the development of novel peptide-based antibiotics. Full article

Influenza is a severe contagious disease caused by influenza A and B viruses. The WHO estimates that annual outbreaks lead to 3–5 million severe infections of which approximately 10% lead to the death of the patient. While vaccination is the cornerstone of prevention, antiviral drugs represent the most important treatment option of acute infections. Only two classes of drugs are currently approved for the treatment of influenza in numerous countries: M2 channel blockers and neuraminidase inhibitors. In some countries, additional compounds such as the recently developed cap-dependent endonuclease inhibitor baloxavir marboxil or the polymerase inhibitor favipiravir are available. However, many of these compounds suffer from poor efficacy, if not applied early after infection. Furthermore, many influenza strains have developed resistances and lost susceptibility to these compounds. As a result, there is an urgent need to develop new anti-influenza drugs against a broad spectrum of subtypes. Natural products have made an important contribution to the development of new lead structures, particularly in the field of infectious diseases. Therefore, this article aims to review the research on the identification of novel lead structures isolated from natural resources suitable to treat influenza infections. Full article

This review describes key aspects of the development of the rVSVΔG-ZEBOV-GP Ebola vaccine and key activities which are continuing to further expand our knowledge of the product. Extensive partnerships and innovative approaches were used to address the various challenges encountered during this process. The rVSVΔG-ZEBOV-GP Ebola vaccine was initially approved by the European Medicines Agency and prequalified by the World Health Organization in November 2019. It was approved by the United States Food and Drug Administration in December 2019 and approved in five African countries within 90 days of prequalification. The development resulted in the first stockpile of a registered Ebola vaccine that is available to support outbreak response. This also provides insights into how the example of rVSVΔG-ZEBOV-GP can inform the development of vaccines for Sudan ebolavirus, Marburg virus, and other emerging epidemic diseases in terms of the types of approaches and data needed to support product registration, availability, and the use of a filovirus vaccine. Full article

Background/aims: Iatrogenic CSF leaks after endoscopic endonasal transsphenoidal surgery remain a challenging entity to manage, typically treated with CSF diversion via lumbar drainage. Objective: To assess the safety and efficacy of high-volume lumbar puncture (LP) and acetazolamide therapy to manage iatrogenic CSF leaks. Methods: We performed a prospective pilot study of four patients who developed iatrogenic postoperative CSF leaks after transsphenoidal surgery and analyzed their response to treatment with concomitant high-volume lumbar puncture followed by acetazolamide therapy for 10 days. Data collected included demographics, intra-operative findings, including methodology of skull base repair and type of CSF leak, time to presentation with CSF leak, complications associated with high-volume LP and acetazolamide treatment, and length of follow-up. Results: Mean patient age was 44.28 years, with an average BMI of 27.4. Mean time from surgery to onset of CSF leak was 7.71 days. All four patients had resolution of their CSF leak at two- and four-week follow-up. Mean overall follow-up time was 179 days, with a 100% CSF leak cure rate at the last clinic visit. No patient suffered perioperative complications or complications secondary to treatment. Conclusion: Although our pilot case series is small, we demonstrate that a high-volume LP, followed by acetazolamide therapy for 10 days, can be considered in the management of post-operative CSF leaks. Full article

Linear cationic venom peptides are antimicrobial peptides (AMPs) that exert their effects by damaging cell membranes. These peptides can be highly specific, and for some, a significant therapeutic value was proposed, in particular for treatment of bacterial infections. A prolific source of novel AMPs are arthropod venoms, especially those of hitherto neglected groups such as pseudoscorpions. In this study, we describe for the first time pharmacological effects of AMPs discovered in pseudoscorpion venom. We examined the antimicrobial, cytotoxic, and insecticidal activity of full-length Checacin1, a major component of the Chelifer cancroides venom, and three truncated forms of this peptide. The antimicrobial tests revealed a potent inhibitory activity of Checacin1 against several bacteria and fungi, including methicillin resistant Staphylococcus aureus (MRSA) and even Gram-negative pathogens. All peptides reduced survival rates of aphids, with Checacin1 and the C-terminally truncated Checacin1¹⁻²¹ exhibiting effects comparable to Spinosad, a commercially used pesticide. Cytotoxic effects on mammalian cells were observed mainly for the full-length Checacin1. All tested peptides might be potential candidates for developing lead structures for aphid pest treatment. However, as these peptides were not yet tested on other insects, aphid specificity has not been proven. The N- and C-terminal fragments of Checacin1 are less potent against aphids but exhibit no cytotoxicity on mammalian cells at the tested concentration of 100 µM. Full article

Introduction: Melanoma brain metastases remain a devastating disease process with poor prognosis. Recently, there has been a surge in studies demonstrating the efficacy of oncolytic virotherapy for brain tumor treatment. Given their specificity and amenability to genetic modification, the authors explore the possible role of oncolytic virotherapy as a potential treatment option for patients with melanoma brain metastases. Methods: A comprehensive literature review including both preclinical and clinical evidence of oncolytic virotherapy for the treatment of melanoma brain metastasis was performed. Results: Oncolytic virotherapy, specifically T-VEC (Imlygic™), was approved for the treatment of melanoma in 2015. Recent clinical trials demonstrate promising anti-tumor changes in patients who have received T-VEC; however, there is little evidence for its use in metastatic brain disease based on the existing literature. To date, only two single cases utilizing virotherapy in patients with metastatic brain melanoma have been reported, specifically in patients with treatment refractory disease. Currently, there is not sufficient data to support the use of T-VEC or other viruses for intracranial metastatic melanoma. In developing a virotherapy treatment paradigm for melanoma brain metastases, several factors must be considered, including route of administration, need to bypass the blood–brain barrier, viral tumor infectivity, and risk of adverse events. Conclusions: Evidence for oncolytic virotherapy treatment of melanoma is limited primarily to T-VEC, with a noticeable paucity of data in the literature with respect to brain tumor metastasis. Given the promising findings of virotherapy for other brain tumor types, oncolytic virotherapy has great potential to offer benefits to patients afflicted with melanoma brain metastases and warrants further investigation. Full article

While the use of crime data has been widely advocated in the literature, its availability is often limited to large urban cities and isolated databases that tend not to allow for spatial comparisons. This paper presents an efficient machine learning framework capable of predicting spatial crime occurrences, without using past crime as a predictor, and at a relatively high resolution: the U.S. Census Block Group level. The proposed framework is based on an in-depth multidisciplinary literature review allowing the selection of 188 best-fit crime predictors from socio-economic, demographic, spatial, and environmental data. Such data are published periodically for the entire United States. The selection of the appropriate predictive model was made through a comparative study of different machine learning families of algorithms, including generalized linear models, deep learning, and ensemble learning. The gradient boosting model was found to yield the most accurate predictions for violent crimes, property crimes, motor vehicle thefts, vandalism, and the total count of crimes. Extensive experiments on real-world datasets of crimes reported in 11 U.S. cities demonstrated that the proposed framework achieves an accuracy of 73% and 77% when predicting property crimes and violent crimes, respectively. Full article

There are numerous ways to theorise about elements of civilisations and societies known as ‘body’, ‘movement’, or ‘physical’ cultures. Inspired by the late Henning Eichberg’s notions of multiple and continually shifting body cultures, this article explores his constant comparative (trialectic) approach via the Mexican martial art, exercise, and human development philosophy—Xilam. Situating Xilam within its historical and political context and within a triad of Mesoamerican, native, and modern martial arts, combat sports, and other physical cultures, I map this complexity through Eichberg’s triadic model of achievement, fitness, and experience sports. I then focus my analysis on the aspects of movement in space as seen in my ethnographic fieldwork in one branch of the Xilam school. Using a bare studio as the setting and my body as principle instrument, I provide an impressionist portrait of what it is like to train in Xilam within a communal dance hall (space) and typical class session of two hours (time) and to form and express warrior identity from it. This article displays the techniques; gestures and bodily symbols that encapsulate the essence of the Xilam body culture, calling for a way to theorise from not just from and on the body but also across body cultures. Full article

Nazi Germany’s “children’s euthanasia” was a unique program in the history of mankind, seeking to realize a social Darwinist vision of a society by means of the systematic murder of disabled children and youths. Perpetrators extinguished “unworthy life” during childhood and adolescence by establishing killing stations, misleadingly labeled Kinderfachabteilungen (“special children’s wards”), in existing medical or other care facilities. Part of a research project on Nazi “euthanasia” crimes and their victims, this paper uses a comparative historical perspective to trace memories of the crimes and the memorialization of their victims at the sites of two of these wards (Eichberg and Kalmenhof in Hesse, Germany). It also discusses the implications of the findings for theorizing mnemonic practices and analyzing ways in which memorials and other sites of memory deal with past trauma and atrocity. Full article