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The 2013-2016 West Africa EBOV epidemic was the biggest EBOV outbreak to date. An analysis of virus-specific CD8+ T-cell immunity in 30 survivors showed that 26 of those individuals had a CD8+ response to at least one EBOV protein. The dominant response (25/26 subjects) was specific to the EBOV nucleocapsid protein (NP). It has been suggested that epitopes on the EBOV NP could form an important part of an effective T-cell vaccine for Ebola Zaire. We show that a 9-amino-acid peptide NP44-52 (YQVNNLEEI) located in a conserved region of EBOV NP provides protection against morbidity and mortality after mouse adapted EBOV challenge. A single vaccination in a C57BL/6 mouse using an adjuvanted microsphere peptide vaccine formulation containing NP44-52 is enough to confer immunity in mice. Our work suggests that a peptide vaccine based on CD8+ T-cell immunity in EBOV survivors is conceptually sound and feasible. Nucleocapsid proteins within SARS-CoV-2 contain multiple class I epitopes with predicted HLA restrictions consistent with broad population coverage. A similar approach to a CTL vaccine design may be possible for that virus.

BackgroundPersistent transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has given rise to a COVID-19 pandemic. Several vaccines, evoking protective spike antibody responses, conceived in 2020, are being deployed in mass public health vaccination programs. Recent data suggests, however, that as sequence variation in the spike genome accumulates, some vaccines may lose efficacy.MethodsUsing a macaque model of SARS-CoV-2 infection, we tested the efficacy of a peptide-based vaccine targeting MHC Class I epitopes on the SARS-CoV-2 nucleocapsid protein. We administered biodegradable microspheres with synthetic peptides and adjuvants to rhesus macaques. Unvaccinated control and vaccinated macaques were challenged with 1 x 108 TCID50 units of SARS-CoV-2, followed by assessment of clinical symptoms, viral load, chest radiographs, sampling of peripheral blood and bronchoalveolar lavage (BAL) fluid for downstream analysis.ResultsVaccinated animals were free of pneumonia-like infiltrates characteristic of SARS-CoV-2 infection and presented with lower viral loads relative to controls. Gene expression in cells collected from BAL samples of vaccinated macaques revealed a unique signature associated with enhanced development of adaptive immune responses relative to control macaques.ConclusionsWe demonstrate that a room temperature stable peptide vaccine based on known immunogenic HLA Class I bound CTL epitopes from the nucleocapsid protein can provide protection against SARS-CoV-2 infection in non-human primates.Graphical Abstract

Magnetized plasma interactions are ubiquitous in astrophysical and laboratory plasmas. Various physical effects have been shown to be important within colliding plasma flows influenced by opposing magnetic fields, however, experimental verification of the mechanisms within the interaction region has remained elusive. Here we discuss a laser-plasma experiment whereby experimental results verify that Biermann battery generated magnetic fields are advected by Nernst flows and anisotropic pressure effects dominate these flows in a reconnection region. These fields are mapped using time-resolved proton probing in multiple directions. Various experimental, modelling and analytical techniques demonstrate the importance of anisotropic pressure in semi-collisional, high-β plasmas, causing a reduction in the magnitude of the reconnecting fields when compared to resistive processes. Anisotropic pressure dynamics are crucial in collisionless plasmas, but are often neglected in collisional plasmas. We show pressure anisotropy to be essential in maintaining the interaction layer, redistributing magnetic fields even for semi-collisional, high energy density physics (HEDP) regimes.

The continuous improvement of high power laser technologies is recasting the prospects of small-scale neutron sources to enable scientific communities and industries performing experiments that are currently offered at extensive accelerator-driven facilities. This paper reports moderation of laser-driven fast neutrons to thermal energies using a compact, modular, moderator assembly. A significant thermal (~25 meV) flux of 10^6 n/sr/pulse was measured from water and plastic moderators in a proof-of-principle experiment employing a relativelymoderate power laser delivering 200 J on the target in 10 ps. Using Monte Carlo N-Particle eXtended simulations, the experimental results are reproduced and discussed.

Objective To observe the effect of scalp acupuncture on the treatment of children with cerebral palsy (CP). Methods Thirty-six children in the USA with cerebral palsy were treated with Chinese scalp acupuncture at the Neuroacupuncture Institute in Santa Fe, New Mexico, USA. Foot motor and sensory area, motor area, speech I area, speech II area, balance area, vision area, apraxia area, and I vision area were selected base on patient's clinical manifestation. Rotating manual stimulation was performed during each session of acupuncture. The retention of needles was 30 minutes. Results These 36 patients received between 3–20 treatments, 5 had complete resolution of their symptom, 14 cases a marked effect, 14 had some effect, and 3 patients experienced no improvement. No adverse events were reported. Conclusion Chinese scalp acupuncture in these 33 cases appears to be an effective treatment for patients with CP and should be considered as an adjunctive therapy for more CP patients. Chinese scalp acupuncture relieved many of these patients' symptoms, increased their quality of life, and reversed many physical disabilities. Some of the patients returned to a normal life. Those treatments have laid a foundation for research into the clinical application of Chinese scalp acupuncture in the treatment of CP.

Currently, no rabies virus-specific antiviral drugs are available. Ranpirnase has strong antitumor and antiviral properties associated with its ribonuclease activity. TMR-001, a proprietary bulk drug substance solution of ranpirnase, was evaluated against rabies virus in three cell types: mouse neuroblastoma, BSR (baby hamster kidney cells), and bat primary fibroblast cells. When TMR-001 was added to cell monolayers 24 h preinfection, rabies virus release was inhibited for all cell types at three time points postinfection. TMR-001 treatment simultaneous with infection and 24 h postinfection effectively inhibited rabies virus release in the supernatant and cell-to-cell spread with 50% inhibitory concentrations of 0.2&ndash, 2 nM and 20&ndash, 600 nM, respectively. TMR-001 was administered at 0.1 mg/kg via intraperitoneal, intramuscular, or intravenous routes to Syrian hamsters beginning 24 h before a lethal rabies virus challenge and continuing once per day for up to 10 days. TMR-001 at this dose, formulation, and route of delivery did not prevent rabies virus transit from the periphery to the central nervous system in this model (n = 32). Further aspects of local controlled delivery of other active formulations or dose concentrations of TMR-001 or ribonuclease analogues should be investigated for this class of drugs as a rabies antiviral therapeutic.

Background Human papillomaviruses (HPV), the causative agents of anogenital warts, are the most prevalent sexually transmitted infectious agents, and wart treatment poses a persistent challenge. We assessed the safety and efficacy of treating HPV with ranpirnase, an endoribonuclease from the northern leopard frog that has been used extensively in Phase III oncology trials. Methods As initial verification of ranpirnase antiviral activity, we assessed its ability to eliminate papilloma-viruses in cultured cells. To further assess its feasibility for treating anogenital warts in humans, we performed a Phase I study. Forty-two male volunteers with genital/ perianal warts were treated topically with three different formulations of 1 mg/ml ranpirnase. Patients were monitored for 8 weeks or until healing. Four patients with HIV were treated in accordance with the compassionate programme but were not evaluated. Results In cultured cells, ranpirnase showed specific activity against HPV-11 with low toxicity (selectivity index >88). The broad applicability of ranpirnase for treating papillomaviruses was verified using the cottontail rabbit papillomavirus. In the clinical study, eight participants were lost-to-follow-up or discontinued due to protocol violation or non-compliance. Among 30 evaluable participants, topical ranpirnase was moderately well-tolerated, with discontinuation by 5 (16.7%) due to adverse reactions. Clinical healing was achieved by 25 participants (83.3%) and 50% improvement by the 5 discontinued participants (16.7%). The median time to clinical healing was 30 days. Conclusions This study provides the first in vitro and clinical evidence of the antiviral efficacy of ranpirnase against HPV and supports assessment of ranpirnase in expanded clinical studies.

Strong magnetic fields of upto 20 T, corresponding to a current of tens of kA were produced in a coil connected to a single-plate of cm2 area irradiated by a kJ-ns laser pulse. The use of such macroscopic plates protects the coil from plasma debris, while maintaining a strong magnetic field for a time-scale much longer than the laser pulse duration. By correlating the measured magnetic field in the coil to the number of electrons emitted from the interaction zone, we deduce that the target capacitance is enhanced by two orders of magnitude because of the plasma sheath in the proximity of the focal spot. The particle-in-cell simulation illustrates the dynamics of sheath potential and current flow through the coil to ground, thus closing the circuit due to the escape of laser-produced hot electrons from the target.

The recent epidemic of Ebola has intensified the need for the development of novel antiviral therapeutics that prolong and improve survival against deadly viral diseases. We sought to determine whether ranpirnase, an endoribonuclease from Rana pipiens with a demonstrated human safety profile in phase III oncology trials, can reduce titers of Ebola virus (EBOV) in infected cells, protect mice against mouse-adapted EBOV challenge, and reduce virus levels in infected mice. Our results demonstrate that 0.50 μg/ml ranpirnase is potently effective at reducing EBOV Zaire Kikwit infection in cultured Vero E6 cells (Selectivity Index 47.8–70.2). In a prophylactic study, a single intravenous dose of 0.1 mg/kg ranpirnase protected 70% of mice from progressive infection. Additionally, in a post-exposure prophylactic study, 100% of female mice survived infection after intraperitoneal administration of 0.1 mg/kg ranpirnase for ten days beginning 1 h post challenge. Most of the male counterparts were sacrificed due to weight loss by Study Day 8 or 9; however, the Clinical Activity/Behavior scores of these mice remained low and no significant microscopic pathologies could be detected in the kidneys, livers or spleens. Furthermore, live virus could not be detected in the sera of ranpirnase-treated mice by Study Day 8 or in the kidneys, livers or spleens by Study Day 12, and viral RNA levels declined exponentially by Study Day 12. Because ranpirnase is exceptionally stable and has a long track record of safe intravenous administration to humans, this drug provides a promising new candidate for clinical consideration in the treatment of Ebola virus disease alone or in combination with other therapeutics.

This article describes the ECVP/ESVP Summer School in Veterinary Pathology, a new annual two-week European training facility established by the European College of Veterinary Pathologists (ECVP) in collaboration with the European Society of Veterinary Pathology (ESVP). The aim of the Summer Schools is to provide Europe-wide, harmonized, top-standard theoretical and practical post-graduate training for veterinarians specializing in veterinary pathology. In particular, it aims to support trainees in veterinary pathology in their individual preparation for the ECVP certifying examination. Ultimately, it aims to provide young pathologists with the skills and knowledge necessary to participate in international, high-quality research and the tools for applying international standards to their own research and for independent study for the ECVP certifying examination, even if they do not work in comparable academic environments and do not have the same level of local support and training. The ECVP/ESVP Summer Schools take place in European countries, with local organization from a university department of veterinary pathology. Each event comprises modules provided by internationally recognized specialists in their specific fields of expertise on different organ systems, diseases of specific species, specific techniques, and specific topics relevant to pathology, forming a cycle of four events to cover all major topics. Every two years a mock exam is organized as a tool to monitor individual progress in preparing for the ECVP certifying examination.

Aprikalim is a potent, specific, and selective opener of ATP-sensitive K+(KATP) channels. By virtue of this pharmacological property, aprikalim affords cardioprotection in experimental models of ischemia/reperfusion injury, and, at higher doses, also causes peripheral or coronary vasodilatation. Direct-acting peripheral vasodilators can cause myocardial lesions, particularly in rats and dogs. However, unexpectedly, aprikalim produced this effect also in monkeys. Thus, the primary aim of this investigation was to assess whether in monkeys these myocardial lesions were the direct or indirect consequence of the vascular effects of aprikalim. Cynomologus monkeys were given the β-adrenoceptor antagonist nadolol (2 mg/kg po, twice daily) for 4 consecutive days. On the third and fourth day of the experiment, they received aprikalim (1 mg/kg po). In another series, two monkeys carrying telemetry transmitters for blood pressure and heart rate measurements were also given aprikalim or its vehicle. Finally, aprikalim (1 mg/kg po for 2 days) or its vehicle was administered to rats which were concurrently treated with the β-adrenoceptor antagonist atenolol (5 mg/kg sc) or its vehicle. In cynomologus monkeys, aprikalim produced focal and multifocal myocardial necrosis of minimal to moderate intensity in or near the papillary muscles of the left ventricle. These effects were abrogated by nadolol. Similarly, necrotic lesions were caused by aprikalim only in those rats which had not been pretreated with atenolol. In monkeys, aprikalim produced a marked and long-lasting decrease in aortic blood pressure, accompanied by an even more prolonged tachycardia. These results demonstrate that aprikalim can produce myocardial necrosis not only in rats but also in monkeys. To our knowledge, this is the first time that such adverse effects are reported for a vasodilator in monkeys. More importantly, these effects were prevented by blocking cardiac β-adrenoceptors. Thus, the myocardial lesions produced by aprikalim may be attributed to its profound and prolonged hemodynamic effects.

Objective When children acquire HIV infection from their mothers (with whom they share at least 50% of their HLA alleles), they acquire virus with a history of encounter with maternal HLA-mediated immune responses. We investigated whether maternal HLA selection pressures on the virus would adversely influence clinical outcomes of HIV-infected children. Methods We tested whether time to AIDS diagnosis or death, among a cohort of 59 HIV-infected children in New York City followed from birth for up to 12 years, was associated with maternally- or paternally-inherited child HLA class I alleles, and with HLA similarity between mother and child. Results HIV-infected children with an HLA allele usually associated with slow disease experienced a slower progression to AIDS or death only if the allele was paternally inherited. If the allele was present in the mother, no association was observed. Children who were homozygous or who shared both alleles with their mothers at more than one HLA class I locus were more likely to progress to AIDS or death than other children (relative hazard, 3.46; 95% confidence interval, 1.24-9.71). Conclusion Genetic similarity between mother and child may compromise the child's capacity to control HIV replication when the virus is acquired from the mother. HLA-mediated selective pressures on the virus in a transmitting mother-infant pair may undermine future HLA-mediated viral control in the child.

Definitive genetic parameters correlating with mother-to-child transmission (MCT) of HIV have not been fully established. We screened for the potential correlation between HLA-G variants and MCT, in a cohort of mother-child pairs. Discordance in exon 2 of HLA-G was significantly more common among non-transmitting (93%) than transmitting mother-child pairs (40%). Our results suggest that mother-child pairs both carrying the identical mutation in HLA-G exon 2 may be at higher risk of MCT of HIV-1.

Low current (0.25, 3 mA) stimulation through a miniature electrode cuff encased around the carotid artery of the rat was used to induce intimal hyperplasia, an important feature of the atherosclerotic plaque and a phenomenon limiting the long term success of angioplasty. Compared to contralateral unstimulated arteries, 11–14 days of daily transmural stimulation of cuffed arteries (20 min period) significantly increased the amount of extracted DNA (diphenylamine colorimetric assay). Low current (0.25 mA) was as effective as 3 mA in producing an increase in extractable DNA. The cuff alone without applied current also stimulated an increase in DNA content but to a smaller degree than in arteries receiving current. Infusion of a calcium channel antagonist, diltiazem, at a dose which achieved therapeutic drug levels, significantly reduced the amount of electrode cuff-induced DNA content but had no effect on the increase in DNA induced by the presence of the cuff without applied current. Gene expression of PDGF-A chain, PDGF-B chain and PDGF-beta receptor (βr) (Northern analysis of extracted carotid RNA) increased within 4 h after electrical stimulation with 3 mA. Lower current (0.25 mA) and the presence of the cuff also enhanced PDGF gene expression but with a delayed onset of several days. The pattern of gene expression for PDGF ligands and βr during the 11–14 days of stimulation differed, but each remained above contralateral control levels. It is concluded that the continued coexpression of PDGF and one of its receptors may contribute to induced hyperplastic changes.

The well qualified representative of the Journal of the American Geriatrics Society gives a succinct, well organized report on the Second WHCoA. It is presented under the headings: Action and Long-Range Planning (the keynotes); Recommendations of the Sections (Education, Employment and Retirement, Physical and Mental Health, Housing Income, Nutrition, Retirement Roles and Activities, Spiritual Well-Being, Transportation, Facilities, Programs and Services, Government and Non-Government Organizations, Planning, Research and Demonstration, and Training); Special Concerns Sessions; and General Sessions and Luncheon Meetings. At the closing Session, the delegates unanimously approved a line of procedure designed to obtain the quickest possible action on the major recommendations of the Conference. There was a general feeling of optimism that the follow-up work had been left in most competent hands.