Oral subunit SARS-CoV-2 vaccine induces systemic neutralizing IgG, IgA and cellular immune responses and can boost neutralizing antibody responses primed by an injected vaccine.

The rapid spread of the COVID-19 pandemic, with its devastating medical and economic impacts, triggered an unprecedented race toward development of effective vaccines. The commercialized vaccines are parenterally administered, which poses logistic challenges, while adequate protection at the mucosal sites of virus entry is questionable. Furthermore, essentially all vaccine candidates target the viral spike (S) protein, a surface protein that undergoes significant antigenic drift. This work aimed to develop an oral multi-antigen SARS-CoV-2 vaccine comprised of the receptor binding domain (RBD) of the viral S protein, two domains of the viral nucleocapsid protein (N), and heat-labile enterotoxin B (LTB), a potent mucosal adjuvant. The humoral, mucosal and cell-mediated immune responses of both a three-dose vaccination schedule and a heterologous subcutaneous prime and oral booster regimen were assessed in mice and rats, respectively. Mice receiving the oral vaccine compared to control mice showed significantly enhanced post-dose-3 virus-neutralizing antibody, anti-S IgG and IgA production and N-protein-stimulated IFN-γ and IL-2 secretion by T cells. When administered as a booster to rats following parenteral priming with the viral S1 protein, the oral vaccine elicited markedly higher neutralizing antibody titres than did oral placebo booster. A single oral booster following two subcutaneous priming doses elicited serum IgG and mucosal IgA levels similar to those raised by three subcutaneous doses. In conclusion, the oral LTB-adjuvanted multi-epitope SARS-CoV-2 vaccine triggered versatile humoral, cellular and mucosal immune responses, which are likely to provide protection, while also minimizing technical hurdles presently limiting global vaccination, whether by priming or booster programs.

Detection of Impending Aggressive Outbursts in Patients with Psychiatric Disorders: Violence Clues from Dogs.

Aggression in psychiatric wards is a continuing matter of concern for both patients and medical staff. Here we have tested the hypothesis that the frequency of such incidents can be reduced with a new strategy of using trained alert dogs that warn of impending violent outbursts. Dogs were positioned among patients in psychiatric wards. Analyses show that the dogs warned of impending aggressive outbursts, responding to signals from a specific patient out of a group of unfamiliar psychotic patients. Their alerts were not a response to stress as canine cortisol levels were not significantly changed. Visual glance was the preferred method used by young dogs to respond to patient. Until a similar electronic technology is developed, trained alert dogs can help caregivers to protect both the patient and those around them from injuries that may otherwise result from aggressive outbursts in psychiatric patients.

When cancer meets quantum mechanics.

To date, classical deterministic Newtonian physics has been used by biologists to describe living processes. However, it is increasingly appreciated that the probabilistic view offered by quantum mechanics more accurately describes the behavior of atoms and materials in all systems. Here, we discuss how the concepts of quantum mechanics can be applied to biological processes involved in cancer. We present a concise summary inspired by Heisenberg's Uncertainty Principle to describe our «Genetic Environmental Field Hypothesis¼. Combining the uncertainties of genetic changes as expressed by epigenetic changes and/or somatic mutations with the uncertainties of environmental changes, cells may become cancerous as a way to increase entropy. Throughout the paper we will utilize the H19 gene system as an example. Using the concepts of quantum mechanics to describe oncological processes may provide novel directions in our understanding of cancer.

Sequence-based design of kinase inhibitors applicable for therapeutics and target identification.

A platform for specifically modulating kinase-dependent signaling using peptides derived from the catalytic domain of the kinase is presented. This technology, termed KinAce, utilizes the canonical structure of protein kinases. The targeted regions (subdomain V and subdomains IX and X) are analyzed and their sequence, three-dimensional structure, and involvement in protein-protein interaction are highlighted. Short myristoylated peptides were derived from the target regions of the tyrosine kinases c-Kit and Lyn and the serine/threonine kinases 3-phosphoinositide-dependent kinase-1 (PDK1) and Akt/protein kinase B (PKB). For each kinase an active designer peptide is shown to selectively inhibit the signaling of the kinase from which it is derived, and to inhibit cancer cell proliferation in the micromolar range. This technology emerges as an applicable tool for deriving sequence-based selective inhibitors for a broad range of protein kinases as hits that may be further developed into drugs. Moreover, it enables identification of novel kinase targets for selected therapeutic indications as demonstrated in the KinScreen application.

Expression of kinase genes in primary hyperparathyroidism: adenoma versus hyperplastic parathyroid tissue.

BACKGROUND: Differentiation between parathyroid hyperplasia and adenoma is difficult and based on the surgeon's skill. Microarrays and other sophisticated research tools generate information about differential gene expression in various tissues. Exploration of genes that express differentially in 1 tissue will enable identification and perhaps development of new methods of preoperative or intraoperative diagnosis. METHODS: RNA was extracted from parathyroid hyperplasia and adenoma tissue and hybridized to a microarray containing 359 human complementary DNAs of known kinase genes. Signals of exposure were scanned and quantified with software for digital image analysis (Atlas-image, v. 2; Clontech Labs Inc, Palo Alto, Calif). The program generates a color schematic comparison view and numeric data in a tabular format for further analysis. RESULTS: The ratio values that are considered significant (< 0.5 or > 1.5) suggest that genes up-regulated in parathyroid adenoma are those responsible for angiogenesis and production of blood vessels. Genes down-regulated in parathyroid adenoma and expressed in hyperplasia are related to a decrease in apoptosis. Moreover, an interesting gene expressed only in the hyperplasia sample is increased in relation to in vivo proliferation activities. CONCLUSIONS: Parathyroid hyperplasia and adenoma are different physiologic conditions. Further analysis of kinase genes involved in angiogenesis and apoptosis will enable design of a chip that concentrates in the different key genes responsible for the transition between hyperplasia and adenoma. Identifying such genes will enable to target both diagnostic and therapeutic approaches.

Possible physiological role of H19 RNA.

The product of the imprinted oncofetal H19 gene is an untranslated RNA of unknown function. With the human cDNA Atlas microarray, we detected differentially expressed genes modulated by the presence of H19 RNA. Many of the genes that are upregulated by H19 RNA are known to contribute to the invasive, migratory, and angiogenic capacities of cells. Moreover, we provided experimental data indicating that whereas H19 RNA did not have any growth advantage for the cells when cultured in 10% fetal calf serum, it did confer an advantage when cells were cultured in serum-poor medium. This observation can be explained in part by the inability of the H19-expressing cells to induce the cyclin-dependent kinase inhibitor p57(kip2) in response to serum stress. Our results favor the possible role of the H19 gene in promoting cancer progression, angiogenesis, and metastasis.

[Viral hemorrhagic fever as a biological weapon].

The viruses that cause hemorrhagic fever belong to four virus families: the Arenaviridae, Bunyaviridae, Filoviridae and Flaviviridae. These viruses are candidates for biological warfare agents because they are stable when aerosolized and cause severe debilitating disease. Research and development regarding the use of these viruses as warfare agents has been performed in the former Soviet Union and other countries. The introduction of these agents into non endemic countries poses a major public health threat to that country. Israel is not endemic for these agents, and therefore, local infection can occur from a traveller (human or animal) from an endemic country or due to intentional dissemination. Major clinical manifestations of hemorrhagic fevers are that of fever, rash, malaise and hemorrhagic signs. Due to the similarity between syndromes, any person with a history of persistent fever and any sign of hemorrhage should be considered as having viral hemorrhagic fever, and appropriate care instituted. Definitive diagnosis requires laboratory testing and is important to identify a possible biological warfare attack and to prepare for appropriate defense. This paper reviews the viruses that cause hemorrhagic fever, and their role as possible warfare agents.

Use of H19 regulatory sequences for targeted gene therapy in cancer.

We present a tumor gene therapy approach based on the use of regulatory sequences of the H19 gene that are differentially expressed between normal and cancer cells. We constructed expression vectors carrying the gene for the A fragment of diphtheria toxin (DT-A) or herpes simplex virus thymidine kinase (HSV-tk), under the control of a 814 bp 5'-flanking region of the H19 gene. The cell killing activity of these constructs was in accordance with the relative activity of the H19 regulatory sequences in the transfected cells. We evaluated the therapeutic potential of the gene expression constructs driven by H19 regulatory sequences in an animal model of bladder cancer induced by subcutaneous injection of syngeneic bladder tumor cell lines. Intratumoral injection of these constructs caused a significant suppression of subcutaneous tumor growth, with no obvious toxicity toward the host.