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PubMed1977

Hyperthermic potentiation: biological aspects and applications to radiation therapy.

Experimental studies have provided evidence that hyperthermia may be an effective agent, either alone or in combination with ionizing radiation, in the treatment of cancer. Results have shown that temperatures in the range of 42 degrees to 45 degrees C: 1) are cytotoxic, with cell lethality showing little or no dependence on levels of oxygenation; 2) inhibit the recovery of cells from sub-lethal and potentially lethal radiation damage while enhancing the levels of lethal damage; and 3) may be combined with x-irradiation in a manner to improve therapeutic ratios. The observed interaction between hyperthermia and x-rays may in part be due to differences in the Age Response Functions and reassortment of cycling cells to these two agents. Hyperthermia may also greatly change repopulation and re-oxygenation parameters in irradiated tumor and normal tissue volumes. An overall consideration of these and other factors is essential in the design of optimal schedules of combined hyperthermia and x-irradiation treatments in the management of malignant disease.

Animals↗

PubMed2025

Phylogenetic and Genetic Evolution Analysis of Complete SFTSV Genome Sequences in Shandong Province, China.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by SFTS virus (SFTSV). Shandong province is one of the epidemic regions with high incidence rate of SFTS. To investigate phylogenetical and genetic evolution characteristics of SFTSV in Shandong province, we isolated SFTSV from suspected patients between April 2023 and October 2024, and then whole SFTSV genomes were amplified and sequenced in this study. A total of 25 new strains were analyzed together 56 strains submitted in Genbank from Shandong province. Phylogenetical and genetic analyses of the data set revealed that four genotypes were co-circulating in Shandong province. C3 genotype was the most common genotype in each year with lower genetic divergence. 298 amino acid substitutions were detected in the four proteins of SFTSV, but only two substitutions (Arg624Lys and Arg962Ser) had been proven to have potential impacts on biological functions. In addition, one reassortment strain (C3/C4/C4 for L, M and S segments) and three recombinant strains were identified. Analysis of selection pressure at the level of amino acid substitutions indicated genes within the four ORFs of SFTSV were all subjected to negative selection. In conclusion, the genetic characteristics and evolutionary mechanism of SFTSV was complex in Shandong province. It is necessary to conduct continuous surveillance to grasp the genetic evolution patterns, and to discover novel prevalent variants in a timely manner.

China↗

PubMed1979

Genetic analysis of tumorigenesis: IV. Chromosome reduction and marker segregation in progeny clones from Chinese hamster cell hybrids.

Hybrid cells produced by the fusion of pairs of cells, one a tumorigenic derivative of CHEF/16 and the other a nontumorigenic derivative of CHEF/18, give rise to clones which are largely tetraploid, but rare reduced hybrids with chromosome counts in the diploid range have been recovered from tumors of hybrid origin. This paper describes the recovery in cell culture of reduced hybrids in the diploid range by selection with 5-bromodeoxyuridine (BrdU) or methylcellulose as well as by growth in culture of cells from excised tumors. All selected subclones were tumorigenic and resistant to BrdU, but they segregated for resistance to 6-thioguanine. Unselected subclones were tetraploid, nontumorigenic, and sensitive to both drugs. These data show that chromosome reassortment as well as extensive chromosome reduction both occur in a small fraction of the population during growth of each hybrid clone.

Animals↗

PubMed2026

Spatiotemporal patterns of Rift Valley fever virus in Africa: a retrospective genomic epidemiology and phylodynamic modelling study.

BACKGROUND: Rift Valley fever virus (RVFV) is a mosquito-borne zoonotic pathogen causing outbreaks in humans and ruminants across Africa and the Arabian Peninsula. Originally restricted to the Great Rift Valley, RVFV has expanded geographically, prompting its classification by WHO as a pathogen of pandemic potential. We investigated the evolutionary and spatial dynamics of RVFV across Africa. METHODS: We used genomic data generated at the International Livestock Research Institute Nairobi genomic laboratory (BioProject PRJNA1106221) and combined with publicly available datasets retrieved from the National Center for Biotechnology (NCBI) GenBank nucleotide database. In retrieving RVFV genome sequences from the NCBI GenBank, we applied the search terms "Rift Valley fever virus segment L AND 6404[SLEN]", "Rift Valley fever virus segment M AND 3885[SLEN]", and "Rift Valley fever virus segment S AND 1520:1690[SLEN]" for L (Large), M (Medium), and S (Small) segments, respectively. For sequences without additional spatiotemporal information, we searched PubMed to extract the associated sequence metadata. We performed molecular clock analysis, phylogenetic inference, phylodynamic modelling (continuous phylogeographic reconstruction), and landscape phylogeography on the three RVFV genome segments (L, M, and S). We aimed to assess evolutionary rates, dispersal patterns, and environmental drivers. Focus was placed on lineage C, the most widely distributed variant. FINDINGS: The global dataset used in this study consisted of large (n=236), medium (n=237), and small (n=247), which were further filtered to exclude potential reassortants and vaccine strains. Genome sequences retrieved from NCBI GenBank database comprised large (n=180), medium (n=184), and small (n=202). The genome sequences from retrospective human and livestock isolates comprised large (n=56), medium (n=53), and small (n=45) collected in Burundi (2018), Kenya (2007, 2018, 2019, 2021, and 2022), and Rwanda (2018 and 2022). Our dataset revealed that RVFV exhibited low overall genetic diversity. Lineage C, however, showed evidence of active evolution, with substitution rates ranging from 3·58 × 10-4 to 9·76 × 10-4 substitutions per site per year. This lineage probably originated in Zimbabwe in the mid-1970s and has since expanded across eastern and southern Africa. Phylogeographic reconstructions revealed rapid spread, with diffusion coefficients exceeding 50 000 km2 per year. INTERPRETATION: Lineage C appears capable of establishing endemic transmission in new regions, with ongoing diversification observed during interepidemic periods. These observations reinforce the value of continuous genomic surveillance, particularly during cryptic transmission phases when adaptive mutations might emerge. Although further evidence is needed, observed trends in climate variability and land-use change point to the potential benefit of targeted surveillance in settings that could be at increased risk, including urban centres and wetlands. FUNDING: This work was supported by the German Federal Ministry for Economic Cooperation and Development, the Rockefeller Foundation, and the Africa Centres for Disease Control and Prevention.

Rift Valley fever virus↗

PubMed2026

Safety, humoral and cellular immune responses to a pre-pandemic adjuvanted influenza A (H5N8) vaccine.

Highly pathogenic avian influenza (HPAI) A(H5) viruses can be transmitted from infected birds to various mammalian species, including humans. Avian influenza viruses (AIVs), members of the Orthomyxoviridae family, possess segmented RNA genomes prone to reassortment, favoring the emergence of novel genetic traits that may alter transmissibility, pathogenicity, and antigenicity. Although no sustained human-to-human transmission has been reported, the potential adaptation of these viruses poses a significant pandemic threat. This study aimed to evaluate the non-clinical safety, toxicity, and humoral immune responses induced by an adjuvanted H5 influenza vaccine in rats and rabbits, to support future clinical safety trials in humans. Male and female Wistar rats and New Zealand rabbits were observed for 14, 28, and 90 days after receiving two intramuscular doses of the H5N8 vaccine (15 μg HA/dose) formulated with the IB160 oil-in-water emulsion adjuvant. No systemic comorbidities, central nervous system alterations, or relevant clinical signs were observed. Hematological parameters remained within normal ranges, with total and differential leukocyte counts showing only minor fluctuations (<1% of total leukocytes). Mild biochemical variations in urea and hepatic transaminase levels were not correlated with histopathological alterations. The vaccine elicited a robust humoral response soon after immunization, with all groups reaching protective HAI-antibody titers. Although antibody levels declined over time, particularly in males, they remained significantly above baseline, indicating durable immunological memory. Furthermore, the vaccine induced a specific cellular immune response, confirmed by IL-2 and TNF production by antigen-specific T lymphocytes in splenic cell cultures after the booster dose. In conclusion, the H5N8 vaccine with the IB160 adjuvant was well tolerated locally and systemically, without compromising vital organ function. The safety and immunogenicity findings are consistent with expectations for adjuvanted influenza vaccines, demonstrating strong and durable humoral and cellular immune responses.

H5N8 influenza vaccine↗

PubMed1978

Studies on enzyme variation in the murine malaria parasites Plasmodium berghei, P. yoelii, P. vinckei and P. chabaudi by starch gel electrophoresis.

Electrophoretic variation of the enzymes glucose phosphate isomerase, 6-phosphogluconate dehydrogenase, lactate dehydrogenase and glutamate dehydrogenase (NADP-dependent) has been studied in the African murine malaria parasites Plasmodium berghei, P. yoelii, P. vinckei and P. chabaudi and their subspecies. Horizontal starch gel electrophoresis was used throughout. The number of isolates examined in each subspecies varied from 1 (P. y. nigeriensis) to 24 (P. c. chabaudi). Extensive enzyme variation was found among isolates of most of the subspecies from which more than two such isolates were available for study. It is clear that the phenomenon of enzyme polymorphism is of common occurrence among malaria parasites. With the exception of P. berghei and P. yoelii, of which all isolates share an identical electrophoretic form of lactate dehydrogenase, no enzyme forms are shared between any of the 4 species of murine plasmodia. By contrast, within each species common enzyme forms are shared among each of the subspecies. The subspecies are nevertheless, distinguished from each other by the electrophoretic forms of at least one enzyme. The distribution and reassortment of enzyme variation among isolates of a single subspecies is in accordance with the concept of malaria parasites as sexually reproducing organisms. The study of variation among parasites present in individual wild-caught rodent hosts demonstrates that natural malarial infections usually comprise genetically heterogeneous populations of parasites. Nevertheless, the number of genetically distinct types of parasite of any one species present in a single infected host appears to be small. Generally not more than 2 or 3 clones of parasite of distinct genetic constitution are present in a single infected animal.

Animals↗

PubMed1979

Segment 8 of the influenza virus genome is unique in coding for two polypeptides.

In previous studies we showed that a ninth polypeptide with a molecular weight of approximately 11,000 (NS2) found in influenza virus-infected cells was unique, that it could be synthesized in vitro, and that its expression in vivo required early protein synthesis. On the basis of these results we suggested that one of the eight genome RNA segments of influenza virus codes for two polypeptides [Lamb, R.A., Etkind, P.R. & Choppin, P.W. (1978) Virology 91, 60-78]. We describe here differences in the electrophoretic mobility of the NS2 polypeptides of different strains of influenza A virus. These results provided further evidence that NS2 is virus coded and also made possible genetic studies using recombinants between two virus strains (HK and PR8) whose NS2 polypeptides differ. These studies showed that the gene for NS2 reassorts with that of the nonstructural polypeptide NS1, which is coded by genome segment 8. A mRNA for NS2 has been separated from that of NS1 and the other viral polypeptides by centrifugation and has been translated in vitro. Hybridization of genome segment 8 to the total mRNAs from infected cells specifically prevented the synthesis of NS2 and NS1. These results indicate that influenza virus genome segment 8 is transcribed into two separate mRNAs that code for two polypeptides, NS1 and NS2. Possible mechanisms for the transcription of the two mRNAs from either contiguous or overlapping genes are discussed.

DNA, Viral↗

PubMed1979

Evolution of human influenza A viruses in nature: recombination contributes to genetic variation of H1N1 strains.

In June of 1977, a new influenza A pandemic was started by strains of the H1N1 serotype. Oligonucleotide fingerprint analysis of the RNA from viruses isolated during the early stage of this pandemic demonstrated that genetic variation among these 1977 strains could be attributed to sequential mutation [Young, J.F., Desselberger, U. & Palese, P. (1979) Cell, 18, 73-83]. Examination of more recent strains revealed that the H1N1 variants that were isolated in the winter of 1978-1979 differed considerably from the H1N1 viruses isolated the previous year. Oligonucleotide and peptide map analysis of the new prototype strain (A/Cal/10/78) suggested that it arose by recombination. It appears that only the HA, NA, M, and NS genes of this virus are derived from the earlier H1N1 viruses and that the P1, P2, P3, and NP genes most likely originate from an H3N2 parent. These data suggest that genetic variation in influenza virus strains of the same serotype is not restricted to mutation alone, but can also involve recombination (reassortment).

Antigens, Viral↗

PubMed2026

Immunogenicity and efficacy of a rabies-based vaccine against highly pathogenic influenza H5N1 virus.

The recent spillover of highly pathogenic influenza A/H5N1 (HPAI-H5N1) viruses to cattle, other mammals, and humans poses a major risk to animal and human health. Virus adaptation to new species highlights the need for effective vaccines for animals and humans. We recently developed a rabies virus-based H5 vaccine encoding the HPAI-H5 antigen and presenting it on the surface of the rabies virus particle. To test the immunogenicity and efficacy of the vaccine in eliciting systemic and mucosal immune response, we vaccinated mice intramuscularly or intranasally with either live or inactivated and adjuvanted vaccine. The vaccine elicited neutralizing antibodies against RABV and H5N1 Influenza virus and protected mice from a lethal challenge with PR8 recombinants reassorted with the HA of clade 1 (Viet Nam 1203) or clade 2.3.4.4b HPAI-H5N1 viruses, highlighting its potential use in mitigating the risk of HPAI-H5N1 pandemic.

Influenza A Virus, H5N1 Subtype↗

PubMed1977

Temperature-sensitive mutants of influenza A virus. XIV. Production and evaluation of influenza A/Georgia/74-ts-1[E] recombinant viruses in human adults.

The two temperature-sensitive (ts) lesions present in influenza A/Hong Kong/68-ts-1[E] (H3N2 68) virus were transferred via genetic reassortment to influenza A/Georgia/74 (H3N2 74) wild-type virus. A recombinant clone possessing both ts lesions and the shutoff temperature of 38 C of the Hong Kong/68 ts donor and the two surface antigens of the Georgia/74 wild-type virus was administered to 32 seronegative adult volunteers. Thirty-one volunteers were infected, of whom only five experienced mild afebrile upper respiratory tract illness. The wild-type recipient virus was a cloned population that induced illness in five of six infected volunteers. Therfore, the attenuation exhibited by the Georgia/74-ts-1[E] virus could reasonably be assumed to be due to the acquisition of the two ts-1[E] lesions by the Georgia/74 wild-type virus. The serum and nasal wash antibody responses of the ts-1[E] vaccinees were equivalent to those of the volunteers who received wild-type virus. The two ts lesions present in the Hong Kong/68-ts-1[E] virus have now been transferred three times to a wild-type virus bearing a new hemagglutinin, and in each instance the new ts recombination exhibited a similar, satisfactory level of attenuation and antigenicity for adults. It seems likely that the transfer of the ts-1[E] lesions to any new influenza virus will regularly result in attenuation of a recombinat virus possessing the new surface antigens.

Animals↗

PubMed1978

The isolation of recombinants between related orbiviruses.

Temperature-sensitive mutants of the related orbiviruses, Wallal and Mudjinbarry, recombine with high frequency when grown in pairs in cell culture. The genome of each virus consists of discrete segments of double-stranded RNA and high frequency recombination suggests that reassortment of genome segments occurs rather than classical recombination. Electrophoresis in acrylamide gels of RNA extracted from the progeny of a cross between Wallal ts 101 and Mudjinbarry ts 3 mutants, revealed that three plaque isolates of 60 tested differed in RNA pattern from each of the parent viruses and from each other. Further analysis of the electrophoretic profiles suggested that the isolates were recombinants with RNA segments derived from each of the parent viruses.

Arboviruses↗

PubMed1978

Cell proliferation in EMT6 tumors treated with single doses of x-rays or hydroxyurea. I. Experimental results.

EMT6 mouse mammary tumors were treated in vivo with 5 mg/mouse of hydroxyurea (HU) or 300 rads of X-rays. The proliferation of the tumor cells was followed for 28 hr after treatment. Changes in the 3H-TdR labeling index, the mitotic index, the specific activity of the 3H-TdR-labeled DNA, and the proportion of suspended, clonogenic cells in the S phase of the cell cycle were examined and compared. Evidence was found for reassortment of the surviving cells in treated tumors into partially synchronous cohorts. The partial synchrony in the proliferation of the surviving cells was not accurately predicted by the changes in the labeling index and the mitotic index. The changes in DNA specific activity proved unacceptable as an indicator of cell proliferation in solid EMT6 tumors treated with low doses of radiation or HU.

Animals↗

PubMed1977

Selection of influenza B virus recombinants and their testing in humans for attenuation and immunogenicity.

The selection of influenza B virus recombinants from plaques in bovine kidney cell monolayers is described. Two sets of recombinants were each derived from parents of high and low virulence for humans, respectively. Recombination frequency was apparently high, and reassortment of genes made it possible to obtain attenuated recombinants containing the surface antigens of the virulent parents. Attenuation and immunogenicity were demonstrated in a series of volunteer trials. However, technique proved less satisfactory than for influenza A viruses which periodically undergo antigenic shift and for which there is a wide choice of parent viruses with distinctive surface antigens. In our two influenza B recombinant series there was appreciable antigenic overlap in the neuraminidases of the parents, even though in both cases these were chronologically widely separated. Another marker used was comparative titer at 35 and 38 degrees C. In practice, technical problems might sometimes make it difficult to ensure rapid production of live influenza B vaccines by recombination.

Antibody Formation↗

PubMed2026

Identification and full genome sequencing of previously unknown sandfly-borne phleboviruses using a newly established capture-based next-generation sequencing approach.

Sandfly-borne phleboviruses cause febrile illness and neuroinvasive disease in humans. While infections are reported in the Mediterranean region, the discovery of previously unknown phleboviruses in sandflies from Kenya suggests a wider geographic distribution. Detection and characterization of novel phleboviruses are often hindered by low-quality and low-viral-load samples. We developed a capture-based target enrichment next-generation sequencing approach that showed a 99%-100% fold enrichment of viral genomes from primary material and provides a robust tool for generating complete genomes of both known and previously unknown viruses. From a collection of 15,652 sandflies in Kenya, we recovered seven complete coding sequences of Embossos, Bogoria, and Kiborgoch viruses, and of two previously unknown phleboviruses, which were named Sosoik and Shable viruses. Sosoik virus shared 83% amino acid identity in its RdRp gene with that of Bogoria virus, while Shable virus shared ca. 88% amino acid identity with viruses of the Salehabad serocomplex. Additionally, a reassortant of Shable virus was detected that possessed an M segment from an undescribed Ponticelli-like virus. DNA barcoding of blood-fed sandflies revealed several potentially novel Sergentomyia species and evidence of host-feeding on humans, livestock, and reptiles, suggesting possibilities for zoonotic transmission. Overall, our findings increase the known genetic diversity of Old World sandfly-borne phlebovirus species from 18 to 25 (by 38.9%), including the detection of viruses from all pathogenic sandfly-borne phlebovirus serocomplexes in East Africa, opening new horizons in disease ecology research.IMPORTANCEKnowledge of the genetic diversity of circulating pathogens is crucial for providing appropriate diagnostics and disease management. This study established a novel capture-based target enrichment next-generation sequencing approach that enabled the near-complete viral genome recovery from primary samples, while native NGS yielded negative or poor-quality results. In addition to the five recently discovered sandfly-borne phleboviruses in Kenya, two previously unknown phleboviruses were detected in sandflies from the same region. The viruses were detected in several sandfly species, which showed diverse host-feeding behaviors, including mixed feeding on humans and chickens. The study significantly advances the understanding of sandfly-borne phleboviruses by uncovering their broader geographic distribution and genetic diversity, particularly in East Africa, highlighting the importance of expanding surveillance efforts beyond traditionally studied regions.

Phlebovirus↗

PubMed1977

Formation of recombinants between snowshoe hare and La Crosse bunyaviruses.

Wild-type recombinants were obtained at high frequency from coinfections of BHK cells involving temperature-sensitive, conditional-lethal mutants of snowshoe hare (SSH) and La Crosse (LAC) bunyaviruses. Analyses of two of the recombinants indicated that they have the genome compositions SSH/LAC/SSH and SSH/LAC/LAC for their respective L, M, and S virion RNA species. This evidence, together with that for the genetic stability of the recombinants, indicates that they were derived by segment reassortment of the competent genome pieces of the parental viruses. The SSH/LAC/SSH recombinant appears, from polypeptide analysis, to have the SSH type of nucleocapsid protein (N), whereas the SSH/LAC/LAC recombinant has the LAC nucleocapsid protein, suggesting that the viral S RNA codes for the N protein.

Animals↗

PubMed1979

Isolation of influenza C virus recombinants.

Recombinants between two different influenza C viruses were isolated. In MDCK (canine kidney) cells, one strain, C/JJ/50, caused lytic plaques, whereas C/JHG/66 virus did not produce clear plaques. From a mixed infection of MDCK cells with C/JHG/66 virus and UV-inactivated C/JJ/50 virus, clones were isolated which possessed the clear-plaque phenotype. Fingerprint analyses indicated that the RNAs of parent viruses had different oligonucleotide patterns and that one of the clones derived from the mixed infection was formed by reassortment of parental genes. This recombinant clone most likely inherited RNAs 1, 2, 3, 6, and 7 from C/JGH/66 virus and RNAs 4 and 5 from C/JJ/50 virus.

Animals↗

PubMed1979

Approaches towards rational antiviral chemotherapy.

Present epidemic influenza is uncontrolled by immuno- or chemoprophylaxis. Mutants of varying antigenic composition arise with relatively high frequency in nature and are able to circumvent herd, or induced, immunity. Also, drug-resistant viruses can be selected in vitro and this resistance can be exchanged to other viruses by gene reassortment. Combined immuno- and chemoprophylaxis may provide a more effective approach to the ultimate control of the disease. Most antiviral compounds have been selected by random screening in the laboratory. Application of more specific enzyme assays such as the virion-associated RNA transcriptase assays may produce other compounds with a defined mode of action - semi-rational chemotherapy. RNA and polypeptide sequence studies are in progress elsewhere to define transcription and translation initiation sites or virus adsorption sites. Such knowledge could lead to a new generation of antiviral compounds. Specific delivery of virus inhibitory compounds is an interesting problem. Liposomes are lipid spheres, and these have been used for the delivery of antiviral compounds.

Antiviral Agents↗

PubMed2025

Mammalian antiviral proteins ZAP and KHNYN can independently restrict CpG-enriched avian viruses.

Zoonotic viruses are an omnipresent threat to global health. Influenza A virus (IAV) transmits between birds, livestock, and humans. Proviral host factors involved in the cross-species interface are well known. Less is known about antiviral mechanisms that suppress IAV zoonoses. We observed CpG dinucleotide depletion in human IAV relative to avian IAV. Notably, human ZAP selectively depletes CpG-enriched viral RNAs with its cofactor KHNYN. ZAP is conserved in tetrapods, but we uncovered that avian species lack KHNYN. We found that chicken ZAP may not affect IAV (PR8) or CpG-enriched IAV (PR8CG). Human ZAP or KHNYN independently restricted CpG-enriched IAV PR8CG by overexpression in chicken cells and by combined knockout in human cells. Additionally, mammalian ZAP-L and KHNYN also independently restricted an avian retrovirus (ROSV). Curiously, platypus KHNYN, the most divergent from eutherian mammals, was also capable of independent restriction of multiple diverse viruses. We suggest that some mammalian KHNYN can act as a bona fide restriction factor with cell-autonomous activity. Furthermore, we speculate that through repeated contact between avian viruses and mammalian hosts, protein changes may accompany CpG-biased mutations or reassortment to evade mammalian ZAP and KHNYN.

Animals↗