Hematopoietic stem cell (HSC) transplantation (HSCT) is used to treat various hematologic disorders. Use of genetically modified mouse models of hematopoietic cell transplantation have been critical in our fundamental understanding of HSC biology and developing approaches for human patients. Pre-clinical studies in animal models provide insight into the journey of transplanted HSCs from infusion to engraftment in bone marrow (BM) niches. Various signaling molecules and growth factors secreted by HSCs and the niche microenvironment play critical roles in homing and engraftment of the transplanted cells. The sustained equilibrium of these chemical and biologic factors ensures that engrafted HSCs generate healthy and durable hematopoiesis. Transplanted healthy HSCs compete with residual host cells to repopulate stem cell niches in the marrow. Stem cell niches, in particular, can be altered by the effects of previous treatments, aging, and paracrine effects of leukemic cells that create inhospitable bone marrow niches that are unfavorable for healthy hematopoiesis. More work to understand how stem cell niches can be restored to favour normal hematopoieis may be key to reducing leukemic relapses following transplant.

ESBL-producing E. coli is a growing public problem in healthcare settings and the community. Between 2009 and 2018, a total of 187 ESBL-producing pathogenic E. coli isolates were confirmed, and clonal complex (CC) 10 was the predominant clone. This study aimed to characterize ESBL-producing pathogenic E. coli CC10 strains obtained from diarrheal patients to improve the understanding of CC10 distribution in the Republic of Korea. A total of 57 CC10 strains were selected for molecular characterizations, such as the identification of serotype, antibiotic resistance genes, genetic environments, plasmid profiles, and the genetic correlation between CC10 strains. In the CC10 isolates, the most prevalent serotype was O25:H16, followed by O6:H16. ESBL genes were identified as blaCTX-M, and the most dominant ESBL gene was blaCTX-M-15 (56%) and blaCTX-M-14 (30%). Most blaCTX-M genes were located on plasmids, and these plasmid profiles were confirmed as IncB/O/K/Z, IncF, IncI1 and IncX1. The mobile elements located up-and down-stream mainly included ISEcp1 (complete or incomplete) and IS903 or orf477 were found, respectively. Phylogenetic analysis showed that the CC10 strains were genetically diverse and divided into several distinct lineages. In this study, we found that CC10 ESBL-producing pathogenic E. coli has been steadily isolated; particularly, CTX-M-15-producing E. coli O25:H16 isolates were the major type related with distribution in CC10 clones during the last decade. Identification of ESBL-producing pathogenic E. coli CC10 isolates highlights the possibility of the emergence of resistant isolates with epidemic potential within this CC. Therefore, continuous monitoring will be conducted to prevent further spread of resistant ESBL-producing E. coli CC10 strains.

Understanding the evolution patterns in patients diagnosed with acute myeloid leukemia (AML) after therapy is relevant due to the dismal outcome still present in refractory or relapsed AML patients. We performed a retrospective, single-center study to evaluate the mutation profile in paired samples obtained at the time of diagnosis and at the onset of progressive or refractory disease in patients diagnosed with AML through a commercial next-generation sequencing (NGS) panel. In total, 62 patients were analyzed. Of these, 28 patients received ICT, and 34 patients underwent low-intensity treatments. In LIT patients, there were emergent mutations at progressive disease in a 64% (22/34) of the patients. Emergent mutations in the RAS-MAPK signaling pathway were observed in 35.9% (12/34) , corresponding to 54.5% of all patients with emergent mutations (12/22). These were found in 12/22 patients that received venetoclax in combination with hypomethylating agents. Six presented mutations in genes related to the RAS-MAPK pathway. Emerging mutations are frequently observed at progressive AML disease after therapy. In patients treated with LIT, mutations in RAS-MAPK signaling pathway might have a key role on the secondary clinical resistance, not only if they are present at diagnosis, becoming a potential target for the development of new drugs.

The genus Eucalyptus is a globally captivated source of hardwood and is well known for its medicinal uses. The hybrid and wild species of Eucalyptus are widely used as exotic plantations due to their renowned potential of adapting to various systems and sites, furthermore, making the species the most extensively propagated. Despite unquestionable progression in biotechnological and tissue culture approaches, the productivity of plantations is still limited often due to the low efficiency of clonal propagation from cuttings. The obtained F1 hybrids yield high biomass and High-quality low-cost raw material for large-scale production, however, the development of hybrid, clonal multiplication, proliferation, and post-developmental studies are still major concerns. This riveting review describes the problems concerned with in-vitro and clonal propagation of Eucalypt plantation; recent advances in biotechnological and tissue culture practices for massive and rapid micro-propagation of Eucalyptus; as well, highlights the Eucalypt germplasm preservation techniques.

The case of a patient with autoimmune haemolytic anaemia and an anastomosing haemangioma, is presented. The main dilemma was whether the haemangioma was the cause or the consequence of the autoimmune haemolytic anaemia and how both processes should be management. The diagnostic methods used are analytical and imaging techniques, which have not been conclusive in the diagnosis of anastomosing haemangiomas. Preoperative corticosteroid treatment does not prevent the recurrence of autoimmune haemolytic anaemia in the postoperative period. Surgical indication is established by the progression of proliferative activity, tumor enlargement and compression of the vena cava over time. Surgical resection of the tumor is the procedure used. The indication for surgical treatment of the anastomosing haemangioma and the decrease in alpha- fetoprotein after tumor resection are the most relevant results, although it increases again after a few weeks. The development of an anastomotic haemangioma may be secondary to autoimmune haemolytic anaemia. Angiogenesis resulting from the formation of erythroblastic islands at the periphery of the tumor and clonal expansions may be a mechanism to compensate for the haemolysis caused by autoimmune haemolytic anaemia

Neuroblastoma is an embryonal tumor arising from the sympathetic central nervous system. The epidermal growth factor (EGF) plays a role in neuroblastoma growth and metastatic behavior. Recently, we have demonstrated that cathepsin D (CD) contrasts EGF-induced neuroblastoma cell growth in 2D by downregulating EGFR/MAPK signaling. Aggressive NB is highly metastatic to the bone and the brain. In the metastatic process, adherent cells detach to form clusters of suspended cells that once reached the metastatic site adhere and form secondary colonies. Whether CD involves in survival of metastatic NB clones is not known. Therefore, in this study we addressed how CD differentially affects cell growth in suspension versus adherent condition. To mimic tumor heterogeneity, we co-cultured transgenic clones silenced for or overexpressing CD. We compared the growth kinetics of such mixed clones in 2D and 3D models in response to EGF, and we found that Over CD clone was advantaged for the growth in suspension, while the CD knocked-down clone was favored for the adherent growth as 2D. The fact that CD plays a dual role in cancer cell growth in 2D and 3D conditions indicates that during clonal evolution subclones expressing different level of CD may arise, which confers survival and growth advantages depending on the metastatic step. Whether CD involves in survival of metastatic NB clones is not known. We propose that epigenetic regulation of CD expression could be an additional strategy to prevent NB metastases.

Under one-health perspective and the worldwide antimicrobial resistance concern, we investigate extraintestinal pathogenic Escherichia coli (ExPEC), uropathogenic E. coli (UPEC), and multidrug resistant (MDR) E. coli from 197 isolates recovered from healthy dogs in Spain between 2013 and 2017. Ninety-one (46.2%) isolates were classified as ExPEC and/or UPEC including 50 clones, among which (i) four clones were dominant (B2-CH14-180-ST127, B2-CH52-14-ST141, B2-CH103-9-ST372 and F-CH4-58-ST64815) and (ii) 15 had been shown to be displayed by previously published isolates causing extraintestinal infections in humans. Twenty-eight (14.2%) isolates were classified as MDR, associated with B1, D and E phylogroups and included 24 clones, of which eight had also been identified among human isolates causing infections. We selected 23 ST372 strains, 21 healthy dogs faecal isolates and two human clinical isolates for whole genome sequencing and built a SNP-tree with these 23 genomes and 174 genomes (128 from canine strains and 46 from human strains) obtained from public databases. The analysis of these 197 genomes allowed to identify six clusters. Cluster 1 comprised 74.6% of the strain genomes that were mostly composed of canine strain genomes (P < 0.00001). Clusters 4 and 6 also included canine strain genomes, while clusters 2, 3 and 5 were significantly associated with human strain genomes. All these findings suggest that dogs are reservoirs of ExPEC, UPEC and MDR E. coli isolates with zoonotic potential.

Escherichia coli is the main pathogen responsible for extraintestinal infections. A total of 196 clinical E. coli consecutively isolated during 2016 in Spain (100 from Lucus Augusti hospital in Lugo) and France (96 from Beaujon hospital in Clichy) were characterized. Phylogroups, clonotypes, sequence types (STs), O:H serotypes, virulence factor (VF)-encoding genes and antibiotic resistance were determined. Approximately 10% of the infections were caused by ST131 isolates in both hospitals and approximately 60% of these infections were caused by isolates belonging to only 10 STs (ST10, ST12, ST58, ST69, ST73, ST88, ST95, ST127, ST131, ST141). ST88 isolates were frequent especially in Spain while ST141 isolates significantly predominated in France. The 23 ST131 isolates displayed four clonotypes: CH40-30, CH40-41, CH40-22 and CH40-298. Only 13 (6.6%) isolates were carriers of ESBL enzymes. However, 37.2% of the isolates were multidrug-resistant (MDR). Approximately 40% of the MDR isolates belonged to only four of the dominant clones (B2-CH40-30-ST131, B2-CH40-41-ST131, C-CH4-39-ST88 and D-CH35-27-ST69). Among the remaining MDR isolates two isolates belonged to B2-CH14-64-ST1193 i.e the new global emergent MDR clone. To our knowledge, it is the first identification of this emergent clone in Spain. Moreover, a hybrid ExPEC/enteroaggregative isolate belonging to A-CH11-54-ST10 clone was identified.

Brain metastases are highly evolved manifestations of breast cancer arising in a unique microenvironment, giving them exceptional adaptability in the face of new extrinsic pressures. The incidence is rising in line with population ageing, and use of newer therapies that stabilise metastatic disease burden with variable efficacy throughout the body. Historically, there has been a widely held view that brain metastases do not respond to circulating therapeutics because the blood-brain-barrier (BBB) restricts their uptake. However, emerging data are beginning to paint a far more complex picture where the brain acts as a sanctuary for dormant, subclinical proliferations that are initially protected by the BBB, but then exposed to dynamic selection pressures as tumours mature and vascular permeability increases. Here, we review key experimental approaches and landmark studies that have charted the genomic landscape of breast cancer brain metastases. These findings are contextualised with the factors impacting on clonal outgrowth in the brain: intrinsic breast tumour cell capabilities required for brain metastatic fitness, and the neural niche, which is initially hostile to invading cells but then engineered into a tumour-support vehicle by the successful minority. We also discuss how late detection, abnormal vascular perfusion and interstitial fluid dynamics underpin the recalcitrant clinical behaviour of brain metastases, and outline active clinical trials in the context of precision management.

Chromosomal instability (CIN), defined by variations in the number or structure of chromosomes from cell to cell, is recognized as a distinctive characteristic of cancer, associated with the ability of tumors to adapt to challenging environments. CIN has been recognized as a source of genetic variation that leads to clonal heterogeneity (CH). Recent findings suggest a potential association between CIN and CH with the prognosis of BC patients, particularly in tumors expressing the epidermal growth factor receptor 2 (HER2+). In fact, information on the role of CIN in other BC subtypes, including luminal B BC, is limited. Additionally, it remains unknown whether CIN in luminal B BC tumors, above a specific threshold, could have a detrimental effect on the growth of human tumors, or if low or intermediate CIN levels could be linked to a more favorable BC patient prognosis when contrasted with elevated levels. Clarifying these relationships could have a substantial impact on risk stratification and the development of future therapeutic strategies aimed at targeting CIN in BC. This study aimed to assess CIN and CH in tumor tissue samples from ten patients with luminal B BC, and compared them with established clinicopathological parameters. The results of our study show that luminal B BC patients exhibit intermediate CIN and stable aneuploidy, both of which correlated with lymphovascular invasion. These findings suggest that evaluating CIN, CH and aneuploidy could improve risk stratification, the prediction of clinical outcomes and future therapeutic approaches in luminal B BC patients.

In the case of indigenous grapevine varieties, the aim of clonal selection is twofold: to improve their technological cultivation problem while preserving the varietal character. As the sensitivity of perennial crops to climate change becomes more pronounced, clonal selection, which is already very time-consuming for perennial woody crops, may take even longer. In Badacsony, clonal selection breeding of the ‘Kéknyelű’ and ‘Juhfark’ varieties was started in the early 2000s. The problem mentioned above in cultivation technology is the poor fertility of ‘Kéknyelű’ (functionally female-flowered variety), while in the case of ‘Juhfark’ the high susceptibility to grey rot (Botrytis). Based on 11 years of data significant difference in yield between clone B.2. and the base variety was found. In this comparison the year clusters also gave different values, as in years belonging to cluster 1 the ’Kéknyelű’ yielded more than in another year. Both clones of ‘Kéknyelű’ matured with significantly lower pH compared to the base variety. ‘Kéknyelű' is renowned for the distinctive variety character of its wine, which is said to be acidic. Given the acidic nature of ‘Kéknyelű’ wine and the expected increase in must degrees and pH due to climate change, these distinctions may be beneficial in the future. Daily meteorological parameters were also recorded in the years under study, and different indexes were calculated for both of varieties for different phenological periods. The years were classified into 3 clusters and the harvest data were analyzed within each cluster. In the case of 'Kéknyelű' our results revealed significant differences in yield between vintage clusters for clone B.2. However, clone B.1 demonstrated distinct KMW and pH values. Both 'Kéknyelű’ clones have produced a substantially higher incidence of Botrytis infection in cluster 2 years than in cluster 3 years. Botrytis infection only showed statistically significant differences between year clusters for ‘Juhfark’. It is intriguing that in most years, the rotting rate was lower in both clones, especially in year clusters 1 and 3 when the overall rate of Botrytis infection was quite low. Our results highlighted the year-round sensitivity of the two varieties studied and the difficulties of clonal selection.

The principal barrier to an HIV-1 cure is the persistence of infected cells harboring replication-competent proviruses despite antiretroviral therapy (ART). HIV-1 transcriptional suppression, referred to as viral latency, is foremost among persistence determinants, as it allows infected cells to evade the cytopathic effects of virion production and killing by cytotoxic T lymphocytes (CTL) and other immune factors. HIV-1 persistence is also governed by cellular proliferation, an innate and essential capacity of CD4+ T cells that both sustains cell populations over time and enables a robust directed response to immunological threats. Yet when HIV-1 infects CD4+ T cells, this capacity for proliferation can counterproductively enable surreptitious HIV-1 propagation without the deleterious effects of viral gene expression in latently infected cells. Over time on ART, the HIV1 reservoir is shaped by both persistence determinants, with selective forces most often favoring clonally expanded infected cell populations harboring transcriptionally quiescent proviruses. Moreover, if HIV latency is incomplete or sporadically reversed in clonal infected cell populations that are replenished faster than they are depleted, such populations could both persist indefinitely and contribute to low-level persistent viremia during ART and viremic rebound if treatment is withdrawn. In this review, select genetic, epigenetic, cellular, and immunological determinants of viral transcriptional suppression and clonal expansion of HIV-1 reservoir T cells, interdependencies among these determinants, and implications for HIV-1 persistence will be presented and discussed.

: For a long time, atherosclerosis has been regarded as a mere lipid deposit in the blood vessels. However, in the recent years a growing body of experimental and clinical evidence have highlighted the role of inflammation and immunity as a central mechanism of disease. Moreover, in the last decade the coming of next-generation sequencing and its application to large human population has broken the barrier between inflammation and cancer. Indeed, acquired mutation in key genes related to the control of hematopoiesis and myeloproliferation have paved the way to establish the new concept of clonal hematopoiesis of indeterminate potential. This phenomenon is being considered not such “indeterminate”, but as an emerging cardiovascular risk factor. Thus, this may explain the mechanisms of myeloproliferation and inflammation in atherosclerosis. And in a bidirectional journey, it has helped to explain the extremely high cardiovascular risk in cancer survivors, in particular in myeloprolfierative neoplasm patients. A deeper understanding of these mechanisms may pave the way for the future early diagnosis and potential preemptive treatments of the leading worldwide cause of death.

Aspergillus fumigatus is a ubiquitous, critical priority human fungal pathogen. Despite its clinical importance, there is limited knowledge regarding the variations of the genome within mitochondria, the powerhouse organelle within eukaryotic cells. In this study, we leveraged publicly available raw, whole genome sequence data from 1939 isolates to investigate the variations in the mitochondrial genomes of A. fumigatus. These isolates were isolated from 22 countries on six continents, as well as from outer space and from within the International Space Station. In total, our analysis revealed 39 mitochondrial single nucleotide polymorphisms (mtSNPs) within this global sample and together, these 39 mtSNPs grouped the 1939 isolates into 79 mitochondrial multilocus genotypes (MLGs). Among the 79 MLGs, 39 were each distributed in at least two countries and 30 were each shared by at least two continents. The two most frequent MLGs were also broadly distributed: MLG11 represented 420 isolates from 11 countries and four continents and while MLG79 represented 418 isolates from 18 countries and five continents, consistent with long-distance dispersals of mitogenomes. Our population genetic analyses of the mtSNPs revealed limited differentiation among continental populations but highly variable genetic differences among national populations, largely due to localized clonal expansions of different MLGs. Phylogenetic analysis and Discriminant Analysis of Principal Components of mtSNPs suggested the presence of at least three mitogenome clusters. Linkage disequilibrium, Index of Association, and phylogenetic incompatibility analyses collectively suggested evidence for mitogenome recombination in natural populations of A. fumigatus. In addition, sequence read depth analyses revealed an average ratio of ~20 mitogenomes per nuclear genome in this global population but the ratios varied among strains within and between certain geographic populations. Together, our results suggest evidence for organelle dynamics, genetic differentiation, recombination, and both widespread and localized clonal expansion of the mitogenomes in the global A. fumigatus population.

The current classification of acute myeloid leukemia (AML) relies largely on genomic alterations. AML with mutated Nucleophosmin1 (NPM1-mut) is the largest of the genetically defined groups, involving about 30% of adult AMLs and is currently recognized as a distinct entity in the actual AML classifications. NPM1-mut AML usually occurs in de novo AML and is associated predominantly with a normal karyotype and relatively favorable prognosis. However, NPM1-mut AMLs are genetically, transcriptionally, and phenotypically heterogeneous. Furthermore, NPM1-mut is a clinically heterogenous group. Recent studies have in part clarified the consistent heterogeneities of these AMLs and have strongly supported the need for an additional stratification aiming to improve the therapeutic response of the different subgroups of NPM1-mut AML patients.

Recently concluded, large-scale cancer genomics studies involving multiregion sequencing of primary tumors and paired metastases appear to indicate that many or most cancer patients have one or more “clonal" mutations in their tumors. Clonal mutations are those that are present in all of a patient’s cancer cells. Clonally mutated proteins can potentially be targeted by inhibitors or E3 ligase small molecule glues, but developing new small molecule drugs for each patient is not feasible currently. Achilles Therapeutics is currently the only company specifically targeting clonal mutations. However, they are doing so with tumor-derived T cells. To address the potential limitations of immunotherapy, I have devised another approach for exploiting clonal mutations, which I call “Oncolytic Vector Efficient Replication Contingent on Omnipresent Mutation Engagement” (OVERCOME). The ideal version of OVERCOME would likely employ a bioengineered facultative intracellular bacterium. The bacterium would initially be attenuated, but (transiently) reverse its attenuation upon clonal mutation detection.

Aimed to obtain purple garlic varieties, 360 bolting bulbs from the Protected Geographical Indication (PGI) “Las Pedroñeras” were selected for their size, and the presence of abundant external scales. After a further selection, 243 out of the 360 bulbs were discarded due to undesired characteristics, as light purple color, high number of small cloves, cloves affected by Fusarium spp. and mites, among other. It was stablished that each bulb would give rise to a family. Thus, 117 families were planted under a random design during season 2021-2022. Either physiological, morphological and phenological traits were assessed for each family, and the affectations by pest and pathogens were also controlled. After the assessment of this trial, 103 out 117 families remained in the program, and were used for the establishment of a second trial the next season. Unlike the first trial, after the evaluations only 23 families remained in the program. There was observed a high variability for most of traits, with a great influence of families. The phenotypic behavior of families was significative influenced by environment, highlighting the need of their assessment under different environmental conditions. The high variability registered for the target sample, opens the possibility to select new garlic varieties from this PGI.

Anticancer regimens for Hodgkin lymphoma (HL) patients include highly genotoxic drugs that have been very successful in killing tumor cells and providing a 90% disease-free survival at five years. However, these treatments do not have a specific cell target, damaging both cancerous and normal cells. Thus, HL survivors have a high risk of developing new primary cancers, both hematologic and solid tumors, that have been related to treatment. Several studies have shown that after-treatment, HL patients and survivors present persistent chromosomal instability, including non-clonal chromosomal aberrations. The frequency and type of chromosomal abnormalities appear to depend on the type of therapy and the cell type examined. For example, MOPP chemotherapy affects hematopoietic and germ stem cells leading to long-term genotoxic effects and azoospermia, while ABVD chemotherapy affects transiently sperm cells, with most of the patients showing recovery of spermatogenesis. Both regimens have long-term effects in somatic cells, presenting non-clonal chromosomal aberrations and genomic chaos in a fraction of non-cancerous cells. This is a source of karyotypic heterogeneity that could eventually generate a more stable population acquiring clonal chromosomal aberrations and leading towards the development of a new cancer.

At the end of 2023 the Whole Mouse Brain Atlas was announced, revealing that there are about 5,300 molecularly defined neuronal types in the mouse brain. We ask whether brain models exist that contemplate how this is possible. The conventional columnar model, implicitly used by the authors of the Atlas, is incapable of doing so with only 20 brain columns (5 brain vesicles with 4 columns each). We argue that definition of some 1,250 distinct progenitor microzones, each producing over time minimally 4-5 neuronal types, may be sufficient. This is nearly achieved presently by the prosomeric model amplified by secondary dorsoventral and anteroposterior microzonation of progenitor areas, plus clonal variation of cell types produced on average by each of them.

Abstract: The study used whole-genome sequencing (WGS) and bioinformatics analysis for the genomic characterization of 60 isolates of Listeria monocytogenes isolated from cattle farms, cattle abattoirs, and retail outlets in Gauteng province, South Africa. The isolates' sequence types (STs), clonal complexes (CCs), and lineages were determined using in silico multilocus sequence typing (MLST). We used BLAST-based analyses to identify virulence and antimicrobial genes, plasmids, proviruses, and the CRISPR-Cas system. The study investigated any association of the detected genes to the origin in the beef production chain of the L. monocytogenes isolates. Overall, in 60 isolates of Listeria monocytogenes, there were 7 STs, 6 CCs, 44 putative virulence factors, 2 resistance genes, 1 plasmid with AMR genes and 3 with conjugative genes, 1 CRISPR gene, and all 60 isolates were positive for proviruses. Among the 7 STs detected, ST204 (46.7%) and ST2 (21.7%) were the most prominent, with ST frequency varying significantly (p<0.001). The predominant CC detected were CC2 (21.7%) and CC204 (46.7%) in lineages I and II, respectively. Of the 44 virulence factors detected, 26 (across Listeria Pathogenicity Islands, LIPIs) were present in all the isolates. The difference in the detection frequency varied significantly (P<0.001). The two AMR genes (fosX and vga(G)) detected were present in all 60 (100%) isolates of L. monocytogenes. The only plasmid, NF033156, was present in 3 (5%) isolates. A CRISPR-Cas system was detected in 6 (10%), and all the isolates carried proviruses. Significant differences were detected in the frequencies of STs and virulence factors regarding the source and sample type of the L. monocytogenes isolates. The presence of both fosX and vga(G) genes in all the isolates from the three industries (cattle farms, abattoirs, and retail outlets) can potentially cause therapeutic implications. Our study, which characterized L. monocytogenes recovered from the three levels in the beef production chain in the country, provides the first evidence of the distribution of the pathogen with potential food safety and therapeutic implications.

Transfer factor is the name given to material derived from activated lymphocytes that is probably composed of a complex of a peptide and a short segment of RNA and which has the reported ability to transfer specific T cell immunity to uncommitted lymphocytes. Many independent groups around the world reported isolating transfer factors between 1955 and 1990 and demonstrating their ability to transfer passive immunity from one animal or individual to another, often within 24 hours of inoculation. Such activity is potentially revolutionary both in making T cell vaccines readily manufacturable and also because the existence of transfer factors would undermine the basic assumptions of the clonal selection theory, which currently dominates immunological theory. Unfortunately, lack of the microanalytical and synthetic techniques required to properly identify transfer factors, combined with safety factors associated with it derivation from blood sources susceptible to HIV and prion infections, put an end to transfer factor research after 1990. This paper reviews the evidence supporting transfer factor activity and suggests that this potentially revolutionary concept be resurrected and subjected to renewed scrutiny in light of CRISPR-Cas mechanisms and because of its potential to make possible T cell vaccination and provide a novel basis for understanding immunological function.

The rate of technical innovation, system interconnection, and advanced communications undoubtedly boost distributed energy networks' efficiency. However, when an additional attack surface is made available, the possibility of an increase in attacks is an unavoidable result. The energy ecosystem's significant variety draws attackers with various goals, making any critical infrastructure a threat, regardless of scale. Outdated technology and other antiquated countermeasures that worked years ago cannot address the complexity of current threats. As a result, robust artificial intelligence cyber-defense solutions are more important than ever. Based on the above challenge, this paper proposes an ensemble transfer learning spiking immune system for adaptive smart grid protection. It is an innovative Artificial Immune System (AIS) that uses a swarm of Evolving Izhikevich Neural Networks (EINN) in an Ensemble architecture, which optimally integrates Transfer Learning methodologies. The effectiveness of the proposed innovative system is demonstrated experimentally in multiple complex scenarios that optimally simulate the modern energy environment. In this way, the proposed system fully automates the strategic security planning of energy networks with computational intelligence methods. It allows the complete control of the digital strategies of the potential infrastructure that frames it, thus contributing to the timely and valid decision-making during cyber-attacks.

Stem/progenitor cell transplantation is a potential novel therapeutic strategy to induce angiogenesis in ischemic tissue, which can prevent major amputation in patients with advanced peripheral artery disease (PAD). Thus, clinicians can use cell therapies worldwide to treat PAD. However, some cell therapy studies did not report beneficial outcomes. Clinical researchers suggested that classical risk factors and comorbidities may adversely affect the efficacy of cell therapy. Some studies have indicated that the response to stem cell therapy varies among patients even in those harboring limited risk factors. This suggested the role of undetermined risk factors, including genetic alterations, somatic mutations, and clonal hematopoiesis. Personalized stem cell-based therapy can be developed by analyzing individual risk factors. These approaches must consider several clinical biomarkers and perform studies (such as genome-wide association studies (GWAS)) on disease-related genetic traits and integrate the findings with those of transcriptome-wide association studies (TWAS) and whole-genome sequencing in PAD. Additional unbiased analyses with state-of-the-art computational methods, such as machine learning-based patient stratification, are suited for predictions in clinical investigations. The integration of these complex approaches into a unified analysis procedure for the identification of responders and non-responders before stem cell therapy, which can decrease treatment expenditure, is a major challenge to increase the efficacy of therapies.