Prometheus's heart: what lies beneath

A heart attack kills off many cells in the heart. Parts of the heart become thin and fail to contract properly following the replacement of lost cells by scar tissue. However, the notion that the same adult cardiomyocytes beat throughout the lifespan of the organ and organism, without the need for a minimum turnover, gives way to a fascinating investigations. Since the late 1800s, scientists and cardiologists wanted to demonstrate that the cardiomyocytes cannot be generated after the perinatal period in human beings. This curiosity has been passed down in subsequent years and has motivated more and more accurate studies in an attempt to exclude the presence of renewed cardiomyocytes in the tissue bordering the ischaemic area, and then to confirm the dogma of the heart as terminally differentiated organ. Conversely, peri-lesional mitosis of cardiomyocytes were discovered initially by light microscopy and subsequently confirmed by more sophisticated technologies. Controversial evidence of mechanisms underlying myocardial regeneration has shown that adult cardiomyocytes are renewed through a slow turnover, even in the absence of damage. This turnover is ensured by the activation of rare clusters of progenitor cells interspersed among the cardiac cells functionally mature. Cardiac progenitor cells continuously interact with each other, with the cells circulating in the vessels of the coronary microcirculation and myocardial cells in auto-/paracrine manner. Much remains to be understood; however, the limited functional recovery in human beings after myocardial injury clearly demonstrates weak regenerative potential of cardiomyocytes and encourages the development of new approaches to stimulate this process.     

Synthetic biology: challenges ahead

This expanding scientific discipline is proving extremely popularand is attracting engineering and system design experts to thefield of Biology. As Bioinformatics and Computational Biology will be essentialcomponents of new technical and scientific developments, itis vital to follow the discussion generated by the recent ESFExploratory Workshop (October 13–16, 2005, Constructingand de-constructing Life, Magalia, Spain) and the 2005 reportof the NEST High-Level Expert Group on Synthetic Biology: ApplyingEngineering to Biology http://www.eurosfaire.prd.fr/nest/documents/pdf/NEST_syntheticbiology_b5_eur21796_en.pdf) Synthetic Biology stands at the meeting-point of two cultures.The first, represented by those interested in ‘deconstructing     

Cancer genome sequencing: the challenges ahead

A major challenge for The Cancer Genome Atlas (TCGA) Project is solving the high level of genetic and epigenetic heterogeneity of cancer. For the majority of solid tumors, evolution patterns are stochastic and the end products are unpredictable, in contrast to the relatively predictable stepwise patterns classically described in many hematological cancers. Further, it is genome aberrations, rather than gene mutations, that are the dominant factor in generating abnormal levels of system heterogeneity in cancers. These features of cancer could significantly reduce the impact of the sequencing approach, as it is only when mutated genes are the main cause of cancer that directly sequencing them is justified. Many biological factors (genetic and epigenetic variations, metabolic processes) and environmental influences can increase the probability of cancer formation, depending on the given circumstances. The common link between these factors is the stochastic genome variations that provide the driving force behind the cancer evolutionary process within multiple levels of a biological system. This analysis suggests that cancer is a disease of probability and the most-challenging issue to the TCGA project, as well as the development of general strategies for fighting cancer, lie at the conceptual level.     

Plant pan-genomics: recent advances,new challenges,and roads ahead

Pan-genomics can encompass most of the genetic diversity of a species or population and has proved to be a powerful tool for studying genomic evolution and the origin and domestication of species, and for providing information for plant improvement. Plant genomics has greatly progressed because of improvements in sequencing technologies and the rapid reduction of sequencing costs. Nevertheless, pan-genomics still presents many challenges, including computationally intensive assembly methods, high costs with large numbers of samples, ineffective integration of big data, and difficulty in applying it to downstream multi-omics analysis and breeding research. In this review, we summarize the definition and recent achievements of plant pan-genomics, computational technologies used for pan-genome construction, and the applications of pan-genomes in plant genomics and molecular breeding. We also discuss challenges and perspectives for future pan-genomics studies and provide a detailed pipeline for sample selection, genome assembly and annotation, structural variation identification, and construction and application of graph-based pan-genomes. The aim is to provide important guidance for plant pan-genome research and a better understanding of the genetic basis of genome evolution, crop domestication, and phenotypic diversity for future studies.     

Metabolomics and the challenges ahead

Eight years have passed since the proposal that the characterizationof mutations with silent phenotypes should be carried out bya global view of metabolism [1]. Since then, the field of metabolomicshas flourished both in the development of new     

Therapeutic siRNA: principles, challenges, and strategies

RNA interference (RNAi) is a remarkable endogenous regulatory pathway that can bring about sequence-specific gene silencing. If harnessed effectively, RNAi could result in a potent targeted therapeutic modality with applications ranging from viral diseases to cancer. The major barrier to realizing the full medicinal potential of RNAi is the difficulty of delivering effector molecules, such as small interfering RNAs (siRNAs), in vivo. An effective delivery strategy for siRNAs must address limitations that include poor stability and non-targeted biodistribution, while protecting against the stimulation of an undesirable innate immune response. The design of such a system requires rigorous understanding of all mechanisms involved. This article reviews the mechanistic principles of RNA interference, its potential, the greatest challenges for use in biomedical applications, and some of the work that has been done toward engineering delivery systems that overcome some of the hurdles facing siRNA-based therapeutics.     

Targeting melanoma by small molecules: challenges ahead

Significant progress has been made in targeting melanoma using small molecule inhibitors, but challenges remain. Here we describe the history of screening approaches in melanoma and their limitations. We propose several approaches to refine our screening models to enhance the discovery process. It is hoped that this discussion will stimulate further improvements in our development of small molecules inhibitors for treatment of melanoma patients.     

Long Covid: where we stand and challenges ahead

Post-acute sequelae of SARS-CoV-2 (PASC), also known as Post-Covid Syndrome, and colloquially as Long Covid, has been defined as a constellation of signs and symptoms which persist for weeks or months after the initial SARS-CoV-2 infection. PASC affects a wide range of diverse organs and systems, with manifestations involving lungs, brain, the cardiovascular system and other organs such as kidney and the neuromuscular system. The pathogenesis of PASC is complex and multifactorial. Evidence suggests that seeding and persistence of SARS-CoV-2 in different organs, reactivation, and response to unrelated viruses such as EBV, autoimmunity, and uncontrolled inflammation are major drivers of PASC. The relative importance of pathogenetic pathways may differ in different tissue and organ contexts. Evidence suggests that vaccination, in addition to protecting against disease, reduces PASC after breakthrough infection although its actual impact remains to be defined. PASC represents a formidable challenge for health care systems and dissecting pathogenetic mechanisms may pave the way to targeted preventive and therapeutic approaches.Subject terms: Infectious diseases, Immunological disorders     

Uncovering Therapeutic Targets FOR Glioblastoma: A Systems Biology Approach

Even though glioblastoma, WHO grade IV (GBM) is one of the most devastating adult cancers, current treatment regimens have not led to any improvements in patient life expectancy or quality of life. The constitutively active EGFRvIII receptor is one of the most commonly mutated proteins in GBM and has been linked to radiation and chemotherapeutic resistance. To define the mechanisms by which this protein alters cell physiology, we have recently performed a phosphoproteomic analysis of EGFRvIII signaling networks in GBM cells. The results of this study provided important insights into the biology of this mutated receptor, including oncogene dose effects and differential utilization of signaling pathways. Moreover, clustering of the phosphoproteomic data set revealed a previously undescribed crosstalk between EGFRvIII and the c-Met receptor. Treatment of the cells with a combination employing both EGFR and c-Met kinase inhibitors dramatically decreased cell viability in vitro. In this perspective, we highlight the use of systems biology as a tool to better understand the molecular basis of GBM tumor biology as well as to uncover non-intuitive candidates for therapeutic target validation.     

COVID-19 vaccines: where we stand and challenges ahead

In the eleven months elapsed since the identification of the SARS-CoV-2 virus and its genome, an exceptional effort by the scientific community has led to the development of over 300 vaccine projects. Over 40 are now undergoing clinical evaluation, ten of these are in Phase III clinical trials, three of them have ended Phase III with positive results. A few of these new vaccines are being approved for emergency use. Existing data suggest that new vaccine candidates may be instrumental in protecting individuals and reducing the spread of pandemic. The conceptual and technological platforms exploited are diverse, and it is likely that different vaccines will show to be better suited to distinct groups of the human population. Moreover, it remains to be elucidated whether and to what extent the capacity of vaccines under evaluation and of unrelated vaccines such as BCG can increase immunological fitness by training innate immunity to SARS-CoV-2 and pathogen-agnostic protection. Due to the short development time and the novelty of the technologies adopted, these vaccines will be deployed with several unresolved issues that only the passage of time will permit to clarify. Technical problems connected with the production of billions of doses and ethical ones connected with the availably of these vaccines also in the poorest countries, are imminent challenges facing us. It is our tenet that in the long run more than one vaccine will be needed to ensure equitable global access, protection of diverse subjects and immunity against viral variants.Subject terms: Immunological disorders, Infectious diseases