Gregor Mendel's seminal publication, "Versuche über Pflanzen-Hybriden" ("Experiments on Plant Hybrids"), which appeared in 1866, is regarded as one of the founding documents of genetics and has therefore been translated several times. In 2016, with the support of the British Society for the History of Science (BSHS), we produced a new online translation of Mendel's paper, alongside a facsimile and transcription of the original German text and an extensive commentary that offered historical and linguistic insights into nearly every sentence. The translation and commentary were made available on the BSHS website and 4 years later were published as a book by Masaryk University Press. In this paper, we build on the introduction to our translation to reflect and include some important developments in the scholarship around Mendel that have taken place since the translation was first published.

While silent in normal differentiated human tissues, telomerase is reactivated in most human cancers. Thus, telomerase is an almost universal oncology target. This update describes preclinical and clinical advancements using a variety of approaches to target telomerase. These include direct telomerase inhibitors, G-quadruplex DNA-interacting ligands, telomerase-based vaccine platforms, telomerase promoter-driven attenuated viruses, and telomerase-mediated telomere targeting approaches. While imetelstat has been recently approved by the Food and Drug Administration (FDA), several other approaches are in late-stage clinical development. The pros and cons of the major approaches will be reviewed.

It is well-known that the rediscovery of Mendelian genetics at the turn of twentieth century offered Darwin's theory a much-needed lifeline, by showing how Fleeming Jenkins' famous "blending" objection could be rebutted. However, Mendelism has another fortuitous consequence for evolutionary biology that is less widely appreciated. By bequeathing the notion of allelism to biology, Mendelism shows how two difficult conceptual issues for evolutionary theory can be resolved. The first issue concerns the notion of population. By definition, evolutionary change is change in the composition of a population, but what is the relevant definition of "population"? The second issue concerns Darwin's notion of "struggle for existence." Is this struggle an essential part of evolution by natural selection or not? In a Mendelian population, these issues can be simply resolved, since the selective competition is at root between alleles at a locus, who are necessarily playing a zero-sum game, rather than between organisms, who may or may not be doing so.

Two things about Mendel were "rediscovered" in 1900: His famous paper of 1865 and the story of his life and long neglect. Unlike the paper, which anyone could read in its entirety, the story came out only gradually, and many of its elements were misconstrued by Western European scientists. They pictured him as a pure scientist like themselves and were puzzled by or disinterested in his career as a clergyman, his intellectual community in far-off Moravia, and the importance to him of practical plant breeding. This paper recapitulates the process of mythmaking that followed the rediscovery, then shows how more recent historical research has been able to undo it and, in a sense, "unrediscover" Mendel.

Whereas Mendelian genetics is an important research program in the life sciences, its school version is problematic. On the one hand, it contains stereotypical representations of Gregor Mendel's work that misrepresent his findings and the historical context. This deprives students from gaining an authentic picture of how science is done. On the other hand, what most students end up learning in schools are extremely simplistic accounts of heredity, whereby alleles directly control traits and phenotypes, and thus exclusively depend on which allele an individual has. Such oversimplifications of Mendelian genetics as those that we still teach in schools were exploited by ideologues in the beginning of the twentieth century to provide the presumed "scientific" basis for eugenics. This paper addresses these problems of the school version of Mendelian genetics, which I call "naive" Mendelian genetics. It also proposes a shift in school education from teaching how the science of genetics is done using model systems to teaching the complexities of development through which heredity is materialized.

In recent years, significant advances have been made in understanding the intricate details of the mechanisms underlying alternative lengthening of telomeres (ALT). Studies of a specialized DNA strand break repair mechanism, known as break-induced replication, and the advent of telomere-specific DNA damaging strategies and proteomic methodologies to profile the ribonucleoprotein composition of telomeres enabled the discovery of networks of proteins that coordinate the stepwise homology-directed DNA repair and DNA synthesis processes of ALT. These networks couple mediators of homologous recombination, DNA template-switching, long-range template-directed DNA synthesis, and DNA strand resolution with SUMO-dependent liquid condensate formation to create discrete nuclear bodies where telomere extension occurs. This review will discuss the recent findings of how these networks may cooperate to mediate telomere extension by the ALT mechanism and their impact on telomere function and integrity in ALT cancer cells.

DNA double-strand break (DSB) repair pathways are crucial for maintaining genome stability and cell viability. However, these pathways can mistakenly recognize chromosome ends as DNA breaks, leading to adverse outcomes such as telomere fusions and malignant transformation. The shelterin complex protects telomeres from activation of DNA repair pathways by inhibiting nonhomologous end joining (NHEJ), homologous recombination (HR), and microhomology-mediated end joining (MMEJ). The focus of this paper is on MMEJ, an error-prone DSB repair pathway characterized by short insertions and deletions flanked by sequence homology. MMEJ is critical in mediating telomere fusions in cells lacking the shelterin complex and at critically short telomeres. Furthermore, studies suggest that MMEJ is the preferred pathway for repairing intratelomeric DSBs and facilitates escape from telomere crisis. Targeting MMEJ to prevent telomere fusions in hematologic malignancies is of potential therapeutic value.

The inner blood-retinal barrier (iBRB) protects the retinal vasculature from the peripheral circulation. Endothelial cells (ECs) are the core component of the iBRB; their close apposition and linkage via tight junctions limit the passage of fluids, proteins, and cells from the bloodstream to the parenchyma. Dysfunction of the iBRB is a hallmark of many retinal disorders. Vascular endothelial growth factor (VEGF) has been identified as the primary driver leading to a dysfunctional iBRB, thereby becoming the main target for therapy. However, a complete understanding of the molecular mechanisms underlying iBRB dysfunction is elusive and alternative therapeutic targets remain unexplored. Calcium (Ca) is a universal intracellular messenger whose homeostasis and dynamics are dysregulated in many pathological disorders. Among the extensive components of the cellular Ca-signaling toolkit, cation-selective transient receptor potential (TRP) channels are broadly involved in cell physiology and disease and, therefore, are widely studied as possible targets for therapy. Albeit that TRP channels have been discovered in the photoreceptors of and have been studied in the neuroretina, their presence and function in the iBRB have only recently emerged. Within this article, we discuss the structure and functions of the iBRB with a particular focus on Ca signaling in retinal ECs and highlight the potential of TRP channels as new targets for retinal diseases.

Three-dimensional (3D) printing can be beneficial to tissue engineers and the regenerative medicine community because of its potential to rapidly build elaborate 3D structures from cellular and material inks. However, predicting changes to the structure and pattern of printed tissues arising from the mechanical activity of constituent cells is technically and conceptually challenging. This perspective is targeted to scientists and engineers interested in 3D bioprinting, but from the point of view of cells and tissues as mechanically active living materials. The dynamic forces generated by cells present unique challenges compared to conventional manufacturing modalities but also offer profound opportunities through their capacity to self-organize. Consideration of self-organization following 3D printing takes the design and execution of bioprinting into the fourth dimension of cellular activity. We therefore propose a framework for dynamic bioprinting that spatiotemporally guides the underlying biology through reconfigurable material interfaces controlled by 3D printers.

Telomere function is critical for genomic stability; in the context of a functional TP53 response, telomere erosion leads to a G/S cell-cycle arrest and the induction of replicative senescence, a process that is considered to underpin the ageing process in long-lived species. Abrogation of the TP53 pathway allows for continued cell division, telomere erosion, and the complete loss of telomere function; the ensuing genomic instability facilitates clonal evolution and malignant progression. Telomeres display extensive length heterogeneity in the population that is established at birth, and this affects the individual risk of a broad range of diseases, including cardiovascular disease and cancer. In this perspective, I discuss telomere length heterogeneity at the levels of the population, individual, and cell, and consider how the dynamics of these essential chromosomal structures contribute to human disease.

This paper argues that the historiography of genetics ∼1900, the formation period of modern science, is too narrow. It lacks attention to plant breeding. Perhaps this omission also narrows the present understanding of fundamental ideas like the genotype/phenotype distinction and the gene concept? There is a mythical story still told in textbooks and at anniversaries: As modern genetics started with the rediscovery of Mendel's laws in 1900, a fateful controversy over continuous or discontinuous variation of heredity between biometricians and Mendelians. Discontinuity appeared as a threat to the Darwinian theory of evolution by natural selection. Only by the 1920s was the problem solved by a theory of population genetics founded on the chromosome theory of heredity. However, in plant breeding ∼1900 ideas of heredity and evolution were closely intertwined, and the combination of discontinuous heredity with continuous Darwinian evolution was an obvious option.

Biology can be viewed from both an organismal and a genic perspective. A good example is W.D. Hamilton's work on inclusive fitness and kin selection, which puts relatedness at the heart of our understanding of social behavior. Relatedness mediates how much an actor should value a specific behavior's effect on a relative compared to the cost incurred to itself. Despite its key explanatory role, relatedness is also a concept marred with misunderstanding. Part of the problem has been that the term has been used in different ways by different people. To help address this, we survey the history of how relatedness has been formally modeled, paying particular attention to how it is conceptualized from both a gene-centric and an organism-centric point of view.

Skeletal muscle is one of the tissues with the highest range of variability in metabolic rate, which, to a large extent, is critically dependent on tightly controlled and fine-tuned mitochondrial activity. Besides energy production, other mitochondrial processes, including calcium buffering, generation of heat, redox and reactive oxygen species homeostasis, intermediate metabolism, substrate biosynthesis, and anaplerosis, are essential for proper muscle contractility and performance. It is thus not surprising that adequate mitochondrial function is ensured by a plethora of mechanisms, aimed at balancing mitochondrial biogenesis, proteostasis, dynamics, and degradation. The fine-tuning of such maintenance mechanisms ranges from proper folding or degradation of individual proteins to the elimination of whole organelles, and in extremis, apoptosis of cells. In this review, the present knowledge on these processes in the context of skeletal muscle biology is summarized. Moreover, existing gaps in knowledge are highlighted, alluding to potential future studies and therapeutic implications.

Gliomas comprise a diverse spectrum of related tumor subtypes with varying biological and molecular features and clinical outcomes. Advances in detailed genetic and epigenetic characterizations along with an appreciation that subtypes associated with developmental origins, including brain location and patient age, have shifted glioma classification from the historical reliance on histopathological features to updated categories incorporating molecular signatures and spatiotemporal incidence. Within a subtype, individual gliomas show cellular heterogeneity, generally containing subpopulations resembling different types of normal glial and progenitor cells. In addition to tumor-autonomous mechanisms of aberrant growth regulation driven by genetic mutations and signaling between tumor cells, interactions with the tumor microenvironment, including neurons, astrocytes, oligodendrocyte precursor cells, and the immune microenvironment play important roles in driving glioma growth and influencing response to treatment. The emerging understanding of the complex contributions of normal brain to glioma growth represents new opportunities for therapeutic advances.

Glial cells play critical roles in the nervous system. Rather than being passive support cells as long thought, they are highly active participants. Recent work has shed new light on their many functions, include regulation of synapse formation and function, control of neural circuits, and neuro-immune interactions. It is also shedding light on the part they play in neurodegenerative diseases and malignancies such as glioma, as well as the process of axonal regeneration and CNS repair.

It is becoming increasingly clear that the dominant, century-old neurocentric view of neurodegeneration is insufficient to explain why certain neurons degenerate, in particular with aging. Genetic studies in patient populations as well as mechanistic and functional studies in animal models altogether implicate nonneuronal cells, especially glia, to play more than bystander roles in neurodegeneration. Throughout the life span, neuronal function and homeostasis are modulated by glia, the functions of which become even more critical with aging. This review highlights key emerging concepts of the role of glia in neurodegeneration.

The nervous system comprises a remarkably diverse and complex network of cell types, which must communicate with one another with speed, reliability, and precision. Thus, the developmental patterning and maintenance of these cell populations and their connections with one another pose a rather formidable task. Emerging data implicate microglia, the resident myeloid-derived cells of the central nervous system (CNS), in spatial patterning and synaptic wiring throughout the healthy, developing, and adult CNS. Importantly, new tools to specifically manipulate microglia function have revealed that these cellular functions translate, on a systems level, to effects on overall behavior. In this review, we give a historical perspective of work to identify microglia function in the healthy CNS, and highlight exciting new discoveries about their contributions to CNS development, maintenance, and plasticity.

A critical link in the chain of force transmission from muscle fiber cross-bridge to bone is the interface between muscle and tendon-the myotendinous junction (MTJ). To meet the challenge of connecting these two tissues, the MTJ is specialized molecularly and morphologically. Distinct transcriptional profiles are evident for the myonuclei at the myofiber tips and a population of mononuclear tendon cells at the MTJ, demonstrating support from both sides in MTJ maintenance. Paradoxically, despite this high degree of specialization, the MTJ remains susceptible to strain (rupture) injury and is often associated with failed tissue healing. Incomplete understanding of the nature of the MTJ and the elements contributing to its plasticity hinder tackling this unsolved clinical challenge. The goal of this review is to summarize key structural and molecular features of the MTJ, discuss MTJ adaptation in response to mechanical (un)loading, aging, and injury, and highlight the major unanswered questions surrounding the MTJ.

The widespread presence of slow-red and fast-white muscles in all vertebrates supports the evolutionary advantage of having two types of motors available for animal movement-a slow economical motor used for most activities, and a fast energetically costly motor used for rapid movements and emergency actions, and actions that require a lot of force. Skeletal muscles are composed of multiple fiber types whose structural and functional properties have only in part been characterized. Further progress in this field is mainly occurring along two directions: Multiomics approaches are providing a global picture of the molecular composition of muscle fibers up to the single fiber and single nucleus level. Signaling studies are identifying many transcription factors and pathways controlling fiber-type specification. These new data should now be integrated into a wider whole-body context by defining the matching between muscle fiber and motor neuron heterogeneity in the neuromuscular system, as well as the relevance of muscle fiber types in systemic homeostatic functions, including metabolism and thermogenesis.

Action potential propagation along myelinated axons requires clustered voltage-gated sodium and potassium channels. These channels must be restricted to nodes of Ranvier where the action potential is regenerated. Several mechanisms have evolved to facilitate and ensure the correct assembly and stabilization of these essential axonal domains. This review highlights the current understanding of the axon-intrinsic and glial-extrinsic mechanisms that control the formation and maintenance of the nodes of Ranvier in both the peripheral (PNS) and central (CNS) nervous systems.