Reflections on Integrins-Past, Present, and Future: The Albert Lasker Basic Medical Research Award.

This Viewpoint discusses the rapid advances in molecular cell biological approaches over the past 50 years and the many avenues for future advances that have been opened, including direct applications for therapeutic and regenerative medicine.

Technological advances in super-resolution microscopy to study cellular processes.

Since its initial demonstration in 2000, far-field super-resolution light microscopy has undergone tremendous technological developments. In parallel, these developments have opened a new window into visualizing the inner life of cells at unprecedented levels of detail. Here, we review the technical details behind the most common implementations of super-resolution microscopy and highlight some of the recent, promising advances in this field.

A Petri nets-based framework for whole-cell modeling.

Whole-cell modeling aims to incorporate all main genes and processes, and their interactions of a cell in one model. Whole-cell modeling has been regarded as the central aim of systems biology but also as a grand challenge, which plays essential roles in current and future systems biology. In this paper, we analyze whole-cell modeling challenges and requirements and classify them into three aspects (or dimensions): heterogeneous biochemical networks, uncertainties in components, and representation of cell structure. We then explore how to use different Petri net classes to address different aspects of whole-cell modeling requirements. Based on these analyses, we present a Petri nets-based framework for whole-cell modeling, which not only addresses many whole-cell modeling requirements, but also offers a graphical, modular, and hierarchical modeling tool. We think this framework can offer a feasible modeling approach for whole-cell model construction.

Trends in cytopathology fellowship positions and vacancies over the past decade.

INTRODUCTION: Cytopathology is one of the most sought-after fellowships within pathology, with a lower fellowship vacancy rate compared with most other subspecialties. The Accreditation Council for Graduate Medical Education (ACGME) actively tracks annual program data for cytopathology fellowship programs, and evaluating this longitudinal data looking at trends in programs and positions over the past 10 years could provide insights into the future of cytopathology and its training programs. METHODS: Data obtained from the ACGME was examined in detail for all ACGME-accredited cytopathology fellowship programs over the past decade (2011-2021). Additional responses from program directors (PDs) from a 2021 American Society of Cytopathology (ASC) survey are also included. RESULTS: The total number of ACGME-approved cytopathology training programs and cytopathology fellowship positions remained relatively constant over the past 10 years, but the vacancy rate and number of programs with 1-2 unfilled spots has gradually but steadily risen over the past 6 years. In a 2021 ASC PD survey with 66% response rate, 53% of PDs reported having recruitment problems at least occasionally and 46% reported an increase in unexpected fellowship openings. CONCLUSIONS: Although the number of cytopathology positions has been relatively constant over the past decade, there has been a recent increase in cytopathology fellowship vacancies that may indicate changes in career choices or the job market, with fellows choosing jobs over additional fellowships, and potentially signal a growing shortage of fellowship-trained, Board-certified cytopathologists in the coming years.

Evolutionary Cell Biology (ECB): Lessons, challenges, and opportunities for the integrative study of cell evolution.

Evolutionary Cell Biology (ECB) has gained increasing attention in the last decades. Here we explore whether ECB is truly inter-disciplinary through the combination of cellular and evolutionary biology to offer evidence-based insights regarding the major questions of cell evolution. Since 2012, ECB asserts to utilize the increasing potential of high-throughput omics data (in silico) with morpho-functional (in situ) information, although challenges remain for a complete integration. For instance, the limited number of model organisms and cultivation techniques available excludes the majority of the extant diversity of cells from the scope of experimental inquiry. At the conceptual level, the simplification of evolutionary processes influenced by cultural views of evolution, such as adaptationism or Scala Naturae, challenges effective interdisciplinary work. Without a profound understanding of evolutionary theory and an integrative view of cell biology, the formulation of questions and experiments properly addressing evolution and diversification of cell complexities can become misleading. In 2009, we advanced the discovery of a nucleolus in the flagellated unicellular eukaryote Giardia lamblia, and studied nucleolus diversity in other lineages via electron microscopy. Since then, studying evolutionary questions at the cellular level became central to our research. We think that new methodological advances are re-shaping and strengthening the ECB research program and opening its door to experimental scientists. For example, the discovery of new archaea and protozoa and subsequent investigations that coupled in situ approaches with in silico approaches has proven that comprehensive morpho-functional information can be obtained that can only be understood through the merging of the cell biological and evolutionary discipline. Motivated by this, we here explore the history, the challenges, and the opportunities of ECB to motivate researchers to join this emergent field of research. We outline elements that contrast the current ECB discipline from previous integrative attempts. We conclude by elucidating the current disciplinary constraints of ECB and propose considerations towards successfully employing ECB to answer questions pertaining to the evolution of cellular complexity.

Is it possible that cells have had more than one origin?

Cells occupy a prominent place in the history of life in Earth. The central role of cellular organization can be understood by the fact that "cellular life" is often used as a synonym for life itself. Thus, most characteristics used to define cell overlap with those ones used to define life. However, innovative scenarios for the origin of life are bringing alternative views to describe how cells may have evolved from the open biological systems named progenotes. Here, using a logical and conceptual analysis, we re-evaluate the characteristics used to infer a single origin for cells. We argue that some evidences used to support cell monophyly, such as the presence of elements from the translation mechanism together with the universality of the genetic code, actually indicate a unique origin for all "biological systems", a term used to define not only cells, but also viruses and progenotes. Besides, we present evidence that at least two biochemical pathways as important as (i) DNA replication and (ii) lipid biosynthesis are not homologous between Bacteria and Archaea. The identities observed between the proteins involved in those pathways along representatives of these two ancestral domains of life are too low to indicate common genic ancestry. Altogether these facts can be seen as an indication that cellular organization has possibly evolved two or more times and that LUCA (the Last Universal Common Ancestor) may not have existed as a cellular entity. Thus, we aim to consider the possibility that different strategies acquired by biological systems to exist, such as viral, bacterial and archaeal were most likely originated independently from the evolution of different progenote populations.

Virtual meeting, real and sound science: report of the 17th Meeting of the Spanish Society for Developmental Biology (SEBD-2020).

The Spanish Society for Developmental Biology (SEBD) organized its 17th meeting in November 2020 (herein referred to as SEBD2020). This meeting, originally programmed to take place in the city of Bilbao, was forced onto an online format due to the SARS-CoV2, COVID-19 pandemic. Although, we missed the live personal interactions and missed out on the Bilbao social scene, we were able to meet online to present our work and discuss our latest results. An overview of the activities that took place around the meeting, the different scientific sessions and the speakers involved are presented here. The pros and cons of virtual meetings are discussed.

Phylodynamics for cell biologists.

Multicellular organisms are composed of cells connected by ancestry and descent from progenitor cells. The dynamics of cell birth, death, and inheritance within an organism give rise to the fundamental processes of development, differentiation, and cancer. Technical advances in molecular biology now allow us to study cellular composition, ancestry, and evolution at the resolution of individual cells within an organism or tissue. Here, we take a phylogenetic and phylodynamic approach to single-cell biology. We explain how "tree thinking" is important to the interpretation of the growing body of cell-level data and how ecological null models can benefit statistical hypothesis testing. Experimental progress in cell biology should be accompanied by theoretical developments if we are to exploit fully the dynamical information in single-cell data.

[Caspase inhibition: From cellular biology and thanatology to potential clinical agents]. / Inhibition des caspases - De la biologie et thanatologie cellulaires au développement clinique de candidats médicaments.

Caspases are a family of cysteine proteases well known for their central roles during apoptosis and inflammation. They also intervene in non-apoptotic regulated cell death pathways and contribute to a large number of physiological mechanisms. The development of therapeutic approaches targeting caspases has generated strong industrial interest since the 1990s, prompting intense research on biological mechanisms, and the development of numerous synthetic inhibitors. Most of these inhibitors are derivatives of peptides or mimetics capable of interacting with the active site of caspases. However, the structural conservation between the different caspases is a challenge for the development of selective inhibitors. To date 5 caspase inhibitors, targeting either Caspase-1, -2 or multiple caspases, have been investigated in clinical settings, and there is still no marketing authorization. The Pan-caspase inhibitor emricasan reached clinical phase III and was proven to be safe but failed to demonstrate efficacy against NASH. Contrary to initial assumptions, selective Caspase-3 inhibitors have not reached the clinical level, while QPI-1007, a siRNA directed against Caspase-2, is currently undergoing a multicentric phase III clinical study for the treatment of ischemic optic neuropathies.

TITLE: Inhibition des caspases - De la biologie et thanatologie cellulaires au développement clinique de candidats médicaments. ABSTRACT: Les caspases sont une famille de cystéines protéases bien connues pour leurs rôles centraux au cours de l'apoptose et de l'inflammation. Elles interviennent aussi dans des voies de mort cellulaire régulées non-apoptotiques, et contribuent à de très nombreux mécanismes physiologiques. Le développement d'approches thérapeutiques ciblant les caspases a engendré un fort intérêt industriel dès les années 1990, suscitant d'intenses recherches sur les mécanismes biologiques, et conduisant à la mise au point de nombreux inhibiteurs synthétiques. La plupart de ces inhibiteurs sont des dérivés de peptides, ou mimétiques, capables d'interagir avec le site actif des caspases. Cependant, la conservation structurelle observée entre les différentes caspases est un défi pour le développement d'inhibiteurs sélectifs. À ce jour, cinq inhibiteurs de caspases ont été évalués pour leur efficacité clinique, mais aucune autorisation de mise sur le marché n'a été délivrée à ce jour. Contrairement aux présomptions initiales, les inhibiteurs sélectifs de la Caspase-3 n'ont pas atteint le stade d'essais cliniques, alors que le QPI-1007, un siARN dirigé contre la Caspase-2, a fait l'objet d'une étude clinique de phase III pour le traitement de neuropathies optiques ischémiques.

A well-engineered path into cell biology and academia.

Winning the American Society for Cell Biology's Women in Cell Biology Mid-career Award is incredibly meaningful to me, as it validates that someone focusing on engineering and applications can be a "real" cell biologist, too. Single-minded devotion to studying a particular biological process is not a prerequisite for a career in science and academia. The more diverse the scientific styles and demographics of scientists who feel welcome, the stronger science will be.

The evolution of a cell biologist.

I am honored and humbled to receive the E. B. Wilson Medal and happy to share some reflections on my journey as a cell biologist. It took me a while to realize that my interest in biology would center on how cells are spatially and dynamically organized. From an initial fascination with cellular structures I came to appreciate that cells exhibit dynamism across all scales-from their molecules, to molecular complexes, to organelles. Uncovering the principles of this dynamism, including new ways to observe and quantify it, has been the guiding star of my work.

Looking back and looking forward: contributions of electron microscopy to the structural cell biology of gametes and fertilization.

Mammalian gametes-the sperm and the egg-represent opposite extremes of cellular organization and scale. Studying the ultrastructure of gametes is crucial to understanding their interactions, and how to manipulate them in order to either encourage or prevent their union. Here, we survey the prominent electron microscopy (EM) techniques, with an emphasis on considerations for applying them to study mammalian gametes. We review how conventional EM has provided significant insight into gamete ultrastructure, but also how the harsh sample preparation methods required preclude understanding at a truly molecular level. We present recent advancements in cryo-electron tomography that provide an opportunity to image cells in a near-native state and at unprecedented levels of detail. New and emerging cellular EM techniques are poised to rekindle exploration of fundamental questions in mammalian reproduction, especially phenomena that involve complex membrane remodelling and protein reorganization. These methods will also allow novel lines of enquiry into problems of practical significance, such as investigating unexplained causes of human infertility and improving assisted reproductive technologies for biodiversity conservation.