Molecular insights into the function, fate, and prospects of stem cells

This article forms a review and an appraisal of the third annual meeting of the International Society for Stem Cell Research (http://www.isscr.org), held in San Francisco on June 23-25, 2005. The focus of the meeting was recent advances in stem cell biology. More than 2,000 scientists from around the world met to discuss stem cell research, clinical applications, and the ethical hurdles facing the field. Major topics highlighted during the meeting included the self-renewal and differentiation of embryonic stem cells as well as adult stem cells. Presentations included diverse topics such as cancer stem cells, tissue-specific stem cells, technology development, and clinical aspects of stem cells. Given the excitement the field has generated, linking basic stem cell research and clinical applications was paramount for discussion at the meeting. With the current resources in molecular biology research, improvements in genetic engineering, postgenomic capabilities, and biotechnological advances, it appears timely that stem cell biology research is headed toward making a major therapeutic contribution to human health.     

Harnessing innate and adaptive immunity for viral vaccine design

The recent Keystone Symposia meeting on HIV Vaccines was held on 21-26 March 2012 in Keystone (CO, USA) back-to-back with the Viral Immunity meeting, creating synergy between the two areas of research. In this short report of the meeting, the authors will highlight three areas of interest that emerged from the two meetings: the recently emerging role of NK cells in modulating dendritic cell function, new data on the importance of dendritic cell antigen processing on priming of adaptive immunity and intriguing data suggesting that narrow targeting of very few protective epitopes restricted by a single MHC class I allele might be sufficient to mediate control of otherwise highly pathogenic SIV infection.     

Shaping the diversity of Th2 cell responses in epithelial tissues and its potential for allergy treatment

Th2 cells have evolved to protect from large helminth infections and to exert tissue protective functions in response to nonmicrobial noxious stimuli. The initiation, maintenance, and execution of these functions depend on the integration of diverse polarizing cues by cellular sensors and molecular programs as well as the collaboration with cells that are coopted for signal exchange. The complexity of input signals and cellular collaboration generates tissue specific Th2 cell heterogeneity and specialization. In this review, we aim to discuss the advances and recent breakthroughs in our understanding of Th2 cell responses and highlight developmental and functional differences among T cells within the diversifying field of type 2 immunity. We will focus on factors provided by the tissue microenvironment and highlight factors with potential implications for the pathogenesis of allergic skin and lung diseases. Especially new insights into the role of immunometabolism, the microbiota and ionic signals enhance the complexity of Th2 cell regulation and warrant a critical evaluation. Finally, we will discuss how this ensemble of established knowledge and recent breakthroughs about Th2 immunobiology advance our understanding of the pathogenesis of allergic diseases and how this could be exploited for future immunotherapies.     

GEFs in growth factor signaling

Evolutionary conserved members of the Ras superfamily of small GTP-binding proteins function as binary molecular switches to control diverse biological processes. In the context of cellular signaling, these include functions in exocytic and endocytic trafficking, as well as roles in signal relay downstream of various cell surface receptors. We previously reviewed roles played by the large family of GTPase, activating proteins in these processes. In this companion review, we highlight recent findings relating to the regulation of another major class of Ras superfamily regulatory proteins, the guanine nucleotide exchange factors.     

The Society for Craniofacial Genetics and Developmental Biology 42nd Annual Meeting

The Society for Craniofacial Genetics and Developmental Biology (SCGDB) 42nd Annual Meeting was held at the MD Anderson Cancer Center in Houston, Texas from October 14–15, 2019. The SCGDB meeting included scientific sessions on the molecular regulation of craniofacial development, cell biology of craniofacial development, signaling during craniofacial development, translational craniofacial biology, and for the first time, a career development workshop. Over a one hundred attendees from 21 states, and representing over 50 different scientific institutions, participated. The diverse group of scientists included cell and developmental biologists and clinical geneticists, promoting excellent discussions about molecular pathways guiding abnormal cell behaviors and the resultant morphological changes to craniofacial development. The results were high‐quality science and a welcoming environment for trainees interested in craniofacial biology.     

GEFs in growth factor signaling

Evolutionary conserved members of the Ras superfamily of small GTP-binding proteins function as binary molecular switches to control diverse biological processes. In the context of cellular signaling, these include functions in exocytic and endocytic trafficking, as well as roles in signal relay downstream of various cell surface receptors. We previously reviewed roles played by the large family of GTPase, activating proteins in these processes. In this companion review, we highlight recent findings relating to the regulation of another major class of Ras superfamily regulatory proteins, the guanine nucleotide exchange factors.     

Profiling distinct mechanisms of tumour invasion for drug discovery: imaging adhesion,signalling and matrix turnover

Recent advances in microscopic imaging technology, fluorescent reporter reagents, 3-dimensional (3D) cell models and multiparametric image analysis have enhanced our ability to model and understand complex cell physiology. Extension of these approaches to live cell, kinetic studies allows further spatial and temporal understanding of a multitude of dynamic functional events, including tumour cell invasion. Recent in vivo and 3D in vitro studies reveal how tumour cells utilize a diverse variety of mechanisms to permit invasion through 3D tissue environments. Such high degrees of diversity and plasticity between invasion mechanisms present a significant challenge to the successful treatment of malignant cancer. This review examines how advances in time-resolved imaging has contributed to the characterization of distinct modes of invasion and their associated molecular mechanisms. Specifically, we highlight the development of fluorescent reporter molecules and their incorporation into more predictive 3D in vitro and in vivo models, to enhance mechanistic analysis of tumour invasion. We also highlight the latest advances in kinetic imaging instrumentation applicable to in vitro and in vivo models of tumour invasion. We discuss how multiparametric image analysis can be used to interpret image data generated by these approaches. We further discuss how these approaches can be integrated into drug discovery pipelines to facilitate evaluation and selection of candidate drugs and novel pharmaceutical compositions, targeting multiple invasive mechanisms.     

Benign and low-grade superficial endothelial cell neoplasms in the molecular era

Vascular tumors are the most common mesenchymal neoplasms of the skin and subcutis, and they encompass a heterogeneous group with diverse clinical, histological, and molecular features, as well as biological behavior. Over the past two decades, molecular studies have enabled the identification of pathogenic recurrent genetic alterations that can be used as additional data points to support the correct classification of these lesions. The purpose of this review is to summarize the available data related to superficially located benign and low-grade vascular neoplasms and to highlight recent molecular advances with the role of surrogate immunohistochemistry to target pathogenic proteins as diagnostic biomarkers.     

Protein synthesis,degradation, and energy metabolism in T cell immunity

T cell activation, proliferation, and differentiation into effector and memory states involve massive remodeling of T cell size and molecular content and create a massive increase in demand for energy and amino acids. Protein synthesis is an energy- and resource-demanding process; as such, changes in T cell energy production are intrinsically linked to proteome remodeling. In this review, we discuss how protein synthesis and degradation change over the course of a T cell immune response and the crosstalk between these processes and T cell energy metabolism. We highlight how the use of high-resolution mass spectrometry to analyze T cell proteomes can improve our understanding of how these processes are regulated.     

Insect immunity: the post-genomic era

Insects have a complex and effective immune system, many components of which are conserved in mammals. But only in the last decade have the molecular mechanisms that regulate the insect immune response--and their relevance to general biology and human immunology--become fully appreciated. A meeting supported by the Centre National de la Récherche Scientifique (France) was held to bring together the whole spectrum of researchers working on insect immunity. The meeting addressed diverse aspects of insect immunity and brought together geneticists working on Drosophila melanogaster with those working on other insects.     

International Society of Neuropathology‐Haarlem Consensus Guidelines for Nervous System Tumor Classification and Grading

Major discoveries in the biology of nervous system tumors have raised the question of how non‐histological data such as molecular information can be incorporated into the next World Health Organization (WHO) classification of central nervous system tumors. To address this question, a meeting of neuropathologists with expertise in molecular diagnosis was held in Haarlem, the Netherlands, under the sponsorship of the International Society of Neuropathology (ISN). Prior to the meeting, participants solicited input from clinical colleagues in diverse neuro‐oncological specialties. The present “white paper” catalogs the recommendations of the meeting, at which a consensus was reached that incorporation of molecular information into the next WHO classification should follow a set of provided “ISN‐Haarlem” guidelines. Salient recommendations include that (i) diagnostic entities should be defined as narrowly as possible to optimize interobserver reproducibility, clinicopathological predictions and therapeutic planning; (ii) diagnoses should be “layered” with histologic classification, WHO grade and molecular information listed below an “integrated diagnosis”; (iii) determinations should be made for each tumor entity as to whether molecular information is required, suggested or not needed for its definition; (iv) some pediatric entities should be separated from their adult counterparts; (v) input for guiding decisions regarding tumor classification should be solicited from experts in complementary disciplines of neuro‐oncology; and (iv) entity‐specific molecular testing and reporting formats should be followed in diagnostic reports. It is hoped that these guidelines will facilitate the forthcoming update of the fourth edition of the WHO classification of central nervous system tumors.     

Molecular aspects of autoimmunity

Sustained humoral and/or cellular autoimmune responses are currently thought to be the primary causes of a wide spectrum of systemic and organ-specific human and animal diseases. Although a very good picture of the immunopathological characteristics of these diseases has emerged, their etiologies remain unknown. Studies initiated to define these diseases at the molecular genetic level were the subject of a recent meeting in Ville D'Esterel, Canada. Because these diseases are diverse and enormously complex, several avenues of investigation have been pursued. The primary focus of this meeting was the tripartite system of immunoglobulin (Ig), T-cell antigen receptor (TCR) and major histocompatibility complex (MHC) genes.     

Proteomics in heart failure: top-down or bottom-up?

The pathophysiology of heart failure (HF) is diverse, owing to multiple etiologies and aberrations in a number of cellular processes. Therefore, it is essential to understand how defects in the molecular pathways that mediate cellular responses to internal and external stressors function as a system to drive the HF phenotype. Mass spectrometry (MS)-based proteomics strategies have great potential for advancing our understanding of disease mechanisms at the systems level because proteins are the effector molecules for all cell functions and, thus, are directly responsible for determining cell phenotype. Two MS-based proteomics strategies exist: peptide-based bottom-up and protein-based top-down proteomics—each with its own unique strengths and weaknesses for interrogating the proteome. In this review, we will discuss the advantages and disadvantages of bottom-up and top-down MS for protein identification, quantification, and analysis of post-translational modifications, as well as highlight how both of these strategies have contributed to our understanding of the molecular and cellular mechanisms underlying HF. Additionally, the challenges associated with both proteomics approaches will be discussed and insights will be offered regarding the future of MS-based proteomics in HF research.     

BAFF, APRIL and human B cell disorders

B cells require signals from multiple sources for their development from precursor cells, and differentiation into effector cells. BAFF has been identified as a critical regulator of B cell development and differentiation. Defects in the production of BAFF and/or expression of its receptors have been associated with a diverse array of human immunopathologies characterised by perturbed B cell function and behaviour, including autoimmunity, malignancy, and immunodeficiency. This review will discuss the role of BAFF in the pathogenesis of these human immune disorders. It will also highlight relevant differences between the function of BAFF in humans and mice and the impact of this on the therapeutic utility of BAFF antagonists in the treatment of different human diseases.     

T follicular helper cell heterogeneity: Time,space, and function

T follicular helper (Tfh) cells play a crucial role in orchestrating the humoral arm of adaptive immune responses. Mature Tfh cells localize to follicles in secondary lymphoid organs (SLOs) where they provide help to B cells in germinal centers (GCs) to facilitate immunoglobulin affinity maturation, class‐switch recombination, and generation of long‐lived plasma cells and memory B cells. Beyond the canonical GC Tfh cells, it has been increasingly appreciated that the Tfh phenotype is highly diverse and dynamic. As naive CD4⁺ T cells progressively differentiate into Tfh cells, they migrate through a variety of microanatomical locations to obtain signals from other cell types, which in turn alters their phenotypic and functional profiles. We herein review the heterogeneity of Tfh cells marked by the dynamic phenotypic changes accompanying their developmental program. Focusing on the various locations where Tfh and Tfh‐like cells are found, we highlight their diverse states of differentiation. Recognition of Tfh cell heterogeneity has important implications for understanding the nature of T helper cell identity specification, especially the plasticity of the Tfh cells and their ontogeny as related to conventional T helper subsets.     

Herpes simplex virus: discovering the link between heparan sulphate and hereditary bone tumours

To gain entry into the host, viruses use host cell surface molecules that normally serve as receptors for other ligands. Herpes simplex virus type 1 (HSV-1) uses heparan sulphate (HS) glycosaminoglycans (GAGs) as receptors for initial attachment to the host cell surface. HS GAGs are both ubiquitous and structurally diverse, and normally serve as critical mediators of interactions between the cell and the extracellular environment. We have used the HS binding ability of HSV-1 to identify the function of a cellular gene, EXT1, which is involved in HS polymerisation. Cellular factors that affect virus growth and replication are often key regulators of the cell cycle and EXT1 is no different-humans with inherited mutations in EXT1 have developmental defects that lead to bone tumours (hereditary multiple exostoses, HME) and sometimes chondrosarcomas. Thus, as a result of using HSV-1 as a molecular probe, a functionally orphaned disease gene now has a defined function. These findings highlight the utility of viruses for investigating important cellular processes.     

Integrative inflammasome activity in the regulation of intestinal mucosal immune responses

The mammalian intestinal tract harbors a vast and diverse ecosystem of microbes that are separated from the sterile host milieu by a single layer of epithelial cells. While this bio-geographical configuration is critical for host biological processes, it imposes a risk for microbial penetration and life-threatening systemic invasion. Inflammasomes are cytosolic multi-protein platforms that sense both microbial and damage-associated molecular patterns and initiate a potent innate immune anti-microbial response. In this review, we will highlight the role of inflammasomes in the orchestration and regulation of the intestinal immune response, focusing on the roles of inflammasomes in maintenance of intestinal homeostasis, enteric infection, auto-inflammation, and tumorigenesis. We highlight the centrality of inflammasome signaling in the complex cross-talk between host mucosal immune arms and the environment, in particular the microflora, with emphasis on the spatial and temporal integration of inflammasome activation with signals from other innate signaling platforms.     

Mammalian distal tubule: physiology, pathophysiology, and molecular anatomy

The distal tubule of the mammalian kidney, defined as the region between the macula densa and the collecting duct, is morphologically and functionally heterogeneous. This heterogeneity has stymied attempts to define functional properties of individual cell types and has led to controversy concerning mechanisms and regulation of ion transport. Recently, molecular techniques have been used to identify and localize ion transport pathways along the distal tubule and to identify human diseases that result from abnormal distal tubule function. Results of these studies have clarified the roles of individual distal cell types. They suggest that the basic molecular architecture of the distal nephron is surprisingly similar in mammalian species investigated to date. The results have also reemphasized the role played by the distal tubule in regulating urinary potassium excretion. They have clarified how both peptide and steroid hormones, including aldosterone and estrogen, regulate ion transport by distal convoluted tubule cells. Furthermore, they highlight the central role that the distal tubule plays in systemic calcium homeostasis. Disorders of distal nephron function, such as Gitelman's syndrome, nephrolithiasis, and adaptation to diuretic drug administration, emphasize the importance of this relatively short nephron segment to human physiology. This review integrates molecular and functional results to provide a contemporary picture of distal tubule function in mammals.