The first independent Ukrainian census in Crimea: Myths,miscoding, and missed opportunities

State-defined identity categories can have a profound impact on individuals’ conception of themselves. Like birth certificates and migration documents, the census is a crucial instrument in producing and maintaining ethnic and racial identities. Recent research suggests that censuses measure preferences, rather than objective data, and can profitably be studied along the lines of political campaigns. This article advances the idea that the next question is whose preference is being recorded. Ethnographic research on the micropolitics of census-taking in Crimea, Ukraine suggest the dynamics between census-takers and ethnic constituencies, as well as instructions from census officials with various ethnic loyalties, have a crucial role to play.     

A kinase-independent role for Aurora A in the assembly of mitotic spindle microtubules in Caenorhabditis elegans embryos

The assembly of a functional mitotic spindle is crucial for achieving successful mitosis. Aurora A kinase is one of the key regulators of mitotic events, including mitotic entry, centrosome maturation and spindle bipolarity. Caenorhabditis elegans Aurora A (AIR-1) is responsible for the assembly of γ-tubulin-independent microtubules in early embryos; however, the mechanism by which AIR-1 contributes to microtubule assembly during mitosis has been unclear. Here we show by live-cell imaging and RNA-mediated interference (RNAi)-based modulation of gene activity that AIR-1 has a crucial role in the assembly of chromatin-stimulated microtubules that is independent of the γ-tubulin complex. Surprisingly, the kinase activity of AIR-1 is dispensable for this process. Although the kinase-inactive form of AIR-1 was detected along the microtubules as well as on centrosomes, the kinase-active form of AIR-1 was restricted to centrosomes. Thus, we propose that AIR-1 has a kinase-dependent role at centrosomes and a kinase-independent role for stabilizing spindle microtubules and that coordination of these two roles is crucial for the assembly of mitotic spindles.     

Modulation of inflammation by autophagy: Consequences for human disease

Autophagy and inflammation are 2 fundamental biological processes involved in both physiological and pathological conditions. Through its crucial role in maintaining cellular homeostasis, autophagy is involved in modulation of cell metabolism, cell survival, and host defense. Defective autophagy is associated with pathological conditions such as cancer, autoimmune disease, neurodegenerative disease, and senescence. Inflammation represents a crucial line of defense against microorganisms and other pathogens, and there is increasing evidence that autophagy has important effects on the induction and modulation of the inflammatory reaction; understanding the balance between these 2 processes may point to important possibilities for therapeutic targeting. This review focuses on the crosstalk between autophagy and inflammation as an emerging field with major implications for understanding the host defense on the one hand, and for the pathogenesis and treatment of immune-mediated diseases on the other hand.     

Plant phenotypic plasticity in a changing climate

Climate change is altering the availability of resources and the conditions that are crucial to plant performance. One way plants will respond to these changes is through environmentally induced shifts in phenotype (phenotypic plasticity). Understanding plastic responses is crucial for predicting and managing the effects of climate change on native species as well as crop plants. Here, we provide a toolbox with definitions of key theoretical elements and a synthesis of the current understanding of the molecular and genetic mechanisms underlying plasticity relevant to climate change. By bringing ecological, evolutionary, physiological and molecular perspectives together, we hope to provide clear directives for future research and stimulate cross-disciplinary dialogue on the relevance of phenotypic plasticity under climate change.     

Potassium channels in cell cycle and cell proliferation

Normal cell-cycle progression is a crucial task for every multicellular organism, as it determines body size and shape, tissue renewal and senescence, and is also crucial for reproduction. On the other hand, dysregulation of the cell-cycle progression leading to uncontrolled cell proliferation is the hallmark of cancer. Therefore, it is not surprising that it is a tightly regulated process, with multifaceted and very complex control mechanisms. It is now well established that one of those mechanisms relies on ion channels, and in many cases specifically on potassium channels. Here, we summarize the possible mechanisms underlying the importance of potassium channels in cell-cycle control and briefly review some of the identified channels that illustrate the multiple ways in which this group of proteins can influence cell proliferation and modulate cell-cycle progression.     

Many stimuli pull the necrotic trigger, an overview

The lab of Jürg Tschopp was the first to report on the crucial role of receptor-interacting protein kinase 1 (RIPK1) in caspase-independent cell death. Because of this pioneer finding, regulated necrosis and in particular RIPK1/RIPK3 kinase-mediated necrosis, referred to as necroptosis, has become an intensively studied form of regulated cell death. Although necrosis was identified initially as a backup cell death program when apoptosis is blocked, it is now recognized as a cellular defense mechanism against viral infections and as being critically involved in ischemia-reperfusion damage. The observation that RIPK3 ablation rescues embryonic lethality in mice deficient in caspase-8 or Fas-associated-protein-via-a-death-domain demonstrates the crucial role of this apoptotic platform in the negative control of necroptosis during development. Here, we review and discuss commonalities and differences of the increasing list of inducers of regulated necrosis ranging from cytokines, pathogen-associated molecular patterns, to several forms of physicochemical cellular stress. Since the discovery of the crucial role of RIPK1 and RIPK3 in necroptosis, these kinases have become potential therapeutic targets. The availability of new pharmacological inhibitors and transgenic models will allow us to further document the important role of this form of cell death in degenerative, inflammatory and infectious diseases.     

External signal–mediated polarized growth in fungi

As the majority of fungi are nonmotile, polarized growth in response to an external signal enables them to search for nutrients and mating partners, and hence is crucial for survival and proliferation. Although the mechanisms underlying polarization in response to external signals has commonalities with polarization during mitotic division, during budding, and fission growth, the importance of diverse feedback loops regulating external signal–mediated polarized growth is likely to be distinct and uniquely adapted to a dynamic environment. Here, we highlight recent advances in our understanding of the mechanisms that are crucial for polarity in response to external signals in fungi, with particular focus on the roles of membrane traffic, small GTPases, and lipids, as well as the interplay between cell shape and cell growth.     

p62: a versatile multitasker takes on cancer

Since its initial discovery as an atypical protein kinase C (PKC)-interacting protein, p62 has emerged as a crucial molecule in a myriad of cellular functions. This multifunctional role of p62 is explained by its ability to interact with several key components of various signaling mechanisms. Not surprisingly, p62 is required for tumor transformation owing to its roles as a key molecule in nutrient sensing, as a regulator and substrate of autophagy, as an inducer of oxidative detoxifying proteins, and as a modulator of mitotic transit and genomic stability; all crucial events in the control of cell growth and cancer.     

Could the glycosylation analysis of seminal plasma clusterin become a novel male infertility biomarker?

Male infertility is becoming a rapidly growing problem around the world, mainly in the highly developed countries. Seminal proteome composition seems to be one of the crucial factors of the proper course of fertilization ‐ clusterin (CLU) is among the most important ones. CLU, as one of the crucial seminal plasma glycoproteins, plays a very important role in sperm capacitation and immune tolerance in the female reproductive tract. CLU is also known as a sensitive marker of oxidative stress. It has six n ‐glycosylation sites and also exhibits chaperone activity. An analysis of changes in the profile and degree of CLU glycosylation may shed some new light on the molecular mechanisms of the fertilization process and may be used as an additional diagnostic marker of male fertility. This study constitutes a review of the recently available literature concerning human seminal CLU, including changes in its glycosylation, analyzed in the context of human reproduction.     

Multi-scale models of lung fibrosis

The architectural complexity of the lung is crucial to its ability to function as an organ of gas exchange; the branching tree structure of the airways transforms the tracheal cross-section of only a few square centimeters to a blood-gas barrier with a surface area of tens of square meters and a thickness on the order of a micron or less. Connective tissue comprised largely of collagen and elastic fibers provides structural integrity for this intricate and delicate system. Homeostatic maintenance of this connective tissue, via a balance between catabolic and anabolic enzyme-driven processes, is crucial to life. Accordingly, when homeostasis is disrupted by the excessive production of connective tissue, lung function deteriorates rapidly with grave consequences leading to chronic lung conditions such as pulmonary fibrosis. Understanding how pulmonary fibrosis develops and alters the link between lung structure and function is crucial for diagnosis, prognosis, and therapy. Further information gained could help elaborate how the healing process breaks down leading to chronic disease. Our understanding of fibrotic disease is greatly aided by the intersection of wet lab studies and mathematical and computational modeling. In the present review we will discuss how multi-scale modeling has facilitated our understanding of pulmonary fibrotic disease as well as identified opportunities that remain open and have produced techniques that can be incorporated into this field by borrowing approaches from multi-scale models of fibrosis beyond the lung.     

Role of osteopontin in dendritic cell shaping of immune responses

Osteopontin (OPN) is a pleiotropic cytokine produced both by immune and non-immune cells and active on different cellular targets. OPN production has been associated with several pathological conditions, including autoimmune diseases (e.g. lupus, multiple sclerosis and rheumatoid arthritis) and cancer. Emerging evidence suggests that the role of OPN has been underestimated, as it seems to be working at multiple levels of immune regulation, such as the shaping of T cell effector responses, the regulation of the tumor microenvironment, and the functional interaction with mesenchymal stromal cells. In this context, dendritic cells (DCs) play a crucial role being both an important source and a cellular target for OPN action. DC family is composed by several cell subsets endowed with specific immune functions. OPN exerts its biological functions through multiple receptors and is produced in different intracellular and secreted forms. OPN production by DC subsets is emerging as a crucial mechanism of regulation in normal and pathological conditions and starts to be exploited as a therapeutic target. This review will focus on the role of DC-derived OPN in shaping immune response and on the complex role of this cytokines in the regulation in immune response.     

A crucial role for antigen-presenting cells and alloantigen expression in graft-versus-leukemia responses

Graft-versus-leukemia (GVL) response after allogeneic bone marrow transplantation (BMT) represents one of the most potent forms of immunotherapy against malignant diseases. Antigen-presenting cells (APCs) are crucial for the induction of graft-versus-host disease (GVHD), the most serious complication of allogeneic BMT, but their role in GVL responses is unclear. Using a series of clinically relevant mouse GVL tumor models, we found that APCs and alloantigen expression on tumors are crucial for GVL. Moreover, APCs of host origin predominated in GVL responses although donor APCs contributed as the acuity of tumor burden decreased.     

Structural exploration of tetrahydroisoquinoline derivatives as HDAC8 inhibitors through multi-QSAR modeling study

Abstract

Histone deacetylase 8 (HDAC8) is one of the crucial HDACs responsible for influencing the epigenetic functions of the body. Overexpression of HDAC8 is found to be involved in numerous disease conditions such as tumorigenesis, cell proliferation, cancer, viral infections, neuronal disorders and other epigenetic diseases. Therefore, inhibition of HDAC8 is a primary method to combat these diseases. In this article, a multi-QSAR modeling study on tetrahydroisoquinoline derivatives was conducted to identify important contributions of the structural features of these compounds toward HDAC8 inhibition. All these QSAR modeling techniques were individually validated and justified the observations of each other. The results implied that the tetrahydroisoquinoline moiety may be effective as a cap group than as a linker moiety for HDAC8 inhibition. Different substitutions at the tetrahydroisoquinoline scaffold were also found to be crucial in modulating HDAC8 inhibition.

Communicated by Ramaswamy H. Sarma     

自噬在发育及干细胞中的作用

自噬是亚细胞膜结构发生动态变化并经溶酶体介导的细胞内蛋白质和细胞器降解的过程。通过平衡细胞内的合成和分解代谢,自噬可以维持细胞内环境稳态。干细胞是具有自我更新能力和多向分化潜能的细胞,对组织器官再生和维持组织稳态有重要作用。近年的研究表明,自噬在维持干细胞功能方面有非常重要的作用,本文综述了自噬的形成过程和分子机制及其在发育及干细胞中的作用。     

Latest developments in tryptophan metabolism: Understanding its role in B cell immunity

One of the most essential and important building blocks of life is the tryptophan amino acid. As such, the pathways surrounding its metabolism are often crucial for the maintenance of proper cell activity and homeostasis. The ratios of tryptophan to kynurenine, mainly mediated by indoleamine 2,3-dioxygenase activity, is a key parameter in the inflammation as well as immunomodulation of both aseptic and septic diseases. As a result, several studies have been published to better understand the mechanisms by which the tryptophan pathways lead to such outcomes. Many have focused on gut health and cells associated with the given environment, the majority of which constitute regulatory T cells and T helper 17 cells. However, recent studies have highlighted the role of this molecular pathway on its capacity to modulate B cells functions and humoral immunity. Accordingly, the focus of this short review is to examine the key tryptophan pathways and their impact on B cells demonstrated by those studies. A better understanding of the role of tryptophan and its metabolites is crucial for its use in disease prevention and treatments.     

Is invasion efficiency in malaria controlled by pre-invasion events?

The invasion efficiency of Plasmodium falciparum merozoites was found to decrease with increasing red blood cell density, a finding relevant to protection strategies against falciparum malaria. The mechanism of this 'density effect' remained unexplained. Searching for possible explanations, we studied selected video recordings of the dynamic events during merozoite invasion and identified a pre-invasion stage as a crucial mediator of invasion efficiency. We suggest that the role of the pre-invasion stage is to induce the apical alignment of the merozoite, and propose a working hypothesis on its mechanism, with a crucial role for elevated intracellular Ca2+.     

Selection of the Best Blood Compartment to Measure Cytidine Deaminase Activity to Stratify for Optimal Gemcitabine or Cytarabine Treatment

Cytidine deaminase (CDA) plays a crucial role in the degradation of cytidine analogs, such as gemcitabine and cytarabine. Several studies showed that a low CDA activity is associated with more toxicity but a higher efficacy, while a high activity will lead to a lower efficacy but less toxicity. A stratified dosing strategy based on the relative CDA activity would increase efficiency. In order to predict these events, a reliable measurement of CDA with a validated method is crucial. We aimed to determine which phenotype assay would be most suitable; a spectrophotometric assay using cytidine as a substrate, or an HPLC assay using gemcitabine as a substrate. In serum and whole blood of 26 volunteers, both assays showed an excellent correlation (R > 0.999), but not in plasma nor in red blood cells. Moreover, there was no difference between males and females.

In conclusion, the spectrophotometric assay seems the most simple and cost-effective test. It should be performed in serum, while it should be normalized on protein content as measured by the Bicinchoninic Acid.     

Use of RNA Tertiary Interaction Modules for the Crystallisation of the Spliceosomal snRNP Core Domain

RNA is known to perform diverse roles in the cell, often as ribonucleoprotein (RNP) particles. While the crystal structure of these RNP particles could provide crucial insights into their functions, crystallographic work on RNP complexes is often hampered by difficulties in obtaining well-diffracting crystals. The small nuclear ribonucleoprotein (snRNP) core domain, acting as an assembly nucleus for the maturation of snRNPs, plays a crucial role in the biogenesis of four of the spliceosomal snRNPs. We have succeeded in crystallising the human U4 snRNP core domain containing seven Sm proteins and a truncated U4 snRNA variant. The most critical factor in our success in the crystallisation was the introduction of various tertiary interaction modules into the RNA that could promote crystal packing without altering the core structure. Here, we describe various strategies employed in our crystallisation effort that could be applied to crystallisation of other RNP particles.     

The role of metals in neurodegenerative diseases.

There is increasing evidence in a number of neurodegenerative diseases that transition metal-mediated abnormalities play a crucial role in disease pathogenesis. In this treatise, we review the role of metal homeostasis as it pertains to alterations in brain function in neurodegenerative diseases. In fact, while there is documented evidence for alterations in transition metal homeostasis, redox-activity and localization, it is also important to realize that alterations in specific copper- and iron-containing metalloenzymes also appear to play a crucial role in the neurodegenerative process.