Ubiquitous Factor Research Articles

Robust hematopoietic specification requires the ubiquitous Sp1 and Sp3 transcription factors

BackgroundBoth tissue-specific and ubiquitously expressed transcription factors, such as Sp-family members, are required for correct development. However, the molecular details of how ubiquitous factors are involved in programming tissue-specific chromatin and thus participate in developmental processes are still unclear. We previously showed that embryonic stem cells lacking Sp1 DNA-binding activity (Sp1ΔDBD/ΔDBD cells) are able to differentiate into early blood progenitors despite the inability of Sp1 to bind chromatin without its DNA-binding domain. However, gene expression during differentiation becomes progressively deregulated, and terminal differentiation is severely compromised.ResultsHere, we studied the cooperation of Sp1 with its closest paralogue Sp3 in hematopoietic development and demonstrate that Sp1 and Sp3 binding sites largely overlap. The complete absence of either Sp1 or Sp3 or the presence of the Sp1 DNA-binding mutant has only a minor effect on the pattern of distal accessible chromatin sites and their transcription factor binding motif content, suggesting that these mutations do not affect tissue-specific chromatin programming. Sp3 cooperates with Sp1ΔDBD/ΔDBD to enable hematopoiesis, but is unable to do so in the complete absence of Sp1. Using single-cell gene expression analysis, we show that the lack of Sp1 DNA binding leads to a distortion of cell fate decision timing, indicating that stable chromatin binding of Sp1 is required to maintain robust differentiation trajectories.ConclusionsOur findings highlight the essential contribution of ubiquitous factors such as Sp1 to blood cell development. In contrast to tissue-specific transcription factors which are required to direct specific cell fates, loss of Sp1 leads to a widespread deregulation in timing and coordination of differentiation trajectories during hematopoietic specification.

Host factors involved in HBV cccDNA formation and transcription

The genome of hepatitis B virus (HBV) is an incomplete double-stranded circular DNA, also known as relaxed circular (RC) DNA. RC-DNA needs to be converted to covalently closed circular (ccc) DNA during the replication process. cccDNA acts as the transcription template for viral RNAs. One of those viral RNAs, pgRNA, acts as the template in the reverse-transcription process, producing minus-DNA and plus-DNA. Subsequently, the two finally form RC-DNA and finish the viral genome replication process. The existence of cccDNA is the key obstacle for curing hepatitis type B and eliminating HBV antigen using medicines such as interferons or nucleos(t)ide analogues (NAs). Many host factors are involved in HBV cccDNA formation and transcription. We summarized some of these host factors and explained their related functions in HBV infection and replication, detailing the mechanisms of cccDNA formation and subsequent transcription. When HBV enters host cells, its surface protein L interacts with the receptor NTCP on the cell surface, allowing HBV to enter through endocytosis and leaving its envelope behind. Subsequently, the HBV genome, the RC-DNA, enters the cell nucleus, and leaves the empty nucleocapsid behind. The genome RC-DNA must convert into cccDNA to start the replication process. Many host factors participate in this process in various ways, including helping to remove special constructions, fixing the gaps and the single stand areas. These host factors include TDP1, TDP2, FEN1 and factors involved in the DNA damage response (DDR) system. This process also requires host DNA polymerase to extend DNA sequences, including POLK, POLH and POLL. cccDNA does not exist independently, but rather it exists in combination with many histones and nonhistones. The epigenetic modification of histone influences cccDNA transcription in various ways. For example, acetylization of H3 and H4 induces transcription and some acetylases such as CBP, p300, PCAF, HAT1, and KAT8 are involved. Interestingly, most of the host acetylases are recruited by two viral proteins, HBX and HBC, suggesting that these two virus proteins may help the virus to kidnap host factors for the benefit of the virus. In addition to epigenetic modification, cccDNA transcription also requires many cis-elements and host transcription factors. Many ubiquitous and liver-enriched host factors such as NF-1, sp-1, TBP, CREB, HNF3, HNF1, HNF4, C/EBP, PPARα, FXR, FTF, PGC-1αcombine with cis-elements in HBV genome, including promoter regions and enhancer regions. This combination induces or inhibits the cccDNA transcription process. In truth, HBV cccDNA formation and transcription processes require more host involvement than this article mentions. Many new factors and interactions as well as key regulators still waiting to be discovered. This article may supply suggestions for research into the detailed mechanism of the two processes of HBV cccDNA.

The political process of Boko Haram insurgency onset: a political relevance model

ABSTRACT As more data emerges on the Boko Haram phenomenon, the controversy over the roots of the insurgency persists. While some emphasise transnational motivational factors based on the Salafist ideology, others focus on diverse local structural factors, including the economy, religion, and politics. Although this article acknowledges the importance of these factors, it argues that these are ubiquitous contextual factors which insufficiently explain the location and timing of the insurgency. By introducing the Political Relevance Model, this article theorises the insurgency onset by focusing on the agency of the local political elites and their relationship with the sect. It finds that the insurgency is rooted in an initial mutually beneficial relationship between the local political elites and a politically relevant group that turned sour, resulting in the attempt by the elites to withdraw the group’s earlier privileges using state coercion which the group frames as state repression requiring violent resistance. These agents have, in their interest, framed this struggle to resonate with the people.

Westernized Diet is the Most Ubiquitous Environmental Factor in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD), a collective term for Crohn disease and ulcerative colitis, is a polygenic disease thought to be triggered by environmental factors. A Western or westernized lifestyle may be a major driver of the growing incidence of IBD. IBD may represent dysregulated mucosal inflammation to gut microbiota. Despite many review articles on environmental factors in IBD, no consensus exists regarding which factor contributes most to trigger the onset of IBD. Identification and recognition of major environmental factors are prerequisite for effective disease treatment and prevention. Representative environmental factors such as smoking, breastfeeding, nonsteroidal anti-inflammatory drugs, antibiotic use in childhood, oral contraceptives, and appendectomy do not correlate with disease onset in most patients with IBD. In contrast, diet appears to be important in most cases of IBD. Diets rich in animal protein (risk factor) and deficient in dietary fiber (preventive factor) are characteristic of westernized diets in affluent societies. Recent research shows that westernized diets are associated with a reduced gut microbial diversity (dysbiosis), which may result in increased susceptibility to IBD and other common chronic diseases. Plant-based diets rich in dietary fiber are associated with increased microbial diversity. Recent reports on IBD therapy that replaced westernized diets with plant-based diets achieved far better outcomes than those previously reported in the literature. We believe that westernized diet-associated gut dysbiosis is the most ubiquitous environmental factor in IBD. Adoption of this concept may have the potential to provide a better quality of life for patients with IBD.

Cross-validation of the demoralization construct in the Revised NEO Personality Inventory.

Demoralization is defined as a pervasive, generalized negative emotional construct present in psychiatric disorders and a variety of medical conditions. Demoralization is also conceptualized as a ubiquitous affective-laden factor common to most forms of psychopathology that increases the magnitude of intercorrelations among putatively distinct psychiatric symptom scales (Tellegen, 1985). Using exploratory structural equation modeling to identify common variance across the revised NEO Personality Inventory (NEO PI-R), a measure of the five-factor model of personality, Noordhof, Sellbom, Eigenhuis, and Kamphuis (2015) constructed an 18-item Demoralization subscale in a Dutch-speaking sample of patients attending a clinic for personality disorders in the Netherlands. In the current study we sought to cross-validate these findings in an English-speaking and diagnostically heterogeneous sample of psychiatric patients (N = 1930) receiving consultation or treatment at a large mental health and addiction center in Canada. Our results support the construct validity of the Demoralization subscale and its capacity to account for demoralization-related variance in the NEO PI-R. We believe these findings support the general tenets of demoralization and the presence of this construct in the NEO PI-R item pool. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The association between subjective maternal stress during pregnancy and offspring clinically diagnosed psychiatric disorders.

Exposure to prenatal stress is a ubiquitous and non-specific risk factor for adverse outcomes in adulthood. In this study, we examined associations between exposure to subjective maternal stress during pregnancy and subsequent diagnosis of psychiatric disorders in offspring. This study used the Helsinki Longitudinal Temperament Cohort, a prospective birth cohort of individuals born between 1 July 1975 and 30 June 1976 in Helsinki, Finland. The sample for this study comprised 3626 infants whose mothers had completed health and well-being assessments during pregnancy which included a measure of self-reported stress. We ran logistic regressions to assess potential associations between prenatal stress and offspring psychiatric disorder in adulthood, identified through the Finnish Hospital Discharge Register. Individuals whose mothers reported stress during pregnancy had significantly greater odds of developing a psychiatric disorder (OR=1.41, 95% CI=1.10-1.81) particularly a mood disorder (OR=1.67, 95% CI=1.10-2.54). These associations remained after adjusting for parental psychiatric history, and other prenatal factors. Individuals exposed to prenatal stress had significantly increased risk of developing psychiatric disorders later in life. This finding highlights the importance of supporting the mental health and emotional well-being of women during pregnancy.

Acclimation temperature changes spermatozoa flagella length relative to head size in brown trout.

ABSTRACTTemperature is a ubiquitous environmental factor affecting physiological processes of ectotherms. Due to the effects of climate change on global air and water temperatures, predicting the impacts of changes in environmental thermal conditions on ecosystems is becoming increasingly important. This is especially crucial for migratory fish, such as the ecologically and economically vital salmonids, because their complex life histories make them particularly vulnerable. Here, we addressed the question whether temperature affects the morphology of brown trout, Salmo trutta L. spermatozoa. The fertilising ability of spermatozoa is commonly attributed to their morphological dimensions, thus implying direct impacts on the reproductive success of the male producing the cells. We show that absolute lengths of spermatozoa are not affected by temperature, but spermatozoa from warm acclimated S. trutta males have longer flagella relative to their head size compared to their cold acclimated counterparts. This did not directly affect sperm swimming speed, although spermatozoa from warm acclimated males may have experienced a hydrodynamic advantage at warmer temperatures, as suggested by our calculations of drag based on head size and sperm swimming speed. The results presented here highlight the importance of increasing our knowledge of the effects of temperature on all aspects of salmonid reproduction in order to secure their continued abundance.

Retinal Pigment Epithelial Cells: The Unveiled Component in theEtiology of Prpf Splicing Factor-Associated Retinitis Pigmentosa.

Pre-mRNA splicing is a critical step in RNA processing in all eukaryotic cells. It consists of introns removal and requires the assembly of a large RNA-protein complex called the spliceosome. This complex of small nuclear ribonucleoproteins is associated with accessory proteins from the pre-mRNA processing factor (PRPF) family. Mutations in different splicing factor-encoding genes were identified in retinitis pigmentosa (RP) patients. A surprising feature of these ubiquitous factors is that the outcome of their alteration is restricted to the retina. Because of their high metabolic demand, most studies focused on photoreceptors dysfunction and associated degeneration. However, cells from the retinal pigment epithelium (RPE) are also crucial to maintaining retinal homeostasis and photoreceptor function. Moreover, mutations in RPE-specific genes are associated with some RP cases. Indeed, we identified major RPE defects in Prpf31-mutant mice: circadian rhythms of both photoreceptor outer segments (POS) phagocytosis and retinal adhesion were attenuated or lost, leading to ultrastructural anomalies and vacuoles. Taken together, our published and ongoing data suggest that (1) similar molecular events take place in human and mouse cells and (2) these functional defects generate various stress processes.

Transcriptome Sequence Analysis Elaborates a Complex Defensive Mechanism of Grapevine (Vitis vinifera L.) in Response to Salt Stress.

Salinity is ubiquitous abiotic stress factor limiting viticulture productivity worldwide. However, the grapevine is vulnerable to salt stress, which severely affects growth and development of the vine. Hence, it is crucial to delve into the salt resistance mechanism and screen out salt-resistance prediction marker genes; we implicated RNA-sequence (RNA-seq) technology to compare the grapevine transcriptome profile to salt stress. Results showed 2472 differentially-expressed genes (DEGs) in total in salt-responsive grapevine leaves, including 1067 up-regulated and 1405 down-regulated DEGs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations suggested that many DEGs were involved in various defense-related biological pathways, including ROS scavenging, ion transportation, heat shock proteins (HSPs), pathogenesis-related proteins (PRs) and hormone signaling. Furthermore, many DEGs were encoded transcription factors (TFs) and essential regulatory proteins involved in signal transduction by regulating the salt resistance-related genes in grapevine. The antioxidant enzyme analysis showed that salt stress significantly affected the superoxide dismutase (SOD), peroxidase (POD), catalase (CAT) and glutathione S-transferase (GST) activities in grapevine leaves. Moreover, the uptake and distribution of sodium (Na+), potassium (K+) and chlorine (Cl−) in source and sink tissues of grapevine was significantly affected by salt stress. Finally, the qRT-PCR analysis of DE validated the data and findings were significantly consistent with RNA-seq data, which further assisted in the selection of salt stress-responsive candidate genes in grapevine. This study contributes in new perspicacity into the underlying molecular mechanism of grapevine salt stress-tolerance at the transcriptome level and explore new approaches to applying the gene information in genetic engineering and breeding purposes.

Retrato a carvão: a gestão do fogo no âmbito da administração florestal e do ordenamento florestal do território. Subsídios para uma perspetiva histórica e de futuro

O fogo constitui um factor ecológico omnipresente no território e na história da gestão dos espaços silvestres em Portugal e é central na formulação das políticas públicas. O artigo aborda 4 temas relevantes para a gestão integrada dos fogos rurais, nomeadamente os regimes do fogo pretéritos e atuais, a evolução da administração pública florestal e das principais linhas de política, o uso do fogo como ferramenta silvícola e o papel dos modelos de intervenção à escala da paisagem na diminuição do risco de incêndio, bem como o seu contributo para o futuro da floresta.

Exploration of biological phenomena of below-background natural radiation

Worldwide, humans are exposed to a mean background radiation dose of about 2.4 mSv per year. Natural background radiation is a constant and ubiquitous environmental factor affecting all living things on this planet, and organisms have evolved in the presence of the natural radiation since the first forms of life appeared on Earth. However, its role in biology is still not completely understood. Here, we summarize the interesting biological responses in organism at below-background radiation and highlight recent development of the studies with molecular based analyses. To date, deprivation of natural background radiation has been carried out with shielding chambers or by conducting experiments in underground laboratories. In recent decades some research groups have reported changes to growth-related biological endpoints in microorganisms and mammalian cells under low-background radiation conditions. Moreover, new technologies, such as DNA microarray and next-generation sequencing, have begun to shed fresh light on the molecular mechanisms of these biological phenomena. Although there is no consistent explanation for the mechanisms so far, such studies might provide clues toward an understanding of the biological responses to natural background radiation.

High serum arsenic and cardiovascular risk factors in patients undergoing continuous ambulatory peritoneal dialysis

The present study aims to assess arsenic accumulation and explore its association with renal function and biomarkers of CVD risk in chronic kidney disease patients receiving continuous ambulatory peritoneal dialysis (CAPD). The serum was collected from 87 CAPD patients and 26 healthy subjects between 2015 and 2016. The arsenic concentration was measured by inductively coupled plasma mass spectrometer. Clinical variables related to CVD risk were determined with automatic biochemical analyzer. Serum arsenic was higher in CAPD patients as compared to healthy volunteers. Moreover, significant differences of BMI, serum phosphorus, eGFR and Ccr were observed among groups. Positive correlation between serum arsenic and serum phosphorus was found (r = 0.453, p < 0.001). While serum arsenic was negatively associated with Ccr (r = −0.328, p = 0.002) and eGFR (r = −0.248, p = 0.020). The logistic regression models revealed that high serum arsenic was related to hyperphosphatemia (ORs, 1.827; 95%CI, 1.145–2.913) after adjusted for the potential confounding factors. Overall, our findings inferred the accumulation of arsenic in CAPD patients. In addition, high serum arsenic was independently associated with the occurrence of hyperphosphatemia, which was a special and ubiquitous CVD risk factor in CAPD patients. This study provided a clue for the association between arsenic and CVD burden in CKD patients. At the same time, it suggested that prevention of arsenic accumulation should be taken into consideration clinically.

An Automated Method to Determine the Performance of Drosophila in Response to Temperature Changes in Space and Time.

Temperature is a ubiquitous environmental factor that affects how species distribute and behave. Different species of Drosophila fruit flies have specific responses to changing temperatures according to their physiological tolerance and adaptability. Drosophila flies also possess a temperature sensing system that has become fundamental to understanding the neural basis of temperature processing in ectotherms. We present here a temperature-controlled arena that permits fast and precise temperature changes with temporal and spatial control to explore the response of individual flies to changing temperatures. Individual flies are placed in the arena and exposed to pre-programmed temperature challenges, such as uniform gradual increases in temperature to determine reaction norms or spatially distributed temperatures at the same time to determine preferences. Individuals are automatically tracked, allowing the quantification of speed or location preference. This method can be used to rapidly quantify the response over a large range of temperatures to determine temperature performance curves in Drosophila or other insects of similar size. In addition, it can be used for genetic studies to quantify temperature preferences and reactions of mutants or wild-type flies. This method can help uncover the basis of thermal speciation and adaptation, as well as the neural mechanisms behind temperature processing.

The expression of serum differentiated protein in patients with renal clear cell carcinoma and its clinical significance

Objective To explore the tumor marker using proteomics techniques and find the serum differentiated protein in patients with renal clear cell carcinoma through the comparison between renal clear cell carcinoma patients and healthy patients, and between the serum protein level before and after surgery. Methods We enrolled 88 patients with renal clear cell carcinoma as the experimental group, 120 patients with cystonephrosis or urinary calculus as the control group. Participants'serum were collected. We followed up the patients in the experimental group after the surgery and collected their blood sample each time. The surface enhanced laser desorption/ionization time of flight mass spectrometry and CM10 weak cation exchange protein chip technique were used to analyze the differentiated protein expression, the ZUCI-PDAS software was used to analyze. Results Three protein with M/Z 15949, 9306, and 5915 were selected as potential biological marker, they were Bcl-2 interacting mediator of cell death, ubiquitous kruppel like factor, and serum amyloid protein 4. Compared with the control group and postoperatively sample, the protein level was significantly different(P<0.05). The accuracy, sensitivity, and specificity of the three protein in diagnosing renal cell carcino-ma were 91.3%(190/208), 89.8%(79/88), (111/120), respectively. Conclusions It is applicable to use surface enhanced laser desorption/ionization time of flight mass spectrometry to explore the differentiated protein, Bcl-2 interacting mediator of cell death, ubiquitous kruppel like factor, and serum amyloid protein 4 are the three potential biological tumor marker in renal clear cell carcinoma. Key words: Kidney Neoplasms; Adenocarcinoma, Clear Cell; Proteins

Bridging angiogenesis and immune evasion in the hypoxic tumor microenvironment.

Hypoxia (low O2) is a ubiquitous microenvironmental factor promoting cancer progression, metastasis, and mortality, owing to the ability of cancer cells to co-opt physiological angiogenic responses. Notwithstanding, the pathophysiological induction of angiogenesis results in an abnormal tumor vasculature, further aggravating hypoxia in a feedforward loop that limits the efficacy of molecular targeted therapies. Recent studies suggest that, besides their canonical roles, angiogenic factors promote a panoply of immunosuppressive effects in the tumor microenvironment. Therefore, intratumoral hypoxia emerges as a hitherto unrecognized mechanism evolutionarily repurposing angiogenic molecules as (patho)physiological immunomodulators. On the other hand, antiangiogenic therapies could be aimed at impeding both tumor growth and immunotolerance toward cancer cells, a beneficial effect that can be countered if hypoxia signaling pathways are left unchecked, leading to therapeutic failure. This review summarizes evidence supporting the hypothesis that hypoxia acts as a common pathophysiological mechanism of resistance to immunotherapeutic and antiangiogenic agents while proposing potential strategies to curtail resistance and mortality in patients bearing solid malignancies.

Co-dependent Assembly of Drosophila piRNA Precursor Complexes and piRNA Cluster Heterochromatin

In Drosophila, the piRNAs that guide germline transposon silencing are produced from heterochromatic clusters marked by the HP1 homolog Rhino. We show that Rhino promotes cluster transcript association with UAP56 and the THO complex, forming RNA-protein assemblies that are unique to piRNA precursors. UAP56 and THO are ubiquitous RNA-processing factors, and null alleles of uap56 and the THO subunit gene tho2 are lethal. However, uap56sz15 and mutations in the THO subunit genes thoc5 and thoc7 are viable but sterile and disrupt piRNA biogenesis. The uap56sz15 allele reduces UAP56 binding to THO, and the thoc5 and thoc7 mutations disrupt interactions among the remaining THO subunits and UAP56 binding to the core THO subunit Hpr1. These mutations also reduce Rhino binding to clusters and trigger Rhino binding to ectopic sites across the genome. Rhino thus promotes assembly of piRNA precursor complexes, and these complexes restrict Rhino at cluster heterochromatin.

Catalysis-Based Total Syntheses of Pateamine A and DMDA-Pat A.

The marine natural product pateamine A (1) and its somewhat simplified designer analogue DMDA-Pat A (2) (DMDA = desmethyl-desamino) are potently cytotoxic compounds; most notably, 2 had previously been found to exhibit a promising differential in vivo activity in xenograft melanoma models, even though the ubiquitous eukaryotic initiation factor 4A (eIF4A) constitutes its primary biological target. In addition, 1 had also been identified as a possible lead in the quest for medication against cachexia, an often lethal muscle wasting syndrome affecting many immunocompromised or cancer patients. The short supply of these macrodiolides, however, rendered a more detailed biological assessment difficult. Therefore, a new synthetic approach to 1 and 2 has been devised, which centers on an unorthodox strategy for the formation of the highly isomerization-prone but essential Z, E-configured dienoate substructure embedded into the macrocyclic core. This motif was encoded in the form of a 2-pyrone ring and unveiled only immediately before macrocyclization by an unconventional iron-catalyzed ring opening/cross-coupling reaction, in which the enol ester entity of the pyrone gains the role of a leaving group. Since the required precursor was readily available by gold catalysis, this strategy rendered the overall sequence short, robust, and scalable. A surprisingly easy protecting group management together with a much improved end game for the formation of the trienyl side chain via a modern Stille coupling protocol also helped to make the chosen route practical. Change of a single building block allowed the synthesis to be redirected from the natural lead compound 1 toward its almost equipotent analogue 2. Isolation and reactivity profiling of pyrone tricarbonyliron complexes provide mechanistic information as well as insights into the likely origins of the observed chemoselectivity.

Tryptophan metabolites kynurenine and serotonin regulate fibroblast activation and fibrosis.

Fibrosis is a pathological form of aberrant tissue repair, the complications of which account for nearly half of all deaths in the industrialized world. All tissues are susceptible to fibrosis under particular pathological sets of conditions. Though each type of fibrosis has characteristics and hallmarks specific to that particular condition, there appear to be common factors underlying fibrotic diseases. One of these ubiquitous factors is the paradigm of the activated myofibroblast in the promotion of fibrotic phenotypes. Recent research has implicated metabolic byproducts of the amino acid tryptophan, namely serotonin and kynurenines, in the pathology or potential pharmacologic therapy of fibrosis, in part through their effects on development of myofibroblast phenotypes. Here, we review literature underlying what is known mechanistically about the effects of these compounds and their respective pathways on fibrosis. Pharmacologic administration of kynurenine improves scarring outcomes in vivo likely not only through its well-characterized immunosuppressive properties but also via its demonstrated antagonism of fibroblast activation and of collagen deposition. In contrast, serotonin directly promotes activation of fibroblasts via activation of canonical TGF-β signaling, and overstimulation with serotonin leads to fibrotic outcomes in vivo. Recently discovered feedback inhibition between serotonin and kynurenine pathways also reveals more information about the cellular physiology of tryptophan metabolism and may also underlie possible paradigms for anti-fibrotic therapy. Together, understanding of the effects of tryptophan metabolism on modulation of fibrosis may lead to the development of new therapeutic avenues for treatment through exploitation of these effects.

Life-history evolution under fluctuating density-dependent selection and the adaptive alignment of pace-of-life syndromes.

We present a novel perspective on life-history evolution that combines recent theoretical advances in fluctuating density-dependent selection with the notion of pace-of-life syndromes (POLSs) in behavioural ecology. These ideas posit phenotypic co-variation in life-history, physiological, morphological and behavioural traits as a continuum from the highly fecund, short-lived, bold, aggressive and highly dispersive 'fast' types at one end of the POLS to the less fecund, long-lived, cautious, shy, plastic and socially responsive 'slow' types at the other. We propose that such variation in life histories and the associated individual differences in behaviour can be explained through their eco-evolutionary dynamics with population density - a single and ubiquitous selective factor that is present in all biological systems. Contrasting regimes of environmental stochasticity are expected to affect population density in time and space and create differing patterns of fluctuating density-dependent selection, which generates variation in fast versus slow life histories within and among populations. We therefore predict that a major axis of phenotypic co-variation in life-history, physiological, morphological and behavioural traits (i.e. the POLS) should align with these stochastic fluctuations in the multivariate fitness landscape created by variation in density-dependent selection. Phenotypic plasticity and/or genetic (co-)variation oriented along this major POLS axis are thus expected to facilitate rapid and adaptively integrated changes in various aspects of life histories within and among populations and/or species. The fluctuating density-dependent selection POLS framework presented here therefore provides a series of clear testable predictions, the investigation of which should further our fundamental understanding of life-history evolution and thus our ability to predict natural population dynamics.

PERK inhibition attenuates the abnormalities of the secretory pathway and the increased apoptotic rate induced by SIL1 knockdown in HeLa cells

Loss-of-function mutations in the SIL1 gene are linked to Marinesco-Sjögren syndrome (MSS), a rare multisystem disease of infancy characterized by cerebellar and skeletal muscle degeneration. SIL1 is a ubiquitous adenine nucleotide exchange factor for the endoplasmic reticulum (ER) chaperone BiP. The complexity of mechanisms by which loss of SIL1 causes MSS is not yet fully understood. We used HeLa cells to test the hypothesis that impaired protein folding in the ER due to loss of SIL1 could affect secretory trafficking, impairing the transport of cargoes essential for the function of MSS vulnerable cells. Immunofluorescence and ultrastructural analysis of SIL1-knocked-down cells detected ER chaperone aggregation, enlargement of the Golgi complex, increased autophagic vacuoles, and mitochondrial swelling. SIL1-interefered cells also had delayed ER-to-plasma membrane transport with retention of Na+/K+-ATPase and procollagen-I in the ER and Golgi, and increased apoptosis. The PERK pathway of the unfolded protein response was activated in SIL1-interfered cells, and the PERK inhibitor GSK2606414 attenuated the morphological and functional alterations of the secretory pathway, and significantly reduced cell death. These results indicate that loss of SIL1 is associated with alterations of secretory transport, and suggest that inhibiting PERK signalling may alleviate the cellular pathology of SIL1-related MSS.