Aberrant Shape Research Articles

Distinct effects of PTST2b and MRC on starch granule morphogenesis in potato tubers.

The molecular mechanisms underpinning the formation of the large, ellipsoidal starch granules of potato tuber are poorly understood. Here, we demonstrate the distinct effects of PROTEIN TARGETING TO STARCH2b (PTST2b) and MYOSIN RESEMBLING CHLOROPLAST PROTEIN (MRC) on tuber starch granule morphology. A gene duplication event in the Solanaceae resulted in two PTST2 paralogs (PTST2a and PTST2b). PTST2b is expressed in potato tubers, and unlike PTST2a, it had no detectable interaction with STARCH SYNTHASE 4. MRC expression was detectable in leaves, but not in tubers. Using transgenic potato lines in the variety Clearwater Russet, we demonstrate that MRC overexpression leads to the formation of granules with aberrant shapes, many of which arise from multiple initiation points. Silencing PTST2b led to the production of striking near-spherical granules, each arising from a single, central initiation point. Contrary to all reported PTST2 mutants in other species, we observed no change in the number of granules per cell in these lines, suggesting PTST2b is specifically involved in the control of starch granule shape. Starch content and tuber yield per plant were not affected by PTST2b silencing, but MRC overexpression led to strong decreases in both parameters. Notably, the spherical granules in PTST2b silencing lines had a distinctively altered pasting profile, with higher peak and final viscosity than the wild type. Thus, PTST2b and MRC are promising target genes for altering starch granule size and shape in potato tubers, and can be used to create novel starches with altered physicochemical and/or functional properties.

Lateral cell polarization drives organization of epithelia in sea anemone embryos and embryonic cell aggregates

One of the first organizing processes during animal development is the assembly of embryonic cells into epithelia. Common features unite epithelialization across select bilaterians, however, we know less about the molecular and cellular mechanisms that drive epithelial emergence in early branching nonbilaterians. In sea anemones, epithelia emerge both during embryonic development and after cell aggregation of dissociated tissues. Although adhesion is required to keep cells together, it is not clear whether cell polarization plays a role as epithelia emerge from disordered aggregates. Here, we use the embryos of the sea anemone Nematostella vectensis to investigate the evolutionary origins of epithelial development. We demonstrate that lateral cell polarization is essential for epithelial organization in both embryos and aggregates. With disrupted lateral polarization, cell contact in the aggregate is not sufficient to trigger epithelialization and further tissue development. Specifically, knockdown of the conserved lateral polarity and tumor suppressor protein Lethal giant larvae (Lgl) disrupts epithelia in developing embryos and impairs the capacity of dissociated cells to epithelialize from aggregates. In contrast to other systems, cells in Nematostella lgl knockdown embryos do not undergo excessive proliferation. Cells with reduced Lgl levels lose their columnar shape and proper positioning of their mitotic spindles and basal bodies. Due to misoriented divisions and aberrant shapes, cells arrange nonuniformly without forming a monolayer. Together our data show that, in Nematostella, Lgl drives epithelialization in embryos and cell aggregates through its effect on cell shape and organelle localization.

Abstract 3006: Morphogen-driven regulation of nuclear shape and its implication for colorectal cancer

Abstract Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide despite improved rates of early detection and development of targeted treatments. Dysregulation of nuclear shape and the emergence of aberrant chromatin architecture correlate with cancer onset and progression, including CRC. Both extrinsic and intrinsic factors, most critically cytoskeletal and nucleoskeletal organization, chromatin architecture, and metabolic signaling, impact nuclear shape. Yet, what precisely determines nuclear shape in health and disease and how it is linked to cell fate and function remains a fundamental open question. In the case of over 75% of CRC cases, the first transformative genetic event is the loss of function in the tumor suppressor gene, adenomatous polyposis coli (APC). Mechanistically, perturbed APC signaling leads to aberrant activation of Wnt/beta-catenin signaling. This pathway is essential for intestinal homeostasis, as is the regulation of proper nuclear shape and function. Here, we aim to decipher the crosstalk between Wnt gradients and nuclear shape regulation in non-transformed and APC-mutated epithelial cells in vitro, as well as in WT and APC-mutant mouse colon tissues. The long-term goal of this work is to test whether a mechanistic link exists between Wnt-driven cellular transformation and the emergence of aberrant nuclear shape and function. Citation Format: Mona A. El Gendi, Solène Hervé, Sudeep Gautam, Yekaterina A. Miroshnikova. Morphogen-driven regulation of nuclear shape and its implication for colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3006.

Short communication: Synchrotron-based elemental mapping of single grains to investigate variable infrared-radiofluorescence emissions for luminescence dating

Abstract. During ionizing irradiation, potassium (K)-rich feldspar grains emit infrared (IR) light, which is used for infrared radiofluorescence (IR-RF) dating. The late-saturating IR-RF emission centred at ∼880 nm represents a promising tool to date Quaternary sediments. In the present work, we report the presence of individual grains in the K-feldspar density fraction displaying an aberrant IR-RF signal shape, whose combined intensity contaminates the sum signal of an aliquot composed of dozens of grains. Our experiments were carried out at the National Synchrotron Light Source (NSLS-II) at the submicron-resolution X-ray spectroscopy (SRX) beamline. We analysed coarse (>90 µm) K-feldspar-bearing grains of five samples of different ages and origin in order to characterize the composition of grains yielding the desired or contaminated IR-RF emission. Using micro-X-ray fluorescence (μ-XRF), we successfully acquired element distribution maps of up to 15 elements (<1 µm resolution) of sections of full grains previously used for IR-RF dating. In keeping with current theories of IR-RF signal production, we observed a trend between the relative proportions of Pb and Fe and the shape of the IR-RF signal, namely that most grains with the desired IR-RF signal shape had high Pb and low Fe contents. Interestingly, these grains were also defined by high Ba and low Ca contents. Our study also represents a proof of concept for mapping the oxidation states of Fe using micro-X-ray absorption near-edge structure spectroscopy (μ-XANES) on individual grains. The high spatial resolution enabled by synchrotron X-ray spectroscopy makes it a powerful tool for future experiments to elucidate long-standing issues concerning the nature and type of defect(s) associated with the main dosimetric trap in feldspar.

Mutations in starch biosynthesis genes affect chloroplast development in wheat pericarp

Starch bioengineering in cereals has produced a plethora of genotypes with new nutritional and technological functionalities. Modulation of amylose content from 0 to 100% was inversely correlated with starch digestibility and promoted a lower glycemic index in food products. In wheat, starch mutants have been reported to exhibit various side effects, mainly related to the seed phenotype. However, little is known about the impact of altered amylose content and starch structure on plant metabolism. Here, three bread wheat starch mutant lines with extreme phenotypes in starch branching and amylose content were used to study plant responses to starch structural changes. Omics profiling of gene expression and metabolic patterns supported changes, confirmed by ultrastructural analysis in the chloroplast of the immature seeds. In detail, the identification of differentially expressed genes belonging to functional categories related to photosynthesis, chloroplast and thylakoid (e.g. CURT1), the alteration in the accumulation of photosynthesis-related compounds, and the chloroplast alterations (aberrant shape, grana stacking alteration, and increased number of plastoglobules) suggested that the modification of starch structure greatly affects starch turnover in the chloroplast, triggering oxidative stress (ROS accumulation) and premature tissue senescence. In conclusion, this study highlighted a correlation between starch structure and chloroplast functionality in the wheat kernel.

Serum and Seminal Plasma Levels of Lead and Arsenic in Cigarette Smokers and Their Relation to the Semen Parameters

Male infertility along with altered semen parameters have been related to smoking. Smoking-related elevations in serum and seminal lead (Pb) and arsenic (As) may play a role in mediating the toxic effects of smoking on seminogram. This research aims to determine whether smoking has any significant impact on Pb and As levels in the seminal plasma and serum, as well as on the various semen parameters, when compared to nonsmokers. In total, 80 adult males were included: 60 smokers and 20 age-matched nonsmokers. Based on the number of cigarettes smoked/day (CPD), the smokers were categorized into mild (1–10), moderate (11–20), and severe (> 20). The analysis of semen was conducted in accordance with the 2010 WHO laboratory manual. Using an atomic absorption spectrophotometer, Pb and As concentrations in the serum and seminal plasma of all groups were determined. Compared to nonsmokers, smokers had a significantly reduced sperm count, motility, and viability, as well as a larger percentage of aberrant forms (P = 0.001, 0.025, 0.034, 0.002 respectively). Smokers had higher Pb concentrations in their serum and seminal fluid than nonsmokers (P = 0.002, 0.001 respectively). Seminal Pb had a significant negative correlation with sperm count (P = 0.004, r = -0.320). Serum Pb levels were found to positively correlate with seminal Pb levels (P 0.001, r = 0.648), and cigarette smokers had substantially greater seminal As levels than nonsmokers (P = 0.024). Sperm viability was strongly inversely related to seminal As (P = 0.042, r = -0.264). Seminal As levels and aberrant sperm shapes were found to be significantly correlated (P = 0.001, r = 0.414). In smokers, a significant positive relationship between seminal As and seminal Pb was observed. Therefore, semen parameters could be adversely affected by smoking through high levels of Pb and As (P = 0.012, r = 0.298).

Dematin Regulates Calcium Mobilization, Thrombosis, and Early Akt Activation in Platelets.

The complex intrinsic and extrinsic pathways contributing to platelet activation profoundly impact hemostasis and thrombosis. Detailed cellular mechanisms that regulate calcium mobilization, Akt activation, and integrin signaling in platelets remain incompletely understood. Dematin is a broadly expressed actin binding and bundling cytoskeletal adaptor protein regulated by phosphorylation via cAMP-dependent protein kinase. Here, we report the development of a conditional mouse model specifically lacking dematin in platelets. Using the new mouse model termed PDKO, we provide direct evidence that dematin is a major regulator of calcium mobilization, and its genetic deletion inhibits the early phase of Akt activation in response to collagen and thrombin agonists in platelets. The aberrant platelet shape change, clot retraction, and invivo thrombosis observed in PDKO mice will enable future characterization of dematin-mediated integrin activation mechanisms in thrombogenic as well as nonvascular pathologies.

Kindlin-3 deficiency leads to impaired erythropoiesis and erythrocyte cytoskeleton.

Kindlin-3 (K3) is critical for the activation of integrin adhesion receptors in hematopoietic cells. In humans and mice, K3 deficiency is associated with impaired immunity and bone development, bleeding, and aberrant erythrocyte shape. To delineate how K3 deficiency (K3KO) contributes to anemia and misshaped erythrocytes, mice deficient in erythroid (K3KO∖EpoR-cre) or myeloid cell K3 (K3KO∖Lyz2cre), knockin mice expressing mutant K3 (Q597W598 to AA) with reduced integrin-activation function (K3KI), and control wild-type (WT) K3 mice were studied. Both K3-deficient strains and K3KI mice showed anemia at baseline, reduced response to erythropoietin stimulation, and compromised recovery after phenylhydrazine (PHZ)-induced hemolytic anemia as compared with K3WT. Erythroid K3KO and K3 (Q597W598 to AA) showed arrested erythroid differentiation at proerythroblast stage, whereas macrophage K3KO showed decreased erythroblast numbers at all developmental stages of terminal erythroid differentiation because of reduced erythroblastic island (EBI) formation attributable to decreased expression and activation of erythroblast integrin α4β1 and macrophage αVβ3. Peripheral blood smears of K3KO∖EpoR-cre mice, but not of the other mouse strains, showed numerous aberrant tear drop-shaped erythrocytes. K3 deficiency in these erythrocytes led to disorganized actin cytoskeleton, reduced deformability, and increased osmotic fragility. Mechanistically, K3 directly interacted with F-actin through an actin-binding site K3-LK48. Taken together, these findings document that erythroid and macrophage K3 are critical contributors to erythropoiesis in an integrin-dependent manner, whereas F-actin binding to K3 maintains the membrane cytoskeletal integrity and erythrocyte biconcave shape. The dual function of K3 in erythrocytes and in EBIs establish an important functional role for K3 in normal erythroid function.

Hemotoxic effects of polyethylene microplastics on mice.

Micro- or nanoplastics, which are fragmented or otherwise tiny plastic materials, have long been a source of environmental worry. Microplastics (MPs) have been well documented to alter the physiology and behavior of marine invertebrates. The effects of some of these factors are also seen in larger marine vertebrates, such as fish. More recently, mouse models have been used to investigate the potential impacts of micro- and nanoplastics on host cellular and metabolic damages as well as mammalian gut flora. The impact on erythrocytes, which carry oxygen to all cells, has not yet been determined. Therefore, the current study aims to ascertain the impact of exposure to various MP exposure levels on hematological alterations and biochemical indicators of liver and kidney functions. In this study, a C57BL/6 murine model was concentration-dependently exposed to microplastics (6, 60, and 600μg/day) for 15days, followed by 15days of recovery. The results demonstrated that exposure to 600μg/day of MPs considerably impacted RBCs' typical structure, resulting in numerous aberrant shapes. Furthermore, concentration-dependent reductions in hematological markers were observed. Additional biochemical testing revealed that MP exposure impacted the liver and renal functioning. Taken together, the current study reveals the severe impacts of MPs on mouse blood parameters, erythrocyte deformation, and consequently, anemic patterns of the blood.

Fabrication of Etoposide-loaded superparamagnetic iron oxide nanoparticles (SPIONs) induced apoptosis in glioma cancer cells

Recent research has shown that etoposide (ETP), an immunomodulatory medication, can have cytotoxic effects. When accompanied by nano-drug delivery, this possibility can lead to a more effective treatment for cancer. This study involved the delivery of ETP via PDA@SPIONs (termed as ETP-PDA@SPIONs), which are superparamagnetic iron oxide nanoparticles (SPIONs) that have been coated with polydopamine (PDA) and utilized to treat C6 and U87 glioma cancer cell lines. The particle diameter, polydispersive index (PDI), zeta potential, and shape of nanoparticles were determined. The fabricated nanoparticles had a mean particle size of 164 ± 7 nm and a − 37 ± 3 mv zeta potential. Cell lines were tested for sensitivity to PDA@SPIONs, free-ETP, and ETP-PDA@SPIONs. On the cell lines, we tested the proliferation of PDA@SPIONs, free-ETP, and PDA@SPIONs loaded with ETP. The cytotoxicity of ETP-PDA@SPIONs was substantially higher than that of free-ETP-treated cells. The cells' morphological changes were examined by dual staining (acridine orange/ethidium bromide, AO/EB) and nuclear staining methods. Interestingly, this inhibitory impact was not ascribed to the known cellular membrane destruction, cell membrane damage, and reactive oxygen species (ROS). Further tests demonstrated that the nanoparticles substantially impacted mitochondrial functioning, resulting in an aberrant mitochondrial shape, and reduced mitochondrial membrane potential (MMP). Future studies into glioma cancer therapy may want to investigate using the proposed ETP-loaded nanoparticles.

Regional shape alteration of left thalamus associated with late chronotype in young adults

ABSTRACT Chronotype reflects individual differences in circadian rhythms and influences individual psychology and behavior. Previous studies found altered subcortical structures are closely related to individual chronotypes. However, these studies have been conducted mainly using voxel-based morphometry and traditional volume measurement methods with certain limitations. This study aimed to investigate subcortical aberrant volume and shape patterns in late chronotypes (LC) young adults compared to early chronotypes (EC) young adults. Magnetic resonance imaging (MRI) scanning and chronotype assessment were performed once for all participants, including 49 LC young adults and 49 matched EC young adults. The morningness and eveningness preferences were assessed using the Chronotype Questionnaire. A vertex-wise shape analysis was conducted to analyze structural MRI data. There were no significant differences in brain tissue volume and subcortical structural volume between groups. LC young adults showed significant regional shape atrophy in the left ventral posterior thalamus compared to EC individuals. A significant correlation was found between the regional shape atrophy of left ventral posterior thalamus and the score of Chronotype Questionnaire in LC young adults. Regional shape alteration of left thalamus was closely related to the chronotype, and LC may be a potential risk factor for sleep-related behavioral and mental problems in young adults. However, the predominantly female sample and the failure to investigate the effect of chronotype on the subcortical structure-function network are limitations of this study. Further prospective studies are needed to investigate the temporal characteristics of thalamic shape changes and consequent behavioral and psychiatric problems in adults with LC.

The Hydrophobin Gene Family Confers a Fitness Trade-off between Spore Dispersal and Host Colonization in Penicillium expansum.

Hydrophobins are small amphipathic surface proteins found exclusively in fungi. In filamentous ascomycetes, one conserved role of a subset of hydrophobins is their requirement for spore dispersal. Other contributions of these proteins to fungal biology are less clear and vary across genera. To determine the functions of hydrophobins in the biology and virulence of this fungus, we created seven single mutants and a septuple-deletion mutant (Δsep) of the entire putative P. expansum hydrophobin gene family. One spore hydrophobin, HfbA, shared 72.56% sequence identity to the Aspergillus fumigatus spore hydrophobin RodA and was required for efficient spore dispersion in P. expansum. The Δsep mutant was likewise reduced in spore dispersal, hypothesized to be due to the aberrant shape and clumping of the Δsep conidia and conidiophores. Additionally, the Δsep mutant presented several differences in physiological traits, including decreased survival in extreme cold temperatures and increased production of several toxic secondary metabolites. Most striking was the unexpected fitness advantage that the Δsep strain displayed in competitive passaging with the wild-type strain on host apple where the mutant significantly increased in percentage of the colonizing population. This work uncovers potential ecological trade-offs of hydrophobin presence in filamentous fungi. IMPORTANCE Hydrophobins are amphipathic secreted proteins uniquely found in filamentous fungi. These proteins self-assemble and constitute the outer most layer of fungal surfaces thus mediating multiple aspects of fungal interactions with their environments. Hydrophobins facilitate spore dispersal, yet a full understanding of the function and need for multiple hydrophobins in fungal species remains elusive. To address the role of this protein family in Penicillium expansum, the causative agent of blue mold disease in pome fruit, all seven putative hydrophobin genes were deleted and the mutant assessed for numerous physiological traits and virulence on fruit. Despite showing a decrease in spore dispersal, the septuple-deletion mutant was more fit than the wild type in competitive pathogenicity tests on apple. Our findings suggest this gene family illustrates a functional trade-off between dispersal and host colonization in P. expansum.

OmpR and Prc contribute to switch the Salmonella morphogenetic program in response to phagosome cues.

Salmonella enterica serovar Typhimurium infects eukaryotic cells residing within membrane-bound phagosomes. In this compartment, the pathogen replaces the morphogenetic penicillin-binding proteins 2 and 3 (PBP2/PBP3) with PBP2SAL /PBP3SAL , two proteins absent in Escherichia coli. The basis for this switch is unknown. Here, we show that PBP3 protein levels drop drastically when S. Typhimurium senses acidity, high osmolarity and nutrient scarcity, cues that activate virulence functions required for intra-phagosomal survival and proliferation. The protease Prc and the transcriptional regulator OmpR contribute to lower PBP3 levels whereas OmpR stimulates PBP2SAL /PBP3SAL production. Surprisingly, despite being essential for division in E. coli, PBP3 levels also drop in non-pathogenic and pathogenic E. coli exposed to phagosome cues. Such exposure alters E. coli morphology resulting in very long bent and twisted filaments indicative of failure in the cell division and elongation machineries. None of these aberrant shapes are detected in S. Typhimurium. Expression of PBP3SAL restores cell division in E. coli exposed to phagosome cues although the cells retain elongation defects in the longitudinal axis. By switching the morphogenetic program, OmpR and Prc allow S. Typhimurium to properly divide and elongate inside acidic phagosomes maintaining its cellular dimensions and the rod shape.

Aberrant hippocampal shape development in young adults with heavy cannabis use: Evidence from a longitudinal study

Cannabis is one of the most commonly used illicit drugs globally. Mounting evidence indicates that cannabis use, particularly consumption during young adulthood, is related to adverse mental and behavioral outcomes and an increased risk of the onset and relapse of psychosis. However, the neuromechanism underpinnings of heavy cannabis use (HCU) in young adults remain largely unknown, and no study has yet investigated the development of hippocampal shape in young adults with HCU. Twenty young adults with HCU and 22 matched non-cannabis-use healthy controls (HCs) were enrolled. Neuroimaging scanning and clinical assessments for all participants were performed at baseline (BL) and 3-year follow-up (FU). The vertex-wise shape analysis was conducted to investigate aberrant hippocampal shape development in young adults with HCU. Aberrant shape development pattern of the hippocampus was observed in young adults with HCU. There was no significant difference in hippocampal shape between the groups at BL, but young adults with HCU at FU exhibited significant shape atrophy of the right dorsal anterior hippocampus related to HCs. In addition, there was a significantly lower growth rate of the right hippocampal shape. Furthermore, there were significant associations of heavy cannabis use, as indicated by the age at onset first and frequent cannabis use, with the growth rate of hippocampal shape in young adults with HCU. The aberrant hippocampal shape development may reflect the effect of heavy cannabis use on young adults and it may be a potential target for heavy cannabis use treatment for young adults.

Senotherapeutics in Cancer and HIV.

Cellular senescence is a stress-response mechanism that contributes to homeostasis maintenance, playing a beneficial role during embryogenesis and in normal adult organisms. In contrast, chronic senescence activation may be responsible for other events such as age-related disorders, HIV and cancer development. Cellular senescence activation can be triggered by different insults. Regardless of the inducer, there are several phenotypes generally shared among senescent cells: cell division arrest, an aberrant shape, increased size, high granularity because of increased numbers of lysosomes and vacuoles, apoptosis resistance, defective metabolism and some chromatin alterations. Senescent cells constitute an important area for research due to their contributions to the pathogenesis of different diseases such as frailty, sarcopenia and aging-related diseases, including cancer and HIV infection, which show an accelerated aging. Hence, a new pharmacological category of treatments called senotherapeutics is under development. This group includes senolytic drugs that selectively attack senescent cells and senostatic drugs that suppress SASP factor delivery, inhibiting senescent cell development. These new drugs can have positive therapeutic effects on aging-related disorders and act in cancer as antitumor drugs, avoiding the undesired effects of senescent cells such as those from SASP. Here, we review senotherapeutics and how they might affect cancer and HIV disease, two very different aging-related diseases, and review some compounds acting as senolytics in clinical trials.

Restoration of Aberrant Shape of Caudate Subregions Associated with Cognitive Function Improvement in Mild Traumatic Brain Injury.

Mild traumatic brain injury (mTBI) is an important but less recognized public health concern. Research shows that altered subcortical structures mediate cognitive impairment in patients with mTBI. This has been performed mostly using voxel-based morphometry methods and traditional volume measurement methods, which have certain limitations. In this study, we conducted a vertex-wise shape analysis to understand the aberrant patterns of caudate subregions and recovery from mTBI. The study involved 36 patients with mTBI and 34 matched healthy controls (HCs) observed at seven days (acute phase) and followed up for one month (subacute phase) post-injury. Different aberrant shapes of the caudate subregions were observed at the acute phase, which revealed atrophy in the bilateral dorsal medial caudate, and increase in the size of the right ventral anterior caudate in patients with mTBI related to HCs. Moreover, specific and significant shape restoration of right dorsal medial caudate in mTBI was observed at the subacute phase, which significantly associated with the cognitive function improvement of the patients. These findings suggest that the restoration of the aberrant shape atrophy of the right dorsal medial caudate plays a vital role in the improvement of cognitive function of patients with mTBI, providing an alternative clinical target for these patients.

An Emerging Role of PRRT2 in Regulating Growth Cone Morphology.

Mutations in the PRRT2 gene are the main cause for a group of paroxysmal neurological diseases including paroxysmal kinesigenic dyskinesia, episodic ataxia, benign familial infantile seizures, and hemiplegic migraine. In the mature central nervous system, the protein has both a functional and a structural role at the synapse. Indeed, PRRT2 participates in the regulation of neurotransmitter release, as well as of actin cytoskeleton dynamics during synaptogenesis. Here, we show a role of the protein also during early stages of neuronal development. We found that PRRT2 accumulates at the growth cone in cultured hippocampal neurons. Overexpression of the protein causes an increase in the size and the morphological complexity of growth cones. In contrast, the growth cones of neurons derived from PRRT2 KO mice are smaller and less elaborated. Finally, we demonstrated that the aberrant shape of PRRT2 KO growth cones is associated with a selective alteration of the growth cone actin cytoskeleton. Our data support a key role of PRRT2 in the regulation of growth cone morphology during neuronal development.

Zonula occludens 2 and Cell-Cell Contacts Are Required for Normal Nuclear Shape in Epithelia.

MAGUK protein ZO-2 is present at tight junctions (TJs) and nuclei. In MDCK ZO-2 knockdown (KD) cells, nuclei exhibit an irregular shape with lobules and indentations. This condition correlates with an increase in DNA double strand breaks, however cells are not senescent and instead become resistant to UV-induced senescence. The irregular nuclear shape is also observed in isolated cells and in those without TJs, due to the lack of extracellular calcium. The aberrant nuclear shape of ZO-2 KD cells is not accompanied by a reduced expression of lamins A/C and B and lamin B receptors. Instead, it involves a decrease in constitutive and facultative heterochromatin, and microtubule instability that is restored with docetaxel. ZO-2 KD cells over-express SUN-1 that crosses the inner nuclear membrane and connects the nucleoskeleton of lamin A to nesprins, which traverse the outer nuclear membrane. Nesprins-3 and -4 that indirectly bind on their cytoplasmic face to vimentin and microtubules, respectively, are also over-expressed in ZO-2 KD cells, whereas vimentin is depleted. SUN-1 and lamin B1 co-immunoprecipitate with ZO-2, and SUN-1 associates to ZO-2 in a pull-down assay. Our results suggest that ZO-2 forms a complex with SUN-1 and lamin B1 at the inner nuclear membrane, and that ZO-2 and cell–cell contacts are required for a normal nuclear shape.

Aberrant nuclear lamina contributes to the malignancy of human gliomas

Glioma is the most common type of tumor in the central nervous system, accounting for around 80% of all malignant brain tumors. Previous studies showed a significant association between nuclear morphology and the malignant progress of gliomas. By virtue of integrated proteomics and genomics analyses as well as experimental validations, we identify three nuclear lamin genes (LMNA, LMNB1, and LMNB2) that are significantly upregulated in glioma tissues compared with normal brain tissues. We show that elevated expressions of LMNB1, LMNB2, and LMNA in glioma cells are highly associated with the rapid progression of the disease and the knockdown of LMNB1, LMNB2, and LMNA dramatically suppresses glioma progression in both in vitro and in vivo mouse models. Moreover, the repression of glioma cell growth by lamin knockdown is mediated by the pRb-mediated G1-S inhibition. On the contrary, overexpression of lamins in normal human astrocytes dramatically induced nuclear morphological aberrations and accelerated cell growth. Together, our multi-omics-based analysis has revealed a previously unrecognized role of lamin genes in gliomagenesis, providing a strong support for the key link between aberrant tumor nuclear shape and the survival of glioma patients. Based on these findings, lamins are proposed to be potential oncogene targets for therapeutic treatments of brain tumors.

Recent brackish water Foraminifera and Ostracoda from two estuaries in Ghana, and their potential as (palaeo)environmental indicators

To improve the indicator value of marginal marine Foraminifera and Ostracoda of Ghana, we analysed 22 surface sediment samples for microfauna. They were obtained from the Keta Lagoon and Densu Estuary covering a salinity range from marine waters to 17.5 and one sample within the hyperhaline range (70). Except one, all samples contain Ostracoda and Foraminifera. There are 34 ostracod species belonging to 24 genera. Dominating is Cyprideis remanei Klie, 1940, other abundant species are Pseudoconcha sp., Pseudoconcha hartmanni Omatsola, 1970, Loxoconcha lacunensis Omatsola, 1970 and Chrysocythere foveostriata Brady, 1870. We found 28 Foraminifera species belonging to 22 genera with the dominant taxa Ammonia sp. and Quinqueloculina spp. There are five associations, which are mainly driven by the hydrological regime and organic pollution. In contrast to a usual diversity trend reflecting high levels of pollution by lower diversity, our results show higher diversity associated with sites of higher pollution levels. The most tolerant (salinity and pollution) ostracod taxon is Cyprideis remanei, which is occurring over the whole salinity range documented as well as in contaminated areas with very high LOI and heavy metal concentrations. In the investigated samples we found many deformed Foraminifera with anomalies like multiple tests, changes in coiling and aberrant shapes of the chambers.Ongoing investigations in estuaries of Ghana are expanding our data set and will provide a better understanding of species-specific reactions of Ostracoda and Foraminifera to anthropogenic pressure.