Pending Questions Research Articles

Molecular mechanism of Fast Endophilin-Mediated Endocytosis.

Endocytosis mediates the cellular uptake of micronutrients and cell surface proteins. Clathrin-mediated endocytosis (CME) is the housekeeping pathway in resting cells but additional Clathrin-independent endocytic (CIE) routes, including Fast Endophilin-Mediated Endocytosis (FEME), internalize specific cargoes and support diverse cellular functions. FEME is part of the Dynamin-dependent subgroup of CIE pathways. Here, we review our current understanding of the molecular mechanism of FEME. Key steps are: (i) priming, (ii) cargo selection, (iii) membrane curvature and carrier formation, (iv) membrane scission and (v) cytosolic transport. All steps are controlled by regulatory mechanisms mediated by phosphoinositides and by kinases such as Src, LRRK2, Cdk5 and GSK3β. A key feature of FEME is that it is not constitutively active but triggered upon the stimulation of selected cell surface receptors by their ligands. In resting cells, there is a priming cycle that concentrates Endophilin into clusters on discrete locations of the plasma membrane. In the absence of receptor activation, the patches quickly abort and new cycles are initiated nearby, constantly priming the plasma membrane for FEME. Upon activation, receptors are swiftly sorted into pre-existing Endophilin clusters, which then bud to form FEME carriers within 10 s. We summarize the hallmarks of FEME and the techniques and assays required to identify it. Next, we review similarities and differences with other CIE pathways and proposed cargoes that may use FEME to enter cells. Finally, we submit pending questions and future milestones and discuss the exciting perspectives that targeting FEME may boost treatments against cancer and neurodegenerative diseases.

The recent advances in non-homologous end-joining through the lens of lymphocyte development

Lymphocyte development requires ordered assembly and subsequent modifications of the antigen receptor genes through V(D)J recombination and Immunoglobulin class switch recombination (CSR), respectively. While the programmed DNA cleavage events are initiated by lymphocyte-specific factors, the resulting DNA double-strand break (DSB) intermediates activate the ATM kinase-mediated DNA damage response (DDR) and rely on the ubiquitously expressed classical non-homologous end-joining (cNHEJ) pathway including the DNA-dependent protein kinase (DNA-PK), and, in the case of CSR, also the alternative end-joining (Alt-EJ) pathway, for repair. Correspondingly, patients and animal models with cNHEJ or DDR defects develop distinct types of immunodeficiency reflecting their specific DNA repair deficiency. The unique end-structure, sequence context, and cell cycle regulation of V(D)J recombination and CSR also provide a valuable platform to study the mechanisms of, and the interplay between, cNHEJ and DDR. Here, we compare and contrast the genetic consequences of DNA repair defects in V(D)J recombination and CSR with a focus on the newly discovered cNHEJ factors and the kinase-dependent structural roles of ATM and DNA-PK in animal models. Throughout, we try to highlight the pending questions and emerging differences that will extend our understanding of cNHEJ and DDR in the context of primary immunodeficiency and lymphoid malignancies.

Growth rate and gain of stimulated Brillouin scattering considering nonlinear Landau damping due to particle trapping

Growth rate and gain of stimulated Brillouin scattering (SBS) considering the reduced Landau damping due to particle trapping has been proposed to predict the growth and average level of SBS reflectivity. Due to particle trapping, the reduced Landau damping has been taken used of to calculate the gain of SBS, which will make the simulation data of SBS average reflectivity be consistent to the Tang model better. Other nonlinear effects such as harmonic generation and pump depletion have been also considered in the later evolution of SBS. This work may solve the pending questions in laser-plasma interaction and have wide applications in parametric instabilities.

A draft genome sequence of the elusive giant squid, Architeuthis dux.

ABSTRACTBackgroundThe giant squid (Architeuthis dux; Steenstrup, 1857) is an enigmatic giant mollusc with a circumglobal distribution in the deep ocean, except in the high Arctic and Antarctic waters. The elusiveness of the species makes it difficult to study. Thus, having a genome assembled for this deep-sea–dwelling species will allow several pending evolutionary questions to be unlocked.FindingsWe present a draft genome assembly that includes 200 Gb of Illumina reads, 4 Gb of Moleculo synthetic long reads, and 108 Gb of Chicago libraries, with a final size matching the estimated genome size of 2.7 Gb, and a scaffold N50 of 4.8 Mb. We also present an alternative assembly including 27 Gb raw reads generated using the Pacific Biosciences platform. In addition, we sequenced the proteome of the same individual and RNA from 3 different tissue types from 3 other species of squid (Onychoteuthis banksii, Dosidicus gigas, and Sthenoteuthis oualaniensis) to assist genome annotation. We annotated 33,406 protein-coding genes supported by evidence, and the genome completeness estimated by BUSCO reached 92%. Repetitive regions cover 49.17% of the genome.ConclusionsThis annotated draft genome of A. dux provides a critical resource to investigate the unique traits of this species, including its gigantism and key adaptations to deep-sea environments.

Viewing Proto-Dravidian from the Northeast


 
 
 Continuing Pfeiffer 1972, Pfeiffer 2018 examines inherited Dravidian etyma of Kurux, one of the most northerly Dravidian languages. After an overview of the book, we discuss problems involved in Pfeiffer’s arguments, methods, and materials. Then we try to narrow down the conditions of some of the sound changes Pfeiffer proposes, in conformity with the Neogrammarian hypothesis of regularity. We also point out that closer study of word-final phonology would answer some of the pending questions of Kurux-Malto morphology. Finally, we argue that phonological and morphological reconstruction can unveil more features to help revise the subgrouping of Kurux-Malto in the Dravidian family.
 
 

The use of autologous fat grafts in breast surgery: A literature review.

Autologous fat injection was first described roughly a century ago and has been used in surgery ever since. In addition to its use in many surgical fields, it is also frequently used for both aesthetic and reconstructive purposes in breast surgery. Since the application of fat grafting in breast surgery has steadily increased, studies investigating its reliability have simultaneously become increasingly common. Previous studies have reported that the use of fat grafting in breast surgery is reliable, but some pending questions remain about its routine use. In order to use fat grafts successfully in breast surgery, it is necessary to be familiar with the structure and content of adipose tissue, the efficacy of adipose stem cell-enriched fat grafts, the oncological safety of fat grafts, and the problems that may occur in the radiological follow-up of patients who undergo fat grafting procedures. In this literature review, we aim to discuss the use of fat grafts in breast surgery by investigating these common problems.

Estrogen Receptors in Epithelial-Mesenchymal Transition of Prostate Cancer.

Prostate cancer (PC) remains a widespread malignancy in men. Since the androgen/androgen receptor (AR) axis is associated with the pathogenesis of prostate cancer, suppression of AR-dependent signaling by androgen deprivation therapy (ADT) still represents the primary intervention for this disease. Despite the initial response, prostate cancer frequently develops resistance to ADT and progresses. As such, the disease becomes metastatic and few therapeutic options are available at this stage. Although the majority of studies are focused on the role of AR signaling, compelling evidence has shown that estrogens and their receptors control prostate cancer initiation and progression through a still debated mechanism. Epithelial versus mesenchymal transition (EMT) is involved in metastatic spread as well as drug-resistance of human cancers, and many studies on the role of this process in prostate cancer progression have been reported. We discuss here the findings on the role of estrogen/estrogen receptor (ER) axis in epithelial versus mesenchymal transition of prostate cancer cells. The pending questions concerning this issue are presented, together with the impact of the available data in clinical management of prostate cancer patients.

Role of innate immune cells in metabolism: from physiology to type 2 diabetes.

Growing evidence suggests that components of the innate immune system play a crucial role in regulating metabolic homeostasis. Macrophages were the primary immune cells to be described in both the white adipose tissue and the pancreatic islets. Therein, their functions, beneficial or detrimental, are extending under steady state and in the context of obesity-induced type 2 diabetes. Other populations, including innate lymphoid cells, are emerging as key sentinels of metabolic tissues and privileged partners of macrophages. The present review will thus explore the phenotype and the role of innate immune cells in metabolic physiology and dysfunction. Discussion will tackle pending questions and future perspectives in the field of immunometabolism.

The Anti-Atlas Pan-African Belt (Morocco): Overview and pending questions

Between the High Atlas and the Saharan platform, the Anti-Atlas of Morocco offers large exposures of Precambrian rocks beneath the moderately folded Paleozoic series. These inliers allow reconstructing a segment of the Pan-African Belt and of its foreland at the northern outskirts of the West African Craton (WAC). From ∼885 Ma to ∼540 Ma, three periods are recognized in the Pan-African cycle. The Tonian–Cryogenian period ends with the obduction of supra-subduction ophiolite and oceanic arc material at ∼640 Ma. The Early Ediacaran period is marked by the development and subsequent closure of a wide marginal basin next to a likely Andean-type arc. The Late Ediacaran period is recorded by subaerial molasse deposits associated with post-collisional high-K calc-alkaline to shoshonitic magmatism. Although a wide consensus has been reached based on the number of new robust datings, several questions still remain pending, which we address taking into account relevant African and European correlations.

Impact‐induced chemical fractionation as inferred from hypervelocity impact experiments with silicate projectiles and metallic targets

AbstractHypervelocity impacts are common in the solar system, in particular during its early phases when primitive bodies of contrasted composition collided. Whether these objects are chemically modified during the impact process, and by what kind of processes, e.g., chemical mixing or gas–liquid–solid fractionation, are still pending questions. To address these issues, a set of impact experiments involving a multielemental doped phonolitic projectile and a metallic target was performed in a 3–7 km s−1 range of impact speeds which are typical of those occurring in the asteroid belt. For each run, both texture and chemistry of the crater and the ejecta population have been characterized. The results show that the melted projectiles largely cover the craters at all speeds, and that melted phonolitic materials are injected into fractures in the crater in the metallic target. Ejecta are generally quenched droplets of silicate impact melt containing metal beads. Some of these beads are extracted from the target, but we propose that some of the Fe metal beads are the result of reduction of FeO. A thin FeO‐SiO2‐rich condensate layer is found at the edge of the crater, suggesting that a limited amount of vapor formed and condensed. LA‐ICP‐MS analyses suggest, however, that within analytical uncertainties, no volatility‐controlled chemical fractionation of trace elements occurred in the ejecta. The main chemical fractionation during impact at such velocities and energies are the result of projectile‐target mixing.

LOGISTIC MODELS OF FRACTAL DIMENSION GROWTH OF URBAN MORPHOLOGY

Urban form can be described with fractal dimension, which is a measurement of space filling of urban evolution. However, how to model and understand the fractal dimension growth of urban morphology are still pending questions. This paper is devoted to the research on the fractal dimension curves of urban growth. The principle of squashing function and empirical evidences are employed to demonstrate the following inference: the fractal dimension time series of a city’s spatial form take on a sigmoid curve. Among various sigmoid functions, the logistic function is the most probable selection. The observational data of fractal dimension of different cities from different sources support this logic judgment. A further discovery is that the fractal dimension curves of cities in the developed countries differ from those in the developing countries. A generalized logistic function is thus proposed to model the fractal dimension curves of different types of cities. The general logistic models can be used to predict the missing values and estimate the growth rates of fractal dimension of city development. Moreover, these models can be utilized to analyze when and where there is a fractal of urban form.

Does mandibular third molar have an impact on dental mandibular anterior crowding? A literature review

Mandibular dental anterior crowding is a common multi-factorial phenomenon. The involvement of the lower third molar remains unclear. These pending questions led us to conduct a literature review to evaluate the impact of the lower third molar on mandibular dental anterior crowding. Twelve articles were selected, published from 1974 to 2014. Four studies were prospective. Sample size ranged from 30 to 9044. The average age was 20.56 years old. Seven studies considered patient with orthodontic treatment. The studies compared two to four groups. Studying tools were radiographs, casts and clinical examinations. Little's irregularity index, TSALD and Ganss ratio were used. In total, 83% of articles (n=10/12) did not find any significant relationship between lower third molar and mandibular dental anterior crowding. However, methods and designs of these studies being questionable, a definite conclusion on the impact of mandibular third molar on mandibular dental anterior crowding cannot be set.

Interlaminar Glia and Other Glial Themes Revisited: Pending Answers Following Three Decades of Glial Research

This review aims to highlight the various significant matters in glial research stemming from personal work by the author and associates at the Unit of Applied Neurobiology (UNA, CEMIC-CONICET), and some of the pending questions. A reassessment and further comments on interlaminar astrocytes—an astroglial cell type that is specific to humans and other non-human primates, and is not found in rodents, is presented. Tentative hypothesis regarding their function and future possible research lines that could contribute to further the analysis of their development and possible role(s), are suggested. The possibility that they function as a separate entity from the “territorial” astrocytes, is also considered. In addition, the potential significance of our observations on interspecies differences in in vitro glial cell dye coupling, on glial diffusible factors affecting the induction of this glial phenotype, and on their interference with the cellular toxic effects of cerebrospinal fluid obtained from l-DOPA treated patients with Parkinson´s disease, is also considered. The major differences oberved in the cerebral cortex glial layout between human and rodents—the main model for studying glial function and pathology—calls for a careful assessment of known and potential species differences in all aspects of glial cell biology. This is essential to provide a better understanding of the organization and function of human and non-human primate brain, and of the neurobiological basis of their behavior.

Indium- and Zinc-Mediated Acyloxyallylation of Protected and Unprotected Aldotetroses-Revealing a Pronounced Diastereodivergence and a Fundamental Difference in the Performance of the Mediating Metal.

The acyloxyallylation of unprotected aldoses was first demonstrated more than a decade ago as a potentially elegant two-carbon homologation of reducing sugars (upon ozonolysis); however, its application in real case syntheses remained scarce. Following up on such a successful showcase and to answer several pending questions about this attractive transformation, we engaged in an in depth methodological reinvestigation. The epimeric tetroses l-erythrose and d-threose in unprotected and protected form were successfully applied to the indium and also zinc-mediated acyloxyallylation, with the latter being a first for an unprotected sugar. The investigation largely benefited from the choice of these more exotic starting materials as it allowed unambiguous identification/quantification of the hexose-products which are available as authentic reference materials. The observed diastereoselectivities indicate a strong substrate control (stereochemistry at O2), and the influence of the reagent’s structure on the selectivity was investigated in great detail. A strong facial diastereodivergence between related protected and unprotected structures was demonstrated and an unexpected, pronounced principle difference in performance between indium and zinc was revealed.

Increasing Diversity of Biological Membrane Fission Mechanisms.

Membrane fission is essential to life. It is required for many fundamental cellular processes, as diverse as cyto- and karyokinesis, organelle division, membrane repair, and membrane trafficking and endocytosis. While membrane fission was originally seen as resulting from the action of mechanoenzymes such as dynamin, it is clear that the reality is more complex. In this review, we propose an updated overview of fission mechanisms, and try to extract essential requirements for each. We also present examples of cellular processes that involve these fission mechanisms. Finally, we list pending questions, whether they are specific to a peculiar fission mechanism or more general to the field.

Revisiting Slavery and the Slave Trade in Ethiopia

Abstract Slavery remains one of the blind spots in the historiography of the Horn of Africa in general and Ethiopia in particular. This is peculiar in light of the fact that in the territories of the Horn slavery left a significant imprint on the sociocultural fabric, and that the ports along the Horn of Africa coast fed the slave trade to the Arab, Ottoman, and Indian Ocean worlds for many centuries. In this article, we highlight some of the research trends on slavery in Africa and discuss slavery and the slave trade in different Ethiopian regions. We also question the public silence around the legacies of slavery in the country. By means of introducing the articles of this special issue, we point towards new, pending, or unresolved research questions.

Comparison of Root Images between Post-Myelographic Computed Tomography and Magnetic Resonance Imaging in Patients with Lumbar Radiculopathy.

ObjectiveTo evaluate the diagnostic value of computed tomography-myelography (CTM) compared to that of magnetic resonance imaging (MRI) in patients with lumbar radiculopathy.MethodsThe study included 91 patients presenting with radicular leg pain caused by herniated nucleus pulposus or lateral recess stenosis in the lumbar spine. The degree of nerve root compression on MRI and CTM was classified into four grades. The results of each imaging modality as assessed by two different observers were compared. Visual analog scale score for pain and electromyography result were the clinical parameters used to evaluate the relationships between clinical features and nerve root compression grades on both MRI and CTM. These relationships were quantified by calculating the receiver-operating characteristic curves, and the degree of relationship was compared between MRI and CTM.ResultsMcNemar’s test revealed that the two diagnostic modalities did not show diagnostic concurrence (p<0.0001). Electromyography results did not correlate with grades on either MRI or CTM. The visual analog pain scale score results were correlated better with changes of the grades on CTM than those on MRI (p=0.0007).ConclusionThe present study demonstrates that CTM could better define the pathology of degenerative lumbar spine diseases with radiculopathy than MRI. CTM can be considered as a useful confirmative diagnostic tool when the exact cause of radicular pain in a patient with lumbar radiculopathy cannot be identified by using MRI. However, the invasiveness and potential complications of CTM are still considered to be pending questions to settle.

Inhibidores de PCSK-9, efectos sobre el cLDL e implicaciones futuras: lo que se debe saber

The discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) in 2003 in families with familial hypercholesterolemia (HF) later generated the development of pharmacological strategies in order to inhibit this protein. Twelve years after this discovery, the first two biological compounds (monoclonal antibodies) were approved, which have been shown to substantially decrease LDL-C and other lipid subfractions.The objective of the present article is to review the history of the discovery of PCSK9, its physiology and pathophysiology and subsequent pharmacological development. The objectives and goals reached to date and the pending questions regarding the efficacy and safety of its clinical use are presented.

Terrestrial Laser Scanning for Forest Inventories—Tree Diameter Distribution and Scanner Location Impact on Occlusion

The rapid development of portable terrestrial laser scanning (TLS) devices in recent years has led to increased attention to their applicability for forest inventories, especially where direct measurements are very expensive or nearly impossible. However, in terms of precision and reproducibility, there are still some pending questions. In this study, we investigate the influence of stand parameters on the TLS-related visibility in forest plots. We derived 2740 stand parameters from Swiss national forest inventory sample plots. Based on these parameters, we defined virtual scenes of the forest plots with the software “Blender”. Using Blender’s ray-tracing features, we assessed the 3D coverage in a cubic space and 2D visibility properties for each of the virtual plots with different scanner placement schemes. We provide a formula to calculate the maximum number of possible hits for any object size at any distance from a scanner with any resolution. Additionally, we show that the Weibull scale parameter describing a stand, in addition to the number of trees and the mean diameter of the dominant 100 trees per hectare, has a significant and relevant influence on the visibility of the sample plot. Furthermore, we show the effectiveness and the efficiency of 40 scanner location patterns. These experiments demonstrate that intuitively distributing scanner locations evenly within the sample plot, with similar distances between locations and from the edge of the sample plot, provides the best overall visibility of the stand.

Room-Temperature Current-Induced Generation and Motion of sub-100 nm Skyrmions.

Magnetic skyrmions are nanoscale windings of the spin configuration that hold great promise for technology due to their topology-related properties and extremely reduced sizes. After the recent observation at room temperature of sub-100 nm skyrmions stabilized by interfacial chiral interaction in magnetic multilayers, several pending questions remain to be solved, notably about the means to nucleate individual compact skyrmions or the exact nature of their motion. In this study, a method leading to the formation of magnetic skyrmions in a micrometer-sized track using homogeneous current injection is evidenced. Spin-transfer-induced motion of these small electrical-current-generated skyrmions is then demonstrated and the role of the out-of-plane magnetic field in the stabilization of the moving skyrmions is also analyzed. The results of these experimental observations of spin torque induced motion are compared to micromagnetic simulations reproducing a granular type, nonuniform magnetic multilayer in order to address the particularly important role of the magnetic inhomogeneities on the current-induced motion of sub-100 nm skyrmions for which the material grains size is comparable to the skyrmion diameter.