The control of translation in the course of gene expression regulation plays a crucial role in plants’ cellular events and, particularly, in responses to environmental factors. The paradox of the great variance between levels of mRNAs and their protein products in eukaryotic cells, including plants, requires thorough investigation of the regulatory mechanisms of translation. A wide and amazingly complex network of mechanisms decoding the plant genome into proteome challenges researchers to design new methods for genome-wide analysis of translational control, develop computational algorithms detecting regulatory mRNA contexts, and to establish rules underlying differential translation. The aims of this review are to (i) describe the experimental approaches for investigation of differential translation in plants on a genome-wide scale; (ii) summarize the current data on computational algorithms for detection of specific structure–function features and key determinants in plant mRNAs and their correlation with translation efficiency; (iii) highlight the methods for experimental verification of existed and theoretically predicted features within plant mRNAs important for their differential translation; and finally (iv) to discuss the perspectives of discovering the specific structural features of plant mRNA that mediate differential translation control by the combination of computational and experimental approaches. The genomic information in plants, similar to other eukaryotes, is implemented via a successive series of biological processes, including transcription and translation as the key events. The current experimental omics tools for genomic monitoring of plant gene expression allow tracking the flow of genetic information from genome to proteome and to metabolome. New experimental approaches, for example, RNA-Seq and DNA microarrays, have given insight into many key mechanisms involved in transcription regulation in plants: the first stage of gene expression and the easiest to study in terms of experimental methodology. The studies of transcriptomes, i.e., the qualitative and quantitative estimation of expression of the entire gene pool on a genome-wide scale, have given convincing evidence of dynamic changes in the transcriptomes of various plant species in both growth and development processes and the impact of environmental factors. Comparative omics studies in plants clearly demonstrate a very modest correlation between the levels of transcription  and translation (the levels of the corresponding proteins in the proteome). Of note, the observed fluctuations in the levels of a transcript do not always lead to changes in the levels of the corresponding protein . This suTranslation is a complex biological process with numerous players, including mRNAs, tRNAs, ribosomes, and manifold protein factors. Undoubtedly, each is important for efficient translation. The mRNAs themselves comprise different regions, namely, the 5’ untranslated region (5’UTR) and coding region (CDS) and 3’ untranslated region (3’UTR), which modulate translation at a number of “checkpoints”: translation initiation, elongation, and termination. In the current view, numerous regulatory elements may be concealed in the nucleotide contexts of these mRNA regions and each of them individually or in combination can determine the development of any transcript in translational process .The paradox of misfit between the levels of mRNAs and their protein products observable in different plant species at all stages of their growth and development as well as upon the impact of various environmental factors focuses the attention of researchers on two key problems, namely (i) detection of the specific sets of differentially-translated transcripts, i.e., the sets of transcripts that are efficiently translated under certain conditions, and the sets of transcripts with repressed or unchanged translation under the same conditions and (ii) clarification of the particular regions or specific structural features of the mRNA nucleotide composition that mediate this differential translational control.This review focuses on the experimental methods for genome-wide analysis of translational control, computational algorithms to search and analyze various regulatory contexts within mRNAs, and approaches for subsequent experimental verification of their correlation with mRNA translation in plants. Currently, we cannot refer to deficiency in publications comprehensively reporting the basic protocols of various methods for genome-wide analyses of translational control in general, including the methods applicable to plant objects. However, reviews that consider and discuss the three key components of the general strategy for identification of regulatory contexts in mRNA that may play a key role in differential translation are still absent in the scientific literature. Our goals here are (i) to consider the experimental approaches aiming to clarify differential translation on a plant genome-wide scale; (ii) to summarize the current data on the computational algorithms used for detection of the specific structural and functional features of key determinants within plant mRNAs and their interrelation with the translation efficiency; (iii) to highlight the methods for experimental verification of existed data and theoretical predictions of the intrinsic features of plant mRNAs important for their differential translation; and (iv) to discuss the ways of decoding the specific structural features of plant mRNA that mediate differential translational control by combining computational and experimental approaches. In general, this review discusses the main and critical steps for each method in this general strategy, areas of their application, and the main results obtained using plant objects and their contribution to our knowledge about the fine mechanisms of translation in plants.Initially, proteomics methods were used to identify the correlation between the observed fluctuations in the expression of a transcript and the actual level of peptides in plants . HoweverArabidopsis thaliana, Nicotiana benthamiana, Solanum lycopersicum, and Oryza sativa, as well as for individual plant tissues ,4140,41]ditions) .A. thaliana protein-coding genes contain uORFs in their mRNA 5’UTRs [Alternative ORFs are among the most abundant regulatory elements in mRNAs; they are frequently present in the 5’ leader regions of eukaryotic mRNAs (designated uORFs). Such uORFs may negatively modulate the translation efficiency of the downstream main ORF. According to the current estimate, approximately 20% of the A 5’UTRs . InitialA 5’UTRs  or experA 5’UTRs ,60,61. TA. thaliana for assessing a sequence-dependent effect of each CPuORF on expression of the main ORF. A comparative analysis of the reporter protein activity of the variants when the translation is controlled by either native CPuORFs or the CPuORFs with introduced frameshift mutations has identified five novel CPuORFs that repress the expression of the main ORF in a sequence-dependent manner. Moreover, it has been convincingly demonstrated that the C-terminal regions of four of these CPuORF-encoded peptides play a crucial role in repressing the translation of the main ORF [A. thaliana CPuORFs in arresting ribosomes during translation was tested in another study. This mechanism of CPuORF action was clarified using toeprinting analysis and the additional experimental evidence was obtained by constructing the following three types of reporter constructs. (i) With the CPuORF initiation codon removed from each reporter construct of the native CPuORF by replacing AUG with AAG; (ii) with frameshift only mutations, introduced to the CPuORF sequences; and (iii) with both removed initiation codon and frameshift mutations in CPuORF sequences. A comparative testing of all types of reporter constructs has shown that removal of the initiation codon from CPuORFs considerably increases the reporter gene expression; the frameshift mutations in CPuORFs also efficiently increase the reporter gene expression, although to a lower degree as compared with the removal of initiation codon; while the simultaneous presence of frameshift mutations and absence of the initiation codon have almost no effect on the reporter gene expression. These results clearly demonstrate that (i) the peptide sequences are partially responsible for strong repressive effects of these CPuORFs on the main ORF expression; (ii) repression of the main ORF expression  depends on CPuORF translation; and (iii) these CPuORFs induce ribosomal arrest and thereby considerably inhibit expression of the main ORF [The approach of frameshift mutations utilizes concurrent introduction of deletions and insertions at −1 and +1 positions; this procedure changes only the amino acid composition of a peptide sequence coded for in CPuORFs but retains the presence and unchanged length of the overlapping CPuORFs d. This mmain ORF . The funmain ORF . Thus, iIt should be emphasized that the selection of a method for assembling reporter constructs is of highest importance, since it is necessary to clone the target regulatory sequences with a reporter gene without the introduction of additional nucleotides, which may influence the translation modulation. The classical restriction–ligation cloning method does not allow generation of such constructs and requires several cloning stages. Several more economical and efficient technologies facilitating and accelerating the design of such constructs have been recently proposed. These technologies make it possible to produce seamless fusions of a “regulatory sequence–reporter gene”. Most of them utilize the recombination between homologous sequences residing at the ends of the DNA fragments to be assembled . For exaThe principle underlying the CPEC method utilizes the polymerase extension mechanism and one DNA polymerase for the in vitro assembly and cloning of sequences in any vector in a single-stage reaction. CPEC allows for an integrated, combinatorial, or multifragment assembly of sequences as well as for routine cloning procedures . Thus, tN. tabacum L. cv. BY2, lettuce, or A. thaliana are used as well as agroinfiltration of leaves  or plant cell suspension culture  [As for the functional assessment of the constructs carrying a target regulatory sequence fused with a reporter gene, two basic experimental approaches are used: they utilized (i) a transient (temporary) and/or (ii) stable (constant) expression of reporter constructs in plants ,71. In tana T87) ,71,72 (Sana T87) ,73.A stable expression of reporter constructs in plants requires production of transgenic plants or transgenic plant cell suspension cultures. This makes it possible to solve increasingly more complex problems of translational control, such as translation regulation under different growth and stress conditions or long-term physiological effects of certain changes in a sequence that modulate translation. In particular, polysome fractionation of control and transgenic plants makes it possible to confirm that the transcript of a reporter gene controlled by a tested regulatory sequence is actually associated with the polysome fraction. Thus, it is possible to assess the translational status of the mRNA of a reporter gene fused with the tested regulatory sequence, including under the effect of stress factors .When using the methods involving both stable and transient expressions, the choice of an adequate control is of a paramount importance to ascertain that the change in expression of the reporter protein is actually associated with the change in translation  ,51.According to the available experimental data, the strategy of reporter systems is in demand for a wide range of studies into individual regulatory sequences or their nucleotide contexts. The use of this strategy gives the unique data on the functional role of target sequences in translation efficiency; however, this strategy is, as a rule, supplemented with other methods. The choice of a particular method depends on the regulatory sequence or its context to be studied be it a full-sized 5’UTR or its regulatory elements, such as RNA G-quadruplex, IRES, uORFs, and so on, which is in part summarized above and is comprehensively described in the corresponding publications.Translation plays a key role in the overall implementation of genetic information and the new knowledge about the intricate and multilevel information encoded in the mRNA sequence are of a paramount importance. The research into translation has revealed many new and interesting facts about the structural and functional role of the mRNA regulatory sequences that mediate differential translation. In particular, this success has been determined by the use of state-of-the-art technologies for assessing the translational statuses of individual mRNA species on a genome-wide scale in combination with computational algorithms and the methods for experimental verification, summarized here .The knowledge on roles of regulatory contexts in mRNA for translation efficiency as well as the combinations of these contexts will require improvement of both experimental approaches and theoretical algorithms. The researchers must have the opportunity not only to precisely determine the correlation between the observed fluctuations in expression of a transcript and the actual content of the corresponding protein in plants, but also to precisely define and estimate the contributions of individual regulatory contexts and their combinations within mRNAs. Correspondingly, the need for development of an integrated information resource for this purpose looks very reasonable. This resource would comprise the information about (i) the experimental methods for assessing the changes in translation on a genome-wide scale, including their modifications and applicability to different plant species; (ii) the resources for analyzing, interpreting, and visualizing the polysome and ribosome profiling data; (iii) the resources for constructing the target sequences of plant transcripts and predicting their characteristics; (iv) the methods for experimental verification of the regulatory codes of the plant transcripts involved in translation modulation; and so on. This will form the background for coordination of the numerous studies and the insight into the fine mechanisms underlying the control of biological processes at the point of translation in plants. Also it will expand the capabilities for future studies and the potential of applications of the mRNA regulatory contexts, including their use in engineering novel plant genotypes carrying the best combinations of the corresponding alleles and the generation of new of transgenes, including the use of genome editing technologies.


Background: The effects of publishing case reports on journal impact factor and their impact on future research in pediatric dentistry has not been clearly evaluated yet. Aim. To assess the relevance and role of case reports in pediatric dentistry. Methods: A systematic review (PROSPERO registration number: CRD42018108621) of all case reports published between 2011 and 2012 in the three major pediatric dentistry journals was performed manually. Data regarding citations of each report were acquired from the Institute for Scientific Information database available online. The authors analyzed information regarding citations  received by each case report and considered their relation with the 2013 journal impact factor. Results: Case reports accounted for almost sixteen per cent of all articles published between 2011 and 2012. The citation rate of case reports was generally low and the highest mean citation was 0.5. This review revealed that 6 (9.52%) case reports had at least 5 citations and that the majority of the citing articles were also case reports (27.78%) or narrative reviews (25%). Conclusions: The publication of case reports affected the journal impact factor in a negative way, this influence is closely related to the percentage of the published case reports. Case reports about innovative topics, describing rare diseases, syndromes, and pathologies were more frequently cited. In medicine, a case report (CR) in scientific literature is the detailed report of the symptoms, signs, diagnosis, treatment, and follow-up of a single clinical observation . CRs maySince CRs are characterized by methodological standards that could be assessed as limitations , they are normally considered the base of the pyramid of clinical evidence . HoweverThe only evident reason for this rejection is the preconception that the publication of the CRs lowers the journal’s impact factor (IF).The IF of a journal is the number of citations, received in a year, of articles published in that journal in the previous two years, divided by the total number of articles published in the same time-frame . IF was As already reported by Nabil and Samman, there are two issues regarding CRs to be investigated. Firstly, the number of citations of CRs in high-ranking journals, as anindicator of the influence of CRs on the IF . SecondlThe present review aims to analyze both the abovementioned issues in order to understand the significance and role of CRs in field of PD.The Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) checklist was used as a guideline for conducting and reporting the present systematic review  13]..13].The protocol for this systematic review was registered on PROSPERO (CRD42018108621).All CRs published in major English language PD journals  from JanStudies were included if they were case-report published in English in a major PD journal  and condExcluded articles included: non-English publications; reports of in vitro or animal experiments; reports of more than 5 patients; articles without complete description of demographic and clinical data of every patient; articles not citable according to the Institute for Scientific Information Web of Science (ISI WOS) and grey literature.Two reviewers (RP and ES) screened and evaluated the titles and abstracts of the retrieved studies independently and in duplicate using the abovementioned inclusion criteria. The assessment of full-text articles was also conducted by the same reviewers. The author supervisor (PG) was involved for solving any disagreements through the discussion.All included CRs were further divided into rare disease or pathology (RDP) or new treatment or diagnostic method (NTD).All information regarding the citations were retrieved from ISI online databases and collected during the third week of August 2018 since the authors expected only minimal changes to the number of citations over the time during which the study was conducted. Reviewers extracted two different data regarding citations: total number of citations received in 2013 in order to give an answer to the first question of this review  and total amount of citations received from the date the CR was citable to the date of data collection in order to answer the second question of the review (the impact of CRs on PD).The screening and the data collecting processes were carried on using specially designed data extraction forms. For studies apparently fitting with the inclusion criteria, or in case of title and abstract not providing sufficient information for a clear decision, the reviewers analyzed the full report. The studies excluded after full-text evaluation along with the reasons for exclusion are reported in The primary outcome was the influence of publication of CRs on journal IF; in order to pursue this purpose, the authors evaluated the number/percentage of CRs present in each PD journal and their relation to the journal IF. With the aim of deeply evaluating the primary outcome for every CR published in the selected journals, the authors retrieved such elements: the total number and mean citations, the influence of the publication topic (RDP or NTD), and of the eventual inclusion of literature review on the citation rate.The secondary outcome was the impact of the publication of CRs on future research in PD; such objective was pursued by retrieving data on the frequency of CRs citations from the day they were citable to the third week of August 2018. The authors recorded the number of citations for each included CR but, besides that, they retrieved all the non-cited CRs and all CRs with at least 5 citations along with all the citing articles. Non-cited CRs and CRs with at least 5 citations were divided according to their topic (RDP or NTD) whereas the citing articles were analyzed collecting data about the citing journals IF and the type of study , systematic review (SR), narrative review, CR, prospective study, retrospective study, cross sectional, editorial) through analysis of their title and abstracts. In the case of insufficient data to categorize the citing articles, the full text was obtained.The final search of the ISI WOS citable CRs published from January 2011 to December 2012 in major English language PD journals retrieved 66 results, respectively: 8 published in the International Journal of Paediatric Dentistry (IJPD); 24 published by the European Journal of Paediatric Dentistry (EJPD) and 9 by the Journal of Clinical Pediatric Dentistry (JCPD). Among these results 2 CRs were excluded since they reported data regarding more than 5 patients and an additional CR was excluded because of lack of complete demographic and clinical data regarding the patient.The flow chart of the search strategy along with references of the three excluded CRs is shown in In the biennium comprised between January 2011 and December 2012, the JCPD published the highest number of CRs followed by EJPD and IJPD; this order remains unchanged even considering the percentage of CRs published on the total articles . When coThe authors, moreover, considered the category of CRs described and they highlighted that CRs describing RDP irrefutably have more citations in all of the analyzed journals . Such CROf all the CRs analyzed, only 6 obtained at least 5 citations considering the time-frame between the availability of the article on ISI WOS and the date of data collection (third week of August 2018). Such 6 CRs were equally distributed among the 3 journals and no proportion between this value and the number of CRs published within each journal was noted. Among the 6 highly cited CRs, there were 5 CRs describing RDP and only 1 CR describing NTD . From thEvidence-based medicine (EBM) is defined as the conscientious, explicit, and judicious use of current best evidence for health care . Even ifAs it regards the biennium 2011–2012, it emerges that the percentage of CRs (16%) published in pediatric dentistry journals represents twice the percentage of CRs (7%) published in general medical journals . The revAlthough this review has analyzed the methodological strictness of the articles citing the CRs, it is not prudent to consider completely correct the data that show a relatively low rate of citations of CRs by SR and RCT (respectively 16.67% and 2.78%) and construe them as a lack of ability to stimulate high-level evidence because it is important to note that the rare nature of some diseases makes it impossible to reach an adequate sample for high-level evidence studies ,34,35,36In conclusion, the publication of CRs remains a relevant focal point for scientific knowledge and it should be continued. Authors and editors should spend more time in carefully considering the information enclosed in the submitted CRs in order to improve its usefulness. When writing a CR on PD topics, authors should consider whether sharing their own results brings real benefits to the PD community and editors should select articles that deal with recent topics and describe RDP, since these will receive a higher number of citations and will influence future research. This review confirms that also in PD journals the publication of CR has a negative effect on their IF proportionally to the percentage of CRs published. Attempts to modify the journal IF could reduce the effect of the publication of CR in it, but this action remains doubtful and should be discussed in future publications.


Retinopathy of prematurity (ROP) is an ocular disorder which affects infants born before 34 weeks of gestation and/or with birth weight of less than 2000 grams. If not detected on time and appropriately managed, it can lead to irreversible blindness.The retinal blood vessels first appear between 15–18 weeks of gestation. These vessels grow outwards from the central part of the retina and extend towards the retinal periphery. The nasal part of the retina is fully vascularised by 36 weeks of gestation followed by the temporal retina which is completely vascularised between 36–40 weeks of gestation age . FollowiThe development of ROP can be divided into two phases - an initial phase of delayed growth of retinal vessels followed by a second phase of retinal vessel proliferation .At birth the lungs of an infant born preterm are immature placing him/her at a high risk of developing abnormally low level of oxygen in arterial blood.To overcome this, the newborn infant is given supplemental oxygen in NICU. Prior to 32 weeks of gestation, the retina is very immature and the retinal metabolic demand is low. This excess oxygen creates retinal hyperoxia and oxygen toxicity, inhibiting the production of VEGF. This is followed by temporary stopping or stoppage of normal retinal growth, and constriction of new immature vessels. As a result, there is a reduction of blood supply to retinal tissue and shortage of oxygen needed for metabolism.With increasing age of the preterm infant the retina matures. There is an increase in metabolic demand and oxygen consumption by the retina, creating a relative decrease in oxygen level. This promotes increase in the level of vascular endothelial growth factor (VEGF), triggering the formation of new blood vessels along the inner retinal surface. A demarcation ridge develops along the retina that separates the central vascularised retina from the peripheral avascular retina .The growth of retinal blood vessels at this stage may restart normally or may progress to significant ROP as seen by an abnormal growth of retinal vessels into the vitreous and over the surface of the retina. These new vessels are weak and underdeveloped failing to fulfill the oxygen demand of retinal tissue resulting in continuous growth of abnormal vessels. There is leakage of fluid or blood from these weak blood vessels. If not treated on time this can result in scarring or traction of the retina leading to retinal detachment and blindness .


The cost-effective production of chemicals in electrolytic cells and the conversion of the radiation energy into electrical energy in photoelectrochemical cells (PECs) require the use of electrodes with large surface area, which possess either electrocatalytic or photoelectrocatalytic properties. In this context nanostructured semiconductors are electrodic materials of great relevance because of the possibility of varying their photoelectrocatalytic properties in a controlled fashion via doping, dye-sensitization or modification of the conditions of deposition. Among semiconductors for electrolysers and PECs the class of the transition metal oxides (TMOs) with a particular focus on NiO interests for the chemical-physical inertness in ambient conditions and the intrinsic electroactivity in the solid state. The latter aspect implies the existence of capacitive properties in TMO and NiO electrodes which thus act as charge storage systems. After a comparative analysis of the (photo)electrochemical properties of nanostructured TMO electrodes in the configuration of thin film the use of NiO and analogs for the specific applications of water photoelectrolysis and, secondly, photoelectrochemical conversion of carbon dioxide will be discussed. Vphoto) could be generated by an electrochemical cell employing either p- or n-type Ge electrodes , upon anchoring of an opportune sensitizer due to the very large surface concentration of active sites on which sensitization takes place  have been considered as electrode materials since the late fifties when a photopotential (DSC), for which the present record is ca. 14% , it appears important to analyse and review the recent developments in the materials science behind the design, production and characterization of semiconducting electrodes with characteristic size of 10−9 m. In particular, the present contribution will focus on the analysis of the electrochemical and photoelectrochemical properties of nanostructured SCs made of transition metal oxides (TMOs) with particular attention to NiO , is the possibility of varying electrochemically/photoelectrochemically the redox states of their constituting units, i.e., metal centers and/or oxygen anions . This is due to the richness of the electrochemical and photoelectrochemical behavior of nanostructured NiO as proved by its direct participation in reversible processes of oxidation and reduction of various nature.Nanostructured SC electrodes made of TMOs with one  in non-aqueous electrolytes and in anhydrous/anaerobic atmosphere generates the voltammetric profile of Figure x in which x accounts for the presence of Ni(III) site in the matrix of the nickel oxide. The latter became an interesting material of research due to its low cost and excellent ion storage property. For example, NiO nanostructures are p-type semiconductors with peculiar magnetic and electric behavior depending on the particle size. A comprehensive analyses of the different nanostructured morphologies, in which NiO could be obtained, falls outside the purpose of the present review work. Furthermore, a recent review paper by Bonomo properly faced this topic  → Ni(III) and Ni(III) → Ni(IV), with the first occurring at lower potential values .The oxidation processes verified at i Figure  are ascri Figure (1)NiO+mEonset = 2.5 V vs. Li+/Li, Figure − (Equations 1 and 2) from the electrolyte to the electrode. This kind of process is generally accompanied by the production of mechanical stress in the electrode  centers can be already present in the pristine nanostructured oxide Hagfeldt . In Equa− to I− . The process of Equation 5 corresponds to the electrochemical n-doping of NiO. It has been verified that electrochemical reduction of NiO affects its electrical conductivity, optical absorption, ionic conduction and magnetic properties  through sensitization with a molecular light absorber which upon optical excitation transfers an electron to a moiety acting as electrocatalytic center for H2 formation . At a large scale the conduction of the latter process through the photoelectrochemical approach would ideally diminish the request of fossil fuels extracted from fields. It has been recognized that the photoelectrochemical reduction of CO2 proceeds efficaciously through two paths  and its successive reaction with CO2 to give selectively hydrogenated products with high energy density or synthetic usefulness; (b) by means of the direct photoelectrochemical reduction of CO2  to the electrocatalytic moiety (Cat) interacting directly with CO2, implies the realization of the following sequence of elementary steps: to CO2;Step of p-SC , for the neutralization/regeneration of the PS moiety and/or the Cat unit that resulted temporarily oxidized for the occurrence of the previous steps (b) and (c).Uptake of one or more electron from p-type for the efficacious photoelectrochemical reduction of CO2 are the combination of Cu2O/CuO in the shape of nanorods  with the adoption of dye-sensitized nanostructured NiO of p-type as photoelectroactive component. Different to DSC, it has been early recognized that the sole light-absorbing unit in the immobilized state is not sufficient to accomplish the photoelectrochemical reduction of H+ for the successive formation of H2 during water splitting (or the reduction of CO2) due to the complexity and the number of chemical reactions that follow the starting electrochemical step of electron transfer. For this reason, the successive development of catalytic units was necessary for the full realization of the wanted photoreduction process at modified NiO. At the present stage the progress on the photoelectrolysis cells for the realization of photoelectrocatalytic reduction processes depends mainly on the nature of the dye-sensitizer and the catalytic units combined in the multifunctional supramolecular assembly PS-Cat (either bridged or separated) rather than on semiconducting NiO cathode., The special attention given by the present review to the analysis of the electrochemical and photoelectrochemical properties of p-type NiO is due to the variety of the (photo)electrochemical processes occurring in NiO electrodes, and the complexity of the kinetics of NiO redox processes. Both characteristics certainly render this system a paradigmatic example for the class of semiconducting TMO electrodes.This review has given an overview on the electrochemical and photoelectrochemical behavior of semiconducting electrodes made of nanostructured transition metal oxides (TMOs) like NiO in the configuration of thin films. The interest in NiO resides primarily in the chemical-physical stability which is imparted by bonds having mixed covalent and ionic character. Such a combination of characters generates an electronic structure characterized by the presence of energy bands and partially delocalized states at the valence level with impartment of semiconducting properties. TMO based semiconductors like NiO are photoactive since such electrode materials can transfer electrons in the desired direction provided that a radiation of opportune energy is absorbed by the TMOs for the primary realization of the hole-electron separation. Unlike the semiconductors based on Si, NiO undergoes reversible electrochemical redox processes in the solid state (either in the dark or illuminated states), and as such represent electroactive species. The occurrence of a NiO-based redox process leads to the doping of the oxide and it is accompanied by charge storage. The latter process is also of great utility for the development of batteries and primary sources of electrical energy based on NiO electrodes. Nanostructuring of NiO is an efficacious tool for modulating of the electrochemical properties, the optical absorption and the characteristics of charge transport. Therefore, the preparation of nanosized NiO gives further opportunities for employing NiO as photoelectroactive materials for the finalities of solar energy conversion , solar fuels generation during water photoelectrolysis, and the photoelectrochemical reduction of COAll authors contributed equally in the compilation of the text, the bibliographic analysis and the preparation of figures and tables. The content of the present contribution has been approved by all authors.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewers TS, IP and handling Editor declared their shared affiliation.


Once considered anomalous structures, transforaminal ligaments are not widely known and the criteria for identifying and classifying them are not universal. They are, however, of potential importance during neurological procedures, as their entrapment might lead to radicular pain.Transforaminal ligaments are not present in all patients, but when they are, the incidence of all types of ligaments is significantly higher, with the most common type being the superior corporotransverse ligament. By diminishing the overall amount of space available for the spinal nerve to pass, many early studies concluded that transforaminal ligaments were the cause of nerve root entrapment, resulting in radicular pain. However, more recent studies conducted have claimed that the ligaments do not cause radicular pain but rather are more for the protection of nerves and vessels.The contribution of transforaminal ligaments to radicular pain is still a topic of debate, but their role in the protection of nerves and vessels is certain. The clinician who performs interventional procedures directed toward the intervertebral foramen and the surgeon operating in this region should have a good working knowledge of the anatomy and proposed functions of the transforaminal ligaments. Once considered anomalous structures, transforaminal ligaments are not widely known and the criteria for identifying and classifying them are not universal. There are five major classifications of transforaminal ligaments: the superior and inferior corporotransverse ligaments, the superior and inferior transforaminal ligaments, and the mid-transforaminal ligament -3. Each The intervertebral foramina allow for the passage of numerous structures, including the root of each spinal nerve, segmental spinal arteries and veins, lymphatics, and recurrent meningeal nerves , 4 Figu.Two broad varieties of ligaments have been found in association with the intervertebral foramina: radiating and transforaminal ligaments . The latWithin the boundary of each intervertebral foramen is a network of ligaments dividing the outlet into multiple subcompartments that contain their own specific anatomical structures . In 1832Upon examination of these 10 cadaveric lumbar spines, Golub and Silverman  reportedThe transforaminal  ligaments are not widely known and were once considered anomalous structures after they had been described in the anatomical study by Golub and Silverman -10. HoweIn their pioneering study on these ligaments in 1969, Golub and Silverman  describeThe two corporotransverse ligaments are mostly distributed in the L5-S1 intervertebral foramen: the superior corporotransverse ligament attaches from the posterolateral corner of the vertebral body to the accessory process of the transverse process of the same vertebra; the inferior corporotransverse ligament connects the same posterolateral corner of a vertebral body to the transverse process below . The traIt must be emphasized that transforaminal ligaments are not always present, but when they are, the overall incidence of all types of these ligaments is approximately 47% .  The moThe anatomical location of the transforaminal ligaments led many early studies to conclude that these condensations of fascia were the cause of nerve root entrapment resulting in radicular pain since they diminished the space available for the spinal nerve to pass -10, 12. This was a comprehensive literature review conducted on the transforaminal ligaments regarding their anatomy and function. Although there have been limited studies of their form and function, the transforaminal ligaments are believed by some to be protective of nerves and vessels traversing the intervertebral foramen while being the cause of radicular pain is still a matter of debate.


The keyhole digging process associated with variable polarity plasma arc (VPPA) welding remains unclear, resulting in poor control of welding stability. The VPPA pressure directly determines the dynamics of the keyhole and weld pool in the digging process. Here, through a high speed camera, high frequency pulsed diode laser light source and X-ray transmission imaging system, we reveal the potential physical phenomenon of a keyhole weld pool. The keyhole depth changes periodically corresponding to the polarity conversion period if the current is same in the electrode negative (EN) phase and electrode positive (EP) phase. There exist three distinct regimes of keyhole and weld pool behavior in the whole digging process, due to the arc pressure attenuation and energy accumulation effect. The pressure in the EP phase is smaller than that of the EN phase, causing the fluctuation of the weld pool free surface. Based on the influence mechanism of energy and momentum transaction, the arc pressure output is balanced by separately adjusting the current in each polarity. Finally, the keyhole fluctuation during the digging process is successfully reduced and welding stability is well controlled. VPPA (Variable Polarity Plasma Arc) keyhole welding is an ideal method to achieve joints made of middle thick aluminum with high quality and efficiency . There aAs a unique characteristic of plasma arc welding, keyhole behavior determines the process stability of plasma arc welding. Keyhole detection research has been carried out in view of DC-PAW (Direct Current Plasma Arc Welding) for steel. Liu et al. ,6,7 direThe above research mainly focused on the keyhole weld pool evolution in a welding quasi-steady state rather than the keyhole digging process. Zheng et al.  pointed Here, we have observed the fluctuation of molten pool surface in the digging process by high speed camera with a high frequency pulsed diode laser light source system. The keyhole boundary in real time was also obtained by an imaging system of an X-ray transmission. In order to analyze the factors influencing the keyhole stability, the plasma arc pressure is measured by the pressure transducer. Combining the energy and momentum balance between electrodes and arc, the physical mechanism of plasma arc pressure was obtained, based on which we optimized the pressure output. Finally, the optimized parameters were verified by the weld formation and weld pool free surface fluctuation situation.A5052P aluminum alloy is adopted as the work piece and the chemical composition is in The setup for observing weld pool free surface is set as shown in In order to clearly observe the weld pool free surface, a telephoto micro lens  with a 640 nm band-pass filter is used to filter out the arc light, a high-frequency pulsed diode laser light source system  to illuminate the weld pool, a high speed video camera (HSVC)  to record the images. The frame rate of HSVC is 2000 fps. The HSVC sends out an electrical pulse signal to the laser light generator at the start moment of shutter opening, ensuring each picture is clear and reducing the effect of laser heat on the weld pool.To understand the plasma arc pressure, and thus to analyze its influence on the digging process, the measurement platform is established as shown in In the digging process of VPPA welding, the variation of free surface of weld pool in one current period is analyzed, as shown in The keyhole boundary is obtained by image edge extracting technology based on the X-ray results, as shown in The keyhole depth with time in the whole digging process is shown in The diagram of keyhole and weld pool during digging process is shown in In addition, the unmelt height becomes small with the increase of the melting depth, leading to heat loss at the weld pool bottom becoming more difficult. Heat gradually accumulates in the unmelt region. The melting speed gets faster. The keyhole digging speed also increases. Predictably, with the keyhole depth increase, the thermal accumulation also increases. The keyhole digging process and thermal accumulation are mutually reinforcing, resulting in the blasting type penetration in the last stage. Through the above analysis, the keyhole instability during digging process mainly occurs in the first two stages. Adjusting the output of plasma arc pressure to stabilize the keyhole state of EN and EP phases is crucial to realizing stable penetration.In order to understand the evolution mechanism of the VPPA pressure and adjust the pressure output reasonably, the energy and momentum balance between electrodes and plasma arc in different polarities is analyzed in Another reason for the pressure reduction in the EP phase is the different physical process on the interaction of the plasma arc and the base metal in EN and EP phases. Tashiro et al.  pointed I is the current, r is the radius of plasma arc. Therefore, the difference of pressure between EN phase and EP phase can be got.Moreover, Basins et al.  pointed Expressed in terms of current density, Equation (2) givesThrough the analysis of momentum and energy balance in the interface between electrodes and plasma arc, we can know that the tungsten temperature increase and cleaning of oxide layer on the surface of base metal during EP phase both result in the decrease of current density. Thus, the arc pressure depends not only on the square of the current but also on the square of arc radius based on the Equations (2) and (3). However, Lin et al.  pointed In this section, the current of the EP phase is adjusted to balance the pressure output. The variation of plasma arc pressure with the change in current can be clearly presented by the distribution contour shown in The weld pool free surface with different EP currents is shown in Through a large amount of welding experiments, it is found that the success rate of forming weld bead is low if the keyhole weld pool fluctuates. It is easy to form cutting. As (1)The keyhole and weld pool fluctuate with the periodic change of plasma arc state during the digging process of VPPA welding, rather than continuously increasing the keyhole depth over time. By observing the keyhole boundary of digging process in real time, it is found that the keyhole depth increases rapidly in the EN phase, but decreases gradually in the EP phase.(2)The three stages of keyhole digging process are found, which are regular periodic fluctuation, violent fluctuation and blasting penetration, respectively. The fluctuation of the second stage is caused by the attenuation of plasma arc pressure due to the increase of the keyhole depth. The positive feedback between the thermal accumulation and the continuous increase in the depth of the keyhole leads to the rapid penetration in the third stage.(3)In order to accurately balance the plasma arc pressure output, the influence mechanism of energy and momentum balance on the pressure is analyzed. The difference between the plasma arc pressure of the EP and EN phases can be effectively reduced if the EP current is 30 A to 50 A larger than that of EN. The pressure balance output can reduce the keyhole weld pool fluctuation in the digging process and improve the welding success rate.This work mainly investigates the stability of keyhole digging process in VPPA welding. Using comprehensive experimental measurement of weld pool free surface, keyhole boundary and plasma arc pressure, the evolution of keyhole weld pool and the influence mechanism of plasma arc pressure are obtained. The specific conclusions are as follows.


As individuals are living longer, in many cases with chronic diseases, there is an increased focus on end-of-life (EOL) planning and decision making. This includes a broad spectrum of choices including advance care planning (ACP) and turning to palliative care or hospice care. Although there has been an increase in palliative and hospice care enrollment and ACP engagement over the past decade, participation remains low for certain subgroups of the population. The purpose of this symposium is to offer insight into reasons for these varying rates of engagement by exploring determinants and barriers to EOL decision making and planning and by examining caregiver knowledge of EOL decision making and planning from the service provider perspective. The first three studies examine various types of influences in EOL decision making and planning. Inoue and colleagues explore factors associated with the length of hospice stay, and Gaines and colleagues examine the impact of environmental characteristics in ACP. Ornstein and colleagues use Denmark registry data to assess the role of kinlessness at the time of death in EOL decision making and healthcare utilization. The final presentation by Noh and colleagues examines how service providers in rural areas perceive community residents’ knowledge of ACP and palliative care. The discussion following these presentations will compare findings across different forms of EOL decision making and planning, consider the impact of the varying methodological approaches used, and highlight implications of these works for potential interventions and policies related to EOL decision making and planning.


Evolutionary Applications includes eleven papers covering a wide range of perspectives and methodologies relevant to understanding genomic variation under domestication.Domestication has been of major interest to biologists for centuries, whether for creating new plants and animal types or more formally exploring the principles of evolution. Such studies have long used combinations of phenotypic and genetic evidence. Recently, the advent of a large number of genomes and genomic tools across a wide array of domesticated plant and animal species has reinvigorated the study of domestication. These genomic data, which can be easily generated for nearly any species, often provide great insight with or without a reference genome. The comparison of genome wide data from domestic and wild species has ignited a wave of insight into human, plant, and animal history with a new range of questions becoming accessible. With this in mind, this issue of  This issue has five broad topics, with the first focused on deleterious mutations in the context of domestication , allow us to learn ever more about the human condition. Together, these articles demonstrate the emergence of a new understanding of how genomewide effects may differ from those at specific loci and how these effects can change dramatically over relatively fast time scales. It also shows how studies of the process of domestication provide tremendous insight into the change in fitness in populations and can be used to improve plant and animal breeding populations and inform other areas of evolutionary biology such as conservation and adaptation in the wild.None declared.


Objective: To report a clinical case of macular retinopathy after laser light exposition.Methods: We described a case of reversible maculopathy in a 29-year-old woman. Retinography and Optical Coherence Tomography were performed.Discussion: Retinopathy due to laser light is an increasingly frequent pathology because of its improper use and the massive sale not regulated by the Internet. These lesions can vary from mild disruptions in the pigmentary epithelium to retinal hemorrhages, retinal ruptures, or macular holes. The depth of the lesion and the involvement of the photoreceptors layer will confer a worse visual prognosis. Conclusion: A correct control of the sale and consumption of these devices are necessary to suppress this completely avoidable pathology. Laser light retinopathy is an increasingly common pathology due to the spread of Internet sales and less control of the safety of laser light devices. Laser lights are often mis-labeled and mis-marketed as toys and they are sold to all kinds of consumers, even children. However, even so-called safe lower-power lasers may produce retinal damage and permanent visual loss [2].The human eye suffers damage as a result of ionization, thermal and photochemical mechanisms when it is exposed to laser light of more than 500 mW of power and between 400 and 1400 nm of wavelength [3]. There is a classification of laser devices according to their power. They are classified from I to IV, those labeled as category IIIb and IV being unfit for consumption .Laser lesions in the posterior pole can range from minimal hypertrophy of the pigment epithelium to the appearance of central serous chorioretinopathy, hemorrhage, choroidal neovascularization, or macular hole [5]. Although the use of low powered lasers is widespread, fearful children may report symptoms only if bilateral visual impairment has occurred [6].Bilateral retinopathy has been reported previously and may be more likely to occur in cases involving mirrors or beam splitters or in patients with alternating fixation . A greater regulation of Internet sale, age restriction of use, and education are essential to avoid the damage of these dangerous devices. An adequate control of the sale to the public of high-power laser devices is necessary to avoid these pathologies either by direct exposure or by the glare of the light [Conflict of interestThere is no conflict of interest. All authors agree with the publication of this manuscript. This clinical investigation was approved by the Ethics Committee of the Hospital Regional of Malaga and adheres to the principles of the Declaration of Helsinki.The patient was informed and signed the informed consent to participate in this study.


The formation of self-generated gradients of iodixanol from a solution of uniform concentration requires the use of vertical or near-vertical rotors. The density profile that is generated depends upon the sedimentation path length of the rotor, centrifugation time, RCF and temperature. Modulation of the starting concentration changes the density range of the gradient. This Protocol Article illustrates the effect of these parameters on gradient shape in a few selected rotors. Because the gradients are formed by the centrifugal field, they are highly reproducible and easy to execute.


Biological signals are the reflection of accumulated action potentials of subdermal tissues of a living being. Its presence signifies the ionic and electrical activities of the muscular and the neural cells in a synchronized manner. Being a mosaic model of a living architecture, the resultant vectors of biological signals have temporal as well as spatial representation. These signals are stochastic in nature. Medical diagnostic tools are prevalent using the support of medical signals. In the course of time, a significant amount of progress has been achieved in the field of medical signal processing for the improvement of the signal-to-noise ratio, extraction of features from those filtered signals, and classification of the extracted signals for clinical applications. This special issue emphasized the recent development of medical signal processing, improvement of algorithms, and wider clinical applications. Entropy-based kernel extraction technique is being used for the analysis of the nonlinear and nonstationary epoch signals. This kind of approach shows robustness in noise reduction. Machine learning algorithms are also being used for real-time feature extraction (pattern extraction) from tympanic temperature profiles. Quadratic support vector machine algorithms were also found to enhance the accuracy of the detection mechanism.Regulation of rehabilitation devices and protocols are also governed by the processing of medical signals. Reference techniques are often used for acquiring surface EMG signals for the activation of the rehabilitation actuators. Consecutive placement of stimulator-detector arrays influences the spatial acquisition of the functional electrical stimulus (FES) and volitional sEMG which can be used for controlling EMG-driven FES neuroprosthesis. Dynamic models are also being used for analyzing and detecting features from sEMG of deltoid muscles, present in the upper arm. The analysis of the signals can be used for the evaluation of the differently abled persons to predict the treatment outcomes. Health monitoring can also be achieved by processing of time-domain biological signals of sub-nanosecond durations. It can even help in predicting the state of the human heart by correlating the activity of the heart muscles and the blood pumping process.Deep recurrent neural networks are also found to be useful tools for predicting features related to the adverse effect of drugs on the human body. In addition to this technique, conditional random fields are also implemented by many researchers for identifying the biological signals from significantly highly correlated background noise due to the subsequent physiological modification after the introduction of the foreign particles within the body. Similarly, the assessment of the trace elements in the human body can also be achieved by extracting features of the biological signals and biomarkers, and subsequently analyzing the features. A neural network can play an important role towards the identification of the continuously adaptable trace elements within the physiological fluids.Biomedical signaling has significant outreach in its clinical application domain. Cerebral arterial stenoses can also be predicted by a nonradioactive technique, namely, photoplethysmography. It involves the employment of an optical detection technique, which is a wavelength-specific process. Corresponding photodetectors are being used to measure the wavelength of the reflected light. Cerebral disorder can also be detected from EEG-fMRI recordings. It involves a rigorous filtering process, which employs a comb filter, followed by a moving-averaged filter for the elimination of the random noises.In this special issue, all the above topics are discussed with their recent state of the art and their corresponding clinical applications.Kunal PalKunal MitraArindam BitSaugat BhattacharyyaAnilesh Dey


It is projected that by 2030, 6 percent of Nigeria’s present population of 180 million will be 60 years and above. However, the extent to which the traditional systems of family support and security can manage the care of the increasing number of older people in the country is not clear as limited studies are available in the country regarding the health burden and Socioeconomic costs of caring for dependent older people. This study is therefore aimed at assessing the health burden and costs of caring for dependent older people in Nsukka, Nigeria. This cross sectional survey involved 1030 randomly selected elderly persons in Nsukka, Nigeria . Structured questionnaire and Focus Group Discussion Guide (FGD) provided the data for the study. The qualitative data were analyzed with descriptive statistics, while regression analysis formed the basis for predicting effects of the variables in the study. The qualitative data from the FGD were analyzed thematically. The findings show that the Nigeria government was largely uninvolved in the care and support for older dependent people; leaving families to negotiate a ‘journey without maps’. Families carried the health burden of care for the elderly with attendant socioeconomic costs. The traditional role of female relatives as caregivers was beginning to give way to paid caregivers. An innovative policy frame work targeted at the needs of older persons in health care, social protection and other forms of intergenerational support is required to supplement inputs from families of the aged in Nigeria.


The increasing number of existing and new chemicals demands ecotoxicological data as well as toxicological data for pre- and postmarketing risk assessments. Although human health has been the major concern in Japanese environmental management, ecosystem health is becoming the big issue as the need for preserving the diversity of ecosystems has been recognized. This recognition is changing the regulatory framework in Japan, resulting in new actions toward establishment of water-quality standards for aquatic organisms and ecotoxicological assessment of existing chemicals. At the same time, the need to assess complex liquids that contain several kinds of chemicals is increasing. The ecotoxicological study of Japanese effluents shows that the present chemical-specific standards are not enough to protect aquatic ecosystems. These two factors encourage the application of ecotoxicological tests as well as the toxicological data.


The field of craniofacial biology has greatly benefited from the progress made the last decades in developmental biology, molecular biology, stem cell biology, and genomics. A detailed description of the action of signaling pathways that are involved in developmental processes has significantly increased our comprehension of the organization and function of molecular networks that are involved in the formation of the craniofacial complex . The ion channel protein TRPM7 mediates the mineralization process of craniofacial hard tissues . The influence of photobiomodulation on the capacity of bone marrow cells to form alveolar and craniofacial bones is also discussed . Calvaria formation is a complex process that necessitates the coordinated action of osteogenic stem cell populations , controlled by specific signaling molecules such as Indian Hedgehog and the transcription factor Gli3 . Palatogenesis is an equally complex process orchestrated by cytoskeleton and extracellular matrix rearrangement  and expression of specific signaling molecules .The influence of systemic glucocorticoid administration in the composition of bone structures of the jaw of mini pigs is reported .The identification of stem cell compartments in conjunction with the discovery of the complex ensemble of signals that creates their microenvironment is essential for a successful regenerative approach. Therefore, the identification and characterization of stem cell niches within dental pulp and the analysis of Notch signals during tooth repair is of prime importance . Similarly, Wnt signaling , VEGF and Hypoxia Inducible Factor  and Syndecan-1  might affect alveolar bone remodeling and periodontal ligament homeostasis.Loss of the alveolar bone that surrounds teeth could be an actor of periodontal pathology, and this process could be controlled via the Chang et al.), Fibroblast Growth Factor 10 , MORN5  and the microRNA Mir23b and Mir133b  are involved in the physiopathology of a variety of tissues and organs of the craniofacial complex. The Wnt pathway controls the growth of dental lamina  from where the future teeth will develop. Retinoic acid , steroids , and Na:K:2Cl Cotransporter-1  control the formation of enamel. Generation of different dental epithelial spheres that contain stem cells might enhance our understanding of enamel formation . Dentin sialophosphoprotein (DSPP) is also very important for proper dentin formation and mutations in the DSPP gene lead to dentinogenesis imperfecta . The role of Nerve Growth Factor pathway is similarly important during human tooth development and repair (Mitsiadis and Pagella). Finally, the Hippo-YAP1/TAZ cascade is important for pituitary stem cell development .Defined molecular mechanisms such as GLI-mediated transcription (The increased knowledge on the development, pathology and regeneration of tissues and organs of the craniofacial complex will most certainly orchestrate a significant shift toward novel diagnostic and therapeutic approaches. Although many questions concerning the mechanisms involved in craniofacial tissues development and regeneration have not yet been resolved, modern imaging tools, mathematics, bioinformatics, and genomics will help to elaborate new concepts and models that will change drastically this field. Further progress in treatments concerning craniofacial tissues and organs depends upon active and vigorous research programs.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


During the development of the cortex distinct populations of Neural Stem Cells (NSCs) are defined by differences in their cell cycle duration, self-renewal capacity and transcriptional profile. A key difference across the distinct populations of NSCs is the length of G1 phase, where the licensing of the DNA replication origins takes place by the assembly of a pre-replicative complex. Licensing of DNA replication is a process that is adapted accordingly to the cell cycle length of NSCs to secure the timed duplication of the genome. Moreover, DNA replication should be efficiently coordinated with ongoing transcription for the prevention of conflicts that would impede the progression of both processes, compromising the normal course of development. In the present review we discuss how the differential regulation of the licensing and initiation of DNA replication in different cortical NSCs populations is integrated with the properties of these stem cells populations. Moreover, we examine the implication of the initial steps of DNA replication in the pathogenetic mechanisms of neurodevelopmental defects and Zika virus-related microcephaly, highlighting the significance of the differential regulation of DNA replication during brain development. The neocortex is a complicated brain region characterized by excessive cell diversity as it is composed by multiple types of neuronal and glial cells assembled in networks that regulate the higher order functions. The cortex derives from the dorsal telencephalon located in the most anterior part of the neural tube through a strictly regulated process that involves diverse types of neural stem cells (NSCs) and more committed neural progenitors (NPCs) organized in discrete zones . ExcitatCoordinated action of morphogens and intrinsic signaling cues leads to the successive generation of the distinct types of NSCs and NPCs during cortical development. These populations differ on their self-renewal ability and differentiation potential. Numerous studies have identified distinct morphological and molecular features that describe the diversity among NPCs , while at the onset of neurogenesis NECs are replaced by apical radial glial cells (aRGs) that remain in contact with the apical membrane and form the ventricular zone (VZ), one of the main proliferating zones of the cortex. During mid neurogenesis a second proliferating zone is established basally of the VZ by intermediate progenitors, which delaminate from the apical membrane and are translocated to the subventricular zone (SVZ). Despite these primary populations, other minor groups of progenitors are also generated over the course of development like the short neural precursors (SNPs) that appear in the VZ and the outer RGs (oRGs) located in the upper boundaries of the SVZ. Here, we will focus on the populations of the apical NSCs that prevail the VZ during the initial stages of cortical generation . A more Neuroepithelial cells consist the first population that reside in the walls of the neural tube. These cells are highly polarized, possessing a basal process that is attached to the basal lamina and an apical process attached to the apical surface in contact with the neural tube lumen . NECs seUpon the onset of neurogenesis at embryonic day (E)10.5 in murine development and until E12.5, NECs are gradually transformed to aRGs, which constitute the main population of NSCs during cortical development. aRGs are also polarized cells exhibiting an apical and a basal process that span the radial axis of the developing cortex and maintain their primary cilium that projects into the newly formed telencephalic vesicles . SimilarDuring cortical development, extrinsic signaling cues derived from the local environment coordinate the proliferation and fate commitment of NSCs. Various fate determinants and signaling pathways impact not only in the genetic program of NSCs by regulating the expression of specific factors, but also in their intrinsic features like their cell cycle and chromatin dynamics . ActivatWithin a complete cell cycle the genetic information must be faithfully duplicated and pass intact to the progeny. Moreover, in the level of multicellular organisms, replication must be coordinated with cell fate decisions that are mediated by complicated transcriptional programs. DNA replication is organized at multiple levels to ensure that genome duplication will be completed within the available time and over- or under- duplication that threatens genome integrity will be avoided. In eukaryotic cells, DNA replication initiates from multiple sites along the genome known as replication origins. Initiation of replication is strictly regulated by a two-step process that involves the formation of a multiprotein complex termed pre-replicative complex (Pre-RC) on the potential origins and is called origins’ licensing, followed by the sequential activation of a subset of origins known as origins’ firing , as both populations have similar cell cycle duration. It is also established that a short G1 phase is an intrinsic property of multipotency as both in ESCs and NECs G1 length increases upon fate commitment . The potlication . Moreovelication .These observations suggest that NECs might also require similar adaptations in the licensing of DNA replication due to their shortened G1 phase, while these features are probably absent from more committed NPCs defined by a longer G1  challenges the successful completion of DNA replication compromising genome stability . NPCs th neurons . Accordi neurons . It thusDuring the expansion phase of the developing cortex, NSCs utilize a high number of origins during DNA replication due to their short cell cycle . Howeverin vitro systems that recapitulate the progressive fate commitment of mouse and human ESCs confirmed the relation between replication timing and gene expression and showed that changes in the timing of replication coordinate with transcriptional activation  is of the main syndromes that has set the link between licensing of DNA replication and brain development. MGS is an autosomal recessive type of primordial dwarfism due to developmental retardation, characterized by proportionate growth deficits, incomplete patellae formation and typical facial features . Severitpatients . The imppatients . Studiespatients . Similarpatients .The microcephaly observed in MGS patients emphasizes the role of proper licensing of DNA replication during brain development . It is eToxoplasma gondii have been also associated with microcephaly  is one of the most known aetiologies of infectious microcephaly, however, congenital infections including the cytomegalovirus or the parasite ocephaly . The impocephaly . Initialocephaly . Interesocephaly . Moreoveocephaly . In lineocephaly . The posDuring the last decade the importance of the dynamic regulation of DNA replication during organismal development has been established . In the Moreover, adaptations in the number of licensed origins and in the replication timing profile permit the integration of the active transcriptional program that operates in NSCs during cortical development. How the plasticity of DNA replication initiation is regulated within the complicated environment of the developing brain and whether it is determined by signaling cues or it is an inherent feature of NSCs remain important questions.Mutations in the genes that express licensing factors have been associated with developmental retardation characterized by microcephaly, stressing the significance of efficient licensing and accurate initiation of DNA replication during brain development. A future direction will be the establishment of animal models for impaired-licensing syndromes, that will permit the detailed analysis of brain development under these conditions. Further insights into the response of NSCs upon DNA replication stress will be critical to our understanding of the pathophysiology of neurodevelopmental syndromes. Accordingly, the possible effects of ZKV in the normal progression of DNA replication is a very intriguing scenario that could explain the preference of the virus in early proliferating NSCs. Deciphering the role of the differential regulation of DNA replication will provide new grounds for research on the mechanisms leading to brain malformations like the hereditary orinfectious microcephaly.AK provided the study material and wrote the manuscript. ZL performed proofreading of the manuscript and approved final version of the manuscript. ST wrote the manuscript, approved final version of the manuscript, and provided financial support.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


This session will address the evolving work of Geriatric Workforce Enhancement Programs (GWEP) to educate and train the primary care workforce and partner with community based organizations to address gaps in healthcare. The inaugural GWEP awardees were announced at the 2015 White House Conference on Aging. In November 2018 the Health Resources and Services Administration (HRSA), released the second GWEP Notice of Funding Opportunity (NoFO). The new funding opportunity reflects current policy priorities. In addition, for the first time in 9 years a Notice of Funding Opportunity was released for the Geriatric Academic Career Award (GACA) program. The return of the GACA program indicates the success of advocacy efforts to increase programs to support geriatric training and the development of geriatric academic professionals. Individual symposiums will explore the policy priorities reflected in the GWEP NoFO including the use of technology for training and care delivery, the age-friendly healthcare and dementia-friendly community initiatives, and value-based care including improving partnership with community based organizations. Additionally, an individual symposium will present the GACA program and discuss the advocacy process leading to the reintroduction of this program. During the last congress advocates of the GWEP and GACA programs supported authorization and funding of geriatric programs. Geriatrics programs describing the work of the GWEPs and GACAs were reinserted into the legislative process, although this reauthorization was not completed. This advocacy process garnered strong bipartisan and agency support. The session will describe these efforts and will conclude with an update on current authorization and appropriation status.


Background: The SAFE strategy  is the World Health Organization (WHO) recommended guideline for the elimination of blindness by trachoma by the year 2020.Objective: While evaluations on the implementation of the SAFE strategy have been done, systematic reviews on the factors that have shaped implementation are lacking. This review sought to identify these factors.Methods: We searched PUBMED, Google Scholar, CINAHL and Cochrane Collaboration to identify studies that had implemented SAFE interventions. The Consolidated Framework for Implementation Research (CFIR) guided development of the data extraction guide and data analysis.Results: One hundred and thirty-seven studies were identified and only 10 papers fulfilled the eligibility criteria. Characteristics of the innovation – such as adaptation of the SAFE interventions to suit the setting and observability of positive health outcomes from pilots – increased local adoption. Characteristics of outer setting – which included strong multisectoral collaboration – were found to enhance implementation through the provision of resources necessary for programme activities. When community needs and resources were unaccounted for there was poor compatibility with local settings. Characteristics of the inner setting – such as poor staffing, high labour turnovers and lack of ongoing training – affected health workers’ implementation behaviour. Implementation climate within provider organisations was shaped by availability of resources. Characteristics of individuals – which included low knowledge levels – affected the acceptability of SAFE programmes; however, early adopters could be used as change agents. Finally, the use of engagement strategies tailored towards promoting community participation and stakeholder involvement during the implementation process facilitated adoption process.Conclusion: We found CFIR to be a robust framework capable of identifying different implementation determinants in low resource settings. However, there is a need for more research on the organisational, provider and implementation process related factors for trachoma as most studies focused on the outer setting. Chlamydia trachomatis. Trachoma is characterised by multiple stages classified according to whether symptoms are associated with (i) active infection commonly observed in children – trachomatous inflammation follicular (TF) and trachomatous inflammation-intense (TI) or (ii) with corneal scarring observed in older children and adults – trachomatous scarring (TS), trachomatous trichiasis (TT) and corneal opacity (CO) [Trachoma is the leading infectious cause of preventable blindness and is thought to be a public health issue in 42 countries globally. It is caused by recurring infection by the bacteria ity (CO) . The obsAlmost 200 million people are thought to be living in trachoma endemic regions, with 1.9 million people suffering from blindness and visual impairment as a result of trachomatous trichiasis and resultant corneal opacities . PrevaleA resolution passed by the World Health Assembly in 1998 called for the elimination of blinding trachoma by the year 2020. The World Health Organization (WHO) through the Global Alliance for the Elimination of Trachoma by the year 2020 (GET 2020) advocates for the implementation of the full SAFE strategy denoting surgery for trichiasis, antibiotic distribution, facial cleanliness and environmental improvement in countries rolling out national trachoma control programmes . It is aThere has been a marked increase in the implementation of the SAFE strategy in endemic countries which can be attributed to increased political commitment towards neglected tropical disease elimination programmes and global efforts to map the burden of trachoma resulting in the availability of accurate data that guides control efforts . NeverthThe aim of this review was to apply the Consolidated Framework for Implementation Research (CFIR) to identify factors acting as barriers and facilitators to the implementation of the SAFE strategy. The selection of CFIR was based on its ability to be applied in conducting comprehensive context assessment across multiple levels of the healthcare system. In conducting the review we identified primary research that reported on influencing factors and used CFIR’s five major domains – inner setting, outer setting, process, characteristics of the intervention and characteristics of the individuals – to analyse the implementation efforts of the SAFE strategy across multiple settings .We conducted an initial scoping literature search to select the most appropriate key terms and search strategies that would meet the review’s objective. A major consideration when developing the final strategy was to make sure that it was highly sensitive to identify all existing literature on perceived barriers and facilitators to SAFE implementation. In our preliminary search we found that the assessment of trachoma interventions was sometimes conducted alongside those of other ocular diseases and perceived determinants to implementation were not always the primary outcomes of interest in studies evaluating SAFE interventions. These studies reported on factors affecting different dimensions of implementation without necessarily referring to them as acceptability, adoption, appropriateness, cost, fidelity, penetration and sustainability . FurtherPrimary research studies that had been published in peer-reviewed journals were included in the review regardless of study design. The articles should have been published between 1998 when the SAFE strategy was adopted as the main WHO guideline for trachoma control and January 2017. The studies must have reported on perceived barriers and facilitators during any of the different phases of implementation. Facilitators and barriers were defined as any factors that promoted or hindered the implementation of any of the SAFE interventions –surgery, antibiotic administration, facial cleanliness or environmental sanitation.The search was restricted to peer-reviewed articles published in English. Editorial and personal opinion articles were excluded. Studies that measure changes in trachoma health literacy, knowledge, awareness and attitudes but do not mention the implementation of SAFE were also excluded from the review.PM conducted the database searches and imported eligible studies into EndNote for reviewer access. The selection of studies was conducted using the Preferred Reporting Items for Systematics Reviews and Meta-Analyses (PRISMA) guidelines. In accordance with the guidelines from the initial 117 studies identified, 20 duplicates were excluded. PM, CJ and JMZ independently screened the titles and abstracts of the articles using the inclusion/exclusion criteria. Wherever discrepancies arose they were discussed and decisions on inclusions made jointly. All the articles that were excluded based on their titles (80) either measured health literacy in general or health literacy, knowledge, awareness and attitudes for specific ocular diseases that were out of the scope of this review such as glaucoma, diabetic retinopathy and age-related macular degeneration. The reference lists of the remaining articles were checked to identify any relevant articles that may not have arisen in the electronic search. A total of 37 abstracts were screened. Given that implementation determinants were not always the primary focus of the studies, abstracts that did not provide a lot of information but were felt to potentially meet the inclusion eligibility criteria were added to those going through a full text review. The full text review of 20 studies was focused mainly on (i) statistical analyses from quantitative findings, (ii) participant quotations in the results section and (iii) interpretive descriptions in the methods and discussion sections. Ten studies were found suitable for inclusion in the review as shown in The heterogeneous nature of the studies that were included in the review called for the use of the Critical Checklist for Public Health. The quality of the studies was gauged based on the validity, credibility and completeness of information presented as it related to (i) the study question; (ii) the study design, sampling, exposures, outcomes, confounders and other aspects of internal validity; (iii) interpretation and population relevance of the results; and (iv) the implications for implementation in their own population and public health practice . Risk ofGuidance on the Conduct of Narrative synthesis in Systematic Reviews was used as the guiding framework for the data extraction and synthesis. The narrative synthesis approach which uses qualitative text to summarise and explore the relationships between data from qualitative and quantitative data was considered appropriate for this review due to the heterogeneity of the studies identified . A good http://www.cfirguide.org/tools.html and used for coding and data extraction. PM, CJ and JMZ independently identified and extracted data and coded it based on the CFIR constructs they were judged to represent. Codes thought to occur in multiple domains were double coded. Comparisons on the coding was done by all the authors and wherever discrepancies arose they were discussed and final codes agreed to by consensus. Using the memo templates textual descriptions and summaries (narratives) with supporting information were recorded for each of the studies. All the authors reviewed the summary memos.A deductive approach using CFIR as the coding framework was used during the preliminary synthesis to map the data. Extracted data included authors, year of publication, study objectives and design, characteristics of the study population, analysis, results and interpretive summaries. Codebook and memo templates with guidance on construct definition were obtained online at Grouping and clustering of the studies was done to allow cross literary comparisons through pattern identification across studies. Thereafter thematic analysis was used to identify the key determinants (themes) within the five CFIR domains. The process of translating the data made it possible for us to explore the differences and similarities in factors identified in the studies. The final stage of the narrative synthesis was the evaluation of the robustness of the analysis process which was done by looking at whether or not the factors identified were credible and comparable to the available implementation science literature as well their appropriateness in answering the review question.Our search yielded 137 articles: 117 from the different search engines and 20 from the reference lists. PRISMA guidelines were used to identify studies that met our specific research objectives . Only 10None of the studies specifically listed implementation outcomes as defined by Proctor et al. as their outcomes of interest but reported on aspects related to their measurement as shown in Two studies reported on varying participation rates (coverage) that are an indication of the feasibility of the implementation efforts ,8. PenetThe different implementation strategies were categorised using the framework described by Wang et al. . VariousThe implementation determinants were grouped into the five major domains of CFIR.The SAFE strategy is a guideline that was developed to address the problem of trachoma on a global/macro level for United Nations member states by the WHO through the Alliance for the Global Elimination of Trachoma by the year 2020. All the studies identified in this review made mention of national trachoma control programmes or other implementing bodies that had adapted the SAFE strategy for their specific contexts. Wherever development and implementation of SAFE programmes was seen as locally driven, such as through the involvement of community organisations, there were higher levels of acceptability. This could be due to an increased sense of ownership and commitment ,18. UtilObserved positive results or stakeholders’ belief in the strength of the evidence base to justify the implementation and subsequent use of SAFE interventions were shown to affect the way certain aspects of the strategy were implemented. In Zambia the decision to use roxithromycin instead of azithromycin for mass drug administration was based on the clinical experience of one of the investigators who had been successfully using it to treat trachoma . The incThe delivery of the SAFE strategy was done using a variety of implementation strategies. Social marketing communication approaches that took into account the unique features of the local communities were found to motivate change by making it easier to discuss changes in hygiene practices ,16,18,20The feasibility of scaling up of the implementation of SAFE was explored in one study which provided strong evidence that the different interventions were effective in reducing the prevalence of active trachoma in a hyper endemic region. Consequently, the Government of Zambia used these findings to begin a national trachoma initiative as a preamble to the creation of a national trachoma eradication programme .An understanding of the needs and resources of communities who would be the recipients of the intervention was found important in ensuring appropriate alignment of SAFE related activities. Key needs of the patients included inadequate water supply and poor sanitation. This was addressed through drilling of wells and building latrines to encourage uptake of better hygiene practices ,15. IntrStrong collaboration between different government agencies and non-governmental organisations was found to be important for the provision of technical and financial support to national trachoma control programmes . DiffereIn areas where all the components of the SAFE strategy had been implemented but there was lack of continuity of care due to poorly developed healthcare systems, trachoma control was affected especially if services such as trichiasis surgery and antibiotics could only be obtained from health facilities . High laImplementation climate was measured by how receptive individuals within implementing agencies were to the SAFE intervention and how the intervention activities were aligned with the routine practices of the organisation. Lack of confidence in the quality of training in trachoma control affected how able the health workers felt they were in implementing the SAFE strategy . TeacherFinancial and technical resources from non-governmental organisations and international donor organisations channelled through government agencies specifically for trachoma control programmes made it possible for successful roll-out of the SAFE strategy –20,22,24The attitudes of targeted populations to the different components of the SAFE strategy and their understanding of the underlying mechanisms through which control strategies work affected effective adoption. In some Gambian communities trachoma was not thought to be infectious and trichiasis was taken to be a symptom of other illnesses, which led to lack of skilled use of SAFE interventions . The norIndividuals who were found to be more confident in their skills and understanding of trachoma control measures are more likely to have better health-seeking behaviour and take up good hygiene practices . Poor awImplementation progress of SAFE interventions was tracked by determining an individual’s proficiency in utilising the different interventions. In one case study participants stopped applying ointment for the prevention of active inflammatory infection as soon as they felt that their symptoms had improved, increasing their chances of reinfection .Developing a course of action to guide the implementation of SAFE activities is thought to increase implementation effectiveness. As a tool for helping to identify how the different components of the strategy would be put in place, all the studies identified in this review used epidemiological data on prevalence rates ,15–22,24Choosing the most appropriate individuals to implement and use an intervention was shown to influence how well it would be received. In the Gambia elderly women who are the custodians of community practice and recipients of lid surgery for trichiasis were found to be instrumental in mobilising young mother to take up SAFE interventions . Their pEvaluating implementation efforts allows the involved stakeholders to learn from their experiences while at the same time mapping the progress they have made towards their implementation goals. In Mali and Guinea Bissau community members were found to have incomplete understanding of certain aspects of trachoma and its spread and control even after SAFE had been implemented, pointing towards the possibility that packaging and design of the health messages was not inappropriate ,21. The The SAFE strategy is a multifaceted intervention which combines multiple implementation strategies to address specific stages of trachoma . The hetintervention source, adaptability, cosmopolitanism, readiness for implementation, planning and engaging. These facilitators mainly fell under characteristic of intervention, outer setting and process domains of CFIR, whereas key barriers included structural characteristics, knowledge and belief about the intervention, self-efficacy and implementation climate representing two domains: inner setting and characteristics of the individual. All five domains of CFIR were found to be of importance during implementation. However, of the 39 constructs some were not identified during the review, including relative advantage, cost, culture, individual identification with organisation, networks and communication. Most of these constructs fell within the inner setting and characteristics of individual domains. This could be due to the nature of the  studies included in the review rather than the role  these two domains play in endemic regions. Future research could explore the use of determinant frameworks such as CFIR and the Theoretical Domains Framework to explore implementation of context-specific determinants.The key facilitators of implementation identified included The use of CFIR also made it possible to see the relationship between implementation strategies, the barriers and facilitators identified and their bearing on intervention and implementation outcomes. Implementation strategies used during the implementation of SAFE in the studies varied but they were tailored to the particular settings in which they were being introduced. Policy-driven strategies enhanced the implementation process by encouraging cosmopolitanism and promoting favourable implementation climate thus making the SAFE interventions appropriate to these settings –20,22,24Overall, our study identified salient factors across multiple settings that are necessary for successful implementation of the SAFE strategy such as community engagement and a desire for change. However, there is a need for more literature characterising the SAFE strategy itself, organisational and provider level factors influencing implementation efforts such as leadership engagement, design of the intervention and its quality, peer pressure, external policies, incentives for implementation and the effect of networks and communication.


Beilstein Journal of Organic Chemistry in 2017 [Beilstein Journal of Organic Chemistry is contributing to the dissemination of mechanochemistry in the field of organic chemistry through a new thematic issue Mechanochemistry II.Since the publication of the first thematic issue on mechanochemistry in the Beilstein Journal of Organic Chemistry will find contributions from renowned global experts in the field of mechanochemistry spanning areas from organic mechanochemistry, supramolecular mechanochemistry to polymer mechanochemistry. Moreover, findings reported in this current thematic issue also contribute to the expansion of synthetic chemistry methodology by mechanochemistry. Importantly, such rapid advancement in applied mechanochemistry is supported by investigations focused on better understanding the fundamental aspects governing mechanochemical transformations.In this new collection of works, the readership of the Beilstein Journal of Organic Chemistry could augment the consolidation of mechanochemistry as an alternative to continue with the development of chemical processes in a more efficient manner.Therefore, I hope the joint efforts made by the authors of these contributions , and the José G. HernándezAachen, June 2019