Initial Event Research Articles

Pulmonary hazard identifications of Graphene family nanomaterials: Adverse outcome pathways framework based on toxicity mechanisms.

Graphene-family nanomaterials (GFNs) are revolutionary new nanomaterials that have attracted significant attention in the field of nanomaterials, but the ensuing problems lie in the potential threats to public health and the ecosystem caused by these nanomaterials. From the perspective of GFN-related health risk assessments, this study reviews the current status of GFN-induced pathological lung events with a focus on the damage caused to different biological moieties (molecular, cellular, tissue, and organ) and the mechanistic relationships between different toxic endpoints. These multiple sites of damage were matched with existing adverse outcome pathways (AOPs) in an online knowledge base to obtain available molecular initiation events (MIEs), key events (KEs), and adverse outcomes (AOs). Among them, the MIEs were discussed in combination with the structure-activity relationship due to the correlation between toxicity and physical and chemical properties of GFNs. Based on the collection of information regarding MIEs, Kes, and AOs in addition to upstream and downstream causal extrapolation, the AOP framework for GFN-induced pulmonary toxicity was developed, highlighting the possible mechanisms of GFN-induced lung damage. This review intended to combine AOP with classic toxicological methods with a view to rapidly and accurately establishing a nanotoxicology infrastructure so as to contribute to public health risk assessment strategies through iteration from and animal models up to the population level.

MicroRNA-27a, downregulated in human obesity, exerts an antiapoptotic function in adipocytes.

Adipocyte apoptosis is a key initial event that contributes to macrophage infiltration into adipose tissue (AT) and thus triggers AT inflammation in obesity. MicroRNA-27a (miR-27a) was shown to mediate the pathological processes of many metabolic disorders; however, whether miR-27a is involved in adipocyte apoptosis of obese AT remains unknown. The present study aimed to investigate the alteration of miR-27a in obese individuals and its antiapoptotic function in adipocytes. In vivo, serum samples and omental adipose tissue from humans as well as epididymal fat pads from mice were collected to detect miR-27a expression. In vitro, 3T3-L1 preadipocytes and mature adipocytes were treated with TNF-α to induce apoptosis and transfected with a mimic for overexpressing miR-27a-3p. The results showed that miR-27a was markedly decreased in the serum and AT of obese human patients and in the AT of high-fat diet-fed mice. Regression analyses revealed that the serum level of miR-27a was correlated with metabolic parameters in human obesity. Notably, TNF-α induced cell apoptosis in both preadipocytes and mature adipocytes, as evidenced by the upregulation of cleaved caspase 3 and cleaved caspase 8 and the ratio of Bax to Bcl-2, while these effects were partly diminished by miR-27a overexpression. In addition, TUNEL and Hoechst 33258 staining verified that miR-27a overexpression markedly inhibited the apoptosis of adipocytes under TNF-α stimulation. Thus, miR-27a was downregulated in the AT of obese subjects with proapoptotic status, and overexpression of miR-27a exerted an antiapoptotic effect on preadipocytes, providing a novel potential target for preventing AT dysfunction.

Mechanical force drives the initial mesenchymal-epithelial interaction during skin organoid development.

Rationale: Stem cells self-organize to form organoids that generate mini-organs that resemble the physiologically-developed ones. The mechanism by which the stem cells acquire the initial potential for generating mini-organs remains elusive. Here we used skin organoids as an example to study how mechanical force drives initial epidermal-dermal interaction which potentiates skin organoids to regenerate hair follicles. Methods: Live imaging analysis, single-cell RNA-sequencing analysis, and immunofluorescence were used to analyze the contractile force of dermal cells in skin organoids. Bulk RNA-sequencing analysis, calcium probe detection, and functional perturbations were used to verify that calcium signaling pathways respond to the contractile force of dermal cells. In vitro mechanical loading experiment was used to prove that the stretching force triggers the epidermal Piezo1 expression which negatively regulates dermal cell attachment. Transplantation assay was used to test the regenerative ability of skin organoids. Results: We found that dermal cell-derived contraction force drives the movement of dermal cells surrounding the epidermal aggregates to trigger initial mesenchymal-epithelial interaction (MEI). In response to dermal cell contraction force, the arrangement of the dermal cytoskeleton was negatively regulated by the calcium signaling pathway which further influences dermal-epidermal attachment. The native contraction force generated from the dermal cell movement exerts a stretching force on the adjacent epidermal cells, activating the stretching force sensor Piezo1 in the epidermal basal cells during organoid culture. Epidermal Piezo1 in turn drives strong MEI to negatively regulate dermal cell attachment. Proper initial MEI by mechanical-chemical coupling during organoid culture is required for hair regeneration upon transplantation of the skin organoids into the back of the nude mice. Conclusion: Our study demonstrated that mechanical-chemical cascade drives the initial event of MEI during skin organoid development, which is fundamental to the organoid, developmental, and regenerative biology fields.

Studies of reliability indicators of pumping units of machine irrigation on the example of the “Namangan” pumping station

The article presents the results of a reliability study, where violations of work are determined based on operational data to create a database for determining reliability indicators and the characteristics associated with them. The numbers of accidents, failures and defects of pumping units of the Namangan pumping station over a 5-year period are shown, and the values of the intensity of the occurrence of the event were calculated. By the method of statistical analysis of the safety of technical means at the stage of operation and analysis of the potentially emergency sequence, the most dangerous scenarios of the types are identified, the sequences of danger, causes, consequences and parameters to be monitored are determined, which will be useful for determining reliability, calculating risk and assessing the safety of pumping units and the pumping station itself. Taking into account that the uptime of pumping units of the PS of machine irrigation is distributed exponentially, the values of the probability of initial events are calculated and graphs of changes in the probabilities of initial events of work for 5 years, as well as work for 60 years PU are plotted.

Spatial Stochastic Model of the Pre-B Cell Receptor.

Survival and proliferation of immature B lymphocytes requires expression and tonic signaling of the pre-B cell receptor (pre-BCR). This low level, ligand-independent signaling is likely achieved through frequent, but short-lived, homo interactions. Tonic signaling is also central in the pathology of precursor B acute lymphoblastic leukemia (B-ALL). In order to understand how repeated, transient events can lead to sustained signaling and to assess the impact of receptor accumulation induced by the membrane landscape, we developed a spatial stochastic model of receptor aggregation and downstream signaling events. Our rule- and agent-based model builds on previous mature BCR signaling models and incorporates novel parameters derived from single particle tracking of pre-BCR on surfaces of two different B-ALL cell lines, 697 and Nalm6. Live cell tracking of receptors on the two cell lines revealed characteristic differences in their dimer dissociation rates and diffusion coefficients. We report here that these differences affect pre-BCR aggregation and consequent signal initiation events. Receptors on Nalm6 cells, which have a lower off-rate and lower diffusion coefficient, more frequently form higher order oligomers than pre-BCR on 697 cells, resulting in higher levels of downstream phosphorylation in the Nalm6 cell line.

What’s in a Nose? A Case Report on Chronic Unilateral Rhinorrhea

Introduction and Importance: Nasal foreign bodies often present acutely following insertion but may be missed by both family and health care providers, remaining in place for weeks, months, or even years after the initial event. Case Presentation: We present the case of a 16-year-old female who presented in-office complaining of intermittent unilateral foul-smelling rhinorrhea. The diagnosis was confirmed by intranasal examination with a speculum, as well as a computed tomography scan. She underwent surgery, removing an eraser top for a pencil with subsequent resolution of symptoms. Discussion: The diagnosis is based on the clinical history, physical examination and is supported by CT and exploratory surgery, this last one being also therapeutic. Conclusion: This case of chronic unilateral rhinorrhea due to a foreign body reinforces the importance of clinical examination as well as full evaluation of the differential diagnosis of both acute and chronic rhinorrhea particularly in small and older children.

Criteria of thermochemical conditions of steam gas explosions in dynamic accident modes at nuclear power units with WWER reactors

The main lessons of the major accident at the Fukushima-Daiichi NPP in 2011 for the nuclear power industry identify the need to model, analyze and develop emergency measures for relatively unlikely events with catastrophic environmental consequences, taking into account multiple failures of safety systems. Steam-gas explosions became one of the main causes of the catastrophic environmental consequences of the Chernobyl and Fukushima accidents. Criteria and conditions for the occurrence of steam-gas explosions in dynamic emergency modes in the "tight" reactor circuit of nuclear power reactor units (NPP) with water-water reactors (WWER) with failures of safety systems valves and emergency steam gas removal are determined by the rate of change of thermodynamic and physico-chemical parameters. A method for determining the criteria and conditions for the occurrence of steam-gas explosions in dynamic accident modes with a "tight" reactor circuit and failure of safety valves for modeling the initial emergency events – seismic effects, falling of massive objects, etc. is presented. The conditions for the occurrence of hydrogen explosions are determined by the maximum rate of increase in the temperature of fuel oil shells, and the conditions for steam explosions are determined by the maximum rate of pressure increase as a result of the intensification of vaporization processes. The criteria for the occurrence of steam explosions in dynamic emergency modes are determined by the maximum pressure amplitude and the propagation speed of acoustic disturbances in the steam volume. And the criteria for hydrogen detonation in dynamic emergency modes are determined by the maximum amplitude of the increase in the temperature of the fuel shells and the average flow rate of the coolant in the active zone of the reactor.

Construction of the Software and Technical Complex of Control Basic Parameters of Reactor Installation

The main problem associated with the operation of nuclear power plants is the problem of correct and timely diagnosis of failure or violation. The mistakes of technologists can lead to severe damage to nuclear power plants, or simply to a reduction in the utilization rate of installed capacity. The personnel make the main mistakes in the conditions of time shortage and being in a stressful situation during the development of an accident, when assessing changes in emergency parameters is not always possible, which leads to incorrect diagnosis of initial events (IE). Any IE leads to the deviation of the monitored parameters from normal values (values that are inherent to normal operation). The operator-technologist needs as soon as possible to determine the parameter (or parameters) for which the change occurs and, by performing a certain sequence of actions, bring their values to the norm. For information support of the operator-technologist is the information computing system (ICS). In the ICS, it is possible to control all parameters affecting the safe operation of the equipment, for each of which there are certain values, the deviation from which may lead to an accident. The paper considers the issues of the need to separate the measured parameters of NPP into separate groups that uniquely characterize the state of the critical security features. In particular, the necessity of consideration as the most important mass parameter of the primary coolant is shown. The issues of level measurement problems in the pressure compensator are discussed as the most important from the point of view of determining the mass of the primary coolant. Methods are proposed for determining the operability of sensors, the method of calculating a reliable level in the volume compensator. Estimates of the computational efficiency of the proposed methods are given.

Management of aseptic non-union of shaft femur using intramedullary nailing combined with bone grafting: a case report

<p>Despite the advances in trauma care, improved surgical techniques, latest implants and therefore the evolution of new adjuvants to healing, biologic agents, non-union still persists thanks to high energy trauma as initial event. Non-union of femur shaft represents a significant socioeconomic problem to the patient, related to prolonged patient morbidity, inability to return to figure, gait abnormality, re-operations and psycho-emotional impairment. Here we discuss the case of such non-union of fracture shaft femur presented to us with shortening of 3.5 cm managed with bone graft and intramedullary nailing. 22-year-old male patient had a history of trauma due to fall from bike due to dash from behind by tractor (high velocity road traffic accident) sustaining injury over right thigh leading to closed fracture mid-shaft femur of the same side treated immediately by femur nailing. After 6 months post-surgery, he noticed swelling over operated thigh which was increasing and causing difficulty in walking. X-rays revealed broken nail, re-operated at the same centre with dynamic compression plating (DCP) probably after freshening the fracture edges using 12-hole DCP, implant failure with whole plate and screw construct extrusion and re-fracture at the same site. This time patient presented to our institute. We planned of implant removal and intramedullary nailing with bone grafting. Management of aseptic femoral non-union with fracture gap of 2.5-4 cm range with intramedullary nailing combined with autologous fibular cortical and cancellous grafts showed good functional results at the end of 1 year post operative interval after prior repetitive failure of implants due to non-union. </p>

Berberine hydrochloride inhibits migration ability via increasing inducible NO synthase and peroxynitrite in HTR-8/SVneo cells

Ethnopharmacological relevanceInadequate trophoblasts migration and invasion is considered as an initial event resulting in preeclampsia, which is closely related to oxidative stress. Berberine hydrochloride (BBR), extracted from the traditional medicinal plant Coptis chinensis Franch., exerts a diversity of pharmacological effects, and the crude drug has been widely taken by most Chinese women to treat nausea and vomit during pregnancy. But there is no research regarding its effects on trophoblast cell function. Aim of the studyThis study aimed to investigate the effect of BBR on human-trophoblast-derived cell line (HTR-8/SVneo) migration ability and its mechanism. Materials and methodsCell viability was detected by CCK-8 assay. The effect of BBR on cells migration function was examined by scratch wound healing assay and transwell migration assay. Intracellular nitric oxide (NO), superoxide (O2−) and peroxynitrite (ONOO−) levels were measured by flow cytometry. The expression levels of inducible NO synthase (iNOS), eNOS, p-eNOS, MnSOD, CuZnSOD, Rac1, NOX1, TLR4, nuclear factor-κB (NF-κB), p-NFκB, pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) in cells were analyzed by Western blotting. Uric acid sodium salt (UA), the scavenger of ONOO−, PEG-SOD (a specific superoxide scavenger), L-NAME (a NOS inhibitor) and antioxidants (Vit E and DFO) were further used to characterize the pathway of BBR action. Results5 μM BBR decreased both the migration distance and the number of migrated cells without affecting cells viability in HTR-8/SVneo cells after 24 h treatment. BBR could increase the level of NO in HTR-8/SVneo cells, and the over-production of NO might be attributable to iNOS, but not eNOS. BBR could increase intracellular O2− levels, and the over-production of O2− is closely related with Rac1 in HTR-8/SVneo cells. The excessive production of NO and O2− further react to form ONOO−, and the increased ONOO− level induced by BBR was blunted by UA. Moreover, UA improved the impaired migration function caused by BBR in HTR-8/SVneo cells. The depressed migration function stimulated by BBR in HTR-8/SVneo cells was diminished by PEG-SOD and L-NAME. Furthermore, BBR increased the expression of IL-6 in HTR-8/SVneo cells, and antioxidants (Vit E and DFO) could decrease the expression of IL-6 and iNOS induced by BBR. ConclusionsBBR inhibits the cell migration ability through increasing inducible NO synthase and peroxynitrite in HTR-8/SVneo cells, indicating that BBR and traditional Chinese medicines containing a high proportion of BBR should be used with caution in pregnant women.

Eukaryotic translation initiation factor eIF4G2 opens novel paths for protein synthesis in development, apoptosis and cell differentiation.

Protein translation is a critical regulatory event involved in nearly all physiological and pathological processes. Eukaryotic translation initiation factors are dedicated to translation initiation, the most highly regulated stage of protein synthesis. Eukaryotic translation initiation factor 4G2 (eIF4G2, also called p97, NAT1 and DAP5), an eIF4G family member that lacks the binding sites for 5' cap binding protein eIF4E, is widely considered to be a key factor for internal ribosome entry sites (IRESs)-mediated cap-independent translation. However, recent findings demonstrate that eIF4G2 also supports many other translation initiation pathways. In this review, we summarize the role of eIF4G2 in a variety of cap-independent and -dependent translation initiation events. Additionally, we also update recent findings regarding the role of eIF4G2 in apoptosis, cell survival, cell differentiation and embryonic development. These studies reveal an emerging new picture of how eIF4G2 utilizes diverse translational mechanisms to regulate gene expression.

Critical features of an in vitro intestinal absorption model to study the first key aspects underlying food allergen sensitization.

New types of protein sources will enter our diet in a near future, reinforcing the need for a straightforward in vitro (cell-based) screening model to test and predict the safety of these novel proteins, in particular their potential risk for de novo allergic sensitization. The Adverse Outcome Pathway (AOP) for allergen sensitization describes the current knowledge of key events underlying the complex cellular interactions that proceed allergic food sensitization. Currently, there is no consensus on the in vitro model to study the intestinal translocation of proteins as well as the epithelial activation, which comprise the first molecular initiation events (ME1-3) and the first key event of the AOP, respectively. As members of INFOGEST, we have highlighted several critical features that should be considered for any proposed in vitro model to study epithelial protein transport in the context of allergic sensitization. In addition, we defined which intestinal cell types are indispensable in a consensus model of the first steps of the AOP, and which cell types are optional or desired when there is the possibility to create a more complex cell model. A model of these first key aspects of the AOP can be used to study the gut epithelial translocation behavior of known hypo- and hyperallergens, juxtaposed to the transport behavior of novel proteins as a first screen for risk management of dietary proteins. Indeed, this disquisition forms a basis for the development of a future consensus model of the allergic sensitization cascade, comprising also the other key events (KE2-5).

Megalin Orchestrates FcRn Endocytosis and Trafficking.

The neonatal Fc receptor (FcRn) is highly expressed in the renal proximal tubule and is important for the reclamation of albumin by cellular transcytosis to prevent its loss in the urine. The initial event of this transcellular transport mechanism is the endocytosis of albumin by the apical scavenger receptors megalin and cubilin. An interaction of megalin and FcRn was postulated, however, evidence is still missing. Similarly, the intracellular trafficking of FcRn remains unknown and shall be identified in our study. Using a Venus-based bimolecular fluorescence complementation system, we detected an interaction between megalin and FcRn in the endosomal compartment, which significantly increased with the induction of endocytosis using albumin or lactoglobulin as a ligand. The interaction between megalin and FcRn occurred at a neutral and acidic pH between the extracellular domains of both proteins. Amnionless, another transmembrane acceptor of cubilin, revealed no interaction with FcRn. With the induction of endocytosis by albumin or lactoglobulin, super resolution microscopy demonstrated a redistribution of megalin and FcRn into clathrin vesicles and early endosomes. This trafficking into clathrin vesicles was impaired in megalin-deficient cells upon albumin-induced endocytosis, supporting the role of megalin in FcRn redistribution. Our results indicate that megalin and FcRn specifically bind and interact within their extracellular domains. The availability of megalin is necessary for the redistribution of FcRn. Megalin, therefore, orchestrates FcRn endocytosis and intracellular trafficking as an early event intranscytosis.

Uterine Smooth Muscle Tumor of Uncertain Malignant Potential – An Unusual Case Report

The term smooth uterine muscle of uncertain malignant potential (STUMP) indicates a group of uterine smooth muscle tumors (SMTs) that cannot be diagnosed unequivocally as benign or malignant. Diagnosis, surgical management, and follow-up of this neoplasm remain controversial, especially in pre-menopausal women with fertility desire, due to the non aggressive behaviour and prolonged survival rate when compared to leiomyosarcomas. Studies of STUMP are limited in population and rarity results in few analysis of its fertility outcomes and oncologic prognosis. STUMP has a lower tumor growth rate and recurrence is often delayed by years after initial event compared to high grade leiomyosarcomas which have an aggressive clinical course and behavior thus making it very important to differentiate stump from leiomyosarcomas .Recurrencerate ranges from 8.7% to 11%.

Ursolic Acid Impairs Cellular Lipid Homeostasis and Lysosomal Membrane Integrity in Breast Carcinoma Cells.

Cancer is one of the leading causes of death worldwide, thus the search for new cancer therapies is of utmost importance. Ursolic acid is a naturally occurring pentacyclic triterpene with a wide range of pharmacological activities including anti-inflammatory and anti-neoplastic effects. The latter has been assigned to its ability to promote apoptosis and inhibit cancer cell proliferation by poorly defined mechanisms. In this report, we identify lysosomes as the essential targets of the anti-cancer activity of ursolic acid. The treatment of MCF7 breast cancer cells with ursolic acid elevates lysosomal pH, alters the cellular lipid profile, and causes lysosomal membrane permeabilization and leakage of lysosomal enzymes into the cytosol. Lysosomal membrane permeabilization precedes the essential hallmarks of apoptosis placing it as an initial event in the cascade of effects induced by ursolic acid. The disruption of the lysosomal function impairs the autophagic pathway and likely partakes in the mechanism by which ursolic acid kills cancer cells. Furthermore, we find that combining treatment with ursolic acid and cationic amphiphilic drugs can significantly enhance the degree of lysosomal membrane permeabilization and cell death in breast cancer cells.

1165: RISK FACTOR AND OUTCOMES FOR RECURRENT PEDIATRIC IN-HOSPITAL CARDIAC ARREST

Introduction: Recurrent in-hospital cardiac arrest (IHCA) is associated with increased morbidity and mortality in adult and pediatric patients. Event and patient-specific factors are associated with the risk for recurrent IHCA. We aimed to describe the risk factors and outcomes of recurrent IHCA in a large pediatric cohort. We hypothesized that patients who suffered recurrent IHCA would have worse survival outcomes. Methods: Retrospective cohort study of patients ≤18 years from the American Heart Association’s Get With The Guidelines®-Resuscitation Registry with single or recurrent IHCA who achieved ROSC and were not placed on ECMO with their initial IHCA. Recurrent IHCA was defined as ≥ 2 IHCAs within the same hospitalization. Categorical variables were expressed as percentages and compared via Chi square test. Continuous variables were expressed as medians with interquartile ranges and compared via rank sum test. Outcomes were assessed in a match cohort based on age, disease category, duration of first arrest, and acuity. Acuity was defined as low if no invasive airway or arterial line was present, defined as medium if one was present, and defined as high if both were present at the time of the IHCA. Results: From January 2010 to January 2022, 2225/10019 (22.2%) pediatric patients experienced a recurrent IHCA. Recurrent IHCA patients compared to single IHCA were more likely to be medical cardiac (21.3% vs. 19%; p=0.01) or trauma patients (7.5% vs. 5.3%; P< 0.001) and have higher acuity (27.8% vs. 22.7%; p< 0.001). Recurrent IHCAs were more likely to occur in the PICU (44.2% vs. 39.6%; p< 0.001) or CICU (11.5% vs. 9.5%; p=0.006) versus other inpatient locations and there was no difference in the duration of arrest. After matching, pediatric patients with a recurrent IHCA had worse survival to hospital discharge (44.1% vs 61.5%; p< 0.001). Conclusions: Higher acuity and ICU location during the initial IHCA event was associated with increased risk for recurrent IHCA in pediatric patients. Additionally, recurrent IHCA is associated with worse survival outcomes in the total cohort and following exact matching.

Positive feedback loop of miR-320 and CD36 regulates the hyperglycemic memory-induced diabetic diastolic cardiac dysfunction

Intensive glycemic control is insufficient for reducing the risk of heart failure among patients with diabetes mellitus (DM). While the "hyperglycemic memory" phenomenon is well documented, little is known about its underlying mechanisms. In this study, a type 1 DM model was established in C57BL/6 mice using streptozotocin (STZ). Leptin receptor-deficient (db/db) mice were used as a model of type 2 DM. A type 9 adeno-associated virus was used to overexpress or knock down miR-320 invivo. Diastolic dysfunction was observed in the type 1 DM mice with elevated miR-320 expression. However, glycemic control using insulin failed to reverse diastolic dysfunction. miR-320 knockdown protected against STZ-induced diastolic dysfunction. Similar results were observed in the type 2 DM mice. Invitro, we found that miR-320 promoted CD36 expression, which in turn induced further miR-320 expression. CD36 was rapidly induced by hyperglycemia at protein level compared with the much slower induction of miR-320, suggesting a positive feedback loop of CD36/miR-320 with CD36 protein induction as the initial triggering event. In conclusion, in DM-induced cardiac injury, miR-320 and CD36 mutually enhance each other's expression, leading to a positive feedback loop and a sustained hyperlipidemic state in the heart.

Mitotic progression and dual spindle formation caused by spindle association of de novo-formed microtubule-organizing centers in parthenogenetic embryos of Drosophila ananassae.

Facultative parthenogenesis occurs in many animal species that typically undergo sexual reproduction. In Drosophila, such development from unfertilized eggs involves diploidization after completion of meiosis, but the exact mechanism remains unclear. Here we used a laboratory stock of Drosophila ananassae that has been maintained parthenogenetically to cytologically examine the initial events of parthenogenesis. Specifically, we determined whether the requirements for centrosomes and diploidization that are essential for developmental success can be overcome. As a primal deviation from sexually reproducing (i.e. sexual) strains of the same species, free asters emerged from the de novo formation of centrosome-like structures in the cytosol of unfertilized eggs. Those microtubule-organizing centers had distinct roles in the earliest cycles of parthenogenetic embryos with respect to mitotic progression and arrangement of mitotic spindles. In the first cycle, an anastral bipolar spindle self-assembled around a haploid set of replicated chromosomes. Participation of at least one microtubule-organizing center in the spindle was necessary for mitotic progression into anaphase. In particular, the first mitosis involving a monastral bipolar spindle resulted in haploid daughter nuclei, one of which was associated with a microtubule-organizing center whereas the other was not. Remarkably, in the following cycle, biastral and anastral bipolar spindles formed that were frequently arranged in tandem by sharing an aster with bidirectional connections at their central poles. We propose that, for diploidization of haploid nuclei, unfertilized parthenogenetic embryos utilize dual spindles during the second mitosis, as occurs for the first mitosis in normal fertilized eggs.

DeepTSS: multi-branch convolutional neural network for transcription start site identification from CAGE data

BackgroundThe widespread usage of Cap Analysis of Gene Expression (CAGE) has led to numerous breakthroughs in understanding the transcription mechanisms. Recent evidence in the literature, however, suggests that CAGE suffers from transcriptional and technical noise. Regardless of the sample quality, there is a significant number of CAGE peaks that are not associated with transcription initiation events. This type of signal is typically attributed to technical noise and more frequently to random five-prime capping or transcription bioproducts. Thus, the need for computational methods emerges, that can accurately increase the signal-to-noise ratio in CAGE data, resulting in error-free transcription start site (TSS) annotation and quantification of regulatory region usage. In this study, we present DeepTSS, a novel computational method for processing CAGE samples, that combines genomic signal processing (GSP), structural DNA features, evolutionary conservation evidence and raw DNA sequence with Deep Learning (DL) to provide single-nucleotide TSS predictions with unprecedented levels of performance.ResultsTo evaluate DeepTSS, we utilized experimental data, protein-coding gene annotations and computationally-derived genome segmentations by chromatin states. DeepTSS was found to outperform existing algorithms on all benchmarks, achieving 98% precision and 96% sensitivity (accuracy 95.4%) on the protein-coding gene strategy, with 96.66% of its positive predictions overlapping active chromatin, 98.27% and 92.04% co-localized with at least one transcription factor and H3K4me3 peak.ConclusionsCAGE is a key protocol in deciphering the language of transcription, however, as every experimental protocol, it suffers from biological and technical noise that can severely affect downstream analyses. DeepTSS is a novel DL-based method for effectively removing noisy CAGE signal. In contrast to existing software, DeepTSS does not require feature selection since the embedded convolutional layers can readily identify patterns and only utilize the important ones for the classification task.This study highlights the key role that DL can play in Molecular Biology, by removing the inherent flaws of experimental protocols, that form the backbone of contemporary research. Here, we show how DeepTSS can unleash the full potential of an already popular and mature method such as CAGE, and push the boundaries of coding and non-coding gene expression regulator research even further.

Holocene initiation and expansion of the southern margins of northern peatlands triggered by the East Asian summer monsoon recession

Northern peatlands represent one of the largest biospheric carbon reservoirs in the world. Their southern margins act as new carbon reservoirs, which can greatly influence the global carbon dynamics. However, the Holocene initiation, expansion and climate sensitivity of these peatlands remain intensely debated. Here we used a compilation of basal peat ages across six isolated peatlands at the southern margins of northern peatlands to address these issues. We found that the earliest initiation event of these peatlands occurred after the Younger Dryas (YD, 12,800–11,700 years ago) period. The second initiation event and rapid expansion occurred since 5 ka cal. BP. The recession of East Asian summer monsoon (EASM) during the YD period and at around 5 ka cal. BP likely played a major role in controlling the initiation and expansion of these peatlands. The rapid expansion of these peatlands possibly contributed to the significant increases in atmospheric methane concentrations during the late Holocene because of the minerotrophic fens status and rapid expansion of them. These ecological processes are different from northern peatlands, indicating the special carbon sink and source implications of these peatlands in the global carbon cycle.