Autism spectrum disorder (ASD) is a genetic heterogeneous neurodevelopmental disorder that is characterized by impairments in social interaction and speech development and is accompanied by stereotypical behaviors such as body rocking, hand flapping, spinning objects, sniffing and restricted behaviors. The considerable significance of the genetics associated with autism has led to the identification of many risk genes for ASD used for the probing of ASD specificity and shared cognitive features over the past few decades. Identification of ASD risk genes helps to unravel various genetic variants and signaling pathways which are involved in ASD. This review highlights the role of ASD risk genes in gene transcription and translation regulation processes, as well as neuronal activity modulation, synaptic plasticity, disrupted key biological signaling pathways, and the novel candidate genes that play a significant role in the pathophysiology of ASD. The current emphasis on autism spectrum disorders has generated new opportunities in the field of neuroscience, and further advancements in the identification of different biomarkers, risk genes, and genetic pathways can help in the early diagnosis and development of new clinical and pharmacological treatments for ASD. Autism spectrum disorder (ASD) is a complex neurological disorder that affects an individual’s development by impairing social interaction and communication and causes stereotypical behaviors that disrupt the anatomy and functional connectivity in the brain. Most common psychiatric comorbidities found to be associated with autism include anxiety and intellectual disability. Individuals with autism have impaired speech , 2 and tMany genes associated with ASD are found in circadian entrainment, which indicates a heterogeneous genetic etiology for ASD . Some raThree independent genome-wide association studies (GWAS) have reported genetic variants commonly associated with autism. Out of these 3 studies, 2 have used 0.5 million single nucleotide polymorphisms (SNPs) and have discovered that they are linked at 5p14.1  and 5p15de novo and inherited events found in pathogenic CNVs involved genes associated with autism, such as CHD2 . A. A105]. de novo microdeletion of SEMA5A in ASD and ID patients [Many GWASs have been performed in ASD , 109–111patients . There wpatients . Replicapatients , 114.Wnt-signaling plays an important role in the differentiation and morphology of neurons, and neurotransmission . This paThe DISC1 gene is associated with Wnt signaling and ASD and is involved in the inhibition of GSK3β that leads to the activation of β-catenin; thus, it acts as a positive regulator of the Wnt/β-catenin signaling . MutatioCanonical Wnt signaling or Wnt/β-catenin signaling plays an important role in the development of synapsis in the pre- and post-synaptic terminals. The release of neurotransmitters at the presynaptic terminal is triggered by the binding of Wnt ligand to a receptor that activates Dishevelled-1 (DVL1). This binds to the pre-synaptic proteins, such as Synapsin-1 (SYN1) and Synaptotagmin (SYT), that are associated with ASD and enhance the clustering of synaptic vesicles (SV’s) and release of neurotransmitters. On the other hand, cell adhesion proteins, such as cadherins and cell adhesion complexes (NLGN/NRXN), play an important role in the modulation of presynaptic terminal activity. Their interaction regulates both excitatory and inhibitory synaptic function, disrupting the E/I balance in the postsynaptic neurons. β-catenin is bound to cadherins and their interaction is essential for the recruitment of SVs to synapses. MET, a receptor for hepatocyte growth factor (HGF), is found to have a genetic link with ASD. MET phosphorylates Tyr-142 of β-catenin and promotes its dissociation from the cadherins leading to its release in the postsynaptic terminal  Figure . Wnt/β-c2+ signaling. Wnt ligands are found to increase the influx of Ca2+ in neurons, and voltage gated Ca2+ sensitive channels, like NMDAR, allows the entrance of Ca2+ in the postsynaptic membrane that allows long term synaptic potentiation (LTP) establishment. Both high and low responses of LTP are associated with ASD. Ca2+ causes the activation of CAMKII, which is involved in the reorganization of cytoskeleton, calcineurin (CaN), a calcium dependent protein phosphatase and protein kinase C (PKC). The activation of CAMKII leads to the activation of transcription factor CREB, causing its translocation to the nucleus, which leads to gene transcription [Activation of the Wnt/β-catenin signaling causes Wnt ligands to bind to the Frizzled-9 (FZD9) receptor that recruits the multi-protein destruction complex consisting of scaffolding proteins (APC and Axin), phosphatases (PP1 and PP2A), and kinases (GSK3β and CK1). This activation inhibits GSK3β and prevents the degradation of β-catenin, thus stabilizing it and translocating it to the nucleus, leading to gene transcription  Figure . Converscription .mTOR, a highly conserved serine/threonine kinase, is important in the regulation of cell growth, cell metabolism and cell survival processes . The catNeurotrophins play an important role in the nervous system and are involved in the regulation of neuronal development, survival, morphogenesis, differentiation and synaptic plasticity , 149. ThERK1/2 are members of the MAPK signaling cascade and play important role in the regulation of cell growth, proliferation, differentiation and apoptosis . MAPK/ERde novo mutation of Glu183 to Val (E183V) in the catalytic domain of CAMKIIα increased dendritic branching and decreased synaptic transmission with reduced dendritic spine density causing ASD-related behaviors in mice [There are many ASD genes that have been associated with different signaling pathways and that contribute to different ASD phenotypes . One suc in mice .Another signaling pathway known as Sonic hedgehog (SHH) plays a major role in the developmental processes of multicellular embryos . It is aRetinoic acid (RA), derived from vitamin A (retinol), is a lipophilic molecule that is essential for vertebrate development and acts as a ligand for retinoic acid receptors (RARs) and retinoid X receptors (RXRs) . VitaminAnother signaling that is found to be associated with ASD is the fibroblast growth factor (FGF) signaling . FGF belThe TGF-β superfamily consists of TGF-β/activin and the bone morphogenetic protein (BMP)/growth that plays an important role in bone organogenesis . BMPs arA common pathophysiological mechanism that is disrupted in ASD is the imbalance in excitatory and inhibitory neurotransmission. The excitatory mechanism is mediated by glutamate, while the inhibitory mechanism is mediated by GABA , 191. StClinical diagnosis of ASD is primarily based on the analysis of complex behavioral and functional changes in patients during their developmental process. Genetic tests such as comparative genomic hybridization and chromosomal microarray (CMA), and G-band karyotyping can be used for the early diagnosis of ASD. CMA has been shown to have higher clinical yield and higher resolution as compared to the G-band karyotyping , 196. KaImprovement of emotional, physical and behavioral symptoms are one of the main aspects in the pharmacological treatment of ASD . To treaA wide range of antiepileptic drugs (AEDs) are used for effective treatment of ASD. AEDs are psychotropic drugs that modulate electrochemical activity in the brain and can induce a positive or negative affect on mood and behavior . One of Although there are no pharmacological treatments that are able to treat the core symptoms of ASD but there are psychotropic drugs that have similar effect as AEDs in alleviating the common symptoms of ASD such as irritability, hyperactivity, lack of focus, mood dysregulation, and social withdrawal .Oxytocin is another pharmacological agent currently being used to treat core ASD symptoms . ControlFurther studies are required to relate the pharmacological treatment with the genomic changes in ASD for better treatment planning. We expect that in few years there will be enough genomic data that can be used for the pharmacological analysis of patients with ASD.The genetic architecture of ASD is heterogeneous and differs in every individual. The current identification of ASD is mostly based on observation of behaviors and the genetics that underlie ASD are still an active area of research. Nevertheless, advancements in the study of various molecular mechanisms encompassing the genetics of autism and the identification of many ASD risk genes have opened a new way to study the pathophysiology of ASD. We envisage that the identification of new biomarkers, risk genes and associated genetic pathways may help in the early diagnosis of ASD, and improvement in clinical and pharmacological treatments of the disorder.


P<0.01). The parameters the average number of upper respiratory tract infections each year , adenoid hypertrophy , tonsil hypertrophy , nasal stenosis  and chronic sinusitis  were independent factors of pediatric OSAHS (P<0.01). The distribution of chronic sinusitis, nasal stenosis, craniofacial features and obesity indicated a gradual increasing trend in the severity of OSAHS (P<0.01). Number of upper respiratory tract infections per year, adenoid hypertrophy, tonsil hypertrophy, chronic sinusitis, nasal stenosis, infections, allergic reactions, craniofacial features and obesity may be potential risk factors of pediatric OSAHS.Pediatric obstructive sleep apnea-hypopnea syndrome is caused by multiple factors. The present study aimed to investigate the potential risks of pediatric obstructive sleep apnea hypopnea syndrome (OSAHS) and their correlation with the disease severity. A total of 338 pediatric patients with OSAHS (polysomnography (PSG) diagnosis) were enrolled between June 2008 and October 2010. These pediatric patients were divided into mild, moderate and severe subgroups according to the obstructive apnea index (OAI) and/or apnea hypoventilation index (AHI). A total of 338 pediatric patients with vocal nodules who were without obstruction of the upper respiratory tract were enrolled as the control group. The patients were analyzed retrospectively. The average number of upper respiratory tract infections each year and tonsil hypertrophy, adenoid hypertrophy, positive serum tIgE, chronic sinusitis, nasal stenosis, craniofacial features and obesity were significantly higher in OSAHS compared with controls ( Pediatric obstructive sleep apnea-hypopnea syndrome (OSAHS) is a breathing disorder characterized by recurrent complete and/or partial upper airway obstruction during sleep; it interrupts normal ventilation in sleep resulting in intermittent hypoxia and hypercapnia, frequent arousals, and sleep fragmentation . It may The majority of the studies have concluded that the main causes of pediatric OSAHS are adenoid hypertrophy and tonsil hypertrophy and that adenotonsillectomy is the main treatment , 4–7 witNevertheless, several different risk factors have been reported for the development of pediatric OSAHS. Redline et al. reported that the incidence rate of OSAHS in African-American children is higher than that noted in other ethnic groups . Thus, iBased on the diagnostic criteria of the “diagnosis and treatment guidelines of pediatric obstructive sleep apnea hypopnea syndrome (Urumqi)” in 2007 , the preDuring the same period, 338 pediatric patients (age and gender matched with those in the case group) with vocal nodules who had complete clinical data were enrolled as the control group. The main symptom of the pediatric patients in the control group was hoarseness, although they had no symptoms of upper airway obstruction such as nasal congestion, mouth breathing and snore. Moreover, the selection criteria for the control group included negative PSG results. The present study was approved by the Ethics Committee of the Fuzhou Children’s Hospital of Fujian province. The study was approved by the institutional review board of the Fuzhou Children’s Hospital of Fujian province (number: 2010–001). The data were anonymous, and the requirement for informed consent was therefore waived.Sleep monitoring was conducted for all the enrolled pediatric patients in the case group. Mouth and nasal airflow, thoracoabdominal breathing movements, blood oxygen saturation, snoring index, EEG, EOG, mandibular electromyography and positions were monitored for at least 8 h of night sleep. According to the diagnostic criteria , the timThe pharynxes of the pediatric patients in the case and the control groups were examined by the method of mouth opening and tongue pressing. The tonsil size was divided into grades I to IV , 21. Grain vitro using the HITACHI MAST CLA multi-allergen detection system (MAST (CLA-1 type), HITACHI, Japan) for all pediatric patients in the case and the control groups. This is a cost effective, compact, and flexible system that measures a patient’s response to several allergens simultaneously with a single serum sample. It is therefore less invasive for the patient, which is of value in children. The results of the tIgE test were classified into six grades based on the diagnostic criteria recommended by the instructions of the detection system . Statistical analysis was carried out by the Chi-square and/or the rank sum tests. Moreover, univariable and multivariable logistic regression analyses were conducted. The parameters that were significantly different as determined by univariable analyses were included in the multivariable logistic regression analysis. The process of parameter inclusion was set to forward . Correlation analysis was conducted by Pearson and/or Spearman correlation analysis. SPSS 17.0 software package was used . A P value of lower than 0.05 (P<0.05) was considered statistically significant.The data were encoded and the authors that performed the statistical analysis were therefore also blind to grouping. The normal distribution of the continuous data was tested by the Kolmogorov-Smirnov test. Continuous data that followed normal distribution were represented by means ± SD, whereas in any other case the median (range) was used. The continuous data between the two groups that followed normal distribution were represented by the student P<0.001). The aforementioned parameters were potential risk factors for the development of pediatric OSAHS, but the incidence of rhinitis was not statistically significant between the two groups (P = 0.132)  .P<0.001), whereas the incidence of nasal stenosis was 8.023 times higher than that noted in the absence of nasal stenosis . The incidence of tonsil hypertrophy was 9.138 times higher than that noted in the absence of tonsil hypertrophy , while the incidence of adenoid hypertrophy was 8.632 times higher than that noted in the absence of adenoid hypertrophy . With an increase in the number of upper respiratory tract infection, OR was increased by 1.395 times . . .P for trend <0.01), suggesting that the larger the adenoids and tonsils, the more prone were the subjects to the development of pediatric OSAHS  compared with grade IV adenoids. In contrast to grade IV adenoids, the OR value for grade II and grade I adenoids was 0.006 (95% CI: 0.003–0.012) and 0.015 (95% CI: 0.007–0.033), respectively. The OR value of pediatric OSAHS with grade III tonsils was 0.182 (95% CI: 0.081–0.409) compared with grade IV tonsils. In contrast to grade IV tonsils, the OR values for grade II and grade I tonsils were 0.053 (95% CI: 0.025–0.115) and 0.008 (95% CI: 0.003–0.018), respectively. The chi-square test revealed that the grading of adenoids and tonsils in the case group gradually increased (ic OSAHS .P<0.01), suggesting that the larger the adenoids and tonsils, the more severe the development of the pediatric OSAHS , moderate disease (n = 92) and severe disease (n = 70) according to the diagnostic criteria of the “diagnosis and treatment guidelines of pediatric obstructive sleep apnea hypopnea syndrome (Urumqi)” in 2007. The results of the rank correlation analysis demonstrated that adenoid hypertrophy and tonsil hypertrophy in the mild, medium and severe subgroups gradually increased , while there was no statistical significance noted with regard to the parameter positive serum total IgE (P = 0.372)  .P <0.05), nasal stenosis , craniofacial features  and obesity  gradually increased compared with the increase of the severity of OSAHS.A linear trend analysis was conducted for chronic sinusitis, nasal stenosis, craniofacial features and obesity, and the results indicated that the distribution of chronic sinusitis , although the parameters of the PSG of the obesity group were significantly elevated compared with those noted in the non-obesity group (P<0.001) (The pediatric patients in the case group were divided into the obesity and non-obesity groups based on whether the pediatric patients were obese. Fisher’s exact test demonstrated that the grading of adenoid and tonsil sizes was not significantly different between the obesity and non-obesity groups (P<0.001) .The findings of the present study suggest that OSAHS can occur at any age in childhood, although the incidence at each age group gradually increased starting from 3 years of age and peaking at 6 years; the incidence gradually decreased after 6 years of age. In addition to the bloom period of pediatric lymphoid tissue hyperplasia, the peak period of upper respiratory tract infection was estimated at the age group of 3 to 6 years. The study of Altken et al. demonstrated that this parameter was susceptible to cold during childhood with an average incidence number of 6 to 8 times/year . In the Although a large number of studies have demonstrated that adenoid and tonsil hypertrophies are considered the main risk factors of pediatric OSAHS , 32, theThe determination of the tonsil size should be conducted with caution. Grade I to II tonsils in the case group were detected by the method of mouth opening and tongue pressing. The data indicated that the embedded type of tonsils accounted for 37.1%. A false impression of small tonsils would easily occur upon examination, using the method of mouth opening and tongue pressing. Wong et al. analyzed in 2002 the relationship between the TP value  and AHI based on the lateral radiography of the nasopharynx. The study concluded that AHI positively correlated with the TP value , suggestPediatric OSAHS is traditionally attributed to adenoid and tonsil hypertrophies, thus nasal lesions are often dismissed. In 2014, Sin et al. demonstrated that nasal resistance of pediatric patients with OSAHS increased significantly and that it was positively correlated with AHI by comparing the nasal resistance between pediatric patients with OSAHS and normal children . In the Since the anterior nares of children  are small and the nasal cavity is narrow, the conditions of the nasal cavity are difficult to be clearly displayed by anterior rhinoscopy, which is prone to misdiagnosis. In addition the presence of nasal diseases may be dismissed. Therefore, the diagnosis of pediatric nasal diseases that depends solely on anterior rhinoscopy is not sufficient. Video laryngoscopy and paranasal sinus CT are considered significant methods used for the diagnosis of nasal diseases. In the present study, 260 patients with chronic sinusitis that were diagnosed by video laryngoscopy were enrolled, and 63 (24.3%) out of 260 exhibited no symptoms of chronic sinusitis by CT examination. In the 169 cases of nasal stenosis that were diagnosed by video laryngoscopy, 117 (69.2%) were caused by nasal mucosal swelling and turbinate hypertrophy, while the remaining 52 cases (30.8%) were caused by nasal septum bulging. In the 52 cases of nasal septum bulging, 5 cases (3.0%) presented with nasal septum deviation by CT scan, while the remaining subjects exhibited thickening of the nasal septum mucosa. The results of nasal diseases in pediatric patients with OSAHS by the two examination methods demonstrated that video laryngoscopy was a significant tool for the diagnosis of pediatric chronic sinusitis. Nevertheless, the occurrence of nasal stenosis and the presence of related anatomical abnormalities in the nasal septum required confirmation by CT examination. The majority of the nasal stenosis cases were caused by rhinitis and chronic sinusitis-induced nasal mucosal swelling, thickening and turbinate hypertrophy, while the anatomical abnormalities such as nasal septum deviation were rare.P< 0.003) [P < 0.001) [The contribution of obesity is controversial in the pathogenesis of pediatric OSAHS. In 1992, Leach et al. failed to report an association between obesity and OSAHS , but in < 0.003) . In 2008< 0.001) . In the < 0.001) , 54–56. Finally, it should be noted that due to the inconsistency of the diagnostic criteria of the pediatric OSAHS, the following diagnostic criteria were used: AHI higher than and/or equal to 5 times/h (≥5 times/h), as recommended by the Chinese guidelines. Nevertheless, relevant studies have used AHI higher than and/or equal to 1 time/h (≥1 time/h) and/or AHI higher than and/or equal to 1.5 times/h (≥1.5 times/h) as the diagnostic criteria. Consequently, inconsistent diagnostic criteria may be one of the causes leading to differences in the risk factors reported by different studies. In 2005, the study by Valera et al. indicated that the tonsil size correlated with the severity of OSHAS in preschool children, although it had no impact on school-age children . The autThe present study exhibits certain limitations. For example, the evaluation of the sample size was not conducted and this was a single center retrospective case-control study. Consequently, all the data were retrospectively analyzed, indicating potential selection, measurement and recall biases. Moreover, the diagnostic criteria of OSAHS were based on the Chinese guidelines. Thus, the results and the comparison with previous studies should be analyzed with caution.In summary, the present study demonstrated that upper respiratory tract infection, allergic reactions-induced adenoid hypertrophy, tonsil hypertrophy, chronic sinusitis, nasal stenosis, certain craniofacial features and obesity may be considered risk factors for the development of pediatric OSAHS. The aforementioned factors correlated with disease severity. Among them, the average number of upper respiratory tract infections each year, adenoid hypertrophy, tonsil hypertrophy, chronic sinusitis and nasal stenosis were independent risk factors for the development of pediatric OSAHS, while craniofacial features and obesity provided a weak association with regard to the upper airway structure in pediatric OSAHS. The determination of the etiology provided the basis for the selection of the treatment methods. Surgery was the main treatment for grade IV adenoids and tonsils, while conservative treatment was the main treatment for grade III adenoids and tonsils. Treatment of rhinitis and chronic sinusitis should be conducted for all pediatric patients regardless of the occurrence of the adenoid and tonsil hypertrophies. The effects of infection, allergic reactions, embedded type of tonsils, craniofacial features and obesity on the occurrence of pediatric OSAHS should be considered during etiology analysis. Taken together, those results suggest that timely treatment of upper respiratory tract infections and control of allergic reactions can reduce tonsil and adenoid hypertrophy and reduce the incidence of OSAHS. Weight loss should also help reduce the incidence of OSAHS.S1 Data(XLSX)Click here for additional data file.


Frontiers in Neuroscience Special Issue). The great majority of the experimental work related to analog signaling, however, concerns the propagation of subthreshold voltage changes from the soma to the axon. Much less attention has been paid to the propagation of subthreshold voltage changes in the opposite direction, from the axon to the soma, or to the propagation of local signals within the axon. In this mini review we will describe these other variants of analog signaling that we call here “antidromic” coupling and “local” coupling.Analog signaling describes the use of graded voltage changes as signals in the axonal compartment. Analog signaling has been described originally in invertebrates but more recent work has established its presence in the mammalian brain . In rece The term “analog signaling” is used to describe the passive propagation of electrical signals among different neuronal compartments. In recent years it became clear that subthreshold or passive  coupling between the somatodendritic and the axonal compartments is far more prevalent than what was expected 15 years ago , is the idea that the axonal compartment may also be the input compartment of a neuron and that some of the signals that originate in the axon may reach the soma and affect neuronal excitability (Middle). This idea challenges Ramón y Cajal’s dynamic polarization theory, that states that information in the nervous system is unidirectional, flowing from the dendrites to the soma to the axon. In antidromic signaling, the signal goes on the contrary from the axon to the soma. The present review discusses this paradoxical, often neglected form of axonal signaling, as well as another form of analog signaling that can be considered a variant of the previous one, “local” signaling, where axonal voltage changes remain confined to the axonal compartment (Right).Even more challenging than this orthodromic analog coupling , Left, itability , Middle.partment , Right.Transmission of electrical signals in the axon can be approached by approximating the axon structure with a cable. The extent of propagation of passive signals in a cable of infinite length at steady state follows an exponential function of distance. The length constant  depends on the cable internal resistance  and on the membrane resistance of the axon .While the value of lambda does not depend on the direction of the signal propagation for an infinite cable, directionality becomes important for finite length axon cables linked to other axonal or somatic compartments. Specifically, the voltage changes produced either in the soma or in the axon by some current injected in the other compartment will depend on the passive characteristics of the target compartment (the soma when the current is injected in the axon and the axon when the current is injected in the soma), that is, input resistance and membrane capacitance. This was recently studied in detail by In their study, Although asymmetric coupling may be a general feature of mammalian neurons, its extent is expected to vary markedly depending on cell size. In smaller and more compact cells, like GABAergic interneurons or cerebellar granule cells, where the somatic input resistance is much higher, the asymmetry may be expected to be smaller than in big cells , which have been originally described in sensory primary afferents of the spinal cord .Axonal, or presynaptic ionotropic receptors have been described in a large variety of neuronal types in the central and peripheral nervous system . The besARs have been found in multiple neuronal cell types, and their mode of action has been studied in detail. In some cases activation of axonal GABAA receptors appeared to be transmitted antidromically to the soma. An early example is a study by A current recorded from the soma of cerebellar molecular layer interneurons  that depends on the released GABA binding back to GABAARs located on the releasing cell . It was shown later by A autoRs can shape MLI firing. In 2010 we extended this work and showed that in MLIs the activation of GABAARs in a single varicosity generates a measurable signal  that can back-propagate to the soma. More recently, we used calcium photolysis in single varicosities to demonstrate that the voltage changes associated with preminis are able to change the cell excitability, probably by modifying AP threshold in the AIS . Therefore, local activation of axonal GABAA receptors in Purkinje cell axons induces a depolarizing signal that is propagated to neighboring varicosities. The upstream signal seems to be axonal firing and subsequent GABAA autoR activation (like in cerebellar interneurons), but other options such as spillover GABA release from neighboring axons, or GABA release from glia, are also possible. Concerning this last possibility, evidence in other systems indicates that the original signal may come from non-neuronal cells, like astrocytes. What kind of signal could give rise to local axonal depolarization in Purkinje cells? In their paper, Zorrilla de San Martín et al. found that Purkinje cells boutons express GABAthe soma . PurkinjHere, it is important to stress the fact that the intra-axonal, local voltage changes, although sub-threshold, can affect release by modulating the availability of voltage-dependent channels in the varicosity and therefore, the shape of the incoming AP. Also, sub-threshold local voltage changes may also affect release without inducing any change in AP shape, for example by modulating the basal calcium levels or the availability of voltage-dependent calcium channels just before release. For an extensive list of references on this issue the reader can consult the recent review by While local analog signaling in the axon domain remains scarcely documented, it is probably even more common than the two other forms of axonal analog signaling, ortho- and antidromic signaling. If some axonal signals reach the soma, as previously discussed, then they must also reach other varicosities, simply because the intervaricosity distance is smaller than the varicosity to soma distance. In the case of long-projecting neurons, such as cortical pyramidal neurons or spinal cord motoneurons, where the axonal length reaches tens and sometimes hundreds of millimeters, local, subthresold axonal signals may hardly ever reach the soma but may have a strong influence on neighboring varicosities. In such a case, the axonal compartment may largely operate independently from the soma, opening new and unexpected possibilities for neuronal computation.So far, we have considered coupling between different axonal compartments for voltage signals in the subthreshold regime. However, it is important to appreciate the fact that local events of high amplitude may reach threshold and evoke spiking activity directly in the distal axon. These locally generated action potentials, called EAPs, differ radically from normal APs that are generated in the axon initial segment. They violate Cajal’s polarization rule and travel backward to the soma. EAPs have been extensively documented in invertebrates (for an excellent review of EAPs see in vitro gamma frequency), EAPs are generated in the axon of CA3 pyramidal cells but fail to reach the soma (in vivo, where they represent around one third of the spiking activity of the neuron (During network oscillations in the hippocampus (the soma  (giving e neuron . InteresIn a recent paper, All the experimental data that has been collected during the past two decades or so has progressively changed our view of the physiology of the axonal compartment. Clearly, the axon cannot be considered as a simple transmission cable, and it rather emerges as a complex computational unit that increases the operational capabilities of the neuron . Today, FT wrote the manuscript and prepared the figure.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Ictalurus punctatus) were immunized with trinitrophenylated-keyhole limpet hemocyanin (TNP-KLH) to examine TNP-specific antibody titers, affinities, antibody-secreting cell (ASC) dynamic changes, and especially the affinity of secreted antibodies by LLPCs post-immunization. We demonstrated that TNP-specific LLPCs were generated starting at week 4 post-immunization, achieved a maximal number at week 8, and maintained a comparable level throughout the 18-week post-immunization period, which was correlated with the dynamics of serum antibody titers and affinity maturation in the response. The LLPCs appeared to mostly reside within, or migrate to, the anterior kidney , but a small portion was also located in the spleen and peripheral blood. The antibodies produced by the LLPCs possessed high affinities, indicating that the generation and development of LLPCs were driven by affinity selection in teleosts. Collectively, the results of this study provide insights toward the evolutionary understanding of the affinity-dependent mechanism of LLPC generation and development.The recent discovery of long-lived plasma cells (LLPCs) in mammals, which provide a constant expression of specific high-affinity antibodies that mediate humoral memory, has caused a dramatic paradigm shift in the study of immunity and vaccine development. In teleost fish, there are few studies regarding the association between LLPCs and antibody production, and the affinity of the antibodies secreted by the LLPCs is poorly understood. In the present study, channel catfish ( In mammals, the existence of long-lived plasma cells (LLPCs) demonstrates a new mechanism to maintain humoral immunity. LLPCs are considered to be a new kind of “memory-providing cell” and survive independent of antigen –4. LLPCsin vitro culture . With TNP-KLH immunization, the TNP-specific titers, affinities, ASCs dynamic changes, and especially the affinity of secreted antibodies by LLPCs post-immunization were studied. Data obtained here showed that anti-TNP-specific LLPCs migrated and survived in the anterior kidney throughout a period of 18 weeks, which correlated with the dynamics of affinity maturation of the serum antibody response. The phenomenon of LLPCs of teleosts secreting high-affinity antibodies provided evolutionary evidence that affinity-driven selection plays a significant role in the generation and development of LLPCs.LLPCs are crucial to providing lifetime protection against pathogenic infections in teleost fish, similar in mammals, which is important for vaccine development for aquaculture. Until now, studies in channel catfish exposed to the protozoan parasite, ma cells , 30, 31.ma cells . Thus, wI. punctatus) were obtained from Guangdong Catfish Breeding Farm in Guangzhou , weighing 600 ± 150 g. They were maintained in a semi-automatic circulating water system (Channel catfish (r system  at 28 ± 1-BSA and TNP8-BSA (The immunogen (TNP-KLH) was prepared as described previously , 32. TNPTNP8-BSA , 27 wereChannel catfish were anesthetized with a 0.04% solution of 3-aminobenzoic acid ethyl ester  prior to immunization. Sixty fish were immunized with 100 μg of TNP-KLH per fish by intraperitoneal injection in a final volume of 100 μL [TNP-KLH in PBS emulsified 1:1 with Freund's complete adjuvant ]. The control group was injected with PBS emulsified with FCA. In order to prepare the serum at 0, 2, 4, 6, 8, 10, 14, and 18 weeks post-immunization (p.i.), five fish were selected at random from each group. Fish were anesthetized with MS-222 , and 1 mL of blood was collected by venipuncture from the caudal vessel and then placed in a sterile 1.5 mL tube. The specific individuals were tracked over the entire immunization period. The blood was centrifuged at 4°C, 500 × g for 10 min, and the serum was collected and stored at −80°C.7 cells/mL in tissue culture medium (TCM). The TCM , which were put into the incubator culture chamber M-624  for 7 or 15 days in an atmosphere of 10% O2, 10% CO2, and 80% N2 , named T1/T8 affinity ELISA. The antibody titers of cell supernatants collected from the leukocytes cultured in vitro were much lower than those of serum antibodies; however, their affinities were able to be detected by the T1/T8 affinity ELISA. Different from the standard antibody titration ELISA, the substrate used in T1/T8 affinity ELISA was tetramethylene benzidine dihydrochloride , according to the previously described protocol  for 2 h at 25°C. The membrane was washed three times, and the membrane wrapped with parafilm was then inserted into a dot-blot apparatus , and 104-106 cells, ex vivo or cultured in vitro for 15 days , and spots were counted on the enlarged photographs. One spot represented an anti-TNP specific ASC. The size of the ELISPOTs was analyzed by Image J software . The bigger the spot size, the stronger was the secreting ability of the cell.ASCs were enumerated by ELISPOT analysis as previously described . Briefly 15 days   and reached the peak at week 6  with logarithmic increases and then began to slowly decline and maintained a stable level during the late immunization . The conThe affinity of TNP-specific antibodies detected by the T1/T8 ratio ELISA showed that the affinity increased at every time point through week 10, 4 weeks past the point at which the maximal titers were observed , indicat6 leukocytes, with a robust early response reaching the maximal value quickly at week 2  did not exhibit any significant change over the process of the immunization  and 15 (LLPCs) days without antigen but in the presence of HU , then decreasing slowly during the late response   were cultured for 15 days in the absence of antigen but in the presence of HU, in order to determine the specific ASC antibody-secreting capacity. An analysis of the spot morphology indicated striking differences among the ASCs from various tissues . The aveex vivo) . These din vitro for 2 weeks and continued to secrete antibodies for months post-immunization   . One corks p.i.) . To accuks p.i.)  in additnly done , 45, 46.r kidney . Howeverr kidney .in vitro for 7 and 15 days to ascertain the number of plasma cells vs. LLPCs  with a large proportion during the immunization. The discovery of the LLPCs and high-affinity antibodies secreted from LLPCs in channel catfish has many implications for the design and delivery of vaccines in teleosts. Successful vaccination may require long-term maintenance of high-affinity antibodies produced by the plasma cells within the anterior kidney. Given that long-term protection to certain pathogens may ultimately depend on the maintenance of LLPCs, it is essential that the mechanisms of LLPC generation, development, and maintenance in the anterior kidney must be delineated. Moreover, the finding of LLPCs secreting high-affinity antibodies may shed light on the evolutionary understanding of the affinity-dependent mechanism of the generation and development of LLPCs.jmye@m.scnu.edu.cn.The datasets analyzed in this manuscript are not publicly available. Requests to access the datasets should be directed to The animal study was reviewed and approved by University Animal Care and Use Committee of the South China Normal University.LW performed the majority of the experimental work, with the assistance of SF in feeding the fish and performing the ELISPOT experiment. XY performed data analysis and graphing. ZG and AW reviewed and polished the manuscript. JY and LW designed the experiments and wrote the main body of the paper.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.


We surely would embrace drug treatments that effectively help most people with depression, but based on work that has contested the validity of mostly industry-sponsored antidepressant trials  is nearly impossible due to residual confounding and correlational noise . With a total sample size of n = 116,477 as in the most recent meta-analysis  are considered clinically irrelevant  or d = 0.5 (“medium” effect size) are arbitrary and should be interpreted with caution , but only an effect size of d = 0.2 when the pooled standard deviation is 10 (2/10 = 0.2). The clinical significance of Cohen's d further depends on the outcome. A d = 0.3 referring to mortality necessarily has more practical relevance than d = 0.3 based on subjective (and often transient) symptom ratings.Here we report Cohen's  caution . Cohen'sd = 0.3 indicates that, first, the outcome of antidepressants and placebo overlap by 88%, second, that only 62% of participants in the antidepressant group score above the mean of the placebo group and, conversely, 38% score below the mean (referred to as Cohen's U3), and, third, that if you pick a person at random from the antidepressant group, he/she will have a minor chance of 58% to have the better outcome than a person picked at random from the placebo group   . Finally at all) , based o at all) , the num at all) , who cal at all) ]. This i at all) , 21 and  at all) , 23. A b at all) ], but fod > 0.8, whereas the effect size of antidepressants is d = 0.3. Moreover, the general medicine drugs with small effect sizes reported in Leucht et al.  than those based on the HAMD-17 (d = 0.32 (Another unsubstantiated objection is that the efficacy of antidepressants is poor due to inadequate psychometric properties of the HAMD-17 . We do  HAMD-17 , 33. Secd = 0.32 . Third, d = 0.32 –30. I.e.A third objection is that critics of antidepressants unjustifiably promote psychotherapy although talk therapy is no better than pharmacotherapy. In response to these concerns we would like to state that we have also written about the limitations and biases in psychotherapy research . We furtThe average treatment effect detailed above, albeit minor, yet is most likely an overestimation due to various systematic biases that inflate the apparent efficacy of antidepressants, including, in particular, unblinding of outcome assessors , 36, 40.First, it has consistently been shown that treatment effects are larger when the outcome is rated by unblinded assessors, thus efficacy estimates are inflated due to assessors' treatment expectancies –44. SecoGiven that the mean drug-placebo difference is only about 2 HAMD-17 points, even a minor bias in symptom-ratings could fully account for antidepressants' treatment effect. Indeed, taking the observer bias into account, Gotzsche  calculatContrary to the predominant interpretation we contend that antidepressants do not work in most patients, given that only 1 of 9 people benefit, whereas the remaining 8 are unnecessarily put at risk of adverse drug effects. To be clear, antidepressants can have strong mental and physical effects in some patients that may be considered helpful for some time , but theMPH drafted the manuscript. MP contributed significantly in writing and critical revision.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.


Since the 2008 economic crisis in Spain, overall fertility has continued to decrease, while urban inequalities have increased. There is a general lack of studies of fertility patterns in small-areas of Spanish cities. We explored the effects of the economic crisis on fertility during three time periods in urban settings in Spain.We studied the distribution of fertility rates among women (15–49 years) from Spain and low-middle income countries (LIC) who were living in 13 Spanish cities. We mapped fertility and the MEDEA socioeconomic deprivation index in small-areas, and analyzed age-related trends in fertility rates. We performed an ecological regression analysis of fertility and the deprivation index in two pre-crisis periods (1999–2003 and 2004–2008) and one crisis period (2009–2013). Fertility rates were calculated and smoothed using the hierarchical Bayesian model (BYM).Higher fertility was generally associated with socioeconomic deprivation, with adjustment for the mothers’ age and nationality. While Spanish citizens tended to delay childbearing throughout the three study periods, fertility increased among Spanish adolescents from deprived urban areas during the economic crisis. There was a general decline in fertility among immigrants after the crisis, especially in southern cities. Overall, fertility appeared to be stable, with higher fertility in more deprived areas.Increased unemployment and changes to government family policies may have contributed to delayed childbearing in Spain. For immigrants, more restrictive immigration policies may have played a crucial role in decreasing fertility rates. Reforming such policies will be key for better reproductive rights and improved fertility rates across all population cohorts in Spain. Fertility refers to the rate of production of offspring and is dependent on several diverse factors: the socioeconomic and political context of the country (government welfare policies); social ; labor-related (employment status and working conditions); and psychosocial and biological factors, such as infertility or individual choices , 2. HealFertility rates in Spain have been decreasing since the 1970s, stabilizing around 2000, and continuing to decrease since 2008 . PreviouAs far as we are aware, the clusters and patterns of fertility have not been analyzed at the level of small-areas in this country. Following the social changes brought about by the crisis in Spain, there is a need to study fertility at the territorial level, and the role played by associated inequality axes such as income and migration. Therefore, the aim of this study is to explore the effect of the economic crisis on the distribution of fertility across small-areas in urban settings in Spain and to consider the role of mothers’ age and nationality.IMCRISES project, we conducted an ecological study of trends during three periods: 1999–2003, 2004–2008 (pre-crisis periods) and 2009–2013 (crisis period), where 2009 was considered as the year when the economic crisis started in Spain . High-income countries were those with a gross national per capita income of ≥$12,056 (see list of high income countries in the World Bank website) .Based on previously described methods , we inclThe dependent variable was fertility rate, as fertility depends on population size. However, fertility variance is inversely proportion to the expected values. Thus, areas with low population tend to have larger estimated variability. We used the hierarchical Bayesian model proposed by Besag, York and Mollié (BYM) to smooth the rate . The modWe used a regression model to analyze the association between fertility and deprivation during the three periods. Deprivation, interactions between periods and their random effects were also taken into account . Regression models provided us with relative risks and their respective intervals. Changes in the deprivation and fertility associations were evaluated through the included interactions. Specifically, we have studied changes between the first and second periods, and the second and third periods. Changes between periods in the relationship between the socioeconomic deprivation index and mortality were evaluated through the interactions between the periods. Specifically, we studied the change between the first and second pre-crisis periods, and between the second pre-crisis period and the crisis period. All analyses used the Integrated Nested Laplace Approximations (INLA) method (INLA package) from the R R.3.1.1) . Details.1 . DetaTable Figure 2) 12.68; relative risk for the crisis period (RR3) 21.33), and could indicate a rise in inequality in certain areas.Figure 2 0.85 to RR3 0.70) where it decreased further.In global across cities, the crisis did not appear to modify the association among 20- to 24-year-olds, whereas among 25-to-34-year-olds. Therefore, the differences in fertility rates between deprived and affluent areas increased among 25–34 year olds from the first to the second pre-crisis period. This positive association decreased or remained stable during the crisis. In contrast to the 15–19 years group, there was a negative association among 35–49-year-olds, i.e. fertility was higher in privileged areas and remained so throughout the crisis. The negative association remained stable during the crisis, except in Barcelona (RR2 1.33 to RR3 1.17). In contrast, there was positive association in Madrid from the first to the pre-crisis periods (RR1 0.98 to RR21.20).There was no change in fertility inequalities across the three periods in the southern and northern regions. In Barcelona, however, the associations between fertility and deprivation became weaker during the crisis .There was a positive association between fertility and deprivation for all LIC women Fig. , among wThe positive association between fertility rate and deprivation index among LIC women was generally consistent in different age groups and in most cities studied. Interestingly, the rate did not change markedly during the crisis. However, the association decreased in LIC women aged 20–24 years in Seville, Cadiz and Bilbao, 25–34 years in Granada, and 25–34 and 35–49 years in Madrid.This study explores socio-economic inequalities in the distribution of fertility in 13 cities in Spain, where fertility rate was general associated with deprivation. However, the distribution varied according to the age and nationality of mothers. Among Spanish adolescents in disadvantaged areas, fertility appeared to increase during the crisis period, and this was also the case for Spanish women older than 34 years from more affluent areas. LIC women were found to have a stable positive association across the three periods, in which the pattern of higher fertility in more deprived areas remained unchanged.Previous studies have noted that fertility in Spain may have responded negatively to the economic downturn , 25. We For instance, the distribution of fertility among Spanish adolescents in Barcelona became more unequal during the crisis. We observed variation in the distribution of fertility in small-areas, where Spanish adolescents from more affluent areas had lower fertility rates, while rates increased in more deprived areas. This may be associated with an increase in unintended pregnancies among adolescents in disadvantaged areas. This trend seemed to be present in other cities in this study. The variation also suggests that the decrease in fertility in this group could be greater in affluent areas. In the case of Barcelona, other proxy indicators suggest the increase in the differences, such as decrease in the use of condoms by adolescents from disadvantaged social classes . PregnanWe found that Spanish women older than 35 years were less likely to have children if they lived in deprived areas, in spite of the economic crisis. Simultaneously, we observed a general trend of delayed childbearing in privileged areas among Spanish women, which is concordant with the overall increase in the average year at conception in Spain . This deImmigrant women living in deprived areas were more likely to have children, which may be due to the higher density of immigrant populations in deprived areas. In the south , the region most affected by the recession and unemployment, fertility among immigrants decreased . EconomiThe most susceptible population groups are immigrants without full Spanish citizenship rights. Therefore, in this study it was more meaningful to address nationality rather than country of origin. However, data on nationality were not available for all participants, the limitation being that people from LIC could also hold another nationality . We analThis study observed a general decline in fertility among women in resource-deprived regions in Spain, which may be associated with the economic recession. Southern Spain, the region with the highest rates of unemployment, showed the greatest decrease in fertility after the crisis, especially among immigrant women from LIC. Restrictive immigration policies may have affected the fertility of LIC women. Inequality tended to increase over time and, similarly, the economic crisis appeared to affect socioeconomic inequalities in fertility among Spanish adolescents. Adolescents living in deprived areas had higher fertility rates, due in part perhaps to an increase unintended pregnancies. In contrast, adult Spanish women from all regions tended to delay childbearing. More accommodating pro-family policies and increased employment will likely help generate improved working and living conditions, to give women in Spain more freedom in deciding when to have a child.Additional file 1. Supplementary methodsAdditional file 2. Supplementary contextual factors of the citiesAdditional file 3. Supplementary file cities mapAdditional file 4. Supplementary results


The NiSx granular film is composed of mangy interconnected ultra-thin NiSx nanoflakes with porous structures. When applied as electrodes for supercapacitors, the ultra-thin nanoflakes can provide more active sites for redox reaction, and the interconnected porous structure has an advantage for electrolyte ions to penetrate into the inner space of active materials quickly. As expected, the obtained NiSx/NF sample exhibited high gravimetric capacitance of 1649.8 F·g−1 and areal capacitance of 2.63 F·cm−2. Furthermore, a gravimetric capacitance of 1120.1 F·g−1 can be maintained at a high current density of 20 mA·cm−2, suggesting a good rate capability. The influence of the different molar ratios of electrodeposition electrolyte (NiNO3 and thiourea) on the morphology and electrochemical properties of NiSx/NF sample was investigated to provide an optimum route for one-step electrodeposition of Ni3S2/NiS composite film. The outstanding performance indicated the Ni3S2/NiS composite film on Ni foam has great potential as an electrode material for supercapacitors.Herein, a facile one-step electrodeposition route was presented for preparing Ni At present, the traditional non-renewable fossil energy represented by oil, coal, and natural gas is rapidly consumed, leading to vigorous development of new energy resources . However, these new energy resources are subject to natural environmental conditions. For example, the efficiency of solar energy is limited in rainy and cloudy weather areas. Therefore, the electrochemical energy storage devices connected with them can solve these energy storage and conversion problems ,2,3,4. A3S2, and Ni3S4, etc.) show a great potential as battery-type materials in the application of supercapacitors, due to their high theoretical specific capacitance, abundant resources, and relatively low cost [3S2 nanoparticles prepared by the mechanical alloying method showed high specific capacitance of 911 F·g−1 [3S2 nanosheets array on Ni foam showed a very high capacitance of about 1000 F·g–1 [3O4@Ni3S2 core-shell nanowire arrays on Ni foam exhibited an ultrahigh specific capacitance of 1710 F·g−1 at 1 A·g−1 [3S2@CoS core-shell arrays is 4.89 F·cm−2 (376.06 F·g−1), which is far larger than that of pure Ni3S2 material  [3S2, and Ni3S4, etc.) as hybrid electrode materials of supercapacitors.Currently, supercapacitors have been widely used in aviation, military, vehicle, and electronic devices; they are some of the research focuses in the field of new energy research; but, their energy density is very low, far lower than that of batteries . Among tlow cost . Howeverlow cost ,14,15. Plow cost , nanowirlow cost , nanorodlow cost ,19, nanolow cost ,21, and low cost  have gre11 F·g−1 . Further11 F·g−1 ,24,25. W00 F·g–1 . Hierarc 1 A·g−1 . In orde7 F·g−1) . However3S2/NiS composite on Ni foam (NiSx/NF) was prepared by one-step electrodeposition using the cyclic voltammetry method. This electrodeposition method is one with green, low-cost, and scalable properties for preparing electrode nanomaterials. As far as we know, it is the first report about the preparation of Ni3S2 and NiS composite by the one-step electrodeposition route. In order to optimize the charge storage performance of the as-prepared Ni3S2/NiS composite materials, we explored the effect of electrodeposition solution concentration on the performance of NiSx/NF electrode materials. NiSx/NF was prepared by electrodeposition using different molar ratios of Ni(NO3)2 and thiourea. The optimum route was obtained by analyzing the morphology, structure, and electrochemical results of the three samples. As expected, the obtained NiSx/NF sample exhibited remarkable specific capacitance (1649.8 F·g−1) and excellent rate capability.In this work, self-supported Ni3)2·6H2O and KOH were purchased from Guangdong Guanghua Sci - Tech Co., Ltd. , and thiourea was purchased from Afar Sally chemical co. LTD . Ni foam  was bought from Shanxi Lizhiyuan Battery Materials Co., Ltd. . All the chemical reagents were used as received without further purification.Chemical reagent Ni(NO3S2/NiS composite (denoted as NiSx/NF) was electrodeposited into the Ni foam by cyclic voltammetry(CV) method using Gamry electrochemical workstation . In a typical synthesis, the electrodeposition process was carried out at a scan rate of 5 mV·s−1 in the range of −1.2–0.2 V for 30 cycles in a three-electrode system with Ni foam as the working electrode, Ag/AgCl as the reference electrode, and Pt as the counter electrode. The electrodeposition solution was prepared by mixing Ni(NO3)2·6H2O and thiourea in 80 mL H2O. The Ni3S2/NiS composite on Ni foam was prepared using a different solution concentration of Ni(NO3)2·6H2O and thiourea. For better comparison, the molar concentration of thiourea was fixed as 0.5 mol/L−1, and the molar concentration of Ni(NO3)2·6H2O was 1, 2.5, and 5 mmol/L−1, respectively. The resulting Ni3S2/NiS composites were denoted as NiSx/NF-1, NiSx/NF-2.5, and NiSx/NF-5, respectively.NiX-ray diffraction (XRD) patterns were obtained by a Rinku Miniflex 600 diffractometer . The morphology and elemental composition of as-prepared NiSx/NF were analyzed using a scanning electron microscope , field-emission scanning electron microscope , and transmission electron microscope , respectively. x/NF as the working electrode, Hg/HgO as the reference electrode, and Pt sheet as the counter electrode. An amount of 6 M KOH aqueous solution was used as electrolyte. The cyclic voltammetry (CV) was performed at scan rates of 2, 5, 10, 20, 30, 40, and 50 mV·s−1 in the range of 0–0.7 V (vs. Hg/HgO) on the Gamry electrochemical workstation , respectively. The galvanostatic charge–discharge (GCD) test was carried out at different current densities of 1, 2, 3, 4 5, 6, 8, 10, 12, 16, and 20 mA·cm−2 on the Arbin electrochemical workstation , respectively. The electrochemical impedance spectroscopy (EIS) measurement was carried out within a frequency response in the range of 0.01–100 kHz and an AC amplitude of 5 mV on the Gamry electrochemical workstation (Reference 3000).The electrochemical measurements were carried out on a three-electrode system with NiSsC, F·g−1) and areal capacitance  were calculated using the following formulas:I, △t, △V, m, and S are the discharge current (A), the discharge time (s), the potential voltage (V), the total mass of the active materials (g), and the geometric area of electrode, respectively.The galvanostatic capacitance (x powder obtained from NiSx/NF electrode are shown in 3S2 planes (PDF#44-1418) and NiS phase (PDF# 12-0041), confirming that the mixed phase of Ni3S2 and NiS was formatted in the as-prepared NiSx composite film. The impurity peaks at 51.8° are attributed to the (200) crystal planes of residual nickel metal (PDF# 04-0850) from Ni foam.The XRD patterns of the NiSx composite on Ni foam prepared using different molar ratios of NiNO3 and thiourea electrolyte. In the low-magnification SEM images 2 increased, the thickness and the wrinkle degree of NiSx film also increased. Meanwhile, some microspheres on the surface of NiSx composite films were observed. The increase of microspheres can provide more active sites for redox reaction, resulting in high specific capacitance of NiSx composite. It is worth noting that large cracks gradually appear in the film when concentration of NiNO3 electrolyte increases. Therefore, the tightness of the film is reduced with the increase of Ni(NO3)2 molar concentration. The expanding transverse crack may cause the NiSx composite film to fall off, resulting in a rapid decline in the capacitance of NiSx composite electrode after repeating charge–discharge tests. More detailed morphology was further observed by field-emission scanning electron microscopy (FE-SEM) and a transmission electron microscope (TEM), as shown in x composite nanoflakes with porous structures, which is advantageous for electrolyte to penetrate into the inner space of active materials quickly. The reasons for the increase of wrinkle degree of NiSx film may be as follows. When the concentration of electrodeposition solution is relatively low, the as-prepared films should be relatively dense. As the arrays of supported NiSx nanoflakes gradually form, the film has porous characteristics, so the film will become more and more rough. The TEM image (x composite nanoflakes were overlapping and interconnected. The energy-dispersive X-ray spectroscopy (EDX) mapping was further employed to investigate the elemental distribution of Ni and S. As shown in x nanosheets.M images a,c,e, Nification b,d,f. AsEM image h furtherx/NF-1, NiSx/NF-2.5, and NiSx/NF-5 were evaluated by a three-electrode system. −1, which indicates the Faraday reaction nature of the NiSx/NF electrode [x/NF-1, NiSx/NF-2.5, and NiSx/NF-5) at the same scan rate of 10 mV·s −1. Usually, the area enclosed by CV curves can reflect the specific capacitance  of active materials. Herein, the sample NiSx/NF-5 shows the largest area enclosed by CV curves between three samples, suggesting that it has the highest areal specific capacitance.The electrochemical performance of samples NiSlectrode . The redlectrode ,31,32. film coated on the Ni foam will increase when the molar concentration of Ni(NO3)2 increases, as shown in x/NF-1, NiSx/NF-2.5, and NiSx/NF-5, it found that the porous structure and the degree of wrinkle of the film increase with the increase of the concentration, which means that the specific surface area of the active electrode materials will increase, and more active points will be exposed to the electrolyte solution. In addition, the microspheres anchored on NiSx film increase gradually as the molar concentration of Ni(NO3)2 increases, which further increases the utilization of active materials. Therefore, the specific capacitance should be enhanced. However, when the thickness and mass loading of the deposited NiSx film are excessive, there is no doubt that it is difficult for electrolyte to penetrate into the inner area of the electrode materials, which leads to the low effective utilization of the active materials. Therefore, it is natural that the mass specific capacitance will be reduced. The galvanostatic charge–discharge (GCD) tests were carried out at different current densities ranging from 1 to 20 mA·cm3S2 microspheres on Ni foam (981.8 F·g−1) [−1) [3S2 on Ni foam with rGO (1462 F·g−1) [3S2 (741 F·g−1) [3S2 nanoparticles on Ni Foam (816.8 F·g−1) [3S2@β-NiS materials (1158 F·g−1) [3S2 (1315 F·g−1) [3S2 and NiS.Compared with other reported materials, the material prepared by our work has obvious performance advantages. The specific capacitance value was higher than those of previous nickel sulfide-based materials as supercapacitor electrodes, for instance: nanosheet-based Ni8 F·g−1) , porous −1) [−1) , Ni3S2 o2 F·g−1) , 3D grap1 F·g−1) , 3D redu8 F·g−1) , Ni3S2@β8 F·g−1) , and gra5 F·g−1) . The enhx/NF-1, NiSx/NF-2.5, and NiSx/NF-5 was used to study the intrinsic electrochemical behavior, and corresponding Nyquist curves are shown in ct). The diameter of the semicircle for the samples  decreases gradually, meaning that charge transfer and ion transfer rate have been improved. Further, the intercept of Nyquist curve at the Z’ axis represents equivalent series resistance (ESR). The ESR values of the NiSx/NF-1, NiSx/NF-2.5, and NiSx/NF-5 electrodes are 0.36, 0.34, and 0.33 Ω, respectively. It also indicates the contact resistance at the interface of the NiSx film and Ni foam was very low.The electrochemical impedance spectroscopy (EIS) of the as-prepared NiSx/NF electrode decreased gradually. After 500 cycles, the capacitance decreased to 50% of the original capacitance, suggesting that the cycle stability of NiSx/NF electrode is not good. Based on SEM images, the cracks in the NiSx film on Ni foam can be observed. The repeated charge and discharge process may cause the loose connection between NiSx and Ni foam, and then NiSx drops off from Ni foam, resulting in the decrease of the capacitance of the NiSx/NF electrode materials.The cycle stability was evaluated by repeating the charge–discharge test for 500 cycles, as shown in 3S2/NiS composite (NiSx/NF) was prepared by electrodeposition on the Ni foam by cyclic voltammetry. Then, the influence of the different molar ratios of NiNO3 and thiourea electrolyte on the morphology and electrochemical properties of NiSx/NF electrode was investigated. The granular morphology and interconnected ultra-thin nanoflakes presented in NiSx thin films can provide more active sites for redox reaction, resulting in high specific capacitance of NiSx/NF. As-obtained NiSx/NF exhibits a high gravimetric capacitance up to 1649.8 F·g−1 at 1 mA·cm−2. Meanwhile, areal capacitance of 2.63 F·cm−2 can be achieved, demonstrating great application potential of Ni3S2/NiS composite.In this paper, the mixed Ni


The ability of organisms to perceive and respond to their environment is crucial to their long-term survival. Recent studies in model organisms identify signaling pathways that perceive environmental stress and cell non-autonomously modify systemic physiology. These pathways often originate in the neurons, where key cells monitor the external environment for changes including food availability, air-quality, and the presence of dangerous toxins. Our previous work identified a key role for serotonin signaling in the induction of flavin-containing monooxygenase-2 (fmo-2) downstream of hypoxic signaling. fmo-2 expression is necessary and sufficient to promote stress resistance and longevity downstream of multiple genetic pathways, making it a useful tool for identifying key components of these pathways. Our current data defines environments, pathways, and signaling molecules that induce fmo-2 and subsequently increase lifespan. Our resulting data define key roles for serotonin signaling and fmo-2 that rely upon the perception of oxygen and food.


A wide variation on the HTLV-1 pVL levels among asymptomatic HTLV-1 carriers was observed with some pVL as high as those observed in symptomatic patients. The asymptomatic HTLV-1 carriers were divided according to the place of birth and the highest levels of pVL were detected among patients from endemics areas from the North of Argentina. Our results reinforce the usefulness of the proviral load would be a prognostic marker of HTLV-1 disease progression. Moreover, host, viral or socio-environmental factors cannot be excluded as determinant of high proviral load.HTLV-1 proviral load (pVL) in peripheral blood mononuclear cell (PBMCs) is proposed as a marker of disease progression but its role still remains controversial. The aim of this study was to evaluate the levels of HTLV-1 pVL in symptomatic patients and asymptomatic HTLV-1 carriers. In this cross-sectional study the pVL was measured by Real Time PCR in 102 asymptomatic carriers and 22 symptomatic patients . We observed that the HTLV-1 pVL was significantly higher in symptomatic patients (median = 4.99 log10 HTLV-1 copies /106 PBMCs) compared to asymptomatic HTLV-1 carriers (median = 4.38 log A. A, . I. I, ..,  or or+ cellcells , . T. T+ cell, , . A. A, [, [, [, [, , no diff10 copies / 106 CMT) are in a high risk for the development of the disease. We consider this finding reinforces the idea that the quantification of the proviral load would be a prognostic marker of disease progression. For all these reasons, we consider that medical and laboratory follow-up by pVL may provide early information of clinical value in the progression from asymptomatic to symptomatic stage; as well as for detecting and treating the early manifestations the HTLV-1 associated disease. In this sense, other studies have revealed that pVL in asymptomatic patients remained stable over time with slight fluctuations [, [In contrast, among the asymptomatic patients, 27% of them had low pVL and 56% had medium pVL levels, still 17% of the patients in this group showed high values similar to those detected among the symptomatic patients. These results suggest that asymptomatic patients with a high level of pVL  in the present study did not have any symptoms or any clinical condition associated with HTLV-I infection moreover the main source in this group were blood donors, who once the diagnosis was performed they received clinical evaluation.In summary, our results indicate that the level of proviral load of HTLV-1 in PBMCs is associated with clinical disease, as HAM/TSP and ATLL. These levels remain low in asymptomatic carriers and high in symptomatic patients. Eventhough, asymptomatic patients from endemic areas in Argentina showed higher levels than those from non-endemic areas from our country. Our data support the hypothesis that HTLV-1 proviral load plays an important role in the pathogenesis of HAM / TSP and ATLL and as a biomarker in the clinical follow up. However, the presence of co-morbidities is another aspect to consider when evaluating the pVL; given that the presence of parasitic and viral co-infections may contribute to the clonal expansion of infected lymphocytes, leading this to an increase in the pVL levels. For these reasons, we consider that it is important to monitor the pVL levels over time and to evaluate the intra- and inter-individual variability. Further studies investigating other factors that might impact on proviral load levels may open new insights on HTLV pathogenesis.S1 STROBE Checklist(DOC)Click here for additional data file.


We aimed to assess the associations of involvement in selected unstructured activities (UA) with health-risk behaviours and academic achievement and the degree to which the participation in organized leisure-time activities (OLTA) changes these associations.Using a sample of 6935 Czech adolescents aged 13 and 15 years, we investigated adolescents’ weekly involvement in hanging out, visiting shopping malls for fun and meeting friends after 8 p.m., OLTA and engagement in three health-risk behaviours and academic achievement.Weekly involvement in the selected UA was associated with higher odds for regular smoking, being drunk, having early sexual intercourse and low academic achievement. Concurrent participation in OLTA did not buffer these negative outcomes, except for sexual experience. However, those highly engaged only in UA were more likely to participate in the health-risk behaviours and report worse academic achievement than those participating in any OLTA concurrently.The selected UA are strongly associated with an increased occurrence of adolescents’ health-risk behaviours and low academic achievement. Concurrent participation in OLTA does not buffer these negative outcomes significantly, but adolescents engaged only in UA consistently report the least favourable outcomes. In western industrialized countries, leisure time comprises approximately half of adolescents’ waking hours, with a slightly higher amount of leisure time recorded in North America than in Europe (Larson and Verma Engagement in unstructured activities (UA) is frequently associated with problematic outcomes, but not all UA can be labelled as risky Bradley . UA thatOrganized leisure-time activities (OLTA) are in fact exactly opposite of such UA, as they are characterized by having a certain structure, a regular schedule, clearly defined goals and rules, focusing on skill-building and being adult-supervised Larson . In contAs is apparent from the findings described in the two preceding paragraphs, the developmental outcomes of OLTA  and UA are contradictory. However, OLTA and UA obviously are not mutually exclusive categories of leisure time. A noteworthy group of U.S. adolescents participate in OLTA and, at the same time, are involved in a range of UA . Given the gender, age, as well as socioeconomic differences both in the leisure time content  study, which was conducted between April and June 2014. The surveyed schools were randomly selected from the database of Ministry of Education, Youth and Sports of the Czech Republic. Out of the 244 schools approached after stratification by region and ratio of primary and secondary schools, 243 gave consent to conduct the survey. At each of the participating schools, one class from the 5th, 7th and 9th grades  was then picked up at random. The questionnaires were administered by trained research assistants during regular class time and in the absence of teachers to minimize potential response bias. Participation in the study was voluntary and anonymous, with no incentives offered to respondents. Prior to administration of the questionnaires, the respondents were notified about the possibility to opt out. The Ethics Committee of the Faculty of Physical Culture, Palacky University, Olomouc, approved the study design (No. 57/2014).daily or two of their valid responses were weekly or more often.. The final sample comprised 6935 adolescents (49.1% boys).There were 16,298 pupils registered in the surveyed classes, and 14,539 of them completed the questionnaires. Thirty pupils refused to take part in the survey, and 1729 pupils were not present at school during the survey, with the most common reason being an illness. Then, we selected only 13- and 15-year-old adolescents, because the questions on UA were not asked to those aged 11 years. Finally, we excluded respondents who were classified as age outliers  or failed to provide data on gender, OLTA or UA. Those missing one or two responses out of the three UA items were only included in the analyses if we could unambiguously classify them as highly engaged in UA, i.e., one of their valid responses was met their friends after 8 o’clock, (b) visited shopping malls for fun or distraction, (c) hung out with their friends in their neighbourhood, park, at playgrounds, etc. We then categorized them into those doing these activities weekly or more often versus those doing them less frequently. We assessed these three activities separately and also derived a composite variable of being involved in any of the unstructured activities on a daily basis or in at least two such activities at least weekly as an indicator of high engagement in UA.We investigated involvement in three various peer-oriented UA. The respondents were asked how often they (a) team sports, individual sports, art schools, youth organizations, leisure centres or after-school clubs, and church meeting/singing. Those involved in at least one OLTA were categorized as participants, while the rest as non-participants. Last, we split the adolescents into four categories based on their leisure-time activities: (1) involved neither in OLTA nor UA, (2) involved only in OLTA, (3) involved both in OLTA and UA, and (4) involved only in UA.Regarding OLTA, the respondents indicated whether they participated in the following six types of activities: In your opinion, what does your class teacher think about your performance compared to your classmates? The responses were dichotomized as above-average achievement (very good/good) versus the remainder (average/below average).We used four dependent variables in our analyses from the pool of the HBSC mandatory questions ?, with dichotomous response option yes versus no. The question was asked only to 15-year-olds.Last, we investigated lifetime experience with early sexual intercourse. This was done using the question car ownership, holidays abroad, having one’s own bedroom, number of computers in the household, number of bathrooms, and dishwasher ownership) were summed up. We then transformed the sum into a fractional rank score (0–1)  developed for the purposes of the HBSC study  with academic achievement and health-risk behaviours using binary logistic regression. This was done in five steps—a crude model (Model 1), adjusted for age and gender (Model 2) and further adjusted for socioeconomic status, as indicated by FAS (Model 3). For the composite variable (at least on UA daily or at least two UA weekly), we also tested the interaction with the association of gender (Model 4) and of age category (Model 5).Next, we tested the ‘buffering effect’ of OLTA on the associations of UA (participation in at least two of them weekly) with academic achievement and health-risk behaviours. The OLTA variable was added to the model, and the ‘buffering effect’ was assessed by the interaction between OLTA and high engagement in UA. To assess the stability of our results, we also ran the regression analyses using the pattern of OLTA participation, as previously derived by cluster analysis  to assess the differences between adolescents involved both in OLTA and UA and the rest of the sample, especially those involved only in UA.Multilevel analyses of the risk behaviours and school-related outcomes on the Czech 2013/2014 HBSC sample did not indicate the data to cluster by school . We limited this risk by administering the questionnaire anonymously in the absence of teachers. Moreover, most of the measures we used were well validated (Currie et al. Weekly involvement in UA, including hanging out, visiting shopping malls for fun and meeting friends after 8 p.m., was associated with significantly low academic achievement, regular smoking, drunkenness and experience with sexual intercourse. If causal, increase in youth-appealing leisure opportunities could lead to prevention of health-risk behaviours through reduction of UA involvement, because time is a finite resource. This was recently observed by Motamedi et al. , particuOur study provides some hints that participation in OLTA may reduce the occurrence of health-risk behaviours, even though the ‘buffering effect’ of organized activities on negative outcomes of UA was not significant. More evidence is needed using more detailed measures of OLTA participation, because the measure we used was only dichotomous. Future research should, therefore, focus on particular dimensions of OLTA participation, such as intensity of participation, engagement or quality of program, with more detailed data on the participation probably providing more cues for understanding and intervening.Involvement in peer-oriented unstructured activities is strongly associated with an increased risk of smoking, getting drunk, experience with sexual intercourse and worse academic achievement in adolescence. Except for sexual experience, concurrent participation in organized activities did not significantly buffer these negative outcomes, but adolescents involved only in unstructured activities were the most at-risk group. They were more likely to smoke, experience sexual intercourse and do worse at school than those involved in organized and unstructured activities concurrently.