With the exponential growth of the Internet of Things (IoT) and cyber-physical systems (CPS), a wide range of IoT applications have been developed and deployed in recent years. To match the heterogeneous application requirements in IoT and CPS systems, many resource-constrained IoT devices are deployed, in which privacy and security have emerged as difficult challenges because the devices have not been designed to have effective security features. With the exponential growth of the Internet of Things (IoT) and cyber-physical systems (CPS), a wide range of IoT applications have been developed and deployed in recent years. To match the heterogeneous application requirements in IoT and CPS systems, many resource-constrained IoT devices are deployed, in which privacy and security have emerged as difficult challenges because the devices have not been designed to have effective security features.Despite many security solutions being developed for the Internet, there are major concerns regarding the resource-constrained environment in IoT, including data encryption, privacy preservation, vulnerabilities, threats, attacks, and controls, among others. To address these privacy and security challenges, appropriate technologies have to be developed for resource-constrained environments in IoT.The basic objective of this Special Issue is to report the most recent research efforts dedicated to strengthening the security and privacy solutions for resource-constrained devices in IoT and CPS systems. Specifically, each manuscript was carefully reviewed by at least two independent experts. All submissions were evaluated for their rigor and quality and their relevance to the topics proposed in this Special Issue. After a rigorous review process, 16 high-quality papers were accepted and included in this Special Issue. We will now briefly introduce the accepted papers.In the paper entitled “A Lightweight Cipher Based on SALSA20 for Resource-Constrained IoT Devices” , Lara etIn the paper entitled “An Incentive Mechanism in Mobile Crowdsourcing Based on Multi-Attribute Reverse Auctions” , Hu et aBouaynaya et al. investigated formal methods to quantify and evaluate the risks associated with information systems in the paper “Exploring Risks Transferred from Cloud-Based Information Systems: A Quantitative and Longitudinal Model” . FurtherThe paper entitled “Efficient Privacy-Preserving Access Control Scheme in Electronic Health Records System” focused on the constrained device access control in e-health records (HER) systems by reducing the computational resources . The proSun et al focused on a compressed-sensing-based fault-tolerant data aggregation in the paper “CS-FCDA: A Compressed Sensing-Based on Fault-Tolerant Data Aggregation in Sensor Networks” . The effIn the paper entitled “BeeKeeper 2.0: Confidential Blockchain-Enabled IoT System with Fully Homomorphic Computation” , Zhou etRahman et al. focused on the joint relay selection and power allocation for cooperative cognitive radio networks in the paper entitled “Joint Relay Selection and Power Allocation through a Genetic Algorithm for Secure Cooperative Cognitive Radio Networks” , which iAlromih et al. investigated a randomized watermarking technique for resource-constrained devices in the paper “A Randomized Watermarking Technique for Detecting Malicious Data Injection Attacks in Heterogeneous Wireless Sensor Networks for Internet of Things Applications” . The expFang, Yang, and Wu went through secure cost-aware data communication in IoT in the paper entitled “Security Cost Aware Data Communication in Low-Power IoT Sensors with Energy Harvesting” . In thisLuo et al. focused on the low-cost security and data integrity scheme in an air quality monitoring system in the paper entitled “On the Security and Data Integrity of Low-Cost Sensor Networks for Air Quality Monitoring” .Alabdulkarim et al. developed a privacy-preserving single decision tree algorithm for resource-constrained IoT devices in the paper entitled “PPSDT: A Novel Privacy-Preserving Single Decision Tree Algorithm for Clinical Decision-Support Systems Using IoT Devices” . This woLara-Nion et al. investigated efficient scalar multiplication for resource-constrained devices in the paper “Energy/Area-Efficient Scalar Multiplication with Binary Edwards Curves for the IoT” . In thisIn the paper entitled “FPGA Modeling and Optimization of a SIMON Lightweight Block Cipher” , Abed etQin et al. proposed a lightweight anomaly detection system for IoT in the paper titled “IMLADS: Intelligent Maintenance and Lightweight Anomaly Detection System for Internet of Things” . This woAl-Otaibi et al. aimed at developing a privacy-preserving vehicular rogue node detection scheme for light devices in IoT and fog computing in the paper entitled “Privacy-Preserving Vehicular Rogue Node Detection Scheme for Fog Computing” . The simShifa et al. proposed a lightweight cipher for H.264 video in IoT in the paper entitled “Lightweight Cipher for H.264 Videos in the Internet of Multimedia Things with Encryption Space Ratio Diagnostics” . This woIn this Special Issue, a wide range of topics are reported that cover ongoing research interests regarding security and privacy solutions for resource-constrained devices in IoT and CPS systems. The team hopes that this Special Issue will make contributions to encouraging IoT security and privacy issues.In conclusion, we sincerely thank all researchers for their sharing of their research works to this special issue and the reviewers for volunteering their time and expertise to carefully reviewing and commenting on all submissions. We would like to thank the sensors EIC and the admin team for their continuous support and guidance.


Current developments and challenges for serial sample delivery at synchrotrons and X-ray free-electron lasers are reviewed, including the new megahertz repetition-rate machines, with an emphasis on liquid injection and high-viscosity extrusion. The high peak brilliance and femtosecond pulse duration of X-ray free-electron lasers (XFELs) provide new scientific opportunities for experiments in physics, chemistry and biology. In structural biology, one of the major applications is serial femtosecond crystallography. The intense XFEL pulse results in the destruction of any exposed microcrystal, making serial data collection mandatory. This requires a high-throughput serial approach to sample delivery. To this end, a number of such sample-delivery techniques have been developed, some of which have been ported to synchrotron sources, where they allow convenient low-dose data collection at room temperature. Here, the current sample-delivery techniques used at XFEL and synchrotron sources are reviewed, with an emphasis on liquid injection and high-viscosity extrusion, including their application for time-resolved experiments. The challenges associated with sample delivery at megahertz repetition-rate XFELs are also outlined. This type of mixing, combined with SFX data collection from a GDVN-generated liquid jet, has been used to capture structural intermediates of a riboswitch binding its ligand ∼10 s after reaction initiation , the mixing process must take place close to the injector tip such that the travel time of the sample from the point of reaction initiation to the X-ray interaction region is short. Moreover, the effect of a non-uniform velocity profile on sample transport must be minimized downstream of the reaction initiation. Interestingly, an investigation of microcrystal flow through capillaries indicated the presence of a depletion zone containing no crystals near the capillary wall, which introduces an intrinsic cutoff of low-speed tails and alleviates flow smearing . High pressures are generally required for this, often in excess of those that can be supplied by an HPLC-based liquid-delivery system. A piston-driven sample reservoir must then be installed between the HPLC and the nozzle, with the piston serving both as a pressure amplifier and as the means of separating the sample from the hydraulic fluid . The high viscosity of an HVE sample precludes GDVN gas focusing, meaning that the extruded free stream is roughly equal in diameter to the inner diameter of the sample capillary, which is typically 50–100 µm. Sample flow rates can be as low as tens of nanolitres per minute; thus, sample efficiency is much higher and sub-milligram sample quantities can be sufficient  exposure time. Thus, the diffraction patterns are not ‘smeared out’ by crystal movement, as shown recently at the SLS  or shorter lipids such as MAG 7.9 , (i) the very same segment must be in the X-ray interaction region simultaneously with the X-ray pulse and not yet have travelled beyond or not yet have reached it, and moreover (ii) it must have passed beyond the interaction region before the next probe pulse. For ultrafast time delays Δt, the jet is essentially still during Δt and only (ii) needs to be considered. For longer time delays  both points (i) and (ii) matter. Point (ii) sets a minimal jet-speed limit and depends on the optical laser diameter and position. Point (i) sets the maximal and potentially another minimal jet speed and/or the distance between reaction initiation and X-ray interaction. For successful TR measurements, the jet speed must therefore be known and, together with other experimental parameters, adjusted where possible. Generally, the jet speed limits TR measurements in the free jet to a maximal time delay of at most a few microseconds for GDVNs, whereas a few seconds may be achieved with HVE.Jet speed is also important for optically triggered TR experiments as it can determine the accessible time delays  and microscopic jet size, which means that tracking a feature over time requires fast time resolution both to prevent blurring and to capture the feature at two or more successive positions. Pulsed (laser) illumination of sufficiently short duration (a few nanoseconds or less) can be used to deliver sharp images of liquid jets  and the displacement of a feature  can be tracked without difficulties using a camera with a reasonable frame rate and magnification  whether they can be used at room or cryogenic temperature.Fixed-target techniques are another means of serially delivering fresh sample for each X-ray exposure. Here, the crystals are immobilized on a substrate, which is then scanned through the X-ray beam. An inherent advantage of this approach is that in principle the geometry and crystal distribution can be arranged such that every crystal on the substrate is probed. Each step in a raster scan must clearly move beyond the area affected by previous probe pulses, which is particularly important at an XFEL. Numerous solid-support approaches have been developed over the years and, depending on the design, they mainly vary in (i) the X-ray background, which can be caused by the substrate itself and by excess mother liquor, (ii) the extent to which they support high-throughput data collection in terms of maximal data-collection rate and high hit rate, (iii) whether only specific crystal sizes or shapes can be accommodated, (iv) crystal handling, et al., 2014et al., 2016et al., 2019Goniometer-based approaches using standard loops and micromeshes or specialized high-density sample-mounting grids have successfully been used at XFELs with larger microcrystals (>20 µm) at cryogenic temperature  etched into silicon and crystals mixed with Paratone N ‘painted’ onto the remaining 50 nm layer of silicon nitride as a support . These windows can be endowed with modified surface properties  to promote random crystal orientations within a silicon mesh and thereby provide an efficient sampling of reciprocal space (Zarrine-Afsar et al., 2015et al., 2016et al., 2017et al., 2015et al., 2015et al., 2015et al., 2015et al., 2016et al., 2015et al., 2016et al., 2017et al., 2015et al., 2016et al., 2017et al., 2015et al., 2017et al., 2016et al., 2017et al., 2017et al., 2018et al., 2018To reduce background scattering even further, silicon chips can incorporate microscopic ‘wells’ (Mueller 4.Despite the increasing variety of sample-delivery techniques, there is no universal technique of choice for serial crystallographic data collection at XFEL or synchrotron sources. Instead, the suitability of a specific technique strongly depends on the investigated system and the experimental aim and conditions. We expect serial sample delivery to remain a rapidly developing field as the number of next-generation synchrotrons and XFELs is increasing, as will the user community.


The structures provide insight into the regulation and specificity of mirolysin, and hint at how it might be inhibited for therapeutic effect.Guevara, Rodriguez-Banqueri  Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia. These pathogens release ‘virulence factors’, molecules that aid their colonization and survival in the subgingival niche and their evasion of the host immune response. Synergistic interactions of the pathogenic microbes with normal oral microbiota lead to a sustained host inflammatory response, degrading periodontal tissues, eroding bone, and ultimately leading to tooth loss. Severe periodontitis affects around 10% of the human population, and health implications are not limited to oral health; the chronic inflammatory conditions precipitated by the disease can extend to systemic manifestations, contributing to risk of cardiovascular and respiratory diseases, diabetes, rheumatoid arthritis, and cancer (Hajishengallis, 2015et al., 2017Periodontitis, commonly known as gum disease, is a chronic inflammatory disease characterized by dysregulation of the oral microbiota in the subgingival space below the gum line (Hajishengallis, 2015T. forsythia. Mirolysin cleaves multiple components of the complement pathway to protect the pathogen against complement-mediated killing, and degrades the antimicrobial peptide LL-37, a human host defense peptide secreted by epithelial and immune cells at sites of infection (Jusko et al., 2015et al., 2017T. forsythia survival and immune evasion, mirolysin offers a potential therapeutic target, yet until now the structural basis for its latency, activation and substrate specificity have not been defined.Proteases are amongst the most abundant virulence factors produced by periodontal pathogens. These enzymes degrade host proteins to feed bacterial growth, and also serve as key mediators of immune-subversive mechanisms, for example by degrading or inactivating endogenous antimicrobial peptides and components of the host complement system (Hajishengallis, 2015IUCrJ, Guevara, Rodriguez-Banqueri et al. report high-resolution crystal structures of promirolysin, defining the mechanism of latency of the precursor protein (Guevara et al., 2020et al., 2018et al., 1999et al., 2018In this issue of 2 between these structural elements, greater than the average buried surface area for protein–protein complexes, which is remarkable given the small size of the 34-residue pro-segment. The pro-segment and catalytic domain interact through a balance of favorable hydrophobic interactions complemented by an array of hydrogen bonds and salt bridges, the same forces that shape affinity and selectivity of intermolecular protein–protein interactions (Xu et al., 1997in trans, and serving as a template for engineering protein-based mirolysin inhibitors of therapeutic utility. Similar approaches have shown promise for engineering therapeutic inhibitors of ADAM family metallopeptidases, based upon their much larger pro-domains (Moss et al., 2007et al., 2016While this basic cysteine switch mechanism of latency is well precedented, the promirolysin structure reveals a surprisingly extensive interface between the pro-segment and the catalytic domain. The zymogen structure reveals a buried surface area of 2302 Ået al. further report a high-resolution structure of active mirolysin bound to a peptide product, providing insight into determinants of substrate specificity of the protease (Guevara et al., 2020et al., 2017et al., 2019Guevara, Rodriguez-Banqueri


Accumulation of dysfunctional and damaged cellular proteins and organelles occurs during aging, resulting in a disruption of cellular homeostasis and progressive degeneration and increases the risk of cell death. Moderating the accrual of these defunct components is likely a key in the promotion of longevity. While exercise is known to promote healthy aging and mitigate age‐related pathologies, the molecular underpinnings of this phenomenon remain largely unclear. However, recent evidences suggest that exercise modulates the proteome. Similarly, caloric restriction (CR), a known promoter of lifespan, is understood to augment intracellular protein quality. Autophagy is an evolutionary conserved recycling pathway responsible for the degradation, then turnover of cellular proteins and organelles. This housekeeping system has been reliably linked to the aging process. Moreover, autophagic activity declines during aging. The target of rapamycin complex 1 (TORC1), a central kinase involved in protein translation, is a negative regulator of autophagy, and inhibition of TORC1 enhances lifespan. Inhibition of TORC1 may reduce the production of cellular proteins which may otherwise contribute to the deleterious accumulation observed in aging. TORC1 may also exert its effects in an autophagy‐dependent manner. Exercise and CR result in a concomitant downregulation of TORC1 activity and upregulation of autophagy in a number of tissues. Moreover, exercise‐induced TORC1 and autophagy signaling share common pathways with that of CR. Therefore, the longevity effects of exercise and CR may stem from the maintenance of the proteome by balancing the synthesis and recycling of intracellular proteins and thus may represent practical means to promote longevity. Accrual and aggregation of these defunct components result in disruption of cellular homeostasis, progressive degeneration, and increases the risk of cell death  is a central regulatory kinase that regulates cellular growth and protein synthesis. This complex is stimulated by nutrient availability , mechanical stress, and growth factors  and is inhibited by nutrient deprivation, energetic stress, and the macrocyclic polyketide rapamycin  has been shown to be a reliable method of lifespan extension and/or moderator of age‐related disease through modulation of autophagic activity in numerous model species ranging from yeast to humans     is one of two functionally and compositionally distinct multi‐protein TOR complexes; the second being TOR complex 2 (TORC2). Both complexes are highly conserved in all known eukaryotic cells  (Honjoh, Yamamoto, Uno, & Nishida, This evidence suggests that normal levels of autophagy may be sufficient to maintain cytosolic proteostasis if the rate of protein and organelle synthesis is reduced; however, it may also be possible that the reduced levels of autophagy observed in older cells may not be linked to aging, but simply offer an indirect reflection of excess TORC1 activity Pani, . At pres4S. cerevisiae and C. elegans to rodents and primates, including humans (Figure Lifespan extension via autophagy has been closely linked to CR (Bergamini, Cavallini, Donati, & Gori, s Figure  (Colman s Figure , and reps Figure . Calorics Figure .Even modest implementations of CR, such as intermittent fasting protocols, can promote health (Brandhorst et al., +‐dependent protein deacetylase also sensitive to energetic challenges, has been implicated in mediating the aging process (Salminen & Kaarniranta, Indeed, it has been observed that long‐term CR is a strong physiological promoter of autophagy, resulting in an upregulation of a number of autophagy‐related modulators and transcripts (Mercken et al., ++ is released from the lysosome into the cytosol, activating calcineurin which dephosphorylates TFEB and promotes its translocation to the nucleus where it initiates the transcription of a number of Atgs and proteins (Palmieri et al., Additionally, TFEB, a transcription factor involved in coordinating the expression of lysosomal and autophagic genes, has been shown to be activated during energy deprivation (Medina et al., Increasingly, autophagic activity has been shown to act as a key mediator of the observed impact of CR on lifespan (Bergamini et al., Some of the first data of long‐term CR on autophagic function in humans were collected from 15 lean and weight‐stable members of the Calorie Restriction Society who had practiced 30% CR for an average of 9.6 years. Upregulation of a number of autophagy modulators and gene and protein expression was noted including AMPK and SIRT family transcripts, ULK1, ATG101, APG12, GAPRAP/GATE‐6, beclin‐1, autophagin‐1, and LC3 gene expression, as well as protein expression of FOXOs, PGC1α, beclin‐1, and LC3 compared to age‐matched controls practicing a typical Western diet (Mercken et al., It is also interesting to note that suppression of the TORC1 pathway has been shown to potentiate longevity beyond the maximum extension achieved with CR alone (Bjedov et al., 5As discussed, energetic stress is a potent stimulator of autophagy; accordingly, exercise has been shown to augment acute autophagic activity in skeletal muscle (Jamart, Benoit, et al., While some data do exist relating to other forms of autophagy (Li et al., +, and ROS levels also are strong instigators of autophagic activity (Vainshtein & Hood, During exercise, autophagy mediates the clearance of proteins and organelles damaged by heat, pH changes, or mechanical stress which likely acts to prevent accumulation of these cytosolic components and maintain myocyte function (Schwalm et al., +, respectively. AMPK and SIRT1 both act to upregulate expression of Atgs by activating FOXO1 and FOXO3, increasing PGC1‐α activity, and inhibiting mTORC1 (Vainshtein & Hood, In part, exercise acts to initiate autophagy in skeletal muscle through the same pathways as CR; namely, AMPK and SIRT1 are sensitive to alterations in AMP and NAD++‐dependent calcineurin where it then activates the CLEAR gene network and the transcription of Atgs and proteins.mTORC1 has also been implicated in regulating autophagy activity through mediating TFEB localization which may be subsequently modulated by exercise and nutrient deprivation (Medina et al., In addition to serving as a means to meet the energetic demands of exercise, autophagy is understood to facilitate exercise in numerous ways in skeletal muscle (Dokladny et al., While exercise‐induced skeletal muscle autophagy is presently the most studied, there are data showing enhanced autophagic activity in other tissues, thus demonstrating acute exercise is capable of instigating a global autophagic response Figure  He, Bas. In theiThese noted systemic autophagic effects suggest exercise could possess a role in modulating some of the age‐related pathologies that autophagy has been reported to be implicated in, which include type 2 diabetes (Gonzalez et al., 6Emerging evidence suggests that the autophagic response to exercise may occur in a biphasic manner in that acute cellular perturbations induce a precipitous increase in autophagic flux occurring acutely following insult and is mediated by posttranslational protein modification (Vainshtein & Hood, 2max has been shown to stimulate autophagic activity in skeletal muscle (Jamart, Benoit, et al., 2max (Moller et al., 2peak (Schwalm et al., Aerobic exercise for 60 min or greater at 55%–70% VO2max did not alter autophagic activity in healthy adults (Masschelein et al., 2max induced autophagy (Moller et al., 2max did not produce a response (Tachtsis et al., Conversely, 20 min of cycling at ~50% VOThese findings help highlight the importance of exercise duration and intensity in stimulating autophagic induction and point to a threshold for activation, likely involving AMPK‐mediated determination of energy insufficiency. Importantly, the extreme elevations in autophagic activity observed with ultra‐endurance performance are likely indicative of excessive muscle damage and energetic protein catabolism, thus offering intriguing implications regarding the J‐shaped relationship observed between mortality and exercise participation (Arem et al., 7Currently, the long‐term effects of exercise on autophagic activity are ill‐characterized; however, they appear mediated by activation of a transcriptional program (Vainshtein & Hood, Skeletal muscle autophagy has been studied following regular exercise. In mice, 3 months of endurance exercise has been reported to produce no changes in resting levels of LC3‐II/LC3‐I ratio within skeletal muscle (Grumati et al., It is also interesting to note that autophagic activity appears to be necessary for the normal adaptations of skeletal muscle (He, Bassik, et al., Given aging is an organismal phenomenon, it is pertinent to establish the global effects of long‐term exercise on autophagy and determine its role beyond exercised skeletal muscle. While evidences exist demonstrating acute exercise is capable of upregulating autophagic activity and/or Atg expression in a number of tissues apart from skeletal muscle including heart (He, Bassik, et al., Ghareghani et al.  reported8Investigation into the mechanisms underpinning lifespan and longevity shows that the appropriate maintenance of the proteome and organelle population is key in the augmentation of lifespan and/or mitigation of many pathologies associated with the aging process (Balch, Morimoto, Dillin, & Kelly, None declared.


Neurobiological models of stress and stress-related mental illness, including post-traumatic stress disorder, converge on the amygdala and the prefrontal cortex (PFC). While a surge of research has reported altered structural and functional connectivity between amygdala and the medial PFC following severe stress, few have addressed the underlying neurochemistry.in vivo MR-spectroscopy (1H-MRS) measurements of glutamate in 26 survivors from the 2011 Norwegian terror attack and 34 control subjects.We combined resting-state functional magnetic resonance imaging measures of amygdala connectivity with et al., 2017) and together suggest long-term impact of a traumatic experience on glutamatergic pathways. Importantly, local glutamatergic metabolite levels predicted the individual amygdala–aMCC and amygdala–vmPFC functional connectivity, and also mediated the observed group difference in amygdala–aMCC connectivity.Traumatized youths showed altered amygdala–anterior midcingulate cortex (aMCC) and amygdala–ventromedial prefrontal cortex (vmPFC) connectivity. Moreover, the trauma survivors exhibited reduced levels of glutamate in the vmPFC which fits with the previous findings of reduced levels of Glx (glutamate + glutamine) in the aMCC (Ousdal Our findings suggest that traumatic stress may influence amygdala–prefrontal neuronal connectivity through an effect on prefrontal glutamate and its compounds. Understanding the neurochemical underpinning of altered amygdala connectivity after trauma may ultimately lead to the discovery of new pharmacological agents which can prevent or treat stress-related mental illness. Twenty-six survivors from the terror attack at Utøya and 34 healthy control subjects between 16 and 25 years were included in the study after giving written informed consent. All data were collected between 21 and 33 months after the terror attack. This study is part of a larger project assessing the effects of traumatic stress during late adolescence on cognition, behaviour and biological measures.et al., et al., The trauma survivors were recruited through written invitation sent out from the Resource Centre for Violence, Traumatic Stress and Suicide Prevention, Western Norway (64% response rate). The control sample was an age-, sex- and education-matched group, who were not involved in the trauma, and were not otherwise related to any of the survivors. In order to obtain information concerning participants’ mental health, the Mini International Neuropsychiatric Interview . All volumes were realigned to the first volume . We used the software default measures, which included (1) >1.5% variance in global signal from scan to scan and (2) >0.5 mm/TR frame-wise displacement. Volumes that exceeded one of these cut-offs were replaced via interpolation. Subjects with more than 20% bad volumes in total were excluded . After artefact correction, all images were spatially normalized to a standard EPI template based on the Montreal Neurological Institute (MNI) reference brain . This method calculated the temporal correlation between brain activation from our seed region and all other brain areas using a General Linear Model (GLM) approach. Following the CompCor strategy as implemented in CONN, nuisance covariates including CSF, white-matter signals and the individual realignment parameters were modelled and regressed out from the analysis. In addition, the data were band-pass filtered (0.008–0.09 Hz).The goal of our analysis was to assess amygdala–prefrontal resting-state connectivity due to the importance of these neurocircuits in stress-related psychiatric disorders -corrected significance of p < 0.05 at the cluster level. In addition, as we had a priori hypotheses regarding amygdala–dACC/aMCC and amygdala–vmPFC connectivity, small volume correction (svc) based on anatomically defined aMCC and vmPFC ROIs and peak-level FWE-corrected p values were used. The anatomically defined ROIs were created using the SPM Wake Forest University (WFU) Pickatlas toolbox .We tested for statistical significance using an initial voxel-wise threshold of et al., a priori for measurements of glutamate levels and related compounds. We obtained 1H-spectra from the vmPFC and the aMCC using a single voxel point resolved spectroscopy (PRESS) sequence. Glx data from the aMCC and the vmPFC voxels have been published previously  were used from the LCModel output. There was an association between Glu/Cr and white as well as grey matter in the vmPFC MRS voxel (see online Supplementary Methods), thus we controlled for voxel white and grey matter in all analyses of the vmPFC Glu/Cr data. We did not obtain aMCC 1H-MRS spectra from three of the controls. Furthermore, vmPFC 1H-spectra data from one trauma survivor and two controls had to be excluded due to poor data quality. Thus, the final sample size for the aMCC 1H-MRS data included 24 controls and 23 trauma survivors, and for the vmPFC 1H-MRS data, 25 controls and 22 trauma survivors.The amygdala is closely connected to the vmPFC and the dACC/aMCC , amygdala–dorsolateral PFC  and amygdala–cerebellum  connectivity. The location of the aMCC cluster accords with a recent meta-analysis which showed that hyperactivity in the aMCC is among the most consistent finding in traumatized subjects which develop PTSD  and amygdala connectivity while controlling for comorbid PTSD and panic disorder. The group differences were robust to adjustments for comorbidity (see online Supplementary Table S2). Except for the group difference in amygdala–dorsolateral PFC connectivity, we also replicated the findings in un-scrubbed data (see online Supplementary Table S3). Thus, the main findings were not dependent on any adjustments made by the ArtRepair software. Finally, a comparison of BA31 functional connectivity between the groups revealed no whole-brain or small-volume significant clusters.Amygdala functional connectivity maps across groups are presented in online Supplementary Fig. S1 with corresponding statistics in online Supplementary Table S1. We observed whole-brain significant group differences in amygdala–aMCC connectivity  = 4.54, p = 0.04, partial η2 = 0.10, t45 = 0.38, p = 0.71) in the aMCC. Mean Glu/Cr values for the vmPFC and the aMCC voxels are presented in online Supplementary Table S4.post-hoc analyses, we explored whether the glutamatergic compounds which displayed significant group differences also predicted inter-individual differences in amygdala functional connectivity. In the first analysis, we regressed individual vmPFC Glu scores onto the individual functional connectivity maps while controlling for vmPFC white and grey matter. The analysis revealed a negative association between vmPFC Glu and amygdala–vmPFC functional connectivity , and should therefore be interpreted with caution. Based on a previous finding of reduced levels of aMCC Glx in the trauma survivors  after controlling for the effect of group.In two separate r = −0.51, p = 0.02), supporting that the reduction of vmPFC Glu developed over time. Previous analyses revealed no association between aMCC Glx and time elapsed since the traumatic event . A second regression showed that the group was associated with aMCC Glx . aMCC Glx was also associated with amygdala–aMCC connectivity . Importantly, adding the aMCC Glx levels as a second predictor of the amygdala–aMCC connectivity removed the effect of the group , and the indirect effect of aMCC Glx on amygdala–aMCC connectivity was significant  and the amygdala in the aftermath of significant stress exposure (Gee et al., et al., et al., et al., et al., et al., et al., et al., In addition to reduced negative connectivity between vmPFC and the amygdala, we found significantly reduced positive connectivity between the amygdala and aMCC in the trauma survivors. The result is in line with studies in subclinical and clinical PTSD groups also finding compromised resting-state amygdala–dACC/aMCC connectivity (Thomason et al., et al., et al., et al., et al., et al., et al., et al., 1H-MRS, which restricts measurements to ‘bulk’ levels of metabolites, and the technical challenges especially related to acquisitions in the most ventral parts of the PFC (de Matos et al., et al., et al., Mounting evidence from animal studies suggests that acute and chronic stress affect Glu neurotransmission in the PFC (Popoli et al., et al., The directionality of the associations is worth reiterating. We have previously reported that traumatic stress was associated with a reduction of aMCC Glx (Ousdal et al., et al., et al., per se. As such, future studies should investigate potential associations between vmPFC Glu and amygdala connectivity in both PTSD patients and trauma-exposed control groups, to understand the association between stress exposure, stress-related psychopathology and amygdala–vmPFC glutamatergic connections. Finally, the association between amygdala functional connectivity and prefrontal glutamatergic metabolites were based on correlations, which do not imply causation. Thus, the present results should be interpreted with caution, bearing in mind the study design and analytic approaches.We acknowledge a potential limitation of the present study rests in the relative small group sizes and the heterogeneity related to the trauma group. This is always likely to be a problem in these types of studies given the variability of response to stressors. Furthermore, we acknowledge that the use of an amygdala ROI and not an independent component analysis when processing the rsfMRI data may be less sensitive to physiological noise (Van Dijk In conclusion, we found that traumatic stress influences functional connectivity between amygdala and medial prefrontal cortical regions, which are regions implicated in emotion generation and regulation. More specifically, trauma-exposed individuals had less positive amygdala–aMCC connectivity and less negative amygdala–vmPFC connectivity compared with a matched group without any trauma exposure. Overall, the results support a model in which traumatic stress is associated with reduced regulation of amygdala responses, both directly and indirectly. The amygdala–aMCC connectivity pattern was mediated by Glx, suggesting that the compromised connectivity in trauma survivors may be secondary to trauma-induced changes in prefrontal glutamatergic pathways. Identifying the neurochemical underpinning of the observed connectivity changes in trauma-exposed individuals may ultimately contribute to new pharmacological treatments of stress-related mental illness.


Capripoxvirus-induced diseases of cattle and sheep, respectively. Despite the extensive vaccination program adopted by Egyptian veterinary authorities, LSD and sheep pox are still prevalent and spread throughout the whole country. The current study was designed for molecular characterization and phylogenetic analysis of LSD virus (LSDV) and Sheep pox virus (SPPV) recovered from field cases in Egypt along with vaccinal strains to assess their genetic relatedness.Lumpy skin disease (LSD) and sheep pox are economically important Skin biopsies were collected from naturally infected cases of LSD in Ismailia (n=3 farms) and Beni-Suef (n=2 farms) Governorates and sheep pox in Beni-Suef (n=1 flock). Virus isolation was carried out on primary ovine fetal kidney and heart cell cultures. DNA was extracted from infected materials  as well as LSDV Neethling vaccine strain and Romanian SPPV vaccine strain. Polymerase chain reaction was performed using oligonucleotide primers targeting the entire open reading frame of G protein-coupled receptors (GPCR) gene and gene sequences were analyzed.Virus isolation on primary ovine fetal kidney and heart cell culture revealed a cytopathic effect at the third passage characterized by rounding of infected cells and margination of nuclear chromatin. Comparative sequence analysis of GPCR gene revealed that Egyptian LSDV isolated from Ismailia and Beni-Suef shared 99:100% nucleotide and amino acid (AA) identities with each other. In comparison to the vaccinal strains, Egyptian LSDV isolates shared 98:99 nucleotide and AA identities with LSDV Neethling vaccine strain and 93:94% with SPPV Romanian vaccine strain. No differences at the nucleotide or AAs were observed between the SPPV vaccine and virulent strains (100% identity). Phylogenetic analyses revealed that LSDV Neethling vaccine strain is more related to field Egyptian LSDV and clustered within the LSDV group while Romanian SPPV vaccine strain clustered in a separate clade with SPPV field isolates.Comparative sequencing and phylogenetic analyses of the GPCR gene reveal a minimal genetic variation between LSDV field isolates from different locations and a close relationship between virulent field strains and homologous vaccines. Capripoxvirus (CaPV)-induced diseases of cattle and sheep, respectively. LSD virus (LSDV) and Sheep pox virus (SPPV) are categorized within the genus CaPV in the family Poxviridae [Lumpy skin disease (LSD) and sheep pox are economically important xviridae .LSD is an acute to subacute disease of cattle characterized by fever, rapid eruption of numerous circumscribed skin nodules, and generalized lymphadenitis -5. The cSheep pox is a highly contagious disease of small ruminants  characteThere is no doubt that vaccination is the most effective way to control CaPV diseases . Due to In Egypt, the Kenyan SGP O-240 vaccine was used during LSD incursion in 2005-2006 . At presIn the current study, G protein-coupled receptors (GPCR) gene was used for molecular characterization and phylogenetic analysis of LSDV and SPPV circulating in the field along with vaccinal strains to assess their genetic relatedness.All animal handling procedures, as well as samples collection and disposal, were approved by the animal care and use committee of the Faculty of Veterinary Medicine, University of Sadat City, Egypt, according to the guidelines and recommendations of the European Communities Council Directive 1986 (86/609/EEC).From June 2015 to September 2016, LSD and sheep pox were suspected among dairy cattle herds located in private farms belonging to Ismailia (n=3) and Beni-Suef (n=2) Governorates and one sheep flock in Beni-Suef Governorate, respectively. All farms were clinically examined and a total of five nodular skin lesions were collected from diseased cattle with skin eruption all over the body while skin lesions were collected and pooled from infected sheep pox flock showing generalized pock lesions. The collected samples were kept at −20°C for virus isolation and polymerase chain reaction (PCR).4 TCID50 of freeze-dried, live, attenuated virus (SIS Neethling-type)from the Republic of South Africa and Romanian SPPV vaccine strain provided from the Pox Department, Veterinary Serum and Vaccine Research Institute, Abbassia, Cairo, Egypt, was used in the molecular study (103 TCID50/ml).South African Neethling vaccine strain  each 1 mL (1 dose) of the vaccine contains 10et al. [Skin biopsies were used for the isolation of LSDV and SPPV according to Tuppurainen et al. . BrieflyDNA was extracted from skin lesions, infected cell culture, LSDV Neethling vaccine strain, and Romanian SPPV strain using a DNA/RNA Extraction Kit  according to the manufacturer’s instructions.et al. [The primers were developed to amplify the entire GPCR gene at position 6961-8119 according to Le Goff et al. . The priet al. [http://Zwww.ncbi.nlm.nih.gov/blast) was initially implemented to establish sequence identity to GenBank accessions. Phylogenetic tree and sequence alignments were generated using MEGAVersion X software. The tree was generated by the neighbor-joining method based on 1000 bootstrapped data sets [PCR amplicons were purified using QIAquick PCR Purification Kit and dispatched to Macrogen™, Seoul, Korea, for DNA sequencing using two additional primers(5´-GATGAGTATTGATAGATACCTAGCTGTAGTT-3´and 5´-TGAGACAATCCAAACCACCAT-3´) according to Le Goff et al. . BLAST aata sets .Fever, skin lesions scattered in different parts of the body , and enlVirus isolation revealed CPE at the third passage on primary ovine fetal kidney and heart cells, characterized by retraction of the cell membrane from surrounding cells, rounding of cells, and margination of the nuclear chromatin .Using primer sequences targeting the entire GPCR gene, a fragment of 1158 bp has been amplified from all DNA extracts . SequencRegarding Romanian SPPV vaccine strain, it was found that AA residues situated in position 10-16 (SATMYNS) in LSDV field isolates are missed in SPPV vaccine; moreover, there are 27 variances in AA motifs between LSDV field isolates and SPPV vaccines were observed along GPCR gene  and 2. OTo represent the evolutionary relationships among field and vaccinal strains of LSDV and SPPV sequenced in this study and available CaPVs in the database, a GPCR-based phylogenetic tree was generated using the neighbor-joining method on nucleic acid sequences. The tree showed three tight genetic clusters  . LSDV faCapripoxviruses field and vaccinal strains based on sequence analysis of GPCR gene.LSD and sheep pox diseases are now considered as endemic diseases in Egypt. Despite the extensive vaccination program adopted by Egyptian veterinary services, LSD and sheep pox are still prevalent and spread throughout the whole country, thereby the present study provides a molecular characterization of LSDV and SPPV recovered from field cases in Egypt and a comparison of A total of five LSDV and one SPPV were isolated from naturally infected animals with typical clinical features of LSD and sheep pox, respectively, after being confirmed by PCR.The complete open reading frames of the GPCR gene of isolated viruses were sequenced along with vaccine strains. Comparative sequence analysis revealed that all of the five LSDV isolates are closely related to each other with a nucleotide and AA identity ranged from 99% to 100% in between confirming the circulation of the same virus strain.Egyptian LSDV field isolates were found more related to LSDV Neethling vaccine where it differs only in four AA substitutions and an AA deletion at positions 30-33.et al. [et al. [The comparative sequence analysis revealed that the 5-end of GPCR gene of SPPV vaccine was characterized by deletion of 21 nucleotides (7-aa) when it compared with LSDV field isolates. This sheep pox gap was recorded in all isolates and vaccine strains located in the database and was considered as a specific signature for SPPV as reported previously by Le Goff et al. . Many va [et al.  and El-T [et al. . Intereset al. [et al. [et al. [Phylogenetically, CaPV was delineated into three clades LSDV, GTPV, and SPPV as previously reported by Rouby et al. , Rouby [et al. , Rouby aet al. , and Maf [et al. . LSDV fa [et al. . The oth [et al.  and rece [et al. .Comparative sequencing and phylogenetic analyses of GPCR gene revealed a minimal genetic variation between different LSDV isolates from different locations and a close relationship between LSDV Neethling vaccine strain and Egyptian field LSDV isolates. GPCR gene possesses specific signatures for LSDV and SPPV at both nucleotide and AA sequences level and cluster them separately according to their host origin.ME designed the study. SRR and AB performed PCR, sequence analysis, and wrote the initial draft of the manuscript. MW and ME revised the manuscript. All authors read and approved the final manuscript.


The aim of this review was to summarize key developments in classification and diagnosis of the idiopathic inflammatory myopathies (IIMs).The recently published European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for the IIMs provide a comprehensive, accurate and data-driven approach to identification of IIM cases appropriate for inclusion in research studies. Further, recent studies have advanced understanding of clinical manifestations of the IIMs and delineated the role of imaging, particularly magnetic resonance.The recent publication of the EULAR/ACR classification criteria will potentially greatly improve IIM research through more accurate case identification and standardization across studies.Future inclusion of newly recognized clinical associations with the MSAs may further improve the criteria's accuracy and utility. Clear and comprehensive understanding of associations between clinical manifestations, prognosis and multisystem involvement can aid diagnostic assessment; recent advances include delineation of such associations and expansion of the role of imaging. The idiopathic inflammatory myopathies (IIMs) are a group of autoimmune diseases characterised by chronic muscle inflammation (myositis), internal organ inflammation and significant morbidity and mortality . The widThis article aims to summarize recently published research pertinent to advances in IIM classification and diagnosis. A Medline search for research articles published between January 2017 and May 2018 was carried out using the MeSH term ‘myositis’. Articles primarily focussing on myositis-specific autoantibodies were excluded, as they will be reviewed in detail in a separate article. The IIMs have traditionally been classified and diagnosed according to the criteria by Bohan and Peter Table  since pu▪▪]. Initial methodology identified 93 candidate variables for inclusion in the classification criteria. Variable domains included pattern of weakness, dermatological manifestations, disease course, systemic manifestations, response to treatment, pattern of muscle biopsy abnormalities, presence of MSAs, electromyogram (EMG) and MRI features.These drawbacks have limited accurate identification of well defined populations suitable for IIM research studies. Therefore, in 2004, the International Myositis Classification Criteria Project (IMCCP) was established with the aim of developing new IIM classification criteria. The IMCCP working committee was formed of experts from adult and paediatric rheumatology, neurology, dermatology, epidemiology and biostatistics. In 2017, the newly developed European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria were published [4Using data from 976 IIM cases and 624 comparators, the combination of candidate variables that could most accurately distinguish between IIM and non-IIM participants was identified. The variables included in the final classification criteria are displayed in Table The likely IIM subtype of each case can also be ascertained, according to the published classification tree Fig. . Subtypeet al. [et al. [www.imm.ki.se/biostatistics/calculators/iim.The EULAR/ACR criteria demonstrated high sensitivity 93%) and specificity 88%) when muscle biopsy data were included. Sensitivity and specificity also remained high when muscle biopsy data were not included: 87 and 82%, respectively. The accuracy of the newly created classification criteria was compared against previously developed criteria, including those by Bohan and Peter [% and speet al. , Targoff [et al. , Dalakas8% when mThe criteria have a number of major strengths. Their development methodology included a large IIM population with non-IIM comparators and considered inclusion of a wide variety of candidate variables. The ease of use and provision of a website-based calculator are also major strengths. Drawbacks include the fact that a majority of the development population were white, thus potentially limiting the criteria's validity in Asian and African populations. Further, MRI and electromyography data were only available in 38 and 29% of cases, thus potentially excluding these variables from the criteria only due to missing data. A limitation of subtype identification is the inability to separately identify IMNM and ASS cases. The inclusion of only one myositis-specific autoantibody (anti-Jo-1) in the classification criteria is a major limitation, as recent studies have illustrated the important and distinctive clinical and subtype associations . TherefoIn summary, the newly developed EULAR/ACR classification criteria for the IIMs provide an accurate method through which clearly defined study populations can be formed, thus potentially improving validity of IIM research.The newly developed classification criteria provide robust methods for identifying IIM cases for research purposes; however, their use is not designed nor recommended for use in clinical practice.Accurate diagnosis of an IIM is key to appropriate treatment instigation, prognostication and prevention of complications. However, diagnosis and subtype identification in clinical settings can be challenging, in part due to potential multisystem involvement and wide variations between subtype manifestations. Currently, no clear diagnostic criteria for the IIMs exist. However, findings from clinically focused research studies can aid a clinician's diagnostic accuracy, identification of factors associated with prognosis and guide investigation of multisystem involvement.et al.[N = 2145). Interestingly, seven of the nine cases also fulfilled criteria for ASS and six cases were positive for anti-Jo-1 antibodies. This study highlights the importance of foot examination in IIM cases when trying to identify cutaneous manifestations. Mamyrova et al.[et al.[Findings from epidemiological and observational studies can inform clinical practice and guide the diagnostic process. A number of observational studies have recently been published and these will be summarized, with a particular focus upon potential clinical applications. Cox et al. recentlyva et al.▪ identifA recent study compared the utility of muscle testing via hand-held dynamometry against manual muscle testing in myositis cases . They reet al.[et al.[∗03, thus indicating a genetic interaction with smoking and IIM development. These studies therefore highlight the importance of ascertaining a patient's smoking history due to its potential diagnostic utility and estimation of ILD risk.Interstitial lung disease (ILD) is an important extramuscular manifestation to consider during the diagnostic process and subsequent assessments. A number of studies have recently investigated risk factors for ILD. A recent study by Schiffenbauer et al. has highl.[et al. in 2012,et al.[et al.[Investigation for predictors of poor survival in 497 IIM-associated ILD cases was carried out by Sato et al.. They idl.[et al. reportedThe role of imaging in IIM diagnosis has expanded in recent years and has a number of capabilities. Imaging techniques, such as MRI, can help identify the presence of myositis, delineate its extent and assess treatment response, through serial scans and also help focus appropriate areas for muscle biopsy, limiting the likelihood of a false negative sample.et al.[et al.[et al.[Studies by both Yao et al.▪ and Andl.[et al. have recl.[et al.▪ also coet al.[et al.[Pinal-Fernandez et al. reportedl.[et al. in 12 biet al.[et al.[Focused MRI scanning can identify focal areas on myositis; however, whole-body MRI offers the ability to completely delineate all muscle groups affected and potentially identify secondary organ involvement and the presence of associated malignancy. Whole-body MRI, as opposed to focused imaging, was advocated by Elessawy et al.▪ as the l.[et al. also repet al.[Other imaging modalities also offer utility in IIM diagnosis. Burlina et al.▪ recentlet al.[Computed tomography (CT) scanning offers detailed assessment of the presence of ILD. A recent study by Ungprasert et al. investiget al.[et al.[The ability to identify cardiac involvement (an uncommon but important extramuscular manifestation) and distinguish from other heart disease has undergone advances recently. The utility of MRI in identifying cardiac involvement has been confirmed in recent years by a small number of studies ,29. Receet al. have recl.[et al. aimed toet al.[Huber et al.▪ confirmAccurate case identification is key to IIM research and the recent publication of the EULAR/ACR classification criteria will potentially greatly improve IIM research through accurate case identification and standardization across studies. Clear diagnosis of the IIMs is important to ensure appropriate diagnosis and treatment instigation. Recent advances in knowledge of clinical features will aid the clinician in prognostication, treatment stratification and investigation for multisystem involvement.None.This work was supported by Medical Research Council (MRC) UK grant MR/N003322/1. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health.There are no conflicts of interest.▪ of special interest▪▪ of outstanding interestPapers of particular interest, published within the annual period of review, have been highlighted as:


To conduct advanced psychometric analysis of Primary Care Assessment Tool (PCAT) in Tibet and identify avenues for metric performance improvement.Measuring progress toward high-performing primary health care can contribute to the achievement of sustainable development goals. The adult version of PCAT is an instrument for measuring patient experience, with key elements of primary care. It has been extensively used and validated internationally. However, only little information is available regarding its psychometric properties obtained based on advanced analysis.We used data collected from 1386 primary care users in two prefectures in Tibet. First, iterative confirmatory factor analysis examined the fit of the primary care construct in the original tool. Then item response theory analysis evaluated how well the questions and individual response options perform at different levels of patient experience. Finally, multiple logistic regression modeling examined the predicative validity of primary care domains against patient satisfaction.A best final structure for the PCAT-Tibetan includes 7 domains and 27 items. Confirmatory factor analysis suggests good fit for a unidimensional model for items within each domain but doesn’t support a unidimensional model for the entire instrument with all domains. Non-parametric and parametric item response theory analysis models show that for most items, the favorable response option (4 = definitely) is overwhelmingly endorsed, the discriminability parameter is over 1, and the difficulty parameters are all negative, suggesting that the items are most sensitive and specific for patients with poor primary care experience. Ongoing care is the strongest predictor of patient satisfaction. These findings suggest the need for some principles in adapting the tool to different health system contexts, more items measuring excellent primary care experience, and update of the four-point response options. Values were also imputed for the ‘not sure/don’t remember’ response option as an alternative to attributing the pre-set value of 2.5. In general, estimates produced with listwise deletion are less efficient than other methods of handling missing data. Therefore, we reported only results using database with ML imputation  imputation method was used to replace the missing values; match age, sex, education, self-rated health status; 295 respondents were excluded because of missing values for the matching variables, leaving 1091 respondents in subsequent analyses. Those excluded were more likely to be female and less educated. To examine the robustness of our conclusion, we excluded all respondents who had at least one missing value on any item (listwise deletion) and repeated all data analyses  by domain was conducted to flag items with low correlations (Pearson <0.20) or low factor loading (<0.30) for potential deletion. We repeated the exploratory factor analysis after deleting each item with low factor loading until all retained items had a factor loading of at least 0.30. The results of exploratory factor analysis guided subsequent confirmatory factor analysis.Then confirmatory factor analysis using structural equation modeling was used to test the goodness of fit of the items to the theoretical domains of the original PCAT. Subsequently, confirmatory factor models were adjusted iteratively based on fit and judgment until the goodness-of-fit statistics were optimized. We also assessed the entire instrument including all domains in our data analysis. First, we included all domains in confirmatory factor analysis. Then we only included the four core domains  in confirmatory factor analysis. The following goodness-of-fit statistics were used: normed fit index (NFI) ≥0.9 indicating good fit, comparative fit index (CFI) ≥0.9 indicating good fit, standardized root mean square residual (SRMR) ≤0.05 indicating acceptable fit.For each domain confirmed as being unidimensional, we examined the distribution of response options of individual items within each domain based on domain performance using nonparametric item response theory analysis. However, we cannot get the exact information of each item performance. To be more precise, two parameter estimates (discriminability and difficulty) were subsequently generated using Samejima’s  grade reWe estimated the correlations between domains to examine how domains were related and whether they demonstrated distinctiveness.Finally, we used logistic regression modeling to examine how primary care domains were associated with patients’ satisfaction with service attitude (one item) and perceived technical quality (one item) of their primary care provider. The five-point Likert response scale for the two items was dichotomized to indicate satisfaction (very satisfied or satisfied) versus dissatisfaction. All domains were put in the same model, and age, sex, education, and self-rated health status were included in the model as covariates. Education level was categorized into three groups: illiterate, primary school, junior high school and above. Self-rated health status was measured by a visual analogue scale with end points of 0 and 100, where 0 corresponds to ‘the worst health status’, and 100 corresponds to ‘the best health’.Descriptive, correlation, and exploratory factor analysis were conducted with SPSS 22.0. ML imputation and confirmatory factor analysis were conducted with LISREL9.1. Nonparametric and parametric item response theory analyses was conducted with SPSS 22.0 and MULTILOG 7.03.Table S1.For first contact access, two of the six items were deleted because of the unacceptable goodness-of-fit statistics (FCA5 and FCA6); and two items fit better in first contact utilization (FCA1 and FCA4), leaving only two items in first contact access and four in first contact utilization. In the eight-item ongoing care, two items were deleted because of unacceptable goodness-of-fit statistics (OC1 and OC7); and a further item (OC8) was removed to improve the goodness-of-fit statistics, leaving a five-item ongoing care scale. The eight-item comprehensiveness subscale showed unacceptable goodness-of-fit statistics on a single factor ; and after removing four of the poorest fitting items, a final four-item comprehensiveness subscale demonstrated good fit . There is no change in items in other domains. The detailed iterative process to finalize the original factor structure was reported in Supplemental Table Table However, either the model including all domains  or the model including only the four core domains  shows unacceptable goodness-of-fit statistics on a single factor, which suggest that the domains included in original PCAT may not measure a common single construct in Tibet context, and it is not appropriate to report a total score.α is over 0.70, indicating good internal consistency of items for all domains except first contact access (0.66) and ongoing care (0.66).The mean of each domain score is lower than the median and negatively skewed, indicating most of patients reporting favorable response answers. The first contact utilization score is the highest (3.66±0.48), while the first contact access score is the lowest (2.94±0.95). Cronbach Non-parametric item response theory graphs were modeled on each unidimensional domain to provide further insight into item performance and reliability. In most items, the option characteristic curve for the response option ‘2 = Probably not’ is overshadowed by other options  and ongoing care (0.60). First contact utilization is also highly correlated with family centeredness (0.54) and ongoing care (0.55). First contact access, comprehensiveness, and community orientation have lower correlation with other domains.The Pearson correlations between the domains indicate the distinctiveness of each domain. Correlation coefficients between domains range from 0.23 to 0.61 and are lower than Cronbach Finally, Table This advanced psychometric analysis of the PCAT-Tibetan versions provides further insight into some of the problematic psychometric properties found in the initial validation analysis, and it suggests avenues to improve the metric performance of the tool. Despite the metric problems, the PCAT-Tibetan domains of first-contact, ongoing care, and coordination with specialists are associated with an increased likelihood of patient satisfaction. This illustrates the potential of the PCAT and underlines the importance of improving the tool to address some of the metric problems. Some of the problems, such as the skewness of item response distribution found in many items, are shared with the original PCAT and other versions; and our results suggest some solutions that could improve performance. Others may be specific to the PCAT-Tibetan version – such as the non-optimal resolution of items relating to First Contact constructs – suggest the need for some principles in adapting the tool to different health system contexts.et al., et al., et al., et al., et al., et al., et al., et al., The widespread use of the PCAT to evaluate primary care in many countries provides an opportunity to compare primary care across different contexts and to support a worldwide movement to improve primary care. Our results show not only the association of the PCAT-Tibetan with patient satisfaction but also other analysis that demonstrated the capacity to distinguish between health-care organizations in Tibet and other regions in China (Wang et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., The negative skewness of item response distribution in many items was noted in the original validation of the long PCAT version (Shi et al., et al., et al., et al., et al., et al., et al., Another metric issue results from offering the ‘not sure/don’t remember’ option. The high rate of endorsing this response option is common in many language versions, especially in Asian countries including Korean, Japanese and Chinese. (Lee et al., et al., et al., et al., et al., α was only 0.38 (Mei et al., et al., et al., et al., et al., et al., et al., Collaborative international work could also address principals for measuring and/or comparing domains that affected health system specificities, for instance, in the access domain. First contact in the PCAT-Tibetan fails to meet optimal psychometric standards of construct validity and internal consistency. Similar problems were also found in other PCAT validation studies in China (Yang et al., et al., et al., In contrast, the domain of ongoing care most strongly predicts patient satisfaction with primary care provider in Tibet. This is consistent with a previous systematic review showing that the most important determinants of satisfaction are the interpersonal relationships and their related aspects of care (Crow This study contributes to the growing international work supporting the relevance and need for valid and reliable measures of the patient experience of health care. Several lessons from PCAT-Tibetan validation study may be shared with our colleagues in low- and middle-income countries. First, the items or content of instruments from developed countries may not be appropriate in other countries. Some specific features of local primary care system may not be reflected in the translated instruments. For example, no items in PCAT could reflect the feature of geographical accessibility, which is a major aspect in Tibet. Some items in comprehensiveness domain are not appropriate in Tibet. Therefore, instead of adapting existed instrument directly, qualitative research is needed to understand the local population preference of primary care first. Second, more items to measure excellent primary care experience should be developed. Most existing items have adequate capacity to discriminate between poor and average performance on different primary care domains. However, items that discriminate clearly between average and good primary care are needed. Further research is required to explore the characteristics of some exemplars with good primary care experience and what the good primary care is from their narratives. Third, the choice of response categories should be careful. The current four-point response scale and its wording in PCAT may not be appropriate in some countries. Several factors could be considered when exploring the appropriate response categories, such as literacy level, response tendency, and judgment making of local population. This could be done through qualitative research.Finally, a summary score of overall primary care experience including all domains, which is often the most used metric when assessing a health system, is not supported by our analysis of PCAT-Tibetan version. However, this psychometrically validated 27-item Tibetan version of PCAT will be useful in monitoring and evaluating the performance of primary care system in Tibet in specific areas, especially in accessibility, continuity, and coordination, which are the priorities of current health reform efforts in Tibet. The health service research is underdeveloped in Tibet, and there is no instrument measuring patient experience that could be used when this study was conducted. We hope this study could bring more researchers’ attention into primary care performance evaluation in Tibet. We also recognize that different policy interventions to achieve primary care functions are inter-related, but each policy has its own priorities. For example, the family doctor contract service model is being developed and expanded now to improve performance in accessibility and continuity; and the transformation of tiered health service delivery system aims to promote collaboration between different health-care providers and to improve coordination. Under this context, PCAT-Tibetan version is a potential useful instrument to evaluate the effectiveness of these policy interventions.


Hyaluronan and proteoglycan link protein 2 (Hapln2) is important for the binding of chondroitin sulfate proteoglycans to hyaluronan. Hapln2 deficiency leads to the abnormal expression of extracellular matrix (ECM) proteins and dysfunctional neuronal conductivity, demonstrating the vital role of Hapln2 in these processes. Studies have revealed that Hapln2 promotes the aggregation of α-synuclein, thereby contributing to neurodegeneration in Parkinson’s disease (PD), and it was recently suggested to be in intracellular neurofibrillary tangles (NFTs). Additionally, the expression levels of Hapln2 showed lower in the anterior temporal lobes of individuals with schizophrenia than those of healthy subjects. Together, these studies implicate the involvement of Hapln2 in the pathological processes of neurological diseases. A better understanding of the function of Hapln2 in the central nervous system (CNS) will provide new insights into the molecular mechanisms of these diseases and help to establish promising therapeutic strategies. Herein, we review the recent progress in defining the role of Hapln2 in brain physiology and pathology. Parkinson’s disease (PD), Alzheimer’s disease (AD) and schizophrenia are neurological diseases characterized by the dysfunction of certain types of neurons , is vital for neuronal conductivity and the formation of the extracellular matrix (ECM), and besides its potential role in the UPP, it has been identified as a contributor to the pathological processes in several neurological disorders. For example, Martins-de-Souza et al.  showed tHAPLN2 revealed seven exons encoding a polypeptide with an estimated molecular mass of 38 kDa (Hirakawa et al., The structure and roles of Hapln2 in the CNS have been studied since around the turn of this century, when an analysis of the gene now known as The hyaluronan and proteoglycan link family of proteins consists of four members: Hapln1, Hapln2, Hapln3, and Hapln4 (Spicer et al., HAPLN2 mRNA is expressed at high levels in the human hippocampus, medulla oblongata, putamen, SN, thalamus, and spinal cord but at lower levels in the cerebellum, cerebral cortex, frontal lobe, and nucleus accumbens. By in situ hybridization, we detected high expression levels of Hapln2 mRNA in the SN, olfactory bulb, red nucleus, cerebellum, brain stem, and hippocampus but relatively weak signals in the cerebral cortex of adult rat brain (Wang et al., Northern blot analyses by Hirakawa et al.  showed tLecticans such as brevican and aggrecan mainly bind to the hyaluronans, which are the major components of the ECM in the brain (Yamaguchi, + channels antibody (Oohashi et al., + channels and the contactin-associated protein (Rasband et al., Northern blot analyses have shown that Hapln2 expression in the mouse brain begins at 20 days after birth and increases with age (Hirakawa et al., + channel clustering coincides with myelination (Bekku et al., + channels. Of note, the clustering of Na+ and K+ channels is critical for saltatory conduction (Oohashi et al., + and K+ channels, flash visual evoked potentials had a longer latency and smaller amplitude in recordings from Hapln2 knockout mice compared with those from wild-type mice (Bekku et al., + channels (Susuki et al., + channel, nodes formation and AP propagation. However, more studies should be performed to clarify the details about the relationship between Hapln2 and the paranodal barriers or the CS in these processes during the development.As NaAs mentioned above, Hapln2 deficiency decreased the expression of ECM-associated proteins (Bekku et al., PD is characterized by the formation of Lewy bodies and selective loss of dopamine neurons in the SN (Liu et al., via proteasome inhibition resulted in the degeneration of dopaminergic neurons in vitro and in vivo (Kikuchi et al., Flow cytometry and immunostaining analyses showed that the overexpression of Hapln2 increased the death of MES23.5 and primary neuronal cells (Wang et al., Immunostaining analysis of MES23.5 cells overexpressing Hapln2 also showed an accumulation of α-synuclein, aggregates of which were found to colocalize with Hapln2 (Wang et al., A variety of environmental and genetic factors have also been implicated in the pathology of AD (Chin-Chan et al., via disruptions of the UPP. Postmortem tissue samples from the hippocampus, superior and middle temporal gyri, parahippocampal gyri, and the inferior parietal lobes of AD patients exhibit signs of reduced proteasome activity compared with those from control subjects (Keller et al., Notably, both AD and PD are age-associated neurodegenerative diseases with characteristic protein aggregates (Bridi and Hirth, in situ hybridization (Wang et al., Although high levels of Hapln2 in the hippocampus were measured by via the degradation of particular substrate proteins (Tsukamoto and Yokosawa, Although the pathophysiology of schizophrenia has not been fully defined, genetic factors, epigenetic elements, and abnormal neurotransmission in the hippocampus are important contributors (Kim et al., Moreover, it has been reported that ECM plays important roles in regulating neurogenesis, axonal outgrowth, synaptogenesis and cell migration (Bandtlow and Zimmermann, As a brain specific-hyaluronan and proteoglycan link protein, Hapln2 plays vital physiological roles in the formation and maintenance of the ECM scaffold. Studies in knockout mice have also revealed that Hapln2 influences neuronal conductivity. Several studies have revealed the involvement of Hapln2 in the pathogenesis of neurological diseases including PD, AD and schizophrenia, which provided new insights into the underlying molecular mechanisms of brain disorders .Current research suggested that Hapln2 was involved in the formation of α-synuclein aggregates in PD pathology and study in AD suggested that Hapln2 might be the component of NFTs aggregates (Minjarez et al., QW, CW, BJ, and CY wrote the manuscript. JC and JZ edited the manuscript. All the authors approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The mental and physical health of individuals with a psychotic illness are typically poor. Access to psychosocial interventions is important but currently limited. Telephone-delivered interventions may assist. In the current systematic review, we aim to summarise and critically analyse evidence for telephone-delivered psychosocial interventions targeting key health priorities in adults with a psychotic disorder, including (i) relapse, (ii) adherence to psychiatric medication and/or (iii) modifiable cardiovascular disease risk behaviours.Ten peer-reviewed and four grey literature databases were searched for English-language studies examining psychosocial telephone-delivered interventions targeting relapse, medication adherence and/or health behaviours in adults with a psychotic disorder. Study heterogeneity precluded meta-analyses.Twenty trials [13 randomised controlled trials (RCTs)] were included, involving 2473 participants . Five of eight RCTs targeting relapse prevention and one of three targeting medication adherence reported at least 50% of outcomes in favour of the telephone-delivered intervention. The two health-behaviour RCTs found comparable levels of improvement across treatment conditions.Although most interventions combined telephone and face-to-face delivery, there was evidence to support the benefit of entirely telephone-delivered interventions. Telephone interventions represent a potentially feasible and effective option for improving key health priorities among people with psychotic disorders. Further methodologically rigorous evaluations are warranted. Life expectancy is 12–19 years shorter than that of the general population Laursen, , with CVet al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Importantly, increasing evidence supports the role of psychological interventions  for improving symptoms . The focus of this review will be on person-delivered interventions using the spoken word  and one or more psychological strategies  and the protocol has been published  were assessed against the 11 item Physiotherapy Evidence Database (PEDro) scale  was assessed using the Collaboration's Risk of Bias tool, as described in the A study was considered to have a positive outcome if more than 50% of the reported outcome measures (primary and secondary) demonstrated a between-group difference in favour of the telephone group at the treatment end. Positive maintenance outcome(s) were identified when this effect was evident at short and/or medium and/or long-term follow-up .Comparability of study design and outcome measures across studies was assessed by a consultant statistician to determine the possibility of conducting meta-analyses on RCTs to examine effects on relapse, medication adherence and smoking and other health behaviours and CVD risk. A narrative synthesis of the findings was conducted, structured around intervention type, outcome, population and methodological quality. As Clinical Guidelines recommend an improved focus on personally meaningful recovery  relative to traditional clinical outcomes (e.g. symptoms and relapse) in mental health care, to help inform clinical practice, the assessment, reporting and/ or change in these additional outcomes is also central to the structure of the review.Across all studies, the total number of participants was 2473, with 867 in relapse prevention, 1273 in medication adherence and 333 in smoking and/or other health risk behaviour studies (see online Supplementary Table S1). The average age was 40.7 years . Overall, the percentage of males across the studies was 50.1%. However, there was a higher percentage of males in studies of schizophrenia samples (64.5%) compared with studies of bipolar (37.7%) and mixed samples (44.2%). No study used a first episode sample.et al.  in favour of TAU  has been argued to be a sufficient alternative (Hansson


In the present contribution, we introduce the eLignin database, use its dataset to map the reported ecological and biochemical diversity of the lignin microbial niches, and discuss the findings.Lignin is a heterogeneous aromatic biopolymer and a major constituent of lignocellulosic biomass, such as wood and agricultural residues. Despite the high amount of aromatic carbon present, the severe recalcitrance of the lignin macromolecule makes it difficult to convert into value-added products. In nature, lignin and lignin-derived aromatic compounds are catabolized by a consortia of microbes specialized at breaking down the natural lignin and its constituents. In an attempt to bridge the gap between the fundamental knowledge on microbial lignin catabolism, and the recently emerging field of applied biotechnology for lignin biovalorization, we have developed the eLignin Microbial Database ( The eLignin database was launched online in March 2017 and aims to bring together the bibliome of this field in one self-contained searchable platform, and thus fill a gap presently not covered by other online biological databases, as well as to demonstrate the high diversity of this microbial niche , as these play an important role in microbial degradation of native lignin and can be applied for enzymatic depolymerzation of technical lignins . Due to the nature of the data collection for eLignin (scientific publications), there will be some overlap with other biological databases such as MetaCyc , manually curated and supplemented with links to relevant entries in other well-established biological and chemical databases  and two fungal phyla (Ascomycota and Basidiomycota) (see Tables Proteobacteria (114 species/strains), Basidiomycota (58 species/strains), Actinobacteria (31 species/strains), Ascomycota (27 species/strains), and Firmicutes (22 species/strains) (Tables Euryarchaeota) is also beginning to emerge  lignin signified by its brown color (hence the name of this group of wood degraders); they are primarily found in softwood ecosystems  currently listed in eLignin are distributed between ta Table . The cliWhen it comes to lignin-degrading activity, fungi tend to be more studied than bacteria because of their higher prevalence of lignolytic secretomes , with Proteobacteria dominating the list with its 114 entries , followed by β-Proteobacteria (27 species/strains), α-Proteobacteria (18 species/strains), and δ-Proteobacteria (3 species/strains), again highlighting that certain types of microbes are greatly enriched in the eLignin bibliome. It can also be noted that many of the organisms in this particular niche have undergone one or several taxonomical reclassifications since they were first isolated and described , with the remainder being Gram-positive (46 species/strains) and unknown/Gram-indeterminate (4 species/strains). This may have implication on studies focusing on, e.g., transport of compounds over membranes (discussed in a separate section below), or when expanding a species’ substrate range by metabolic engineering. In the latter case, the difference in total GC content in the genome that is in general seen between Gram-positives and Gram-negatives (Muto and Osawa Although fungi are known as the main degraders of the lignin macropolymer (as described in the previous subsection), there are a substantial number of studies that describe delignifying bacteria. Tian et al. reviewed the topic and performed phylogeny on 57 lignin-degrading and 463 laccase-encoding prokaryotes that led them to propose that screening for laccases genes may be a good way to detect new lignin-degrading species  extension of the lignin microbial niche.Five archaeal isolates—classified in niche subgroup 2  via acetyl-CoA  to evaluate the physiology of the microbial niche  monoaromatic compounds tend to be more commonly studied across all phyla. Note that there are no Acidobacteria or Spirocheates in the eLignin bibliome that have been reported to degrade natural/technical lignins and di-/oligoaromatics.Similar to how fundamental and applied studies on lignin focus on a few model organisms, many studies use a few common model aromatic model compounds that represent different funneling pathways  , coniferyl alcohol , and p-coumaryl branch (no methoxy groups)  they catabolize: the sinapyl branch (two methoxy groups), coniferyl branch (one methoxy group), and the see Fig. . Within see Fig. . Funnelisee Fig. , is anotIn a lot of bibliome studies, the substrate specificity of a species is presented without going into the intracellular conversion mechanisms nor reporting evidence of a specific funneling pathway. Therefore, in order to be able to use the eLignin dataset to look at pathway diversity, we developed a prediction algorithm to infer funneling branches from reported substrates from the literature. This is possible since many of the funneling branches are linear, e.g., ferulic acid is degraded via vanillin, and any species that have been reported to grow on these compounds and their intermediates can then be theoretically inferred to have the coniferyl branch Fig. . Cinnamip-coumaric (H) branches seem by far to be the most abundant in niche 2. This might be correlated to the number of methoxy groups -derived monomers. Spruce lignosulfonate has for instance been reported to yield vanillin, guaiacol, acetovanillone, and vanillic acid (Pérez and Tuck Amycolatopsis sp. ATCC 39116 (Pometto III et al. Comamonas sp. B-9 (Chen et al. Rhodotorula rubra IFO 889 (Huang et al. Sphingobium sp. SYK-6 (Katayama et al. Acetobacterium woodii NZva16 (Bache and Pfennig Rhizobium sp. YS-1r (Jackson et al. Oceanimonas doudoroffii JCM21046T (Numata and Morisaki Exophiala jeanselmei CBS 658.76 (Middelhoven Many lignin valorization studies apply chemical depolymerization since microbial enzymatic breakdown of lignin is a very slow process taking many weeks (Fackler et al. Although the chemical structure of many aromatic compounds allow them to passively diffuse through the lipid bilayers of biological membranes (Engelke et al. Acinetobacter baylyi ADP1 (Collier et al. Bradyrhizobium japonicum USDA110 (Michalska et al. Klebsiella pneumoniae M5a1 (Xu et al. Pseudomonas putida KT2440 (Nishikawa et al. Rhodopseudomonas palustris CGA009 (Giuliani et al. Sinorhizobium meliloti 1024 (Michalska et al. Sphingobium sp. SYK-6 (Mori et al. Corynebacterium glutamicum ATCC 13032 (Chaudhry et al. Lactobacillus plantarum WCFS1 (Reverón et al. Rhodococcus jostii RHA1 (Otani et al. Pseudomonas isolate that excreted vanillyl alcohol during growth on vanillin as a tolerance mechanism to handle excess vanillin that was not catabolized to vanillic acid fast enough, but the mechanism by which vanillyl alcohol was transported out of the cell has not been elucidated yet (Ravi et al. Current knowledge on bacterial aromatic transporters mostly focuses on Gram-negative bacteria which have a cell envelope with two lipid bilayers separated by a periplasmic space: the outer and the inner membrane Nikaido . Some GrThe interest for lignin as an underexploited carbon source has markedly increased during the last two decades, as evidenced by the exponential increase in published papers on lignin valorization (Abejón et al. The microbiological aspects of lignin and aromatics degradation have a long history with a vast bibliome, and the need for resources such as the eLignin database will continue to grow as the field expands. In the future, we expect to further implement in eLignin a number of discussed features including improved prediction algorithms, lignolytic communities, and substrates that cannot be converted by a given organism. Economically feasible lignin valorization will require advanced metabolic engineering and thorough knowledge on microbial physiology. In that context, the objective of eLignin is not only to generate new overviews of the field but also to fuel new research ideas and engineering strategies and thus become an operational tool for studies on the microbiological aspect of lignin degradation, catabolism, and valorization.


Synapse loss has detrimental effects on cellular communication, leading to network disruptions within the central nervous system (CNS) such as in Alzheimer’s disease (AD). AD is characterized by a progressive decline of memory function, cognition, neuronal and synapse loss. The two main neuropathological hallmarks are amyloid-β (Aβ) plaques and neurofibrillary tangles. In the brain of AD patients and in mouse models of AD several morphological and functional changes, such as microgliosis and astrogliosis around Aβ plaques, as well as dendritic and synaptic alterations, are associated with these lesions. In this review article, we will summarize the current literature on synapse loss in mouse models of AD and discuss current and prospective treatments for AD. Synapse loss has harmful effects on cellular communication, leading to network disruption in the central nervous system (CNS). The communication of billions of neurons within the mammalian brain generates and controls memory, thoughts and emotions. In a neuronal network with different cells, the transfer of information is coordinated at specialized compartments such as the synapse. Synapses are contact points between two neurons, where they communicate by passing ions or neurotransmitter across the synaptic cleft. Synapses can have excitatory or inhibitory effects on the target cells, depending on the released signals. The formed synapses are not rigid but rather dynamic and can either strengthen, shrink or even get lost. Considering the critical role of synapses under physiological conditions, it is not surprising that a severe loss of synaptic integrity can cause substantial disorders such as neurodegenerative diseases  which currently affects 46 million people worldwide Prince, . Over a Besides aging, new genetic risk factors for AD were reported recently in GWAS, such as ApoJ/Clusterin, PICALM, complement receptor 1 (CR1), TREM2 and sialic-binding immunoglobulin (Ig)-like lectin CD33  (Kuchibhotla et al., Astrocytes represent the most abundant cell type in the brain. They are involved in synapse formation and elimination, synaptic plasticity and activity. Due to their essential role in brain function it is likely that astrocyte dysfunction results in progression of neurodegenerative diseases. Similar to microglia, reactive astrocytes surround senile Aβ plaques in the brain of AD patients and in mouse models of AD. They become reactive as indicated by their hypertrophic processes and increased expression of GFAP (Wisniewski and Wegiel, Further investigations of neuron-glia signaling pathways and their disruption in neurodegenerative diseases are necessary for the development of new successful therapies that are promising due to the early involvement of glia in the disease process.Although our knowledge regarding the mechanism underlying AD pathogenesis has improved over the last decades, there is still no cure available. Moreover, open questions concerning memory and synapse loss, as well as gliosis and related neuronal damage, still remain (De Strooper and Karran, In vivo imaging of 3xTg-AD mice revealed spine loss on dystrophic dendrites positive for hyperphosphorylated tau in areas without plaques (Bittner et al., Most current therapeutic approaches focused on the reduction of Aβ levels and Aβ plaque load by inhibiting or modifying the generation of Aβ. Other attempts tried to target the tau protein instead (Roberson et al., In vivo 2-photon imaging allows to explore structural plasticity of synapses in living mice, even for long-time periods (Grutzendler et al., in vivo 2-photon imaging and followed dendritic spines and axonal boutons over the course of several weeks in APPS1 mice. Pre- and postsynaptic structures showed an enhanced instability in the vicinity of Aβ plaques (Grutzendler and Gan, Prime targets for AD therapies are β- and γ-secretase inhibitors. Numerous inhibitors currently undergo clinical trials (May et al., in vivo imaging experiments (Filser et al., Unfortunately, the inhibition of BACE1 is known for its mechanism-based side-effects. Conditional deletion of BACE1 in 5xFAD mice resulted in reduced Aβ plaque load and improved synaptic function, determined by LTP and contextual fear conditioning experiments (Hu et al., The oligomeric form of Aβ is often considered as the toxic form. Immunotherapy against Aβ oligomers had little effect on synapse loss in the vicinity of Aβ plaques but abolished synapse loss further away from plaques (Dorostkar et al., To date, it remains an open question whether such Aβ lowering strategies will be successful. Therefore, alternative treatment options should be considered. Mice exposed to an environmental enrichment developed enhanced numbers of new dendritic spines, excitatory synapses and dendritic branches on pyramidal neurons (Mora et al., Besides the physical degeneration of synapses in AD and other neurodegenerative diseases, it is unclear which role glial cells play during the process of synapse loss. Further research will hopefully provide more insights into the role of glial cells and their contribution to synapse loss, in particular at earlier pre-depositing stages when synapses are already vulnerable. Future preclinical treatment approaches should combine pharmacological, non-pharmacological and behavioral studies.SZ-W and MM-L contributed equally to this work, wrote the manuscript, read and approved the final manuscript.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.


Ocular surface disease is an umbrella term that includes a variety of complex pathologies such as Stevens–Johnson syndrome, mucous membrane pemphigoid, limbal stem cell insufficiency, dry eye disease, and ocular graft-versus-host disease. Regardless of the underlying disease process, ocular surface failure may result in inflammatory and infectious complications and potentially devastating visual loss. Early diagnosis and appropriate treatment of ocular surface disease require a high level of expertise as these conditions can be extremely challenging even for experienced clinicians. Although key issues in the management of patients with complex ocular surface disease still remain controversial, recent advances in diagnostics and therapeutics have enhanced our armamentarium and allow for improved clinical outcomes.in vivo confocal microscopy, the morphology of two types of vortex keratopathy: amiodarone-induced keratopathy and the Fabry disease-associated keratopathy. Finally, Moschos et al. explore the psychological aspects and the incidence of depression in patients with symptomatic keratoconus.In our special issue on ocular surface disease, Wróbel-Dudzińska et al. report on the clinical efficacy of platelet-rich plasma in the management of neurotrophic corneal ulcer, showing promising clinical results. Hazarbassanov et al. assess the effect of osmoprotection in the management of dry eye disease after refractive surgery in a randomized controlled double-blind clinical trial, while Moussa et al. investigate the effect of different prostaglandin analogues on the ocular surface of patients with primary open-angle glaucoma. Krysik et al. report on indications, outcomes, and complications of penetrating keratoplasty for ocular surface disease-related pathologies in a tertiary referral center, whereas Sun et al. analyze the therapeutic effects of corneal debridement combined with intrastromal voriconazole in a patient series with recalcitrant fungal keratitis. Ikegawa et al. investigate, with the aid of Zisis GatzioufasSamer HamadaSotiria PaliouraThe authors declare that they have no conflicts of interest.


Innate immunity against pathogen infection by membrane-localized receptors is evolutionarily conserved among eukaryotes  and receptor-like proteins (RLPs) ; and (2) VIGS in N. benthamiana avoids gene function redundancy and allows for simultaneous silencing of multiple homologous genes (Wang et al., The VIGS-based approach for identification of PRRs has advantages over methods that rely on map-based cloning and Arabidopsis T-DNA insertion lines (Zipfel et al., N. benthamiana recognizes XEG1, a widely distributed MAMP in microbial taxa (N. benthamiana can identify XEG1 family proteins secreted by various microbes. Therefore, RXEG1 could potentially be used to protect a broad range of plants, especially other solanaceous plant species such tomatoes, whereby high disease resistance might be achieved through genetic engineering or by spraying.In addition to identifying and characterizing PRRs, elucidating the mechanisms by which PRRs perceive microbial attack will significantly advance our understanding of plant innate immunity. The comprehensive and intensive work of Wang et al.  revealedial taxa . When miial taxa . Wang etial taxa  demonstrWang et al.  identifiCurrently, the recognition of certain MAMPs remains restricted to solanaceous plants (Wang et al., WW drafted the manuscript. SW and WW revised the manuscript. SW draw 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.


Geriatrics infusion and transformation of community-based settings to support “aging in place” is complex. It requires a customized approach that engages multiple stakeholders who are invested in systems redesign and process change. Rowan University School of Osteopathic Medicine’s NJ Geriatrics Workforce Enhancement Program, in partnership with an affordable housing facility operated by Fair Share Housing/Northgate II, and Rutgers University School of Nursing (RSoN), implemented a Resident Health Risk Assessment (RHRA) tool as part of an interprofessional community-based training experience for health professions students. The goal was to identify health risks that impact a resident’s ability to age in place and implement a person-centered intervention plan. Multi-level stakeholder engagement and ongoing rapid cycle quality improvement catalyzed changes in structure and process for all partners. Results included refinement of an interprofessional clinical rotation, introduction of competency attainment into the orientation process, and resource reallocation to support data collection.