Recent advances in prostate cancer (PC) research unveiled real androgen receptor (AR) functions in castration-resistant PC (CRPC). Moreover, AR still accelerates PC cell proliferation via the activation of several mechanisms . New-generation AR signaling-targeted agents, inhibiting extremely the activity of AR, were developed based on these incontrovertible mechanisms of AR-induced CRPC progression. However, long-term administration of AR signaling-targeted agents subsequently induces the major problem that AR (complete)-independent CRPC cells present neither AR nor prostate-specific antigen, including neuroendocrine differentiation as a subtype of AR-independent CRPC. Moreover, there are few treatments effective for AR-independent CRPC with solid evidence. This study focuses on the transformation mechanisms of AR-independent from AR-dependent CRPC cells and potential treatment strategy for AR-independent CRPC and discusses them based on a review of basic and clinical literature. Androgen receptor (AR) signaling is a hallmark of prostate cancer (PC). Moreover, androgen deprivation therapy (ADT) is highly effective in most patients with metastatic PC. However, resistance eventually develops, leading to a lethal phenotype known as metastatic castration-resistant PC (mCRPC) . An impoAlthough neuroendocrine (NE) PC (NEPC) rarely arises de novo and accounts for <2% of patients at the time of PC diagnosis , treatmeSeveral therapies have been developed and approved over the last decade, suggesting the importance of sequencing systemic therapy in mCRPC. The prognosis for mCRPC is generally reported to be 15–32 months depending on the nature of the clinical trial . Most mCPoint mutations in the AR gene were found in 10–30% of CRPC patients ,14. The AR gene amplification was found in 20–30% of CRPC patients, which is uncommon in hormone-naïve PC, resulting in AR overexpression ,22. An eMore recent studies have identified splice variants of ARs (AR-Vs) that are constitutively activated by the loss of the C-terminal LBD ,30,31. AGrowth factors such as insulin-like growth factor-1 (IGF-1), keratinocyte growth factor, and epidermal growth factor (EGF) activate AR and allow the induction of transactivation of AR target genes under low androgen conditions . IGF-1 hAlong with growth factors, a variety of cytokines activate AR as well. The NF-κB signaling pathway, which is constitutively expressed in many different types of cancer and involved in tumor formation and progression , regulatThe phosphatidylinositol-3 kinase (PI3K)/AKT pathway is an important player in the CRPC deterioration process. The loss of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) protein, a negative inhibitor of the PI3K/AKT pathway, has been identified in almost all metastatic PC. Its activation has been associated with the CPRC development in a variety of preclinical models ,50. MicrThe canonical Wnt pathway is also thought to be associated with the CRPC deterioration process. Moreover, β-catenin, which is a major downstream effector of the Wnt pathway, acts as an important AR coactivator, augmenting AR-mediated transcription . More inAcquired resistance to abiraterone acetate and enzalutamide may occur via increased expression of the glucocorticoid receptor (GR), which share response elements with AR in multiple gene targets . In addiIn 2013, the Prostate Cancer Foundation assembled a working committee on the molecular biology and pathologic classification of NE differentiation in PC and proposed a new pathological classification of NEPC . These sMore potent ADT regimens targeting AR itself and androgen biosynthetic pathways have recently led to the emergence of resistance mechanisms independent of AR activity. This lethal mCRPC appears to adapt to ADT via lineage plasticity, rather than as a result of the emergence of resistance mutations, and adopt a phenotype that is no longer dependent on AR signaling and its expression. These tumors have NE features, a stem or basal cell-like phenotype, altered kinase signaling, and epigenetic modification ,65. The Molecular features in NEPC include reduced or absent AR signaling; retinoblastoma 1 (RB1) loss; tumor protein p53 (TP53) loss; N-Myc amplification; Aurora Kinase A (AURKA) gain; upregulation of BRN2, sex determining region Y-box 2 (SOX2), or paternally expressed imprinted gene 10 (PEG10); downregulation of RE1-silencing transcription factor (REST); altered DNA methylation; and increased polycomb-mediated gene silencing through enhancer of zeste homolog 2 (EZH2) ,69,70,71In contrast, placental gene PEG10 is highly expressed in NEPC and is dynamically regulated by AR and E2F/RB pathways during NEPC development ,82. ThusThe use of NE serum markers appears to be more suitable to diagnose NEPC as the majority of NE cells store neuropeptides in cytoplasmic granules, including chromogranin A (CgA) and neuron-specific enolase (NSE). The serum levels of these neuropeptides are associated with the degree of NE differentiation in PC cells .Published data report a correlation between the number of NE cells in the prostate-expressing CgA and serum CgA levels. An initial increase in serum CgA may indicate a disease that is only weakly sensitive to androgen deprivation. Furthermore, serum levels of CgA can potentially increase at the moment of metastatic spread. Therefore, CgA can be used as a tumor volume marker .Although serum levels of NSE do not correlate directly with marker expression in pathological specimens, it is significantly higher in PC with metastatic cases than in localized forms . In contPro-GRP has been identified as a biomarker for small-cell lung cancer (SCLC), an NE tissue differentiation disorder, and has been suggested to be useful in combination with NSE in monitoring the treatment of established SCLC . In cont®) and somatostatin receptor scintigraphy (SRS), a radiolabeled somatostatin analog with high binding affinity to the SSTR, can be useful to evaluate disease extension [Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) is useful for SCLC staging because the detection rate of primary and metastatic lesions is very high due to the strong FDG accumulation . Identifxtension ,101 and xtension ,103. Intxtension . Moreovextension .NEPC is diagnosed by morphological confirmation of small-cell carcinoma by hematoxylin-eosin staining and expression of NE markers by immunostaining. However, no clear diagnostic method or definition exists. In contrast, an autopsy report of 31 men who expired due to CRPC showed that a selection of NE markers was expressed in 78% of the metastatic sites . TypicalAlthough NEPC currently lacks an effective treatment, platinum-containing combination chemotherapies  following SCLC are mainly being employed for NEPC based on The National Comprehensive Cancer Network (NCCN) . In a phMoreover, a rationale for immune checkpoint inhibitors (ICIs) therapy may exist based on SCLC data. However, studies focused on NEPC have not yet been reported. A recent phase-I trial of nivolumab plus ipilimumab for advanced rare genitourinary tumors, including small cell/NEPC, is ongoing (NCT03333616). In addition to existing treatments, some of the molecules identified as being involved in NEPC progression can be potentially targeted. Currently, alisertib, a drug that inhibits the interaction between N-Myc and AURKA, showed exceptional responses in a subset of patients with NEPC in a phase-II trial . MoreoveRecent data showed that Trop2 is a driver of metastatic PC with NE phenotype via poly-ADP ribose polymerase 1 (PARP1). PARP1 inhibition in Trop2-driven NEPC significantly reduces NE function, tumor growth, and metastatic colonization in vivo, suggesting that PARP1 inhibitors may be a promising therapeutic strategy for metastatic PC expressing high levels of Trop2 .Importantly, some mCRPC did not express AR markers or NE differentiation . PhenotyDNPC may have overlapping epigenomic changes with NEPC. Lineage plasticity in DNPC, for example, may be driven by epigenetic reprogramming mediated by polycomb repressive complex 1 (PRC1). Moreover, PRC1 activity in DNPC leads to the upregulation of CCL2, resulting in bone and visceral metastases, stem cell properties, and the formation of an immunosuppressive tumor microenvironment . TherefoDNPC was reported to have elevated fibroblast growth factor (FGF) signaling in the autocrine and paracrine manner, contributing to the avoidance of AR dependence. Moreover, FGF/MAPK pathway was activated in this DNPC . FGF ligOther mechanisms include that overexpression of C-Myc and PTEN loss synergistically induce genomic instability and enable lethal metastatic PC development without not only NE features but also sarcomatoid differentiation . FurtherUnfortunately, no standard treatments for DNPC exist because of the loss of potential targets such as AR signaling and NE lineage. From the above background, FGF/MAPK blockade suppressed the growth of DNPC in vitro and in vivo, suggesting that FGF/MAPK inhibition may be particularly effective against mCRPC with a PSA-null phenotype . The treTargeting CCL2 signaling, driven downstream of PRC1, is also attractive. Experimental reports have shown that stimulation of androgen-independent PC cells with CCL2 increased proliferation during cabazitaxel treatment, while CCR2 antagonist suppressed the proliferation of cabazitaxel-resistant PC cells during cabazitaxel treatment . Many stPrecision medicine based on genetic testing may be worth considering for DNPC, for which no breakthrough treatment exists. In particular, a recent study suggested that men with metastatic PC are a population enriched in genetic defects in DNA repair and the overall frequency of germline abnormalities in genes involved in maintaining DNA integrity is 11.8% . AlteratIn 2017, the US Food and Drug Administration approved the use of pembrolizumab, an anti-PD-1 antibody, for patients with solid tumors with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), whose disease has progressed with prior therapy, and for whom no alternative treatment is available. ICIs have been shown the potential for sustained efficacy although the MSI-H/dMMR molecular phenotype has been reported to be rare in PC. Approximately 2% and 3.1% of 1048 and 1033 patients with PC had MSI-H  and MSI-Bipolar androgen therapy (BAT) refers to an innovative treatment approach for mCRPC that consists of the association of testosterone injections with regular ADT to reach transient supraphysiological testosterone levels . SeveralComparisons of the complex spectrum of phenotypes in three subsets of CRPC  are summarized in


Processing and control systems based on artificial intelligence (AI) have progressively improved mobile robotic exoskeletons used in upper-limb motor rehabilitation. This systematic review presents the advances and trends of those technologies. A literature search was performed in Scopus, IEEE Xplore, Web of Science, and PubMed using the PRISMA  methodology with three main inclusion criteria: (a) motor or neuromotor rehabilitation for upper limbs, (b) mobile robotic exoskeletons, and (c) AI. The period under investigation spanned from 2016 to 2020, resulting in 30 articles that met the criteria. The literature showed the use of artificial neural networks (40%), adaptive algorithms (20%), and other mixed AI techniques (40%). Additionally, it was found that in only 16% of the articles, developments focused on neuromotor rehabilitation. The main trend in the research is the development of wearable robotic exoskeletons (53%) and the fusion of data collected from multiple sensors that enrich the training of intelligent algorithms. There is a latent need to develop more reliable systems through clinical validation and improvement of technical characteristics, such as weight/dimensions of devices, in order to have positive impacts on the rehabilitation process and improve the interactions among patients, teams of health professionals, and technology. The proper functioning of the limbs of the human body plays a fundamental role in people’s health. When these limbs are temporarily or permanently affected, significant motor difficulties appear. Currently, there is a rapid growth of disability-related diseases worldwide. In a global context, the World Report on Disability  highlighWhen it comes to the most common problems that trigger neuromotor impairment, stroke is recurrent in all populations . Its varFrom a rehabilitation perspective, the effectiveness of a traditional treatment depends on the skill of therapists, their previous experience in treating similar cases, and their ability to formulate successful rehabilitation plans ,8. UsualAlthough the application of assessment and therapeutic systems based on robotic exoskeletons started in the past two decades  and has This offers a new opportunity for the development of robust and reliable systems, enabling the recovery of lost motor control due to accidental injury or illness ,16. The The implementation of computational techniques based on artificial intelligence (AI) embedded in robotic exoskeletons for rehabilitation, and the development of lighter, portable, and ergonomic systems ,20, reprThis systematic review includes articles published in Scopus, IEEE Xplore, Web of Science, and PubMed between January 2016 and November 2020. The focus of the review is on wearable and ergonomic robotic exoskeletons for the upper limbs, whose control, data collection, or processing systems are based on AI algorithms. A large number of studies report an increase in the use of different artificial neural network (ANNs) architectures, and the mixing of traditional control techniques with intelligent or adaptive optimisers, creating robust or hybrid systems.The use of AI-based techniques has been recognised as able to enrich the rehabilitation process by providing a comprehensive assessment of a patient’s performance and increasing the confidence of final users  when interacting with robots for rehabilitation.As far as the mobility of these devices is concerned, the current trend is towards reductions in weight and dimensions to promote performance in activities of daily living (ADLs) and therefore increase independence, but it was necessary in some cases to reduce the degrees of freedom (DoF) in order to have more compact systems.This section describes a detailed methodology used to conduct the literature review, which was driven by the guidelines described in the PRISMA method: Preferred Reporting Items for Systematic Reviews and Meta-Analyses . An applEligibility criteria included articles: (i) written in English, (ii) published between January 2016 and November 2020, (iii) reporting the use of robotic exoskeletons on the upper limbs, (iv) for use in rehabilitation, (v) implementing artificial intelligence-based processing or control systems, (vi) reporting mobile, portable, or wearable devices, (vii) found in the field of engineering, computer science, or medicine, and (viii) written in a paper, review, or conference paper form, with full-text availability.With regard to the (ii) eligibility criterion, the timeframe was shortened to the last five years due to the rapid technological advancements in the development of robotic exoskeletons for upper limb rehabilitation.It is noted that the development of applied AI-based techniques in this field started at the end of 2015, which represents the first point for looking in closer detail at the trend that will guide future research.For the initial information collection, a search of the reported literature was performed in Scopus, IEEE Xplore, Web of Science, and PubMed databases. Search queries were formulated with multiple keywords falling within topics already described in the eligibility criteria, and applied to the title, abstract, or keywords fields.The keywords were: (i) Assistive technologies: “powered exoskeleton”; “robotic exoskeleton”; “active exoskeleton”; exosuit, “powered orthosis”; “robotic orthosis”; “active orthosis.” (ii) Device type: “wearable”; “mobile”; “portable.” (iii) Control technologies: “intellig*”; adaptive”; “net*”; “artificial neur*”; “ANN”; “learn*”. (iv) Body segment: “upper limb*”; “arm”; “forearm”; “shoulder”; “elbow.” (v) Medical application: “rehabilitation”, “physical therapy”; “impairment”; “health.” The keywords used in the search stage led to the documents for the systematic review. However, the documents obtained were screened to ensure that all eligibility criteria were met. For example, documents that were not accessible in full text and documents that were duplicated in different databases were removed, as detailed below.The systematic review process begun with the identification of 163 documents in the search stage. The after the screening stage, 31 duplicate documents were removed, along with 16 additional documents that were not full-text nor the proper text type. Finally, 86 documents were removed, as they did not fit the objective of this review. This process resulted in the inclusion and analysis of a total of 30 documents, which are presented in this research. The results section contains the presentation and analysis of the selected documents. A narrative style is adopted to present the main conclusions, and additional information on the characteristics of the studies, the goals reached, and their contributions. In a general way, as summarised in This article has reviewed the final 30 articles with four different approaches: (i) a general description of the information sources; (ii) technical characteristics of the device: weight, dimensions, portability, and materials used in its manufacturing; (iii) information processing and control techniques based on AI; and (iv) the nature of the medical application on the upper limb. It is important to note that On a preliminary basis, most research articles reported the development of robotic exoskeletons, representing 87% of the studies, whereas 13% of final documents reported the usage of commercial developments. Besides, the recent development of soft robotic exoskeletons (6.3%), able to provide a new way of transferring motion by means of non-conventional structures, is highlighted.Finally, Robotic exoskeletons have different design features that highlight their importance for inclusion as technology for assessment and treatment. Within these characteristics, those inherent to the design and construction of the device stand out, from the choice of suitable materials to factors such as weight, portability, and the developed exoskeleton type. The characteristics related to the functioning of the device are highlighted, referring specifically to exoskeleton contributions in the movement and the range of motion in the upper limb of the human body. The characteristics described are some of the physical properties displayed in the developments, and the operating modes. These elements are detailed below.The physical characteristics of robotic exoskeletons determine their applicability in the healthcare field. As mentioned in several studies, a compact, lightweight, and aesthetically pleasant robotic rehabilitation system is attractive for use in the clinical setting . AlthougWithin the reviewed literature, the wearable exoskeletons were particularly noteworthy, representing 53% of the documents included see a. In thiIn both cases, the logic and activation support were carried out in an ergonomic backpack and not directly on the upper limb. Other developments that reported cable-based actuators  do not hIn general, robotic exoskeletons that reported the use of 3D printed structures are usually characterised by their low weight and good mechanical properties that allow their use in rehabilitation. Within this segment, the developments with the highest degree of portability were reported in ,26,29,42In ,32, lighIn detail, some documents ,37 showeGuo et al.  points oThe same robotic structure was used in three different documents ,43,47. TComplex and wearable or mobile structures are shown in ,31,41,55Other robotic exoskeletons of a mobile nature account for 30% of the reviewed studies. Although they are portable and are not in need for fixed structures in the operation, they require a longer setup time due to their complexity, dimensions, or weight. Therefore, mobile exoskeletons are candidates for use in physical recovery only within a controlled rehabilitation environment. An example is reported in , where aFinally, some studies reporting semi-mobile devices were found (17%). These devices require additional support structures, limiting patient mobility in different environments, and therefore the versatility of the proposed device ,53,54,59The advances shown in  have proThe most frequently developed type of robotic exoskeleton is the hard exoskeleton, corresponding to 84% of the reviewed literature see b. Rigid Some of the developments shown in this literature review corresponded to rigid bilateral systems ,34,49,55Other developments were reflected in the 12% of the reviewed literature corresponding to soft exoskeletons, which lack a rigid structure. Soft–type exoskeletons ,51 promoFinally, there are some minor advances (4%) that report the use of soft structures added to some features of completely rigid exoskeletons. For example, an effective passive orthosis design was shown in , featuriAs regards the structural materials used in the reviewed devices, 30% of the developments showed mixtures of two or more materials in their structures see c. The adIt is also common to find structures formed by a wide variety of metals 27%), which provided rigidity to the structures %, which ,41,45,52With the rise of additive manufacturing and 3D printers, a growing number of developments have reported the use of fully printed structures, using for example acrylonitrile butadiene styrene (ABS), polylactic acid (PLA), or nylon type plastic parts, representing 23% of the literature. As a specific case, in ,29,33, tFinally, a small percentage of studies reported the use of different types of soft or semi-rigid materials ,50,51, cThe characteristics related to the functioning of robotic exoskeletons reported in the literature can be clustered according to the movement contribution type and the number of degrees of freedom (DoF). In the rehabilitation of motor or neuromotor function, four control modes are generally considered: (i) active mode, (ii) passive mode, (iii) assisted mode, and (iv) resisted mode . The actEach of these monitoring modes is brought into rehabilitation systems and provides a range of medically quantified outcomes, as each monitoring mode emphasises a specific type of recovery . ControlMulti-ModeDocuments such as ,44,46,55The robotic orthosis presented by Sangha  was desiIn , six modFinally, the development shown in  has provActive ModeVarious developments ,26,31,42Complex systems have implemented an active operation mode ,41,48,50As regards compact active exoskeletons, in the paper of Lambelet et al.  an electFinally,  providedPassive ModeExoskeletons with a passive operation mode are appropriate to support upper limbs of the patients as they eliminate the gravitational load and provide the user with the opportunity to perform the necessary rehabilitation tasks. Under this umbrella, the studies ,38 were In more comprehensive works, the different capabilities of the passive mode are explored , focusinThe DoFs of the robotic exoskeleton determine the possible movements over one or multiple joints of the upper limb. As a general rule, the higher the number of degrees of freedom, the more actuators are needed . This leOne DoFThe articles that present one DoF are rather abundant, representing 39% of the reviewed literature b. These The use of a single DoF simplifies the design process in terms of driving mechanisms that allow proper joint mobility, but increases the complexity of the controller.Other works characterised by one DoF were presented in ,45,46: tTwo DoFsThe articles featuring a design with two DoFs constituted 23% of the reviewed literature b. IndeedOn the other hand,  presentsThree DoFsThe developments that presented designs with three DoFs constituted 19% of the reviewed literature b. SpecifOther developments are presented in ,42; mostFour or more DoFsArticles with four DoFs or more also constituted 19% b. Some oIt is remarkable how this development has paved the way for subsequent research, such as the Recupera rehabilitation systems ,53 and tAlthough less complex but still robust, the developments shown in ,31,37 inIn detail,  stated tAn article has presented the implementation of four DoFs . This syFinally, the most sophisticated work was carried out by Varghese et al. , where tThe recent use of advanced data acquisition, processing, and control techniques based on AI made possible the development of robust control strategies that can outperform classic approaches implemented in biomechatronic systems, including robotic exoskeletons ,67. SomeIt is established that the basis for the development of AI-based processing and control systems should aim at (i) performing an intention detection; (ii) offering modulation of the control scheme of a human–robot task (arbitration); and (iii) providing feedback during training exercises .Artificial neural networks (ANNs) have historically represented one the pillars of biomechatronics and intelligent systems . ThroughWithin the studies included in this systematic review, ANNs take a central role: in fact, 33% of the articles show the exclusive use of ANNs, which represent the main intelligent technique for the processing and control of wearable robotic exoskeletons for the rehabilitation of the upper limbs.Two works from the Northwestern Polytechnical University in China ,47 standUsing a similar approach, the articles ,43,48 prAlthough other studies used EMG signals , the appAdvanced implementations based on ANNs are shown in  where thA radial basis function neural network was implemented as a control method in , which aThe design of the control strategy shown in  was alsoTo close this sub-section, Samper-Escudero et al. , extendiThe adaptive-based algorithm techniques encompass a wide variety of intelligent control and processing system developments implemented in mechatronic applications . These tIn general, adaptive algorithms represent 17% of the reviewed literature, being one of the booming methods for intelligent processing and control in rehabilitation robotic exoskeletons. Since it is a family of stochastic algorithms and not a particular technique , it is nThe development shown in  made useIn  a torqueSimilarly, in  an adaptOther developments presented in the literature ,35 has sProcessing and control algorithms based on sliding modes and fuzzy logic represent a small proportion (7%) of the reviewed literature. The evolution of these control techniques leads to robust systems that are being explored in mechanical devices. These algorithms find application when there is the influence of parametric uncertainties due to modelling errors, non-linearity, and external disturbances , conditiIn the literature review, sliding-mode control strategies are presented in Zhao et al. , where tOn the other hand, fuzzy logic techniques have made it possible to improve existing sliding techniques , providiWithin the reviewed documents, a system based on fuzzy rules merged sliding mode control components (AF-SMC) , which wThe combination of two or more AI-based techniques is common in the reviewed literature, representing 23% of the articles. The mixed techniques enable the improvement of the characteristics of the controllers based on individual algorithms, where performance is usually measured in terms of optimisation of the parameters within the control algorithms. The mixed techniques found in the literature reviewed are mentioned below.Adaptive algorithms provide dynamic optimisation of the parameters of a common artificial neural network to achieve greater efficiency, resulting in artificial adaptive neural networks .Since ANNs traditionally learn internal representations by adjusting the weights of the network connections, the inclusion of an adaptive algorithm improves learning by retropropagation through non-linear optimisation theory. This approach is useful when the learning process of an ANN is affected by accuracy flaws in the numerical computation, and environmental changes that cause unpredictable deviations of the parameter values from the original configuration .In the development proposed by Seeland et al.  an alterFinally,  shows anThe interaction between ANNs and fuzzy logic-based controllers is similar to the one just reported for adaptive algorithms. Neuro-fuzzy systems are able to compute optimal values of parameters used in traditional neural networks by implementing soft rules that belong to the fuzzy domain .Although the combination of these two types of intelligent processing techniques is not completely new ,86, it pIn the work carried out at the Universiti Teknologi Petronas  a non-inFinally, in  EEG signThe combination of adaptive control and fuzzy logic systems enable updating the parameters of the fuzzy controller during the fitting process. Additionally, adaptive fuzzy control can provide an efficient method for modelling more complex non-linear systems such as robotic exoskeletons with multiple degrees of freedom .The main contributions of this adaptive-fuzzy systems consist in ensuring the uniformity of the constraints of the control system, regardless of the uncertainties and disturbances affecting the exoskeleton . This prAlthough this approach was addressed in , researcFinally, other varied techniques involving artificial intelligence have a significant rate of 20% of the literature, where optimised techniques of classical controllers are predominant. As a starting point, the review by Zaroug , stated Specifically, in the work carried out by the University of Malaysia in Pahang , severalOther intelligent processing techniques are shown in , where aFinally, papers such as ,37,41 shRegardless of the approach and techniques selected for intelligent systems, AI-based algorithms improve data collection by providing constant and accurate feedback on the performed movement, increasing the versatility and robustness of automatic control of robotic exoskeletons for rehabilitation ,92.Robotic exoskeletons can be used in physical therapy in different ways. The application in the healthcare field depends on the amount of assistance provided by the exoskeletons, the kind of rehabilitation or therapy implemented, and the upper limb joints available for training. A summary of the above characteristics is presented in Specifically, in terms of the actively assisted joint by the robotic exoskeleton a, 49% ofThe 35% of reviewed articles were identified as contributing to the medical field as active assistance to patient mobility b. This mTypical examples of this type of system are shown in ,38, wherThe results shown in , has demRobotic exoskeletons that directly target upper-limb motor rehabilitation, either at the muscular or musculoskeletal level, represent 52% of the total articles included in the review b. For thThe development shown in  underlinOther articles indicate the applicability of the system to motor rehabilitation in presence of diverse motor restrictions ,29, turnSeveral systems have reported the implementation of the motor rehabilitation function by learning the movement path through repetitive actions of the musculoskeletal system ,43,45,47In-depth studies have shown some devices that can assist both the rehabilitation process and the measurement of users’ physiological parameters in the rehabilitation process, making this approach more comprehensive . SpecifiStudies reporting diagnostic and neuromotor rehabilitation aids are more scarce than other types of advances, being included in only 13% of the documents b. DeveloOther devices help the neuromotor rehabilitation function by making use of neuro-interfaces, as proposed in  where thDevices with dual or leader-follower architectures are essential for neuromotor rehabilitation. Specifically, in  it was rThe role of training with robotic systems oriented to neurorehabilitation is demonstrated by different models of commercial devices developed for this purpose ,97. It mUpper limb rehabilitation systems based on robotic exoskeletons have increasingly gained ground in non-engineering areas. It is important to strive for a multidisciplinary approach to make the technology more accessible, extending its potential applicability to the general public .From the mechanical standpoint, the design of exoskeletons must be oriented towards more flexible, adaptable, wearable, and lightweight structures, as some of the devices do not yet fully meet these criteria ,49,52,53In terms of portability, many of the exoskeletons addressed in this review do not clearly or explicitly states about the power supply of the device, which makes it difficult to establish the impact of batteries or other power sources on the current design of these robotic rehabilitation devices. Beyond that, there is insufficient information about the power consumption of rehabilitation systems and their interconnection with the outside world through various communication technologies , thereby limiting the scope of this review. From this, the need for more reports on these critical aspects of portable robotic rehabilitation systems is evident, and for further scientific development in the area.Some architectures that involve the simultaneous operation of more than one exoskeletal system or that show reflex behaviour are highlighted ,34,49. HThe collection of patients’ physiological parameters is a core element in the development of exoskeleton-based robotic systems, as these features can lead to significant improvements in robot control ,43,48,54Focusing on information collection and fusion techniques applied to the development of exoskeletal systems, it is important to note that EMG-based technologies provide reliable results, so their adoption is a cornerstone for the development of future devices. With this in mind, data fusion techniques are a key issue in the evolution of exoskeletons, as they allow the extraction of a wider set of characteristics and functional ranges from various devices ,53,54,55The clinical validation of these technologies is crucial, as this paves the way to the inclusion of such technologies as support in the rehabilitation process . It is cAI has provided the basis for the development of more reliable systems. Zaroug  emphasisConsidering the developments involving self-adaptive AI-based systems, independently of the used technique ,28,46, pAdditionally, it is noteworthy the use of AI-based signal processing or control techniques that may bring with it some design limitations, as current AI systems may still suffer from poor explainability , expliciFinally, further exploration is recommended in approaches related to neuromotor rehabilitation and EEG signal acquisition systems, since while some advances address the topic ,34,41,46It can be stated that existing robotic exoskeletons have shown significant applications to upper limb rehabilitation. Beyond that, it has been demonstrated through the reviewed literature that the different robotic rehabilitation devices provide advantages for patients when directly compared to more traditional rehabilitation techniques, allowing healthcare specialists to have a tool which not only enhances patient progress, but also provides clear and objective information about the effectiveness and improvement of the rehabilitation workflow.However, it becomes evident that there is still a need of further research to improve the mechanical structure of these devices and to implement intelligent algorithms in order to provide compact and wearable tools really usable in the neuromotor and musculoskeletal rehabilitation. There is also a need for the integration of greater expertise across multiple disciplines, and the inclusion of medical judgement from therapists or rehabilitation specialists to provide critical feedback regarding the assessment and validation of patients when using robotic rehabilitation systems. This allows the clinical evaluation of technological developments to be relevant, effective and under standardised protocols by qualified professionals .In the last two decades, robotic exoskeletons for the upper limbs have gained great scientific interest in the areas of engineering and healthcare. They are able to provide assistance and quantitative assessments during the rehabilitation of the upper limbs. In addition, a major boost has been given by the deployment of such devices to hospitals and rehabilitation centres.As indicated in the analysis, the researchers’ interest is focused on the development of exoskeletons based on control techniques embedding AI, covering 87% of the reviewed studies. The design of improved control strategies for robotic exoskeletons by merging information from different sources was driven forward in the last five years.The focus is on signal processing and control systems based on ANNs (33%) and other mixed intelligent techniques (50%), as they provide better results compared to classical control strategies. The effectiveness of the processing and control systems can be improved, but requires additional research efforts to implement algorithms able to detect the real patient’s intention.The rapid evolution of robotics and AI is radically changing the traditional rehabilitation treatments of patients. Eighty-nine percent of the studies reviewed show that the application of medical technology to physical therapy processes speeds up or improves the patient’s recovery process when compared to rehabilitation programs based solely on physical therapy sessions. Sixteen percent of studies corresponding to mobile or portable exoskeletons are able to provide direct assistance to the treatment of neuromotor injuries. This will potentially contribute to the partial or total treatment of high severity pathologies in an effective way.The implementation of rehabilitation programs based on portable technological devices offers a way to redefine physical therapies, which requires immediate actions for the rapid adoption of such devices in the clinical practice.In contrast, there are also some key elements that need to be investigated in further detail. As a roadmap, the priority should be given to developing robotic rehabilitation exoskeletons that are both ergonomic and portable, as some of them still rely on additional physical support structures. The existence of an increasing number of fully wearable devices is highlighted (53%), where the use of this type of exoskeleton provides increased mobility and allows patients to improve their neuromotor skills during ADLs. In this context, functional rehabilitation of the upper extremities can offer a wide range of solutions even outside the clinical settings.The reviewed studies point out the need to continue ongoing research in order to provide a more integrated and comprehensive framework based on the above-mentioned technologies. This will also increase their reliability and their adoption in the rehabilitation units. Lastly, there is also a critical need to develop fully explainable or deducible Artificial Intelligence systems, which will enable synergistic and transparent work between new and improved rehabilitation systems and healthcare professionals. As the AI field is constantly evolving, it is expected that recent advances in the explainability of machine learning and deep learning models will be incorporated by the researchers in the area of engineering and rehabilitation.The current status of upper limb rehabilitation systems based on portable robotic exoskeletons shows that some relevant gaps should be filled in, where intelligent control and information processing systems can play key roles. In addition, with the improvement of materials and the incorporation of better mechanical designs, the capabilities of exoskeletons can be largely improved.


To identify mechanisms that facilitate functional diversification among these transcription factor paralogs, we studied them in an equivalent cellular context. Analysis of chromatin and sequence suggest that divergent binding, and corresponding gene regulation, are driven by different abilities of AR and GR to interact with relatively inaccessible chromatin. Divergent genomic binding patterns can also be the result of subtle differences in DNA binding preference between AR and GR. Furthermore, the sequence composition of large regions (>10 kb) surrounding selectively occupied binding sites differs significantly, indicating a role for the sequence environment in guiding AR and GR to distinct binding sites. The comparison of binding sites that are shared shows that the specificity paradox can also be resolved by differences in the events that occur downstream of receptor binding. Specifically, shared binding sites display receptor-specific enhancer activity, cofactor recruitment and changes in histone modifications. Genomic deletion of shared binding sites demonstrates their contribution to directing receptor-specific gene regulation. Together, these data suggest that differences in genomic occupancy as well as divergence in the events that occur downstream of receptor binding direct functional diversification among transcription factor paralogs.The glucocorticoid (GR) and androgen (AR) receptors execute unique functions  This was shown for paralogous TFs from different families with divergent binding mainly occurring at medium- and low-affinity binding sites (The interplay between transcription factors (TFs), genomic DNA binding sites and the chromatin context in which recognition sequences are embedded plays a pivotal role in specifying where, when, and at which level genes are expressed. Differences in the DNA binding specificity among TFs can guide them to distinct genomic loci and allow TFs to carry out unique functions by regulating unique sets of target genes . Howeverng sites ,7. The dng sites ,9. Anothng sites . Of noteng sites . Finallyng sites . Howevere.g. in gene expression, genome-wide binding and the chromatin landscape, that occur upon their activation. Two members of the steroid receptor family are the androgen receptor (AR) and the glucocorticoid receptor (GR). Despite their nearly identical DNA binding interface, the physiological roles of the hormones that activate AR (androgen) and GR (glucocorticoids), are different , AQP3 enhancer (hg19: chr9:33 437 258–33 437 811) and the AQP3 enhancer with AR binding site mutations (AQP3-Deleted and AQP3-AGA → TGT) were ordered as a gBlock (IDT) or GeneStrand (Eurofins)  to geneU2OS cells stably transfected with rat GRα (U2OS-GR)  were groTransient transfections to test of gene regulation patterns observed in the clonal U2OS-AR and U2OS-GR cell lines could be recapitulated were done as follows: On day 1, 400 000 U2OS cells were transfected with 400ng or 800 ng of either empty pcDNA3, the AR-expression construct or pcDNA3-rat GRα using the 4D-Nucleofector (Lonza) in 20 μl nucleocuvette strips using program CM-104. Cells were transferred to two wells of a 24-well plate, incubated overnight before adding either 100 nM Dex or 0.1% ethanol as vehicle control (for GR) or either 5 nM R1881 or 0.1% dmso as vehicle control (for AR). After 24 h, mRNA was isolated using the RNeasy kit from Qiagen, reverse transcribed using the PrimeScript One Step Kit (Takara) and analyzed by qPCR using primers as listed in To test the activity of individual STARR reporters, 1 million U2OS cells were transfected using the Nucleofector 2b with 2 μg Plasmid DNA using kit V (Lonza) according the manufacturer's instructions.3H-]dexamethasone (Dex)  in the presence or absence of a 10 μM (100×) excess of unlabeled Dex for 45 min. U2OS-AR were treated with 100 nM [3H]-R1881  in the presence or absence of a 10 μM (100×) excess of unlabeled R1881 for 45 min. After five washes with ice-cold PBS, the ligand was extracted by adding 250 μl of ethanol for 45 min and quantified by liquid scintillation counting. Specific activity of [3H]-Dex and [3H]-R1881 and the number of cells per well were used to calculate the number of bound [3H] molecules per cell. Specific steroid binding was calculated as the difference between total and nonspecific binding.Hormone binding assays were performed essentially as described . In brieTotal protein from equal amounts of cells was separated on a NuPage Gradient 4–12% Bis–Tris Mini Gel (Invitrogen), transferred to a PVDF membrane, and incubated with either anti-AR  or anti-actin  antibodies followed by incubation with secondary antibodies conjugated with horseradish peroxidase . Proteins were visualized using the SuperSignal West Dura Extended Duration Substrate (ThermoFisher).For U2OS-GR, the RNA-seq data was from previous studies ,27, ArraGFP (CAAACTCATCAATGTATCTTATCATG) and RPL19 (GAGGCCAGTATGTACAGACAAAGTGG) which was used for data normalization. qPCR and data analysis were done as described (RNA was isolated using a RNeasy Mini Kit (Qiagen). For the analysis of cells transfected with STARR reporters, total RNA was reverse-transcribed with the PrimeScript One Step Kit (Takara) using gene-specific primers for escribed . For allChIP assays were performed using the following antibodies: GR, N499 (2 μl/ChIP); AR, polyclonal antibody PG-21 ; H3K27ac, C15410196 (Diagenode 1 μg/ChIP); Med1, A300-793A ; EP300, C15200211 ; H3K4me1, C15410194 (Diagenode 1 μg/ChIP); H3K9me3, C15410193 (Diagenode 1 μg/ChIP); H3K27me3, C1541095 (Diagenode 1 μg/ChIP).ChIP-seq data for GR replicate 1  is from SRA accession number SRP020242 . ChIP-seChIP assays for subsequent analysis by qPCR were done as described  with theATAC-seq data for GR  is from a previous study , ArrayExFor the analysis of ATAC experiments by qPCR, DNA fragments were amplified using p5 and p7 primers, two-sided size selected using AMPure XP beads (Beckman Coulter) and analyzed by qPCR using the primers listed in Transfection of U2OS-AR or U2OS-GR cells. Five million cells were transfected with 5 μg of DNA FAIRE-STARR library plasmid using the Amaxa Nucleofector kit V (Lonza). For each condition, four transfections were pooled and seeded into two 15 cm dishes with medium containing PKR  and TBK1/IKK inhibitors  at a final concentration of 0.5 μM per inhibitor to suppress the type I interferon response  were from a previous study . Cells were plated and the next day we selected for transfected cells by refeeding cells with medium containing puromycin (10 μg/ml). Twenty-four hours later, surviving cells were trypsinized and seeded to isolate single-cell-derived clonal lines. To genotype single cell-derived clonal lines, genomic DNA was isolated using the Blood and Tissue kit (Qiagen), the targeted region was amplified by PCR using primers spanning the target region . The maximum allowed precursor mass tolerance was 50 ppm and 0,6 Da for fragment ion masses. Trypsin was chosen as cleavage specificity allowing two missed cleavages. Carbamidomethylation (C) was set as a fixed modification, while oxidation (M) and deamidation (NQ) were used as variable modifications. False discovery rates for peptide and protein identification were set to 1% and as additional filter Mascot peptide ion score >20 or Sequest HT XCorr >1 was set. The PD output file containing the abundances was loaded into Perseus (version 1.6.1.3) LFQ intensities were log2-transformed and the proteins were filtered for at least 66% valid values. Missing values were replaced by imputation based on the standard settings of Perseus, i.e. a normal distribution using a width of 0.3 and a downshift of 1.8. Differentially enriched proteins were called using a t-test. Data corresponding to RIME experiments was plotted using ggplot2 package in R. The geneset enrichment analysis was performed using GSEA-R (https://github.com/GSEA-MSigDB/GSEA_R)  ,36.Paired end 50bp reads from Illumina sequencing were mapped against the human hg19 reference genome using STAR  options, defaultLfcShrink function in DESeq2 R package  >1.5 were designated as significant upregulated genes. As a result, 777 and 364 upregulated genes (187 shared) were identified for GR and AR respectively.Differentially expressed genes (DEGs) between the hormone-treated samples and vehicle condition samples were identified both for AR (24 h post hormone treatment versus control) and GR (4 h post hormone treatment versus control) using the  1.24.0, ). Genes http://broadinstitute.github.io/picard/) (MarkDuplicates) was used to remove duplicate reads. BigWig tracks for genome browser visualization were generated with deepTools v3.4.1 (ChIP-seq reads were mapped with Bowtie2 v2.1.0  options) were mas v3.4.1  bamCovers v3.4.1  with a qs v3.4.1  and remos v3.4.1  as well Shared and receptor-specific peaks were obtained with BEDtools intersect. GR-specific peaks at regions of low accessibility were obtained by sorting the ATAC-seq signal (vehicle control treatment) of U2OS-GR cells in descending order at all GR-specific peaks (±250 bp around the peak center) using computeMatrix from deepTools and subsequently extracting the bottom 17 125. Peak calling was performed on ATAC-seq data (vehicle control treatment) in U2OS-AR cells and on ATAC-seq data (vehicle control treatment) in U2OS-GR cells using MACS2 v2.1.2   of shared and receptor-specific peaks were generated with computeMatrix (options: reference-point) and plotHeatmap from deepTools v3.4.1 , using bP-value <0.05 and log2(fold change) >1.5 for either AR or GR; Shared: adjusted P-value <0.05 and log2(fold change) >1.5 for both AR and GR; non-regulated: adjusted P-value <0.5 and 0.5 > log2(fold change) > 0.Receptor-specific and non-regulated genes were defined as follows: receptor-specific: adjusted For each gene, we scanned a 60-kb genomic window centered on transcriptional start sites (TSSs) for overlap with each peak file  using bedtools window. The size of the window to assign peaks to genes was guided by the observation that the correlation between transcriptional regulation by either GR or AR and peaks decreases with increasing distance from the TSS. The 60 kb window yielded a reasonable number of genes while the presence of a peak in this window still increases the chance that a nearby gene is regulated substantially when compared to genes that lack a peak in this window. TSS annotations of genes (hg19) were obtained from the NCBI RefSeq database using the SeqMiner package . To makeStatistical tests were performed using the Fisher Exact test on 2 × 2 contingency tables comparing the number of genes in each differential gene category that have specific binding events to the number of non-regulated genes that have corresponding binding events.FAIRE-STARR-seq (window ±250 bp), H3K27ac, AR/GR ChIP-seq or ATAC-seq mean signal (window ±2 kb around the peak center) was plotted for shared peaks of the different gene categories (for categorization see: Intersect binding and gene regulation) using deepTools v3.4.1  computeMMotif enrichment analysis at AR and GR binding sites was performed with AME  of the ME value was <10–30 for either AR or GR. Alternatively, the top 7 motif logos are shown.were scanned for the JASPAR 2018 CORE Vertebrates Clustering motifs . ControlGC content profiles were generated at all AR-specific and all GR-specific peaks as well as at high accessibility AR- and GR-specific peaks. The high accessibility regions were obtained by sorting the ATAC-seq signal (vehicle treatment) at all AR- or GR-specific peaks (±250 bp around the peak center) of the respective cell line in descending order and extracting the top 3296 peaks. Next, the hg19 reference genome was binned into 50 bp bins with the BEDtools v2.27.1  makewindAQP3 enhancer sequence [hg19: chr9:33437258-33437811], it was scanned for the AR (JASPAR ID MA0007.1-3) and GR (JASPAR ID MA0113.1-3) motif using the JASPAR CORE database  and GR  ChIP-seq peaks from a previous study  were dowdatabase . A totaldatabase .P-value threshold for motif matches was <10–4.The ExoProfiler package was used to generate footprint profiles . For AR normTransform in DESeq2  and two genes each that are either GR-specific (GILZ and IGFBP1) or AR-specific (AQP3 and SIGLEC14). This suggests that the receptor-specific regulation observed for these genes is caused by differences between the two steroid receptors, however we cannot rule out that some of the differences might be due to clonal differences between the two cell lines examined. The number of repressed genes was much smaller for AR . We ∼3–5 nM, . At lowe∼3–5 nM, . Previou∼3–5 nM, . Consist∼3–5 nM, . The incNext, we investigated if GR binding at regions of low chromatin accessibility might contribute to GR-dependent gene regulation. Therefore, we filtered GR-specific peaks for those mapping to relatively inaccessible chromatin (‘Pioneering GR-peaks’) and intersected them with the different categories of regulated genes. In line with a role in regulating gene expression, we found that these low-accessibility GR peaks are enriched near genes regulated by GR Figure . TogetheDifferences in DNA-binding specificity between related TFs can induce differential binding and gene regulation . To studin vitro study we find that the difference extends far beyond the core motif and its direct flanks (>10 kb) arguing that the sequence composition of a large region surrounding the binding site might play a role in directing receptor-selective recruitment.Next we repeated the AME analysis however this time using AR-specific peaks as background for GR-specific peaks  and vise-versa to identify motifs that are selectively enriched. Interestingly, the top AR-specific motifs were mostly AT-rich whereas the top motifs for GR-specific peaks were often high in GC content suggesting that the sequence composition of selectively occupied regions is different Figure . AccordiTo compare the events that occur downstream of AR and GR binding, we assayed the effect of hormone treatment on several chromatin features. First, we compared changes in chromatin accessibility by analyzing ATAC-seq signal after hormone treatment. In agreement with published data ,64, bothNext, we analyzed the effects of hormone treatment on histone modifications. Specifically, we analyzed H3K27ac as a marker for active enhancers and indicator of enhancer activity as well as H3K4me1 as a marker of active and primed enhancers ,66. ConsAQP3 gene shows activation by AR but not by GR  shows an increase in STARR-seq signal in U2OS-AR cells upon hormone treatment whereas no such increase is observed for GR . This method combines formaldehyde fixation of intact cells to stabilize protein complexes with immunoprecipitation of a protein of interest and finally mass spectrometry for protein identification . We perfNext, we compared the RIME data between AR and GR to identify proteins that interact in a receptor-specific manner Figure . AnalysiTaken together, our proteomic data suggests that GR and AR recruit distinct sets of transcriptional co-regulator proteins which may contribute to receptor-specific gene regulation.AQP3 and GILZ, we find that receptor-specific regulation is observed at more than one hormone concentration and time-point  was blunted upon siRNA-mediated knockdown of Med14, whereas GILZ activation was unaffected by the knock-down of either Med1 or Med14. Thus, the GR-specific interaction with the mediator complex we found in our study might play a role in facilitating the regulation of some GR-specific target genes, whereas other mechanisms are in play at other GR-specific target genes. This indicates that for individual genes, different cofactors address the rate-limiting step of the Pol 2 transcription cycle for gene activation which could either be limited by the level of PolII recruitment, initiation of elongation. In this scenario, receptor-specific gene activation from shared binding sites would occur when different cofactors are recruited by AR and GR.Numerous studies have shown that differential genomic targeting is a mechanism that can generate functional diversification among paralogous TFs. However, paradoxically when comparing the genome-wide binding patterns of paralogous TFs, a large fraction of peaks typically overlaps. For example, when comparing AR and GR, receptor-specific binding only explains receptor-specific regulation for a subset of genes with many receptor-specific target genes only harboring nearby binding sites that are shared Figure ). Here,  Figures  and 6. Tn or not . Moreoven or not . For insIn summary, our study suggests that both divergence in genomic occupancy and diversity in the events that occur downstream of binding contribute to functional diversification among TF paralogs .RNA-seq in U2OS-AR (24h R1881/dmso): E-MTAB-9622FAIRE-STARR-seq in U2OS-AR and U2OS-GR (14h R1881/dmso or 14h dex/etoh): E-MTAB-9614ATAC-seq in U2OS-AR (4h R1881/dmso): E-MTAB-9606AR ChIP-seq in U2OS-AR  + GR ChIP-seq inU2OS-GR : E-MTAB-9616All histone modifications  in U2OS-AR and U2OS-GR : E-MTAB-9617gkab185_Supplemental_FilesClick here for additional data file.


Hyperglycemia is a common manifestation in the course of severe disease and is the result of acute metabolic and hormonal changes associated with various factors such as trauma, stress, surgery, or infection. Numerous studies demonstrate the association of adverse clinical events with stress hyperglycemia. This article briefly describes the pathophysiological mechanisms which lead to hyperglycemia under stressful circumstances particularly in the pediatric and adolescent population. The importance of prevention of hyperglycemia, especially for children, is emphasized and the existing models for the prediction of diabetes are presented. The available studies on the association between stress hyperglycemia and progress to type 1 diabetes mellitus are presented, implying a possible role for stress hyperglycemia as part of a broader prognostic model for the prediction and prevention of overt disease in susceptible patients. The term stress hyperglycemia (SH) refers to a transient increase in plasma glucose levels  during acute illness or physical or psychological stress, which subsides when the stressful condition resolves . Common Stress hyperglycemia is considered a normal metabolic response to acute stress . It deveThe studies selected for this review were identified using the PubMed, Scopus, and Web of Science electronic databases. We searched for scientific literature published in English up to January 2021. Combinations of the following search terms were applied: “stress hyperglycemia,” “acute hyperglycemia,” “stress hyperglycemia and type 1 diabetes mellitus,” “pediatric hyperglycemia,” “type 1 diabetes screening,” “type 1 diabetes prediction.” Additional references were retrieved from reviewing the references cited in the original articles.During stressful conditions, glucose homeostasis is disrupted both in terms of glucose metabolism and insulin sensitivity and secretion . The strE. Coli and Vibrio Cholerae has long been related to stress hyperglycemia, with its prevalence ranging from 9.4 to even 20% in some reports, as a result of a stress response to hypovolemia  , the preovolemia .via dialysate solutions used in peritoneal dialysis or in the form of parenteral nutrition and intravenous glucose solutions often results in SH, and recent policies suggest the administration of low-calorie parenteral nutrition as a preventive measure , insulinoma antigen-2 (IA-2), and zinc transporter 8 (ZnT8) . The preThe most firmly established factor is the presence of family history , 33, witBreastfeeding and the introduction to cow's milk have long been a matter of debate. On the one hand, Mayer et al.  reportedPerinatal conditions are important determinants of future T1DM development. In a meta-analysis of 20 observational studies, the risk of T1DM was higher in children born by cesarean section (OR: 1.23); the mechanisms are yet to be elucidated . A positCytomegalovirus, rubella, and enteroviruses have all been associated with T1DM , 52. LowWhether stress hyperglycemia could be a trigger factor for overt T1DM is not clear. As non-diabetic patients are able to compensate insulin resistance by increasing insulin secretion, it seems logical to assume that the presence of stress hyperglycemia could imply some degree of pre-existing β-cell dysfunction. In addition, hyperglycemia in the context of acute illness provokes the overexpression of the insulin-independent glucose transporters GLUT-1, GLUT-2, and GLUT-3, which leads to excessive glucose uptake and, thus, to increased glycolysis and oxidative phosphorylation in peripheral tissues . The con2, who were hospitalized due to stress hyperglycemia, were studied for the presence of metabolic syndrome or GAD65 autoantibodies. Although no cases of overt T1DM were found, the prevalence of insulin resistance, measured by the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), was 16% during follow-up (Stress hyperglycemia is a well-established risk factor for type 2 diabetes in adults. In the study by Plummer et al. , among 2ollow-up . Howeverollow-up . It was On the other hand, several reports have risen serious doubts as to whether SH can predispose to T1DM either by itself or in combination with other factors. In a study by Bhisitkul et al. , all chiper se cannot be considered an accurate risk factor for future T1DM and, therefore, screening methods including antibody testing or oral glucose tolerance tests are not indicated in children and adolescents presenting only with this clinical manifestation and without other risk factors. However, it seems that, when combined with other risk factors such as a positive family history of T1DM and the presence of autoimmunity, stress hyperglycemia can indeed be the very first sign of disrupted β-cell function and, thus, a part of a broader prediction model which can be applied to genetically prone children and distinguish those individuals who are at greatest risk and, thus, in need of a tighter and more prolonged follow-up.Stress hyperglycemia is a normal homeostatic response to acute stress, which is characterized by increased glycogenolysis and gluconeogenesis along with insulin resistance. It has a high prevalence in the pediatric population, with febrile conditions, respiratory infections and medications being among the most common causes. However, apart from its protective effects, its significance as a warning sign for future progression to T1DM has been a matter of research and controversy. T1DM is a disease with a clear genetic origin, but genetic screening cannot easily be applied to the general population and, even more importantly, genetic susceptibility alone is not sufficient to predict whether a child will ever develop the overt disease. Therefore, antibody testing and environmental factors such as breastfeeding, maternal age, delivery by cesarean section, birth weight, and viral infections have been under the spotlight as possible components of diagnostic algorithms and predictive models which can readily be available on a broad scale. Research data, albeit relatively scarce, have shown that stress hyperglycemia TA, EK, and VL performed the literature review and drafted the manuscript. AG, AK, SK-N, and AR provided guidance and edits. All authors 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.


There is a tendency for reducing TR in MRI experiments with multi-band imaging. We empirically investigate its benefit for the group-level statistical outcome in task-evoked fMRI.β’s of each first-level model fit and carried it to the group-level analysis. The number of activated voxels and the t value of the group-level analysis as well as a goodness-of-fit measure were used as surrogate markers of data quality for comparison.Three visual fMRI data sets were collected from 17 healthy adult participants. Multi-band acquisition helped vary the TR . Because these data sets capture different temporal aspects of the haemodynamic response (HRF), we tested several HRF models. We computed a composite descriptive statistic, H, from Increasing the temporal sampling rate did not provide a universal improvement in the group-level statistical outcome. Rather, both the voxel-wise and ROI-averaged group-level results varied widely with anatomical location, choice of HRF and the setting of the TR. Correspondingly, the goodness-of-fit of HRFs became worse with increasing the sampling frequency.Rather than universally increasing the temporal sampling rate in cognitive fMRI experiments, these results advocate the performance of a pilot study for the specific ROIs of interest to identify the appropriate temporal sampling rate for the acquisition and the correspondingly suitable HRF for the analysis of the data.The online version contains supplementary material available at 10.1007/s10334-021-00918-z. After the development of in-plane parallel imaging methods in the 1990’s,  slice-wiA reasonable supposition is that increasing the temporal sampling rate (i.e. shorter repetition time (TR)) should improve the detection of blood-oxygen-level-dependent (BOLD) signal . The beIndeed, in resting-state functional magnetic resonance imaging (fMRI), MB imaging has shown utility , 9. HoweThe physiological response to neural activity is highly variable across anatomical regions  as well The overarching aim of this study was to empirically assess whether MB imaging data would provide a universal benefit regardless of anatomical area of the brain or the HRF used. In a realistic expectation, we hypothesized that such benefit, even if universally detectable, would likely be modulated by the anatomical location and/or the HRF model used. Therefore, we systematically tested five different HRF models in four different occipito-temporal regions of interest.Each of the 21 healthy, right-handed human volunteers signed a written informed consent before undergoing a scanning session. Both the consent form and the scanning protocol were approved by the Health Registration and Training Centre (ENKK006641/2016/OTIG) and were in accordance with Helsinki Declaration of 1964 and its subsequent amendments. Four participants were excluded: one for excessive motion during the experiment, while three others had incomplete data. The remaining 17 participants  form the group described in this study. These data were utilized from a previous study with a separate aim that investigated the efficiency of MB sequences for different measurement durations [All magnetic resonance imaging (MRI) data were collected on a 3 T Siemens Magnetom Prisma scanner  and the vendor’s 64ch receive-only head and neck coil (52 channels used for acquisition). Three different fMRI data sets were collected with 2D gradient echo echo-planar imaging (EPI)  with thrThe imaging protocol also included a 1.0 mm isotropic resolution 3D T1-weigthed MPRAGE sequence  with TR/http://psychtoolbox.org/credits).The above fMRI data were used to capture brain activity in response to a blocked event-related visual task paradigm Fig.  20]. Vo. Vo20]. All analyses were performed in Matlab  relying on the SPM12 software package  and custBefore statistical analysis, each fMRI dataset was realigned to the first volume of each time-series, co-registered to the anatomical image of the same individual  and normalized to MNI152 space before being smoothed with a 6 mm FWHM 3D Gaussian kernel. As part of the GLM, high-pass filtering and pre-whitening were also implemented. Each data set was also segmented into tissue components and the GM segment was thresholded to include those above a probability of 0.1 .the canonical HRF model (CAN)the canonical HRF model plus its temporal derivative (TD)the canonical HRF model plus both its temporal and dispersion derivatives (DD)the finite impulse response model (FIR)a combination of three gamma functions (GAM)Five commonly used, , 25, 26 Importantly, these models provide varying flexibility by relying on different sets of basis functions that vary in number and shape. Furthermore, CAN is widely adopted in fMRI studies owing to its simple interpretability. Including temporal and dispersion derivatives enable the consideration of small variation in the timing and duration of the hemodynamic response, respectively. Finally, FIR and GAM are more flexible models for GLM fit with the former fitting to each time point from the onset of the stimulus a separate delta function.H, as an estimate of the HRF amplitude and used it in subsequent statistical analyses.Because these models differ in complexity and hence in the number of parameter estimates each of them yields through the GLM fit, direct comparison and interpretation are nontrivial. Therefore, for each of the models, we computed a single descriptive statistic, H. Adding the derivative term to the CAN model will require one additional term but make the model more robust against slight time variation in BOLD response. Fitting both terms but using only the non-derivative term may induce amplitude bias due to the delay difference between the model and the measured time series. To counteract this effect, the estimated amplitude is calculated by incorporating the derivative term ) provided the contrasts for the voxel-wise analyses of the main effects and the interaction term. Maps were thresholded at p < 0.001, uncorrected.The main effect of MB acceleration and HRF model as well as their interaction were formally investigated with two separate analyses. In one of these analyses, the ROI average of the effect size, R2) for GLM fit with the help of the SPM MACS toolbox, [R2 values were evaluated both voxel-wise and within the ROIs by averaging across the participants to compare HRFs or averaging across both subjects and HRFs to compare MB factors. The adjusted R2 is an improved GoF measure that considers model complexity and penalizes the fit in relation to the number of variables in the model [Apart from the group-level t statistics, we extracted the adjusted goodness-of-fit (GoF) coefficient . Although in each ROI either MB4 or MB6 outperformed MB1 on average, the differences were sometimes minimal (e.g. MB1 vs MB4 in FFA), MB1 could be better (e.g. MB1 vs MB4 in EBA) and MB6 was not the overall winner.The t 5 Fig. . To asset values with respect to HRFs and MB factors  results in lower SNR. Therefore, methods that reduce TR will often coincidentally reduce SNR as well.Lowering TR is achievable through various means. Although we utilized MB acceleration to maintain full coverage of the brain, it is imperative to state that the fluctuating benefit of the increased temporal sampling rate . Rather, a practically implementable recommendation is to perform a small pilot study with various TRs for the specific stimulus and cohort to identify the most appropriate settings for the full experiment involving the entire group of participants.Supplementary Figure S1. Confirmation of the appropriate usage of the FIR HRF in the group-level analysis. Time course of the fitted FIR HRF for both hemisphere (columns) and each MB factor (rows) in each ROI. The time courses were extracted from the centre of each ROI and point-wise averaged across the entire group. In this study, the mean amplitude of the FIR between 4–6 s from each participant was taken to the group-level analysis. FFA fusiform face area, OFA occipital face area, PPA parahippocampal place area, EBA extrastriate body area (TIFF 11971 KB)Supplementary Figure S2. Group-level voxel-wise adjusted R2 values of the GoF evaluation are given after averaging across participants (top) or after averaging across both participants and the separate evaluations with the five different HRF models. These voxel-wise results corroborate the evaluations within the ROIs as given in Fig. 4. All axial slices are displayed at z = 0, while the sagittal and coronal slices on the bottom are at x = 42 and y =  − 74, respectively. CAN Canonical HRF, TD Canonical HRF + its time derivative, DD Canonical HRF + both its temporal and dispersion derivatives, FIR finite impulse response HRF, GAM combination of three gamma functions (TIFF 8853 KB)Below is the link to the electronic supplementary material.


LAr and L-ArBeO  were investigated by MP2 and coupled-cluster calculations, and by symmetry-adapted perturbation theory. The nature of the stabilizing interactions was also assayed by the method recently proposed by the authors to classify the chemical bonds in noble-gas compounds. The comparative analysis of the LAr and L-ArBeO unraveled geometric and bonding effects peculiarly related to the σ-hole at the Ar atom of ArBeO, including the major stabilizing/destabilizing role of the electrostatic interactionensuing from the negative/positive molecular electrostatic potential of L at the contact zone with ArBeO. The role of the inductive and dispersive components was also assayed, making it possible to discern the factors governing the transition from the (mainly) dispersive domain of the LAr, to the σ-hole domain of the L-ArBeO. Our conclusions could be valid for various types of non-covalent interactions, especially those involving σ-holes of respectable strength such as those occurring in ArBeO. The structure, stability, and bonding character of some exemplary  Oveσ-hole ,7,8,9 inσ-hole ,11  of the molecular electrostatic potential (MEP) [ea0−3 isodensity surface [VS,max is generally  positive. Thus, σ-holes typically behave as electrophilic centers, able to promote by contact with a ligand a complex blend of electrostatic, polarization (including induction and charge transfer), and dispersion contributions. The detailed assay of these terms, and of their dependence on the type and the strength of the interaction, are, indeed, of major interest in the study of NCIs. In a recent study [σ-hole effects by exploring the changes occurring when pure (or nearly pure) dispersive contacts wereconverted into σ-hole interactions. The investigated systems were inspired, in particular, by already-established evidence concerning the complexes of the noble-gas atoms (Ng) with beryllium Lewis acids, particularly BeO [σ-hole on Ng, andexplored the MEP of the NgBeO. The calculations actually confirmed a σ-hole already appreciable in ArBeO, and only slightly more pronounced in KrBeO and XeBeO. We thus focused on the simplest L-ArBeO , and compared their bonding situation with that of their “dispersive” cousins, LAr [LAr, the L-ArBeO were unraveled as structurally more compact, and this mirrored increased values of the SAPT interaction energies (with respect to the L + Ar and L + ArBeO dissociation limits). The two most affected binding components were, in particular, the electrostatic and the inductive, theirincreases seemingly being related to the electrostatic potential of L, and to its polarizability [LAr and L-ArBeO, including L = N2, CO, F2, Cl2, ClF, HCl, and NH3. The MEP of these ligands ranges, in fact, between definitely-negative to definitely-positive values, and this should magnify any effect arising from the contact with the σ-hole of ArBeO. The obtained results, discussed in the present article, actually confirmed this expectation, and furnished insights that could be useful in discussing other types ofσ-holecomplexes.al (MEP)  (customa surface ), and thnt study , we sougarly BeO . It is, ins, LAr . To thisins, LAr ,21, and ins, LAr ,23,24 tozability . Furtherzability , likewiszability ,26,to thLAr and L-ArBeO, their predicted data, and an estimate of their accuracy. Then follows the SAPT analysis of the LAr and L-ArBeO, the former being discussed first as reference systems to best highlight the σ-hole effects occurring in the complexes of L-ArBeO. The LAr and L-ArBeO are then compared in terms of our proposed descriptors of bonding character. The most relevant conclusions are providedin The paper is organized as follows. H = F + V + W, where F = AF + BF is the sum of the Fock operators for monomers A and B, V is the intermolecular interaction operator, and W = AW + BW is the sum of the Møller-Plesset fluctuation operators. The latter are defined as XW = XH – XF, where XH is the total Hamiltonian of monomer X. The th-/first-/second-/third-order intramonomer electron correlation correction to V and W, respectively. The notations in subscript indicate the classical (Coulombic) electrostatic energy (elst), the exchange term that results from the antisymmetrization of the wave-function (exch), the induction energy (ind) (including the charge transfer), and the dispersion energy (disp). The “r” indicates that a given component has been computed by including the coupled Hartree-Fock (HF) response for the perturbed system. The The bonding analysis was first accomplished by SAPT ,21. In tThe terms of Equation (1) were grouped so to express H(r) [Ωs enclosed by the s(r) = 0.4 reduced-density gradient (RDG) isosurface [ρ(r) [Ωs, the total electronic charge enclosed by Ωs, N(Ωs), the average electron density over Ωs, ρs(ave) = N(Ωs)/Ωs, and the average, maximum, and minimum values of H(r) over Ωs, sH. As discussed previously [H(r) partitions the atomic space in two well-recognizable regions, namely an inner one of negative values, indicated as H–(r), and an outer one of positive values, indicated as H+(r). The boundary of these regions falls at a distance R– that is typical of each atom; at this distance, H(r = R−) = 0. Interestingly, when two atoms form a chemical bond, their H−(r) and H+(r) regions combine in modes that signal the nature of the interaction. Particularly for the Ng-X bonds, it is possible to distinguish three types of interactions, indicated as A, B, or C. Our method of bonding analysis ,23,24 reH(r) ,27,28, aosurface ,30 assocce [ρ(r) . Ancillaeviously , the H(rH+(r) regions, and part of the contour lines of their inner H−(r) regions, the bond appearing as a continuous region of negative values of H(r), plunged in a zone of positive values. The interaction is topologically-signed by a  critical point of the H(r) (denoted as the HCP) falling on the bond axis. Exemplary in this regard is the N-N bond of the N2 moiety of the N2-Ar and the linear N2-ArBeO shown in 2-ArBeO is, instead, a showcase of interactions of type B. In these contacts, the H−(r) region of Ng is, again, overlapped with the H−(r) region of the binding partner, but (i) no HCP exists on the bond axis, and (ii) the Ng-X inter-nuclear region includes a (more or less wide) region of positive H(r). Finally, the N-Ar bonds of N2-Ar and N2-ArBeO are illustrative examples of interactions of type C. In contacts like these, the Ng and the binding partner overlap only part of their H+(r) regions, their H−(r) regions remaining, instead, perfectly closed, and separated by a (more or less wide) region of positive H(r). The bond thus appears as two clearly distinguishable H−(r) regions, separated by a region of positive values of H(r).In interactions of type A, the atoms overlap all the contour lines of their i) it is of type A, and (ii) the electron density at the BCP, ρ(BCP) is at least 0.08 ea0−3. This is the case of the N2 moiety of the N2-Ar and N2-ArBeO shown in H(r) over Ωs. If the function was, invariably, positive over the entire volume, the interaction wasassigned as non-covalent (nCov). If the function waspartially or fully negative, the Ng-X wasassigned as partially-covalent (pCov), and distinguished as H+/−, H−/+, and H−, the superscript indicating that, over Ωs, the H(r) was ranging from negative to positive, but, on the average, was positive (H+/−) or negative (H−/+) or, that it is invariably negative (H−). Interactions of type C involving a single Ng atom, such as the N2-Ar shown in LAr (vide infra) were also assayed in terms of the degree of polarization of Ng, DoP(Ng). This index measures, in essence, the deformation of the H−(r) region of Ng arising from the interaction with X [H−(r) region of Ng along the axis formed by Ng and the Ng-X BCP, and H−(r) region of the free atom. The positive/negative sign of the DoP signal Ng atoms polarized toward/opposite to X, and the magnitude of the DoP is related to the extent of the polarization. Illustrative examples of the effective use of this index are providedin Refs. [Any Ng-X is assigned as covalent (Cov) if  , the cous3p2d1f mid-bond functions [s and three p functions with exponents 0.9, 0.3, 0.1, two d functions with exponents 0.6 and 0.2, and one f function with exponent 0.3) placed at the mid-point of any Ar-X distance .The SAPT ,21 calcuunctions ,40 (threρ(r) [H(r) [ρ(r) is defined by the equation [The functions investigated in the bonding analysis werethe ρ(r) , the H(rr) [H(r) ,27,28, ar) [H(r) ,30. The equation :(7)ρr=∑iH(r) is the sum of the kinetic energy density G(r) and the potential energy density V(r):The G(r) is given by the equation:V(r) is evaluated [The presentlyemployed definition ,41 of thvaluated  from theThe RDG is defined by the equation ,30:(11)ss(r) isosurfaces  appear among atoms undergoing any type of interaction, the NCIs emerging, in particular, by considering the spatial regions of low ρ(r). The low-s(r)/low-ρ(r) isosurfaces are, in turn, mapped in terms of the sign (λ2) × ρ(r), λ2 being the second eigenvalue (λ1<λ2<λ3) of the Hessian matrix of ρ(r). In essence, the sign of λ2 is used to distinguish between attractive (λ2< 0) and repulsive (λ2> 0) interactions, and the value of ρ(r) is exploited to rank the corresponding strength. In the present study, we also calculated the integral of a given property P (particularly the ρ(r) and the H(r))over the volume Ωs enclosed by the s(r) = 0.4 isosurface at around the BCP located on any Ar-X bond path, P(Ωs). This integration was accomplished by producing an orthogonal grid of points that enclosed the isosurface and applying the formula:P(ri) is the value of P at the grid point ri, and xd, yd, and zd are the grid step sizes in the x, y, and z directions, respectively (xd = yd = zd = 0.025 a0). The summation is carried out on all grid points ri having RDG < s.Low-value ρ(r), the H(r), and the s(r) were analyzed with the Multiwfn (version 3.8.dev) [H(r) were also produced with the Multiwfn, and included the standard contour lines belonging to the patterns ±k × 10n , together with the contour lines corresponding to the critical points specifically located from the topological analysis of the H(r).The 3.8.dev)  using th3.8.dev) . The twoLAr includedthe diatomic HeAr, NeAr, and ArAr, the linear and T-shaped (N2)Ar, (F2)Ar, and (Cl2)Ar, the linear isomeric (CO)Ar, (FCl)Ar, (HF)Ar, and (HCl)Ar, and the H3N-Ar structure of C3v symmetry. These species were explored at both the MP2/aVTZ and CCSD(T)/aVTZ level of theory, andinvariably characterized as true minima on the potential energy surface (PES). The only exceptions were the OC-Ar and the H3N-Ar, both featuring a doublydegenerate imaginary absorption (number of imaginary frequencies NIMAG = 2). As shown in LAr were, invariably, quite similar, and the MP2/aVTZAr-X distances featured a mean unsigned deviation (MUD) from the CCSD(T)/aVTZ values of only 0.0385 Å.We also ascertained  were investigated at the predictably accurate MP2/aVTZ. The connectivities and bond distances of all the presently investigated LAr and L-ArBeO are thus shown in T1 diagnostics , and the bonding analysis. The obtained results are shown in LAr, the computed −1) with other accurate theoretical estimates already available from the literature [LAr performed at the MP2/aVTZ and CCSD(T)/aVTZ levels of theory furnished strictly similar results. These findings, overall, support the good accuracy of the data reported in The MP2/aVTZ structures of the terature ,53,54,55LAr(dissociation limit: L + Ar). The complexes of Ng with neutral speciesare, in general, perceived as typical van der Waalsmolecules [LNg may include, however, electrostatic, inductive, and even charge-transfer contributions [LAr, whose decomposed L, particularly on the values that this function takes for the various ligands at the VS,max or VS,min occurring on the outer elongation of the bond axis or perpendicular to it. We could locate these critical points on any probed isodensity surface , and, as shown in ea0−3 isodensity surfaces using the MP2/aVTZ-optimized geometries.We first discussthe SAPT data of the olecules , held toibutions . IllustrtSAPTsee  clearlyuLAr and the position of the VS,max or VS,min of the involved ligand. In essence, the anisotropy of the electron density of L directed the Ar atom toward the stationary point(s) on the PES. Depending on L, however, the potential locally-experienced by Ar was quite different, and ranged  of NH3  to the definitely positive one at the VS,max(H) of HF , passing through the only slightly-positive values of He , Ne , Ar , and at the VS,max(perp) of F2  and Cl2 . Interestingly, as expected from the results of our recent studies on other numerous Ng complexes [vide supra) of the various LAr  was dramatically affected by the ligation with BeO. As shown in −1, the Ar atom appeared as definitely positive, with a seemingly uniform MEP at around 48 kcal mol−1. However, as shown in −1, the MEP of Ar emerged as clearly anisotropic, and featured a VS,max of 50.9 kcal mol−1 on the outer prolongation of the Ar-Be axis. This maximum signs a σ-hole arising from the polarization of Ar by BeO toward the inner region of the Ar-Be bond.The only slightly positive electrostatic potential of Ar  with those of the corresponding LAr. We first discuss the changes occurring in the electrostatic component of the interaction. In this regard, based on the data quoted in VS,max or VS,min was negative or only slightly-positive , the L-ArBeO was invariably negative, and higher in magnitude than that of the corresponding LAr. The LAr, and the Ar-X distance wasshorterby ca. 0.2−0.4 Å, the contraction arriving up to ca. 0.65 Å for L = NH3. These systems include the Ng-ArBeO , the linear N2-ArBeO, OC-ArBeO, CO-ArBeO, ClF-ArBeO, and HF-ArBeO, the T-shaped F2-ArBeO and Cl2-ArBeO, and the C3v isomer H3N-ArBeO.All these species are also characterized as true minima on the MP2/aVTZ PES, the only exception being the T-shaped Cl2-ArBeO, featuring a single imaginary frequency (NIMAG = 1)  see . Accordi PES see . All theof L see .L-ArBeO clearly emerges by examining some exemplary situations. Thus, the higly negative S,MinV(N) of NH3of −37.25kcal mol−1produced a Eelst of the H3N-ArBeO as negative as ca. −6.9 kcal mol−1  to H3N-ArBeO . It is also of interest to compare the N2-ArBeO with the isomeric OC-ArBeO and CO-ArBeO. The S,MinV(N) of N2, −8.53 kcal mol−1was more negative than the S,MinV(O) of CO, −4.12, and this produced a 2-ArBeO  that was more negative than that of the CO-ArBeO . This is opposite to the trend across N2-Ar and CO-Ar, whose −1, respectively. Conversely, the S,MinV(C) of CO of -14.04 kcal mol−1produced a −1) that was more negative than that of N2-ArBeO, the difference of −0.57 kcal mol−1 decisively determining the 2-ArBeO . As a matter of fact, in the absence of this electrostatic stabilization, the 2-Ar and OC-Ar were, essentially, the same .The major role of the electrostatic component in determining the stability of the ol−1 see . The EelLAr to the corresponding L-ArBeO. At variance with the LAr, however, the values of L. This finding was, indeed, not unexpected, as this energy term expectedly mirrors the mutual polarization of L and ArBeO. This suggestion is partially supported by the graph plotted in L-ArBeO on the experimental polarizability α of L [3N-ArBeO, and the linear Cl2-ArBeO), whose occurrencesclearly suggestthat various factors conceivably contributed to this energy component. In any case, for any L-ArBeO, the percentage contribution L-ArBeO, and the MEP of L. This also producedthe positive correlation shown in L-ArBeO, and the MEP of L. In any case, not unexpectedly, the absolute values of As for the inductive component of the interaction, its magnitude invariably increased(becamemore negative) when going from any y α of L ,66,67,68–21% see . As showLAr and L-ArBeO were assigned as nCov(C). Likewise, the exemplary N2-Ar and linear N2-ArBeO shown in −(r) regions of any L and Ar or ArBeO, were, in fact, invariably well separated and plunged in a zone of positive values of H(r); the latter wasalso invariably positive over Ωs. However, as shown in LAr to the corresponding L-ArBeO, the bond indices, particularly the N(Ωs) and the ρs(ave), underwentappreciable changes that were, in particular, clearly related to the changes occurring in their SAPT terms (vide supra). Thus, for the Ng-ArBeO , the linear N2-ArBeO, OC-ArBeO, CO-ArBeO, ClF-ArBeO, and HF-ArBeO, the T-shaped F2-ArBeO and Cl2-ArBeO, and the C3v isomer H3N-ArBeO, the values of both N(Ωs) and ρs(ave) were higher than those predicted for the corresponding LAr. This suggests tighter interactions, well consistent with the SAPT prediction of L-ArBeO complexes more stable than the LAr. On the other hand, for the T-shaped N2-ArBeO, and the linear F2-ArBeO and Cl2-ArBeO, the values of the two bond indices werelower than those predicted for the corresponding LAr, in good agreement with the lower stability of the L-ArBeO predicted by the SAPT analysis. This confirms the sensitivity of our proposed method in catching even subtle differences in the bonding character of the Ng complexes.In keeping with the results of the SAPT analysis, all the presently-investigated L-ArBeO with their “dispersive” cousins LAr allowed us to highlight structural and stability effects peculiarly related to the σ-hole of ArBeO. Consistent with the electrostatic model of NCIs [L-ArBeO were clearly related to the values of the MEP at the VS,max or VS,min of L, and ranged from negative (attractive) to positive (repulsive) values depending on the negative/positive value of the MEP. The percentage contribution of L-ArBeO with respect to the LAr. The positive σ-hole of ArBeO also increased the inductive component of the interactionby an extent roughly related to the polarizability of L. The latter effects were, however, less pronounced than those occurring for the electrostatic component, the LAr. In the absence of the σ-hole on Ar, the contribution of the electrostatic component wasonly minor, and nearly constant at around ca. 12−22% of the attractive stabilization. The interaction was, indeed, invariably dominated by the dispersion, even though the nearly null value of the electrostatic potential of Ar allowed us to recognize the direct influence of the MEP of L on the inductive component of the interaction. Our reached conclusions could be valid for other types of NCIs, especially those involving σ-holes of respectable strength such as those occurring in ArBeO. In this regard, there is, certainly, room for further future investigation.The comparison of the  of NCIs ,59, the