Aortic pathologies in general require a multidisciplinary approach and decision-making to integrate elements of clinical acuity, vascular pathology, individual comorbidity, and risk assessment; thus, ideally it is a center with access to multiple imaging modalities and expertise in all treatment options. Besides classic open surgical options, endovascular procedures have been accepted for a variety of aortic pathologies. More recently, novel transcatheter interventions even to the proximal aorta have been introduced, particularly for patients unfit for open surgery. Nevertheless, the role of transesophageal echocardiography to guide percutaneous aortic interventions is not well established, notwithstanding the growing potential as an ancillary tool to guide the procedure and document success. Thoracic endovascular aortic repair (TEVAR) has been accepted as an important therapeutic modality for treatment of acute and chronic aortic pathologies, such as acute aortic syndromes and chronic aneurysms of the descending aorta.The advantages of ultrasound in the assessment of patients with aortic diseases, in comparison with other imaging modalities, are availability and cost-effectiveness, as well as mobility to be used at the bedside in unstable patients or in theater.The role of transesophageal echocardiography (TEE) in the assessment of the thoracic aorta and acute aortic syndromes is well recognized.Video 1Three-dimensional (3D) transesophageal echocardiography (TEE) image of entry point in aortic dissection.Video 2Three-dimensional (3D) transesophageal echocardiography (TEE) image of pulsatile and small true lumen and large false lumen in a patient with aortic dissection.Acute aortic syndromes include a spectrum of conditions such as classic aortic dissection (AD), intramural hematoma (IMH), symptomatic penetrating aortic ulcers (PAUs), and traumatic aortic lesions.Given the proximity between esophagus and aorta, the diagnostic accuracy of TEE for AD is superior to that of TTE and comparable to contrast-enhanced computed tomography (CT) imaging. The reported sensitivity of 86 to 100% and specificity of 90 to 100%Diagnostic proof of dissection relies on separating TL from FL; the TL is usually smaller in size with higher flow velocity and pulsatile flow in systole on color DopplerDuring an intervention, advancing and withdrawing the probe can help differentiate when both TL and FL appear initially similar in size. This maneuver permits tracking of each lumen along the aorta, where characteristic features of TL or FL can become more evident, as the presence of spontaneous contrast related to slow flow in the FL or systolic pulsatility in the TL. Attention should be paid at tracking the lumens in complex dissections with spiroid course, when all echocardiographic parameters that help identify each lumen correctly must be reassessed frequently. In addition, TEE is useful to identify proximal retrograde extension of a distal dissection into the aortic root, potential involvement of coronary arteries, dysfunction of the aortic valve, and presence of pericardial effusion . PericaEndovascular management has become widely accepted as an important treatment modality in complicated and high-risk Type B dissection.Preprocedural TEE should focus on both confirming the underlying aortic pathology and providing quantitative approximation of aortic dimensions and flows in TL and FL. Importantly, before starting an endovascular procedure, the proximal ascending aorta needs to be evaluated to exclude its involvement. A general look at cardiac structures and ventricular function is easily performed, with focus on assessment of aortic valve anatomy and function, left and right ventricular function, and presence of intracavity thrombus that could potentially be dislodged during fast right ventricular pacing maneuvers .Video 3Three-dimensional (3D) transesophageal echocardiography (TEE) image of intraprocedural echocardiography, guiding advance of wires inside the true lumen.During the procedure, TEE is instrumental for a correct identification of the TL and accurate placement of wires within it, before any stent-graft deployment. Fluoroscopy alone may fail to ascertain wire positioning and movement along the TL, particularly in cases of spiral course. When a separate pigtail catheter is needed for angiography or the stent-graft is advanced, proper positioning inside the TL is easy to confirm by TEE; thus, every time a wire or a catheter is introduced, TEE can ascertain its position along the aorta during the manipulations by the operators .Immediately after stent-graft placement, TEE can assess the full expansion of the stent-graft and the successful exclusion of either FL or aneurysmal sac. A “smoke” phenomenon in the FL is a good sign to indicate sealing of an entry tear and initiation of thrombosis. Color Doppler imaging is helpful in detecting residual flow inside the FL or endovascular leaks that would require additional intervention. Persistence of FL perfusion usually indicates failure to close an entry tear or problems with stent-graft apposition, damage to the stent struts, or presence of secondary entry points distal to the stent-graft. Type I endoleaks are located at the proximal edge of the stent and are identified as high jet velocity jets with continuous flow into the FL or aneurysmal sac. In these cases, further balloon dilatation of the stent-graft, a second stent-graft, or even open surgery may be required. The sensitivity of TEE to detect residual leaks in the acute phase (after the stent-graft deployment) is higher than fluoroscopy or CT due to its excellent spatial and temporal resolution and Doppler signal.The concept of TEVAR for Type A AD has recently been applied in selected cases. Optimistic contrast-enhanced CT-based studies have described up to 50% of patients with proximal dissection possibly amenable to an endovascular approachCT angiography plays a major role in planning the intervention in this highly selected population. Features like the distance between coronary arteries, aortic valve, and neck vessels to entry tears and the length of a safe landing zone are important to be addressed prior to intervention. An entry tear located in the mid-ascending aorta not extending to supra-aortic vessels or aortic root characterizes the most suitable pathology. The absence of an acceptable proximal landing zone is the most common exclusion criterion for endovascular repair, when the necessary distances to coronaries and aortic valve are not confirmed. Identification of entry points in the distal ascending aorta is not always possible on TEE, but TEE can provide indispensable information in the planning of the procedure: such as exclusion of aortic root or coronary artery involvement, assessment of ventricular function, and both degree and mechanism of aortic valve regurgitation. In cases of significant valve dysfunction or entrapment of coronary arteries by the FL, TEVAR would not be an option and surgical repair or medical palliation could be the only choices.Unlike CT, TEE is able to provide intraoperative guidance and monitoring that can be crucial for procedures in this anatomical location. Similar to a TEVAR procedure for Type B dissection, in a case of endovascular treatment of proximal dissection a guidewire will be inserted retrogradely from a femoral access. For good support during the delivery and the deployment of the stent-graft, the stiff guidewire is placed across the valve into the left ventricle via a pigtail catheter. TEE can confirm the proper positioning of wires and catheters inside the TL and help detect complications such as entrapment of wires or catheters in the mitral subvalvular apparatus, damage to the aortic valve, or pericardial effusion from myocardial perforation.TEE should confirm the correct expansion and positioning of the stent, ongoing FL-induced thrombosis, and lack of complications such as stent migration or coronary artery entrapment.In the treatment of aortic aneurysms in the descending thoracic aorta, TEVAR has demonstrated lower early mortality rates than open surgery. For this reason, TEVAR is the preferred option for treatment when aortic diameter exceeds 55 mm. In recent years, combinations of endovascular stenting at different levels of the aorta, including the arch, and thoracic aorta have evolved. Future directions will include focus on the preservation of flow in the side branches.IMH and PAU are two entities that can coexist or be identified separately. Each of them can affect the proximal or descending thoracic aorta, although they are more frequently located in the latter.Coarctation of the aorta is a congenital condition that involves increased stiffness of the aortic wall and focal narrowing , potentially reducing distal perfusion. Postductal coarctation, with the narrowing occurring distally to the origin of the left subclavian artery, is the most commonly encountered form of coarctation in adults. Percutaneous treatment of native coarctation or re-coarctation has become the firstline approach in current practice and is usually performed with balloon dilatation followed by stenting of the coarctation site.Ancillary interventional techniques have been proposed to promote FL thrombosis and prevent aneurysmal degeneration. Incomplete or partial FL thrombosis has been associated with increased mortality, as has elevated diastolic pressure in the FL, which increases both wall tension and the risk of distal aneurysmal degeneration or rupture.FL intervention to promote remodeling and thrombosis(FLIRT)Endovascular repair in hereditary connective tissue disorders: Patients with Marfan disease have a higher tendency to develop late aortic complications such as retrograde dissection or rupture. Imaging studies based on both ultrasound and CT have tried to investigate the possible related mechanisms.Percutaneous interventions in the aortic arch,including hybrid interventions, remain a challenging field, although potentially technically feasible and likely beneficial in highly selected cases. The role of TEE in this type of procedure is limited by suboptimal visualization of the origin of all the supra-aortic branches and the interposition of the left bronchus.Contrast-enhanced echocardiographyincreases the likelihood of detecting an intimal flap and helps in anatomic definition of the aorta to plan individual treatment strategies.Intravascular ultrasoundhas the advantage to visualize the flap beyond the diaphragm level, down to the abdominal aorta. Previous experience in TEVAR guidance has shown potential to identify multiple entries and FL thrombosis after an intervention, but the identification of endoleak was less accurate than with TEE. In addition, simultaneous imaging and delineation of intracardiac anatomy is not possible with intravascular ultrasound.3D printing modelshave emerged in recent years as an additional tool to help understand complex underlying anatomy. As for aortic diseases, initial studies of aortic aneurysm and dissection have shown encouraging results, and further development of this supportive technology may be helpful in the teaching and planning of percutaneous aortic procedures.Fusion imaging using a combination of CT reconstructions and fluoroscopyhas shown promising results in terms of reduction of the amount of contrast and radiation exposure.TEE is a semi-invasive procedure and may therefore carry a small risk of procedural complications.Endovascular interventions on the aorta are an attractive alternative to surgery, with expanding applications in the aging population, some of which are already established as preferable options over open surgery under certain circumstances.


Objective: Molecular subtyping is an important procedure for prognosis and targeted therapy of breast carcinoma, the most common type of malignancy affecting women. Immunohistochemistry (IHC) analysis is the widely accepted method for molecular subtyping. It involves the assessment of the four molecular biomarkers namely estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and antigen Ki67 using appropriate antibody reagents. Conventionally, these biomarkers are assessed manually by a pathologist, who finally combines individual results to identify the molecular subtype. Molecular subtyping necessitates the status of all the four biomarkers together, and to the best of our knowledge, no such automated method exists. This paper proposes a novel deep learning framework for automatic molecular subtyping of breast cancer from IHC images. Methods and procedures: A modified LadderNet architecture is proposed to segment the immunopositive elements from ER, PR, HER2, and Ki67 biomarker slides. This architecture uses long skip connections to pass encoder feature space from different semantic levels to the decoder layers, allowing concurrent learning with multi-scale features. The entire architecture is an ensemble of multiple fully convolutional neural networks, and learning pathways are chosen adaptively based on input data. The segmentation stage is followed by a post-processing stage to quantify the extent of immunopositive elements to predict the final status for each biomarker. Results: The performance of segmentation models for each IHC biomarker is evaluated qualitatively and quantitatively. Furthermore, the biomarker prediction results are also evaluated. The results obtained by our method are highly in concordance with manual assessment by pathologists. Clinical impact: Accurate automated molecular subtyping can speed up this pathology procedure, reduce pathologists’ workload and associated costs, and facilitate targeted treatment to obtain better outcomes. I.Breast carcinoma is the most common cancer type worldwide and the leading cause of cancer-related deaths among women. As per the latest GLOBOCAN report The factors that influence the growth of different subtypes vary substantially. For the best outcome, each molecular subtype of cancer needs to be treated differently. The most common and cost-effective way of molecular subtyping is immunohistochemistry (IHC) analysis The conventional pathology procedure for molecular subtyping is predominantly a manual process. Here, the pathologists assess the aforementioned biomarkers in the chemically stained biopsy specimen of cancer patients by visual analysis through a microscope. The high-power field under observation is labeled as positive or negative for the three biomarkers  based on visual analysis of the color response. For Ki67, a cell proliferation status as Low/Intermediate/High is assigned based on the number of Ki67 immunopositive cells. Once the individual assessments of all four biomarkers are completed, these outcomes are used to identify the molecular subtype, as shown in The manual procedure of molecular subtyping is tedious, error-prone, and has high inter-observer variability Deep learning has been in the forefront of methodologies adopted in several works on medical image analysis recently 1)A deep learning-based fully automated system is proposed for molecular subtyping of breast cancer using the IHC images of the biomarkers ER, PR, HER2, and Ki67.2)An improved LadderNet architecture is proposed for the semantic segmentation of IHC images. The proposed architecture improves segmentation accuracy compared to the state-of-the-art architectures.The main contributions of this work can be summarized as follows.The proposed system to classify breast carcinomas based on immunohistochemical markers will reduce the manhours and report generating time. Conventionally, pathologists evaluate each immunomarker stained section/slide independently or as a consensus, collates all four markers’ data, and then comments on the final subtype. This is time-consuming and introduces interobserver variability unless reported as a consensus. The proposed system would speed up the process and spare the pathologist for higher-level interpretations. It would help overcome interobserver variability, promoting appropriate and timely patient care. The system would help pathologists and oncologists to plan hormone therapy/chemotherapy for individual patients, paving the way for precision medicine.Rest of this paper is organized in the following manner. In II.Automated assessment of individual breast cancer biomarkers has attracted considerable research interest. However, to our knowledge, there is only one published work on automated molecular subtyping by analyzing all the four biomarker images The biomarker Ki67 is an indicator of cell proliferation rate and hence tumor growth. Niazi et al. HER2 is a protein present in cell membranes that facilitates the proliferation of cells. Overexpression of HER2 is linked to tumor growth and forms an important factor in molecular subtyping. Tuominen et al. It is observed in our literature study that most of the existing methods for molecular biomarker status prediction of breast cancer address prediction of one or at most two of the four essential biomarkers of breast cancer molecular subtyping. Moreover, none of the existing methods target molecular subtyping as an outcome. In the proposed method, we address these research gaps in the current literature. We have collected samples of all the four biomarkers from multiple patients and implemented a comprehensive automated system for molecular subtyping of breast cancer, using deep learning-based image analysis. For the components ER and PR, our system follows the Allred scoring system III.Molecular subtyping of breast cancer requires the assessment of four important biomarkers’ presence in tumor tissues. The proposed method uses CNN based semantic segmentation to separate the relevant cellular elements such as nuclei and cell membranes that express the presence of these biomarkers. Image samples of biomarkers - ER, PR, Ki67, and HER2 are analyzed separately, and the response is assessed according to the clinical guidelines and the molecular subtype is determined as per the St. Gallen International Expert Consensus A.The proposed method uses digitized biopsy slides of biomarkers: ER, PR, HER2, and Ki67 images captured at 40X magnification. The dataset is collected from Kasturba Medical College, Mangalore, India, and it consists of 600 slide images from 15 breast cancer patients. There are 150 images per biomarker, and each image has a spatial resolution of B.Color intensity differences in the IHC images express the presence or absence of targeted antigens in the corresponding biopsy specimen Refer . In ER aThe final biomarker scoring is highly influenced by the accuracy of estimating the immunopositive and immunonegative cell elements from the IHC images of the biomarkers. Though the number of target classes is different for the biomarkers, the IHC slide images share some common characteristics such as the shades in biomarker color response and the background color. Hence, the proposed semantic segmentation model is designed to segment immunopositive elements from all four IHC image types. The model uses an improved LadderNet architecture, consisting of two encoder-decoder U-Net modules connected serially with customized skip connections and convolution blocks.1)The proposed segmentation model is inspired from the LadderNet architecture 1)A downsampled output from 2)Encoder output from the same level 3)An upsampled output from 4)An upsampled and deconvoluted output from The proposed model aims at providing more learnable paths to the basic LadderNet architecture. The architecture of the proposed segmentation model is represented in The additional skip connections in the proposed architecture also create more data flow paths. Hence, the overall architecture acts as an ensemble of multiple fully convolutional neural networks and the learning paths are adaptively selected based on the nature of input image samples. The multi-scale feature concatenation and the adaptive selection of learning paths provide an optimal segmentation performance over different types of images. These benefits of the proposed architecture help to use the same architecture to segment the four types of biomarker images. The architecture also uses residual convolution blocks for feature extraction and strided convolution for downsampling feature space in the encoding path.Class imbalance is a major challenge faced in the current IHC image analysis. The regions of pathological relevance typically occupy only a small image area, leading to instability in the learning pattern. The dataset shows a skewed ratio of pixels belonging to different classes. Among the target classes, the pixel distribution is quite unbalanced and, in the order, background function  which isFocal Tversky Loss (FTL) allows better control over the learning performance using the parameter In the proposed architecture, both the left and right encoder-decoder modules use 16 filters each at level 0, and the number of filters in each subsequent level is increased by a factor of two. All convolution and deconvolution layers  use ReLU activation followed by batch normalization, and SoftMax activation is used in the final classification layer. The input layer that accepts images of size C.The segmentation stage extracts target objects such as different classes of nuclei and cell membrane from IHC images. The segmentation output may contain noise elements and overlapped cells. Hence, a post-processing stage is introduced to reduce the misclassified pixels from the segmentation output and separate the target objects in each image. We applied the watershed segmentation method D.The biomarker scoring for each IHC image is conducted separately for the molecular subtype prediction. In the case of ER and PR images, the counts of positive nuclei  and negative nuclei are obtained using connected component analysis of the segmented mask. The Allred Scoring system is used to determine the ER/PR status, where each sample is assigned with a Proportion Score (PS) and an Intensity Score (IS) low (PI < 14%), intermediate  is calculated using intensity and completeness of the cell membrane, as per the American Society of Clinical Oncology (ASCO) Intensity is obtained using a shallow CNN classifier which takes the HER2 image as input and classifies the membrane as faint or intense. The completeness of cell membranes is determined by computing the percentage of membrane over a specific radius outside each nucleus. The final HER2 scoring is made based on the intensity and completeness of the cell membrane as shown in HER2 scoring is based on two factors - After computing the patient-level biomarker statuses for ER, PR, HER2, and Ki67, they are combined to determine the molecular subtype, based on the medical guidelines for treatment planning as shown in IV.The experimental setup, training methodology, ablation study over different design choices in the proposed architecture, quantitative and qualitative results, and the performance comparison of the proposed model with state-of-the-art IHC biomarker analysis methods are included in this section.A.All experiments are conducted using the Google Colab environment and NVIDIA®DGX-® machine loaded with Canonical Ubuntu OS, Dual 20-Core Intel®Xeon E5-2698 v4 CPU @2.2 GHz, 512 GB of RAM, and 8X NVIDIA®Tesla®V100 GPU with 32GB dedicated memory.B.The proposed deep CNN model of depth 4 with an input size of He normal initializer is used for initializing kernel weights in all segmentation models, and each model is trained from scratch for 50 epochs.Best performance is observed using a batch size of four and dropout (with a rate of 0.1) in the decoding layers. C.The performance of segmentation models for each IHC biomarker is evaluated qualitatively and quantitatively. Qualitative analysis of ER, PR, and Ki67 segmentation involves verifying whether all the immunopositive nuclei are segmented and classified into the correct classes specified in the ground truth. In HER2, the nuclei and cell membrane need to be accurately segmented without obscuring each other. To our knowledge, no automated methods for molecular subtyping based on all four IHC images have been found in the literature, and thus we compared our results to state-of-the-art segmentation models in each biomarker category. For ER and PR, we compared the result of our improved LadderNet with the state-of-the-art HScoreNet Molecular subtyping depends on detecting responses of cell elements like nuclei and cell membrane to IHC reagents and estimating the number of nuclei belonging to different classes is highly significant. Hence, an object-wise evaluation is also performed to check the ability of the model to predict the cell elements correctly. The object-wise results and the biomarker status prediction performance are shown in The encouraging results obtained for the proposed system point to the possibility of its further development and fine-tuning towards routine clinical application. Implementation of the proposed system in routine clinical practice can be done via integration with software systems currently in use with microscopes for slide image acquisition and analysis, or as an independent application. This system can run on the same computer system associated with the microscope in small clinics, or it can be deployed in an intranet or cloud environment to cater to the needs of large clinics and distributed chain of clinics. Amendments are required in the existing pathology procedures to enable the use of such systems in clinical practice. Regulatory agencies like the USA’s Food and Drug Agency (FDA) V.Automatic molecular subtyping of breast cancer leads to better prognostication and targeted therapy by avoiding several issues with the manual procedure. This article proposes a deep learning-based system for molecular subtyping of breast cancer using IHC biomarker images. A CNN architecture is proposed to segment various cell elements from digitized IHC images of the breast tissues that express the presence of molecular biomarkers ER, PR, Ki67, and HER2. After segmentation, post-processing based on connected component analysis is performed to count the cell elements that belong to different classes, followed by the biomarker score computation. By individually analyzing all four biomarkers from the same patient, the proposed method emulates the routine procedure followed by a pathologist while eliminating the inherent problems in manual analysis. The segmentation performance of the proposed model is compared with state-of-the-art approaches and demonstrates the improvement in the segmentation performance. Being one of the pioneering attempts to automate molecular subtyping using IHC image analysis, we see tremendous potential for future enhancements in this task. With more data, it is possible to improve the segmentation performance further to develop automated assistive technologies for clinical trials.


We discuss research ethics challenges experienced while running a discrete choiceexperiment administered to caregivers of children with treatment resistant pediatricepilepsy. We highlight ethical considerations around the study design of the discretechoice experimental paradigm that pertain to vulnerability of and caregiving burden on thepopulation, imbalance of benefit-to-load of participation, and limitations of culturalmeaningfulness and generalizability. Discrete choice experiments (DCE) have been used since 1983 to identifypreference-sensitive variables where multiple, equally valid options exist .DCEs foEven the best designed medical research with human participants will fail, however, if notwell-suited to its target population, and this includes the full range of ethicalconsiderations from consent to confidentiality. While there exist ethics guidelines toassist researchers in applying ethical principles , it is tWe were successful in obtaining a sufficient number of responses with the physician DCEbased on the preparatory qualitative study , but unsThe first step to the caregiver DCE study was to determine which attributes were mostimportant to the target population. DCEs are underpinned by random utility theory -Lancaster’s theory - of demand . The thefeatures of the intervention: risks and benefits, with an emphasis on anaversion to perceived invasiveness; 2) decision drivers: trust in theclinical team, treatment costs; and, 3) resources: quality of availableinformation about neurotechnological options. Overall, caregivers’ definition of treatmentsuccess is more expansive than the single variable of seizure freedom favored byclinicians.In this initial qualitative study, caregivers with affected children were recruited tosemi-structured focus groups or interviews at one of four major epilepsy centers in Easternand Western Canada and the USA (n = 22) . ConsentDoes this drivedecision-making?” Selecting attributes is a balance between including the mostimportant features while limiting the number of attributes so that the complexity of thetasks for the respondent is manageable. The risk, otherwise, is non-attendance, inconsistentresponses across choice tasks, and increased drop-out rates  #H18-02783.Nine responders completed the English-language DCE choice sets, including the demographicsquestions; 10 completed only the DCE choice sets; 15 went past the introduction and consentpages but failed to proceed into the choice sets; 5 began the choice sets and but terminatedbefore completion. There were no responses to either the French or Spanish versions.While the simplicity of the DCE exercise and the familiarity of making choices in real-lifesituations has been cited as important strengths of the approach , the resWhile we took into account strategies and recommendations of past studies on themethodology of DCE that have addressed ways to reduce cognitive load and low response rates, the choWe note independently that the requirement for only 6-8 attributes all ultimately relatedto biomedical aspects of candidate neurotechnologies, and excluded variables involvingdiverse cultural views about interventions on the brain. For participants for whom whollybiomedical explanations of disease is not sufficient, or for those living in rural andremote geographic regions with challenging access to advances to new technologies , therelThe suitability of DCEs to certain vulnerable populations, however vulnerability isdefined, is a matter not only of economics and science, but of research ethics. Respect forpersons is violated if burden – i.e., risk – exceeds benefit. Context matters. Inclusivityis at stake given the technical limitations and cognitive load elements of the approach.Meeting the goal of justice is a challenge if implementation falls short of meaningfulness.More discussion surrounding appropriate methodology and patient engagement during studyplanning and design that draws upon The discussion above highlights an under estimation of the cognitive burden andvulnerability of caregiving populations that may limit, or at least challenge, theappropriateness of DCE methodology. A means to assess the vulnerability of caregivingpopulations prior to the onset of research outset would lead to special design features andprotections if necessary . The disEthical Reproducibility byThe responsibility of investigators to choose and fully disclose not only the properscientific method to answer a research question, but also one that is ethically best suitedto a population of interest was discussed in


Over the last few decades, the advancements in nanotechnology have prompted developments in various fields of research, especially in the area of biomedical science. For example, many research groups have extensively studied the application of nanomaterials for imaging and therapeutic. To probe the complex biological environment of the human body, it is essential for nanomaterials to possess the necessary properties to deal with different situations and yield various valuable information for in-depth analysis. The development of bioinspired nanomaterials brought about numerous advantages such as traversing the circulatory system while avoiding immune responses or achieving specific targeting of disease sites. In this editorial, we will briefly summarize the findings and discussions that were presented in each of the accepted articles.Shih et al. that summarize the design principles of bioinspired interfaces. Several discussions were made in the mini-review including recent progress of different cell membrane coatings for nanoparticle (NP), surface modification techniques for NPs, and the functionalization of NPs with geometric property variations. It should be noted that most discussions were made based on imaging and therapeutic applications. In the last part of the mini-review, future perspectives for NP design were elaborated to provide the readers with key ideas for further developments in this research field.We start off with a mini-review article by Vincy et al., comprehensive discussions were made regarding red blood cell-derived particles. Synthetic strategies, characterization methodology, and applications were enumerated in detail. In addition, the review article also provides key insight into the current state of clinical translation as well as the challenges that it may face during the transition from lab to clinical applications.In the review article by Due to the growing interest in NP-related applications, much research focusing on various aspects of the field of NP study has surfaced over the years. Therefore, we include three original research articles that describe interesting therapeutic applications of NPs, such as inhibition of cancer cell proliferation or improvement in drug delivery efficiency.Mochizuki et al. proposed an X-ray sensitizer that was based on the surface functionalization of organosilica NPs with sub-nm-sized gold NPs. The synthesized NPs were further modified with polyethyleneimine and tested against 4T1 mouse mammary tumor cells. As shown in the result, the tumor cells displayed significant inhibition of cell proliferation and an increase in cell death by X-ray irradiation at 8Gy after being treated with the synthesized NP. Furthermore, it was demonstrated that the NP can act as an oxidant, which can induce DNA damage by mitochondrial deactivation. Thus promoting non-apoptotic cell death via radiotherapy.Chen et al. investigated the effect of surface charge and size dependency of mesoporous silica nanoparticles (MSNs) for penetrating the blood-brain barrier (BBB). They discovered that the ideal condition for MSN to permeate the BBB in larval zebrafish was negative surface charged and small particle size (50 nm). The potential applications for brain disease treatment were shown when they conducted the test with doxorubicin-loaded MSNs and obtained promising results.In another study, Chen et al., they have demonstrated that the vessel permeability of NPs at the lower size limit was found to be dependent on the mouse strain and surface charge of the NPs. This work could provide valuable insights to other research groups if anionic NPs were employed in their study.For most NP-related studies in cancer therapy, NPs were often subjected to the enhanced permeation and retention (EPR) effect for tumor uptake. In order to exploit this property, NPs were often designed to reach lower size limits. However, in the work by In order to provide a more macroscopic view of the applications of nanomaterials, we include original research articles that describe fluorescence imaging of extracellular potassium ions and novel antimicrobial surface coating materials. We hope that by including these articles, the readers will have a better understanding of various kinds of nanomaterials that can be applied in different situations.Sato et al.). The potassium-sensing oligonucleotide enables real-time imaging of cytoplasmic potassium ion concentrations, which could be an important indicator when monitoring potassium ion concentration in vivo.The fluorescence imaging technique involving the use of a conjugate of a quadruplex structure-forming oligonucleotide with a peptide incorporating a Förster Resonance Energy Transfer (FRET) chromophore pair was proposed by  and enhanced biocompatibility with mammalian cells. They further modified the polymer to enhance the protein adsorption and mammalian/bacterial cell binding resistance capabilities, thus producing a copolymer with both antimicrobial and antifouling properties.The future of nanotechnology is moving towards the development of nanomaterials with multiple integrated functions which could expand the range of applications. For instance, the development of hybrid NPs enables imaging and therapeutic functions simultaneously . There i


We demonstrate that the facile ion exchange is an efficient method to exchange to any alkali metal cation of sulfate half esters, with exchange rates between 76 and 89%. The ability to form liquid crystalline order in rest was observed by the presence of birefringence patterns and followed the Hofmeister series prediction of a decreasing ability to form anisotropy with an increasing element number. However, we observed the K-CNC rheology and birefringence as a stand-out case within the series of alkali metal modifications, with dynamic moduli and loss tangent indicating a network disruptive effect compared to the other counter cations, whereas observation of the development of birefringence patterns in flow showed the absence of self- or dynamically-assembled liquid crystalline order.Sulfate groups on cellulose particles such as cellulose nanocrystals (CNCs) provide colloidal stability credit to electrostatic repulsion between the like-charged particles. The introduction of sodium counter cations on the sulfate groups enables drying of the CNC suspensions without irreversible aggregation. Less is known about the effect of other counter cations than sodium on extending the properties of the CNC particles. Here, we introduce the alkali metal counter cations, Li In. In+ andc system . This abNa+ ions . Observaharacter ,37. Howeyl group . The sys+, K+, Rb+, and Cs+ can be achieved from the acid form, although the conversion to the H-form was only partial. This gives an indication that the exchange to the alkali metal cations does not require the intermediate acid form but can be achieved via the simple approach of excess cations in water suspension followed by dialysis. The cations with higher atomic numbers, i.e., larger ion sizes, generally tend to form stronger viscoelastic gels, as reflected in the behavior of the dynamic moduli of the metal cation CNCs. The choice of cation is potentially able to modulate the liquid crystalline behavior of CNC suspension in static and dynamic (flow) states, although the mechanism remains unelucidated.A facile method using excess of alkali metal cations led to the exchange of the counterion on CNCs. The modifications did not result in the loss of sulfate-half ester groups and represents a non-invasive way to modify CNC surfaces. Although full conversion of Na-CNC to H-CNC cannot be realized by HCl treatment, the exchange to Li


There is no doubt that the symptoms of depression is the loss of appetite and loss the ability to taste food. However there is unanswered question how depression disorder impact different preferences of food tastes, which was sought to be explored in this study.were to evaluate changes in characteristics of food tastes in patients with depressive disorder and healthy controls; and to find the association with clinical expression of depressive severity.74 patients with depressive disorder  and 38 healthy controls, 18 to 55 age old, were included into this study. The subjects were interviewed using the sociodemographic and the food sensory questionnaires. The severity of depression was rated using Montgomery-Asberg Depression Rating Scale (MADRS).There were significantly more patients with depressive disorder in comparison to healthy controls preferred non-spicy taste of food  and non-sour taste of food , without significant differences in preference of salty and sweet food tastes. Among study patients with depressive disorder, the majority (71.6%) suffered from moderate severe depression, 23 % - severe depression and 5.4 % had mild severity depression. The preferences of tastes of the food  were independent of the severity of the depressive disorder (p>0.05)Patients with depressive disorder prefer non-spicy and non-sour food tastes, without differences in salty and sweet foods; it have found independent of the severity of the depressive disorder.


Burrowing mammals are important ecosystem engineers, especially in open ecosystems where they create patches that differ from the surrounding matrix in their structure or ecosystem functions.We evaluated the fine-scale effects of a subterranean ecosystem engineer, the Lesser blind mole rat on the vegetation composition of sandy dry grasslands in Hungary. In this model system we tested whether the characteristics of the patch (mound size) and the matrix  influence the structural and functional contrasts between the mounds and the undisturbed grasslands. We sampled the vegetation of 80 mounds and 80 undisturbed grassland plots in four sites, where we recorded the total vegetation cover, and the occurrence and cover of each vascular plant species. We used two proxies to characterise the patches (mounds) and the matrix (undisturbed grassland): we measured the perimeter of the mounds and estimated the total vegetation cover of the undisturbed grasslands. First, we compared the vegetation characteristics of the mounds and the surrounding grasslands with general linear models. Second, we characterised the contrasts between the mounds and the undisturbed grassland by relative response indices (RRIs) of the vegetation characteristics studied in the first step.i.e., the contrast between the patches and the matrix was the largest in the more closed grasslands.Species composition of the vegetation of the mounds and undisturbed grasslands was well separated in three out of the four study sites. Mounds were characterised by lower vegetation cover, lower cover of perennial graminoids, and higher diversity, and evenness compared to undisturbed grasslands. The contrast in vegetation cover between mounds and undisturbed grasslands increased with decreasing patch size. Increasing vegetation cover in the matrix grasslands increased the contrasts between the mounds and undisturbed grasslands in terms of total cover, perennial graminoid cover, diversity, and evenness. Our results suggest that mole rat mounds provide improved establishment conditions for subordinate species, because they are larger than other types of natural gaps and are characterised by less intense belowground competition. The ecosystem engineering effect,  Ecosystem engineer organisms create patches that differ from the surrounding matrix in their structure or ecosystem functions . In thise.g., African mole-rats or blesmols, Bathyergidae family, e.g., blind mole rats, Spalacidae family, Subterranean rodents inhabit open landscapes, including open woodland savanna in Africa ) mounds on the vegetation composition of dry grasslands in Hungary. In this model system we tested whether the characteristics of the patch (mound size) and the matrix  influence the structural and functional contrasts between the mounds and the undisturbed grasslands. We tested the following hypotheses: (i) Mounds have a more open vegetation structure, and different species composition and diversity patterns compared to the undisturbed grasslands. (ii) Vegetation of larger mounds is less affected by the edge effect so the structural and functional contrasts between the mounds and the undisturbed grasslands decrease with increasing mound size. (iii) The structural and functional contrasts between the vegetation of mounds and the undisturbed grasslands increase with increasing vegetation cover in the grassland matrix. As mole rats create a large number of mounds locally in an ecosystem type where gap dynamics are crucial driver of the vegetation composition, the study system is ideal for testing these hypotheses.The aim of our study was to evaluate the fine-scale effect of Lesser blind mole rat ) superspecies complex includes several morphologically very similar but genetically isolated species  transsylvanicus taxon, while in Ásotthalom and Baja sites the Nannospalax (leucodon) montanosyrmiensis taxon occurs according to Festuca pseudovina, F. rupicola, F. vaginata and Koeleria glauca. The sites provide habitat to several protected grassland plant species, such as Astragalus varius, Colchicum arenarium, and the strictly protected Pulsatilla flavescens  and the matrix (undisturbed grassland): the perimeter of the mounds and the total vegetation cover of the undisturbed grasslands. We calculated the Shannon diversity and the evenness of the vegetation in each sampling unit.vs undisturbed grassland), and site was used as a random factor in the models. In the analysis, the following dependent variables were used: total vegetation cover, cover of perennial graminoids, species richness, Shannon diversity, and evenness.First, we compared the vegetation characteristics of the mounds and the surrounding grasslands with general linear models, where the fixed factor was the microsite type (mound M − XG)/(XM + XG); where XM is the value of a dependent variable  in a mound and XG is the value of the same dependent variable in the undisturbed grassland plot paired with the adjacent mound plot. Value of RRI ranges between −1 and +1. The closer |RRI| is to 1, the higher the contrast between the mounds and the undisturbed grasslands. With generalized linear mixed models (GLMMs), we tested the effects of patch size (fixed factor) and total vegetation cover in matrix grassland (fixed factor) on the contrasts between the mounds and the undisturbed grasslands . Study site was used as random factor. GLMs and GLMMs were calculated using SPSS 17.0.Second, we characterised the contrasts between the mounds and the undisturbed grassland by relative response indices RRIs,  of the vWe applied non-metric multidimensional scaling (NMDS) using Bray-Curtis index of dissimilarity to test differences in the species composition of the mounds and undisturbed grasslands in CANOCO 5.0 program . We madePulsatilla flavescens), four occurred both on mounds and grassland plots  and one only in undisturbed grassland plots . For the complete list of the recorded species, please see We recorded in total 112 vascular plant species, out of which 102 species occurred on mounds and 93 in undisturbed grassland plots. Nineteen species occurred exclusively on mounds and ten exclusively in the grassland plots. Sixty-four species were more frequent on mounds than in the undisturbed grasslands, 18 occurred with the same frequency, and 30 species were more frequent in the undisturbed grasslands. Out of the six protected plant species recorded at the study sites, one occurred only on mounds (Festuca spp.) and some typical perennial forb species  of the studied dry grasslands characterised the undisturbed grasslands. Vegetation of mounds were characterised by several disturbance-tolerant species .Species composition of the vegetation of the mounds and undisturbed grasslands was well separated in three of the study sites , whilst it showed considerable similarity in the case of the Baja site . The domp = 0.003), lower cover of perennial graminoids , higher Shannon diversity  and evenness  compared to undisturbed grasslands (p = 0.080).Mounds were characterised by lower vegetation cover , which is a potential limitation of our study. However, this potential bias is consistent in all the 80 pairs of mounds and control plots, as these paired treatments were always situated at the same distance (1 m) from each other.We found that Lesser blind mole rats created patches with different structural attributes  compared to the surrounding sand grassland. The vegetation of the mounds and undisturbed grasslands was different in terms of total vegetation cover, cover of perennial graminoids as well as Shannon diversity and evenness, which confirmed our first hypothesis. This suggests that the mole rats play an important role in the gap dynamics in the study system. We found a more open vegetation with lower cover of perennial graminoids on the mounds, which is a general pattern observed on mounds of various burrowing mammals  mounds on the vegetation of alpine meadows in the Tibetean Plateau  mounds in Ethiopian grasslands found that the mounds were characterised by lower cover of the dominant species and higher cover of subordinate plants  occurred both on the mounds and in the intact grasslands. This implies that mounds are not unique establishment microsites for the majority of plant species; however, mounds can provide improved establishment opportunities for subordinate species, due to the low level of competition by perennial graminoids. There was no difference between the species richness of the mounds and the undisturbed grasslands, but vegetation patches on the mounds were more diverse and the species were more evenly distributed compared to the undisturbed grassland matrix.i.e., that the contrasts between the mounds and the undisturbed grasslands decrease with increasing mound size, was partly supported: in case of total vegetation cover, smaller mounds were more different from the undisturbed grasslands than larger ones. This suggests that the height of the mounds (approximately 20 cm) and their steep slopes provide a sharp vegetation boundary which prevents the clonal growth of the surrounding vegetation on the mound. The colonization of the mounds by plants is probably driven by random dispersal processes , and a higher number of incoming diaspores can be expected on the larger surface of larger patches. Also, besides total vegetation cover, we found that mound size did not affect the other studied variables. Even there was variation in mound size they were rather small so the effect of patch size might be relevant in other scales.Our second hypothesis, We confirmed our third hypothesis as the contrasts between the vegetation of mounds and undisturbed grasslands were higher in the more closed grasslands. This suggests that the importance of the ecosystem engineering effect is the highest in the more closed grasslands, where the engineer organisms increase more the structural and functional heterogeneity of the ecosystem. For the conservation of the plant species associated to dry grasslands, creating proper establishment microsites is crucial . Our resWe found that the subterranean mole rats create patches in temperate sandy grasslands that differ from the undisturbed grasslands in species composition and vegetation characteristics. The contrast between the vegetation of the mounds and undisturbed grasslands were the sharpest in grasslands with more closed vegetation cover. We suggest that the contrasts between the patches and the matrix, which was proposed in this study as a proxy for the strength of the engineering effect, can be a useful variable also in other studies. The effects of patch and matrix characteristics on the contrasts should be studied in other ecosystems and other organisms for a deeper understanding of the mechanisms beyond ecosystem engineering.10.7717/peerj.14582/supp-1Supplemental Information 1Click here for additional data file.10.7717/peerj.14582/supp-2Supplemental Information 2Value of RRI ranges between −1 and +1. The closer is |RRI| to 1, the higher the contrast between the patches and the matrix. Positive RRI scores indicate that the particular variable has larger values in the mounds, while negative RRI scores indicate that the particular variable has larger values in the matrix grasslands. Lines are fitted for visualising linear relationships. Continuous lines denote significant relationships, while dashed lines denote non-significant relationships.Click here for additional data file.10.7717/peerj.14582/supp-3Supplemental Information 3Value of RRI ranges between −1 and +1. The closer is |RRI| to 1, the higher the contrast between the patches and the matrix. Positive RRI scores indicate that the particular variable has larger values in the mounds, while negative RRI scores indicate that the particular variable has larger values in the matrix grasslands. Lines are fitted for visualising linear relationships. Continuous lines denote significant relationships, while dashed lines denote non-significant relationships.Click here for additional data file.


Dear Editor,Insect Bite-Like Reaction (IBLR) is a rare skin disorder, which is associated with hematologic malignant neoplasms such as leukemia and malignant lymphoma.An 84-year-old male was diagnosed with ALK-negative ALCL and treated with chemotherapy  in a hospital, which produced complete remission. Two years later, he visited a clinic complaining of pruritic nodules on his hands and back. Biopsy taken from a nodule on his hand revealed prominent lymphocytes in the epidermis, around blood vessels and sweat glands in the dermis as well as diffuse eosinophil infiltration , and he He visited the same clinic again complaining of nodules with mild pruritus on both cheeks four months after the first visit . PhysicaSkin eruptions are common in patients with hematologic malignant neoplasms. Barzilai et al first reported a case of IBLR in which the patient presented with pruritic red papules, nodules, and plaques without insect bite.The exact pathogenesis of IBLR is still unknown. IBLR has been defined as a disease with nonspecific cutaneous eruption, in contrast to leukemia cutis, which is associated with specific cutaneous lesions. Bairey et al. reported that IBLR was not related to the activity of CLL.In our case, PN presented on the patient’s hands and back four months before the appearance of IBLR on his face. ALCL did not recur when these skin diseases appeared. Topical corticosteroids led to the rapid improvement of the IBLR eruption, though IBLR is typically a refractory disease. Biopsy specimens from the back (PN) and the cheek (IBLR) showed infiltration of many eosinophils and CD4 positive non-neoplastic T-cells . These hNone declared.Tatsuhiko Mori: Designed the study; performed the research and contributed to the analysis and interpretation of data; wrote the initial draft of the manuscript; read and approved the final version of the manuscript.Kinuko Irie: Performed the research and contributed to analysis and interpretation of data; read and approved the final version of the manuscript.Toshiyuki Yamamoto: Designed the study; assisted in the preparation of the manuscript; read and approved the final version of the manuscript.None declared.


The habenula is a complex neuronal population integrated in a pivotal functional position into the vertebrate limbic system. Its main afference is the stria medullaris and its main efference the fasciculus retroflexus. This neuronal complex is composed by two main components, the medial and lateral habenula. Transcriptomic and single cell RNAseq studies have unveiled the morphological complexity of both components. The aim of our work was to analyze the relation between the origin of the axonal fibers and their final distribution in the habenula. We analyzed 754 tracing experiments from Mouse Brain Connectivity Atlas, Allen Brain Map databases, and selected 12 neuronal populations projecting into the habenular territory. Our analysis demonstrated that the projections into the medial habenula discriminate between the different subnuclei and are generally originated in the septal territory. The innervation of the lateral habenula displayed instead a less restricted distribution from preoptic, terminal hypothalamic and peduncular nuclei. Only the lateral oval subnucleus of the lateral habenula presented a specific innervation from the dorsal entopeduncular nucleus. Our results unveiled the necessity of novel sorts of behavioral experiments to dissect the different functions associated with the habenular complex and their correlation with the distinct neuronal populations that generate them. It is located in the most dorsal part of the alar plate of prosomere 2 (Puelles and Rubenstein12) and receives projections from the forebrain, via the stria medullaris (sm), and projects to the basal mesencephalon and rostral rhombencephalon through the fasciculus retroflexus .The habenula (Hb), an important brain region linking the limbic forebrain to the midbrain and rostral hindbrain4; Fig. 5; Fig. 6. According to topographic, cytochemical, morphological and immunocytochemical criteria, the habenular subdivision described in rat was also shown in the mouse brain7. A detailed transcriptomic characterization corroborated the subnuclei previously described in the mouse Hb . The fasciculated sm courses through the most dorsal aspect of the prethalamic prosomere, known as the prethalamic eminence, carrying axons from its multiple origins, caudally into the thalamic prosomere to reach the Hb complex.The sm is the main afferent tract to the Hb complex. This highly fasciculated tract contains fibers originated from different neuronal populations located in the secondary prosencephalon , preoptic regions and septum3. This description was later confirmed and completed, concluding that the LHb receives inputs from the substantia innominata , dorsal entopeduncular nucleus (EPD)22 and lateral hypothalamic area (LHA)25. It must be highlighted that it was recently described that almost all the neuronal populations projecting to the Hb in the chick are colonized by tangentially migrated glutamatergic neurons originated from the prethalamic eminence27. There are three heterochronic migratory streams, by which the prethalamic eminence populates hypothalamic, preoptic, pallidal and septal regions27. The specific pattern of innervation produced by the different afferent neuronal populations in the LHb or MHb subnuclei has been poorly studied. Only the specific innervation of the LHbLO by the EPD has been described previously28.It has been described that sm fibers originate in the hypothalamic, pallidal and septal territories. The MHb reportedly receives inputs from the triangular septal nucleus (TRS), the septofimbrial nucleus (SF), the septal area, the bed nucleus of the anterior commissure (BAC), and from hypothalamic entopeduncular neurons30. More specifically, the dorsal aspect of the MHb has been related to exercise motivation, regulation of the hedonic state, intrinsic reinforcement circuit and aversive behaviors33. The ventral aspect of the MHb has been involved in drug addiction, anxiety, and depression31. Therefore, the vertebrate MHb is related to emotional behavior33. In contrast, the LHb has been considered as an anti-reward system and appears associated to behavioral and motivational control. In fact, the LHb is involved in regulation of aversion, stress, sleep, mood and maternal behavior35. Results obtained in behavioral experiments point out to a LHb relation with learned helplessness response as well as reward, aversion or punishment behavior40 and depression45.A selective source of innervation thus possibly underlies different functions associated to the Hb components. In general, the MHb has been associated with the mediation of analgesic, autonomic, reward, anxiety and fear responsesOur present aim is to analyze the possible differential innervation of the multiple habenular subnuclei considering the differential origin of their afferent fibers. The observed distribution was confronted with the subnuclear organization and location of limbic system functions associated to the habenula.10 as examples of Hb subnuclear organization markers . The images, form rostral to caudal, were color-coded and overlapped by Adobe Software. In the MHb, Asic4 nicely labelled the MHbS and the MHbD subnuclei, while Spon1 was expressed in the MHbVl subnucleus and Myo16 in the remaining MHb ventral components , the medial septal nucleus (MS), the septofimbrial nucleus (SF) and the bed nucleus of the stria terminalis, mediocentral division (BST). The TS Fig. A projectIn summary, the MHb dorsal area is principally innervated by TS, SF and medio central BST while the three ventral MHb subnuclei have differential innervations. The medial part is innervated by the TS, the central part by the MS and the lateral part by the SF. Note that in the case of the MHbD we cannot exclude that some of the positive fibers are not terminals but passaging fibers to others nuclei due to the location of the sm.The LHb receives projections originated from different brain regions. We detected terminals originated from the preoptic area and others parts of the subpallium, terminal and peduncular hypothalamus. The GFP + fibers displayed a diffuse distribution in the LHb when compared to the MHb pattern.We found four populations from the preoptic area, terminal hypothalamus and subpallial area: the lateral preoptic area (LPO), the medial preoptic area (MPO) and the anterior hypothalamic nucleus (AHN) and the substantia innominate (SI). The LPO injection in the preoptic area Fig. A illustrFour neuronal populations were identified in the peduncular hypothalamus: the paraventricular hypothalamic nucleus (PVH), the dorsomedial hypothalamic nucleus (DMH), the lateral hypothalamic area (LHA) and the dorsal entopeduncular nucleus (EPD). The PVH injection Fig. A demonst10 demonstrated the presence of various neurotransmitters-related cell types in this neuronal complex. We checked these neurotransmitter-related patterns testing whether their distribution coincides with habenular subnuclear subdivisions.The Hb single cell RNAseq experimentsvGluT1 signal was prevalent in all the MHb , but no specific BAC injection was found in the Allen database. Therefore, the dorsal MHb is under the influence of BST, TS and SF, while the ventral MHb is controlled by SF, TS and MS. Functionally, the dorsal MHb region (MHbD and MHbS) is related to exercise motivation, hedonic state regulation and primary reinforcement learning33. Therefore, these functions may be regulated by BST, TS/BAC and SF innervation. The fact that both subnuclei are innervated by different neuronal populations suggests that the functions related to them may be separated between both subnuclei. New and more selective behavioral experiments are needed to dissect the specific function of each dorsal MHb subnucleus. The ventral MHb region is related to anxiety, depression and drug addiction learning47. This MHb territory is subdivided in three subnuclei from medial to lateral . These subnuclei are each innervated by selective neuronal populations. The ventromedial, central and lateral subnuclei are projected upon by the TS/BAC, MS and SF, respectively. This selective innervation also indicates, as in the dorsal MHb, that each ventral subnucleus may be involved in a different function or that collaboration among them is needed for the cited behavioral phenomena . It is remarkable that almost all the neuronal populations projecting to the MHb belong to the septal territory. This innervation is strongly compartmentalized and the four different sets of axons target specific MHb subnuclei. The BST  specifically innervates the MHbS, the SF targets the MHbVl and the MHbD, the TS reaches the MHbD and MHbVm and finally, the MS innervates the MHbVc. It has been described that the TS innervation of the MHb is accompanied by fibers from the bed nucleus of the anterior commissure  attending to its different psychobiological functions. The lateral area is related to avoidance behavior to aversive stimuli while the medial part has been involved in despair, helplessness, anhedonia responses and in sleep and circadian rhythmshttps://connectivity.brain-map.org) offers Adult Mouse Connectivity Atlas as an image database of axonal projections labeled by viral (rAAV) tracers and visualized using serial two-photon tomography from 2994 experiments.The Allen Mouse Brain Atlas (© 2021 Allen Institute for Brain Science. Mouse Brain Connectivity. Available at: 3) or by projection density, which means the fraction of the area occupied by signal compared to the whole structure. The mouse strains used included wild type and transgenic cre lines. Nevertheless, the rAAV used did not include specific sequences to interact with the cre endonuclease.This resource contains several tools to search through its experiments. The Source Search tool, allows the search of experiments by injection site (Filter source Structures) filtered by mouse line, tracer type and the presence of Intrinsic Signal Images. The Target Search tool allows a "virtual retrograde" search that localizes experiments based on projections located in the structures of interest. Finally, the Spatial Search allows the user to choose either a target signal or injection site based on a voxel selection that retrieves all the experiments with positive signal. The injection summary includes primary and secondary injection structures, the stereotaxic injection Bregma coordinates, the mouse strain, tracer type and the calculated injection summary (%) for the rAAV. The Image Viewer allows to browse the experiment in 2-D and panning through the 140 coronal slices of each experiment. The histogram shows the quantified signal in each structure either by projection volume . Adobe Photoshop (version 22.1.1) was used for the photo editing program and Adobe Illustrator (version 25.1) was used to generate the figures.All the gene expression images were downloaded from Allen Institute for Brain Science. [Supplementary Information.


An anomalous systemic arterial supply to the lung lobes is a rare congenital pulmonary vascular malformation. Current treatments include thoracoscopic lobectomy, anatomical segmentectomy, simple ligation and arterial embolization. However, the optimal treatment remains controversial.A 29-year-old man was diagnosed with anomalous systemic arterial supply to the left lower lobe through contrast-enhanced computed tomography and three-dimensional reconstruction. He underwent coil embolization of the anomalous artery and was followed up for 1 year.Blockage of the blood flow of the anomalous systemic artery alone does not improve the blood supply of the pulmonary artery to lung tissue and thus cannot restore normal gas exchange through the blood-gas barrier. Coil embolization of the anomalous arterial supply can cause early postoperative pulmonary infarction. An anomalous systemic arterial supply to the lung lobes is a rare congenital pulmonary vascular malformation, with that occurring to the basal segments of the left lower lobe being most common. In 1946, Pryce defined this condition as intralobar pulmonary sequestration but later realized that this disorder was significantly different from pulmonary sequestration . Althougvia auscultation of the heart and lungs. Ultrasonography revealed no abnormalities in the structure or function of the heart, and pulmonary function was normal.A 29-year-old man with intermittent hemoptysis (10 ml/episode) after physical activity sought treatment 1 year ago at our hospital. He became tired easily after regular physical activity. Computed tomography angiography (CTA) and three-dimensional computed tomography (3DCT) reconstruction showed a robust artery arising from the descending aorta, which was adjacent to the inferior pulmonary vein and approximately 2 cm in diameter. Branches of the artery intertwined with the inferior pulmonary vein in the basal segments. The superior segmental artery was present, whereas the basilar arterial trunk was absent. The structure of the bronchus in the left lower lobe was normal, and no lung tissue sequestration was noted . After cvia coil embolization to preserve as much lung tissue as possible and protect pulmonary function and obtained the patient's consent. The procedure was uneventful (After multidisciplinary treatment (MDT) by thoracic surgery, vascular surgery and interventional radiology, we decided to perform interventional therapy eventful . Howevereventful . SeriousAt the 3-month follow-up, his hemoptysis had subsided completely, and his fatigue after physical activity had improved significantly. After 1 year of embolization, CTA and 3D reconstruction of the pulmonary arteries revealed that the anomalous systemic artery was completely blocked by the coils; the distal arterial branch was atrophic, and the accompanying inferior pulmonary venous branch showed no blood return. The inferior left pulmonary artery and the superior segmental vein remained unchanged . No coilControversy exists regarding whether an anomalous systemic arterial supply to normal lungs is different from typical pulmonary sequestration. According to Pryce's classification, an anomalous systemic blood supply to the basal segments is considered a type of pulmonary sequestration . HoweverAlthough the cause of this disorder remains unclear, most researchers agree that it may be due to plexiform lesions of the primitive pulmonary arterial branches in the embryonic stage, which cause the primitive branches from the aorta to supply the lung buds instead of degenerating. Branches of the pulmonary artery from the lower lobe, i.e., the basal segments, are usually absent , 8. DiffCough, expectoration and recurrent pneumonia are the most common symptoms of patients with pulmonary sequestration . Unlike The current standard treatment for pulmonary sequestration is surgical resection. For symptomatic patients with extralobar or intralobar sequestration, surgical options include lobectomy, wedge resection, and anatomical segment resection , 15. TheThe main symptom of the patient reported in this study was hemoptysis. Preoperative contrast-enhanced CT and 3D reconstruction of the pulmonary arteries showed that the patient's anomalous systemic artery originated from the descending thoracic aorta and supplied the basal segments of the left lower lobe. No obvious abnormalities in the bronchial tree were observed, though the pulmonary artery was absent from the basal segments. The pulmonary artery developed normally in the superior segment, and only one vein in the superior segment drained to the inferior pulmonary vein. Based on comprehensive analysis of the patient's medical history and imaging findings, we performed embolization of the anomalous systemic artery. The patient developed severe pulmonary infarction after the intervention; with rescue treatments, his condition gradually stabilized at 1 week. CTA and 3D reconstruction of the pulmonary arteries at 1 year after the intervention showed complete occlusion of the anomalous artery and atrophy of the accompanying inferior pulmonary vein in the basal segments. No compensatory growth of the pulmonary arteries was observed, and the basal segments of the left lower lobe were partially collapsed, with interstitial exudation.The goal of treating hemoptysis through embolization was achieved in this patient. However, the pulmonary infarction that occurred during treatment increased his risk and caused the patient to develop scar tissue in response to the treatment, and the basal segments of the left lower lobe were left functionless. Through this case study, it can be concluded that blockage of the blood flow of an anomalous systemic artery alone does not improve the blood supply of the pulmonary artery to the lung tissue and thus cannot restore normal gas exchange through the blood-gas barrier. To confirm whether a reserved lung segment benefits patients, a study with a large sample size and long-term follow-up is needed. Overall, application of contrast-enhanced CT and 3D reconstruction of the pulmonary arteries can aid in the diagnosis and treatment of this disorder.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by Ethics Committee of the Fourth Hospital of China Medical University (EC-2020-KS-043). The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.ZW prepared the initial manuscript. XY edited and submitted the manuscript. ZW and XY drafted the article and gave final approval of the version to be published. BX and DZ were involved in the diagnosis and treatment of the patient. All authors have read and approved the final manuscript.This work was supported by Scientific Research Projects of Education Department of Liaoning Province (#ZF2019024).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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Surgery of brain tumors still represents a challenge for neurosurgeons, especially if these lesions are located close to or eventually infiltrate functionally-eloquent brain networks . The goaIn recent years we have witnessed a paradigm shift in knowledge about how the brain works: the historical localizationist interpretation of brain functional organization has been recently replaced by the hodotopical model, in which brain functions do not correspond to fixed anatomical areas but rely on complex cortico-subcortical networks with huge plastic potential . Neuroplin-vivo connectomic analysis of the brain functional organization in every single patient. Those analyses enable a personalized strategy for surgical resection and post-operative rehabilitation and neurological recovery, resulting in a better patients' outcome and quality of life.All these different imaging and neurophysiological advanced techniques, or specific combinations of them, provide a unique and modern Nevertheless, the integration of information provided by these modern tools requires a multidisciplinary approach and a strong collaboration between different professionals, including neuroscientists, neurologists, neuroradiologists, neuropsychologists, and neurosurgeons with strong expertise in the field. A comprehensive review of the technical aspects of such a multidisciplinary approach for connectomics analysis before and during surgery of brain tumors is still lacking. The present Article Collection attempted to provide new insights into novel multidisciplinary approaches to perform advanced connectomics analysis of brain functional organization through the description of the modern pre- and intraoperative electrophysiological and neuroimaging techniques to plan and achieve the maximal safe resection of brain tumors, as well as the illustration of novel neuromodulation approaches based on advanced brain stimulation techniques used to disclose neuroplasticity phenomena, and promote neurological reorganization before surgery.Umana et al. performed an updated systematic review and meta-analysis of literature regarding the use of nTMS mapping before brain tumor surgery: the authors confirmed that nTMS is a safe technique that, in association with DES, improves brain mapping and the extent of tumor resection, thus favoring a better patients' postoperative outcome. Similarly, a study by Haddad et al. summarized the current evidence supporting the efficacy of preoperative nTMS mapping in improving the surgical planning, tumor resection, and postoperative outcome in brain tumor patients. However, the nTMS motor mapping is useful not only to plan tumor surgical resection but also to define a safer radiotherapy plan: Dzierma et al. demonstrated that, in patients with motor-eloquent brain metastases, the inclusion of nTMS motor information into the radiotherapy treatment planning is possible with a straightforward workflow and can achieve reduced doses to the nTMS-defined motor area without compromising coverage of the planning target volume. Finally, three different studies demonstrated that the nTMS motor mapping can also be used to reveal preoperative alterations of the cortical excitability in patients with motor-eloquent brain tumors that could be related to and predict the occurrence of motor deficits .Among preoperative neurophysiological tools for connectomic analysis, navigated TMS (nTMS) is one of the most widely diffused in Neurosurgical Departments all over the world. Several studies demonstrated nTMS provides a reliable mapping of the motor cortex and language cortical areas, thus allowing neurosurgeons to plan the safest surgical strategy to remove brain tumors close to these networks –13. In tWeiss Lucas et al. here proposed a novel robust and reliable picture naming tool, optimized for clinical use, to map and monitor language functions in brain tumor patients during preoperative nTMS mapping and awake surgery. On the other hand, Hazem et al. in their study proposed a novel target for the nTMS preoperative mapping of language cortical areas: in particular, they demonstrated that the posterior middle frontal gyrus, including the area 55b, is an important integration cortical hub for both dorsal and ventral streams of language and can be successfully used as a target for the nTMS language cortical mapping.However, the nTMS cortical mapping of complex functions, including language, is more difficult and reliable than mapping the motor cortex. Raffa et al. submitted a paper demonstrating nTMS can be used also for mapping the cortical areas of the right parietal lobe involved in visuospatial abilities. The authors reported that the nTMS mapping of these areas, in combination with the tractography of the superior longitudinal fascicle (SLF), can be used to plan and achieve the maximal safe resection of brain tumors located in the right parietal lobe, without inducing a worsening of patients' visuospatial abilities.A few data are currently available about the possibility to use nTMS for mapping cortical areas involved in brain functions other than language. Narayana et al. performed a study demonstrating that TMS is a safe, reliable, and effective tool to map eloquent cortices also in a series of 36 young children (3 years old or younger). In this study the TMS mapping improved understanding the risk-benefit ratio prior to surgery and facilitated surgical planning aimed at preserving motor, speech, and language functions.All the previous studies refer to the nTMS cortical mapping in adult brain tumor patients. However, in the previous literature, only anecdotic reports analyzed the feasibility of the nTMS mapping in children. Rosenstock et al. demonstrated that the nTMS motor mapping can be successfully combined with the tractography of the corticospinal tract to stratify patients with motor-eloquent tumors before surgery, distinguishing between patients with a high vs. low risk of developing new postoperative motor deficits. Such a stratification is particularly useful during surgery, by helping neurosurgeons to interpret ambiguous intraoperative monitoring phenomena (such as irreversible MEP amplitude decrease ≤50%) and to adjust the subcortical stimulation intensity. In another study, Fekonja et al. showed that the analysis of tractography measurements along the corticospinal tract (regardless of using a deterministic or probabilistic approach) is useful to stratify patients with motor-eloquent gliomas by disclosing tumor-induced changes in the structural integrity of the tract in the affected hemisphere.Nevertheless, the nTMS mapping enables only the visualization of the cortical areas of functional networks  that must be preserved during the resection of the tumor. Therefore, the data from nTMS cortical mapping must be combined with the tractography of the respective subcortical pathways, aiming at the preoperative identification of the entire functional network –16. RoseIus et al. in their study, computed the tractography of the superior longitudinal fascicle (SLF) and inferior fronto-occipital fascicle (IFOF) to stratify patients with language-eloquent low-grade gliomas. In particular, the authors demonstrated that the comparison of quantitative parameters resulting from the DTI tractography between the tumoral vs. the healthy hemisphere is useful to assess the risk of post-operative transient language impairment in these patients. Moreover, Di Cristofori et al. performed a review to analyze the current literature evidence about the possible role of the preoperative assessment of the asymmetry of the arcuate fascicle (AF) by DTI tractography for the preoperative risk assessment of patients undergoing surgical resection of gliomas. They also reported the usefulness of the analysis of AF asymmetry in the health vs. affected hemisphere to predict recovery from aphasia and reorganization of the language brain network even after surgical damage. Finally, Zoli et al. reported an interesting study demonstrating that DTI tractography of the AF is useful not only for planning the safest surgical strategy for tumor resection but also to analyze some along-tract DTI metrics that can provide useful information for differentiating low-grade and high-grade tumors. Another important subcortical white matter tract involved in the language network, the Frontal Aslant Tract (FAT), has been analyzed in the study La Corte et al. The authors performed a systematic review of the literature about the FAT anatomical connectivity and functional roles, thus providing an overview for practical neurosurgical applications in patients with brain tumors: they also eventually suggested the evaluation of FAT integrity by tractography could be useful to plan a safer surgery and to reduce post-operative deficits in patients with language-eloquent brain tumors.A similar preoperative patient stratification can be achieved also in cases of language-eloquent tumors by performing the tractography of fascicles involved in the language network. Ciavarro et al. performed a very interesting study proposing a novel motor task for a more accurate preoperative localization of the motor cortex in brain tumor patients: the proposed visual-triggered finger movement task (VFMT) resulted to be more reliable than the standard finger-tapping task for the identification of the hand-knob region and showed good correspondence to intraoperative DES. They concluded the VFMT could be very helpful for planning the safest surgical strategy in patients with motor-eloquent tumors.Another important preoperative tool to identify functional networks before brain tumor surgery is fMRI. Nevertheless, some concerns about its accuracy, especially in comparison with nTMS, have been reported in the literature . In partDuffau, in his Editorial discussed all the potential applications of NIBS to elicit neuroplasticity and facilitate reoperation for low-grade glioma relapse. Moreover, Lang et al. performed a very interesting proof of concept pilot study demonstrating that transcranial direct current stimulation (tDCS) can be used to modify the connectivity of the sensorimotor network in glioma patients. Such a pioneering study confirms the potential usefulness of neuromodulation by NIBS even in the clinical practice, for safer surgical management of brain tumors. Finally, Leao et al. demonstrated that neuromodulation may be used also for the treatment of specific medical conditions, such as tinnitus. The authors reported that low-frequency repetitive TMS to the right dorsolateral prefrontal cortex in patients affected by vestibular schwannomas can result in a significant acute but limited long-term effect on tinnitus.Recently, neuromodulation by non-invasive brain stimulation (NIBS) has been proposed in the literature as a novel strategy to increase the safety of surgical resection of brain tumors. This strategy aims to promote neuroplasticity and connectivity changes in brain functional networks at surgical risk, thus allowing a “shift” of eloquent structures far away from the tumor. The father of the hodotopical revolution, Barbagallo et al., in their study, demonstrated the importance of a multimodal approach based on different intraoperative imaging techniques  to achieve the maximal safe resection of high-grade gliomas and to improve the patients' postoperative outcome. Giammalva et al. performed a systematic review to assess the role of preoperative connectivity analysis and intraoperative brain mapping to guide the supratotal resection (SpTR) of gliomas, also analyzing the clinical impact of SpTR. They concluded SpTR is related to a longer overall and progression-free survival along with preserving neuro-cognitive functions and quality of life. Herbet et al. reported a perspective article highlighting the possibility to map advanced cognitive functions and behaviors  during wide-awake surgery. Finally, Sala et al., propose a very interesting opinion study, suggesting novel strategies for the intraoperative assessment of brain connectivity in the anesthetized patient. The aim is to overcome the limitations of the standard neurophysiological mapping and monitoring techniques during asleep surgery and increase the safety of brain tumor resection when awake surgery is not feasible.Apart from preoperative techniques, also intraoperative imaging, neurophysiological and neuropsychological tools play an important role in achieving the safe surgical resection of brain tumors. In conclusion, this Article Collection includes several remarkable studies summarizing the state-of-the-art of modern preoperative and intraoperative brain stimulation and neuroimaging techniques for performing connectomic analysis and promoting neuroplasticity in brain tumor patients. The scope is to highlight the most novel strategies to enhance knowledge about brain functional organization in brain tumor patients, aiming to improve their surgical treatment and outcome. We believe this Collection will encourage future clinical studies on this fascinating topic and open novel, tailored, safer, and hopefully more effective therapeutic perspectives for patients harboring brain tumors.GR, TP, AB, and AG: conceptualization, collection of the data, writing of the draft, and revision of the final manuscript. All authors are accountable for the content of the work.Matters of Activity. Image Space Material funded by the Deutsche Forschungsgemeinschaft  under Germany's Excellence Strategy—EXC 2025−390648296.This editorial and the article collection have been funded by a grant from the European Social Fund (FSE), Call PON Ricerca e Innovazione 2014-2020—AIM Attraction and International Mobility, Activity AIM1839117-3, Line 1, Area SNSI Salute (CUP J44I18000280006), Recipient: GR, BIOMORF Department, University of Messina, Italy. TP acknowledges the support of the Cluster of Excellence 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Neuropsychiatric diseases are complex diseases that are poorly understood despite collective attempts to explain the neurobiology of these disorders. These changes in behavior may result from but not restricted to defective neuronal or glial development, alterations in neurotransmitters and many other factors which adds to disease complexity. Many studies in recent years focused on identifying the genetic basis of the disease by identifying the loci involved in disease manifestation reflecting changes in brain function. More importantly, recent evidence points to a role for epigenetic regulation in developing neuropsychiatric disorders. Several advanced methods have been developed to understand the link between environmental changes and neuropsychiatric disorders through epigenetic signaling and chromatin remodeling. Since our chromatin is accessible to pharmaceutical treatment, this opens new avenues to alternative treatment modalities of psychiatric diseases. This Research Topic comprises eight papers that highlighted the global epigenetic mechanisms involved in certain psychiatric disorders in addition to some in depth understanding of the effect of selective epigenetic modifiers in mouse models. In addition, some studies focused on the impact of antipsychotic drugs on gene regulation in different cell types while analyzing its pharmaco-epigenomic response. In line within the same therapeutic theme, the effect of blocking histone deacetylase was studied in transgenic mouse models of Alzheimer's disease (AD) and its effect on disease progression.Lee et al. addressed the use of atypical epigenetic and/or consequent transcriptional alterations as biomarkers of early-stage Schizophrenia. The review highlighted the importance of early stage diagnosis of schizophrenia to prevent disease-associated neural impairments by using well validated biomarkers for schizophrenia. One way of modeling schizophrenia that was suggested is the use of patient-derived iPSC cellular models and organoid technologies. These methods may enhance the assessment of specific cell-subtypes in a wide range of brain cells early in its disease development. Single-cell level analyses have already been used and improved characterization of schizophrenia and this was further elaborated in the review , a member of HADC family, is involved in the epigenetic control of neuronal plasticity, stress response, and cognitive functions Wood, . A studyAnderson and Taniguchi focused on histone acetylation and histone methylation in a brain region important for drug-related behaviors and also discussed how experimentally altering epigenetic regulators via addictive compounds or brain region-specific manipulations demonstrate the importance of epigenetic proteins in the behavioral effects of drugs. They also discussed future directions for the field of epigenetic studies in the behavioral effects of addictive drugs and suggested how to use these insights to develop efficacious treatments.A review by Du et al. aimed to identify global and site-specific epigenetic changes by antipsychotics and those shared by different classes of antipsychotics. To do this, they performed a comprehensive DNA methylation analysis of human neuroblastoma cells cultured with different antipsychotics . This may be the first study to examine the common effect of two distinctive antipsychotics on DNA methylation in human neuroblastoma cells.A study by Takasu et al. investigated whether histone acetylation regulates kainate-induced gamma oscillations and their important regulator, fast-spiking interneurons, using acute hippocampal slices of AD model mice. They found impairment of gamma oscillation in AD model mice, accompanied with activity of fast spiking interneurons in basal and activated states. HDAC inhibitor SAHA rescued activity of fast spiking interneurons in the activated state in AD mice. The reversal of gamma oscillation deficits by HDAC inhibition appears to be a potential therapeutic target for treating cognitive impairment in AD patients.A study by Kawatake-Kuno et al. summarized the roles of epigenetic molecules associated with neural plasticity and behavioral regulation in animal models of depression and those that have been suggested to be involved in human major depressive disorder (MDD) patients. They especially focused on sex-related differences in epigenetic signatures in patients with MDD and animal models. They concluded that translational implications for bridging research in human depression and animal models will provide a better understanding of how epigenetic mechanisms contribute to the etiology and pathophysiology of depression.A review by Rowland et al. reviewed genetic regulation in ASD. The focus of their review was on mutations in the neuronal version of BAF (nBAF). Mutations in this gene (BAF53B) have been shown to lead to the development of ASD and other intellectual disorders. The expression of nBAF is tied to neuronal differentiation and coordination of synaptic genes across brain development. Using neurons from patients with BAF53B when both copies of the gene are deleted led to the disruption of dendritic spine formation. Model systems have shown that the heterozygous loss of Baf53b severely impacts synaptic plasticity and long-term memory. This can be reversed with the reintroduction of Baf53b. Mice that survive the Baf53b deletion display ASD-related behaviors, including social impairments and repetitive behaviors. The review concludes to say mutations in Baf53b and nBAF provide novel avenues to pursue therapeutic advances for treating ASD symptoms in children.Autism Spectrum Disorder (ASD) is a complex disease in which the causes remain unknown , the Lebanese National Council for Scientific Research (L-CNRS) and the King Hussein Cancer Research Award. NMJ was supported by a grant from the American Heart Association (20AIREA35050015).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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This special issue is built around the topic of neuroplasticity-induced changes in functional networks as a result of language recovery after brain lesions. As we know, Aphasia knowledge has first relied on the seminal clinical-anatomical works describing the “zone du language” and attached bundles  segments to language on a cohort of chronic left hemispheric stroke PWA. They found that the left long segment of the AF contributes to naming abilities, while the anterior part to fluency and naming, and the posterior one to comprehension. These results highlight the important contributions of the AF fiber pathways to language impairments and point to the posterior segment of this tract as being most crucial for supporting residual language abilities. Kourtidou et al. investigate possible mechanisms of right hemisphere compensation by studying chronic PWA. Using diffusion tensor imaging (DTI) and correlating language performance with radial diffusivity (RD) in the right hemisphere homologs of damaged left structure, they argue in favor of compensatory roles of the right hemisphere tracts in language functions when the LH networks are disrupted. Finally, in the study by Lwi et al. on a group of chronic left post-stroke PWA, the authors confirm the critical role of intact posterior left middle temporal gyrus in the recovery of auditory comprehension. The study also highlights that spontaneous recovery of auditory comprehension can continue beyond the first-year post-stroke, independently of age and gender. The role of the cerebellum as part of the language network, and in aphasia recovery is addressed in an innovative multiple case study by Geva et al.. Detailed analysis of four patients with cerebellar lesions suggests that focal damage to the right posterior cerebellum, particularly to lobule IX, may induce sentence comprehension and production impairments, demonstrating the contribution of such structure to language processing.Then, a series of articles approach, through clinical-neuroimaging investigations, the role of specific white matter structures in language impairment. They offer interesting insights on the role of subcortical reorganization in interpreting different aphasia symptoms and their recovery. LaCroix et al. found that PWA engage left perilesional regions during language comprehension and right hemispheric areas in language production, relying generally on similar cognitive-linguistic neural resources for language as controls. Finally, a last behavioral study by Masson-Trottier et al. addresses the role of bilingualism in aphasia recovery and more specifically, the effect of French Phonological Component Analysis—a training approach which uses phonological cues associated with the target word to elicit naming. The authors compared monolingual and bilingual PWA performance both at the linguistic and cognitive control level to examine the structural impact of the left hemispheric lesion location on right hemisphere structural data. Results show that bilinguals improved more than monolinguals in picture naming and narrative discourse tasks potentially due to enhanced cognitive control abilities, which could be supported by right hemisphere neural reserve.The last two studies focused on more general principles of aphasia recovery. In a Meta- Analysis using an original method of activation likelihood estimates across 44 published fMRI and PET studies to characterize the functional reorganization in left post-stroke PWA, In sum, this special issue points to the variety of linguistic and non-linguistic networks sustaining recovery following brain damage, providing evidence for their potential role in language recovery. Please enjoy the reading.J-MA wrote the first draft and reviewed the manuscript. AA and PM introduced their own input and reviewed the manuscript. SK checked and edited the manuscript. All authors contributed to the article and approved the submitted version.