Comparative Anatomic Analysis of Neuronavigated Transmastoid-Infralabyrinthine Approaches for Jugular Fossa Pathologies: Short Anterior Rerouting Versus Nonrerouting and Tailored Nonrerouting Techniques.

BACKGROUND AND OBJECTIVES: Access to the jugular fossa pathologies (JFPs) via the transmastoid infralabyrinthine approach (TI-A) using the nonrerouting technique (removing the bone anterior and posterior to the facial nerve while leaving the nerve protected within the fallopian canal) or with the short-rerouting technique (rerouting the mastoid segment of the facial nerve anteriorly) has been described in previous studies. The objective of this study is to compare the access to Fisch class C lesions (JFPs extending or destroying the infralabyrinthine and apical compartment of the temporal bone with or without involving the carotid canal) between the nonrerouting and the short-rerouting techniques. Also, some tailored steps to the nonrerouting technique (NR-T) were outlined to enhance access to the jugular fossa (JF) as an alternative to the short-rerouting technique. METHODS: Neuronavigated TI-A was performed using the nonrerouting, tailored nonrerouting, and short-rerouting techniques on both sides of 10 human head specimens. Exposed area, horizontal distance, surgical freedom, and horizontal angle were calculated using vector coordinates for nonrerouting and short-rerouting techniques. RESULTS: The short-rerouting technique had significantly higher values than the NR-T ( P < .01) for the exposed area (169.1 ± SD 11.5 mm 2 vs 151.0 ± SD 12.4 mm 2 ), horizontal distance (15.9 ± SD 0.6 mm vs 10.6 ± SD 0.5 mm 2 ), surgical freedom (19 650.2 ± SD 722.5 mm 2 vs 17 233.8 ± SD 631.7 mm 2 ), and horizontal angle (75.2 ± SD 5.1° vs 61.7 ± SD 4.6°). However, adding some tailored steps to the NR-T permitted comparable access to the JF. CONCLUSION: Neuronavigated TI-A with the short-rerouting technique permits wider access to the JF compared with the NR-T. However, the tailored NR-T provides comparable access to the JF and may be a better option for class C1 and selected class C2 and C3 JFPs.

An α-helical peptide-based plasmonic biosensor for highly specific detection of α-synuclein toxic oligomers.

BACKGROUND: α-Synuclein (αS) aggregation is the main neurological hallmark of a group of neurodegenerative disorders, collectively referred to as synucleinopathies, of which Parkinson's disease (PD) is the most prevalent. αS oligomers are elevated in the cerebrospinal fluid (CSF) of PD patients, standing as a biomarker for disease diagnosis. However, methods for early PD detection are still lacking. We have recently identified the amphipathic 22-residue peptide PSMα3 as a high-affinity binder of αS toxic oligomers. PSMα3 displayed excellent selectivity and reproducibility, binding to αS toxic oligomers with affinities in the low nanomolar range and without detectable cross-reactivity with functional monomeric αS. RESULTS: In this work, we leveraged these PSMα3 unique properties to design a plasmonic-based biosensor for the direct detection of toxic oligomers under label-free conditions. SIGNIFICANCE AND NOVELTY: We describe the integration of the peptide in a lab-on-a-chip plasmonic platform suitable for point-of-care measurements of αS toxic oligomers in CSF samples in real-time and at an affordable cost, providing an innovative biosensor for PD early diagnosis in the clinic.

A Targetable N-Terminal Motif Orchestrates α-Synuclein Oligomer-to-Fibril Conversion.

Oligomeric species populated during α-synuclein aggregation are considered key drivers of neurodegeneration in Parkinson's disease. However, the development of oligomer-targeting therapeutics is constrained by our limited knowledge of their structure and the molecular determinants driving their conversion to fibrils. Phenol-soluble modulin α3 (PSMα3) is a nanomolar peptide binder of α-synuclein oligomers that inhibits aggregation by blocking oligomer-to-fibril conversion. Here, we investigate the binding of PSMα3 to α-synuclein oligomers to discover the mechanistic basis of this protective activity. We find that PSMα3 selectively targets an α-synuclein N-terminal motif (residues 36-61) that populates a distinct conformation in the mono- and oligomeric states. This α-synuclein region plays a pivotal role in oligomer-to-fibril conversion as its absence renders the central NAC domain insufficient to prompt this structural transition. The hereditary mutation G51D, associated with early onset Parkinson's disease, causes a conformational fluctuation in this region, leading to delayed oligomer-to-fibril conversion and an accumulation of oligomers that are resistant to remodeling by molecular chaperones. Overall, our findings unveil a new targetable region in α-synuclein oligomers, advance our comprehension of oligomer-to-amyloid fibril conversion, and reveal a new facet of α-synuclein pathogenic mutations.

A new classification of parasagittal bridging veins based on their configurations and drainage routes pertinent to interhemispheric approaches: a surgical anatomical study.

OBJECTIVE: Opening the roof of the interhemispheric microsurgical corridor to access various neurooncological or neurovascular lesions can be demanding because of the multiple bridging veins that drain into the sinus with their highly variable, location-specific anatomy. The objective of this study was to propose a new classification system for these parasagittal bridging veins, which are herein described as being arranged in 3 configurations with 4 drainage routes. METHODS: Twenty adult cadaveric heads (40 hemispheres) were examined. From this examination, the authors describe 3 types of configurations of the parasagittal bridging veins relative to specific anatomical landmarks (coronal suture, postcentral sulcus) and their drainage routes into the superior sagittal sinus, convexity dura, lacunae, and falx. They also quantify the relative incidence and extension of these anatomical variations and provide several preoperative, postoperative, and microneurosurgical clinical case study examples. RESULTS: The authors describe 3 anatomical configurations for venous drainage, which improves on the 2 types that have been previously described. In type 1, a single vein joins; in type 2, 2 or more contiguous veins join; and in type 3, a venous complex joins at the same point. Anterior to the coronal suture, the most common configuration was type 1 dural drainage, occurring in 57% of hemispheres. Between the coronal suture and the postcentral sulcus, most veins (including 73% of superior anastomotic veins of Trolard) drain first into a venous lacuna, which are larger and more numerous in this region. Posterior to the postcentral sulcus, the most common drainage route was through the falx. CONCLUSIONS: The authors propose a systematic classification for the parasagittal venous network. Using anatomical landmarks, they define 3 venous configurations and 4 drainage routes. Analysis of these configurations with respect to surgical routes indicates 2 highly risky interhemispheric surgical fissure routes. The risks are attributable to the presence of large lacunae that receive multiple veins (type 2) or venous complex (type 3) configurations that negatively impact a surgeon's working space and degree of movement and thus are predisposed to inadvertent avulsions, bleeding, and venous thrombosis.

A glimpse into the structural properties of α-synuclein oligomers.

α-Synuclein (αS) aggregation is the main neurological hallmark of a group of debilitating neurodegenerative disorders, collectively referred to as synucleinopathies, of which Parkinson's disease is the most prevalent. αS oligomers formed during the initial stages of aggregation are considered key pathogenic drivers of disease onset and progression, standing as privileged targets for therapeutic intervention and diagnosis. However, the structure of αS oligomers and the mechanistic basis of oligomer to fibril conversion are yet poorly understood, thereby precluding the rational formulation of strategies aimed at targeting oligomeric species. In this review, we delve into the recent advances in the structural and mechanistic characterization of αS oligomers. We also discuss how these advances are transforming our understanding of these elusive species and paving the way for oligomer-targeting therapeutics and diagnosis.

aSynPEP-DB: a database of biogenic peptides for inhibiting α-synuclein aggregation.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, yet effective treatments able to stop or delay disease progression remain elusive. The aggregation of a presynaptic protein, α-synuclein (aSyn), is the primary neurological hallmark of PD and, thus, a promising target for therapeutic intervention. However, the lack of consensus on the molecular properties required to specifically bind the toxic species formed during aSyn aggregation has hindered the development of therapeutic molecules. Recently, we defined and experimentally validated a peptide architecture that demonstrated high affinity and selectivity in binding to aSyn toxic oligomers and fibrils, effectively preventing aSyn pathogenic aggregation. Human peptides with such properties may have neuroprotective activities and hold a huge therapeutic interest. Driven by this idea, here, we developed a discriminative algorithm for the screening of human endogenous neuropeptides, antimicrobial peptides and diet-derived bioactive peptides with the potential to inhibit aSyn aggregation. We identified over 100 unique biogenic peptide candidates and ensembled a comprehensive database (aSynPEP-DB) that collects their physicochemical features, source datasets and additional therapeutic-relevant information, including their sites of expression and associated pathways. Besides, we provide access to the discriminative algorithm to extend its application to the screening of artificial peptides or new peptide datasets. aSynPEP-DB is a unique repository of peptides with the potential to modulate aSyn aggregation, serving as a platform for the identification of previously unexplored therapeutic agents. Database URL:  https://asynpepdb.ppmclab.com/.

Management of a challenging dura-embedded anterior inferior cerebellar artery loop during a retrosigmoid hearing-preserving vestibular schwannoma resection: microsurgical technique and operative video. Illustrative case.

BACKGROUND: Anatomical variants of the anterior inferior cerebellar artery (AICA), such as an anomalous "AICA loop" embedded in the dura and bone of the subarcuate fossa, increase the complexity and risk of vestibular schwannoma resections. Classically, osseous penetrating AICA loops are the most challenging to mobilize, as the dura must be dissected and the surrounding petrous bone must be drilled to mobilize the AICA away from the surgical corridor and out of harm. OBSERVATIONS: The authors present a rare case of a dura-embedded, osseous-penetrating AICA loop encountered during a hearing-preserving retrosigmoid approach in which they demonstrate safe and efficient microdissection and mobilization of the AICA loop without having to drill the surrounding bone. LESSONS: Although preoperative recognition of potentially dangerous AICA loops has been challenging, thin-sliced petrous bone computed tomography scanning and high-quality magnetic resonance imaging can be useful in preoperative diagnosis. Furthermore, this report suggests that a retrosigmoid approach is superior, as it allows early intradural recognition and proximal vascular control and facilitates more versatile mobilization of AICA loops.

Microneurosurgical treatment of a small perimesencephalic pure pial arterial malformation: an under-recognized etiology of angiographically occult subarachnoid hemorrhage. Illustrative case.

BACKGROUND: Pial arterial malformations (PAMs) are rare vascular lesions consisting of dilated tortuous arteries without venous drainage. Current PAM understanding is limited by the lesion's rarity, limited anatomopathological studies, and frequent misclassifications. OBSERVATIONS: A 23-year-old male experienced two spontaneous subarachnoid hemorrhages (SAHs) over 6 months with initially unremarkable diagnostic cerebral angiograms. Magnetic resonance imaging (MRI) and angiography after the second SAH revealed a small perimesencephalic ovoid lesion within the left crural cistern, between the left superior and posterior cerebral arteries, appearing to be an exophytic cavernoma, a thrombosed aneurysm, or a hemorrhagic tumor. Microsurgical resection was achieved with a pterional craniotomy and anterior clinoidectomy. The resected lesion was characteristic of a pure PAM arising from superior cerebellar arterial branches. LESSONS: Small pure PAMs can be deceitfully dynamic lesions causing episodes of hemorrhage, complete thrombosis (angiographically occult), recanalization, and rehemorrhage. Small thrombosed vascular malformations or aneurysms should be included in differential diagnoses of angiographically occult SAH. MRI can be diagnostic, but the true angioarchitecture can only be elucidated with microneurosurgery. The only definitive cure is removal. The microneurosurgical strategy should account for worst-case scenarios, provide adequate skull base exposures, and include bypass revascularization options when thrombosed aneurysms are encountered.

Arabidopsis metacaspase MC1 localizes in stress granules, clears protein aggregates, and delays senescence.

Stress granules (SGs) are highly conserved cytoplasmic condensates that assemble in response to stress and contribute to maintaining protein homeostasis. These membraneless organelles are dynamic, disassembling once the stress is no longer present. Persistence of SGs due to mutations or chronic stress has been often related to age-dependent protein-misfolding diseases in animals. Here, we find that the metacaspase MC1 is dynamically recruited into SGs upon proteotoxic stress in Arabidopsis (Arabidopsis thaliana). Two predicted disordered regions, the prodomain and the 360 loop, mediate MC1 recruitment to and release from SGs. Importantly, we show that MC1 has the capacity to clear toxic protein aggregates in vivo and in vitro, acting as a disaggregase. Finally, we demonstrate that overexpressing MC1 delays senescence and this phenotype is dependent on the presence of the 360 loop and an intact catalytic domain. Together, our data indicate that MC1 regulates senescence through its recruitment into SGs and this function could potentially be linked to its remarkable protein aggregate-clearing activity.

Feasibility assessment of the Eye Scan Ultrasound System for cataract characterization and optimal phacoemulsification energy estimation: protocol for a pilot, nonblinded and monocentre study.

BACKGROUND: Cataracts are lens opacifications that are responsible for more than half of blindness cases worldwide, and the only treatment is surgical intervention. Phacoemulsification surgery, the most frequently performed cataract surgery in developed countries, has associated risks, some of which are related to excessive phacoemulsification energy levels and times. The protocol proposed in herein will be used to evaluate the feasibility of a new experimental medical device, the Eye Scan Ultrasound System (ESUS), for the automatic classification of cataract type and severity and quantitative estimation of the optimal phacoemulsification energy. METHODS: The pilot study protocol will be used to evaluate the feasibility and safety of the ESUS in clinical practice. The study will be conducted in subjects with age-related cataracts and on healthy subjects as controls. The procedures include data acquisition with the experimental ESUS, classification based on the Lens Opacity Classification System III (LOCS III, comparator) using a slit lamp, contrast sensitivity test, optical coherence tomography, specular microscopy and surgical parameters. ESUS works in A-scan pulse-echo mode, with a central frequency of 20 MHz. From the collected signals, acoustic parameters will be extracted and used for automatic cataract characterization and optimal phacoemulsification energy estimation. The study includes two phases. The data collected in the first phase (40 patients, 2 eyes per patient) will be used to train the ESUS algorithms, while the data collected in the second phase (10 patients, 2 eyes per patient) will be used to assess the classification performance. System safety will be monitored during the study. DISCUSSION: The present pilot study protocol will evaluate the feasibility and safety of the ESUS for use in clinical practice, and the results will support a larger clinical study for the efficacy assessment of the ESUS as a diagnostic tool. Ultimately, the ESUS is expected to represent a valuable tool for surgical planning by reducing complications associated with excessive levels of phacoemulsification energy and surgical times, which will have a positive impact on healthcare systems and society. The study is not yet recruiting. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04461912 , registered on July 8, 2020.

CARs-DB: A Database of Cryptic Amyloidogenic Regions in Intrinsically Disordered Proteins.

Proteome-wide analyses suggest that most globular proteins contain at least one amyloidogenic region, whereas these aggregation-prone segments are thought to be underrepresented in intrinsically disordered proteins (IDPs). In recent work, we reported that intrinsically disordered regions (IDRs) indeed sustain a significant amyloid load in the form of cryptic amyloidogenic regions (CARs). CARs are widespread in IDRs, but they are necessarily exposed to solvent, and thus they should be more polar and have a milder aggregation potential than conventional amyloid regions protected inside globular proteins. CARs are connected with IDPs function and, in particular, with the establishment of protein-protein interactions through their IDRs. However, their presence also appears associated with pathologies like cancer or Alzheimer's disease. Given the relevance of CARs for both IDPs function and malfunction, we developed CARs-DB, a database containing precomputed predictions for all CARs present in the IDPs deposited in the DisProt database. This web tool allows for the fast and comprehensive exploration of previously unnoticed amyloidogenic regions embedded within IDRs sequences and might turn helpful in identifying disordered interacting regions. It contains >8,900 unique CARs identified in a total of 1711 IDRs. CARs-DB is freely available for users and can be accessed at http://carsdb.ppmclab.com. To validate CARs-DB, we demonstrate that two previously undescribed CARs selected from the database display full amyloidogenic potential. Overall, CARs-DB allows easy access to a previously unexplored amyloid sequence space.

Intracranial Aneurysms in Loeys-Dietz Syndrome: A Multicenter Propensity-Matched Analysis.

BACKGROUND: Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized by a classic triad of hypertelorism, bifid uvula and/or cleft palate, and generalized arterial tortuosity. There are limited data on the prevalence and rupture risk of intracranial aneurysms (IAs) in the setting of LDS, with no established guidelines. OBJECTIVE: To analyze the prevalence and rupture risk of IA in LDS. METHODS: Electronic medical records of patients with a confirmed diagnosis of LDS and available cerebrovascular imaging were reviewed. Patients were divided into 2 groups based on the presence of IA. Unmatched and propensity-matched analyses were used to identify potential risk factors for aneurysm formation. RESULTS: Records of 1111 patients were screened yielding a total of 60 patients with a diagnosis of LDS. Eighteen (30%) patients had IA, 4 (22.2%) of whom had multiple aneurysms for a total of 24 IAs. Twenty-three (95.8%) aneurysms were located in the anterior circulation; none of them were ruptured. On unmatched analysis, age ( P = .015), smoking history ( P = .034), hypertension ( P = .035), and number of extracranial aneurysms ( P < .001) were significantly higher in patients with IA. After matching for age, sex, race, stroke history, family history, and extracranial aneurysms, smoking history ( P = .009) remained significant. CONCLUSION: Patients with LDS have an increased risk of IAs, especially with a history of smoking. The prevalence rate of IAs in our series was 30%. Screening imaging should be considered at diagnosis, and patients should be encouraged to abstain from smoking. Further studies are needed to elucidate the risk of IA rupture and treatment considerations in this unique population.

Prediction of the Effect of pH on the Aggregation and Conditional Folding of Intrinsically Disordered Proteins with SolupHred and DispHred.

Proteins microenvironments modulate their structures. Binding partners, organic molecules, or dissolved ions can alter the protein's compaction, inducing aggregation or order-disorder conformational transitions. Surprisingly, bioinformatic platforms often disregard the protein context in their modeling. In a recent work, we proposed that modeling how pH affects protein net charge and hydrophobicity might allow us to forecast pH-dependent aggregation and conditional disorder in intrinsically disordered proteins (IDPs). As these approaches showed remarkable success in recapitulating the available bibliographical data, we made these prediction methods available for the scientific community as two user-friendly web servers. SolupHred is the first dedicated software to predict pH-dependent aggregation, and DispHred is the first pH-dependent predictor of protein disorder. Here we dissect the features of these two software applications to train and assist scientists in studying pH-dependent conformational changes in IDPs.

The small aromatic compound SynuClean-D inhibits the aggregation and seeded polymerization of multiple α-synuclein strains.

Parkinson's disease is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, as well as the accumulation of intraneuronal proteinaceous inclusions known as Lewy bodies and Lewy neurites. The major protein component of Lewy inclusions is the intrinsically disordered protein α-synuclein (α-Syn), which can adopt diverse amyloid structures. Different conformational strains of α-Syn have been proposed to be related to the onset of distinct synucleinopathies; however, how specific amyloid fibrils cause distinctive pathological traits is not clear. Here, we generated three different α-Syn amyloid conformations at different pH and salt concentrations and analyzed the activity of SynuClean-D (SC-D), a small aromatic molecule, on these strains. We show that incubation of α-Syn with SC-D reduced the formation of aggregates and the seeded polymerization of α-Syn in all cases. Moreover, we found that SC-D exhibited a general fibril disaggregation activity. Finally, we demonstrate that treatment with SC-D also reduced strain-specific intracellular accumulation of phosphorylated α-Syn inclusions. Taken together, we conclude that SC-D may be a promising hit compound to inhibit polymorphic α-Syn aggregation.

Anatomical Engineering and 3D Printing for Surgery and Medical Devices: International Review and Future Exponential Innovations.

Three-dimensional printing (3DP) has recently gained importance in the medical industry, especially in surgical specialties. It uses different techniques and materials based on patients' needs, which allows bioprofessionals to design and develop unique pieces using medical imaging provided by computed tomography (CT) and magnetic resonance imaging (MRI). Therefore, the Department of Biology and Medicine and the Department of Physics and Engineering, at the Bioastronautics and Space Mechatronics Research Group, have managed and supervised an international cooperation study, in order to present a general review of the innovative surgical applications, focused on anatomical systems, such as the nervous and craniofacial system, cardiovascular system, digestive system, genitourinary system, and musculoskeletal system. Finally, the integration with augmented, mixed, virtual reality is analyzed to show the advantages of personalized treatments, taking into account the improvements for preoperative, intraoperative planning, and medical training. Also, this article explores the creation of devices and tools for space surgery to get better outcomes under changing gravity conditions.

A Response to: Letter to the Editor Regarding "Cost-Effectiveness of the 13-Valent Pneumococcal Conjugate Vaccine (PCV13) Versus Lower-Valent Alternatives in Filipino Infants".

This communication seeks to address the questions of Dhere and colleagues in their letter on our study "Cost-effectiveness of the 13-valent pneumococcal conjugate vaccine (PCV13) versus lower-valent alternatives in Filipino infants." We hope to provide clarity on each of the three potential misunderstandings of our cost-effectiveness analysis that were raised by Dhere and colleagues.

Is a cure for Parkinson's disease hiding inside us?

α-Synuclein (a-syn) oligomers and fibrils are behind neurodegeneration in Parkinson's disease (PD), but therapeutically targeting them is challenging. Amphipathic and cationic helical peptides inhibit amyloid formation and suppress neurotoxicity by selectively binding the solvent-accessible regions in these toxic species. Can endogenous peptides, like LL-37, constitute a new therapeutic paradigm in PD?

A3D 2.0 Update for the Prediction and Optimization of Protein Solubility.

Protein aggregation propensity is a property imprinted in protein sequences and structures, being associated with the onset of human diseases and limiting the implementation of protein-based biotherapies. Computational approaches stand as cost-effective alternatives for reducing protein aggregation and increasing protein solubility. AGGRESCAN 3D (A3D) is a structure-based predictor of aggregation that takes into account the conformational context of a protein, aiming to identify aggregation-prone regions exposed in protein surfaces. Here we inspect the updated 2.0 version of the algorithm, which extends the application of A3D to previously inaccessible proteins and incorporates new modules to assist protein redesign. Among these features, the new server includes stability calculations and the possibility to optimize protein solubility using an experimentally validated computational pipeline. Finally, we employ defined examples to navigate the A3D RESTful service, a routine to handle extensive protein collections. Altogether, this chapter is conceived to train and assist A3D non-experts in the study of aggregation-prone regions and protein solubility redesign.