Abnormal Folding Research Articles

Motor Neuron Diseases

The motor neuron diseases (MNDs) are a family of diseases commonly categorized by their propensity to affect upper or lower motor neurons and by their mode of inheritance. The chapter provides some content on infectious MNDs caused by viral infections affecting the motor neurons in the anterior horn of the spinal cord. However, the chapter devotes most of its attention to the inherited and sporadically occurring MNDs. The majority of research into adult MND focuses on amyotrophic lateral sclerosis (ALS) due to its high prevalence, rapid progression, and phenotypical similarities between its inherited form and its sporadic form. As our knowledge of genetic mechanisms underlying ALS pathology has grown, common themes have emerged. These include abnormalities in RNA biology, axonal transport, protein folding, and inflammatory responses. These themes currently drive much of the direction in ALS experimental therapy development. It is clear that MND is complex and involves several different molecular pathways. Given this complexity, ALS might not be a single disease entity, and if this is the case, treatment approaches may need to be targeted to specific pathologies rather than all ALS patients on a broad scale. Chapter content is enhanced by tables outlining the types of MNDs, criteria for supporting a diagnosis, first-line workup, the genes associated with ALS, ALS efficacy outcome measures, symptom management of ALS, and spinal muscular atrophy classification. Mechanisms of ALS are illustrated, and clinical photographs demonstrate symptoms. This review contains 5 figures, 14 tables and 253 references Keywords: motor neuron disease, amyotrophic lateral sclerosis, electromyography, Guillain-Barré syndrome

Motor Neuron Diseases

The motor neuron diseases (MNDs) are a family of diseases commonly categorized by their propensity to affect upper or lower motor neurons and by their mode of inheritance. The chapter provides some content on infectious MNDs caused by viral infections affecting the motor neurons in the anterior horn of the spinal cord. However, the chapter devotes most of its attention to the inherited and sporadically occurring MNDs. The majority of research into adult MND focuses on amyotrophic lateral sclerosis (ALS) due to its high prevalence, rapid progression, and phenotypical similarities between its inherited form and its sporadic form. As our knowledge of genetic mechanisms underlying ALS pathology has grown, common themes have emerged. These include abnormalities in RNA biology, axonal transport, protein folding, and inflammatory responses. These themes currently drive much of the direction in ALS experimental therapy development. It is clear that MND is complex and involves several different molecular pathways. Given this complexity, ALS might not be a single disease entity, and if this is the case, treatment approaches may need to be targeted to specific pathologies rather than all ALS patients on a broad scale. Chapter content is enhanced by tables outlining the types of MNDs, criteria for supporting a diagnosis, first-line workup, the genes associated with ALS, ALS efficacy outcome measures, symptom management of ALS, and spinal muscular atrophy classification. Mechanisms of ALS are illustrated, and clinical photographs demonstrate symptoms. This review contains 5 figures, 14 tables and 253 references Keywords: motor neuron disease, amyotrophic lateral sclerosis, electromyography, Guillain-Barré syndrome

Motor Neuron Diseases

The motor neuron diseases (MNDs) are a family of diseases commonly categorized by their propensity to affect upper or lower motor neurons and by their mode of inheritance. The chapter provides some content on infectious MNDs caused by viral infections affecting the motor neurons in the anterior horn of the spinal cord. However, the chapter devotes most of its attention to the inherited and sporadically occurring MNDs. The majority of research into adult MND focuses on amyotrophic lateral sclerosis (ALS) due to its high prevalence, rapid progression, and phenotypical similarities between its inherited form and its sporadic form. As our knowledge of genetic mechanisms underlying ALS pathology has grown, common themes have emerged. These include abnormalities in RNA biology, axonal transport, protein folding, and inflammatory responses. These themes currently drive much of the direction in ALS experimental therapy development. It is clear that MND is complex and involves several different molecular pathways. Given this complexity, ALS might not be a single disease entity, and if this is the case, treatment approaches may need to be targeted to specific pathologies rather than all ALS patients on a broad scale. Chapter content is enhanced by tables outlining the types of MNDs, criteria for supporting a diagnosis, first-line workup, the genes associated with ALS, ALS efficacy outcome measures, symptom management of ALS, and spinal muscular atrophy classification. Mechanisms of ALS are illustrated, and clinical photographs demonstrate symptoms. This review contains 5 figures, 14 tables and 253 references Keywords: motor neuron disease, amyotrophic lateral sclerosis, electromyography, Guillain-Barré syndrome

Presurgical Radiologic Delineation of Popliteal Pterygium Syndrome: Case Report

Popliteal pterygium refers to the presence of an abnormal triangular fold of connective tissue occuring in the knee extending from the ischium to the os calcis. The popliteal artery and peroneal nerve are abnormally located within or adjacent to the pterygium. Since their preservation is important, knowledge of their exact location before surgery is essential. Hence, the role of preoperative imaging. We present here the radiologic features of a popliteal pterygium and the position of neurovascular structures in 18 months-old boy referred to radiology department for presurgical delineation. MRI is the imaging test of choice for the presurgical delineation in children who are candidate to surgical correction of contractures of popliteal pterygium. It may depict the popliteal artery and posterior tibial and peroneal nerves either in the normal position or abnormally located to the pterygium.

Disruption of the Ubiquitin-Proteasome System and Elevated Endoplasmic Reticulum Stress in Epilepsy.

The epilepsies are a broad group of conditions characterized by repeated seizures, and together are one of the most common neurological disorders. Additionally, epilepsy is comorbid with many neurological disorders, including lysosomal storage diseases, syndromic intellectual disability, and autism spectrum disorder. Despite the prevalence, treatments are still unsatisfactory: approximately 30% of epileptic patients do not adequately respond to existing therapeutics, which primarily target ion channels. Therefore, new therapeutic approaches are needed. Disturbed proteostasis is an emerging mechanism in epilepsy, with profound effects on neuronal health and function. Proteostasis, the dynamic balance of protein synthesis and degradation, can be directly disrupted by epilepsy-associated mutations in various components of the ubiquitin-proteasome system (UPS), or impairments can be secondary to seizure activity or misfolded proteins. Endoplasmic reticulum (ER) stress can arise from failed proteostasis and result in neuronal death. In light of this, several treatment modalities that modify components of proteostasis have shown promise in the management of neurological disorders. These include chemical chaperones to assist proper folding of proteins, inhibitors of overly active protein degradation, and enhancers of endogenous proteolytic pathways, such as the UPS. This review summarizes recent work on the pathomechanisms of abnormal protein folding and degradation in epilepsy, as well as treatment developments targeting this area.

EP220: Expanding the phenotypic spectrum of COLEC10-related 3MC syndrome: A glimpse into COLEC10-related 3MC syndrome in the Ashkenazi Jewish population

3MC syndrome is a clinical entity comprising four rare autosomal recessive disorders: Carnevale, Mingarelli, Malpuech, and Michels syndromes, characterized by variable expression of facial dysmorphia, cleft lip/palate, postnatal growth deficiency, hearing loss, cognitive impairment, craniosynostosis, radioulnar synostosis, and genital and vesicorenal anomalies. 3MC syndrome was initially described to be associated with bi-allelic pathogenic variants in the COLEC11 and MASP1 genes. Recently, bi-allelic pathogenic variants in COLEC10 have been described to be associated with 3MC syndrome. Features of COLEC10-related 3MC syndrome included short stature, blepharoptosis and epicanthus inversus, cleft lip/palate, and skeletal anomalies of the digits. The proteins encoded by COLEC11, MASP1, and COLEC10 form an intricate protein network that is important in regulating the lectin complement pathway. Syndromic features seen in 3MC syndrome are thought to be due to disruption of the chemoattractant properties that influence neural crest cell (NCC) migration. We identified seven individuals from three families of Ashkenazi Jewish descent with homozygosity of the novel c.311G>T (p.Gly104Val) variant in the COLEC10 gene (NM_006438.3) and phenotype consistent with 3MC syndrome. Individuals were retrospectively identified through the Dor Yeshorim screening program based on their genotype of the c.311G>T (p.Gly104Val) variant. The carrier frequency was calculated based on 21,887 individuals of Jewish descent. Samples were obtained anonymously through the Dor Yeshorim screening program between March 2020 and March 2021. Molecular protein modeling was completed. COLEC10 amino acid sequence was obtained, and then predictive protein models from I-Tasser were generated. Using PyMOL Molecular Graphic System 2.3.4 the effect the p.Gly104Val substitution in the COLEC10 protein model was analyzed. Clinical characteristics of the seven identified individuals included variable features of bilateral cleft lip and palate, radioulnar synostosis, short stature, hearing loss, and congenital heart defects. Similar facial features included hypertelorism, ptosis, prominent forehead, semicircular eyebrows, periorbital fullness, and broad nose. All individuals had reported normal intelligence. Carrier screening for the c.311G>T (p.Gly104Val) variant identified 164 heterozygotes out of 16,497 individuals of Ashkenazi Jewish descent, giving a carrier frequency of 1 in 101 or 0.99%. There were no heterozygotes identified out of 3,097 individuals of Sephardic Jewish descent and there were 13 heterozygotes out of 2,293 individuals of mixed Ashkenazi and Sephardic Jewish descent. Molecular protein modeling showed that the p.Gly104Val substitution alters local conformation. We identified a novel variant in the COLEC10 gene likely representative of a founder variant in the Ashkenazi Jewish population. Homozygosity of this variant is associated with variable features of 3MC syndrome. Given the observed carrier frequency, the lower than expected number of affected individuals may be due to the extreme phenotypic variability that includes clinically undiagnosed and variable presentations of the syndrome, even within the same family. Molecular protein modeling suggested that the p.Gly104Val variant results in abnormal protein folding. Abnormal protein folding has previously been shown to affect the secretion of the COLEC10 protein, leading to abnormal NCC migration, resulting in the observed craniofacial and skeletal anomalies associated with 3MC syndrome. COLEC10-related 3MC syndrome should be considered in the differential diagnosis for individuals with short stature, radioulnar synostosis, cleft lip and palate, and characteristic facial features.

Targeting the Unfolded Protein Response as a Disease-Modifying Pathway in Dementia.

Dementia is a global medical and societal challenge; it has devastating personal, social and economic costs, which will increase rapidly as the world’s population ages. Despite this, there are no disease-modifying treatments for dementia; current therapy modestly improves symptoms but does not change the outcome. Therefore, new treatments are urgently needed—particularly any that can slow down the disease’s progression. Many of the neurodegenerative diseases that lead to dementia are characterised by common pathological responses to abnormal protein production and misfolding in brain cells, raising the possibility of the broad application of therapeutics that target these common processes. The unfolded protein response (UPR) is one such mechanism. The UPR is a highly conserved cellular stress response to abnormal protein folding and is widely dysregulated in neurodegenerative diseases. In this review, we describe the basic machinery of the UPR, as well as the evidence for its overactivation and pathogenicity in dementia, and for the marked neuroprotective effects of its therapeutic manipulation in murine models of these disorders. We discuss drugs identified as potential UPR-modifying therapeutic agents—in particular the licensed antidepressant trazodone—and we review epidemiological and trial data from their use in human populations. Finally, we explore future directions for investigating the potential benefit of using trazodone or similar UPR-modulating compounds for disease modification in patients with dementia.

Review on the Injury and Repair Mechanism of Skeletal Muscle Contusions

We reviewed the injury and repair mechanism of skeletal muscle contusions (SMC), it is explained in five aspects, such as the theories of myosatellite cell proliferation and differentiation, Ca²⁺ mediated membrane repair, endoplasmic reticulum stress (ERS) and autophagy. Muscle regeneration plays an important role in the repair of SMC, it relies on the differentiation of surrounding satellite cells to restore muscle function. The signal pathways involve in the regulation of myoblast differentiation of myosatellite cells mainly including RBP-J κ/Notch signal, Wnt signal and P13K/Akt/mTOR signal pathway. Notch signal pathway regulates the self-renewal and differentiation of myosatellite cells to maintain the homeostasis of muscle stem cells. And P13K/Akt/mTOR signal pathway has a positive regulation effect on myoblast differentiation of myosatellite cells and can promote skeletal muscle regeneration. However, current research on the role of Wnt signal pathway in the regeneration of mature muscle is controversial, and more studies are needed in the future. Ca²⁺ mediated membrane repair is essential for the survival of muscle cells after SMC. Ca²⁺ is blocked due to structural damage or functional decline of calcium pump after SMC, leading to calcium depletion in the endoplasmic reticulum (ER). Ca²⁺ dysregulation contributes to abnormal protein production by promoting mitochondrial reactive oxygen species (ROS) production and disrupting protein folding in the ER, thus, the abnormal folding protein in the ER is increased. Once the retention and aggregation of which exceeds its threshold value, ERS occurs. Excessive ERS can mediate autophagy through PKC or FAM134B pathways. Autophagy maintains homeostasis through the self-degradation of abnormal organelles or misfolded proteins. As for the mechanism of autophagy in the repair of SMC, in addition to the induction of excessive ERS, it has been reported that SMC induces insufficient oxygen supply to local tissues, promotes the production of a large number of ROS or activation of AMPK signal pathway, and then induces mitochondrial autophagy, which maintains the stability of mitochondria and saves energy consumption, so as to achieve the purpose of promoting repair after SMC. Although the injury and repair mechanism of SMC is complex, there are some crossovers between the above theories. Therefore, the research on the injury and repair mechanism of SMC can be further explored around the above theories, to clarify how the above different theories play a synergistic role in different stages of injury and repair after SMC.

Amyloid fishing: β-Amyloid adsorption using tailor-made coated titania nanoparticles

Amyloidoses are a family of diseases characterized by abnormal protein folding that leads to fibril aggregates, amyloids. Extensive research efforts are devoted to developing inhibitors to amyloid aggregates. Here we set to explore functionalized titania (TiO2) nanoparticles (NPs) as potential amyloid inhibiting agents. TiO2 NPs were coated by a catechol derivative, dihydroxy-phenylalanine propanoic acid (DPA), and further conjugated to the amyloids' specific dye Congo-Red (CR). TiO2-DPA-CR NPs were found to target mature fibrils of β-amyloid (Aβ). Moreover, coated NPs incubated with Aβ proteins suppressed amyloid fibrillation. TiO2-DPA-CR were found to target amyloids in solution and induce their sedimentation upon centrifugation. This work demonstrates the potential utilization of TiO2-DPA NPs for labeling and facilely separating from solution mature amyloid fibrils.

Recent Advances in Our Molecular and Mechanistic Understanding of Misfolded Cellular Proteins in Alzheimer's Disease (AD) and Prion Disease (PrD).

Naturally occurring neuron-abundant proteins including amyloid Aβ42 peptide and the microtubule-associated protein tau (MAPT) can, over time and under pathological situations, assume atypical conformations, altering their normal biological structure and function, and causing them to aggregate into insoluble and neurotoxic intracellular inclusions. These misfolded proteins ultimately contribute to the pathogenesis of several progressive, age-related and ultimately lethal human neurodegenerative disorders. The molecular mechanism of this pathological phenomenon of neuronal protein misfolding lends support to the ‘prion hypothesis’, which predicts that the aberrant folding of endogenous natural protein structures into unusual pathogenic isoforms can induce the atypical folding of other similar brain-abundant proteins, underscoring the age-related, progressive nature and potential transmissible and spreading capabilities of the aberrant protein isoforms that drive these invariably fatal neurological syndromes. The abnormal folding and aggregation of host proteins is a consistent feature of both amyloidopathies and tauopathies that encompass a continuous spectrum of brain diseases that include Alzheimer’s disease (AD), prion disorders (PrD) such as scrapie in sheep and goats (Bovidae), experimental prion infection of rodents (Muridae), Creutzfeldt–Jakob disease (CJD) and Gerstmann–Sträussler–Scheinker syndrome (GSS) in humans (Hominidae), and other fatal prion-driven neurological disorders. Because AD patients accumulate both misfolded tau and Aβ peptides, AD may be somewhat unique as the first example of a ‘double prion disorder’. This commentary will examine current research trends in this fascinating research area, with a special emphasis on AD and PrD, and the novel pathological misfolded protein processes common to both intractable neurological disorders.

Hepato-Duodeno-Colic Fold and Sessile Sigmoid Colon – Rare Peritoneal Bands in Abdomen

The presence of aberrant peritoneal folds is one of the differential diagnoses of intestinal obstruction in the pediatric population. Therefore, knowing the variations in the attachment pattern of peritoneum and its folds is essential. In this context, we report a rare peritoneal fold found during the routine human cadaveric dissection of the abdomen, which is attached superiorly to the liver including the gallbladder and inferiorly extended as a bilaminar fold with one attaching to duodenum and other to transverse colon. In addition, the sigmoid colon was completely plastered to the posterior pelvic wall. This variant peritoneal fold is named as hepato-duodeno-colic ligament and is described in detail with its clinical context. The knowledge regarding this abnormal peritoneal fold would be highly useful for surgeons while planning laparoscopic procedures in the upper quadrant of the abdomen.

Aggregation and spread of synuclein in Parkinson's disease

The vast majority of neurodegenerative diseases are associated with an accumulation of undegraded and aggregated proteins. Hence the word proteinopathies is now used to refer to these neurodegenerative diseases. The synucleinopathies are one component of them, in particular in Parkinson's disease. The neuropathological features of Parkinson's disease are the progressive loss of dopamine neurons in the midbrain and the formation of aggregates composed mainly of a-synuclein protein. Experimental evidence suggests that under pathological conditions, normal soluble a-synuclein protein adopts an abnormal folding and subsequently aggregates, with a propensity to spread throughout the central nervous system. This review article discusses the specifics of a-synuclein aggregation and emerging mechanisms for understanding its spread and aims at providing a molecular explanation for the progression of the disease in humans.

Computational pipeline for the generation and validation of patient-specific mechanical models of brain development

The human brain develops from a smooth cortical surface in early stages of fetal life to a convoluted one postnatally, creating an organized ensemble of folds. Abnormal folding patterns are linked to neurodevelopmental disorders. However, the complex multi-scale interactions involved in cortical folding are not fully known yet. Computational models of brain development have contributed to better understand the process of cortical folding, but still leave several questions unanswered. A major limitation of the existing models is that they have basically been applied to synthetic examples or simplified brain anatomies. However, the integration of patient-specific longitudinal imaging data is key for improving the realism of simulations. In this work we present a complete computational pipeline to build and validate patient-specific mechanical models of brain development. Starting from the processing of fetal brain magnetic resonance images (MRI), personalised finite-element 3D meshes were generated, in which biomechanical models were run to simulate brain development. Several metrics were then employed to compare simulation results with neonatal images from the same subjects, on a common reference space. We applied the computational pipeline to a cohort of 29 subjects where fetal and neonatal MRI were available, including controls and ventriculomegaly cases. The neonatal brain simulations had several sulcal patterns similar to the ones observed in neonatal MRI data. However, the pipeline also revealed some limitations of the evaluated mechanical model and the importance of including patient-specific cortical thickness as well as regional and anisotropic growth to obtain more realistic and personalised brain development models.Statement of Significance: Computational modelling has emerged as a powerful tool to study the complex process of brain development during gestation. However, most of the studies performed so far have been carried out in synthetic or two-dimensional geometries due to the difficulties involved in processing real fetal data. Moreover, as there is no correspondence between meshes, comparing them or assessing whether they are realistic or not is not a trivial task. In this work we present a complete computational pipeline to build and validate patient-specific mechanical models of brain development, mainly based on open-source tools.

ANTIULCER ACTIVITY OF PLACENTAL CRYOEXTRACT IN EXPERIMENTAL INDOMETHACIN-INDUCED ULCEROGENESIS

Aim. The side effects associated with the use of indometacin are noted by about 30-60% of patients, therefore, in this context the problem of adverse event rate reduction is still relevant today. Cryopreserved placental extract (CEP) attracted our attention as a means of pathogenetic correction of the ulcerogenic action of indomethacin. The aim of the paper is to characterize the antiulcer activity of cryopreserved placenta extract on a model of indomethacin-induced ulcerogenesis.
 Materials and Methods. In vivo experimental studies were performed on 28 nonlinear laboratory male rats weighing 200-220 g. Acute indomethacin-induced gastrointestinal injury was replicated by a single injection of indomethacin at 60 mg/kg in rats. Euthanasia of animals was performed after 4 hours after indomethacin administration.
 Results and Discussion. Macroscopic evaluation of the condition of the gastric mucosa showed that all animals had numerous pinpoint hemorrhages, and 49.2% of rats had mild hyperemia and abnormal folding. Evaluation of the condition of the small intestinal mucosa showed that 57.1% of rats injected with indomethacin alone had 11.1±4.1 ulcers per 10 cm of mucosa length. Prophylactic administration of esomeprazole led to a statistically significant (p<0.05) attenuation of the ulcerogenic effect of indomethacin on the gastric mucosa - the mean score of the mucosa was 3.9 times lower than in control rats and was 0.9±0.26.
 Conclusions. The combined use of indomethacin and CEP was associated with a 1.9-fold lower ulcer index as compared with rats administered indomethacin only, thus demonstrating the gastroprotective activity of CEP. In contrast to esomeprazole, the introduction of CEP has a pronounced enteroprotective effect, as indicated by the absence of damage to small intestinal mucosa in rats treated with the studied cryoextract and indomethacin.

In Cellulo Crystallization of Human Neuraminidase 1 and Biological Roles of N-Glycans.

Human neuraminidase 1 (NEU1) is a lysosomal glycosidase that cleaves the terminal sialic acids of sialylglycoconjugates. NEU1 is biosynthesized in the endoplasmic reticulum (ER) lumen as an N-glycosylated protein. NEU1 also associates with cathepsin A (CTSA) in ER, migrates to lysosomes, and exerts catalytic activity. Extraordinary in cellulo crystallization of NEU1 protein in ER despite carrying three N-glycans per molecule at N186, N343, and N352, respectively, were observed when the single human NEU1 gene was overexpressed in mammalian cells. In this study, we first purified the NEU1 from the isolated crystals produced by the HEK293 NEU1-KO cell transiently overexpressing the normal NEU1 and found that the N-glycans were high-mannose or complex types carrying terminal sialic acids. The result suggests that a part of NEU1 crystals were formed or transported to the Golgi apparatus. Second, we compared the effects of single amino acid substitution at the N-sequons, including N186Q, N343Q, and N352Q, each one N-glycan reduction from one NEU1 molecule. We demonstrated that N186Q mutant protein with low enzyme activity and formed a few amounts of smaller crystals. The N343Q mutant exhibited half of the normal intracellular activity, but the numbers and sizes of crystals were almost the same as those of normal NEU1. The N352Q mutant exhibited almost the same activity as the normal enzyme. The numbers of the N352Q crystals were smaller than those of normal NEU1. According to these findings, the N186Q NEU1 protein should have lower stability in ER due to abnormal folding. The second N-glycan at the N343-sequon has little effect on self-aggregation of NEU1. The third N-glycan at the N352-sequon contributes to the self-aggregation of NEU1. We also demonstrated that the three NEU1 mutants associate with the relatively excessive CTSA and migrate to lysosomes.

Progress of researches on mechanisms of acupuncture in treatment of Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disease, and acupuncture has shown potential advantages in the treatment. By analyzing the experimental researches on acupuncture therapy of PD over the past 10 years, the authors find that acupuncture can play a therapeutic role by regulating multiple targets such as basal ganglia neurotransmitter disorder, oxidative stress, abnormal protein folding, immune inflammatory response, apoptosis, neural stem cells and calcium homeostasis. Although the mechanism of acupuncture in the treatment of PD is widely studied, there is still a lack of systematic, in-depth and high-quality research, and the mechanism of acupuncture therapy has not reached a consensus. In the future, the potential mechanisms including mitochondrial dysfunction and intestinal flora should be further studied.

The role of voice rest after micro-laryngeal surgery for benign vocal fold lesions

To compare post-operative vocal outcomes of a voice rest regimen versus no voice restrictions following micro-laryngeal surgery for benign glottic lesions. This was a combined prospective and retrospective cohort study on 167 patients who underwent micro-laryngeal surgery for benign focal fold lesion removal. Participants were divided into two regimens: standard voice rest (n = 92) or no voice restriction (n = 75). The primary outcome was post-operative vocal improvement, evaluated using voice handicap index questionnaire (VHI-10), GRBAS scale, and computerised acoustic analysis (shimmer, jitter, and the harmonic-to-noise ratio). The secondary outcome was emergence of vocal fold mucosal abnormalities in the immediate post-operative period. Parameters were collected at baseline and at the last clinical visit. There was no statistically significant difference between the voice rest and no-voice rest groups regarding baseline parameters of age, gender, laryngeal pathology, and voice use. Improvement in GRBAS scale values and VHI-10 scores between pre- and post-operative periods between groups did not demonstrate any statistically significant differences (P = 0.5303 and P = 0.1457, respectively). Similarly, the results of computerized voice analysis also showed no differences between groups in terms of shimmer (P = 0.9590), jitter (P = 0.5692), and harmonic-to-noise ratio (P = 0.1871). No correlation was found between the post-operative vocal fold's mucosal abnormalities and the type of voice rest regimen. Voice quality and wound healing were similar regardless of the type of voice rest regimen applied. No voice rest at all was as good as voice rest after micro-laryngeal surgery.

Biosemiotics comprehension of PrP code and prion disease

Prions or PrPSc (prion protein, Scrapie isoform) are proteins with an aberrant three-dimensional conformation that present the ability to alter the three-dimensional structure of natively folded PrPC (prion protein, cellular isoform) inducing its abnormal folding, giving raise to neurological diseases known as Transmissible spongiforms encephalopathies (TSEs) or prion diseases. In this work, through a biosemiotic study, we will analyze the molecular code of meanings that are known in the molecular pathway of PrPC and how it is altered in prion diseases. This biosemiotic code presents a socio-semiotic correlate in organisms that could be unraveled with the ultimate goal of understanding the code of signs that mediates the process. Finally, we will study recent works that indicate possible relationships in the code between prion proteins and other proteins such as the tau protein and alpha-synuclein to evaluate if it is possible that there is a semiotic expansion of the PrP code and prion diseases in the meaning recently expounded by Prusiner, winner of the Nobel Prize for describing these unusual pathological processes.

Decreased Cortical Folding of the Fusiform Gyrus and Its Hypoconnectivity with Sensorimotor Areas in Major Depressive Disorder

Background: Neuroimaging studies have revealed abnormal cortical folding pattern and disruptive functional connectivity in major depressive disorder (MDD). Combining structure and function in the same population may further our understanding of the neuropathological mechanisms of MDD. Method: Sixty-two patients with MDD and 61 healthy controls (HCs) underwent structural and resting-state functional magnetic resonance imaging (MRI). Group differences in the cortical folding (measured by local gyrification index (LGI)) were analyzed in FreeSurfer. Taking the brain regions with significant group differences in LGI as seed regions, the resting-state functional connectivity analysis was further conducted to explore the corresponding functional connectivity alterations. Results: Comparing with HCs, patients with MDD showed significantly decreased LGI in the right fusiform gyrus (cohen's d = 0.70). In the seed-based functional connectivity analysis, we found that compared with HCs, patients with MDD showed decreased functional connections between the right fusiform gyrus with sensorimotor areas (precentral and postcentral gyrus) (cohen's d = 1.32) and right superior temporal gyrus (cohen's d = 0.94). Limitations: Main limitations are the relatively small sample size and the cross-sectional study design. Conclusion: Decreased LGI in the right fusiform gyrus, as well as decreased functional connectivity between the right fusiform gyrus and the sensorimotor area and right superior temporal gyrus, appears to play a role in the pathophysiology of MDD.

The Evolution of the Hallmarks of Aging.

The evolutionary theory of aging has set the foundations for a comprehensive understanding of aging. The biology of aging has listed and described the “hallmarks of aging,” i.e., cellular and molecular mechanisms involved in human aging. The present paper is the first to infer the order of appearance of the hallmarks of bilaterian and thereby human aging throughout evolution from their presence in progressively narrower clades. Its first result is that all organisms, even non-senescent, have to deal with at least one mechanism of aging – the progressive accumulation of misfolded or unstable proteins. Due to their cumulation, these mechanisms are called “layers of aging.” A difference should be made between the first four layers of unicellular aging, present in some unicellular organisms and in all multicellular opisthokonts, that stem and strike “from the inside” of individual cells and span from increasingly abnormal protein folding to deregulated nutrient sensing, and the last four layers of metacellular aging, progressively appearing in metazoans, that strike the cells of a multicellular organism “from the outside,” i.e., because of other cells, and span from transcriptional alterations to the disruption of intercellular communication. The evolution of metazoans and eumetazoans probably solved the problem of aging along with the problem of unicellular aging. However, metacellular aging originates in the mechanisms by which the effects of unicellular aging are kept under control – e.g., the exhaustion of stem cells that contribute to replace damaged somatic cells. In bilaterians, additional functions have taken a toll on generally useless potentially limited lifespan to increase the fitness of organisms at the price of a progressively less efficient containment of the damage of unicellular aging. In the end, this picture suggests that geroscience should be more efficient in targeting conditions of metacellular aging rather than unicellular aging itself.