Potency of SARS-CoV-2 on Ocular Tissues

The current COVID-19 pandemic has affected more than 100 million people and resulted in morbidity and mortality around the world. Even though the disease caused by SARS-CoV-2 is characterized by respiratory tract involvement, previous and recent data also indicates ocular manifestation. Not surprisingly, cell entry point of the virus, ACE2 receptor, is widely expressed in ocular tissues ranging from conjunctiva to retina. Despite the sensibility of ocular tissues, the sophisticated defense mechanism of the eye might eliminate viral transmission. Nevertheless, the potential of systemic transmission through the nasolacrimal duct may not be eliminated. In the case of ocular involvement, the disease outcomes might be as treatable as conjunctivitis or as serious as retinal degeneration and the treatment regimen vary accordingly. Within these contingencies, our aim with this chapter is to shed light on molecular bases of SARS-CoV-2 infection, systemic invasiveness following ocular transmission, manifestation and permanent effects on ocular tissues

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

PMA functions as an autophagy inhibitor through activation of a serine threonine kinase

Serine-threonine kinases have vital roles in various signalling pathways such as proliferation, differentiation and apoptosis. Thus, they served as crucial players in health and disease including cancer. Isozymes of these families show tissue specific expression patterns and function specifically in different pathways. Autophagy is another major process in the cell which degrades long-lived, non-functional organelles and proteins to sustain the homeostasis. Moreover, as well as serine threonine kinases, autophagy was also found to relate with cancer in different stages. To date, relationship between serine-threonine protein kinases and autophagy has not been well studied. Therefore, we utilized PMA which is one of the three different activatory signals of this kinase family to activate the certain subgroup and we studied the role of these kinases on autophagy regulation

Identification of a serine-threonine kinase as a novel autophagic regulator

Phospholipid dependent Serine/Threonine kinases are shown to be involved in cellular mechanisms and disease related pathways. Upon different intracellular stimuli, these kinases are activated and functions. Several chemical analogues such as Phorbol 12-Mystrate 13-Acetate (PMA) and Ceramide were synthesized to mimic intracellular stimuli to study function of these kinases. For several of these kinases, activation is dependent on both PMA and a Calcium ionophore such as ionomycin. Strikingly, deregulation of these kinases has been identified in several cancers. Recent studies showed that autophagy, which evolutionary conserved cellular degradation mechanism to maintain homeostasis, is also involved in carcinogenesis. According to literature, there are no robust studies to show the interaction between autophagy and serine threonine kinases. Thus, in our study we focused to identify a novel Ser/Thr kinases involved in regulation of autophagy in cancer

Diagnosing an 11-Year-Old Girl with Narcolepsy in a Child Psychiatry Unit: A Case Presentation

Narcolepsy is a chronic disorder that might cause severe morbidity and functional deterioration with a wide range of complicated symptoms and without any clearly identified etiology. The condition is even more difficult to diagnose in children as clinical picture and clusters of symptoms that vary extremely. With this report, we aimed to present, and discuss an 11-year-old case diagnosed with narcolepsy in a child psychiatry unit along with relevant literature. Psychiatric assessment of the case that applied to our child psychiatry unit was carried out by using Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) criteria. Detailed clinical examination, neurological tests and imaging modalities as well as polysomnography were performed. The case was diagnosed,and followed up as having narcolepsy after completion of processes of evaluation, and differential diagnosis. She demonstrated clinical improvement with a combined treatment regimen of methylphenydate-OROS and behavioral therapy for sleep pattern and hygiene. She is still being followed up in our unit. Since narcolepsy is a rarely seen condition encountered in child psychiatry settings and symptoms might mimic other neurological and psychiatric conditions, its earlier recognition is a remote possibility. Therefore, we believe that we, as child psychiatrists, need to bear this disorder in our minds for differential diagnosis. Since current treatment options mainly target visible symptoms, developing novel treatment strategies directed towards underlying etiology will carry importance. In that sense, we believe that increasing the number of case studies and clinical researches in this understudied field of child psychiatry shall contribute greatly to more improved understanding of the disorder

The Effect of Dysfunctional Ubiquitin Enzymes in the Pathogenesis of Most Common Diseases

Ubiquitination is a multi-step enzymatic process that involves the marking of a substrate protein by bonding a ubiquitin and protein for proteolytic degradation mainly via the ubiquitin–proteasome system (UPS). The process is regulated by three main types of enzymes, namely ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligases (E3). Under physiological conditions, ubiquitination is highly reversible reaction, and deubiquitinases or deubiquitinating enzymes (DUBs) can reverse the effect of E3 ligases by the removal of ubiquitin from substrate proteins, thus maintaining the protein quality control and homeostasis in the cell. The dysfunction or dysregulation of these multi-step reactions is closely related to pathogenic conditions; therefore, understanding the role of ubiquitination in diseases is highly valuable for therapeutic approaches. In this review, we first provide an overview of the molecular mechanism of ubiquitination and UPS; then, we attempt to summarize the most common diseases affecting the dysfunction or dysregulation of these mechanisms

Dipeptidyl peptidase IV production by solid state fermentation using alternative fungal sources

WOS: 000312424500007The present work was carried out for the production of dipeptidyl peptidase IV (DPP IV; EC 3.4.14.5) using Aspergillus, Penicillium, and Rhizopus strains under solid state fermentation conditions. Response surface methodology was applied for the optimization of the selected operational variables (corn flour, initial moisture content, and cultivation time) for DPP IV activity as the response. The optimal parameters of DPP IV activity for the independent variables, namely the amount of corn flour (% w/w), initial moisture content (% w/w), and cultivation time (days), were evaluated to be 2.44%, 60.85%, and 4.69 days, respectively, using Aspergillus awamori T116. The response for these results was also shown to be in very close agreement with the experimental data.TUBITAKTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [105T195]We thank Sevket Karacanci (PhD) for using the Design Expert software (version 7.1.6, Stat-Ease, Inc.). This study was supported by TUBITAK, project number 105T195

Protein Kinase C Isozymes and Autophagy during Neurodegenerative Disease Progression

Protein kinase C (PKC) isozymes are members of the Serine/Threonine kinase family regulating cellular events following activation of membrane bound phospholipids. The breakdown of the downstream signaling pathways of PKC relates to several disease pathogeneses particularly neurodegeneration. PKC isozymes play a critical role in cell death and survival mechanisms, as well as autophagy. Numerous studies have reported that neurodegenerative disease formation is caused by failure of the autophagy mechanism. This review outlines PKC signaling in autophagy and neurodegenerative disease development and introduces some polyphenols as effectors of PKC isozymes for disease therapy