How Neutrophils Shape the Immune Response: Reassessing Their Multifaceted Role in Health and Disease.

Neutrophils are the most abundant of the circulating immune cells and are the first to be recruited to sites of inflammation. Neutrophils are a heterogeneous group of immune cells from which are derived extracellular traps (NETs), reactive oxygen species, cytokines, chemokines, immunomodulatory factors, and alarmins that regulate the recruitment and phenotypes of neutrophils, macrophages, dendritic cells, T cells, and B cells. In addition, cytokine-stimulated neutrophils can express class II major histocompatibility complex and the internal machinery necessary for successful antigen presentation to memory CD4+ T cells. This may be relevant in the context of vaccine memory. Neutrophils thus emerge as orchestrators of immune responses that play a key role in determining the outcome of infections, vaccine efficacy, and chronic diseases like autoimmunity and cancer. This review aims to provide a synthesis of current evidence as regards the role of these functions of neutrophils in homeostasis and disease.

Neutrophil extracellular traps and thrombogenesis in COVID-19 patients.

COVID-19 has caused significant morbidity and mortality around the world. Recent reports point toward the "cytokine storm" as core of pathogenesis in SAR-CoV-2-induced acute lung injury, acute respiratory distress syndrome (ARDS), coagulopathy, and multiorgan failure. We have presented clinical data here wherein cytokine levels in COVID-19 patients do not match typical cytokine storm seen in ARDS. Interestingly, COVID-19 patients in early disease present with hypoxemia with no significant respiratory dysfunction. In addition, it is reported that hospitalized COVID-19 patients have a high incidence of thrombotic complications, especially involving the pulmonary vasculature. We hypothesized that core to pathogenesis of COVID-19 is the dysregulation of neutrophils, which culminates in excessive release of neutrophil extracellular traps (NETs). Recently, an increasing amount of NETs have been seen in sera of severe COVID-19 patients. We have discussed here mechanisms involved which lead to thrombogenesis and vasculitis because of excessive release of NETs.

Vertical integration of head, neck, and special senses module in undergraduate medical curriculum.

Vertical integration is believed to increase motivation by providing context for the learning. In this quasi-experimental study, cohort I took two horizontally integrated modules: structure and function of head, neck, and special senses in the second year, and pathophysiology and clinical sciences in the third year. Cohort II took a combined, vertically integrated module in the second year. Data from the questionnaire and examination scores were compared. Response rate was 80.1% (125/156) for cohort I and 57.6% (98/170) for cohort II. Response to the statement that vertical integration provides context to basic sciences was mixed with a higher agreement in cohort II (51.5 vs. 37.2%; P = 0.04). Cohort II was least satisfied with the appropriateness of self-study time (52.0 vs. 34.7%; P = 0.01). However, cohort II felt that the basic sciences lectures (90.8 vs. 69.4%; P < 0.01) and the clinical skills sessions (85.7 vs. 62.1%; P < 0.01) were more effective. Cohort II was less satisfied with clinical lectures (80.6 vs. 56.1%; P < 0.01) and was less confident in achieving clinical learning objectives (72.8 vs. 40.8%; P < 0.01). Mean multiple-choice questions and problem-based learning scores were similar. However, the short-answer question score was higher for cohort I [82.48 (SD 14.9) vs. 70.74 (SD 17.9); P < 0.01]. Overall, the idea of early vertical integration had a mixed response. It improved the effectiveness of basic sciences lectures and clinical skills sessions. Achievement of clinical learning outcomes was compromised. A disparity in the module's duration and curricular content, and students' ability to grasp clinical concepts and faculty's expectations are the possible reasons. Increased duration and better communication with clinical faculty may improve early introduction of vertical integration.

Implementation of structured team-based review enhances knowledge consolidation and academic performance of undergraduate medical students studying neuroscience.

Team-based learning (TBL) provides a systematic approach to teaching and learning and promotes critical thinking and enhances medical educational activities and professional development. TBL-based didactic methodology has proven beneficial in enhancing learning and consolidating key educational concepts throughout educational curricula. Such areas of application include neuroscience, which is traditionally considered to be one of the most difficult disciplines to be taught in undergraduate medical courses to the point where the scientific literature reports "neurophobia" among undergraduate medical students. Herein, we report the design and application of a modified version of TBL, which we termed team-based review (TBR) throughout two cohorts of undergraduate medical students undertaking neuroscience. We show that our TBR methodology enhanced student understanding of neuroscience, increasing average marks and grades achieved in final exams, while also increasing the proportion of students obtaining higher grades. Application of TBR also improved marks obtained by students throughout continuous assessment (midterms, TBL, and problem-based learning grades). In surveys taken following final exams, students strongly felt that TBR enhanced their learning experience and aided knowledge acquisition, consolidation, and exam preparation. Collectively, we show that TBR-based methodology was effective in enhancing the student learning experience and performance in neuroscience and could potentially be successfully used to enhance performance and learning in other subjects in the undergraduate medical curriculum.

Medical education dilemma: How can we best accommodate basic sciences in a curriculum for 21st century medical students? 1.

Over the years, the medical curriculum has been changed to accommodate a variety of evolving disciplines and an exploding scientific knowledge of the basic sciences to prepare "a competent physician" of the 21st century. Therefore, we must be innovative in our approach of curricular development if we wish to continue to incorporate new basic sciences knowledge in the face of decreasing contact hours to satisfy the buzz word, "integration". Certainly, the challenges are phenomenal. The question how to best integrate basic sciences, is not easy to answer as the objectives of the courses and outcome vary from one medical school to another and the fact is, one size does not fit all. However, if we believe that basic sciences are the language of medicine and foundation of clinical knowledge, then we must resolve this ongoing dilemma by introducing basic sciences through a better alignment in a given curriculum. The purpose of this review is to evaluate different curricular models for their basic sciences content and address their strengths and weaknesses. In addition, we will introduce a spiral design to integrate basic sciences for senior students. Finally, we will provide some insight as to how learning and retention of basic science content can be sustained.

The Integrated Clinical Anatomy Program at Alfaisal University: an innovative model of teaching clinically applied functional anatomy in a hybrid curriculum.

Anatomy has historically been a cornerstone in medical education regardless of specialty. It is essential for physicians to be able to perform a variety of tasks, including performing invasive procedures, examining radiological images, performing a physical examination of a patient, etc. Medical students have to be prepared for such tasks, and we can assist this by changing the way that we educate students in medical schools. Thus, newer medical curricula need to be designed according to needs of future physicians. In this report, we describe a unique program called the Integrated Clinical Anatomy Program (ICAP). The ICAP was developed at the College of Medicine of Alfaisal University in the Kingdom of Saudi Arabia. Here, we describe the unique features of this program, including the structure and facilities of the Anatomy Resource Center. The Anatomy Resource Center plays a pivotal role in engaging the students for faculty-directed structured laboratory sessions as well as peer-assisted uniform student-centered learning. The ICAP has shown great promise, as reflected by early results from a nationwide progress test. Students from all years of the Alfaisal University medical school scored significantly higher than the national average on the anatomy and physiology component of the nationwide progress test examination, with P values of 0.0179 and 0.0015, respectively. We believe that the ICAP can be used as a model for teaching clinically applied functional anatomy to medical students in a hybrid curriculum around the world.

Assessment of first-year medical students' perceptions of teaching and learning through team-based learning sessions.

Team-based learning (TBL) is an emerging teaching and learning strategy being employed in medical schools. The College of Medicine at Alfaisal University has adopted a TBL approach as an instructional method for first-year medical students. The aim of the present study was to describe the TBL method employed at Alfaisal University College of Medicine and to assess first-year medical students' perceptions of this learning modality for the anatomy- and physiology-based blocks/courses in organ systems form of curriculum. A five-point Likert scale questionnaire was structured based on Kirkpatrick's theory and assessed three major domains: reaction, learning, and behavior. Confirmatory factor analysis (CFA) and Cronbach's α-coefficient tests were used to assess the validity and reliability of the construct, respectively. CFA showed an adequate validity of the survey and Cronbach's α revealed an acceptable internal uniformity (0.69). A total of 185 respondents rated reaction, learning, and behavior toward introduction of TBL as 3.53 ± 1.01, 3.59 ± 1.12, and 3.57 ± 1.12, respectively. Excellent students rated TBL highly in all major domains compared with borderline students (reaction, behavior, and learning domains with P values of <0.049, <0.035, and <0.031, respectively). Students who had prior teamwork experience rated TBL higher in terms of their learning experience compared with those who were rarely involved in team work. This study demonstrated that Alfaisal University first-year medical students perceived TBL positively as a teaching and learning strategy for functional anatomy, and prior involvement in teamwork and academic performance correlates with higher ratings of TBL.

Pharmacological effects of Ibuprofen on learning and memory, muscarinic receptors gene expression and APP isoforms level in pre-frontal cortex of AlCl3-induced toxicity mouse model.

UNLABELLED: Aluminium metal (Al) has been implicated in the etiology of many neurodegenerative diseases, most commonly the Alzheimer's disease (AD). Al causes biochemical defects by affecting the neurotransmitters level, causes conformational changes in amyloid ß protein and increases amyloid accumulation in brain. AIM: This study was aimed at evaluating neuroprotective effect of Ibuprofen (IBU) (25 mg/kg/day for 12 days) in AlCl3-induced (150 mg/kg/day for 12 days) toxicity. METHODS: Treated mice were subjected to learning and memory tests. Cholinergic muscarinic receptors (mAChR; M1-M5) and APP isoforms (APP695, APP770 and APP common) gene expression were carried out from the pre-frontal cortex area. RESULTS: Profound effect on learning and memory was observed in IBU treated group along with enhanced expression of M1 mAChR (0.40 ± 0.03; p < 0.01) compared to AlCl3-induced toxicity group (0.05 ± 0.02). Fear memory was improved in IBU treated group (89.68 ± 2.58, p < 0.01) as compared to AlCl3-induced toxicity group (54.58 ± 8.21). Discrimination index in social novelty test in IBU treated group was improved (81.13 ± 8.71; p < 0.05), compared to AlCl3-induced toxicity group (46.28 ± 5.55). Similarly, recognition memory of IBU treated group in novel object recognition test (NOB) was retained (66.85 ± 5.60; p < 0.05) as compared to AlCl3-induced toxicity group (33.06 ± 11.80). CONCLUSION: IBU demonstrated memory enhancing effect, however, its effect on the APP isoforms expression in pre-frontal cortex needs further studies.

Undergraduate research: an innovative student-centered committee from the Kingdom of Saudi Arabia.

INTRODUCTION: Concern has been expressed in recent times whether medical schools have adapted sufficiently to cater for the increasing demand of physician-scientists. Studies have shown that research involvement at the undergraduate level is vital to accommodate this growing need. Enhanced communication skills, improved problem-solving abilities and better future employment opportunities are among the other many benefits of undergraduate research (UR). Herein, we report projects run by a unique student driven undergraduate research committee (URC) at Alfaisal University, Riyadh, Saudi Arabia aimed at providing the future generation of physicians training opportunities for pursuing a research intensive career. METHODS: The article describes the unique structure of the URC and provides an in-depth description of the various programs and activities used in promoting students' research activities. We analyzed students' perception of URC activities via a questionnaire and analyzed research-output of the first graduating batches through their publication record. RESULTS: Overall, more than 60% of the graduating students were involved in the various research programs offered by the URC and around 50% published in peer-reviewed journals with an average impact factor of 2.4. CONCLUSIONS: Research involvement by medical students is an essential need of the twenty-first century and models like URC could provide crucial platform for research training to the new generation of physician-scientists.

The summer premedical program for matriculating medical students: a student-led initiative.

The freshman academic year is one of the most difficult years that a medical student experiences in his/her academic life at a medical school. Freshmen are frequently faced with several challenges, such as adaptation to a new academic environment and its associated different methods of teaching, learning, skills, and assessment. The aim of this study was to describe a 4-wk innovative summer premedical program developed by senior medical students at the College of Medicine, Alfaisal University, in an attempt to improve/smooth the experience(s) of prospective freshmen. This report describes the objectives/strategies/methodologies used to tackle the top three identified freshman challenges, namely, 1) advancement of the academic/scholastic/educational background, 2) the development of college-required skills to succeed and excel in the freshman year, and 3) adaption to the college environment. At the end of the program, a survey was conducted to evaluate the effectiveness of the summer premedical program. Seventy-two students attended this program over the past three summers from 2010 to 2012, and twenty-nine students answered the survey with a response rate of 74.1%. Overall, >90% of the survey respondents reported an improvement in their understanding of basic medical science, integration, presentation skills, medical terminology, and junior-senior relationships. Furthermore, the survey highlighted the need for more focus on skills such as time management, participation in large-group discussions, and use of electronic resources, as >50% of respondents reported no improvement in these areas. In conclusion, this is the first report, to our knowledge, that describes a program developed by senior medical students to improve the experience of freshmen.

Gut-Modulating Agents and Amyotrophic Lateral Sclerosis: Current Evidence and Future Perspectives.

Amyotrophic Lateral Sclerosis (ALS) is a highly fatal neurodegenerative disorder characterized by the progressive wasting and paralysis of voluntary muscle. Despite extensive research, the etiology of ALS remains elusive, and effective treatment options are limited. However, recent evidence implicates gut dysbiosis and gut-brain axis (GBA) dysfunction in ALS pathogenesis. Alterations to the composition and diversity of microbial communities within the gut flora have been consistently observed in ALS patients. These changes are often correlated with disease progression and patient outcome, suggesting that GBA modulation may have therapeutic potential. Indeed, targeting the gut microbiota has been shown to be neuroprotective in several animal models, alleviating motor symptoms and mitigating disease progression. However, the translation of these findings to human patients is challenging due to the complexity of ALS pathology and the varying diversity of gut microbiota. This review comprehensively summarizes the current literature on ALS-related gut dysbiosis, focusing on the implications of GBA dysfunction. It delineates three main mechanisms by which dysbiosis contributes to ALS pathology: compromised intestinal barrier integrity, metabolic dysfunction, and immune dysregulation. It also examines preclinical evidence on the therapeutic potential of gut-microbiota-modulating agents (categorized as prebiotics, probiotics, and postbiotics) in ALS.

Unraveling the epigenetic fabric of type 2 diabetes mellitus: pathogenic mechanisms and therapeutic implications.

Type 2 diabetes mellitus (T2DM) is a rapidly escalating global health concern, with its prevalence projected to increase significantly in the near future. This review delves into the intricate role of epigenetic modifications - including DNA methylation, histone acetylation, and micro-ribonucleic acid (miRNA) expression - in the pathogenesis and progression of T2DM. We critically examine how these epigenetic changes contribute to the onset and exacerbation of T2DM by influencing key pathogenic processes such as obesity, insulin resistance, ß-cell dysfunction, cellular senescence, and mitochondrial dysfunction. Furthermore, we explore the involvement of epigenetic dysregulation in T2DM-associated complications, including diabetic retinopathy, atherosclerosis, neuropathy, and cardiomyopathy. This review highlights recent studies that underscore the diagnostic and therapeutic potential of targeting epigenetic modifications in T2DM. We also provide an overview of the impact of lifestyle factors such as exercise and diet on the epigenetic landscape of T2DM, underscoring their relevance in disease management. Our synthesis of the current literature aims to illuminate the complex epigenetic underpinnings of T2DM, offering insights into novel preventative and therapeutic strategies that could revolutionize its management.

Urinary Biomarkers for Lupus Nephritis: A Systems Biology Approach.

Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disorder. Kidney involvement, termed lupus nephritis (LN), is seen in 40-60% of patients with systemic lupus erythematosus (SLE). After the diagnosis, serial measurement of proteinuria is the most common method of monitoring treatment response and progression. However, present treatments for LN-corticosteroids and immunosuppressants-target inflammation, not proteinuria. Furthermore, subclinical renal inflammation can persist despite improving proteinuria. Serial kidney biopsies-the gold standard for disease monitoring-are also not feasible due to their inherent risk of complications. Biomarkers that reflect the underlying renal inflammatory process and better predict LN progression and treatment response are urgently needed. Urinary biomarkers are particularly relevant as they can be measured non-invasively and may better reflect the compartmentalized renal response in LN, unlike serum studies that are non-specific to the kidney. The past decade has overseen a boom in applying cutting-edge technologies to dissect the pathogenesis of diseases at the molecular and cellular levels. Using these technologies in LN is beginning to reveal novel disease biomarkers and therapeutic targets for LN, potentially improving patient outcomes if successfully translated to clinical practice.

Unveiling the Web: Exploring the Multifaceted Role of Neutrophil Extracellular Traps in Ocular Health and Disease.

Neutrophil extracellular traps (NETs) play an essential role in antimicrobial defense. However, NETs have also been shown to promote and mediate a wide spectrum of diseases, including cancer, diabetes mellitus, cardiovascular diseases, and ocular diseases. Data regarding NETs in ocular diseases remain limited. In physiological conditions, NETs protect the eye from debris and cleave proinflammatory cytokines, including several interleukins. On the other hand, NETs play a role in corneal diseases, such as dry eye disease and ocular graft-versus-host disease, where they promote acinar atrophy and delayed wound healing. Additionally, NET levels positively correlate with increased severity of uveitis. NETs have also been described in the context of diabetic retinopathy. Although increased NET biomarkers are associated with an increased risk of the disease, NETs also assist in the elimination of pathological blood vessels and the regeneration of normal vessels. Targeting NET pathways for the treatment of ocular diseases has shown promising outcomes; however, more studies are still needed in this regard. In this article, we summarize the literature on the protective roles of NETs in the eye. Then, we describe their pathogenetic effects in ocular diseases, including those of the cornea, uvea, and retinal blood vessels. Finally, we describe the therapeutic implications of targeting NETs in such conditions.

Biosensing of Alpha-Fetoprotein: A Key Direction toward the Early Detection and Management of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is currently one of the most prevalent cancers worldwide. Associated risk factors include, but are not limited to, cirrhosis and underlying liver diseases, including chronic hepatitis B or C infections, excessive alcohol consumption, nonalcoholic fatty liver disease (NAFLD), and exposure to chemical carcinogens. It is crucial to detect this disease early on before it metastasizes to adjoining parts of the body, worsening the prognosis. Serum biomarkers have proven to be a more accurate diagnostic tool compared to imaging. Among various markers such as nucleic acids, circulating genetic material, proteins, enzymes, and other metabolites, alpha-fetoprotein (AFP) is a protein marker primarily used to diagnose HCC. However, current methods need a large sample and carry a high cost, among other challenges, which can be improved using biosensing technology. Early and accurate detection of AFP can prevent severe progression of the disease and ensure better management of HCC patients. This review sheds light on HCC development in the human body. Afterward, we outline various types of biosensors (optical, electrochemical, and mass-based), as well as the most relevant studies of biosensing modalities for non-invasive monitoring of AFP. The review also explains these sensing platforms, detection substrates, surface modification agents, and fluorescent probes used to develop such biosensors. Finally, the challenges and future trends in routine clinical analysis are discussed to motivate further developments.

Bioengineered Organoids Offer New Possibilities for Liver Cancer Studies: A Review of Key Milestones and Challenges.

Hepatic cancer is widely regarded as the leading cause of cancer-related mortality worldwide. Despite recent advances in treatment options, the prognosis of liver cancer remains poor. Therefore, there is an urgent need to develop more representative in vitro models of liver cancer for pathophysiology and drug screening studies. Fortunately, an exciting new development for generating liver models in recent years has been the advent of organoid technology. Organoid models hold huge potential as an in vitro research tool because they can recapitulate the spatial architecture of primary liver cancers and maintain the molecular and functional variations of the native tissue counterparts during long-term culture in vitro. This review provides a comprehensive overview and discussion of the establishment and application of liver organoid models in vitro. Bioengineering strategies used to construct organoid models are also discussed. In addition, the clinical potential and other relevant applications of liver organoid models in different functional states are explored. In the end, this review discusses current limitations and future prospects to encourage further development.

Aptasensors Are Conjectured as Promising ALT and AST Diagnostic Tools for the Early Diagnosis of Acute Liver Injury.

Abnormal levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in human serum are the most sensitive indicator of hepatocellular damage. Because liver-related health problems are directly linked to elevated levels of ALT and AST, it is important to develop accurate and rapid methods to detect these enzymes for the early diagnosis of liver disease and prevention of long-term liver damage. Several analytical methods have been developed for the detection of ALT and AST. However, these methods are based on complex mechanisms and require bulky instruments and laboratories, making them unsuitable for point-of-care application or in-house testing. Lateral flow assay (LFA)-based biosensors, on the other hand, provide rapid, accurate, and reliable results, are easy to operate, and are affordable for low-income populations. However, due to the storage, stability, batch-to-batch variations, and error margins, antibody-based LFAs are considered unaffordable for field applications. In this hypothesis, we propose the selection of aptamers with high affinity and specificity for the liver biomarkers ALT and AST to build an efficient LFA device for point-of-care applications. Though the aptamer-based LFA would be semiquantitative for ALT and AST, it would be an inexpensive option for the early detection and diagnosis of liver disease. Aptamer-based LFA is anticipated to minimize the economic burden. It can also be used for routine liver function tests regardless of the economic situation in each country. By developing a low-cost testing platform, millions of patients suffering from liver disease can be saved.

Bispecific Antibodies in Hematological Malignancies: A Scoping Review.

Bispecific T-cell engagers (BiTEs) and bispecific antibodies (BiAbs) have revolutionized the treatment landscape of hematological malignancies. By directing T cells towards specific tumor antigens, BiTEs and BiAbs facilitate the T-cell-mediated lysis of neoplastic cells. The success of blinatumomab, a CD19xCD3 BiTE, in acute lymphoblastic leukemia spearheaded the expansive development of BiTEs/BiAbs in the context of hematological neoplasms. Nearly a decade later, numerous BiTEs/BiAbs targeting a range of tumor-associated antigens have transpired in the treatment of multiple myeloma, non-Hodgkin's lymphoma, acute myelogenous leukemia, and acute lymphoblastic leukemia. However, despite their generally favorable safety profiles, particular toxicities such as infections, cytokine release syndrome, myelosuppression, and neurotoxicity after BiAb/BiTE therapy raise valid concerns. Moreover, target antigen loss and the immunosuppressive microenvironment of hematological neoplasms facilitate resistance towards BiTEs/BiAbs. This review aims to highlight the most recent evidence from clinical trials evaluating the safety and efficacy of BiAbs/BiTEs. Additionally, the review will provide mechanistic insights into the limitations of BiAbs whilst outlining practical applications and strategies to overcome these limitations.

Low-Cost Point-of-Care Monitoring of ALT and AST Is Promising for Faster Decision Making and Diagnosis of Acute Liver Injury.

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are important liver enzymes in clinical settings. Their levels are known to be elevated in individuals with underlying liver diseases and those consuming hepatotoxic drugs. Serum ALT and AST levels are crucial for diagnosing and assessing liver diseases. Serum ALT is considered the most reliable and specific candidate as a disease biomarker for liver diseases. ALT and AST levels are routinely analyzed in high-risk individuals for the bioanalysis of both liver function and complications associated with drug-induced liver injury. Typically, ALT and AST require blood sampling, serum separation, and testing. Traditional methods require expensive or sophisticated equipment and trained specialists, which is often time-consuming. Therefore, developing countries have limited or no access to these methods. To address the above issues, we hypothesize that low-cost biosensing methods (paper-based assays) can be applied to the analysis of ALT and AST levels in biological fluids. The paper-based biodetection technique can semi-quantitatively measure ALT and AST from capillary finger sticks, and it will pave the way for the development of an inexpensive and rapid alternative method for the early detection and diagnosis of liver diseases. This method is expected to significantly reduce the economic burden and aid routine clinical analysis in both developed and underdeveloped countries. The development of low-cost testing platforms and their diagnostic utility will be extremely beneficial in helping millions of patients with liver disorders.

Tackling the glial scar in spinal cord regeneration: new discoveries and future directions.

Axonal regeneration and functional recovery are poor after spinal cord injury (SCI), typified by the formation of an injury scar. While this scar was traditionally believed to be primarily responsible for axonal regeneration failure, current knowledge takes a more holistic approach that considers the intrinsic growth capacity of axons. Targeting the SCI scar has also not reproducibly yielded nearly the same efficacy in animal models compared to these neuron-directed approaches. These results suggest that the major reason behind central nervous system (CNS) regeneration failure is not the injury scar but a failure to stimulate axon growth adequately. These findings raise questions about whether targeting neuroinflammation and glial scarring still constitute viable translational avenues. We provide a comprehensive review of the dual role of neuroinflammation and scarring after SCI and how future research can produce therapeutic strategies targeting the hurdles to axonal regeneration posed by these processes without compromising neuroprotection.