bluuebunny/crossref_metadata_2025 huggingface dataset:
Amyloid-Directed Antibodies: Past, Present, and Future
Authors: Noorda Keith , Noorda Kevin , Sabbagh Marwan N. , Bertelson John , Singer Jonathan , Decourt Boris
Published: December 2024

Background: Alzheimer’s disease (AD) is the most common neurodegenerative disorder in patient demographics over 65 years old causing debilitating cognitive impairment. Most commonly, AD is diagnosed clinically as “probable AD”, and definitive diagnosis is confirmed through postmortem brain autopsies to detect extracellular amyloid-β (Aβ) plaques and intraneuronal hyperphosphorylated tau tangles. The exact mechanism causing AD is still unknown, but treatments for AD have been actively investigated. Currently, immunotherapies have shown substantial promise in reducing the pathologic and clinical signs of AD. Objective: This review aims to evaluate passive immunotherapies deemed to have promise for further development and use in the treatment of AD. Methods: Immunotherapies were selected via a narrative review of medications that have potential clinical effectiveness with a status of FDA accepted, FDA fast-track, FDA status pending, or emerging therapies poised to pursue FDA approval. Results: This review has yielded two anti-Aβ monoclonal antibodies (mAb) that are currently fully FDA approved, one mAb granted FDA fast-track status, two therapies on hold, three discontinued medications, and three promising emerging therapies. Conclusions: We conclude that, in the near future, passive immunotherapies will be the preferred and evidence-based method of treatment for AD with the presence of brain Aβ deposits for both symptom management and potential slowing of disease progression. Specifically, lecanemab and donanemab will require further clinical studies to optimize patient selection based on safety profiles. Despite some key limitations, these two drugs are paving the way for disease-modifying treatments in patients displaying early signs of amyloid pathology.
Immunotherapy in Alzheimer’s Disease: Current Status and Future Directions
Authors: Vashisth Kshitij , Sharma Shivani , Ghosh Shampa , Babu M. Arockia , Ghosh Soumya , Iqbal Danish , Kamal Mehnaz , Almutary Abdulmajeed G. , Jha Saurabh Kumar , Ojha Shreesh , Bhaskar Rakesh , Jha Niraj Kumar , Sinha Jitendra Kumar
Published: December 2024

Alzheimer’s disease (AD) is a progressive neurological disorder characterized by memory loss, cognitive decline, and behavioral changes. Immunotherapy aims to harness the immune system to target the underlying pathology of AD and has shown promise as a disease-modifying treatment for AD. By focusing on the underlying disease pathogenesis and encouraging the removal of abnormal protein aggregates in the brain, immunotherapy shows promise as a potential treatment for AD. The development of immunotherapy for AD began with early attempts to use antibodies to target beta-amyloid. The amyloid hypothesis which suggests that the accumulation of beta-amyloid in the brain triggers the pathological cascade that leads to AD has been a driving force behind the development of immunotherapy for AD. However, recent clinical trials of monoclonal antibodies targeting amyloid-β have shown mixed results, highlighting the need for further research into alternative immunotherapy approaches. Additionally, the safety and efficacy of immunotherapy for AD remain an area of active investigation. Some immunotherapeutic approaches have shown promise, while others have been associated with significant side effects, including inflammation of the brain. Sleep has a significant impact on various physiological processes, including the immune system, and has been linked to the pathogenesis of AD. Thus, improving sleep quality and duration may benefit the immune system and potentially enhance the effectiveness of immunotherapeutic approaches for AD. In this review, we discussed the promises of immunotherapy as a disease-modifying treatment for AD as well as possible methods to improve the efficacy and safety of immunotherapy to achieve better therapeutic outcomes.
BACE1 Inhibitors for Alzheimer’s Disease: Current Challenges and Future Perspectives
Authors: Coimbra Judite R.M. , Resende Rosa , Custódio José B.A. , Salvador Jorge A.R. , Santos Armanda E.
Published: December 2024

Disease-modifying therapies (DMT) for Alzheimer’s disease (AD) are highly longed-for. In this quest, anti-amyloid therapies take center stage supported by genetic facts that highlight an imbalance between production and clearance of amyloid-β peptide (Aβ) in AD patients. Indeed, evidence from basic research, human genetic and biomarker studies, suggests the accumulation of Aβ as a driver of AD pathogenesis and progression. The aspartic protease β-site AβPP cleaving enzyme (BACE1) is the initiator for Aβ production. Underpinning a critical role for BACE1 in AD pathophysiology are the elevated BACE1 concentration and activity observed in the brain and body fluids of AD patients. Therefore, BACE1 is a prime drug target for reducing Aβ levels in early AD. Small-molecule BACE1 inhibitors have been extensively developed for the last 20 years. However, clinical trials with these molecules have been discontinued for futility or safety reasons. Most of the observed adverse side effects were due to other aspartic proteases cross-inhibition, including the homologue BACE2, and to mechanism-based toxicity since BACE1 has substrates with important roles for synaptic plasticity and synaptic homeostasis besides amyloid-β protein precursor (AβPP). Despite these setbacks, BACE1 persists as a well-validated therapeutic target for which a specific inhibitor with high substrate selectivity may yet to be found. In this review we provide an overview of the evolution in BACE1 inhibitors design pinpointing the molecules that reached advanced phases of clinical trials and the liabilities that precluded adequate trial effects. Finally, we ponder on the challenges that anti-amyloid therapies must overcome to achieve clinical success.
CT1812, a Small Molecule Sigma-2 Receptor Antagonist for Alzheimer’s Disease Treatment: A Systematic Review of Available Clinical Data
Authors: Thitilertdecha Premrutai , Brimson James Michael
Published: December 2024

Background: Alzheimer’s disease (AD) is of growing concern worldwide as the demographic changes to a more aged population. Amyloid-β (Aβ) deposition is thought to be a key target for treating AD. However, Aβ antibodies have had mixed results, and there is concern over their safety. Studies have shown that the sigma-2 receptor (σ-2R)/TMEM97 is a binding site for Aβ oligomers. Therefore, targeting the receptor may be beneficial in displacing Aβ oligomers from the brain. CT1812 is a σ-2R/TMEM97 antagonist that is effective in preclinical studies of AD and has been entered into clinical trials. Objective: The objective of this study was to systematically review the safety and efficacy of CT1812 for the treatment of AD. Methods: Between June and August 2023, we searched the primary literature (PubMed, Scopus, Google Scholar, etc.) and clinical trials databases (http://www.clinicaltrails.gov). The extracted data is evaluated within this manuscript. Results: CT1812 is relatively safe, with only mild adverse events reported at doses up to 840 mg. CT1812 can displace Aβ in the clinical studies, in line with the preclinical data. Studies have investigated brain connectivity and function in response to CT1812. However, the cognitive data is still lacking, with only one study including cognitive data as a secondary outcome. Conclusions: CT1812 safely works to displace Aβ; however, whether this is enough to prevent/slow the cognitive decline seen in AD remains to be seen. Longer clinical trials are needed to assess the efficacy of CT1812; several trials of this nature are currently ongoing.
Oxidative Stress in Alzheimer’s Disease: The Shortcomings of Antioxidant Therapies
Authors: Pappolla Miguel A. , Martins Ralph N. , Poeggeler Burkhard , Omar Rawhi A. , Perry George
Published: December 2024

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by gradual and progressive cognitive decline leading to dementia. At its core, the neuropathological features of AD include hallmark accumulations of amyloid-β and hyperphosphorylated tau proteins. Other harmful processes, such as oxidative stress and inflammation, contribute to the disease’s neuropathological progression. This review evaluates the role of oxidative stress in AD, placing a spotlight on the disappointing outcomes of various antioxidant clinical trials. Several hypotheses are discussed that might elucidate the failures of these therapies in AD. Specifically: 1) The paradoxical and overlooked harmful implications of prooxidant intermediates, particularly stemming from conventional antioxidants like vitamins E and C; 2) The challenges and failure to appreciate the issue of bioavailability—epitomized by the dictum “no on-site protection, no protection”—and the preeminent, yet often ignored, role played by endogenous antioxidant enzymes in combating oxidative stress; 3) The influence of unrecognized etiologies, such as latent infectious agents and others, as foundational drivers of oxidative stress in AD; 4) The underestimation of the complexity of oxidative mechanisms and the necessity of multi-targeted therapeutic approaches, such as those provided by various diets; and 5) The limitations of clinical trial designs in fully capturing the effects of antioxidants on AD progression. This article also examines the outcomes of select clinical trials while highlighting the challenges and barriers these therapies pose, offering insights into potential mechanisms to overcome their marginal success.
Melatonin in Alzheimer’s Disease: Literature Review and Therapeutic Trials
Authors: Steinbach Marilyn J. , Denburg Natalie L.
Published: December 2024

There are currently no effective treatments to prevent, halt, or reverse Alzheimer’s disease (AD), the most common cause of dementia in older adults. Melatonin, a relatively harmless over-the-counter supplement, may offer some benefits to patients with AD. Melatonin is known for its sleep-enhancing properties, but research shows that it may provide other advantages as well, such as antioxidant and anti-amyloidogenic properties. Clinical trials for melatonin use in AD have mixed results but, overall, show modest benefits. However, it is difficult to interpret clinical research in this area as there is little standardization to guide the administration and study of melatonin. This review covers basic biology and clinical research on melatonin in AD focusing on prominent hypotheses of pathophysiology of neurodegeneration and cognitive decline in AD (i.e., amyloid and tau hypotheses, antioxidant and anti-inflammation, insulin resistance and glucose homeostasis, the cholinergic hypothesis, sleep regulation, and the hypothalamic-pituitary-adrenal axis and cortisol). This is followed by a discussion on pending clinical trials, considerations for future research protocols, and open questions in the field.
A Randomized-Controlled Trial Targeting Cognition in Early Alzheimer’s Disease by Improving Sleep with Trazodone (REST)
Authors: Eyob Estelle , Shaw Jacob S. , Bakker Arnold , Munro Cynthia , Spira Adam , Wu Mark , Rabinowitz Jill A. , Peters Matthew , Wanigatunga Sarah , Zipunnikov Vadim , Thompson Richard , Burhanullah M. Haroon , Leoutsakos Jeannie-Marie , Rosenberg Paul , Greenberg Barry
Published: December 2024

Alzheimer’s disease (AD) is a leading cause of mortality and morbidity among aging populations worldwide. Despite arduous research efforts, treatment options for this devastating neurodegenerative disease are limited. Sleep disturbances, through their link to changes in neural excitability and impaired clearance of interstitial abnormal protein aggregates, are a key risk factor for the development of AD. Research also suggests that the neuroprotective effects of sleep are particularly active during slow wave sleep. Given the strong link between sleep disturbance and AD, targeting sleep in the prodromal stages of AD, such as in mild cognitive impairment (MCI), represents a promising avenue for slowing the onset of AD-related cognitive decline. In efforts to improve sleep in older individuals, several pharmacologic approaches have been employed, but many pose safety risks, concern for worsening cognitive function, and fail to effectively target slow wave sleep. Trazodone, a safe and widely used drug in the older adult population, has shown promise in inducing slow wave sleep in older adults, but requires more rigorous research to understand its effects on sleep and cognition in the prodromal stages of AD. In this review, we present the rationale and study design for our randomized, double-bind, placebo-controlled, crossover trial (NCT05282550) investigating the effects of trazodone on sleep and cognition in 100 older adults with amnestic MCI and sleep complaints.
Genistein, a Phytoestrogen, Delays the Transition to Dementia in Prodromal Alzheimer’s Disease Patients
Authors: Viña José , Borrás Consuelo , Mas-Bargues Cristina
Published: December 2024

Alzheimer’s disease is recognized as a complex condition influenced by multiple factors, necessitating a similarly multifaceted approach to treatment. Ideally, interventions should prioritize averting the progression to dementia. Given the chronic nature of the disease, long-term management strategies are required. Within this framework, lifestyle modifications and dietary supplements emerge as appealing options due to their minimal toxicity, limited side effects, and cost-effectiveness. This study presents findings from a double-blind, placebo-controlled bicentric pilot clinical trial, demonstrating the significant cognitive preservation associated with genistein, a phytoestrogen found in soy and various other dietary sources, among individuals with prodromal Alzheimer’s disease. Our prior investigation utilizing APP/PS1 mice elucidated the specific mechanisms through which genistein operates, including anti-amyloid-β, antioxidant, anti-inflammatory, and antiapoptotic effects. These findings underscore the potential of identifying bioactive compounds from dietary sources for the management of Alzheimer’s disease.
Metformin as a Potential Prevention Strategy for Alzheimer’s Disease and Alzheimer’s Disease Related Dementias
Authors: Tahmi Mouna , Benitez Richard , Luchsinger José A.
Published: December 2024

Background: Metformin is a safe and effective medication for type 2 diabetes (T2D) that has been proposed to decrease the risk of aging related disorders including Alzheimer’s disease (AD) and Alzheimer’s disease related disorders (ADRD). Objective: This review seeks to summarize findings from studies examining the association of metformin with AD/ADRD related outcomes. Methods: This is a narrative review of human studies, including observational studies and clinical trials, examining the association of metformin with cognitive and brain outcomes. We used PubMed as the main database for our literature search with a focus on English language human studies including observational studies and clinical trials. We prioritized studies published from 2013 until February 15, 2024. Results: Observational human studies are conflicting, but those with better study designs suggest that metformin use in persons with T2D is associated with a lower risk of dementia. However, these observational studies are limited by the use of administrative data to ascertain metformin use and/or cognitive outcomes. There are few clinical trials in persons without T2D that have small sample sizes and short durations but suggest that metformin could prevent AD/ADRD. There are ongoing studies including large clinical trials with long duration that are testing the effect of metformin on AD/ADRD outcomes in persons without T2D at risk for dementia. Conclusions: Clinical trial results are needed to establish the effect of metformin on the risk of AD and ADRD.
The Therapeutic Potential of Yoga for Alzheimer’s Disease: A Critical Review
Authors: Brown Adriel , Bayley Peter J.
Published: December 2024

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and behavioral changes, significantly impacting the quality of life of affected individuals and their caregivers. While pharmacological treatments offer limited relief, nonpharmacological interventions, like yoga, have gained attention for their potential therapeutic benefits. This critical review synthesizes findings from various studies on the feasibility, adherence, physical function, cognitive improvements, inflammatory markers, neuroprotection, and mood and behavioral changes associated with yoga interventions for older adults with AD. Despite these promising results, further research with randomized controlled trials, larger sample sizes, control groups, longitudinal follow-ups, standardized protocols, and diverse populations is necessary to confirm these benefits and understand the long-term effects of yoga on AD progression. This critical review highlights yoga’s potential as a valuable nonpharmacological intervention in the holistic management of AD.
Positron Emission Tomography/Computed Tomography Imaging in Therapeutic Clinical Trials in Alzheimer’s Disease: An Overview of the Current State of the Art of Research
Authors: Triumbari Elizabeth Katherine Anna , Chiaravalloti Agostino , Schillaci Orazio , Mercuri Nicola Biagio , Liguori Claudio
Published: December 2024

The integration of positron emission tomography/computed tomography (PET/CT) has revolutionized the landscape of Alzheimer’s disease (AD) research and therapeutic interventions. By combining structural and functional imaging, PET/CT provides a comprehensive understanding of disease pathology and response to treatment assessment. PET/CT, particularly with 2-deoxy-2-[fluorine-18]fluoro-D-glucose (18F-FDG), facilitates the visualization of glucose metabolism in the brain, enabling early diagnosis, staging, and monitoring of neurodegenerative disease progression. The advent of amyloid and tau PET imaging has further propelled the field forward, offering invaluable tools for tracking pathological hallmarks, assessing treatment response, and predicting clinical outcomes. While some therapeutic interventions targeting amyloid plaque load showed promising results with the reduction of cerebral amyloid accumulation over time, others failed to demonstrate a significant impact of anti-amyloid agents for reducing the amyloid plaques burden in AD brains. Tau PET imaging has conversely fueled the advent of disease-modifying therapeutic strategies in AD by supporting the assessment of neurofibrillary tangles of tau pathology deposition over time. Looking ahead, PET imaging holds immense promise for studying additional targets such as neuroinflammation, cholinergic deficit, and synaptic dysfunction. Advances in radiotracer development, dedicated brain PET/CT scanners, and Artificial Intelligence-powered software are poised to enhance the quality, sensitivity, and diagnostic power of molecular neuroimaging. Consequently, PET/CT remains at the forefront of AD research, offering unparalleled opportunities for unravelling the complexities of the disease and advancing therapeutic interventions, although it is not yet enough alone to allow patients’ recruitment in therapeutic clinical trials.
Concept Design of an Electric 100-Passenger Ship
Authors: Ostrovska Victoria , Slapničar Vedran , Andrišić Josip , Lalović Igor
Published: December 2024

This paper focuses on the concept design of a passenger ship tailored to accommodate the needs of 100 passengers, distinguished by its fully electric propulsion with batteries for electric energy storage and the integration of solar panels. Operates in year-round navigation short-sea services, with a typical operational profile of approximately 3 nautical miles distance followed by 30 minutes of sailing and 30 minutes of charging time, targeting a service speed of 7–8 knots. The benefits of the catamaran passenger ship are given as a sustainable coastal means of sea transportation that incorporates technologies to enhance comfort, operational efficiency, and environmental sustainability. As a result, the developed concept design incorporates an inclusive general arrangement for the required number of passengers. Following that, a hull form was created in terms of the efficiency of the electric propulsion, while the power was obtained by several methods. Evaluation of masses and the definition of the centre of gravity allowed for stability calculations for six scenarios, according to the Croatian Register of Shipping. Lastly, the ship’s operational profile was learned, and the energy balance and battery pack calculations and options were performed with sensitivity analysis for the possible solutions of the range of displacements.
Updated Steel Weight Estimation for Cruise Ship Concept Design
Authors: Utzeri Samuele , Braidotti Luca , Norcia Nicola , Marino’ Alberto
Published: December 2024

Estimating the steel weight of ships during the early conceptual stages is of the utmost importance since it represents about 50% of the lightship weight of the ship. From a technical standpoint, it significantly affects cargo capacity, design speed, stability, and ship safety, thus requiring an accurate estimation. The steel weight is usually evaluated using simple empirical formulations during the concept design, mainly based on the ship’s main particulars. Those formulas are derived by statistical analysis of past projects and can be applied only for the specific ship type (or types) included in the considered database. In the literature, many formulas are present mainly related to cargo ships. Currently, no empirical formulation is available for cruise ships that are applicable in the very early conceptual stages. The present study aims to identify an empirical formulation for estimating the steel weight of a luxury cruise ship based on calibrating a set of existing empirical formulas.
Structural Design and Analysis of River Floating Passenger Terminal
Authors: Andrić Jerolim , Uroda Tomislav , Tomičić Mateja , Četković Dinko , Borčić Kornelija
Published: December 2024

The paper discusses and highlights the basic challenges in the structural design of a 70-meter river floating passenger terminal. It is designed as a multi-deck floating object characterized by a large superstructure with a specific shape, equipped with solar and glass panels and the absence of transverse/longitudinal bulkheads. The height of the superstructure is larger compared to the height of the lower hull and its influence on longitudinal strength should be considered in the very early design phase. Croatian Register of Shipping (CRS) Rules for the Classification of Inland Navigation Vessels Part 2 – HULL AND HULL EQUIPMENT, July 2021 were used to define design loads, corrosion deductions, safety factors, etc. The main results and challenges have been briefly presented for the preliminary design phase where global structural response has been evaluated based on the full-ship FE model. Feasibility structural calculation due to yielding and buckling issues has been performed following criteria given in CRS Rules and a feasible design solution has been proposed.
Analysis and Modeling of the Ship Machinery Module
Authors: Barić Irena , Rubeša Rajko , Hadjina Marko , Matulja Tin
Published: December 2024

In the competitive shipbuilding industry, gaining a competitive advantage between shipyards is necessary. A competitive and sustainable shipyard process must constantly be monitored to increase productivity, efficiency, and quality. One of the major concerns in modern shipbuilding is achieving efficient ship outfitting, particularly for high value-added ships. Maximizing the level of the ship’s equipment installation before launching is one of the essential goals in modern shipyards while outfitting after the launching tends to be reduced to a minimum. Therefore, this paper will analyze the current situation in the observed shipyard in general, mainly the ship modular outfitting concept, which could improve its characteristics and impact the ship production process. Hence, the modular outfitting approach’s benefits, requirements, and potential drawbacks will be discussed. The module assembly and installation activities will be established as a case study, including all necessary resources for the selected machinery module. A network diagram with a critical path will be provided for analysis while a digital computer 3D modelling and visualization of module assembly and installation is developed. Furthermore, such model authors plan to use in further research as a basis for ship design and production digital integration to support the digital transition of the shipbuilding industry.
Leveraging Artificial Intelligence to Enhance Leisure Sailing Experience
Authors: Pagani Laura , Gemelli Paolo
Published: December 2024

This paper explores the transformative potential of artificial intelligence (AI) in revolutionizing leisure sailing experiences. Traditionally, leisure activities such as sailing have offered limited opportunities for personalization. However, recent advancements in AI enable dynamic customization of onboard environments based on individuals’ emotions and preferences. Using leisure sailing as a case study, this paper demonstrates how AI can be leveraged to create personalized and engaging experiences. By analyzing real-time data from onboard sensors, AI systems can adjust environmental factors such as lighting, music, ventilation, colours, and furniture layout to optimize comfort and enjoyment. The paper also delves into the technical challenges of implementing AI in leisure sailing, including data collection, real-time processing, and ethical considerations around privacy and consent. It emphasizes the potential for AI to enhance the leisure experience, inspiring further research and development in this area. In conclusion, this paper envisions a future where AI is seamlessly integrated into leisure sailing, creating tailored, immersive experiences that maximize participant comfort and enjoyment.
Rehabilitation of chronic post-stroke visual field defect with	computer-assisted training
Authors: Julkunen Laura , Tenovuo Olli , Jääskeläinen Satu , Hämäläinen Heikki
Published: December 2024

Purpose. Our aim was to study whether homonymous visual field defects could be restored in chronic stroke patients (N = 5) using computer-assisted training, and whether the possible beneficial effect could be maintained. Visual evoked potential (VEP) recordings were applied to evaluate whether they could demonstrate the possible training effects at the cortical level.

Methods. We applied a specially designed computer program in the training. Subjective assessment, static and kinetic perimetry, and pattern reversal hemifield VEP recordings were used to detect the possible changes.

Results. Two patients showed improvements immediately after the training in static perimetry. Further improvements were detected at a later follow-up in three patients. With kinetic perimetry, improvements were detected in three patients. The visual field defect was detected with VEP recordings in four patients before the training, and improvements could be verified with the method in three patients, two of which clearly improved in the static perimetry as well.

Conclusions. In three patients, the visual defect diminished with the computer-assisted method. It seems evident that visual field defects resulting from stroke can be partially restored even in the chronic phase.
CGP 3466 increases survival of cultured fetal dopaminergic	neurons
Authors: Matarredona Esperanza R. , Meyer Morten , Seiler Rolf W. , Widmer Hans R.
Published: December 2024

Purpose: To analyze the effects of CGP 3466, a compound structurally related to deprenyl, on survival and function of fetal ventral mesencephalic dopaminergic neurons.

Methods: Free-floating roller tube (FFRT) cultures of rat (E14) ventral mesencephalon were treated with CGP 3466 [10-8 M] for 7 days. Tyrosine hydroxylase (TH) and glial fibrillary acidic protein (GFAP) immunocytochemistry was performed to allow analysis of dopaminergic neurons and astroglial cells, respectively. Lactate dehydrogenase activity in the culture medium served as a measure of cell death. Control and CGP 3466 treated cultures were grafted into 6-hydroxydopamine-lesioned rats, and graft survival and function evaluated 9 weeks posttransplantation.

Results: FFRT cultures treated with CGP 3466 contained significantly more (two fold) surviving TH-immunoreactive (-ir) neurons and decreased lactate dehydrogenase activity in the culture medium compared to controls. The actions of CGP 3466 seem not to be mediated by astroglial cells, since GFAP-ir cell numbers and GFAP protein levels did not differ between the groups. CGP 3466 pretreatment of donor cultures did not improve TH-ir cell survival in the grafts nor did it alter functional recovery as compared to controls.

Conclusions: CGP 3466 is an effective survival factor for cultured midbrain dopaminergic neurons. However, CGP 3466 pretreatment does not ameliorate survival and function of the dopaminergic neurons after grafting into a rat model of Parkinson's disease.
Activation of A$_3$ receptors by endogenous	adenosine inhibits synaptic transmission during hypoxia in rat cortical	neurons
Authors: Hentschel S. , Lewerenz A. , Nieber K.
Published: December 2024

Purpose: The aim of our study was to characterize the influence of A $_3$ receptors on synaptic potentials (PSPs) in pyramidal cells from the rat cingulate cortex during hypoxia. METHODS: Intracellular recordings ($n=49$) were taken from slice preparations. PSPs were evoked by electrical stimulation.

Results: Hypoxia (95%NA $_2$ -5%COA $_2$ , 5 min) reduced the amplitude of the PSPs significantly. The effect was more pronounced in the presence of adenosine re-uptake inhibitor S-(p-nitrobenzyl)-6-thioguanosine (NBTG) and deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA); the effect was completely reversed by bovine adenosine deaminase. Hypoxic inhibition induced after A $_1$ receptor blockade with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) in the presence of NBTG was completely reversed by the A $_3$ antagonist 9-chloro-2-(2-furanyl)-5-[(phenylacetyl)amino]-1,2,4-triazolo[1,5-c]quinazoline (MRS 1220), indicating the involvement of A $_3$ receptors in hypoxic PSP inhibition. This was confirmed by A $_3$ agonist NA $^6$ -(3-iodobenzyl)-adenosine-5'-N-methylcarboxamide (IB-MECA) inhibiting PSPs. The effect of IB-MECA was blocked by the rat A $_3$ receptor-selective antagonist 3-propyl-6-ethyl-5-[(ethylthio)carbonyl]-2-phenyl-4-propyl-3-pyridinecarboxylate (MRS 1523) and was not observed in the presence of G-protein inhibitor guanosine-5'-O-2-thiodiphosphate (GDP-β-S).

Conclusion: We conclude that a high level of endogenous adenosine, which occurs during hypoxia, activates A $_3$ receptors. Their activation contributes to PSP inhibition by adenosine during hypoxia.
Dimeric fibroblast growth factor-2 enhances functional recovery	after focal cerebral ischemia
Authors: Berry David , Ren JingMei , Kwan Chi-Pong , Sietsma Dana K. , Sasisekharan Ram , Finklestein Seth P.
Published: December 2024

Purpose: The purpose of this study was to examine the effects of dimerized basic fibroblast growth factor (dFGF), a novel engineered growth factor, in a model of functional recovery following focal cerebral infarction (stroke) in rats.

Methods: A focal stroke was made in mature male rats by occlusion of the middle cerebral artery (MCA). dFGF was administered by intracisternal injection at one and three days after stroke. Tests to evaluate sensorimotor recovery of the contralateral limbs were done during the next three weeks after stroke.

Results: dFGF significantly enhanced recovery of sensorimotor function in limb placing and body swing tests compared to vehicle treatment. There were no differences in body weight or infarct volume in dFGF- vs. vehicle-treated animals.

Conclusions: dFGF represents a potential treatment to enhance functional recovery after stroke and offers several advantages over bFGF, including stability and independence from extracellular heparan sulfates.
A genetic fusion GDNF-C fragment of tetanus toxin prolongs	survival in a symptomatic mouse ALS model
Authors: Ciriza J. , Moreno-Igoa M. , Calvo A.C. , Yague G. , Palacio J. , Miana-Mena F.J. , Muñoz M.J. , Zaragoza P. , Brûlet P. , Pinzolas R. y Osta
Published: December 2024

Purpose: Amyotrophic Lateral Sclerosis (ALS) is a paralyzing disorder that kills individuals within three to five years of onset without any possibility for effective treatment. One proposed therapy has been the use of neurotrophic factors to inhibit the apoptosis of motorneurones. At the present, one way to deliver neurotrophic factors after intramuscular injection to the motor neurones is through the use of adenoviral vectors. An alternative strategy is the use of the atoxic C fragment of tetanus toxin (TTC) as a neurotrophic factor carrier for motorneurones.

Methods: We have produced the recombinant protein fusion Glial Derived Neurotrophic Factor and C fragment of tetanus toxin (GDNF-TTC) and we have tested its antiapoptotic activity in degeneration culture cells and in the symptomatic SOD $^{G93A}$ transgenic animal model for ALS.

Results: We demonstrated that GDNF-TTC induces the neuronal survival Akt kinase pathway in mouse cortical culture neurons and~maintains its antiapoptotic neuronal activity in Neuro2A cells. Moreover, we have found that genetic fusion is able to increase survival by 9 days and improves life quality in symptomatic ALS animal models.

Conclusion: These results suggest that recombinant GDNF-TTC fusion protein intramuscular injections provide a potential therapy for ALS treatment.
Neural correlates of recovery from acute hemispatial	neglect
Authors: Thimm M. , Fink G.R. , Sturm W.
Published: December 2024

Purpose: To investigate the neural correlates associated with recovery from acute spatial neglect resulting from right hemispheric stroke.

Methods: Four neglect patients were investigated both behaviourally and by fMRI at an acute (18 ± 5 days) and at a chronic stage (123 ± 18 days) post stroke.

Results: At the second assessment all patients showed substantial behavioural improvements. These were associated with an increase of neural activity in the right middle frontal gyrus, right inferior parietal cortex, right inferior temporal gyrus/fusiform gyrus, left superior temporal gyrus/angular gyrus and left anterior cingulate gyrus. Decreased neural activity at the second assessment was found in the right parahippocampal gyrus and left fusiform gyrus.

Conclusions: The pattern of neural reorganisation comprises areas of a right hemisphere fronto-parietal attentional network and corresponding left hemisphere areas suggesting a compensatory recruitment of analogous contralesional areas. Interestingly, a more complex pattern of neural changes was observed in the fusiform gyri which have previously been implicated in lateralised directed spatial attention. There was an increase in the right hemisphere and a decrease in the left hemisphere. This pattern of recovery is reminiscent of a "push-pull" pattern previously described for the dorsal parietal cortex by Corbetta et al. (2005) in the recovery from spatial neglect.
Proteoglycans in the central nervous system: Plasticity,	regeneration and their stimulation with chondroitinase ABC
Authors: Kwok Jessica C.F. , Afshari Fardad , García-Alías Guillermo , Fawcett James W.
Published: December 2024

After injury to the mammalian central nervous system (CNS), neurons are not able to regenerate their axons and recovery is limited by restricted plasticity. Axon regeneration is inhibited by the presence of the various inhibitory molecules, including chondroitin sulfate proteoglycans (CSPGs) which are upregulated around the injury site. Plasticity after the end of critical periods is restricted by extracellular matrix changes, particularly the formation of CSPG-containing perineuronal nets. Enzymatic removal of chondroitin sulfate (CS) chains with chondroitinase ABC promotes axon regeneration and reactivates plasticity. This review details the structures and properties of the different CSPGs in the normal and damaged CNS, the use of the enzyme chondroitinase ABC to promote neural regeneration and plasticity, and discusses mechanisms of action and possible therapeutic uses of this enzyme.
Mechanisms of CNS myelin inhibition: Evidence for distinct and	neuronal cell type specific receptor systems
Authors: Giger Roman J. , Venkatesh Karthik , Chivatakarn Onanong , Raiker Stephen J. , Robak Laurie , Hofer Thomas , Lee Hakjoo , Rader Christoph
Published: December 2024

Following injury to the adult mammalian central nervous system, regenerative growth of severed axons is very limited. The lack of neuronal repair is often associated with significant functional deficits, and depending on the severity of injury, may result in permanent paralysis distal to the site of injury. A detailed understanding of the molecular mechanisms that limit neuronal growth in the injured spinal cord is an important step toward the development of specific strategies aimed at restoring functional connectivity lost as a consequence of injury. While rapid progress is being made in defining the molecular identity of CNS growth inhibitory constituents, comparatively little is known about their receptors and downstream signaling mechanisms. Emerging new evidence suggests that the mechanisms for myelin inhibition are likely to be complex, involving multiple and distinct receptor systems that may operate in a redundant manner. Furthermore, the relative contribution of a specific ligand-receptor system to bring about growth inhibition may greatly vary among different neuronal cell types. Myelin-associated glycoprotein (MAG), for example, employs different mechanisms to inhibit neurite outgrowth of cerebellar, sensory, and retinal ganglion neurons in vitro. Nogo-A harbors distinct growth inhibitory regions, which employ different signaling mechanisms. The Nogo-66 receptor 1 (NgR1), a shared ligand binding component in a receptor complex for Nogo-66, MAG, and OMgp, participates in neuronal growth cone collapse to acutely presented myelin inhibitors, but is dispensable for longitudinal neurite outgrowth inhibition on substrate-bound Nogo-66, MAG, OMgp, or crude CNS myelin in vitro. Consistent with the idea of cell-type specific mechanisms for myelin inhibition, different types of CNS neurons possess very different regenerative capacities and respond differently to experimental treatment strategies in vivo. We speculate that differences in regenerative axonal growth among different fiber systems are a reflection of their intrinsic ability to elongate axons and their distinct cell surface receptor profiles to respond to the growth inhibitory extracellular milieu. The existence of cell type specific mechanisms to impair regenerative axonal growth in the CNS may have important implications for the development of treatment strategies. Depending on the fiber tract injured, different ligand-receptor systems may need to be targeted in order to elicit robust and long-distance regenerative axonal growth.
Transplantation of embryonic neurones to replace missing spinal	motoneurones
Authors: Nógrádi Antal , Szabó András
Published: December 2024

Loss of spinal motoneurones results in severe functional impairment. The most successful way to replace missing motoneurones is the use of embryonic postmitotic motoneurone grafts. It has been shown that grafted motoneurones survive, differentiate and integrate into the host cord. If grafted motoneurones are provided with a suitable conduit for axonal regeneration (e.g. a reimplanted ventral root) the grafted cells are able to grow their axons along the whole length of the peripheral nerves to reach muscles in the limb and restore function. Grafted motoneurones show excellent survival in motoneurone-depleted adult host cords, but the developing spinal cord appears to be an unfavourable environment for these cells. The long term survival and maturation of the grafted neurones are dependent on the availability of a nerve conduit and one or more target muscles, no matter whether these are ectopic nerve-muscle implants or limb muscles in their original place.

Thus, grafted and host motoneurones induce functional recovery of the denervated limb muscles when their axons regenerate into an avulsed and reimplanted ventral root. On the other hand, motoneurone-enriched embryonic grafts placed into a hemisection cavity in the cervical spinal cord induce axonal regeneration from great numbers of host motoneurones, possibly by the bridging effect of the grafts. In this case the regenerating host motoneurones reinnervate their original target muscles while the graft provides few axons for the reinnervation of muscles.

These results suggest that reconstruction of the injured spinal cord with embryonic motoneurone-enriched spinal cord graft is a feasible method to improve severe functional motor deficits.
Retrograde viral transduction of cortical pyramidal neurons from	the spinal cord
Authors: Groutsi F. , Mason M.R.J. , Anderson P.N. , Martins S. , Anesti M. , Coffin R.S. , Campbell G.
Published: December 2024

Purpose: The primary motor pathway, the corticospinal tract, is a major target for spinal cord regeneration studies. One way of improving the regeneration of corticospinal axons is to introduce regeneration-associated genes into cortical motor neurons using viral vector delivery.

Methods: We used an engineered Herpes Simplex virus (HSV1) with the EF1α promoter encoding either LacZ or GFP to transduce cortical neurons through retrograde transport following the injection of vector into adult rat striatum or spinal cord. After three-days to one-month post-injection, sections of brain and spinal cord were viewed with fluorescence microscopy or processed for LacZ histochemistry.

Results: Many layer V motor cortical neurons were transduced following striatal injections. These were not corticospinal neurons as they were not fluorogold-labelled following tracer injection into spinal cord. Corticospinal neurons in both hemispheres were, however, transduced following direct vector injections into the dorsal column of spinal cord, yielding 250–400 transduced corticospinal neurons per animal. No non-pyramidal neurons or thalamic neurons were transduced by spinal injections.

Conclusions: Therefore, this HSV1.EF1α vector is highly effective for the transduction of corticospinal neurons without direct injection into the brain and could be used to introduce regeneration-relevant genes into these neurons with the aim of regenerating the corticospinal tract.
Dopaminergic neurons derived from BG01V2, a variant of human	embryonic stem cell line BG01
Authors: Vazin Tandis , Chen Jia , Spivak Charles E. , Amable Rose , Gabitzsch Emily , Lee Chun-Ting , Lupica Carl R. , Freed William J.
Published: December 2024

Background and Purpose: Human embryonic stem cells (hESC) are considered a renewable source of dopamine producing neurons, and are of particular interest for their potential clinical use in Parkinson's disease. In this study, we characterized human dopaminergic neurons generated by stromal-derived inducing activity (SDIA) from BG01V2, a strain of human embryonic stem cell line, BG01, characterized by a chromosome 17 trisomy. Similar chromosomal changes have been repeatedly observed in hESC cultures in different laboratories, indicating the importance of chromosome 17 for growth and adaptation of hESC to culture. Methods: We investigated in vitro proliferation of differentiating cells using a BrDU incorporation assay, and monitored the cell population in long term cultures. Despite the cytogenetic abnormality, TH+ neurons were postmitotic at all stages of differentiation. After 30 days of differentiation, cell division ceased in 91% of the overall population of cells in the culture, indicating intact cell cycle regulation. Results: Expression of midbrain specific marker genes (Otx2, Pax5, Msx-1) showed differentiation of hESC-derived neural progenitor cells into midbrain specific dopamine neurons. These neurons expressed the dopamine transporter (DAT), and displayed functional DAT activity and electrical excitability. Conclusions: TH+ cells derived from the BG01V2 hESC line using SDIA are postmitotic and have functional characteristics of normal dopaminergic neurons.
Confluências artísticas na Cultura Iberoamericana (1600-1850): O mundo de Robert C. Smith (1912-1975)
Authors: Ferreira Silvia
Published: December 2024

Impulsado por una curiosidad incisiva y dotado de una preparación académica superior y una
sensibilidad refinada, el historiador del arte norteamericano Robert C. Smith (1912-1975)
desempeñó un papel pionero en el estudio y la difusión del arte luso-brasileño en los siglos XVII
y XVIII. Las confluencias artísticas que detectó entre dos mundos conectados pero distantes y
diferentes, en los que cada uno impactaba y renovaba al otro, son estudiadas y difundidas en
un contexto internacional.
Towards a More Resilient Healthcare Sector in Post-COVID-19 Pandemic in Jordan
Authors: Mowafi Omar , Al-Hasan Melina , Khamees Basheer A. , AL Hasan Rima , Al-Zu'bi Zu'bi M.F. , Al Kurdi Barween
Published: December 2024

This study explores the desirable conditions for the Health Sector Governance in post-COVID-19 pandemic Jordan. A primary qualitative approach was used with semi-structured interviews carried out with eighteen public sector doctors and hospital managers in Jordan. The results of the study indicate that there is a need for the health care sector of Jordan to be improved through governance change. Moreover, there is a need for rapid communication between stakeholders, fast financial decision-making processes, establishment of pandemic-specific emergency rooms, more coordination between public and private health sectors, a national health care database, and a system for emergency classification in hospitals. This would help in ensuring that immediate measures are taken which are focused on the providing immediate care to patients.
Extracellular vesicles: mediators of cell communication and emerging roles in biomedical research
Authors:   Korean Institute for Functional Medicine, Seo In-Ho
Published: December 2024

Extracellular vesicles (EVs) are critical mediators of intercellular communication, playing vital roles in various physiological and pathological processes. These nanometer-sized vesicles, which include exosomes, microvesicles, and apoptotic bodies, carry proteins, lipids, and nucleic acids that relay biological information between cells. Exosomes, ranging from 30 to 150 nm, are particularly important in cell signaling, immune regulation, and tissue regeneration. EVs have been implicated in the progression of diseases such as cancer, neurodegenerative, and cardiovascular diseases, showcasing their potential as diagnostic biomarkers and therapeutic tools. For instance, stem cell-derived EVs promote tissue regeneration, whereas cancer cell-derived EVs facilitate tumor growth and metastasis while aiding immune evasion. Recent studies indicate that EVs can be used to rejuvenate aged cells and mitigate age-related diseases. However, several challenges remain in EV research, such as the lack of standardized methods for isolation and characterization, as well as issues related to heterogeneity and clinical scalability. Advancing techniques for large-scale production and safety assessments is crucial for their clinical translation. Understanding the multifaceted roles of EVs is essential for future diagnostic and therapeutic innovations.