Targeting TrkB–PSD-95 coupling to mitigate neurological disorders

Tropomyosin receptor kinase B(TrkB)signaling plays a pivotal role in dendritic growth and dendritic spine formation to promote learning and memory.The activity-dependent release of brain-derived neurotrophic factor at synapses binds to pre-or postsynaptic TrkB resulting in the strengthening of synapses,reflected by long-term potentiation.Postsynaptically,the association of postsynaptic density protein-95 with TrkB enhances phospholipase Cγ-Ca^(2+)/calmodulin-dependent protein kinaseⅡand phosphatidylinositol 3-kinase-mechanistic target of rapamycin signaling required for long-term potentiation.In this review,we discuss TrkB-postsynaptic density protein-95 coupling as a promising strategy to magnify brain-derived neurotrophic factor signaling towards the development of novel therapeutics for specific neurological disorders.A reduction of TrkB signaling has been observed in neurodegenerative disorders,such as Alzheimer's disease and Huntington's disease,and enhancement of postsynaptic density protein-95 association with TrkB signaling could mitigate the observed deficiency of neuronal connectivity in schizophrenia and depression.Treatment with brain-derived neurotrophic factor is problematic,due to poor pharmacokinetics,low brain penetration,and side effects resulting from activation of the p75 neurotrophin receptor or the truncated TrkB.T1 isoform.Although TrkB agonists and antibodies that activate TrkB are being intensively investigated,they cannot distinguish the multiple human TrkB splicing isoforms or cell type-specific functions.Targeting TrkB–postsynaptic density protein-95 coupling provides an alternative approach to specifically boost TrkB signaling at localized synaptic sites versus global stimulation that risks many adverse side effects.

Additive neurorestorative effects of exercise and docosahexaenoic acid intake in a mouse model of Parkinson’s disease

There is a need to develop interventions to slow or reverse the degeneration of dopamine neurons in Parkinson’s disease after diagnosis.Given that preclinical and clinical studies suggest benefits of dietary n-3 polyunsaturated fatty acids,such as docosahexaenoic acid,and exercise in Parkinson’s disease,we investigated whether both could synergistically interact to induce recovery of the dopaminergic pathway.First,mice received a unilateral stereotactic injection of 6-hydroxydopamine into the striatum to establish an animal model of nigrostriatal denervation.Four weeks after lesion,animals were fed a docosahexaenoic acid-enriched or a control diet for the next 8 weeks.During this period,the animals had access to a running wheel,which they could use or not.Docosahexaenoic acid treatment,voluntary exercise,or the combination of both had no effect on(i)distance traveled in the open field test,(ii)the percentage of contraversive rotations in the apomorphine-induction test or(iii)the number of tyrosine-hydroxylase-positive cells in the substantia nigra pars compacta.However,the docosahexaenoic acid diet increased the number of tyrosine-hydroxylase-positive terminals and induced a rise in dopamine concentrations in the lesioned striatum.Compared to docosahexaenoic acid treatment or exercise alone,the combination of docosahexaenoic acid and exercise(i)improved forelimb balance in the stepping test,(ii)decreased the striatal DOPAC/dopamine ratio and(iii)led to increased dopamine transporter levels in the lesioned striatum.The present results suggest that the combination of exercise and docosahexaenoic acid may act synergistically in the striatum of mice with a unilateral lesion of the dopaminergic system and provide support for clinical trials combining nutrition and physical exercise in the treatment of Parkinson’s disease.

Brain-derived neurotrophic factor signaling in the neuromuscular junction during developmental axonal competition and synapse elimination

During the development of the nervous system,there is an overproduction of neurons and synapses.Hebbian competition between neighboring nerve endings and synapses performing different activity levels leads to their elimination or strengthening.We have extensively studied the involvement of the brain-derived neurotrophic factor-Tropomyosin-related kinase B receptor neurotrophic retrograde pathway,at the neuromuscular junction,in the axonal development and synapse elimination process versus the synapse consolidation.The purpose of this review is to describe the neurotrophic influence on developmental synapse elimination,in relation to other molecular pathways that we and others have found to regulate this process.In particular,we summarize our published results based on transmitter release analysis and axonal counts to show the different involvement of the presynaptic acetylcholine muscarinic autoreceptors,coupled to downstream serine-threonine protein kinases A and C(PKA and PKC)and voltage-gated calcium channels,at different nerve endings in developmental competition.The dynamic changes that occur simultaneously in several nerve terminals and synapses converge across a postsynaptic site,influence each other,and require careful studies to individualize the mechanisms of specific endings.We describe an activity-dependent balance(related to the extent of transmitter release)between the presynaptic muscarinic subtypes and the neurotrophin-mediated TrkB/p75NTR pathways that can influence the timing and fate of the competitive interactions between the different axon terminals.The downstream displacement of the PKA/PKC activity ratio to lower values,both in competing nerve terminals and at postsynaptic sites,plays a relevant role in controlling the elimination of supernumerary synapses.Finally,calcium entry through L-and P/Q-subtypes of voltage-gated calcium channels(both channels are present,together with the N-type channel in developing nerve terminals)contributes to reduce transmitter release and promote withdrawal of the most unfavorable nerve terminals during elimination(the weakest in acetylcholine release and those that have already become silent).The main findings contribute to a better understanding of punishment-rewarding interactions between nerve endings during development.Identifying the molecular targets and signaling pathways that allow synapse consolidation or withdrawal of synapses in different situations is important for potential therapies in neurodegenerative diseases.

Multifaceted superoxide dismutase 1 expression in amyotrophic lateral sclerosis patients:a rare occurrence?

Amyotrophic lateral sclerosis(ALS)is a neuromuscular condition resulting from the progressive degeneration of motor neurons in the cortex,brainstem,and spinal cord.While the typical clinical phenotype of ALS involves both upper and lower motor neurons,human and animal studies over the years have highlighted the potential spread to other motor and non-motor regions,expanding the phenotype of ALS.Although superoxide dismutase 1(SOD1)mutations represent a minority of ALS cases,the SOD1 gene remains a milestone in ALS research as it represents the first genetic target for personalized therapies.Despite numerous single case reports or case series exhibiting extramotor symptoms in patients with ALS mutations in SOD1(SOD1-ALS),no studies have comprehensively explored the full spectrum of extramotor neurological manifestations in this subpopulation.In this narrative review,we analyze and discuss the available literature on extrapyramidal and non-motor features during SOD1-ALS.The multifaceted expression of SOD1 could deepen our understanding of the pathogenic mechanisms,pointing towards a multidisciplinary approach for affected patients in light of new therapeutic strategies for SOD1-ALS.

Telencephalic stab wound injury induces regenerative angiogenesis and neurogenesis in zebrafish:unveiling the role of vascular endothelial growth factor signaling and microglia

After brain damage,regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals,suggesting a close link between these processes.However,the mechanisms by which these processes interact are not well understood.In this work,we aimed to study the correlation between angiogenesis and neurogenesis after a telencephalic stab wound injury.To this end,we used zebrafish as a relevant model of neuroplasticity and brain repair mechanisms.First,using the Tg(fli1:EGFP×mpeg1.1:mCherry)zebrafish line,which enables visualization of blood vessels and microglia respectively,we analyzed regenerative angiogenesis from 1 to 21 days post-lesion.In parallel,we monitored brain cell proliferation in neurogenic niches localized in the ventricular zone by using immunohistochemistry.We found that after brain damage,the blood vessel area and width as well as expression of the fli1 transgene and vascular endothelial growth factor(vegfaa and vegfbb)were increased.At the same time,neural stem cell proliferation was also increased,peaking between 3 and 5 days post-lesion in a manner similar to angiogenesis,along with the recruitment of microglia.Then,through pharmacological manipulation by injecting an anti-angiogenic drug(Tivozanib)or Vegf at the lesion site,we demonstrated that blocking or activating Vegf signaling modulated both angiogenic and neurogenic processes,as well as microglial recruitment.Finally,we showed that inhibition of microglia by clodronate-containing liposome injection or dexamethasone treatment impairs regenerative neurogenesis,as previously described,as well as injury-induced angiogenesis.In conclusion,we have described regenerative angiogenesis in zebrafish for the first time and have highlighted the role of inflammation in this process.In addition,we have shown that both angiogenesis and neurogenesis are involved in brain repair and that microglia and inflammation-dependent mechanisms activated by Vegf signaling are important contributors to these processes.This study paves the way for a better understanding of the effect of Vegf on microglia and for studies aimed at promoting angiogenesis to improve brain plasticity after brain injury.

Drosophila models used to simulate human ATP1A1 gene mutations that cause Charcot-Marie-Tooth type 2 disease and refractory seizures

Certain amino acids changes in the human Na^(+)/K^(+)-ATPase pump,ATPase Na^(+)/K^(+)transporting subunit alpha 1(ATP1A1),cause Charcot-Marie-Tooth disease type 2(CMT2)disease and refractory seizures.To develop in vivo models to study the role of Na^(+)/K^(+)-ATPase in these diseases,we modified the Drosophila gene homolog,Atpα,to mimic the human ATP1A1 gene mutations that cause CMT2.Mutations located within the helical linker region of human ATP1A1(I592T,A597T,P600T,and D601F)were simultaneously introduced into endogenous Drosophila Atpαby CRISPR/Cas9-mediated genome editing,generating the Atpα^(TTTF)model.In addition,the same strategy was used to generate the corresponding single point mutations in flies(Atpα^(I571T),Atpα^(A576T),Atpα^(P579T),and Atpα^(D580F)).Moreover,a deletion mutation(Atpα^(mut))that causes premature termination of translation was generated as a positive control.Of these alleles,we found two that could be maintained as homozygotes(Atpα^(I571T)and Atpα^(P579T)).Three alleles(Atpα^(A576T),Atpα^(P579)and Atpα^(D580F))can form heterozygotes with the Atpαmut allele.We found that the Atpαallele carrying these CMT2-associated mutations showed differential phenotypes in Drosophila.Flies heterozygous for Atpα^(TTTF)mutations have motor performance defects,a reduced lifespan,seizures,and an abnormal neuronal morphology.These Drosophila models will provide a new platform for studying the function and regulation of the sodium-potassium pump.

Locally Enhanced Flow and Electric Fields Through a Tip Effect for Efficient Flow‑Electrode Capacitive Deionization

Low-electrode capacitive deionization(FCDI)is an emerging desalination technology with great potential for removal and/or recycling ions from a range of waters.However,it still suffers from inefficient charge transfer and ion transport kinetics due to weak turbulence and low electric intensity in flow electrodes,both restricted by the current collectors.Herein,a new tip-array current collector(designated as T-CC)was developed to replace the conventional planar current collectors,which intensifies both the charge transfer and ion transport significantly.The effects of tip arrays on flow and electric fields were studied by both computational simulations and electrochemical impedance spectroscopy,which revealed the reduction of ion transport barrier,charge transport barrier and internal resistance.With the voltage increased from 1.0 to 1.5 and 2.0 V,the T-CC-based FCDI system(T-FCDI)exhibited average salt removal rates(ASRR)of 0.18,0.50,and 0.89μmol cm^(-2) min^(-1),respectively,which are 1.82,2.65,and 2.48 folds higher than that of the conventional serpentine current collectors,and 1.48,1.67,and 1.49 folds higher than that of the planar current collectors.Meanwhile,with the solid content in flow electrodes increased from 1 to 5 wt%,the ASRR for T-FCDI increased from 0.29 to 0.50μmol cm^(-2) min^(-1),which are 1.70 and 1.67 folds higher than that of the planar current collectors.Additionally,a salt removal efficiency of 99.89%was achieved with T-FCDI and the charge efficiency remained above 95%after 24 h of operation,thus showing its superior long-term stability.

Evidence supporting the relationship between maternal asthma and risk for autism spectrum disorders

During pregnancy,maternal immune activation(MIA),due to infection,chronic inflammatory disorders,or toxic exposures,can result in lasting health impacts on the developing fetus.MIA has been associated with an increased risk of neurodevelopmental disorders,such as autism spectrum disorder(ASD)in the offspring.ASD is characterized by increased repetitive and stereotyped behaviors and decreased sociability.As of 2020,1 in 36 children are diagnosed with ASD by the age of 8 years,with ASD rates continuing to increase in prevalence in USA(Tamayo et al.,2023).Post-mortem brain studies,biomarker and transcriptomic studies,and epidemiology studies have provided compelling evidence of immune dysregulation in the circulation and brain of individuals diagnosed with ASD.Currently,the etiology of ASD is largely unknown,however,genetic components and environmental factors can contribute to increased susceptibility.Maternal allergic asthma(MAA),a form of MIA,has been identified as a potential risk factor for developing neurodevelopmental disorders(Patel et al.,2020).Asthma is a chronic inflammatory condition driven by a T-helper type(TH)2 immune response.

Targeting harmful effects of non-excitatory amino acids as an alternative therapeutic strategy to reduce ischemic damage

The involvement of the excitatory amino acids glutamate and aspartate in ce rebral ischemia and excitotoxicity is well-documented.Nevertheless,the role of non-excitatory amino acids in brain damage following a stroke or brain trauma remains largely understudied.The release of amino acids by necrotic cells in the ischemic core may contribute to the expansion of the penumbra.Our findings indicated that the reversible loss of field excitato ry postsynaptic potentials caused by transient hypoxia became irreversible when exposed to a mixture of just four non-excitatory amino acids(L-alanine,glycine,L-glutamine,and L-serine)at their plasma concentrations.These amino acids induce swelling in the somas of neurons and astrocytes during hypoxia,along with permanent dendritic damage mediated by N-methyl-D-aspartate receptors.Blocking N-methyl-D-aspartate receptors prevented neuronal damage in the presence of these amino acids during hypoxia.It is likely that astroglial swelling caused by the accumulation of these amino acids via the alanine-serine-cysteine transporter 2 exchanger and system N transporters activates volume-regulated anion channels,leading to the release of excitotoxins and subsequent neuronal damage through N-methyl-D-aspartate receptor activation.Thus,previously unrecognized mechanisms involving non-excitatory amino acids may contribute to the progression and expansion of brain injury in neurological emergencies such as stroke and traumatic brain injury.Understanding these pathways co uld highlight new therapeutic targets to mitigate brain injury.

Effect of sodium nitroprusside on the microrheological properties of red blood cells in different media

Red blood cell(RBC)aggregation as well as their deformation significantly affects blood microrheology.These processes depend on various factors,one of which is concentration of the nitric oxide,one of the main signaling molecule in the bloodstream.The purpose of this study was to investigate the effect of nitric oxide on the microrheological properties of red blood cells(RBCs)in RBC samples of various media after the addition of nitric oxide donor sodium nitroprusside in vitro.Microrheological properties were measured using laser aggregometer and ektacytometer based on diffuse light scattering and diffraction of laser light on a suspension of RBCs,respectively.The study found that heparin-stabilized blood showed increased RBC aggregation and deformation with sodium nitroprusside concentrations of 100,and 200M,while EDTA-stabilized blood showed slightly decreased aggregation and unchanged deformation.With washed RBCs in dextran solution,the addition of sodium nitroprusside(in the concentrations of 100,and 200M)resulted in decreased aggregation and increased deformation.These-ndings aid in our understanding of nitric oxide's effect on RBC microrheological properties.

Oral candidiasis and potential risk factors among disabled and nondisabled in Al-Baha region, Saudi Arabia

BACKGROUND Oral candidiasis(OC)is an oral health disease that could influence patients’oral health quality of life.AIM To estimate prevalence of OC among disabled and non-disabled individuals and its potential risk factors in the Al-Baha region,Saudi Arabia.METHODS An observational cross-sectional study was carried out among 148 disabled and non-disabled participants.The technique of concentrated oral rinse employing the Sabouraud Dextrose Agar medium accompanied with 0.05%chloramphenicol was conducted to assess and isolate candida.Oral examination using the World Health Organization guidelines was conducted to examine participants’oral hea-lth status.A pre-designed questionnaire was also used to evaluate sociodemo-graphic,medical history,and oral hygiene habits of the studied population.RESULTS Out of 148 participants(n=57,38%)had colonized candida.None of the studied population had visible Candida lesions.However,Candida was found in the oral rinses without the subject presenting any lesions or issues caused by Candida(asymptomatic colonization).The most common prevalent OC among participants were Candida albicans,Candida glabrata,Candida dubliniensis,Candida krusei,Candida tropicalis,and Candida parapsilosis(n=35,61%;n=8,14%;n=6,10%;n=5,9%;n=2,4%;and n=1,2%)respectively.Diabetes,smoking,poor plaque,and gingival status were key potential risk factors that significantly associated with candida’s density and presence(P=0.001,P=0.001,P=0.01,and P=0.01)respectively.Disability status had no statistically significant effect on presence and density of Candida.CONCLUSION The prevalence of OC is almost third of the studied population;thus,may provoke a need to develop preventive strategies to reduce the OC rate and establish solid treatment plans.

Effects of mesoscale gravity waves on sporadic E simulated by a one-dimensional dynamic model

In addition to being driven by tidal winds,the sporadic E(Es)layers are modulated by gravity waves(GWs),although the effects are not yet comprehensively understood.In this article,we discuss the effects of mesoscale GWs on the Es layers determined by using a newly developed model,MISE-1D(one-dimensional Model of Ionospheric Sporadic E),with low numerical dissipation and high resolution.Driven by the wind fields resolved by the high-resolution version of the Whole Atmosphere Community Climate Model with thermosphere and ionosphere extension(WACCM-X),the MISE-1D simulation revealed that GWs significantly influence the evolution of the Es layer above 100 km but have a very limited effect at lower altitudes.The effects of GWs are diverse and complex,generally including the generation of fluctuating wavelike structures on the Es layer with frequencies similar to those of the GWs.The mesoscale GWs can also cause increases in the density of Es layers,or they can disperse or diffuse the Es layers and increase their thickness.In addition,the presence of GWs is a key factor in sustaining the Es layers in some cases.

Prediction of the Photofading of Selected Derivatives of 5-(4-X-Phenylazo)-3-Cyano-1-(H or Ethyl)-6-Hydroxy-4-Methyl-2-Pyridone: Theoretical Studies, Comparison of AM1 and PM3 Methods

We analysed the photooxidation reaction in the electro-(1O2) and nucleophilic (O2•−) reaction of 2-pyridone azo derivatives. First, we calculated the energy (enthalpies) of tautomers formation, which is a measure of durability and the probability of their formation. We performed the light fastness calculations of the monoazopyridone dyes. Using the semi-empirical methods of quantum chemistry AM1 and PM3, the reactivity indicators of superdelocalisability (SrE(N)) and the electron density distribution in ground state on the highest occupied HOMO orbital and the lowest unoccupied excited state LUMO in 2-pyridone phenylazo derivatives were calculated. Superdelocalisability coefficients enable the stability to oxidising agents of various chemical molecules depending on the tautomeric forms in which they may occur. The results of the electron density calculations at the HOMO and LUMO boundary orbitals allow to determine the tendency to electrophilic attack with singlet oxygen 1O2 or nucleophilic attack of the superoxide anion O2•−on a specific atom in the molecule. The structure of the dyes was optimised with MM+, MD and AM1 or PM3 until a constant energy value was achieved with a convergence criterion of 0.01 kcal/mol.

3D Printing of Tough Hydrogel Scaffolds with Functional Surface Structures for Tissue Regeneration

Hydrogel scaffolds have numerous potential applications in the tissue engineering field.However,tough hydrogel scaffolds implanted in vivo are seldom reported because it is difficult to balance biocompatibility and high mechanical properties.Inspired by Chinese ramen,we propose a universal fabricating method(printing-P,training-T,cross-linking-C,PTC&PCT)for tough hydrogel scaffolds to fill this gap.First,3D printing fabricates a hydrogel scaffold with desired structures(P).Then,the scaffold could have extraordinarily high mechanical properties and functional surface structure by cycle mechanical training with salting-out assistance(T).Finally,the training results are fixed by photo-cross-linking processing(C).The tough gelatin hydrogel scaffolds exhibit excellent tensile strength of 6.66 MPa(622-fold untreated)and have excellent biocompatibility.Furthermore,this scaffold possesses functional surface structures from nanometer to micron to millimeter,which can efficiently induce directional cell growth.Interestingly,this strategy can produce bionic human tissue with mechanical properties of 10 kPa-10 MPa by changing the type of salt,and many hydrogels,such as gelatin and silk,could be improved with PTC or PCT strategies.Animal experiments show that this scaffold can effectively promote the new generation of muscle fibers,blood vessels,and nerves within 4 weeks,prompting the rapid regeneration of large-volume muscle loss injuries.

Customized scaffolds for large bone defects using 3D‑printed modular blocks from 2D‑medical images

Additive manufacturing(AM)has revolutionized the design and manufacturing of patient-specific,three-dimensional(3D),complex porous structures known as scaffolds for tissue engineering applications.The use of advanced image acquisition techniques,image processing,and computer-aided design methods has enabled the precise design and additive manufacturing of anatomically correct and patient-specific implants and scaffolds.However,these sophisticated techniques can be timeconsuming,labor-intensive,and expensive.Moreover,the necessary imaging and manufacturing equipment may not be readily available when urgent treatment is needed for trauma patients.In this study,a novel design and AM methods are proposed for the development of modular and customizable scaffold blocks that can be adapted to fit the bone defect area of a patient.These modular scaffold blocks can be combined to quickly form any patient-specific scaffold directly from two-dimensional(2D)medical images when the surgeon lacks access to a 3D printer or cannot wait for lengthy 3D imaging,modeling,and 3D printing during surgery.The proposed method begins with developing a bone surface-modeling algorithm that reconstructs a model of the patient’s bone from 2D medical image measurements without the need for expensive 3D medical imaging or segmentation.This algorithm can generate both patient-specific and average bone models.Additionally,a biomimetic continuous path planning method is developed for the additive manufacturing of scaffolds,allowing porous scaffold blocks with the desired biomechanical properties to be manufactured directly from 2D data or images.The algorithms are implemented,and the designed scaffold blocks are 3D printed using an extrusion-based AM process.Guidelines and instructions are also provided to assist surgeons in assembling scaffold blocks for the self-repair of patient-specific large bone defects.

Epdemiology and Treatment of Pseudarthrosis of Long Bones in the Servce D Orthopedics-Traumatology of the University Hospital of Donka

Introduction: Pseudarthrosis (PSA) of the diaphysis of long bones still remains a current problem, despite improvements in the treatment of these fractures. Our study aims to study the epidemiological and therapeutic aspects of PSA of the diaphysis of long bones. Method: This retrospective work concerns 30 cases of non-union of the diaphysis of long bones treated in the orthopedic and trauma surgery department at Donka National Hospital, during a period of 18 months from January 1, 2019 to June 30, 2020. Results: We recruited 30 patients, 80% of whom were male, with an average age of 39.9 years. Public road accidents (AVP) represented the main cause of fractures of the diaphysis of long bones 87%, they were open in 25 cases or 83%. The fractures were located in the middle 1/3 of the diaphysis of the long bones in 50% of cases. Treatment of initial fractures was traditional in 21 cases, orthopedic in 2 cases and surgical in 7 cases. It was aseptic nonunion in 28 cases (93%) and septic nonunion in 2 cases. They were hypertrophic in 7 cases, slightly hypertrophic in 5 cases, oligotrophic in 11 cases, atrophic in 6 cases and with bone defect in 1 case. The treatment was based on osteosynthesis including 16 cases of screwed “PV” plate: 7 cases of centromedullary “ECM” nailing, 2 cases of external fixator, 1 case of broaching and 4 cases of Plastering. The results according to ASAMI criteria on an anatomical level were excellent in 19 cases, good in 3 cases and poor in 3 cases, with a union rate of 76%. And 5 patients undergoing consolidation. Conclusion: Based on the literature data and the experience of our department, the true treatment of PSA requires correct management of the initial fracture without forgetting the interest in preventing AVP which appears to be an element essential, making it possible to reduce the incidence of fractures of the diaphysis.

A novel approach to the dynamic response analysis of Euler-Bernoulli beams resting on a Winkler soil model and subjected to impact loads

This work presents a novel approach to the dynamic response analysis of a Euler-Bernoulli beam resting on a Winkler soil model and subjected to an impact loading.The approach considers that damping has much less importance in controlling the maximum response to impulsive loadings because the maximum response is reached in a very short time,before the damping forces can dissipate a significant portion of the energy input into the system.The development of two sine series solutions,relating to different types of impulsive loadings,one involving a single concentrated force and the other a distributed line load,are presented.This study revealed that when a simply supported Euler-Bernoulli beam,resting on a Winkler soil model,is subject to an impact load,the resulting vertical displacements,bending moments and shear forces produced along the span of the beam are considerably affected.In particular,the quantification of this effect is best observed,relative to the corresponding static solution,via an amplification factor.The computed impact amplification factors,for the sub-grade moduli used in this study,were in magnitude greater than 2,thus confirming the multiple-degree-of-freedom nature of the problem.

A New Proof for Congruent Number’s Problem via Pythagorician Divisors

Considering Pythagorician divisors theory which leads to a new parameterization, for Pythagorician triplets ( a,b,c )∈ ℕ 3∗ , we give a new proof of the well-known problem of these particular squareless numbers n∈ ℕ ∗ , called congruent numbers, characterized by the fact that there exists a right-angled triangle with rational sides: ( A α ) 2 + ( B β ) 2 = ( C γ ) 2 , such that its area Δ= 1 2 A α B β =n;or in an equivalent way, to that of the existence of numbers U 2 , V 2 , W 2 ∈ ℚ 2∗ that are in an arithmetic progression of reason n;Problem equivalent to the existence of: ( a,b,c )∈ ℕ 3∗ prime in pairs, and f∈ ℕ ∗ , such that: ( a−b 2f ) 2 , ( c 2f ) 2 , ( a+b 2f ) 2 are in an arithmetic progression of reason n;And this problem is also equivalent to that of the existence of a non-trivial primitive integer right-angled triangle: a 2 + b 2 = c 2 , such that its area Δ= 1 2 ab=n f 2 , where f∈ ℕ ∗ , and this last equation can be written as follows, when using Pythagorician divisors: (1) Δ= 1 2 ab= 2 S−1 d e ¯ ( d+ 2 S−1 e ¯ )( d+ 2 S e ¯ )=n f 2;Where ( d, e ¯ )∈ ( 2ℕ+1 ) 2 such that gcd( d, e ¯ )=1 and S∈ ℕ ∗ , where 2 S−1 , d, e ¯ , d+ 2 S−1 e ¯ , d+ 2 S e ¯ , are pairwise prime quantities (these parameters are coming from Pythagorician divisors). When n=1 , it is the case of the famous impossible problem of the integer right-angled triangle area to be a square, solved by Fermat at his time, by his famous method of infinite descent. We propose in this article a new direct proof for the numbers n=1 (resp. n=2 ) to be non-congruent numbers, based on an particular induction method of resolution of Equation (1) (note that this method is efficient too for general case of prime numbers n=p≡a ( ( mod8 ) , gcd( a,8 )=1 ). To prove it, we use a classical proof by induction on k , that shows the non-solvability property of any of the following systems ( t=0 , corresponding to case n=1 (resp. t=1 , corresponding to case n=2 )): ( Ξ t,k ){ X 2 + 2 t ( 2 k Y ) 2 = Z 2 X 2 + 2 t+1 ( 2 k Y ) 2 = T 2 , where k∈ℕ;and solutions ( X,Y,Z,T )=( D k , E k , f k , f ′ k )∈ ( 2ℕ+1 ) 4 , are given in pairwise prime numbers.2020-Mathematics Subject Classification 11A05-11A07-11A41-11A51-11D09-11D25-11D41-11D72-11D79-11E25 .

Detection of Burned Areas through Spectral Indices Analysis of Sentinel-2A Satellite Images in the Abokouamékro Wildlife Reserve (Central, Côte D’Ivoire)

In Côte d’Ivoire, the recurring and unregulated use of bushfires, which cause ecological damage, presents a pressing concern for the custodians of protected areas. This study aims to enhance our comprehension of the dynamics of burnt areas within the Abokouamékro Wildlife Reserve (AWR) by employing the analysis of spectral indices derived from satellite imagery. The research methodology began with the calculation of mean indices and their corresponding spectral sub-indices, including NDVI, SAVI, NDWI, NDMI, BAI, NBR, TCW, TCG, and TCB, utilizing data from the Sentinel-2A satellite image dated January 17, 2022. Subsequently, a fuzzy classification model was applied to these various indices and sub-indices, guided by the degree of membership α, with the goal of effectively distinguishing between burned and unburned areas. Following the classification, the accuracies of the classified indices and sub-indices were validated using the coordinates of 100 data points collected within the AWR through GPS technology. The results revealed that the overall accuracy of all indices and sub-indices declines as the degree of membership α decreases from 1 to 0. Among the mean spectral indices, NDVI-mean, SAVI-mean, NDMI-mean exhibited the highest overall accuracies, achieving 97%, 95%, and 90%, respectively. These results closely mirrored those obtained by sub-indices using band 8 (NDVI-B8, SAVI-B8, and NDMI-B8), which yield respective overall accuracies of 93%, 92%, and 89%. At a degree of membership α = 1, the estimated burned areas for the most effective indices encompassed 2144.38 hectares for NDVI-mean, 1932.14 hectares for mean SAVI-mean, and 4947.13 hectares for mean NDMI-mean. A prospective approach involving the amalgamation of these three indices could have the potential to yield improved outcomes. This study could be a substantial contribution to the discrimination of bushfires in Côte d’Ivoire.

Insights into the structural biology of G-protein coupled receptors impacts drug design for central nervous system neurodegenerative processes

In the last few years, there have been important new insights into the structural biology of G-protein coupled receptors. It is now known that allosteric binding sites are involved in the affinity and selec- tivity of ligands for G-protein coupled receptors, and that signaling by these receptors involves both G-protein dependent and independent pathways. The present review outlines the physiological and pharmacological implications of this perspective for the design of new drugs to treat disorders of the central nervous system. Specifically, new possibilities are explored in relation to allosteric and or- thosteric binding sites on dopamine receptors for the treatment of Parkinson＇s disease, and on muscarinic receptors for Alzheimer＇s disease. Future research can seek to identify ligands that can bind to more than one site on the same receptor, or simultaneously bind to two receptors and form a dimer. For example, the design of bivalent drugs that can reach homo/hetero-dimers of D2 dopa- mine receptor holds promise as a relevant therapeutic strategy for Parkinson＇s disease. Regarding the treatment of Alzheimer＇s disease, the design of dualsteric ligands for mono-oligomeric mus- carinic receptors could increase therapeutic effectiveness by generating potent compounds that could activate more than one signaling pathway.