Noninvasive brain stimulation techniques offer promising therapeutic and regenerative prospects in neurological diseases by modulating brain activity and improving cognitive and motor functions.Given the paucity of kn...Noninvasive brain stimulation techniques offer promising therapeutic and regenerative prospects in neurological diseases by modulating brain activity and improving cognitive and motor functions.Given the paucity of knowledge about the underlying modes of action and optimal treatment modalities,a thorough translational investigation of noninvasive brain stimulation in preclinical animal models is urgently needed.Thus,we reviewed the current literature on the mechanistic underpinnings of noninvasive brain stimulation in models of central nervous system impairment,with a particular emphasis on traumatic brain injury and stroke.Due to the lack of translational models in most noninvasive brain stimulation techniques proposed,we found this review to the most relevant techniques used in humans,i.e.,transcranial magnetic stimulation and transcranial direct current stimulation.We searched the literature in Pub Med,encompassing the MEDLINE and PMC databases,for studies published between January 1,2020 and September 30,2024.Thirty-five studies were eligible.Transcranial magnetic stimulation and transcranial direct current stimulation demonstrated distinct strengths in augmenting rehabilitation post-stroke and traumatic brain injury,with emerging mechanistic evidence.Overall,we identified neuronal,inflammatory,microvascular,and apoptotic pathways highlighted in the literature.This review also highlights a lack of translational surrogate parameters to bridge the gap between preclinical findings and their clinical translation.展开更多
Stroke is the second leading cause of death worldwide with about 50% of survivors being chronically disabled(Donkor,2018).The behavioral improvement seen in stroke patients in the first weeks after a stroke is contrib...Stroke is the second leading cause of death worldwide with about 50% of survivors being chronically disabled(Donkor,2018).The behavioral improvement seen in stroke patients in the first weeks after a stroke is contributed by behavioral compensation, reorganization in somatotopic maps and activity in peri-infarct but also distant regions which are connected to the stroke area as supported by animal studies.展开更多
Hypothalamic receptors for neuropeptide Y, melaninconcentrating hormone, melanocortins and orexins/ hypocretins as well as for the downstream signaling corticotrophic factor have been discussed broadly for their influ...Hypothalamic receptors for neuropeptide Y, melaninconcentrating hormone, melanocortins and orexins/ hypocretins as well as for the downstream signaling corticotrophic factor have been discussed broadly for their influence on food intake and reward but also on several psychiatric disorders. For the development of non-peptide ligands for the in vivo detection of alterations in density and affinity of such G-protein coupled (GPCRs) peptide receptors the requirements to affinity and pharmacokinetics have been shifted to thresholds markedly distict from classical GPCRs to dissociation constants ported originally as potential therapeutics in the treatment of obesity among which some are suitable candidates for labeling as PET or SPECT-tracers providing receptor affinities even below 0.1 nM. These could be unique tools not only for better understanding of the mechanism of obesity but also for investigations of extrahypothalamic role of “feeding receptors” at the interface between neuroendocrine and mental diseases.展开更多
Pituitary adenylate cyclase activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) have been known for decades to mediate neuroendocrine and vasodilative actions via G-protein-coupled receptors of Clas...Pituitary adenylate cyclase activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) have been known for decades to mediate neuroendocrine and vasodilative actions via G-protein-coupled receptors of Class B. These are targets of imaging probes for positron emission tomography (PET) or single photon emission tomography (SPECT) in tumor diagnostics and tumor grading. However, they play only a subordinate role in the development of tracers for brain imaging. Difficulties in development of non-peptide ligands typical for cerebral receptors of PACAP and VIP are shared by all members of Class B receptor family. Essential landmarks have been confirmed for understanding of structural details of Class B receptor molecular signalling during the last five years. High relevance in the explanation of problems in ligand development for these receptors is admitted to the large N-terminal?ectodomain markedly different from Class A receptor binding sites and poorly suitable as orthosteric binding sites for the most small-molecule compounds. The present study is focused on the recently available receptor ligands for PAC1, VPAC1 and VPAC2 receptors as well as potential small-molecule lead structures suitable for use in PET or SPECT. Recently, biaryl, cyanothiophene and pentanamide structures with affinities in nM-range have been proposed as non-peptide ligands at VPAC1 and VPAC2 receptors. However, most of these ligands have been classified as non-competitive related to the orthosteric binding site of endogenous peptide ligands of VPAC receptors. For PAC1 receptors have been identified hydrazide compounds for which an inhibitory and potentially competitive mechanism of receptor binding has been postulated based on molecular docking studies.展开更多
Neuropeptide receptors of the brain and spinal cord are parts of the pain circuits targeted by analgesic drugs. Some of these receptors have been found in the central nervous system as well as in intracranial vascular...Neuropeptide receptors of the brain and spinal cord are parts of the pain circuits targeted by analgesic drugs. Some of these receptors have been found in the central nervous system as well as in intracranial vascular structures and achieved revival of attention because of their role in acute and chronic pain syndromes. A number of them are of high clinical relevance for e.g. migraine. Others participate in symptoms of rare diseases like amyotrophic lateral sclerosis. Here we will focus on five of the neuropeptide receptors and their non-peptide ligands potentially or already successfully used as PET probes. Opioid receptors and neurotensin receptors are known to mediate analgesic actions. Bradykinin and calcitonin gene-related peptide (CGRP) receptors are known to be involved in the regulation of vascular tone and inflammatory responses, and neurokinin receptors play a role in the occurrence of pain perception in a rather indirect manner. Most experiences as PET tracers have been gathered with opioid receptor ligands and neurokinin receptor ligands. The most innovative fields revealed by the studies summarized in this report are the ligands of κ opioid receptors and CGRP receptors for which a first PET tracer was presented recently.展开更多
The human striatum is essential for both lowand high-level functions and has been implicated in the pathophysiology of various prevalent disorders,including Parkinson's disease(PD)and schizophrenia(SCZ).It is know...The human striatum is essential for both lowand high-level functions and has been implicated in the pathophysiology of various prevalent disorders,including Parkinson's disease(PD)and schizophrenia(SCZ).It is known to consist of structurally and functionally divergent subdivisions.However,previous parcellations are based on a single neuroimaging modality,leaving the extent of the multi-modal organization of the striatum unknown.Here,we investigated the organization of the striatum across three modalities—resting-state functional connectivity,probabilistic diffusion tractography,and structural covariance—to provide a holistic convergent view of its structure and function.We found convergent clusters in the dorsal,dorsolateral,rostral,ventral,and caudal striatum.Functional characterization revealed the anterior striatum to be mainly associated with cognitive and emotional functions,while the caudal striatum was related to action execution.Interestingly,significant structural atrophy in the rostral and ventral striatum was common to both PD and SCZ,but atrophy in the dorsolateral striatum was specifically attributable to PD.Our study revealed a cross-modal convergent organization of the striatum,representing a fundamental topographical model that can be useful for investigating structural and functional variability in aging and in clinical conditions.展开更多
Neuroimaging techniques such as magnetic resonance imaging(MRI)and positron emission tomography provide unique in vivo data to analyze structural and functional connectivity of the whole brain.Recent advances in small...Neuroimaging techniques such as magnetic resonance imaging(MRI)and positron emission tomography provide unique in vivo data to analyze structural and functional connectivity of the whole brain.Recent advances in small animal neuroimaging have opened new opportunities for the study of structure-function interactions in healthy and diseased brain networks,which are essential to develop therapies targeting network reorganization associated with functional improvement.展开更多
Neuropeptide and chemokine receptors of the G protein-coupled receptor (GPCR) family belong to different classes and subgroups providing different docking sites and special binding behavior at extracellular and also t...Neuropeptide and chemokine receptors of the G protein-coupled receptor (GPCR) family belong to different classes and subgroups providing different docking sites and special binding behavior at extracellular and also transmembrane domains for small molecules potentially suitable for positron emission tomography (PET). The contribution gives an overview updating developments of small-molecule, nonpeptide ligands at a selection of peptide and chemokine receptors, expressed in neurons and microglia of the brain, regarding the last five years. Orexin 1 and orexin 2 receptors (OX1R;OX2R) and neuropeptide Y1 and Y2 receptors (NPY1R, NPY2R) were chosen as representatives of Class A neuropeptide receptors, chemokine receptor CX3C (CX3CR1) as Class A, protein-activated receptor, highly expressed in activated microglia, and corticotropin releasing factor receptor 1 (CRFR1) as representative Class B1 receptor. Structural differences between binding domains and their endogenous ligands as well as parallel expression in different types of cells and generally low density of these receptors in brain tissue are factors making the search for selective and sensitive ligands more difficult than for classical GPCR receptors. Main progress in ligand development is observed for NPY receptor antagonists and orexin receptor antagonists. For orexin receptors, search for suitable ligands can be supported with modelling approaches, as recently the complete molecular structure of these receptors is available. Small molecules, binding at CRFR1, as for other Class B1 receptor ligands, in PET and investigations of pharmacodynamics revealed rather allosteric binding modes, although, the complete crystal structure of CRFR1 as prototype of Class B1 provides, hitherto, improved possibilities for understanding binding mechanisms. Highly specific as a marker of microglia among?the GPCRs, CX3CR1 is focused as target of PET during inflammation of brain and spinal cord.展开更多
Hemispheric asymmetries can be seen as one of the evolutionary adaptations that allowed the human brain to muster more complex cognitive processes than other primates.In this vein,the study published by Cheng et al.[1...Hemispheric asymmetries can be seen as one of the evolutionary adaptations that allowed the human brain to muster more complex cognitive processes than other primates.In this vein,the study published by Cheng et al.[1]presents a pivotal investigation of both the regional and connectional asymmetries within the inferior parietal lobule(IPL)in human,chimpanzee,and macaque.By investigating 4 sub-divisions of the IPL across the three species,Cheng and colleagues showed that the macroanatomical and connectional architecture of the IPL became more asymmetric throughout the primate lineage.While macaques show little to no structural asymmetries,chimpanzees display a more asymmetric architecture but with both leftward and rightward asymmetries in various connections.In contrast,the human IPL displayed the highest number of asymmetries among the three species with a clear tendency towards more lateralization.This evolutionary trend towards a more lateralized organization of the IPL may have accompanied an improved command of tool-use,stronger forelimb asymmetries,and the increasing complexity of communicative behavior.展开更多
Neurological disorders including neurodegeneration(e.g.,Alzheimer’s disease and Parkinson’s disease)and acute injuries(e.g.,stroke and traumatic brain injury)are the leading cause group of disability-adjusted life y...Neurological disorders including neurodegeneration(e.g.,Alzheimer’s disease and Parkinson’s disease)and acute injuries(e.g.,stroke and traumatic brain injury)are the leading cause group of disability-adjusted life years and the second leading cause group of deaths.Different to other tissues,the adult brain retains only a very limited repair potential.Adult neurogenesis,the lifelong generation of new neurons,declines with age and in degenerative diseases,such as Alzheimer’s disease.Nevertheless,independently of age,the proliferation and migration of endogenous stem cells is stimulated after brain injuries and might be related to recovery processes(Adamczak et al.,2017).The limited number of endogenous stem cells during adulthood is one of the major limitations for an efficient regeneration of the injury affected brain regions.Therefore,the transplantation of neural stem or progenitor cells(NSCs/NPCs)is extensively studied in mouse models and applied in first clinical trials with the aim to replace dysfunctional or lost neural cells and thus to restore brain function.展开更多
Charcoal marketing is the main activity in the Gbegamey district of Cotonou. The aim of the study was to determine the effects of charcoal marketing on the environment and health of the Gbegamey population. A mixed de...Charcoal marketing is the main activity in the Gbegamey district of Cotonou. The aim of the study was to determine the effects of charcoal marketing on the environment and health of the Gbegamey population. A mixed descriptive and evaluative design was adopted. Data were collected using an interview guide, a structured non-participatory observation grid and air quality analysis equipment (PCE RCM 8 air quality detector;Carbon monoxide meter AS 87000A and Anemometer AM 4812) among charcoal traders, food vendors and residents living near charcoal sales outlets, selected by non-probabilistic purposive sampling, and were analysed with reference to national regulatory provisions and WHO recommendations (2022). 57 people, including 26 shopkeepers, were surveyed. Their average age was 45, with extremes of 25 and 65. The effects of charcoal marketing on health and the environment were known to 23 traders, who unfortunately did not adopt any protective measures. Some of the health effects mentioned were rheumatic and cardiovascular diseases. Pollutants (PM1: 96 µg/m3, PM2.5: 161 µg/m3, PM10: 206 µg/m3, CO: 185 mg/m3) were present in the coal-selling environment at Gbegamey. According to the respondents, respiratory diseases (42.31%), rheumatic diseases (30.77%) and cardiovascular diseases (11.54%) affected the traders, while respiratory diseases (51.61%) affected the general population. The marketing of charcoal in the Gbegamey district generates a high concentration of pollutants in the atmosphere. The activity needs to be monitored in order to limit its effects.展开更多
Cement is made by grinding several raw materials. The cement industry contributes to the development of any society. Benin has four cement companies, including Sèkandji. Exposure to cement dust can cause a number...Cement is made by grinding several raw materials. The cement industry contributes to the development of any society. Benin has four cement companies, including Sèkandji. Exposure to cement dust can cause a number of ailments. Cement production also contributes to the emission of greenhouse gases (GHGs), which contribute to global warming. The study aims to assess the effects of cement dust on the environment and on the health of the population of Sekandji. This was a cross-sectional study with descriptive and quantitative aims, conducted from May 21 to June 23, 2024. Data were collected using an interview guide from people living in the vicinity of the cement plant, who gave their informed consent to participate in the study. An observation grid was used to assess the environment. Particulate matter was sampled in the immediate vicinity of the cement plant using an AM-4812 anemometer and an air quality monitor. Sampling was non-probabilistic and purposive. Targets were selected for reliability and accuracy of data collection. Data collection was carried out using Kobo Collect software for data collected with the interview guide. Excel 2013 was used for data analysis, tables and graphs, and Microsoft Word 2013 for data entry. A total of 105 residents were selected in the vicinity of the cement plant. The average age of respondents was 35, with a minimum of 20 and a maximum of 50. The dominant age group was between 30 and 39. Males (70) dominated, with a sex ratio equal to 2. The vast majority of respondents (92.38%) said they had noticed or heard about an increase in health problems since the cement plant was set up. However, 70.48% of respondents claimed to have no information on the effects of cement production on the environment. Few respondents (29.52%) were aware of the effects of cement production on the environment. Respiratory, dermatological and ocular disorders were cited as being linked to cement. PM2.5 and PM10 particles were present in very high proportions in the air. The implementation of a serious industrialization policy that takes urbanization into account will guarantee the health safety of the population.展开更多
In the present paper we address the general problem of selective electrodynamic interactions between DNA and protein,which is motivated by decades of theoretical study and our very recent experimental findings providi...In the present paper we address the general problem of selective electrodynamic interactions between DNA and protein,which is motivated by decades of theoretical study and our very recent experimental findings providing a first evidence for their activation.Inspired by the Davydov and Holstein-Fröhlich models describing electron motion along biomolecules,and using a model Hamiltonian written in second quantization,the timedependent variational principle is used to derive the dynamical equations of the system.We demonstrate the efficacy of this second-quantized model for a well-documented biochemical system consisting of a restriction enzyme,EcoRI,which binds selectively to a palindromic six-base-pair target within a DNA oligonucleotide sequence to catalyze a DNA doublestrand cleavage.The time-domain Fourier spectra of the electron currents numerically computed for the DNA fragment and for the EcoRI enzyme,respectively,exhibit a cross-correlation spectrum with a sharp co-resonance peak.When the target DNA recognition sequence is randomized,this sharp co-resonance peak is replaced with a broad and noisy spectrum.Such a sequence-dependent charge transfer phenomenology is suggestive of a potentially rich variety of selective electrodynamic interactions influencing the coordinated activity of DNA substrates,enzymes,transcription factors,ligands,and other proteins under realistic biochemical conditions characterized by electron-phonon excitations.展开更多
Dear Editor,Adeno-associated virus(AAV)is one of the most powerful vectors for exogenous gene delivery.1 However,the risks associated with the high dosages of AAV administration that are required to achieve meaningful...Dear Editor,Adeno-associated virus(AAV)is one of the most powerful vectors for exogenous gene delivery.1 However,the risks associated with the high dosages of AAV administration that are required to achieve meaningful effects limit the applicability of this method.Generally,AAV only presents cell autonomous manner in infected cells.Besides,mosaic genetic editing or gene therapy would trigger global biological function restore by above 30–40%infective ratio in heart diseases.展开更多
In a recent study published in Nature,Lynch et al.1 reported a consistent spatial expansion of the resting state salience network in subjects with major depression.The expansion was already present in children who lat...In a recent study published in Nature,Lynch et al.1 reported a consistent spatial expansion of the resting state salience network in subjects with major depression.The expansion was already present in children who later developed depression and remained stable over time in patients with depression,indicating a trait-like behavior of the observed endophenotype.展开更多
基金funded by the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation):project ID 431549029-SFB 1451the Marga-und-Walter-Boll-Stiftung(#210-10-15)(to MAR)a stipend from the'Gerok Program'(Faculty of Medicine,University of Cologne,Germany)。
文摘Noninvasive brain stimulation techniques offer promising therapeutic and regenerative prospects in neurological diseases by modulating brain activity and improving cognitive and motor functions.Given the paucity of knowledge about the underlying modes of action and optimal treatment modalities,a thorough translational investigation of noninvasive brain stimulation in preclinical animal models is urgently needed.Thus,we reviewed the current literature on the mechanistic underpinnings of noninvasive brain stimulation in models of central nervous system impairment,with a particular emphasis on traumatic brain injury and stroke.Due to the lack of translational models in most noninvasive brain stimulation techniques proposed,we found this review to the most relevant techniques used in humans,i.e.,transcranial magnetic stimulation and transcranial direct current stimulation.We searched the literature in Pub Med,encompassing the MEDLINE and PMC databases,for studies published between January 1,2020 and September 30,2024.Thirty-five studies were eligible.Transcranial magnetic stimulation and transcranial direct current stimulation demonstrated distinct strengths in augmenting rehabilitation post-stroke and traumatic brain injury,with emerging mechanistic evidence.Overall,we identified neuronal,inflammatory,microvascular,and apoptotic pathways highlighted in the literature.This review also highlights a lack of translational surrogate parameters to bridge the gap between preclinical findings and their clinical translation.
文摘Stroke is the second leading cause of death worldwide with about 50% of survivors being chronically disabled(Donkor,2018).The behavioral improvement seen in stroke patients in the first weeks after a stroke is contributed by behavioral compensation, reorganization in somatotopic maps and activity in peri-infarct but also distant regions which are connected to the stroke area as supported by animal studies.
文摘Hypothalamic receptors for neuropeptide Y, melaninconcentrating hormone, melanocortins and orexins/ hypocretins as well as for the downstream signaling corticotrophic factor have been discussed broadly for their influence on food intake and reward but also on several psychiatric disorders. For the development of non-peptide ligands for the in vivo detection of alterations in density and affinity of such G-protein coupled (GPCRs) peptide receptors the requirements to affinity and pharmacokinetics have been shifted to thresholds markedly distict from classical GPCRs to dissociation constants ported originally as potential therapeutics in the treatment of obesity among which some are suitable candidates for labeling as PET or SPECT-tracers providing receptor affinities even below 0.1 nM. These could be unique tools not only for better understanding of the mechanism of obesity but also for investigations of extrahypothalamic role of “feeding receptors” at the interface between neuroendocrine and mental diseases.
文摘Pituitary adenylate cyclase activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) have been known for decades to mediate neuroendocrine and vasodilative actions via G-protein-coupled receptors of Class B. These are targets of imaging probes for positron emission tomography (PET) or single photon emission tomography (SPECT) in tumor diagnostics and tumor grading. However, they play only a subordinate role in the development of tracers for brain imaging. Difficulties in development of non-peptide ligands typical for cerebral receptors of PACAP and VIP are shared by all members of Class B receptor family. Essential landmarks have been confirmed for understanding of structural details of Class B receptor molecular signalling during the last five years. High relevance in the explanation of problems in ligand development for these receptors is admitted to the large N-terminal?ectodomain markedly different from Class A receptor binding sites and poorly suitable as orthosteric binding sites for the most small-molecule compounds. The present study is focused on the recently available receptor ligands for PAC1, VPAC1 and VPAC2 receptors as well as potential small-molecule lead structures suitable for use in PET or SPECT. Recently, biaryl, cyanothiophene and pentanamide structures with affinities in nM-range have been proposed as non-peptide ligands at VPAC1 and VPAC2 receptors. However, most of these ligands have been classified as non-competitive related to the orthosteric binding site of endogenous peptide ligands of VPAC receptors. For PAC1 receptors have been identified hydrazide compounds for which an inhibitory and potentially competitive mechanism of receptor binding has been postulated based on molecular docking studies.
文摘Neuropeptide receptors of the brain and spinal cord are parts of the pain circuits targeted by analgesic drugs. Some of these receptors have been found in the central nervous system as well as in intracranial vascular structures and achieved revival of attention because of their role in acute and chronic pain syndromes. A number of them are of high clinical relevance for e.g. migraine. Others participate in symptoms of rare diseases like amyotrophic lateral sclerosis. Here we will focus on five of the neuropeptide receptors and their non-peptide ligands potentially or already successfully used as PET probes. Opioid receptors and neurotensin receptors are known to mediate analgesic actions. Bradykinin and calcitonin gene-related peptide (CGRP) receptors are known to be involved in the regulation of vascular tone and inflammatory responses, and neurokinin receptors play a role in the occurrence of pain perception in a rather indirect manner. Most experiences as PET tracers have been gathered with opioid receptor ligands and neurokinin receptor ligands. The most innovative fields revealed by the studies summarized in this report are the ligands of κ opioid receptors and CGRP receptors for which a first PET tracer was presented recently.
基金supported by the National Natural Science Foundation of China (Grant Nos.12002404 and 52171329)the Key-Area Research and Development Program of Guangdong Province (Grant Nos.2020B1111010002 and 2020B1111010004)+1 种基金the Natural Science Foundation of Guangdong Province of China (Grant No.2022A1515012084)the Fundamental Research Funds for the Central Universities,Sun Yat-sen University.
基金This work was supported by the Deutsche Forschungsgemeinschaft(GE 2835/1-1,El 816/4-1)the Helmholtz Portfolio Theme 4 Supercomputing and Modelling for the Human Brain'and the European Union's Horizon 2020 Research and Innovation Programme under Grant Agreement No.785907(HBP SGA2)We gratefully acknowledge financial support from the China Scholarship Council(201606750003).
文摘The human striatum is essential for both lowand high-level functions and has been implicated in the pathophysiology of various prevalent disorders,including Parkinson's disease(PD)and schizophrenia(SCZ).It is known to consist of structurally and functionally divergent subdivisions.However,previous parcellations are based on a single neuroimaging modality,leaving the extent of the multi-modal organization of the striatum unknown.Here,we investigated the organization of the striatum across three modalities—resting-state functional connectivity,probabilistic diffusion tractography,and structural covariance—to provide a holistic convergent view of its structure and function.We found convergent clusters in the dorsal,dorsolateral,rostral,ventral,and caudal striatum.Functional characterization revealed the anterior striatum to be mainly associated with cognitive and emotional functions,while the caudal striatum was related to action execution.Interestingly,significant structural atrophy in the rostral and ventral striatum was common to both PD and SCZ,but atrophy in the dorsolateral striatum was specifically attributable to PD.Our study revealed a cross-modal convergent organization of the striatum,representing a fundamental topographical model that can be useful for investigating structural and functional variability in aging and in clinical conditions.
基金financial support by the Friebe Foundation:project ID T0498/28960/16the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation):project ID 431549029-SFB 1451.
文摘Neuroimaging techniques such as magnetic resonance imaging(MRI)and positron emission tomography provide unique in vivo data to analyze structural and functional connectivity of the whole brain.Recent advances in small animal neuroimaging have opened new opportunities for the study of structure-function interactions in healthy and diseased brain networks,which are essential to develop therapies targeting network reorganization associated with functional improvement.
文摘Neuropeptide and chemokine receptors of the G protein-coupled receptor (GPCR) family belong to different classes and subgroups providing different docking sites and special binding behavior at extracellular and also transmembrane domains for small molecules potentially suitable for positron emission tomography (PET). The contribution gives an overview updating developments of small-molecule, nonpeptide ligands at a selection of peptide and chemokine receptors, expressed in neurons and microglia of the brain, regarding the last five years. Orexin 1 and orexin 2 receptors (OX1R;OX2R) and neuropeptide Y1 and Y2 receptors (NPY1R, NPY2R) were chosen as representatives of Class A neuropeptide receptors, chemokine receptor CX3C (CX3CR1) as Class A, protein-activated receptor, highly expressed in activated microglia, and corticotropin releasing factor receptor 1 (CRFR1) as representative Class B1 receptor. Structural differences between binding domains and their endogenous ligands as well as parallel expression in different types of cells and generally low density of these receptors in brain tissue are factors making the search for selective and sensitive ligands more difficult than for classical GPCR receptors. Main progress in ligand development is observed for NPY receptor antagonists and orexin receptor antagonists. For orexin receptors, search for suitable ligands can be supported with modelling approaches, as recently the complete molecular structure of these receptors is available. Small molecules, binding at CRFR1, as for other Class B1 receptor ligands, in PET and investigations of pharmacodynamics revealed rather allosteric binding modes, although, the complete crystal structure of CRFR1 as prototype of Class B1 provides, hitherto, improved possibilities for understanding binding mechanisms. Highly specific as a marker of microglia among?the GPCRs, CX3CR1 is focused as target of PET during inflammation of brain and spinal cord.
文摘Hemispheric asymmetries can be seen as one of the evolutionary adaptations that allowed the human brain to muster more complex cognitive processes than other primates.In this vein,the study published by Cheng et al.[1]presents a pivotal investigation of both the regional and connectional asymmetries within the inferior parietal lobule(IPL)in human,chimpanzee,and macaque.By investigating 4 sub-divisions of the IPL across the three species,Cheng and colleagues showed that the macroanatomical and connectional architecture of the IPL became more asymmetric throughout the primate lineage.While macaques show little to no structural asymmetries,chimpanzees display a more asymmetric architecture but with both leftward and rightward asymmetries in various connections.In contrast,the human IPL displayed the highest number of asymmetries among the three species with a clear tendency towards more lateralization.This evolutionary trend towards a more lateralized organization of the IPL may have accompanied an improved command of tool-use,stronger forelimb asymmetries,and the increasing complexity of communicative behavior.
基金supported by German Research Foundation DFG(AS-464/1-1)
文摘Neurological disorders including neurodegeneration(e.g.,Alzheimer’s disease and Parkinson’s disease)and acute injuries(e.g.,stroke and traumatic brain injury)are the leading cause group of disability-adjusted life years and the second leading cause group of deaths.Different to other tissues,the adult brain retains only a very limited repair potential.Adult neurogenesis,the lifelong generation of new neurons,declines with age and in degenerative diseases,such as Alzheimer’s disease.Nevertheless,independently of age,the proliferation and migration of endogenous stem cells is stimulated after brain injuries and might be related to recovery processes(Adamczak et al.,2017).The limited number of endogenous stem cells during adulthood is one of the major limitations for an efficient regeneration of the injury affected brain regions.Therefore,the transplantation of neural stem or progenitor cells(NSCs/NPCs)is extensively studied in mouse models and applied in first clinical trials with the aim to replace dysfunctional or lost neural cells and thus to restore brain function.
文摘Charcoal marketing is the main activity in the Gbegamey district of Cotonou. The aim of the study was to determine the effects of charcoal marketing on the environment and health of the Gbegamey population. A mixed descriptive and evaluative design was adopted. Data were collected using an interview guide, a structured non-participatory observation grid and air quality analysis equipment (PCE RCM 8 air quality detector;Carbon monoxide meter AS 87000A and Anemometer AM 4812) among charcoal traders, food vendors and residents living near charcoal sales outlets, selected by non-probabilistic purposive sampling, and were analysed with reference to national regulatory provisions and WHO recommendations (2022). 57 people, including 26 shopkeepers, were surveyed. Their average age was 45, with extremes of 25 and 65. The effects of charcoal marketing on health and the environment were known to 23 traders, who unfortunately did not adopt any protective measures. Some of the health effects mentioned were rheumatic and cardiovascular diseases. Pollutants (PM1: 96 µg/m3, PM2.5: 161 µg/m3, PM10: 206 µg/m3, CO: 185 mg/m3) were present in the coal-selling environment at Gbegamey. According to the respondents, respiratory diseases (42.31%), rheumatic diseases (30.77%) and cardiovascular diseases (11.54%) affected the traders, while respiratory diseases (51.61%) affected the general population. The marketing of charcoal in the Gbegamey district generates a high concentration of pollutants in the atmosphere. The activity needs to be monitored in order to limit its effects.
文摘Cement is made by grinding several raw materials. The cement industry contributes to the development of any society. Benin has four cement companies, including Sèkandji. Exposure to cement dust can cause a number of ailments. Cement production also contributes to the emission of greenhouse gases (GHGs), which contribute to global warming. The study aims to assess the effects of cement dust on the environment and on the health of the population of Sekandji. This was a cross-sectional study with descriptive and quantitative aims, conducted from May 21 to June 23, 2024. Data were collected using an interview guide from people living in the vicinity of the cement plant, who gave their informed consent to participate in the study. An observation grid was used to assess the environment. Particulate matter was sampled in the immediate vicinity of the cement plant using an AM-4812 anemometer and an air quality monitor. Sampling was non-probabilistic and purposive. Targets were selected for reliability and accuracy of data collection. Data collection was carried out using Kobo Collect software for data collected with the interview guide. Excel 2013 was used for data analysis, tables and graphs, and Microsoft Word 2013 for data entry. A total of 105 residents were selected in the vicinity of the cement plant. The average age of respondents was 35, with a minimum of 20 and a maximum of 50. The dominant age group was between 30 and 39. Males (70) dominated, with a sex ratio equal to 2. The vast majority of respondents (92.38%) said they had noticed or heard about an increase in health problems since the cement plant was set up. However, 70.48% of respondents claimed to have no information on the effects of cement production on the environment. Few respondents (29.52%) were aware of the effects of cement production on the environment. Respiratory, dermatological and ocular disorders were cited as being linked to cement. PM2.5 and PM10 particles were present in very high proportions in the air. The implementation of a serious industrialization policy that takes urbanization into account will guarantee the health safety of the population.
文摘In the present paper we address the general problem of selective electrodynamic interactions between DNA and protein,which is motivated by decades of theoretical study and our very recent experimental findings providing a first evidence for their activation.Inspired by the Davydov and Holstein-Fröhlich models describing electron motion along biomolecules,and using a model Hamiltonian written in second quantization,the timedependent variational principle is used to derive the dynamical equations of the system.We demonstrate the efficacy of this second-quantized model for a well-documented biochemical system consisting of a restriction enzyme,EcoRI,which binds selectively to a palindromic six-base-pair target within a DNA oligonucleotide sequence to catalyze a DNA doublestrand cleavage.The time-domain Fourier spectra of the electron currents numerically computed for the DNA fragment and for the EcoRI enzyme,respectively,exhibit a cross-correlation spectrum with a sharp co-resonance peak.When the target DNA recognition sequence is randomized,this sharp co-resonance peak is replaced with a broad and noisy spectrum.Such a sequence-dependent charge transfer phenomenology is suggestive of a potentially rich variety of selective electrodynamic interactions influencing the coordinated activity of DNA substrates,enzymes,transcription factors,ligands,and other proteins under realistic biochemical conditions characterized by electron-phonon excitations.
基金This work was supported by the National Natural Science Foundation of China(81741025 and 81700360)Technology Project of Sichuan Province of China(2020YFS0102).
文摘Dear Editor,Adeno-associated virus(AAV)is one of the most powerful vectors for exogenous gene delivery.1 However,the risks associated with the high dosages of AAV administration that are required to achieve meaningful effects limit the applicability of this method.Generally,AAV only presents cell autonomous manner in infected cells.Besides,mosaic genetic editing or gene therapy would trigger global biological function restore by above 30–40%infective ratio in heart diseases.
基金supported by the Ministry for Culture and Research NRW(Kooperationsplattformen 2022)supported by the Federal Ministry of Education and Research(BMBF)and the Max Planck Society(MPG).
文摘In a recent study published in Nature,Lynch et al.1 reported a consistent spatial expansion of the resting state salience network in subjects with major depression.The expansion was already present in children who later developed depression and remained stable over time in patients with depression,indicating a trait-like behavior of the observed endophenotype.
