Exploring cerebral structural and functional abnormalities in a mouse model of post-traumatic headache induced by mild traumatic brain injury

Mild traumatic brain injury(mTBI)-induced post-traumatic headache(PTH)is a pressing public health concern and leading cause of disability worldwide.Although PTH is often accompanied by neurological disorders,the exact underlying mechanism remains largely unknown.Identifying potential biomarkers may prompt the diagnosis and development of effective treatments for mTBI-induced PTH.In this study,a mouse model of mTBI-induced PTH was established to investigate its effects on cerebral structure and function during short-term recovery.Results indicated that mice with mTBI-induced PTH exhibited balance deficits during the early post-injury stage.Metabolic kinetics revealed that variations in neurotransmitters were most prominent in the cerebellum,temporal lobe/cortex,and hippocampal regions during the early stages of PTH.Additionally,variations in brain functional activities and connectivity were further detected in the early stage of PTH,particularly in the cerebellum and temporal cortex,suggesting that these regions play central roles in the mechanism underlying PTH.Moreover,our results suggested that GABA and glutamate may serve as potential diagnostic or prognostic biomarkers for PTH.Future studies should explore the specific neural circuits involved in the regulation of PTH by the cerebellum and temporal cortex,with these two regions potentially utilized as targets for non-invasive stimulation in future clinical treatment.

Brain structural plasticity in rats subjected to early binocular enucleation characterized by high resolution anatomical magnetic resonance imaging and diffusion tensor imaging

Visual deprivation leads to structural neuroplasticity in the blind subjects,including gray matter(GM)and white matter(WM)atrophy and alterations in structural connectivity.The rat model of binocular enucleation(BE)is a frequently used animal model for studying brain plasticity induced by early blindness.Yet few neuroimaging studies have been performed on this model to investigate whether or not the BE rats have image phenotypes similar to or comparable to,those observed in the early blind subjects.The current study aimed to assess brain structural plasticity in BE rats using anatomical magnetic resonance imaging(MRI)and diffusion tensor imaging(DTI).The results demonstrated that early BE at postnatal day 4(P4)caused almost complete degeneration of optic nerve(ON)and optic chiasma(OCH),atrophy in a number of visual and non-visual structures,including optic tract(OT),dorsal lateral geniculate nucleus(DLG)and corpus callosum(CC).The BE rats also exhibited impairments of WM microstructural integrity in the OT,and reduction of structural connectivity between the normal-appearing visual cortex(VC)and somatosensory/motor cortices at 4 months of age,likely as manifestations of deafferentationinduced maldevelopment.The structural neuroplasticity in BE rats observable to structural MRI parallels largely with what has been reported in blind subjects,suggesting that longitudinal neuroimaging studies on animal models of sensory deprivation can provide insights into how the brain changes its wiring and function during development/adaption in response to the lack of sensory stimuli.

Evaluation of injuries caused by coronavirus disease 2019 using multi-nuclei magnetic resonance imaging

The ongoing pandemic of coronavirus disease 2019(COVID-19)has been a great burden for the healthcare system in many countries because of its high transmissibility,severity,and fatality.Chest radiography and computed tomography(CT)play a vital role in the diagnosis,detection of complications,and prognostication of COVID-19.Additionally,magnetic resonance imaging(MRI),especially multi-nuclei MRI,is another important imaging technique for disease diagnosis because of its good soft tissue contrast and the ability to conduct structural and functional imaging,which has also been used to evaluate COVID-19-related organ injuries in previous studies.Herein,we briefly reviewed the recent research on multi-nuclei MRI for evaluating injuries caused by COVID-19 and the clinical 1 H MRI techniques and their applications for assessing injuries in lungs,brain,and heart.Moreover,the emerging hyperpolarized 129Xe gas MRI and its applications in the evaluation of pulmonary structures and functional abnormalities caused by COVID-19 were also reviewed.

Overexpression of Sirt6 ameliorates sleep deprivation induced-cognitive impairment by modulating glutamatergic neuron function

Sleep benefits the restoration of energy metabolism and thereby suppo rts neuronal plasticity and cognitive behaviors.Sirt6 is a NAD+-dependent protein deacetylase that has been recognized as an essential regulator of energy metabolism because it modulates various transcriptional regulators and metabolic enzymes.The aim of this study was to investigate the influence of Sirt6 on cerebral function after chronic sleep deprivation(CSD).We assigned C57BL/6J mice to control or two CSD groups and subjected them to AAV2/9-CMV-EGFP or AAV2/9-CMV-Sirt6-EGFP infection in the prelimbic cortex(PrL).We then assessed cerebral functional connectivity(FC) using resting-state functional MRI,neuron/astrocyte metabolism using a metabolic kinetics analysis;dendritic spine densities using sparse-labeling;and miniature excitato ry postsynaptic currents(mEPSCs) and action potential(AP) firing rates using whole-cell patchclamp recordings.In addition,we evaluated cognition via a comprehensive set of behavioral tests.Compared with controls,Sirt6 was significantly decreased(P<0.05) in the PrL after CSD,accompanied by cognitive deficits and decreased FC between the PrL and accumbens nucleus,piriform cortex,motor co rtex,somatosensory co rtex,olfactory tubercle,insular cortex,and cerebellum.Sirt6 ove rexpression reve rsed CSD-induced cognitive impairment and reduced FC.Our analysis of metabolic kinetics using [1-13C] glucose and [2-13C] acetate showed that CSD reduced neuronal Glu4and GABA2synthesis,which could be fully restored via forced Sirt6 expression.Furthermore,Sirt6 ove rexpression reversed CSD-induced decreases in AP firing rates as well as the frequency and amplitude of mEPSCs in PrL pyramidal neurons.These data indicate that Sirt6 can improve cognitive impairment after CSD by regulating the PrL-associated FC network,neuronal glucose metabolism,and glutamatergic neurotransmission.Thus,Sirt6 activation may have potential as a novel strategy for treating sleep disorder-related diseases.

Acute effect of twice-daily 15 mA transcranial alternating current stimulation on treatment-resistant depression: a case series study

Totheeditor:Major depressive disorder(MDD)is a principal cause of disability worldwide and is often associated with high morbidity and mortality rates.Although there are several therapies available for the treatment of depression,about one-third of patients with MMD will not respond to two or more antidepressant drugs with different mechanisms;the patients are then referred to as having treatment-resistant depression(TRD).Patients with TRD have a poorer quality of life,greater economic burden and increased suicidal behaviours.Therefore,new antidepressant treatments that are effective,safe,long-lasting and tolerable are needed.Ketamine infusion,intranasal esketamine and transcranial magnetic stimulation(TMS)have been used to treat early stage TRD.’A recent review suggests that electroconvulsive therapy(ECT)may be superior to ketamine for reducing depression severity in the acute treatment of TRD.

An integrated microfluidics platform with high-throughput single-cell cloning array and concentration gradient generator for efficient cancer drug effect screening

Background:Tumor cell heterogeneity mediated drug resistance has been recognized as the stumbling block of cancer treatment.Elucidating the cytotoxicity of anticancer drugs at single-cell level in a high-throughput way is thus of great value for developing precision therapy.However,current techniques suffer from limitations in dynamically characterizing the responses of thousands of single cells or cell clones presented to multiple drug conditions.Methods:We developed a new microfluidics-based“SMART”platform that is Simple to operate,able to generate a Massive single-cell array and Multiplex drug concentrations,capable of keeping cells Alive,Retainable and Trackable in the microchambers.These features are achieved by integrating a Microfluidic chamber Array(4320 units)and a sixConcentration gradient generator(MAC),which enables highly efficient analysis of leukemia drug effects on single cells and cell clones in a high-throughput way.Results:A simple procedure produces 6 on-chip drug gradients to treat more than 3000 single cells or single-cell derived clones and thus allows an efficient and precise analysis of cell heterogeneity.The statistic results reveal that Imatinib(Ima)and Resveratrol(Res)combination treatment on single cells or clones is much more efficient than Ima or Res single drug treatment,indicated by the markedly reduced half maximal inhibitory concentration(IC50).Additionally,single-cell derived clones demonstrate a higher IC_(50) in each drug treatment compared to single cells.Moreover,primary cells isolated from two leukemia patients are also found with apparent heterogeneity upon drug treatment on MAC.Conclusions:This microfluidics-based“SMART”platform allows high-throughput single-cell capture and culture,dynamic drug-gradient treatment and cell response monitoring,which represents a new approach to efficiently investigate anticancer drug effects and should benefit drug discovery for leukemia and other cancers.

Engineered AAV13 variants with enhanced transduction and confined spread

Precise targeting of specific regions within the central nervous system(CNS)is crucial for both scientific research and gene therapy in the context of brain diseases.Adeno-associated virus 13(AAV13)is known for its restricted diffusion range within the CNS,making it an ideal choice for precise labeling and administration within small brain regions.However,AAV13 mediates relatively low expression of target genes.Here,we introduced specifically engineered modifications to the AAV13 capsid protein to enhance its transduction efficiency.We first constructed AAV13-YF by mutating tyrosine to phenylalanine on the surface of the AAV13 capsid.We then inserted the 7m8 peptide,known to enhance cell transduction,into positions 587/588 and 585/586 of the AAV13 capsid,resulting in two distinct variants named AAV13-587-7m8 and AAV13-585-7m8,respectively.We found that AAV13-YF exhibited superior in vitro infectivity in HEK293T cells compared to AAV13,while AAV13-587-7m8 and AAV13-585-7m8 showed enhanced CNS infection capabilities in C57BL/6 mice,with AAV13-587-7m8 infection retaining a limited spread range.These modified AAV13 variants hold promising potential for applications in gene therapy and neuroscience research.

Ingenious liquid-observed vapor exchange (LOVE) NMR method revealing how sugars protect dry protein structure

Recently,Gary et al.published an article elucidating how sugars contribute to the protection of dry protein structure.They utilized an ingenious liquid-observed vapor exchange(LOVE)nuclear magnetic resonance(NMR)method,providing valuable insights into the protection mechanism of sugars during the drying process.The details of their study can be found in the article available at https://doi.org/10.1021/acs.biochem.2c00692.

MODEL SELECTION METHOD BASED ON MAXIMAL INFORMATION COEFFICIENT OF RESIDUALS

The traditional model selection criterions try to make a balance between fitted error and model complexity. Assumptions on the distribution of the response or the noise, which may be misspecified, should be made before using the traditional ones. In this ar- ticle, we give a new model selection criterion, based on the assumption that noise term in the model is independent with explanatory variables, of minimizing the association strength between regression residuals and the response, with fewer assumptions. Maximal Information Coe^cient （MIC）, a recently proposed dependence measure, captures a wide range of associ- ations, and gives almost the same score to different type of relationships with equal noise, so MIC is used to measure the association strength. Furthermore, partial maximal information coefficient （PMIC） is introduced to capture the association between two variables removing a third controlling random variable. In addition, the definition of general partial relationship is given.

Modulation of Gut Microbiota in Pathological States

The human microbiota is an aggregate of microorganisms residing in the human body, mostly in the gastrointestinal tract （GIT）. Our gut microbiota evolves with us and plays a pivotal role in human health and disease. In recent years, the microbiota has gained increasing attention due to its impact on host metabolism, physiology, and immune system development, but also because the perturbation of the microbiota may result in a number of diseases. The gut microbiota may be linked to malignancies such as gastric cancer and colorectal cancer. It may also be linked to disorders such as nonalcoholic fatty liver disease （NAFLD）; obesity and diabetes, which are characterized as ＂lifestyle diseases＂ of the industrial- ized world; coronary heart disease; and neurological disorders. Although the revolution in molecular technologies has provided us with the necessary tools to study the gut microbiota more accurately, we need to elucidate the relationships between the gut microbiota and several human pathologies more precisely, as understanding the impact that the microbiota plays in various diseases is fundamental for the development of novel therapeutic strategies. Therefore, the aim of this review is to provide the read- er with an updated overview of the importance of the gut microbiota for human health and the poten- tial to manipulate gut microbial composition for purposes such as the treatment of antibiotic-resistant Clostridium difficile （C difficile） infections. The concept of altering the gut community by microbial intervention in an effort to improve health is currently in its infancy. However, the therapeutic implications appear to be very great. Thus, the removal of harmful organisms and the enrichment of beneficial mi- crobes may protect our health, and such efforts will pave the way for the development of more rational treatment options in the future.

NMR assignments and characterization of the DNA-binding domain of Arabidopsis transcription factor WRKY11--Dedicated to Professor Xiuwen Han on the occasion of her 80th birthday

The WRKY proteins are a family of plant-specific transcription factors(TFs)that are widely involved in plant development and anti-stress responses.Arabidopsis WRKY11(AtWRKY11)functions in regulating plant defense against abiotic stress and belongs to the Ild subgroup of WRKY TFs.We herein report the expres sion,purification and preliminary structural characterization of AtWRKY11 DNA-binding domain(DBD)using solution NMR Almost complete backbone chemical shift assignments of AtWRKY11-DBD have been ob-tained.Chemical shift-based secondary structure analysis suggests that AtWRKY11-DBD may exhibit local conformational diferences from the X-ray structure of the C-terminal WRKY domain of AtWRKY1,particularly in the β1 and β5 strands.Our current study provides the basis for further structural and interactional studies.

Covalent organic framework shows high isobutene adsorption selectivity from C_(4) hydrocarbons:Mechanism of interpenetration isomerism and pedal motion

Adsorption and separation of C_(4) hydrocarbons are crucial steps in petrochemical processes.Employment of porous materials for enhancing the separation efficiency have paid much attention.Covalent-organic frameworks of diamond-topology,dia-COFs,often exhibit unique structural properties such as interpenetration isomerism and pedal motion.Herein,in order to get a deep insight into the structure-performance correlation of such dia-COFs,a series of dia-COF materials have been proposed and theoretically investigated on the C_(4) separation.It is found that these dia-COFs display an excellent adsorption and separation property towards isobutene with respect to other C_(4) hydrocarbons(i.e.,1,3-butadiene,1-butene,2-cis-butene,2-trans-butene,isobutane and n-butane).What’s more,the correlation between the topology parameters and experimental synthesis feasibility has been established for COF-300(dia-cN),and the unreported COF-300(dia-c3) is predicted to be experimentally feasible synthesized.Our findings not only provide a deep insight into the mechanism of topology characteristics of dia-COFs on C_(4) adsorption and separation properties but also guide the design and synthesis of novel highly-effective porous materials.

Balancing sub‐reaction activity to boost electrocatalytic urea synthesis using a metal‐free electrocatalyst

Electrocatalytic urea synthesis via coupling of nitrate with CO_(2)is considered as a promising alternative to the industrial urea synthetic process.However,the requirement of sub-reaction(NO_(3)RR and CO_(2)RR)activities for efficient urea synthesis is not clear and the related reaction mechanisms remain obscure.Here,the construction,breaking,and rebuilding of the sub-reaction activity balance would be accompanied by the corresponding regulation in urea synthesis,and the balance of sub-reaction activities was proven to play a vital role in efficient urea synthesis.With rational design,a urea yield rate of 610.6 mg h−1 gcat.−1 was realized on the N-doped carbon electrocatalyst,superior to that of noble-metal electrocatalysts.Based on the operando SRFTIR measurements,we proposed that urea synthesis arises from the coupling of^(*)NO and^(*)CO to generate the key intermediate of^(*)OCNO.This work provides new insights and guidelines into urea synthesis from the aspect of activity balance.

Targeted Catalytic Cracking to Olefins(TCO):Reaction Mechanism,Production Scheme,and Process Perspectives

Light olefins are important organic building blocks in the chemicals industry.The main low-carbon olefin production methods,such as catalytic cracking and steam cracking,have considerable room for improvement in their utilization of hydrocarbons.This review provides a thorough overview of recent studies on catalytic cracking,steam cracking,and the conversion of crude oil processes.To maximize the production of light olefins and reduce carbon emissions,the perceived benefits of various technologies are examined.Taking olefin generation and conversion as a link to expand upstream and downstream processes,a targeted catalytic cracking to olefins(TCO)process is proposed to meet current demands for the transformation of oil refining into chemical production.The main innovations of this process include a multiple feedstock supply,the development of medium-sized catalysts,and a diameter-transformed fluidizedbed reactor with different feeding schemes.In combination with other chemical processes,TCO is expected to play a critical role in enabling petroleum refining and chemical processes to achieve low carbon dioxide emissions.

Co-localization of two-color rAAV2-retro confirms the dispersion characteristics of efferent projections of mitral cells in mouse accessory olfactory bulb

The accessory olfactory bulb(AOB), located at the posterior dorsal aspect of the main olfactory bulb(MOB), is the first brain relay of the accessory olfactory system(AOS), which can parallelly detect and process volatile and nonvolatile social chemosignals and mediate different sexual and social behaviors with the main olfactory system(MOS). However, due to its anatomical location and absence of specific markers, there is a lack of research on the internal and external neural circuits of the AOB. This issue was addressed by singlecolor labeling and fluorescent double labeling using retrograde rAAVs injected into the bed nucleus of the stria terminalis(BST), anterior cortical amygdalar area(ACo), medial amygdaloid nucleus(MeA), and posteromedial cortical amygdaloid area(PMCo) in mice. We demonstrated the effectiveness of this AOB projection neuron labeling method and showed that the mitral cells of the AOB exhibited efferent projection dispersion characteristics similar to those of the MOB. Moreover, there were significant differences in the number of neurons projected to different brain regions, which indicated that each mitral cell in the AOB could project to a different number of neurons in different cortices. These results provide a circuitry basis to help understand the mechanism by which pheromone information is encoded and decoded in the AOS.

Brain-wide N2cG compensation permits glycoprotein-deleted rabies virus to trace neural circuits across multiple synapses

Rabies-viruses-based retrograde tracers can spread across multiple synapses in a retrograde direction in the nervous system of rodents and primates,making them powerful tools for determining the structure and function of the complicated neural circuits of the brain.However,they have some limitations,such as posing high risks to human health and the inability to retrograde trans-synaptic label inputs from genetically-de¯ned starter neurons.Here,we established a new retrograde trans-multi-synaptic tracing method through brain-wide rabies virus glycoprotein(RVG)compensation,followed by glycoprotein-deleted rabies virus(RV-△G)infection in specific brain regions.Furthermore,in combination with the avian tumor virus receptor A(TVA)controlled by a cell-type-specific promoter,we found that EnvA-pseudotyped RV-△G can mediate e±cient retrograde trans-multi-synaptic transduction from cell-type-specific starter neurons.This study provides new alternative methods for neuroscience researchers to analyze the input neural networks of rodents and nonhuman primates.

Anatomical Evidence for the Neural Connection from the Emotional Brain to Autonomic Innervation in the Anterior Chamber Structures of the Eye

Objective Previous studies have shown that the autonomic nervous system(ANS),which can be affected by emotions,is important in the occurrence or progression of glaucoma.The autonomic innervation distributed in the anterior chamber(AC)structures might play an efferent role in the neural regulation of intraocular pressure(IOP).This study aimed to investigate the anatomic neural connection from the emotional brain to autonomic innervation in the AC.Methods A retrograde trans-multisynaptic pseudorabies virus encoded with an enhanced green fluorescent protein(PRV531)and non-trans-synaptic tracer FAST Dil were injected into the right eye of mice,respectively.Fluorescent localization in the emotional brain and preganglionic nuclei was studied.Five and a half days after PRV531 injection into the right AC,fluorescent signals were observed in several emotional brain regions,including the amygdala,agranular insular cortex,lateral septal nuclei,periaqueductal gray,and hypothalamus.Autonomic preganglionic nuclei,including Edinger-Westphal nucleus,superior salivatory nucleus,and intermediolateral nucleus,were labeled using PRV531.Results The sensory trigeminal nuclei were not labeled using PRV531.The fluorescence signals in the nuclei mentioned above showed bilateral distribution,primarily on the ipsilateral side.Seven days after injecting FAST Dil into the AC,we observed no FAST Dil-labeled neurons in the central nervous system.Conclusion Our results indicate a neural connection from the emotional brain to autonomic innervation in the AC,which provides anatomical support for the emotional influence of IOP via the ANS.

Adolescent alcohol exposure changes RNA modifications in adult brain by mass spectrometry-based comprehensive profiling analysis

Alcohol consumption is one of the leading causes of death worldwide.Adolescence is a critical period of structural and functional maturation of the brain.Adolescent alcohol use can alter epigenetic modifications.However,little is known on the long-term effects of alcohol consumption during adolescence on RNA epigenetic modifications in brain.Herein,we systematically explored the long-term effects of alcohol exposure during adolescence on small RNA modifications in adult rat brain tissues by comprehensive liquid chromatography-electrospray ionization-tandem mass spectrometry(LC-ESI-MS/MS)analysis.We totally detected 26 modifications in small RNA of brain tissues.Notably,we observed most of these modifications were decreased in brain tissues.These results suggest that alcohol exposure during adolescence may impose a long-lasting impact on RNA modifications in brain tissues.This is the first report that alcohol use during adolescence can alter RNA modifications in adult brain.Collectively,this study suggests a long-term adverse effects of alcohol consumption on brain from RNA epigenetics angle by comprehensive mass spectrometry analysis.

Detection of a temporal salient object benefits from visual stimulus-specific adaptation in avian midbrain inhibitory nucleus

Food and predators are the most noteworthy objects for the basic survival of wild animals,and both are often deviant in both spatial and temporal domains and quickly attract an animal’s attention.Although stimulus-specific adaptation(SSA)is considered a potential neural basis of salient sound detection in the temporal domain,related research on visual SSA is limited and its relationship with temporal saliency is uncertain.The avian nucleus isthmi pars magnocellularis(Imc),which is central to midbrain selective attention network,is an ideal site to investigate the neural correlate of visual SSA and detection of a salient object in the time domain.Here,the constant order paradigm was applied to explore the visual SSA in the Imc of pigeons.The results showed that the firing rates of Imc neurons gradually decrease with repetitions of motion in the same direction,but recover when a motion in a deviant direction is presented,implying visual SSA to the direction of a moving object.Furthermore,enhanced response for an object moving in other directions that were not presented ever in the paradigm is also observed.To verify the neural mechanism underlying these phenomena,we introduced a neural computation model involving a recoverable synaptic change with a“center-surround”pattern to reproduce the visual SSA and temporal saliency for the moving object.These results suggest that the Imc produces visual SSA to motion direction,allowing temporal salient object detection,which may facilitate the detection of the sudden appearance of a predator.

Human islet amyloid polypeptide oligomers stabilized and probed by MAS NMR

The capture and characterization of oligomers are extremely important in the studies of amyloid aggregation of proteins and peptides.Oligomers are critical intermediates that can impact the structures of amyloid fibrils.Moreover,it is widely accepted that oligomers are the most toxic species along the aggregation pathway[1e4].The studies of oligomers are believed to shed light on the molecular mechanism of amyloid fibrillation and probably the medical clues for related diseases.In vitro investigations of amyloid oligomers are challenging due to their transient and polymorphic nature[5].This is particularly evident in the case of human type-2 diabetes-associated islet amyloid polypeptide(hIAPP),which tends to rapidly form polymorphic fibrils within minutes[6].Notably,hIAPP demonstrates a higher propensity for rapid aggregation compared to other amyloid proteins such as a-synuclein[7].