Robust autofocusing propagation in turbulence

Turbulence in complex environments such as the atmosphere and biological media has always been a great challenge to the application of beam propagation in optical communication, optical trapping and manipulation. To overcome this challenge, this study comprehensively investigates the robust propagation of traditional Gaussian and autofocusing beams in turbulent environments. In order to select stable beams that exhibit high intensity and high field gradient at the focal position in complex environments, Kolmogorov turbulence theory is used to simulate the propagation of beams in atmospheric turbulence based on the multi-phase screen method. We systematically analyze the intensity fluctuations, the variation of the coherence factor and the change in the scintillation index with propagation distance. The analysis reveals that the intensity fluctuations of autofocusing beams are significantly smaller than those of Gaussian beams, and the coherence of autofocusing beams is better than that of Gaussian beams under turbulence. Moreover, autofocusing beams exhibit less oscillation than Gaussian beams, indicating that autofocusing beams propagate in complex environments with less distortion and intensity fluctuation. Overall, this work clearly demonstrates that autofocusing beams exhibit higher stability in propagation compared with Gaussian beams, showing great promise for applications such as optical trapping and manipulation in complex environments.

Regulation of specific abnormal calcium signals in the hippocampal CA1 and primary cortex M1 alleviates the progression of temporal lobe epilepsy

Temporal lobe epilepsy is a multifactorial neurological dysfunction syndrome that is refractory,resistant to antiepileptic drugs,and has a high recurrence rate.The pathogenesis of temporal lobe epilepsy is complex and is not fully understood.Intracellular calcium dynamics have been implicated in temporal lobe epilepsy.However,the effect of fluctuating calcium activity in CA1 pyramidal neurons on temporal lobe epilepsy is unknown,and no longitudinal studies have investigated calcium activity in pyramidal neurons in the hippocampal CA1 and primary motor cortex M1 of freely moving mice.In this study,we used a multichannel fiber photometry system to continuously record calcium signals in CA1 and M1 during the temporal lobe epilepsy process.We found that calcium signals varied according to the grade of temporal lobe epilepsy episodes.In particular,cortical spreading depression,which has recently been frequently used to represent the continuously and substantially increased calcium signals,was found to correspond to complex and severe behavioral characteristics of temporal lobe epilepsy ranging from gradeⅡto gradeⅤ.However,vigorous calcium oscillations and highly synchronized calcium signals in CA1 and M1 were strongly related to convulsive motor seizures.Chemogenetic inhibition of pyramidal neurons in CA1 significantly attenuated the amplitudes of the calcium signals corresponding to gradeⅠepisodes.In addition,the latency of cortical spreading depression was prolonged,and the above-mentioned abnormal calcium signals in CA1 and M1 were also significantly reduced.Intriguingly,it was possible to rescue the altered intracellular calcium dynamics.Via simultaneous analysis of calcium signals and epileptic behaviors,we found that the progression of temporal lobe epilepsy was alleviated when specific calcium signals were reduced,and that the end-point behaviors of temporal lobe epilepsy were improved.Our results indicate that the calcium dynamic between CA1 and M1 may reflect specific epileptic behaviors corresponding to different grades.Furthermore,the selective regulation of abnormal calcium signals in CA1 pyramidal neurons appears to effectively alleviate temporal lobe epilepsy,thereby providing a potential molecular mechanism for a new temporal lobe epilepsy diagnosis and treatment strategy.

Metabolic regulation of innate immunity in cancer immunotherapy

Innate immunity,originally recognized as the primary defense mechanism against pathogenic infections,has also been shown to have an important role in anti-tumor immunity.Host cells recognize cytosolic DNA and RNA,which triggers a cascade of signaling events via nucleic-acid sensing receptors,including endosomal Toll-like receptors(TLRs),cytoplasmic cyclic GMP-AMP synthase(cGAS)for double-stranded DNA sensing,and cytoplasmic retinoic acid-inducible gene I(RIG-I)for double-stranded RNA detection.

Allogenic microglia replacement:A novel therapeutic strategy for neurological disorders

Microglia are resident immune cells in the central nervous system(CNS)that play vital roles in CNS development,homeostasis and disease pathogenesis.Genetic defects in microglia lead to microglial dysfunction,which in turn leads to neurological disorders.The correction of the specific genetic defects in microglia in these disorders can lead to therapeutic effects.Traditional genetic defect correction approaches are dependent on viral vectorbased genetic defect corrections.However,the viruses used in these approaches,including adeno-associated viruses,lentiviruses and retroviruses,do not primarily target microglia;therefore,viral vector-based genetic defect corrections are ineffective in microglia.Microglia replacement is a novel approach to correct microglial genetic defects via replacing microglia of genetic defects with allogenic healthy microglia.In this paper,we systematically review the history,rationale and therapeutic perspectives of microglia replacement,which would be a novel strategy for treating CNS disorders.

Harnessing innate immune pathways for therapeutic advancement in cancer

The innate immune pathway is receiving increasing attention in cancer therapy.This pathway is ubiquitous across various cell types,not only in innate immune cells but also in adaptive immune cells,tumor cells,and stromal cells.Agonists targeting the innate immune pathway have shown profound changes in the tumor microenvironment(TME)and improved tumor prognosis in preclinical studies.However,to date,the clinical success of drugs targeting the innate immune pathway remains limited.Interestingly,recent studies have shown that activation of the innate immune pathway can paradoxically promote tumor progression.The uncertainty surrounding the therapeutic effectiveness of targeted drugs for the innate immune pathway is a critical issue that needs immediate investigation.In this review,we observe that the role of the innate immune pathway demonstrates heterogeneity,linked to the tumor development stage,pathway status,and specific cell types.We propose that within the TME,the innate immune pathway exhibits multidimensional diversity.This diversity is fundamentally rooted in cellular heterogeneity and is manifested as a variety of signaling networks.The pro-tumor effect of innate immune pathway activation essentially reflects the suppression of classical pathways and the activation of potential pro-tumor alternative pathways.Refining our understanding of the tumor's innate immune pathway network and employing appropriate targeting strategies can enhance our ability to harness the anti-tumor potential of the innate immune pathway and ultimately bridge the gap from preclinical to clinicalapplication.

Neuronal and synaptic adaptations underlying the benefits of deep brain stimulation for Parkinson’s disease

Deep brain stimulation(DBS)is a well-established and effective treatment for patients with advanced Parkinson’s disease(PD),yet its underlying mechanisms remain enigmatic.Optogenetics,primarily conducted in animal models,provides a unique approach that allows cell type-and projection-specific modulation that mirrors the frequency-dependent stimulus effects of DBS.Opto-DBS research in animal models plays a pivotal role in unraveling the neuronal and synaptic adaptations that contribute to the efficacy of DBS in PD treatment.DBS-induced neuronal responses rely on a complex interplay between the distributions of presynaptic inputs,frequency-dependent synaptic depression,and the intrinsic excitability of postsynaptic neurons.This orchestration leads to conversion of firing patterns,enabling both antidromic and orthodromic modulation of neural circuits.Understanding these mechanisms is vital for decoding position-and programming-dependent effects of DBS.Furthermore,patterned stimulation is emerging as a promising strategy yielding long-lasting therapeutic benefits.Research on the neuronal and synaptic adaptations to DBS may pave the way for the development of more enduring and precise modulation patterns.Advanced technologies,such as adaptive DBS or directional electrodes,can also be integrated for circuit-specific neuromodulation.These insights hold the potential to greatly improve the effectiveness of DBS and advance PD treatment to new levels.

Memory Trace for Fear Extinction:Fragile yet Reinforceable

Fear extinction is a biological process in which learned fear behavior diminishes without anticipated reinforcement,allowing the organism to re-adapt to ever-changing situations.Based on the behavioral hypothesis that extinction is new learning and forms an extinction memory,this new memory is more readily forgettable than the original fear memory.The brain’s cellular and synaptic traces underpinning this inherently fragile yet reinforceable extinction memory remain unclear.Intriguing questions are about the whereabouts of the engram neurons that emerged during extinction learning and how they constitute a dynamically evolving functional construct that works in concert to store and express the extinction memory.In this review,we discuss recent advances in the engram circuits and their neural connectivity plasticity for fear extinction,aiming to establish a conceptual framework for understanding the dynamic competition between fear and extinction memories in adaptive control of conditioned fear responses.

Brainstem opioid peptidergic neurons regulate cough reflexes in mice

Cough is a vital defensive reflex for expelling harmful substances from the airway.The sensory afferents for the cough reflex have been intensively studied.However,the brain mechanisms underlying the cough reflex remain poorly understood.Here,we developed a paradigm to quantitatively measure cough-like reflexes in mice.Using this paradigm,we found that prodynorphin-expressing(Pdyn+)neurons in the nucleus of the solitary tract(NTS)are critical for capsaicin-induced cough-like reflexes.These neurons receive cough-related neural signals from Trpv1+vagal sensory neurons.The activation of Pdyn+NTS neurons triggered respiratory responses resembling cough-like reflexes.Among the divergent projections of Pdyn+NTS neurons,a glutamatergic pathway projecting to the caudal ventral respiratory group(cVRG),the canonical cough center,was necessary and sufficient for capsaicin-induced cough-like reflexes.These results reveal that Pdyn+NTS neurons,as a key neuronal population at the entry point of the vagus nerve to the brainstem,initiate cough-like reflexes in mice.

Non-canonical role of the ATR pathway in axon regeneration as a mechanosensitive brake

DNA damage has been linked to neuropathology.Diverse DNA damage response(DDR)pathways help preserve DNA integrity in the nervous system during both the developmental and mature stages.Mutations of factors in various signaling pathways responsive to different types of DNA damage have been associated with developmental syndromes with neurological symptoms(McKinnon,2009;Araújo and Kuraoka,2019;Khokhlova et al.,2020).

Functional Autapses Form in Striatal Parvalbumin Interneurons but not Medium Spiny Projection Neurons

Autapses selectively form in specific cell types in many brain regions.Previous studies have also found putative autapses in principal spiny projection neurons(SPNs)in the striatum.However,it remains unclear whether these neurons indeed form physiologically functional autapses.We applied whole-cell recording in striatal slices and identified autaptic cells by the occurrence of prolonged asynchronous release(AR)of neurotransmitters after bursts of high-frequency action potentials(APs).Surprisingly,we found no autaptic AR in SPNs,even in the presence of Sr^(2+).However,robust autaptic AR was recorded in parvalbumin(PV)-expressing neurons.The autaptic responses were mediated by GABA_(A) receptors and their strength was dependent on AP frequency and number.Further computer simulations suggest that autapses regulate spiking activity in PV cells by providing self-inhibition and thus shape network oscillations.Together,our results indicate that PV neurons,but not SPNs,form functional autapses,which may play important roles in striatal functions.

The ubiquitin codes in cellular stress responses

Ubiquitination/ubiquitylation,one of the most fundamental post-translational modifications,regulates almost every critical cellular process in eukaryotes.Emerging evidence has shown that essential components of numerous biological processes undergo ubiquitination in mammalian cells upon exposure to diverse stresses,from exogenous factors to cellular reactions,causing a dazzling variety of functional consequences.Various forms of ubiquitin sig-nals generated by ubiquitylation events in specific milieus,known as ubiquitin codes,constitute an intrinsic part of myriad cellular stress responses.These ubiquitination events,leading to proteolytic turnover of the substrates or just switch in functionality,initiate,regulate,or supervise multiple cellular stress-associated responses,supporting adaptation,homeostasis recovery,and survival of the stressed cells.In this review,we attempted to summarize the crucial roles of ubiquitination in response to different environmental and intracellular stresses,while discussing how stresses modulate the ubiquitin system.This review also updates the most recent advances in understanding ubiquitination machinery as well as different stress responses and discusses some important questions that may warrant future investigation.

Myosin Va‑dependent Transport of NMDA Receptors in Hippocampal Neurons

N-methyl-D-aspartate receptor(NMDAR)trafficking is a key process in the regulation of synaptic efficacy and brain function.However,the molecular mechanism underlying the surface transport of NMDARs is largely unknown.Here we identified myosin Va(MyoVa)as the specific motor protein that traffics NMDARs in hippocampal neurons.We found that MyoVa associates with NMDARs through its cargo binding domain.This association was increased during NMDAR surface transport.Knockdown of MyoVa suppressed NMDAR transport.We further demonstrated that Ca^(2+)/calmodulin-dependent protein kinase Ⅱ(CaMKⅡ)regulates NMDAR transport through its direct interaction with MyoVa.Furthermore,MyoVa employed Rab11 family-interacting protein 3(Rab11/FIP3)as the adaptor proteins to couple themselves with NMDARs during their transport.Accordingly,the knockdown of FIP3 impairs hippocampal memory.Together,we conclude that in hippocampal neurons,MyoVa conducts active transport of NMDARs in a CaMKII-dependent manner.

DNA bridging of FOXP3 ladder-like multimer: Unveiling a novel transcriptional regulation paradigm

In the latest issue of Nature,Zhang et al.characterized a novel ladder-like structure of FOXP3-DNA interaction involving FOXP3 multimerization and remote DNA bridging through a combination of biochemistry,structural biology,cell biology,and bioinformatics analyses.1 In this commentary,we highlight their key findings and provide our insights into the research paradigm for further exploration of a novel transcriptional regulation mode as well as a therapeutic strategy from the structural aspects of the FOXP3 complex(Figure 1).

Immunology reshapes neuroscience,and neuroscience reshapes immunology

As a result of evolution,our body has evolved into a sophisticated system in which various tissues and organs cooperate in a highly orchestrated manner.Few tissues or organs operate in isolation.The brain serves as the command center of our body and is relatively isolated from the peripheral system due to the presence of the blood-brain barrier(BBB).This barrier prevents direct and extensive interaction between blood cells,plasma molecules,and brain cells,contributing to the longstanding perception of the brain as an“immune-privileged”area.Consequently,neuroscientists and immunologists historically conducted separate research with minimal overlap between these two disciplines.However,this perspective has undergone reconsideration over the past few decades.

SH2B1 Tunes Hippocampal ERK Signaling to Influence Fluid Intelligence in Humans and Mice

Fluid intelligence is a cognitive domain that encompasses general reasoning, pattern recognition, and problem-solving abilities independent of task-specific experience. Understanding its genetic and neural underpinnings is critical yet challenging for predicting human development, lifelong health, and well-being. One approach to address this challenge is to map the network of correlations between intelligence and other constructs. In the current study, we performed a genome-wide association study using fluid intelligence quotient scores from the UK Biobank to explore the genetic architecture of the associations between obesity risk and fluid intelligence. Our results revealed novel common genetic loci (SH2B1, TUFM, ATP2A1, and FOXO3) underlying the association between fluid intelligence and body metabolism. Surprisingly, we demonstrated that SH2B1 variation influenced fluid intelligence independently of its effects on metabolism but partially mediated its association with bilateral hippocampal volume. Consistently, selective genetic ablation of Sh2b1 in the mouse hippocampus, particularly in inhibitory neurons, but not in excitatory neurons, significantly impaired working memory, short-term novel object recognition memory, and behavioral flexibility, but not spatial learning and memory, mirroring the human intellectual performance. Single-cell genetic profiling of Sh2B1-regulated molecular pathways revealed that Sh2b1 deletion resulted in aberrantly enhanced extracellular signal-regulated kinase (ERK) signaling, whereas pharmacological inhibition of ERK signaling reversed the associated behavioral impairment. Our cross-species study thus provides unprecedented insight into the role of SH2B1 in fluid intelligence and has implications for understanding the genetic and neural underpinnings of lifelong mental health and well-being.

Broadband meta-converters for multiple Laguerre-Gaussian modes

Metasurface provides miniaturized devices for integrated optics.Here,we design and realize a meta-converter to transform a plane-wave beam into multiple Laguerre-Gaussian(LG)modes of different orders at various diffraction angles.The metasurface is fabricated with Au nano-antennas,which vary in length and orientation angle for modulation of both the phase and the amplitude of a scattered wave,on a silica substrate.Our error analysis suggests that the metasurface design is robust over a 400 nm wavelength range.This work presents the manipulation of LG beams through controlling both radial and azimuthal orders,which paves the way in expanding the communication channels by one more dimension(i.e.,radial order)and demultiplexing different modes.

Unlimited source of human microglia inspiring physiopathological and translational studies of the central nervous system

The retinal organoid is a vital model for studying retinal development and related diseases, especially for the human retina(Jin et al., 2019). The retina constitutes an integral part of the central nervous system(CNS) and originates from neuroectodermal cells during organogenesis.

Oocyte TET3: an epigenetic modifier responsible for maternal inheritance of glucose intolerance

In a recent paper published in Nature,Chen et al.provide a new perspective on how glucose tolerance of the offspring is affected by pregestational hyperglycaemia.1 They showed that oocytes isolated from hyperglycemic mice transmit the impaired glucose homeostasis to the offspring via epigenetic modifications,and insufficiency of oocyte TET3 dioxygenase is indispensable for this process.

Novel Microglia-based Therapeutic Approaches to Neurodegenerative Disorders

prominent immune cells in the central nervous system,microglia constantly monitor the environment and provide neuronal protection,which are important functions for maintaining brain homeostasis.In the diseased brain,microglia are crucial mediators of neuroinflammation that regulates a broad spectrum of cellular responses.In this review,we summarize current knowledge on the multifunctional contributions of microglia to homeostasis and their involvement in neurodegeneration.We further provide a comprehensive overview of therapeutic interventions targeting microglia in neurodegenerative diseases.Notably,we propose microglial depletion and subsequent repopulation as promising replacement therapy.Although microglial replacement therapy is still in its infancy,it will likely be a trend in the development of treatments for neurodegenerative diseases due to its versatility and selectivity.

Defect self-assembly of metal-organic framework triggers ferroptosis to overcome resistance

The emergence of multidrug treatment resistance presents a hurdle for the successful chemotherapy of tumours.Ferroptosis,resulting from the iron-dependent accumulation of lipid peroxides,has the potential to reverse multidrug resistance.However,simultaneous delivery of the iron sources,ferroptosis inducers,drugs,and enhanced circulation carriers within matrices remains a significant challenge.Herein,we designed and fabricated a defect self-assembly of metal-organic framework(MOF)-red blood cell(RBC)membrane-camouflaged multi-drug-delivery nanoplatform for combined ferroptosis-apoptosis treatment of multidrug-resistant cancer.Ferroptosis and chemotherapeutic drugs are embedded in the centre of the iron(III)-based MOF at defect sites by coordination with metal clusters during a one-pot solvothermal synthesis process.The RBC membrane could camouflage the nanoplatform for longer circulation.Our results demonstrate that this defect self-assembly-enabled MOF-membrane-camouflaged nanoplatform could deplete the glutathione,amplify the reactive oxidative species oxidative stress,and enable remarkable anticancer properties.Our work provides an alternative strategy for overcoming multidrug resistance,which could regulate the fluidity and permeability of the cell membrane by ferroptosis to downregulate of P-glycoprotein protein expression by ferroptosis.This defect self-assembly-enabled MOF-membrane-camouflaged multi-drug-delivery nanoplatform has great therapeutic potential.