Cell-type-specific optogenetic fMRI on basal forebrain reveals functional network basis of behavioral preference.

The basal forebrain (BF) is a complex structure that plays key roles in regulating various brain functions. However, it remains unclear how cholinergic and non-cholinergic BF neurons modulate large-scale functional networks and their relevance in intrinsic and extrinsic behaviors. With an optimized awake mouse optogenetic fMRI approach, we revealed that optogenetic stimulation of four BF neuron types evoked distinct cell-type-specific whole-brain BOLD activations, which could be attributed to BF-originated low-dimensional structural networks.

Whole-brain in vivo base editing reverses behavioral changes in Mef2c-mutant mice.

Whole-brain genome editing to correct single-base mutations and reduce or reverse behavioral changes in animal models of autism spectrum disorder (ASD) has not yet been achieved. We developed an apolipoprotein B messenger RNA-editing enzyme, catalytic polypeptide-embedded cytosine base editor (AeCBE) system for converting C·G to T·A base pairs. We demonstrate its effectiveness by targeting AeCBE to an ASD-associated mutation of the MEF2C gene (c.

A tool kit of highly selective and sensitive genetically encoded neuropeptide sensors.

Neuropeptides are key signaling molecules in the endocrine and nervous systems that regulate many critical physiological processes. Understanding the functions of neuropeptides in vivo requires the ability to monitor their dynamics with high specificity, sensitivity, and spatiotemporal resolution. However, this has been hindered by the lack of direct, sensitive, and noninvasive tools.

Neuronal activity-induced, equilibrative nucleoside transporter-dependent, somatodendritic adenosine release revealed by a GRAB sensor.

The purinergic signaling molecule adenosine (Ado) modulates many physiological and pathological functions in the brain. However, the exact source of extracellular Ado remains controversial. Here, utilizing a newly optimized genetically encoded GPCR-Activation-Based Ado fluorescent sensor (GRAB), we discovered that the neuronal activity-induced extracellular Ado elevation is due to direct Ado release from somatodendritic compartments of neurons, rather than from the axonal terminals, in the hippocampus.

Adenosine-independent regulation of the sleep-wake cycle by astrocyte activity.

Astrocytes play a crucial role in regulating sleep-wake behavior, and adenosine signaling is generally thought to be involved. Here we show multiple lines of evidence supporting that modulation of the sleep-wake behavior by astrocyte Ca activity could occur without adenosine signaling. In the basal forebrain and the brainstem, two brain regions that are known to be essential for sleep-wake regulation, chemogenetically-induced astrocyte Ca elevation significantly modulated the sleep-wake cycle.

REM sleep is associated with distinct global cortical dynamics and controlled by occipital cortex.

The cerebral cortex is spontaneously active during sleep, yet it is unclear how this global cortical activity is spatiotemporally organized, and whether such activity not only reflects sleep states but also contributes to sleep state switching. Here we report that cortex-wide calcium imaging in mice revealed distinct sleep stage-dependent spatiotemporal patterns of global cortical activity, and modulation of such patterns could regulate sleep state switching. In particular, elevated activation in the occipital cortical regions (including the retrosplenial cortex and visual areas) became dominant during rapid-eye-movement (REM) sleep.

A high-performance genetically encoded fluorescent indicator for in vivo cAMP imaging.

cAMP is a key second messenger that regulates diverse cellular functions including neural plasticity. However, the spatiotemporal dynamics of intracellular cAMP in intact organisms are largely unknown due to low sensitivity and/or brightness of current genetically encoded fluorescent cAMP indicators. Here, we report the development of the new circularly permuted GFP (cpGFP)-based cAMP indicator G-Flamp1, which exhibits a large fluorescence increase (a maximum ΔF/F of 1100% in HEK293T cells), decent brightness, appropriate affinity (a K of 2.

The emergence of the uniquely human α7 nicotinic acetylcholine receptor gene and its roles in inflammation.

The uniquely human CHRFAM7A gene is evolved from the fusion of two partially duplicated genes, ULK4 and CHRNA7. Transcription of CHRFAM7A gene produces a 1256-bp open reading frame (ORF) that encodes duplicate α7-nAChR (dup-α7-nAChR), in which a 27-aminoacid peptide derived from ULK4 gene replaces the 146-aminoacid N-terminal extracellular domain of α7-nAChR, and the rest protein domains are exactly the same as those of α7-nAChR. In vitro, dup-α7-nAChR has been shown to form hetero-pentamer with α7-nAChR and dominant-negatively inhibits the channel functions of the latter.

Total synthesis of (±)-mersicarpine following a 6- radical cyclization.

Described is a total synthesis of racemic mersicarpine from diethyl 4-oxopimelate. The synthetic route takes advantage of a 2-indolyl radical cyclization to construct the pyrido[1,2-]indole scaffold bearing the all-carbon quaternary stereocenter.

The Biphasic Effect of Retinoic Acid Signaling Pathway on the Biased Differentiation of Atrial-like and Sinoatrial Node-like Cells from hiPSC.

Background And Objectives: Although human-induced pluripotent stem cells (hiPSC) can be efficiently differentiated into cardiomyocytes (CMs), the heterogeneity of the hiPSC-CMs hampers their applications in research and regenerative medicine. Retinoic acid (RA)-mediated signaling pathway has been proved indispensable in cardiac development and differentiation of hiPSC toward atrial CMs. This study was aimed to test whether RA signaling pathway can be manipulated to direct the differentiation into sinoatrial node (SAN) CMs.

Cardiac Expression of Esophageal Cancer-Related Gene-4 is Regulated by Sp1 and is a Potential Early Target of Doxorubicin-Induced Cardiotoxicity.

Esophageal Cancer-Related Gene 4 (Ecrg4) expressed in cardiomyocytes and the cardiac conduction system is downregulated during cardiac ischemia and atrial fibrillation. To explore whether Ecrg4 plays any role in doxorubicin (DOX)-induced cardiotoxicity. Rats and neonatal rat cardiomyocytes (NRCMs) were employed to study the effect of DOX on Ecrg4 transcription.

Genetically engineered exosomes display RVG peptide and selectively enrich a neprilysin variant: a potential formulation for the treatment of Alzheimer's disease.

Exosome is a promising next generation nano-based drug delivery vehicle. However, the unknown molecular mechanisms underlying its natural tissue tropism and the relatively low quantity of naturally enriched molecules of therapeutic value hamper exosome's clinical application. The aim of the research was to create a targeted and highly efficacious exosome formulation for the treatment of Alzheimer's disease (AD).

p53 Promotes Differentiation of Cardiomyocytes from hiPSC through Wnt Signaling-Mediated Mesendodermal Differentiation.

Background And Objectives: Manipulating different signaling pathways via small molecules could efficiently induce cardiomyocytes from human induced pluripotent stem cells (hiPSC). However, the effect of transcription factors on the hiPSC-directed cardiomyocytes differentiation remains unclear. Transcription factor, p53 has been demonstrated indispensable for the early embryonic development and mesendodermal differentiation of embryonic stem cells (ESC).

Hierarchy in sensory processing reflected by innervation balance on cortical interneurons.

Sensory processing is subjected to modulation by behavioral contexts that are often mediated by long-range inputs to cortical interneurons, but their selectivity to different types of interneurons remains largely unknown. Using rabies-virus tracing and optogenetics-assisted recording, we analyzed the long-range connections to various brain regions along the hierarchy of visual processing, including primary visual cortex, medial association cortices, and frontal cortices. We found that hierarchical corticocortical and thalamocortical connectivity is reflected by the relative weights of inputs to parvalbumin-positive (PV) and vasoactive intestinal peptide-positive (VIP) neurons within the conserved local circuit motif, with bottom-up and top-down inputs preferring PV and VIP neurons, respectively.

A genetically encoded sensor for measuring serotonin dynamics.

Serotonin (5-HT) is a phylogenetically conserved monoamine neurotransmitter modulating important processes in the brain. To directly visualize the release of 5-HT, we developed a genetically encoded G-protein-coupled receptor (GPCR)-activation-based 5-HT (GRAB) sensor with high sensitivity, high selectivity, subsecond kinetics and subcellular resolution. GRAB detects 5-HT release in multiple physiological and pathological conditions in both flies and mice and provides new insights into the dynamics and mechanisms of 5-HT signaling.

An optimized acetylcholine sensor for monitoring in vivo cholinergic activity.

The ability to directly measure acetylcholine (ACh) release is an essential step toward understanding its physiological function. Here we optimized the GRAB (GPCR-activation-based ACh) sensor to achieve substantially improved sensitivity in ACh detection, as well as reduced downstream coupling to intracellular pathways. The improved version of the ACh sensor retains the subsecond response kinetics, physiologically relevant affinity and precise molecular specificity for ACh of its predecessor.

Regulation of sleep homeostasis mediator adenosine by basal forebrain glutamatergic neurons.

Sleep and wakefulness are homeostatically regulated by a variety of factors, including adenosine. However, how neural activity underlying the sleep-wake cycle controls adenosine release in the brain remains unclear. Using a newly developed genetically encoded adenosine sensor, we found an activity-dependent rapid increase in the concentration of extracellular adenosine in mouse basal forebrain (BF), a critical region controlling sleep and wakefulness.

Palladium-catalyzed α-arylation of indolin-3-ones.

A method for the catalytic α-arylation of indolin-3-ones was developed. The catalytic system comprising Pd(dba) and PAd was found to be optimal for the transformation. The protocol features broad functional group compatibility in that a range of arylated indoxyl derivatives bearing a fully substituted carbon center was synthesized with high efficiency.

A Genetically Encoded Fluorescent Sensor Enables Rapid and Specific Detection of Dopamine in Flies, Fish, and Mice.

Dopamine (DA) is a central monoamine neurotransmitter involved in many physiological and pathological processes. A longstanding yet largely unmet goal is to measure DA changes reliably and specifically with high spatiotemporal precision, particularly in animals executing complex behaviors. Here, we report the development of genetically encoded GPCR-activation-based-DA (GRAB) sensors that enable these measurements.

Synthesis of 3-(2-Olefinbenzyl)-4H-chromen-4-one through Cyclobenzylation and Catalytic C-H Bond Functionalization Using Palladium(II).

An efficient strategy for synthesizing 3-(2-olefinbenzyl)-4H-chromen-4-one in two steps was developed. The first step is a cyclobenzylation reaction between (E)-3-(dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-one and benzyl bromide to produce homoisoflavonoid. The second step involves intermolecular Pd-catalyzed π-chelating-assisted C-H bond olefination.

[Chemical Exchange Saturation Transfer Imaging of Creatine Metabolites: a 3.0 T MRI Pilot].

Objective: To determine the feasibility of using chemical exchange saturation transfer (CEST) imaging to measure creatine (Cr) metabolites with 3.0 T MR.

Methods: Phantoms containing different concentrations of Cr under various pH conditions were studied with CEST sequence on 3.

Cardioprotective effect of total saponins from three medicinal species of Dioscorea against isoprenaline-induced myocardial ischemia.

Ethnopharmacological Relevance: As folk medicines used in China since 1950s, Dioscorea nipponica Makino (DN), D. panthaica Prain et Burkill (DP), and D. zingiberensis C.

A systematic review of the botanical, phytochemical and pharmacological profile of Dracaena cochinchinensis, a plant source of the ethnomedicine "dragon's blood".

"Dragon's blood" is the name given to a deep red resin obtained from a variety of plant sources. The resin extracted from stems of Dracaena cochinchinensis is one such source of "dragon's blood". It has a reputation for facilitating blood circulation and dispersing blood stasis.

Study on the effect of kidney transplantation on the health of the patients' offspring: a report on 252 Chinese children.

Even though the incidence of pregnancies in the female recipients is lower and also chronic renal disease in male patients is associated with impaired spermatogenesis, the health of the children born to these patients was not studied. In this report, we discuss information on the growth and development of offspring of 248 male and female kidney recipient patients. Physical and routine clinical measurements of the 252 offspring (129 male and 123 female) born to these transplantation patients were made along with the intelligence tests.

Unwanted pregnancy among Chinese renal transplant recipients.

Objectives: To investigate the occurrence of unwanted pregnancies among renal transplant recipients and to identify major contributing factors.

Methods: A total of 647 women of childbearing age who had received a renal transplant at one of the five participating hospitals in China were enrolled in the study and administered a questionnaire that collected information on their reproductive health, pregnancies, and awareness and use of contraceptive methods.

Results: Of the 647 eligible patients, 98 (15%) reported 133 unwanted pregnancies post-transplantation.