Whole-brain spatial organization of hippocampal single-neuron projectomes.

Mapping single-neuron projections is essential for understanding brain-wide connectivity and diverse functions of the hippocampus (HIP). Here, we reconstructed 10,100 single-neuron projectomes of mouse HIP and classified 43 projectome subtypes with distinct projection patterns. The number of projection targets and axon-tip distribution depended on the soma location along HIP longitudinal and transverse axes. Many projectome subtypes were enriched in specific HIP subdomains defined by spatial transcriptomic profiles. Furthermore, we delineated comprehensive wiring diagrams for HIP neurons projecting exclusively within the HIP formation (HPF) and for those projecting to both intra- and extra-HPF targets. Bihemispheric projecting neurons generally projected to one pair of homologous targets with ipsilateral preference. These organization principles of single-neuron projectomes provide a structural basis for understanding the function of HIP neurons.

Learning-prolonged maintenance of stimulus information in CA1 and subiculum during trace fear conditioning.

Temporal associative learning binds discontiguous conditional stimuli (CSs) and unconditional stimuli (USs), possibly by maintaining CS information in the hippocampus after its offset. Yet, how learning regulates such maintenance of CS information in hippocampal circuits remains largely unclear. Using the auditory trace fear conditioning (TFC) paradigm, we identify a projection from the CA1 to the subiculum critical for TFC. Deep-brain calcium imaging shows that the peak of trace activity in the CA1 and subiculum is extended toward the US and that the CS representation during the trace period is enhanced during learning. Interestingly, such plasticity is consolidated only in the CA1, not the subiculum, after training. Moreover, CA1 neurons, but not subiculum neurons, increasingly become active during CS-and-trace and shock periods, respectively, and correlate with CS-evoked fear retrieval afterward. These results indicate that learning dynamically enhances stimulus information maintenance in the CA1-subiculum circuit during learning while storing CS and US memories primarily in the CA1 area.

A Virtual Reality Platform for Context-Dependent Cognitive Research in Rodents.

Animal survival necessitates adaptive behaviors in volatile environmental contexts. Virtual reality (VR) technology is instrumental to study the neural mechanisms underlying behaviors modulated by environmental context by simulating the real world with maximized control of contextual elements. Yet current VR tools for rodents have limited flexibility and performance (e.g., frame rate) for context-dependent cognitive research. Here, we describe a high-performance VR platform with which to study contextual behaviors immersed in editable virtual contexts. This platform was assembled from modular hardware and custom-written software with flexibility and upgradability. Using this platform, we trained mice to perform context-dependent cognitive tasks with rules ranging from discrimination to delayed-sample-to-match while recording from thousands of hippocampal place cells. By precise manipulations of context elements, we found that the context recognition was intact with partial context elements, but impaired by exchanges of context elements. Collectively, our work establishes a configurable VR platform with which to investigate context-dependent cognition with large-scale neural recording.

An intein-split transactivator for intersectional neural imaging and optogenetic manipulation.

The cell-type-specific recording and manipulation is instrumental to disentangle causal neural mechanisms in physiology and behavior and increasingly requires intersectional control; however, current approaches are largely limited by the number of intersectional features, incompatibility of common effectors and insufficient gene expression. Here, we utilized the protein-splicing technique mediated by intervening sequences (intein) and devised an intein-based intersectional synthesis of transactivator (IBIST) to selectively control gene expression of common effectors in multiple-feature defined cell types in mice. We validated the specificity and sufficiency of IBIST to control fluorophores, optogenetic opsins and Ca2+ indicators in various intersectional conditions. The IBIST-based Ca2+ imaging showed that the IBIST can intersect five features and that hippocampal neurons tune differently to distinct emotional stimuli depending on the pattern of projection targets. Collectively, the IBIST multiplexes the capability to intersect cell-type features and controls common effectors to effectively regulate gene expression, monitor and manipulate neural activities.

A Conjugated Figure-of-Eight Oligoparaphenylene Nanohoop with Adaptive Cavities Derived from Cyclooctatetrathiophene Core.

A fully conjugated figure-of-eight nanohoop is presented with facile synthesis. The molecule's lemniscular skeleton features the combination of two strained oligoparaphenylene loops and a flexible cyclooctatetrathiophene core. Its rigid yet guest-adaptive cavities enable the formation of the peanut-like 1:2 host-guest complexes with C60 or C70 , which have been confirmed by X-ray crystallography and characterized in solution. Further computational studies suggest notable geometric variations and non-covalent interactions of the cavities upon binding with different fullerenes, as well as overall conjugation comparable to cycloparaphenylenes.

[Fentanyl attenuates air-puff stimulus-evoked field potential response in the cerebellar molecular layer via inhibiting interneuron activity in mice].

Fentanyl as a synthetic opioid works by binding to the mu-opioid receptor (MOR) in brain areas to generate analgesia, sedation and reward related behaviors. As we know, cerebellum is not only involved in sensory perception, motor coordination, motor learning and precise control of autonomous movement, but also important for the mood regulation, cognition, learning and memory. Previous studies have shown that functional MORs are widely distributed in the cerebellum, and the role of MOR activation in cerebellum has not been reported. The aim of the present study was to investigate the effects of fentanyl on air-puff stimulus-evoked field potential response in the cerebellar molecular layer using in vivo electrophysiology in mice. The results showed that perfusion of 5 µmol/L fentanyl on the cerebellar surface significantly inhibited the amplitude, half width and area under the curve (AUC) of sensory stimulation-evoked inhibitory response P1 in the molecular layer. The half-inhibitory concentration (IC50) of the fentanyl-induced suppression of P1 amplitude was 4.21 µmol/L. The selective MOR antagonist CTOP abolished fentanyl-induced inhibitory responses in the molecular layer. However, application of CTOP alone increased the amplitude and AUC of P1. Notably, fentanyl significantly inhibited the tactile stimulation-evoked response of molecular layer interneurons (MLIs) and the spontaneous firing of MLIs. The results suggest that fentanyl attenuates air-puff stimulus-evoked field potential response in the cerebellar molecular layer via binding to MOR to restrain the spontaneous and evoked firing of MLIs.

[Impacts of shading on seedling growth and mineral accumulation in Paeonia lactiflora]. / é®è«å¤„ç†å¯¹èŠè¯å¹¼è‹—ç”Ÿé•¿å’ŒçŸ¿è´¨è¥å »ç§¯ç´¯çš„å½±å“.

Shading is one of the important strategies to protect seedlings of Paeonia lactiflora. The effects of shading treatments on seedling growth and mineral accumulation of Duolun P. lactiflora were investigated in a greenhouse experiment to provide guidance for P. lactiflora cultivation. One week after emergence, seedlings were treated with 20%, 40%, 60% or 80% shading for two months, with no-shading as the control (CK). The results showed that shading treatments significantly increased plant height by 19.9%, 31.1%, 52.9%, and 63.7%, respectively. However, shading significantly reduced the root mass ratio and root to shoot ratio by 21.5%, 23.6%, 29.2%, 41.8% and 40.6%, 44.0%, 50.9%, 63.2%, respectively. Moreover, 40%, 60% and 80% shading significantly increased specific leaf area by 77.0%, 84.1% and 65.2%, and significantly increased chlorophyll content by 92.3%, 128.7%, 98.1%, and increased carotenoid content by 86.9%, 113.1% and 90.5%, respectively. The treatments of 40%, 60%, and 80% shading significantly decreased root biomass by 61.4%, 74.3% and 78.6%, respectively. Compared with CK, 20%, 40% and 80% shading, the 60% shading treatment increased root phosphorus content by 245.7%, 65.9%, 40.5% and 10.3%, increased potassium content by 102.9%, 131.7%, 57.0%, 63.3% and magnesium content by 131.3%, 55.1%, 40.4%, 7.7%, respectively. 60% shading was an appropriate shading intensity for P. lactiflora seedling cultivation based on local conditions in Duolun.

Fentanyl Inhibits Air Puff-Evoked Sensory Information Processing in Mouse Cerebellar Neurons Recorded in vivo.

Aim: To examine the effects of fentanyl, a potent mu-opioid receptor (MOR) agonist, on-air puff-evoked responses in Purkinje cells (PCs), and molecular layer interneurons (MLIs) using in vivo patch-clamp recordings in anesthetized mice. Methods: Male mice 6-8 weeks-old were anesthetized and fixed on a custom-made stereotaxic frame. The cerebellar surface was exposed and perfused with oxygenated artificial cerebrospinal fluid (ACSF). Patch-clamp recordings in the cell-attached mode were obtained from PCs and MLIs. Facial stimulation by air-puff of the ipsilateral whisker pad was performed through a pressurized injection system. Fentanyl citrate, CTOP, and H-89 dissolved in ACSF were perfused onto the cerebellar surface. Results: Fentanyl significantly inhibited the amplitude and area under the curve (AUC) of sensory stimulation-evoked inhibitory responses in PCs. Although fentanyl did not influence the frequency of simple spikes (SSs), it decreased the pause of SS. The IC50 of the fentanyl-induced suppression of the P1 response amplitude was 5.53 µM. The selective MOR antagonist CTOP abolished fentanyl-induced inhibitory responses in PCs. However, the application of CTOP alone increased the amplitude, AUC of P1, and the pause of SS. Notably, fentanyl significantly inhibited the tactile-evoked response of MLIs but did not affect their spontaneous firing. The fentanyl-induced decrease of inhibitory responses in PCs was partially prevented by a PKA inhibitor, H-89. Conclusions: These results suggest that fentanyl binds to MORs in MLIs to reduce GABAergic neurotransmission in MLI-PC projections and one potential mechanism is via modulation of the cAMP-PKA pathway.

Mineral Elements and Active Ingredients in Root of Wild Paeonia lactiflora Growing at Duolun County, Inner Mongolia.

Roots of wild Paeonia lactiflora are often used as herbs in traditional Chinese medicine. In this study, the contents of potassium (K), calcium (Ca), phosphorus (P), magnesium (Mg), iron (Fe), manganese (Mn), copper (Cu), and zinc (Zn) and the concentrations of three active ingredients such as paeoniflorin (PF), catechin (CA) and benzoic acid (BA) in roots of wild P. lactiflora collected from Duolun County of Inner Mongolia in China were evaluated. The results showed that the mean contents of eight elements followed the following order: Ca > K > P > Mg > Fe > Zn > Mn > Cu, and the concentrations of three active ingredients decreased in the order: PF > CA > BA. It was found that PF concentration was positively correlated with the contents of Fe and Mn. However, the concentration of CA was linearly decreased with Mg content. Moreover, BA concentration showed positive linear dependence upon the contents of P and Mn. Results of stepwise regression analyses showed that 39.2% of the variance in PF concentration could be explained by Fe content, whereas 28.1% of the CA concentration changes could be explained by Mg content; moreover, 42.5% of the variance in BA concentration could be accounted for by the combination of Mn and P contents. In a word, the concentrations of active ingredients in roots of P. lactiflora can be changed by adjusting mineral elements levels in roots to meet the need of appropriate quality control of P. lactiflora.

Effects of Substitutional Dopants on the Photoresponse of a Polyoxotitanate Cluster.

In this paper, using a simple method, 17 isostructural polyoxotitanates (POTs) were synthesized, including the pristine [Ti12O16(O(i)Pr)16], the monodefected [Ti11O13(O(i)Pr)18], and the heterometal-doped [Ti11O14(O(i)Pr)17(ML)] (M = Mg, Ca, Zn, Cd, Co, or Ni; L = Cl, Br, I, or NO3). The electronic structures of these POTs were determined by UV-vis spectroscopy and DFT calculations. Upon UV irradiation of the POTs, electron spin resonance showed the formation of Ti(III) under anaerobic conditions and superoxide (O2(•-)) in the presence of O2. The photoactivities of the POTs were then probed with Ti(III) production and short-circuit photocurrent experiments. The photophysical processes were studied using steady-state and transient photoluminescence. The results show that within the very similar structures, the deexcitation processes of the photoexcited POTs can be greatly affected by the dopants, which result in enhanced or decreased photoactivities. Co and Ni doping enhances the absorption of the visible light accompanied by serious loss of UV photoactivities. On the other hand, a Ti vacancy (in [Ti11O13(O(i)Pr)18]) does not reduce the band gap of a POT but improves the UV photoactivities by serving as surface reaction site. The POTs were then used as molecular models of titanium oxide nanoparticles to understand some important issues relevant to doped titanate, i.e., coordination environment of the dopant metal, electronic structure, photoactivities, and photophysical processes. Our present findings suggest that for solar energy harvesting applications of titanium oxides like photocatalysis and solar cells substitution of titanium atoms by transition metal ions (like Co and Ni) to extend the absorption edges may not be an efficient way, while loading of Ti vacancies is very effective.

[Effects of fermented cattle dung on the growth and development of Tenebrio molitor larvae].

In order to make use of and industrialize the animal dung from large cattle farms, this paper explored the feasibility of using Tenebrio molitor to digest and utilize cattle dung. Cattle dung was mixed with the conventional feed (65% wheat bran, 30% corn flour, and 5% bean pulp) of T. molitor in definite proportions, and fermented with effective microorganisms (EM). The fermented products containing 60% and 80% of cattle dung (FD1 and FD2, respectively) were selected to feed T. molitor larvae, and the effects of the fermented products on the growth curve, death rate, pupation rate, and antioxidant system of the larvae were compared. Compared with CK (conventional deed), the FD1 made the developmental duration of the larvae prolonged by 10 days and the larvae's death rate upraised somewhat, but made the single larva's total food intake, average body mass, crude fat content, and ratio of unsaturated to saturated fat acids increased by 49%, 28%, 26%, and 32%, respectively (P < 0.05), and the activity of larvae's antioxidant system improved significantly, showing a remarkable adaptability of the larvae to FD1. Unlike FD1, FD2 displayed definite disadvantages in most test growth indicators, as compared with CK, indicating that T. molitor larvae had weak adaptability to FD2. Our findings suggested that using FD1 to feed the 3rd instar of T. molitor larvae would have good practical prospects in industrializing cattle dung.

N3-arylmalonamides: a new series of thieno[3,2-b]pyridine based inhibitors of c-Met and VEGFR2 tyrosine kinases.

A family of thieno[3,2-b]pyridine based small molecule inhibitors of c-Met and VEGFR2 were designed based on lead structure 2. These compounds were shown to have IC(50) values in the low nanomolar range in vitro and were efficacious in human tumor xenograft models in mice in vivo.

N-(4-(6,7-Disubstituted-quinolin-4-yloxy)-3-fluorophenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides: a novel series of dual c-Met/VEGFR2 receptor tyrosine kinase inhibitors.

A series of N-(4-(6,7-disubstituted-quinolin-4-yloxy)-3-fluorophenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting c-Met and VEGFR2 tyrosine kinases was designed and synthesized. The compounds were potent against these two enzymes with IC(50) values in the low nanomolar range in vitro, possessed favorable pharmacokinetic profiles and showed high efficacy in vivo in several human tumor xenograft models in mice.

Constrained (l-)-S-adenosyl-l-homocysteine (SAH) analogues as DNA methyltransferase inhibitors.

Potent SAH analogues with constrained homocysteine units have been designed and synthesized as inhibitors of human DNMT enzymes. The five membered (2S,4S)-4-mercaptopyrrolidine-2-carboxylic acid, in 1a, was a good replacement for homocysteine, while the corresponding six-member counterpart was less active. Further optimization of 1a, changed the selectivity profile of these inhibitors. A Chloro substituent at the 2-position of 1a, compound 1d, retained potency against DNMT1, while N(6) alkylation, compound 7a, conserved DNMT3b2 activity. The concomitant substitutions of 1a at both 2- and N(6) positions reduced activity against both enzymes.

SAR around (l)-S-adenosyl-l-homocysteine, an inhibitor of human DNA methyltransferase (DNMT) enzymes.

The inhibitory activity of base-modified SAH analogues and the specificity of inhibiting human DNMT1 and DNMT3b2 enzymes was explored. The 6-amino group was essential while the 7-N of the adenine ring of SAH could be replaced by CH- without loss of activity against both enzymes. The introduction of small groups at the 2-position of the adenine moiety favors DNMT1 over DNMT3b2 inhibition whereas alkylation of the N(6)-amino moiety favors the inhibition of DNMT3b2 enzyme.

N-(3-fluoro-4-(2-arylthieno[3,2-b]pyridin-7-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides: a novel series of dual c-Met/VEGFR2 receptor tyrosine kinase inhibitors.

A series of N-(3-fluoro-4-(2-arylthieno[3,2-b]pyridin-7-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting c-Met and VEGFR2 tyrosine kinases was designed and synthesized. The compounds were potent against these two enzymes with IC(50) values in the low nanomolar range in vitro, possessed favorable pharmacokinetic profiles and showed high efficacy in vivo in several human tumor xenograft models in mice.

Discovery of a novel and potent series of thieno[3,2-b]pyridine-based inhibitors of c-Met and VEGFR2 tyrosine kinases.

A series of thieno[3,2-b]pyridine-based inhibitors of c-Met and VEGFR2 tyrosine kinases is described. The compounds demonstrated potency with IC(50) values in the low nanomolar range in vitro while the lead compound also showed in vivo activity against various human tumor xenograft models in mice. Further exploration of this class of compounds is underway.

Functionalized glycomers as growth inhibitors and inducers of apoptosis in human glioblastoma cells.

The effects of functionalized aryl beta-D-glycopyranosides (glycomers) on the proliferation, survival, and apoptosis of human glioblastoma cells in culture were evaluated as a way to control tumor progression. The results showed that inhibition of growth and/or induction of apoptosis can be achieved by these molecules in human glioblastoma cells. Inhibition of DNA synthesis precedes induction of apoptosis and growth inhibition. The substituents at C-1, C-2, C-3,C-4, and C-6 on the pyranosidic scaffold are important to modulate the action and the efficacy of these molecules. Human fibroblasts and brain-derived endothelial cells were less sensitive to glycomers than tumor cells. Thus, functionalized aryl beta-D-glycopyranosides represent a new class of molecules potentially able to control the progression of brain tumors.