Disrupted presynaptic nectin1-based neuronal adhesion in the entorhinal-hippocampal circuit contributes to early-life stress-induced memory deficits.

The cell adhesion molecule nectin3 and its presynaptic partner nectin1 have been linked to early-life stress-related cognitive disorders, but how the nectin1-nectin3 system contributes to stress-induced neuronal, circuit, and cognitive abnormalities remains to be studied. Here we show that in neonatally stressed male mice, temporal order and spatial working memories, which require the medial entorhinal cortex (MEC)-CA1 pathway, as well as the structural integrity of CA1 pyramidal neurons were markedly impaired in adulthood. These cognitive and structural abnormalities in stressed mice were associated with decreased nectin levels in entorhinal and hippocampal subregions, especially reduced nectin1 level in the MEC and nectin3 level in the CA1. Postnatal suppression of nectin1 but not nectin3 level in the MEC impaired spatial memory, whereas conditional inactivation of nectin1 from MEC excitatory neurons reproduced the adverse effects of early-life stress on MEC-dependent memories and neuronal plasticity in CA1. Our data suggest that early-life stress disrupts presynaptic nectin1-mediated interneuronal adhesion in the MEC-CA1 pathway, which may in turn contribute to stress-induced synaptic and cognitive deficits.

Adult-onset neuronal nuclear inclusion disease presenting with mental and behavioral disorders: A case report and literature review.

Neuronal nuclear inclusion disease (NIID) is a rare and chronic progressive neurological degenerative disease. We presented a 68-year-old man with paroxysmal orientation disorder 1 year prior, mental and behavioral disorders for 2 days, and confirmed the diagnosis of NIID with skin biopsy. We suggest that patients with atypical clinical symptoms showed characteristic high signal in the dermatomedullary junction on DWI; NIID should be considered.

Effects of anthocyanins on bread microstructure, and their combined impact on starch digestibility.

Several studies have confirmed the reduction of starch digestibility with anthocyanins in food systems via mechanisms of enzyme inhibition. However, starch-polyphenol interactions may also contribute to this reduction, by modifying food microstructures and physicochemical properties of starch. The interactions among anthocyanins, starch digestibility, and food microstructures are significant to clarify the digestion processes of fortified food systems, but its interrelationship lacks clarity. Hence, we aim to evaluate the effects of black rice anthocyanin extract (BRAE) incorporation on the microstructural changes of wheat bread, in relation to overall digestibility. Overall, BRAE incorporation demonstrated a dose-dependent reduction in starch digestibility. Physicochemical analyses reflected that BRAE incorporation decreased starch gelatinisation and increased crystallinity. Microscopic imaging revealed differentiating microstructural characteristics of starch and gluten with BRAE incorporation, supporting the reduction in digestibility. Our results conclusively demonstrate that BRAE incorporation in bread suppresses starch digestibility not only through enzyme inhibition, but also food microstructural modifications.

Generation of patterned kidney organoids that recapitulate the adult kidney collecting duct system from expandable ureteric bud progenitors.

Current kidney organoids model development and diseases of the nephron but not the contiguous epithelial network of the kidney's collecting duct (CD) system. Here, we report the generation of an expandable, 3D branching ureteric bud (UB) organoid culture model that can be derived from primary UB progenitors from mouse and human fetal kidneys, or generated de novo from human pluripotent stem cells. In chemically-defined culture conditions, UB organoids generate CD organoids, with differentiated principal and intercalated cells adopting spatial assemblies reflective of the adult kidney's collecting system. Aggregating 3D-cultured nephron progenitor cells with UB organoids in vitro results in a reiterative process of branching morphogenesis and nephron induction, similar to kidney development. Applying an efficient gene editing strategy to remove RET activity, we demonstrate genetically modified UB organoids can model congenital anomalies of kidney and urinary tract. Taken together, these platforms will facilitate an enhanced understanding of development, regeneration and diseases of the mammalian collecting duct system.

Tactile modulation of memory and anxiety requires dentate granule cells along the dorsoventral axis.

Touch can positively influence cognition and emotion, but the underlying mechanisms remain unclear. Here, we report that tactile experience enrichment improves memory and alleviates anxiety by remodeling neurons along the dorsoventral axis of the dentate gyrus (DG) in adult mice. Tactile enrichment induces differential activation and structural modification of neurons in the dorsal and ventral DG, and increases the presynaptic input from the lateral entorhinal cortex (LEC), which is reciprocally connected with the primary somatosensory cortex (S1), to tactile experience-activated DG neurons. Chemogenetic activation of tactile experience-tagged dorsal and ventral DG neurons enhances memory and reduces anxiety respectively, whereas inactivation of these neurons or S1-innervated LEC neurons abolishes the beneficial effects of tactile enrichment. Moreover, adulthood tactile enrichment attenuates early-life stress-induced memory deficits and anxiety-related behavior. Our findings demonstrate that enriched tactile experience retunes the pathway from S1 to DG and enhances DG neuronal plasticity to modulate cognition and emotion.

Polymer-Based Device Fabrication and Applications Using Direct Laser Writing Technology.

Polymer materials exhibit unique properties in the fabrication of optical waveguide devices, electromagnetic devices, and bio-devices. Direct laser writing (DLW) technology is widely used for micro-structure fabrication due to its high processing precision, low cost, and no need for mask exposure. This paper reviews the latest research progresses of polymer-based micro/nano-devices fabricated using the DLW technique as well as their applications. In order to realize various device structures and functions, different manufacture parameters of DLW systems are adopted, which are also investigated in this work. The flexible use of the DLW process in various polymer-based microstructures, including optical, electronic, magnetic, and biomedical devices are reviewed together with their applications. In addition, polymer materials which are developed with unique properties for the use of DLW technology are also discussed.

Dorsal CA1 interneurons contribute to acute stress-induced spatial memory deficits.

Exposure to severely stressful experiences disrupts the activity of neuronal circuits and impairs declarative memory. GABAergic interneurons coordinate neuronal network activity, but their involvement in stress-evoked memory loss remains to be elucidated. Here, we provide evidence that interneurons in area CA1 of the dorsal hippocampus partially modulate acute stress-induced memory deficits. In adult male mice, both acute forced swim stress and restraint stress impaired hippocampus-dependent spatial memory and increased the density of c-fos-positive interneurons in the dorsal CA1. Selective activation of dorsal CA1 interneurons by chemogenetics disrupted memory performance in the spatial object recognition task. In comparison, anxiety-related behavior, spatial working memory and novel object recognition memory remained intact when dorsal CA1 interneurons were overactivated. Moreover, chemogenetic activation of dorsal CA1 interneurons suppressed the activity of adjacent pyramidal neurons, whereas a single exposure to forced swim stress but not restraint stress increased the activity of CA1 pyramidal neurons. However, chemogenetic inhibition of dorsal CA1 interneurons led to spatial memory impairments and failed to attenuate acute stress-induced memory loss. These findings suggest that acute stress may overactivate interneurons in the dorsal CA1, which reduces the activity of pyramidal neurons and in turn disrupts long-term memory.

A comparative study of Gaussian and non-Gaussian diffusion models for differential diagnosis of prostate cancer with in-bore transrectal MR-guided biopsy as a pathological reference.

Background Although several studies have been reported on evaluating the performance of Gaussian and different non-Gaussian diffusion models on prostate cancer, few studies have been reported on the comparison of different models on differential diagnosis for prostate cancer. Purpose To compare the utility of various metrics derived from monoexponential model (MEM), biexponential model (BEM), stretched-exponential model (SEM) based diffusion-weighted imaging (DWI) and diffusion kurtosis imaging (DKI) in the differential diagnosis of prostate cancer. Material and Methods Thirty-three patients underwent magnetic resonance imaging (MRI) examination. Multi-b value and multi-direction DWIs were performed. In-bore MR-guided biopsy was performed. Apparent diffusion coefficient (ADC), pure molecular diffusion (ADCslow), pseudo-diffusion coefficient (ADCfast), perfusion fraction (f), water molecular diffusion heterogeneity index (α), distributed diffusion coefficient (DDC), non-Gaussian diffusion coefficient (MD), and mean kurtosis (MK) values were calculated and compared between cancerous and non-cancerous groups. Receiver operating characteristic (ROC) analysis was performed for all parameters and models. Results ADC, ADCslow, DDC, and MD values were significantly lower while MK value was significantly higher in prostate cancer than those of prostatitis and benign prostatic hyperplasia. ADC, ADCslow, DDC, MD, and MK could discriminate between tumor and non-tumorous lesions (area under the curve, 0.856, 0.835, 0.866, 0.918, and 0.937, respectively). MK was superior to ADC in the discrimination of prostate cancer. DKI was superior to MEM in the discrimination of prostate cancer. Conclusions Parameters derived from both Gaussian and non-Gaussian models could characterize prostate cancer. DKI may be advantageous than DWI for detection of prostate cancer.

Suppressed Calbindin Levels in Hippocampal Excitatory Neurons Mediate Stress-Induced Memory Loss.

Calbindin modulates intracellular Ca2+ dynamics and synaptic plasticity. Reduction of hippocampal calbindin levels has been implicated in early-life stress-related cognitive disorders, but it remains unclear how calbindin in distinct populations of hippocampal neurons contributes to stress-induced memory loss. Here we report that early-life stress suppressed calbindin levels in CA1 and dentate gyrus (DG) neurons, and calbindin knockdown in adult CA1 or DG excitatory neurons mimicked early-life stress-induced memory loss. In contrast, calbindin knockdown in CA1 interneurons preserved long-term memory even after an acute stress challenge. These results indicate that the dysregulation of calbindin in hippocampal excitatory, but not inhibitory, neurons conveys susceptibility to stress-induced memory deficits. Moreover, calbindin levels were downregulated by early-life stress through the corticotropin-releasing hormone receptor 1-nectin3 pathway, which in turn reduced inositol monophosphatase levels. Our findings highlight calbindin as a molecular target of early-life stress and an essential substrate for memory.

Protective effect of Naoxintong against cerebral ischemia reperfusion injury in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Naoxintong (NXT), a renowned traditional Chinese medicine in China, has been used for the treatment of acute and chronic cardio-cerebrovascular diseases in clinic for more than 20 years. AIM OF THE STUDY: To evaluate the potential neuroprotective effect of NXT against ischemia reperfusion (I/R) injury in mice and investigate the underlying mechanisms. MATERIALS AND METHODS: Focal cerebral I/R injury in adult male CD-1 mice was induced by transient middle cerebral artery occlusion (tMCAO) for 1h followed by reperfusion for 23h. Mice were randomly divided into five groups: Sham group; tMCAO group; Vehicle group; NXT-treated groups at doses of 0.36g/kg and 0.54g/kg. The effects of NXT on murine neurological function were estimated by neurological defect scores, infarct volume and brain water content at 24h after tMCAO. Immunohistochemistry and Western blot were used to detect the expression of LOX-1, pERK1/2 and NF-κB at 24h after tMCAO. qRT-PCR was used to detect the expression of LOX-1 and NF-κB at 24h after tMCAO. RESULTS: Compared with Vehicle group, 0.54g/kg group of NXT significantly ameliorated neurological outcome, infarction volume and brain water content, decreased the expression of LOX-1, pERK1/2 and NF-κB (P<0.05). CONCLUSION: NXT protected the mice brain against I/R injury, and this protection maybe associated with the down-regulation of LOX-1, pERK1/2 and NF-κB expression.

Effect of Geometrical Asymmetry on the Phase Behavior of Rod-Coil Diblock Copolymers.

The effect of geometrical asymmetry ß (described by the length-diameter ratio of rods) on the rod-coil diblock copolymer phase behavior is studied by implementation of self-consistent field theory (SCFT) in three-dimensional (3D) position space while considering the rod orientation on the spherical surface. The phase diagrams at different geometrical asymmetry show that the aspect ratio of rods ß influences not only the order-disorder transition (ODT) but also the order-order transition (OOT). By exploring the phase diagram with interactions between rods and coils plotted against ß, the ß effect on the phase diagram is similar to the copolymer composition f. This suggests that non-lamellae structures can be obtained by tuning ß, besides f. When the rods are slim compared with the isotropic shape of the coil segment (ß is relatively large), the phase behavior is quite different from that of coil-coil diblock copolymers. In this case, only hexagonal cylinders with the coil at the convex side of the interface and lamella phases are stable even in the absence of orientational interaction between rods. The phase diagram is no longer symmetrical about the symmetric copolymer composition and cylinder phases occupy the large area of the phase diagram. The ODT is much lower than that of the coil-coil diblock copolymer system and the triple point at which disordered, cylinder and lamella phases coexist in equilibrium is located at rod composition fR = 0.66. In contrast, when the rods are short and stumpy (ß is smaller), the stretching entropy cost of coils can be alleviated and the phase behavior is similar to coil-coil diblocks. Therefore, the hexagonal cylinder phase formed by coils is also found beside the former two structures. Moreover, the ODT may even become a little higher than that of the coil-coil diblock copolymers due to the large interfacial area per chain provided by the stumpy rods, thus compensating the stretching entropy loss of the coils.

Chrysophanol inhibits NALP3 inflammasome activation and ameliorates cerebral ischemia/reperfusion in mice.

The most effective way to contain cerebral ischemic injury is reperfusion; however, reperfusion itself may result in tissue injury, for which inflammatory damage is one of the main causative factors. NALP3 inflammasome is a multiprotein complex. It consists of NALP3, ASC, and caspase-1, whose function is to switch on the inflammatory process. Chrysophanol is an extract from plants of Rheum genus and it possesses many pharmacological effects including its anti-inflammation activity. In this study, the effects of chrysophanol in cerebral ischemia/reperfusion and the potential mechanisms were investigated. Male CD1 mice were subject to transient middle cerebral artery occlusion (tMCAO). The NALP3 inflammasome activation status and its dynamic expression during the natural inflammatory response induced by tMCAO were first profiled. The neuroprotective effects of chrysophanol were then assessed and the potential mechanisms mediating the observed neuroprotection were then explored. Physical parameters including neurological deficit, infarct size, brain edema, and BBB permeability were measured at 24 h after tMCAO. Confocal microscopy, Western blotting, immunohistochemistry, and qRT-PCR techniques were utilized to analyze the expression of NALP3 inflammasome and IL-1 ß . Our results indicated that the brain tissue damage during cerebral ischemia/reperfusion is accompanied by NALP3 inflammasome activation. Chrysophanol could inhibit the activation of NALP3 inflammasome and protect cerebral ischemic stroke.

Pericentrin contains five NESs and an NLS essential for its nucleocytoplasmic trafficking during the cell cycle.

Pericentrin, a conserved centrosomal component, provides the structural scaffold to anchor numerous centrosomal proteins, and thus plays an essential role in the organization and function of the centrosome and the mitotic spindle. Although pericentrin was shown to localize in the cytoplasm and reported to be sensitive to leptomycin B (LMB), a specific inhibitor of Crm1, the regions within pericentrin that serve as signals for transporting in and out of the nucleus have not yet been identified. In this study, we identified five novel nuclear export signals (NESs) in pericentrin with diverse export activities. All of the five NESs could bind to Crm1 in a LMB-sensitive way when mediating the nuclear export of pericentrin. We also demonstrated that the region of amino acids 8-42 in pericentrin contains a tripartite nuclear localization signal (NLS) consisting of three clusters of basic amino acids. The NLS of pericentrin binds to importin beta directly or via the adaptor importin alpha to form the import complex, which could be disrupted by RanQ69L, a dominant-negative Ran GTPase possessing high affinity for importin beta. Furthermore, we found that mutation of the NESs in full-length pericentrin results in both nuclear and cytoplasmic localization, and mutation of the NLS abolishes the nuclear import of pericentrin. On the basis of these results, we suggest that the NESs and NLS of pericentrin are essential for its subcellular localization and nucleocytoplasmic trafficking during the cell cycle.