[Noradrenaline modulates the spontaneous firing activities of Purkinje cells via α2-adrenergic receptor in mouse cerebellar cortex].

Cerebellar Purkinje cells (PCs) exhibit two types of discharge activities: simple spike (SS) and complex spike (CS). Previous studies found that noradrenaline (NA) can inhibit CS and bidirectionally regulate SS, but the enhancement of NA on SS is overwhelmed by the strong inhibition of excitatory molecular layer interneurons. However, the mechanism underlying the effect of NA on SS discharge frequency is not clear. Therefore, in the present study, we examined the mechanism underlying the increasing effect of NA on SS firing of PC in mouse cerebellar cortex in vivo and in cerebellar slice by cell-attached and whole-cell recording technique and pharmacological methods. GABAA receptor was blocked by 100 µmol/L picrotoxin in the whole process. In vivo results showed that NA significantly reduced the number of spikelets of spontaneous CS and enhanced the discharge frequency of SS, but did not affect the discharge frequency of CS. In vitro experiments showed that NA reduced the number of CS spikelets and after hyperpolarization potential (AHP) induced by electrical stimulation, and increased the discharge frequency of SS. NA also reduced the amplitude of excitatory postsynaptic current (EPSC) of parallel fiber (PF)-PC and significantly increased the paired-pulse ratio (PPR). Application of yohimbine, an antagonist of α2-adrenergic receptor (AR), completely eliminated the enhancing effect of NA on SS. The α2-AR agonist, UK14304, also increased the frequency of SS. The ß-AR blocker, propranolol, did not affect the effects of NA on PC. These results suggest that in the absence of GABAA receptors, NA could attenuate the synaptic transmission of climbing fiber (CF)-PC via activating α2-AR, inhibit CS activity and reduce AHP, thus enhancing the SS discharge frequency of PC. This result suggests that NA neurons of locus coeruleus can finely regulate PC signal output by regulating CF-PC synaptic transmission.

Utilizing deep ocean water in yeast fermentation for enhanced mineral-rich biomass production and fermentative regulation by proteomics modulation.

Deep Ocean Water (DOW) is rich in minerals and serves as a natural source of nutrients. However, due to the inorganic nature of these minerals, cultivating yeast in DOW could aid in the fermentation process, and simultaneously, the yeast can assimilate the minerals from DOW, resulting in a mineral-enriched yeast biomass. Focusing on three DOW sources off the eastern coast of Taiwan (TT-1, HL-1, HL-2), we fermented various yeast strains of Saccharomyces cerevisiae. Therefore, this study investigates the effects of DOW on yeast growth, alcohol dehydrogenase activity, and the biological absorption of mineral ions by the yeast. Additionally, this research employs two-dimensional electrophoresis techniques to examine how the absorbed minerals influence the regulation of yeast proteins, thereby affecting biomass and metabolism. In the result, S. cerevisiae BCRC 21689 demonstrated a remarkable ability to bio-absorb minerals such as magnesium, calcium, potassium, and zinc from DOW, enhancing its growth and fermentation performance. Proteomic analysis revealed significant shifts in the expression of 21 proteins related to glycolytic and energy metabolism, alcohol metabolism, and growth regulation, all influenced by DOW's mineral-rich environment. This indicates that DOW's mineral content is a key factor in upregulating essential enzymes in glycolytic metabolism and alcohol dehydrogenase. An increase in proteins involved in synthesis and folding processes was also observed, leading to a substantial increase in yeast biomass. This study underscores the potential of DOW as a natural enhancer in yeast fermentation processes, enriching the yeast with diverse minerals and modulating proteomic expression to optimize yeast growth and fermentation.

Disorder-order transformation and significant dislocation motion cooperating with a surprisingly large hysteretic magnetic transition in a nickel-bisdithiolene spin system.

The compound [4'-CF3bzPy][Ni(mnt)2] (1) (where 4'-CF3bzPy = 1-(4'-(trifluoromethyl)benzyl)pyridinium and mnt(2-) = maleonitriledithiolate) was synthesized and displays a magnetic bistability with a surprisingly large thermal hysteresis loop (~49 K). X-ray crystallographic studies reveal that in the high-temperature (HT) phase the anions and cations form mixed stacks, with alternating anion dimers (AA) and cation dimers (CC) in an ...AACCAACC... fashion along the crystallographic a + b direction, and disordered CF3 groups in the cations are aligned into a molecular layer parallel to the crystallographic (001) plane. However, in the low-temperature (LT) phase, the c-axis length of the unit cell is roughly doubled, and the asymmetric unit switches from one [4'-CF3bzPy][Ni(mnt)2] pair in the HT phase to two [4'-CF3bzPy][Ni(mnt)2] pairs. Most interestingly, the CF3 group in the cations becomes ordered, and the conformation of one of two crystallographically different cations changes significantly. A dislocation motion between the neighboring molecular layers emerges as well. The analyses of the magnetic susceptibilities and the density functional theory calculations suggest that the antiferromagnetic exchange interaction within one of two types of [Ni(mnt)2]2(2-) dimers in the LT phase is much stronger than that within the [Ni(mnt)2]2(2-) dimer in the HT phase. The lattice reorganization during this phase transition is proposed to be responsible for the wide thermal hysteresis loop.

Integrated Chinese and Western medicine in the treatment of a patient with podocyte infolding glomerulopathy: A case report.

BACKGROUND: Podocyte infolding glomerulopathy (PIG) is a newly described and rare glomerular disease. To date, only approximately 40 cases have been reported globally. CASE SUMMARY: A 26-year-old female patient presented to our hospital with a complaint of intermittent edema of both lower limbs over the past 2 years. The patient was diagnosed with PIG. She was prescribed corticosteroid therapy in other hospitals during the initial stage, to which she had responded poorly and had developed femoral head necrosis. Therefore, we administered immunosuppressants, renin-angiotensin system inhibitors, combined with traditional Chinese medicine. The patient was followed for 1 year, during which her clinical condition improved. CONCLUSION: Integrated Chinese and Western medicine may be effective for PIG treatment, which requires active intervention to improve prognosis.

The proton conduction behavior of two 1D open-framework metal phosphates with similar crystal structures and different hydrogen bond networks.

Two open-framework zinc phosphates [C3N2H12][Zn(HPO4)2] (1) and [C6N4H22]0.5[Zn(HPO4)2] (2) were synthesized via hydrothermal reaction and characterized by powder X-ray diffraction, thermogravimetric analysis and scanning electron microscopy. Both compounds have a similar crystal structure and macroscopic morphology. However, the difference in equilibrium cations, in which the propylene diamine is for 1 and the triethylenetetramine is for 2, results in a significant distinction in the dense hydrogen grid. The diprotonated propylene diamine molecule in 1 is more favorable for forming a hydrogen-bond network in three dimensions than in 2, in which the twisted triethylenetetramine forms a hydrogen bond grid with the inorganic framework only in two dimensions owing to its large steric effect. This distinction further leads to a disparity in the proton conductivity of both compounds. The proton conductivity of 1 can reach 1.00 × 10-3 S cm-1 under ambient conditions (303 K and 75% RH) and then increase to 1.11 × 10-2 S cm-1 at 333 K and 99% RH, which is the highest value among the open-framework metal phosphate proton conductors operated in the same conduction. In contrast, the proton conductivity of 2 is four orders of magnitude smaller than 1 at 303 K and 75% RH and two orders smaller than 1 at 333 K and 99% RH.

Replenished microglia partially rescue schizophrenia-related stress response.

Background: Microglia play an important role in the maintenance of brain and behavioral homeostasis. The protective effect of microglial replenishment was reported in neurological diseases, but whether microglial therapy would benefit psychiatric disorders such as schizophrenia has been unclear. As schizophrenia is a stress-vulnerable disorder and psychosocial stress promotes inflammation and microglial activation, we aim to understand how microglial replenishment works in stress-associated schizophrenia. Methods: We used a CSF1R-mediated pharmacological approach to study repopulated microglia (repMg) in a cohort of mice (n = 10/group) undergoing chronic unpredictable stress (CUS). We further studied a cohort of first-episode schizophrenia (FES, n = 74) patients who had higher perceived stress scores (PSS) than healthy controls (HCs, n = 68). Results: Reborn microglia attenuated CUS-induced learned hopelessness and social withdrawal but not anxiety in mice. Compared to control, CUS- or repMg-induced differentially expressed genes (DEGs) in the prefrontal cortex regulated nervous system development and axonal guidance. CUS also caused microglial hyper-ramification and increased engulfment of synaptophysin and vesicular glutamate transporter-2 by microglia and astrocytes, which were recovered in CUS + repMg (all p < 0.05). Moreover, FES patients had smaller hippocampal fimbria than HCs (p < 1e-7), which were negatively associated with PSS (r = -0.397, p = 0.003). Blood DEGs involved in immune system development were also associated with PSS and the right fimbria more prominently in FES patients than HCs (Zr, p < 0.0001). The KCNQ1 was a partial mediator between PSS and fimbria size (ß = -0.442, 95% CI: -1.326 ~ -0.087). Conclusion: Microglial replenishment may potentially benefit psychiatric disorders such as schizophrenia.

Enhanced Anxiety and Olfactory Microglial Activation in Early-Stage Familial Alzheimer's Disease Mouse Model.

Anxiety is a known comorbidity and risk factor for conversion to neuroinflammation-mediated dementia in patients with Alzheimer's disease (AD). Here, we investigated if anxiety occurred as an early endophenotype of mutant familial AD (5 × FAD) male mice and the underlying neuroinflammatory mechanisms. We observed that compared to wildtype (WT) littermates, 5 × FAD mice showed enhanced anxiety at as early as 2 months old (mo). Interestingly, these 5 × FAD male mice had concomitantly increased mRNA levels of pro-inflammatory cytokines such as interleukin 1 beta (Il1b) and tumor necrosis factor (Tnf) in the olfactory bulb (OB) but not the frontal cortex (FC). Increased expression of Tnf in the OB was significantly correlated with the anxious behavior in the FAD but not WT mice. Furthermore, we found more prominent microglial activation and morphological changes in the OB of 2 mo 5 × FAD mice, while only microglial ramification was seen in the FC. To understand if neuroinflammatory changes in the FC could occur at a later stage, we studied 5~6 mo male mice and found that Il1b, interleukin 18 (Il18), and Tnf were upregulated in the FC at this older age. Furthermore, we observed that numbers of microglia and macrophage as well as microglial synaptic pruning, as indicated by phagocytosis of presynaptic component of vesicular glutamate transporter-2, were increased in the OB but not the FC of 5~6 mo 5 × FAD mice. Our findings demonstrated the OB as a more sensitive brain region than the cerebral cortex for microglia-mediated neuroinflammation in association with anxiety in FAD mice and supported the notion that the OB can be an early-stage biomarker in AD.

Monocytic Subsets Impact Cerebral Cortex and Cognition: Differences Between Healthy Subjects and Patients With First-Episode Schizophrenia.

Monocytes are a highly heterogeneous population subcategorized into classical, intermediate and nonclassical subsets. How monocytes and their subsets may shape brain structures and functions in schizophrenia remains unclear. The primary goal of this cross-sectional study was to investigate monocytic subsets and their specific signature genes in regulation of cerebral cortical thickness and cognitive functions in first-episode schizophrenia (FES) patients. Whole-blood RNA sequencing of 128 FES patients and 111 healthy controls (HCs) were conducted and monocyte-specific differentially expressed genes were further analyzed. The MATRICS Consensus Cognitive Battery (MCCB) test, cortical neuroimaging and flow cytometric staining of peripheral blood monocytic subsets were performed among the participants. Significant changes in expressions of 54 monocytic signature genes were found in patients, especially for intermediate and nonclassical monocytic subsets with the most outstanding alterations being downregulated S100 Calcium Binding Protein A (S100A) and upregulated Interferon Induced Transmembrane Protein (IFITM) family members, respectively. Meanwhile, percentage of blood nonclassical monocytes was decreased in patients. Cortical thicknesses and MCCB performance were expectantly reduced and weaker intra-relationships among monocytic signature genes and cortices, respectively, were noted in patients compared to HCs. Monocytic genes were negatively associated with both cortical thicknesses and cognition in HCs, which was interestingly weakened or even reversed in patients, with nonclassical monocytic genes showing the greatest statistical significance. This study reveals that while monocytes may have negative effects on brain structure and cognition, the ameliorated phenomenon observed in schizophrenia may reflect an (mal)adaptive change of monocytes at early stage of the disorder.

Glial receptor PLXNB2 regulates schizophrenia-related stress perception via the amygdala.

Stress is a trigger for the development of psychiatric disorders. However, how stress trait differs in schizophrenia patients is still unclear. Stress also induces and exacerbates immune activation in psychiatric disorders. Plexins (Plxn) and its ligands semaphorins (Sema) are important cellular receptors with plural functions in both the brain and the immune system. Recently, the role of Plxn/Sema in regulation of neuroinflammation was also noticed. Here, when investigating immune mechanisms underlying stress susceptibility in schizophrenia, we discovered the role of Plxnb2 in stress response. Patients of first-episode schizophrenia (FES) with high stress (FES-hs, n=51) and low stress (FES-ls, n=50) perception and healthy controls (HCs) (n=49) were first recruited for neuroimaging and blood bulk RNA sequencing (RNA-seq). A mouse model of chronic unpredictable stress (CUS) and intra-amygdaloid functional blocking of Plxnb2 were further explored to depict target gene functions. Compared to HCs, FES-hs patients had bigger caudate and thalamus (FDR=0.02&0.001, respectively) whereas FES-ls patients had smaller amygdala (FDR=0.002). Blood RNA-seq showed differentially expressed PLXNB2 and its ligands among patient groups and HCs (FDR<0.05~0.01). Amygdaloid size and PLXNB2 level were both negatively correlated with stress perception (p<0.01&0.05, respectively), which fully mediated the amygdaloid positive association with PLXNB2 expression (ß=0.9318, 95% CI: 0.058~1.886) in FES-hs patients. In mice, Plxnb2 was enriched in astrocytes and microglia and CUS reduced its expression in astrocytes (p<0.05). Inhibition of amygdaloid Plxnb2 by its functional blocking monoclonal antibody (mAb)-102 induced mice anxiety (p<0.05), amygdaloid enlargement (p<0.05), and microglial ramification (p<0.001) compared to saline. These data suggest that PLXNB2 regulates amygdala-dependent stress responses.

Combination of Multiple Hemodialysis Modes: Better Treatment Options for Patients Under Maintenance Hemodialysis.

PURPOSE: Chronic renal failure has become a major public health concern and treatment strategies are urgently needed. We aimed to investigate whether combination of hemodialysis modes was superior to regular hemodialysis for patients under maintenance hemodialysis. PATIENTS AND METHODS: A total of 144 patients with end-stage renal failure (ESRF) were enrolled in this single-center retrospective study. Patients received regular hemodialysis (HD) were included in HD group (n=52), patients received regular HD plus hemodiafiltration (HDF) in HD/HDF group (n=47), patients received the combination of regular HD, HDF and hemoperfusion (HP) in HD/HDF/HP group (n=45). After 1-month and 24-months treatment, therapeutic effects were assessed in terms of nutritional status, control of complications, dialysis adequacy, mean arterial pressure (MAP), infection rate and living quality. RESULTS: When patients received 1-month treatment, there were no statistically significant differences among three groups. After 24-months treatment, patients in HD/HDF and HD/HDF/HP group presented with better dialysis adequacy, lower MAP and infection rate, higher serum albumin, hemoglobin and calcium levels, lower serum phosphorus and intact parathyroid hormone levels, lower incidence of malnutrition and the Hamilton Depression Scale score, higher the Barthel Index score than HD group (P<0.05). The levels of calcium, phosphorus and intact parathyroid hormone in HD/HDF/HP group were lower than those in HD/HDF group (P<0.05). CONCLUSION: Our finding highly indicated that combination of hemodialysis modes was superior to regular HD for patients with ESRF in nutritional status, control of complications, dialysis adequacy, and living quality.

Differences of Microglia in the Brain and the Spinal Cord.

Microglia were previously regarded as a homogenous myeloid cell lineage in the mammalian central nervous system (CNS). However, accumulating evidences show that microglia in the brain and SC are quite different in development, cellular phenotypes and biological functions. Although this is a very interesting phenomenon, the underlying mechanisms and its significance for neurological diseases in association with behavioral and cognitive changes are still unclear. How microglia differ between these two regions and whether such diversity may contribute to CNS development and functions as well as neurological diseases will be discussed in this Perspective.

Propofol Inhibits Cerebellar Parallel Fiber-Purkinje Cell Synaptic Transmission via Activation of Presynaptic GABAB Receptors in vitro in Mice.

Propofol is a widely used intravenous sedative-hypnotic agent, which causes rapid and reliable loss of consciousness via activation of γ -aminobutyric acid A (GABAA) receptors. We previously found that propofol inhibited cerebellar Purkinje cells (PC) activity via both GABAA and glycine receptors in vivo in mice. We here examined the effect of propofol on the cerebellar parallel fiber (PF)-PC synaptic transmission in mouse cerebellar slices by whole-cell recording technique and pharmacological methods. We found that following blockade of GABAA and glycine receptors activity, propofol reversely decreased the amplitude of PF-PC excitatory postsynaptic currents (PF-PC EPSCs), and significantly increased paired-pulse ratio (PPR). The propofol-induced decrease in amplitude of PF-PC EPSCs was concentration-dependent. The half-inhibitory concentration (IC50) of propofol for inhibiting PF-PC EPSCs was 4.7 µM. Notably, the propofol-induced changes in amplitude and PPR of PF-PC EPSCs were abolished by GABAB receptor antagonist, saclofen (10 µM), but not blocked by N-methyl-D-aspartate receptor (NMDA) receptor antagonist, D-APV (50 µM). Application of the GABAB receptor agonist baclofen induced a decrease in amplitude and an increase in PPR of PF-PC EPSCs, as well masked the propofol-induced changes in PF-PC EPSCs. Moreover, the propofol-induced changes in amplitude and PPR of PF-PC EPSCs were abolished by a specific protein kinase A (PKA) inhibitor, KT5720. These results indicate that application of propofol facilitates presynaptic GABAB receptors, resulting in a depression of PF-PC synaptic transmission via PKA signaling pathway in mouse cerebellar cortex. The results suggest that the interaction with GABAB receptors may contribute to the general anesthetic action of propofol.

Comparative Analysis of the Rats' Gut Microbiota Composition in Animals with Different Ginsenosides Metabolizing Activity.

Following oral intake of Panax ginseng, major ginsenosides are metabolized to deglycosylated ginsenosides by gut microbiota before absorption into the blood. As the composition of gut microbiota varies between individuals, metabolic activities are significantly different. We selected 6 rats with low efficiency metabolism (LEM) and 6 rats with high efficiency metabolism (HEM) from 60 rats following oral administration of Panax ginseng extract, and analyzed their gut microbiota composition using Illumina HiSeq sequencing of the 16S rRNA gene. The components of gut microbiota between the LEM and HEM groups were significantly different. Between the 2 groups, S24-7, Alcaligenaceae, and Erysipelotrichaceae occupied most OTUs of the HEM group, which was notably higher than the LEM group. Furthermore, we isolated Bifidobacterium animalis GM1 that could convert the ginsenoside Rb1 to Rd. The result implies that these specific intestinal bacteria may dominate the metabolism of Panax ginseng.

Observation of hysteretic magnetic phase transitions coupled with orientation motion of ions and dielectric relaxation in a one-dimensional nickel-bis-dithiolene molecule solid.

The second polymorph, the ß-crystal, of the nickel-bis-dithiolene compound [4'-CF3bzPy][Ni(mnt)2], where 4'-CF3bzPy = 1-(4'-trifluoromethylbenzyl)pyridinium and mnt(2-) = maleonitriledithiolate, was obtained. The variable-temperature single crystal structures, magnetic behavior in 1.8-300 K and dielectric nature in 123-373 K have been investigated for the ß-crystal. This polymorph experiences two hysteretic magnetic phase transitions in a narrow temperature region (190-217 K) with the thermal hysteresis loops ca. 6 K and ca. 11 K. The two hysteretic magnetic phase transitions are coupled with two isostructural phase transitions (IPTs), respectively, which are driven by the novel step-wise dynamic orientation motion of the anion and cation in the ß-crystal. There is an absence of a dielectric anomaly in the structural transformation temperature interval. However, a dielectric relaxation, related to the dipole motion of polar CF3 groups in the cations under an ac electrical field, emerges in the high-temperature phase.