Intracellular tau accumulation forming neurofibrillary tangles is hallmark pathology of Alzheimer's disease (AD), but how tau accumulation induces synapse impairment is elusive. By overexpressing ...human full‐length wild‐type tau (termed hTau) to mimic tau abnormality as seen in the brain of sporadic AD patients, we find that hTau accumulation activates JAK2 to phosphorylate STAT1 (signal transducer and activator of transcription 1) at Tyr701 leading to STAT1 dimerization, nuclear translocation, and its activation. STAT1 activation suppresses expression of N‐methyl‐D‐aspartate receptors (NMDARs) through direct binding to the specific GAS element of GluN1, GluN2A, and GluN2B promoters, while knockdown of STAT1 by AAV‐Cre in STAT1flox/flox mice or expressing dominant negative Y701F‐STAT1 efficiently rescues hTau‐induced suppression of NMDAR expression with amelioration of synaptic functions and memory performance. These findings indicate that hTau accumulation impairs synaptic plasticity through JAK2/STAT1‐induced suppression of NMDAR expression, revealing a novel mechanism for hTau‐associated synapse and memory deficits.
Synopsis
Tau accumulation, one hallmark of Alzheimer's disease, induces synaptic impairment by activating JAK2/STAT1 signaling, which transcriptionally suppresses N‐methyl‐D‐aspartate receptors. Downregulation of STAT1 ameliorates synaptic function and memory performance in mice.
Accumulation of hTau triggers JAK2‐dependent STAT1 dimerization, activation and nuclear translocation.
STAT1 activation directly suppresses N‐methyl‐D‐aspartate receptor expression.
Downregulation of STAT1 rescues hTau‐induced N‐methyl‐D‐aspartate receptor suppression.
Tau accumulation, one hallmark of Alzheimer's disease, induces synaptic impairment by activating JAK2/STAT1 signaling, which transcriptionally suppresses N‐methyl‐D‐aspartate receptors. Downregulation of STAT1 ameliorates synaptic function and memory performance in mice.
Enzymatic pretreatment of activated sludge, food waste and their mixture for enhanced methane production. Display omitted
•Fungal mash rich in hydrolytic enzymes was produced from cake waste.•The CH4 ...production was improved after pretreatment of biosolids with fungal mash.•54.3% of volume reduction of biosolids was achieved after anaerobic co-digestion.•WWTPs may become an energy producer via anaerobic co-digestion of biosolids.
In the present study, the in-situ produced fungal mash rich in hydrolytic enzymes was used for the pretreatment of activated sludge, food waste and their mixture prior to anaerobic digestion. The enzymatic pretreatment of activated sludge mixed with food waste resulted in the production of 3.72g/L glucose and 51mg/L free amino nitrogen, equivalent to 7.65g/L soluble chemical oxygen demand (SCOD) within 24h, accompanied with 19.9% of volatile solids (VS) reduction. After pretreatment of activated sludge and food waste by fungal mash, 19.1% and 21.4% of VS reduction were achieved respectively. Furthermore, the bio-methane yield of mixed waste pretreated with fungal mash was found to be 2.5 times higher than activated sludge without pretreatment, with a further VS reduction of 34.5%. These suggest a total VS reduction of 54.3% in the proposed anaerobic system with the pretreatment by fungal mash. Theoretical estimation further revealed that about 678millionkWh of electrical energy could be potentially recovered annually through the co-digestion of mixed waste activated sludge and food waste after the pretreatment with fungal mash in Singapore. In this case, the energy produced was higher than energy consumed by wastewater treatment. It was demonstrated in this study that the pretreatment of mixed activated sludge and food waste by in-situ produced fungal mash would be a promising option for enhancing biomethane production as well as for maximizing volume reduction of mixed waste via anaerobic co-digestion.
Biothiols, such as cysteine (Cys) and homocysteine (Hcy), play very crucial roles in biological systems. Abnormal levels of these biothiols are often associated with many types of diseases. ...Therefore, the detection of Cys (or Hcy) is of great importance. In this work, we have synthesized an excellent “OFF‐ON” phosphorescent chemodosimeter 1 for sensing Cys and Hcy with high selectivity and naked‐eye detection based on an IrIII complex containing a 2,4‐dinitrobenzenesulfonyl (DNBS) group within its ligand. The “OFF‐ON” phosphorescent response can be assigned to the electron‐transfer process from IrIII center and C^N ligands to the DNBS group as the strong electron‐acceptor, which can quench the phosphorescence of probe 1 completely. The DNBS group can be cleaved by thiols of Cys or Hcy, and both the 3MLCT and 3LC states are responsible for the excited‐state properties of the reaction product of probe 1 and Cys (or Hcy). Thus, the phosphorescence is switched on. Based on these results, a general principle for designing “OFF‐ON” phosphorescent chemodosimeters based on heavy‐metal complexes has been provided. Importantly, utilizing the long emission‐lifetime of phosphorescence signal, the time‐resolved luminescent assay of 1 in sensing Cys was realized successfully, which can eliminate the interference from the short‐lived background fluorescence and improve the signal‐to‐noise ratio. As far as we know, this is the first report about the time‐resolved luminescent detection of biothiols. Finally, probe 1 has been used successfully for bioimaging the changes of Cys/Hcy concentration in living cells.
Seeing sense: An excellent “OFF–ON” phosphorescent chemodosimeter for sensing cysteine (Cys) and homocysteine (Hcy) with high selectivity and naked‐eye detection based on an IrIII complex has been developed (see scheme). The time‐resolved luminescent assay of this probe for sensing Cys was achieved by using the long emission lifetime of phosphorescence, which can eliminate interference from short‐lived background fluorescence and improve the signal‐to‐noise ratio. The probe has been used for the bioimaging of changes in Cys/Hcy concentration in living cells.
A ternary polymer memory device based on a single polymer with on‐chain Ir(III) complexes is fabricated by combining multiple memory mechanisms into one system. Excellent ternary memory ...performances—low reading, writing, and erasing voltages and good stability for all three states—are achieved.
Due to their unique advantages, single atoms and clusters of transition metals are expected to achieve a breakthrough in catalytic activity, but large‐scale production of active materials remains a ...challenge. In this work, a simple solvent‐free one‐step annealing method is developed and applied to construct diatomic and cluster active sites in activated carbon by utilizing the strong anchoring ability of phenanthroline to metal ions, which can be scaled for mass productions. Benefiting from the synergy between the different metals, the obtained sub‐nano‐bimetallic atom‐cluster catalysts (FeNiAC‐NC) exhibit high oxygen reduction reactions (ORR) activity (E1/2 = 0.936 V vs. RHE) and a small ORR/oxygen evolution reaction (OER) potential gap of only 0.594 V. An in‐house pouch Zn‐air battery is assembled using an FeNiAC‐NC catalyst, which demonstrates a stability of 1000 h, outperforming previous reports. The existence of clusters and their effects on catalytic activity is analyzed by density functional theory calculations to reveal the chemistry of nano‐bimetallic atom‐cluster catalysts.
A simple solvent‐free one‐step annealing method is developed and applied to construct diatomic and cluster active sites in activated carbon by utilizing the strong anchoring ability of phenanthroline to metal ions, which can be scaled for mass production. The synergy between the two metals results in excellent catalytic activity in an in‐house pouch Zn‐air battery.
To report the 12-month results of the first human uterus transplantation case using robot-assisted uterine retrieval. This type of transplantation may become a treatment for permanent uterine factor ...infertility.
Case study.
University hospital.
A 22-year-old woman with complete müllerian agenesis who underwent a previous surgery for vaginal reconstruction. The live uterine donor was her mother.
The uterus transplantation procedure consisted of robot-assisted uterine procurement, orthotopic replacement and fixation of the retrieved uterus, revascularization, and end-to-side anastomoses of bilateral hypogastric arteries and ovarian-uterine vein to the bilateral external iliac arteries and veins.
Data from preoperative investigations, surgery, and follow-up (12 months).
The duration of the donor and recipient surgeries were 6 and 8 hours, 50 minutes, respectively. No immediate perioperative complications occurred in the recipient or donor. The recipient experienced menarche 40 days after transplant surgery, and she has had 12 menstrual cycles since the surgery. No rejection episodes occurred in the recipient.
These results demonstrate the feasibility of live-donor uterine transplantation with a low-dose immunosuppressive protocol and the role of DaVinci robotic assistance during human uterine procurement.
XJZT12Z06.
The number of patients with non-human immunodeficiency virus (HIV) related pneumocystis carinii pneumonia (PCP) is increasing with widespread immunosuppressive treatment. We performed a meta-analysis ...to describe the clinical characteristics and factors associated with outcomes of PCP in HIV-negative patients. A total of 13 studies including 867 patients with non-HIV related PCP was included. The overall mortality for non-HIV patients with PCP was 30.6%. The most common underlying disorder for the development of PCP is hematological malignancies (29.1%), followed by autoimmune disease (20.1%), organ or bone marrow transplantation (14.0%), and solid tumors (6.0%). Risk factors associated with increased mortality rate including old age, female sex, longer time from onset of symptoms to diagnosis, respiratory failure, solid tumors, high lactate dehydrogenase, low serum albumin, bacterial, and aspergillus co-infection, etc (
< 0.05). Adjunctive corticosteroid and PCP prophylaxis was not shown to improve the outcome of PCP in non-HIV patients (
> 0.05). Our findings indicate that mortality in non-HIV patients with PCP is high. Improved knowledge about the prognostic factors may guide the early treatment.
As one of the most promising optoelectronic materials, polymers that contain phosphorescent IrIII complexes have attracted more and more interest in recent years. They are a class of well‐known ...electroluminescent materials with excellent performance. So far, efficient green‐, red‐, and white‐emitting polymer light‐emitting diodes based on polymers with on‐chain IrIII complexes have been realized successfully. For the realization of this class of polymer material, IrIII complexes (as energy guest) can be introduced into the main‐chain or side‐chain of polymers (as energy host). In this article, we summarize the design principles, synthetic routes, structure–property relationships, and applications in optoelectronic devices of polymers that contain phosphorescent IrIII complexes.
As one of the most promising optoelectronic materials, polymers that contain phosphorescent IrIII complexes have attracted more and more interest in recent years. They have been applied successfully in polymer light‐emitting diodes. In this article, the design principles, synthetic routes, structure–property relationships, and applications in optoelectronic devices of polymers that contain phosphorescent IrIII complexes are summarized.
Abnormal activation of the extrasynaptic N‐methyl‐d‐aspartate receptor (NMDAR) contributes to the pathogenesis of Alzheimer's disease (AD). Ceftriaxone (Cef) can improve cognitive impairment by ...upregulating glutamate transporter‐1 and promoting the glutamate–glutamine cycle in an AD mouse model. This study aimed to investigate the effects of Cef on synaptic plasticity and cognitive‐behavioral impairment and to unravel the associated underlying mechanisms. We used an APPswe/PS1dE9 (APP/PS1) mouse model of AD in this study. Extrasynaptic components from hippocampal tissue homogenates were isolated using density gradient centrifugation. Western blot was performed to evaluate the expressions of extrasynaptic NMDAR and its downstream elements. Intracerebroventricular injections of adeno‐associated virus (AAV)‐striatal enriched tyrosine phosphatase 61 (STEP61) and AAV‐STEP61‐shRNA were used to modulate the expressions of STEP61 and extrasynaptic NMDAR. Long‐term potentiation (LTP) and Morris water maze (MWM) tests were performed to evaluate the synaptic plasticity and cognitive function. The results showed that the expressions of GluN2B and GluN2BTyr1472 in the extrasynaptic fraction were upregulated in AD mice. Cef treatment effectively prevented the upregulation of GluN2B and GluN2BTyr1472 expressions. It also prevented changes in the downstream signals of extrasynaptic NMDAR, including increased expressions of m‐calpain and phosphorylated p38 MAPK in AD mice. Furthermore, STEP61 upregulation enhanced, whereas STEP61 downregulation reduced the Cef‐induced inhibition of the expressions of GluN2B, GluN2BTyr1472, and p38 MAPK in the AD mice. Similarly, STEP61 modulation affected Cef‐induced improvements in induction of LTP and performance in MWM tests. In conclusion, Cef improved synaptic plasticity and cognitive behavioral impairment in APP/PS1 AD mice by inhibiting the overactivation of extrasynaptic NMDAR and STEP61 cleavage due to extrasynaptic NMDAR activation.
Glutamate receptor GLT‐1 damage leads to increased perisynaptic glutamate concentration in Alzheimer's disease (AD), which activates extrasynaptic N‐methyl‐d‐aspartate receptor (eNMDAR) and its downstream signaling and causes impairment of synaptic plasticity and cognition. The results showed that ceftriaxone downregulated eNMDAR expression, inhibited eNMDAR‐STEP61 and p38 MAPK signaling, and improved impairments of long‐term potentiation (LTP) and Morris water maze in AD mice. The STEP61‐mediated modulation of eNMDAR confirmed the hypothesis that ceftriaxone exerts anti‐AD effects by improving GLT‐1 impairment and inhibiting the activation of eNMDAR and its downstream signals.
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