Low temperature soldering technology based on superhydrophobic copper microlayer.

Cu-Cu soldering is realized under certain pressure and low temperature conditions by using a surface silver film to modify the copper microlayer structure, thus solving the problems of high thermal stress and signal delay aggravation caused by high temperature in the traditional reflow soldering process. The copper microlayer modified with silver film is obtained by electrodeposition. The surface substructure of the Cu microlayer is a nano cone-shaped protrusion. The diameter of the bottom of the cone is 500 nm∼1 µm, and the height of the cone is 1∼2 µm. The thickness of the silver film is about 320 nm, and the modification of the copper layer with silver film can effectively prevent the oxidation of the copper layer. Two silver-modified copper microlayers are placed in face-to-face contact as a soldering couple. A certain pressure and low temperature are applied to the contact area to realize the soldering and interconnection. The morphology of the soldered interface and the average shear strength of the soldered joints are analyzed by scanning electron microscopy, transmission electron microscopy and solder joint tester. It is found that under the optimal soldering parameters of soldering temperature 220 °C, soldering pressure 20 MPa and soldering time 20 min, the nano-conical projections of the Cu micrometer layer are inserted into each other to produce a physical blocking effect. The highly surface-meltable silver film effectively connects the surrounding copper layer as an intermediate buffer layer. The average shear strength of soldering joints is significantly increased. Heat treatment experiments have shown that the average shear strength can be effectively increased by heat treatment for an appropriate period of time. Prolonged exposure to heat has little effect on the average shear strength. With the special morphology of the copper microlayer structure and the nano-size effect of the silver layer, soldering can be done at low temperatures. The quality of the soldering interface is good and small soldering dimensions can be obtained.

Stability of soil slope in Almaty covered with steel slag under the effect of rainfall.

The issue of rainfall-induced slope failure has attracted more attention from geotechnical engineers as a consequence of global warming. Current cumulative waste disposal has generated scientific interest in the utilization of waste materials in geotechnical design for climate change adaptation measures. Taking into consideration the effect of slope height and angle, steel slag-a waste product derived from the production of steel-was investigated as a slope cover against rainfall. To assess the stability of the slope and the infiltration of water into the soil, numerical analyses were conducted using both SEEP/W and SLOPE/W software in conjunction with rainfall conditions. Based on the findings, it can be concluded that increasing the slope's elevation and inclination will have an adverse effect on its safety factor. Steel slag can nevertheless be utilized for minimizing rainwater infiltration into the slope, as indicated by the pore-water pressure variations and graphs of the safety factor versus time. For a 20-m slope height, steel slag slopes have demonstrated a lower factor of safety difference in comparison to the initial slope without remediation. Regardless of slope angle and slope height, the safety factor reduces marginally during rainfall.

STING Agonist cGAMP Attenuates Sleep Deprivation-Induced Neuroinflammation and Cognitive Deficits via TREM2 Up-Regulation.

Sleep deprivation (SD) has been associated with several adverse effects, including cognitive deficit. Emerging evidence suggests microglia-associated neuroinflammation is a potential trigger of cognitive deficit after SD. Stimulator of interferon genes (STING) constitutes an important factor in host immune response to pathogenic organisms and is found in multiple cells, including microglia. STING is involved in neuroinflammation during neuronal degeneration, although how STING signaling affects SD-induced neuroinflammation remains unexplored. In the present study, the chronic sleep restriction (CSR) model was applied to examine the effects of STING signaling on cognition. The results revealed that cGAMP, a high-affinity and selective STING agonist, significantly improved cognitive deficit, alleviated neural injury, and relieved neuroinflammation in CSR mice by activating the STING-TBK1-IRF3 pathway. Moreover, triggering receptor expressed on myeloid cells 2 (TREM2) was upregulated in CSR mice treated with cGAMP, and this effect was abolished by STING knockout. TREM2 upregulation induced by cGAMP regulated the microglia from pro-inflammatory state to anti-inflammatory state, thereby relieving neuroinflammation in CSR mice. These findings indicate cGAMP-induced STING signaling activation alleviates SD-associated neuroinflammation and cognitive deficit by upregulating TREM2, providing a novel approach for the treatment of SD-related nerve injury.

Expression level of neutrophil extracellular traps in peripheral blood of patients with chronic heart failure complicated with venous thrombosis and its clinical significance.

OBJECTIVE: Previous studies have reported that neutrophil extracellular traps (NETs) have been identified to be involved in thrombosis, but the clinical value in chronic heart failure (CHF) patients with venous thrombosis is unclear. This study focused on the expression level of NETs in the peripheral blood of patients with CHF complicated with venous thrombosis and its clinical value. METHODS: 80 patients with CHF were included and divided into 2 groups according to the occurrence of venous thrombosis, and the expression levels of NETs in peripheral venous blood and lesion veins of the patients were detected through fluorescent staining. Myeloperoxidase-DNA (MPO-DNA) and citrullinated histone H3 (CitH3), markers of NETs, were detected by enzyme linked immunosorbent assay kit. The receiver operating characteristic (ROC) curve was used to analyze the value of peripheral venous blood NETs in the diagnosis of venous thrombosis in CHF patients, while the relationship between NETs in peripheral and lesion veins was analyzed by a unitary linear regression model. RESULTS: The results showed that the concentration of NETs, MPO-DNA, and CitH3 in CHF patients combined with venous thrombosis was markedly higher than that in patients without venous thrombosis, and the concentration of NETs, MPO-DNA, and CitH3 in lesion venous blood was notably higher than that in peripheral venous blood. Binary logistics regression analysis showed that NETs in peripheral venous blood were an independent risk factor for venous thrombosis in patients with heart failure. The unitary linear regression model fitted well, indicating a notable positive correlation between NETs concentrations in peripheral and lesion veins. The area under the ROC curve for diagnosing venous thrombosis was 0.85, indicating that peripheral blood NETs concentration levels could effectively predict venous thrombosis in CHF patients. CONCLUSION: The expression level of NETs was high in the peripheral blood of CHF patients combined with venous thrombosis and was the highest in lesion venous blood. NETs levels in peripheral blood had the value of diagnosing venous thrombosis in CHF patients, and the concentrations of NETs in peripheral and lesion veins are markedly positively correlated.

Intramolecular Ni-catalyzed reductive coupling enables enantiodivergent synthesis of linoxepin.

A nickel-catalyzed reductive tandem cyclization of the elaborated ß-bromo acetal with a dibenzoxepin scaffold was invented to strategically construct the remaining two rings in linoxepin. The generated diasterodivergent intermediates could be easily converted to both enantiomers of this unique cyclolignan molecule via facile oxidations, thus realizing enantiodivergent total synthesis of linoxepin for the first time.

RUNX1 facilitates heart failure progression through regulating TGF-ß-induced cardiac remodeling.

Background: Heart failure is caused by acute or chronic cardiovascular diseases with limited treatments and unclear pathogenesis. Therefore, it is urgent to explore new therapeutic targets and reveal new pathogenesis for heart failure. Methods: We carried out heart failure animal model by transverse aortic arch constriction (TAC) in mice. The left ventricular internal diameter diastole (LVIDd), left ventricular internal diameter systole (LVIDs), and ejection fraction (EF) value were detected using ultrasound and myocardial fibrosis was evaluated by Masson stain assay. Cell apoptosis in myocardial tissues were detected by TUNEL immunofluorescence stain. Signal pathway analysis was performed by dual-luciferase reporter assay and western blot. Results: Our results showed that inhibition of RUNX1 led to remission of cardiac enlargement induced by TAC in mice. Inhibition of RUNX1 also caused raise of EF and FS value under TAC-induced condition. Besides, RUNX1 inhibition mice showed decreased myocardial fibrosis area under TAC-induced condition. RUNX1 inhibition caused decrease of apoptotic cell rate in myocardial tissues under TAC. Interestingly, we found that RUNX1 could promote the activation of TGF-ß/Smads in dual-luciferase reporter assay. Interpretation: We illustrated that RUNX1 could be considered as a new regulator of myocardial remodeling by activating TGF-ß/Smads signaling. Based on this, we concluded that RUNX1 may be developed as a new therapeutic target against heart failure in the future. In addition, this study also provide a new insight for the etiological study on heart failure.

Activation of the Hippocampal DRD2 Alleviates Neuroinflammation, Synaptic Plasticity Damage and Cognitive Impairment After Sleep Deprivation.

Sleep loss is commonplace nowadays and profoundly impacts cognition. Dopamine receptor D2 (DRD2) makes a specific contribution to cognition, although the precise mechanism underlying how DRD2 affects the cognitive process after sleep deprivation remains unclear. Herein, we observed cognitive impairment and impaired synaptic plasticity, including downregulation of synaptophysin and PSD95, decreased postsynaptic density thickness, neuron complexity, and spine density in chronic sleep restriction (CSR) mice. We also observed downregulated hippocampal DRD2 and Cryab expression in the CSR mice. Meanwhile, NF-κB translocation from the cytoplasm to the nucleus occurred, indicating that neuroinflammation ensued. However, hippocampal delivery of the DRD2 agonist quinpirole effectively rescued these changes. In vitro, quinpirole treatment significantly decreased the release of proinflammatory cytokines in microglial supernatant, indicating a potential anti-neuroinflammatory effect of Drd2/Cryab/NF-κB in CSR mice. Our study provided the evidence that activation of the Drd2 may relieve neuroinflammation and improve sleep deprivation-induced cognitive deficits.

A Real-Time Evaluation Algorithm for Noncontact Heart Rate Variability Monitoring.

Noncontact vital sign monitoring based on radar has attracted great interest in many fields. Heart Rate Variability (HRV), which measures the fluctuation of heartbeat intervals, has been considered as an important indicator for general health evaluation. This paper proposes a new algorithm for HRV monitoring in which frequency-modulated continuous-wave (FMCW) radar is used to separate echo signals from different distances, and the beamforming technique is adopted to improve signal quality. After the phase reflecting the chest wall motion is demodulated, the acceleration is calculated to enhance the heartbeat and suppress the impact of respiration. The time interval of each heartbeat is estimated based on the smoothed acceleration waveform. Finally, a joint optimization algorithm was developed and is used to precisely segment the acceleration signal for analyzing HRV. Experimental results from 10 participants show the potential of the proposed algorithm for obtaining a noncontact HRV estimation with high accuracy. The proposed algorithm can measure the interbeat interval (IBI) with a root mean square error (RMSE) of 14.9 ms and accurately estimate HRV parameters with an RMSE of 3.24 ms for MEAN (the average value of the IBI), 4.91 ms for the standard deviation of normal to normal (SDNN), and 9.10 ms for the root mean square of successive differences (RMSSD). These results demonstrate the effectiveness and feasibility of the proposed method in emotion recognition, sleep monitoring, and heart disease diagnosis.

Reducing complement activation during sleep deprivation yields cognitive improvement by dexmedetomidine.

BACKGROUND: Sleep loss and its associated conditions (e.g. cognitive deficits) represent a large societal burden, but the underlying mechanisms of these cognitive deficits remain unknown. This study assessed the effect of dexmedetomidine (DEX) on cognitive decline induced by sleep loss. METHODS: C57BL/6 mice were subjected to chronic sleep restriction (CSR) for 20 h (5 pm-1 pm the next day) daily for 7 days, and cognitive tests were subsequently carried out. The neuromolecular and cellular changes that occurred in the presence and absence of DEX (100 µg kg-1, i.v., at 1 pm and 3 pm every day) were also investigated. RESULTS: CSR mice displayed a decline in learning and memory by 12% (P<0.05) in the Y-maze and by 18% (P<0.01) in the novel object recognition test; these changes were associated with increases in microglial activation, CD68+ microglial phagosome counts, astrocyte-derived complement C3 secretion, and microglial C3a receptor expression (all P<0.05). Synapse elimination, as indicated by a 66% decrease in synaptophysin expression (P=0.0004) and a 45% decrease in postsynaptic density protein-95 expression (P=0.0003), was associated with the occurrence of cognitive deficits. DEX activated astrocytic α2A adrenoceptors and inhibited astrocytic complement C3 release to attenuate synapse elimination through microglial phagocytosis. DEX restored synaptic connections and reversed cognitive deficits induced by CSR. CONCLUSIONS: The results demonstrate that complement pathway activation associated with synapse elimination contributes to sleep loss-related cognitive deficits and that dexmedetomidine protects against sleep deprivation-induced complement activation. Dexmedetomidine holds potential for preventing cognitive deficits associated with sleep loss, which warrants further study.

Dexmedetomidine attenuates sleep deprivation-induced inhibition of hippocampal neurogenesis via VEGF-VEGFR2 signaling and inhibits neuroinflammation.

Long periods of sleep deprivation (SD) have serious effects on health. While the α2 adrenoceptor agonist dexmedetomidine (DEX) can improve sleep quality for patients who have insomnia, the effect of DEX on cognition and mechanisms after SD remains elusive. C57BL/6 mice were subjected to 20 h SD daily for seven days. DEX (100 µg/kg) was administered intravenously twice daily (at 1:00 p.m. and 3:00 p.m.) during seven days of SD. We found that systemic administration of DEX attenuated cognitive deficits by performing the Y maze and novel object recognition tests and increased DCX+, SOX2+, Ki67+, and BrdU+NeuN+/NeuN+ cell numbers in the dentate gyrus (DG) region of SD mice by using immunofluorescence, western blotting, and BrdU staining. DEX did not reverse the decrease in DCX+, SOX2+, or Ki67+ cell numbers in SD mice after administration of the α2A-adrenoceptor antagonist BRL-44408. Furthermore, the vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) expression was upregulated in SD+DEX mice compared with SD mice. Luminex analysis showed that the neurogenic effects of DEX were possibly related to the inhibition of neuroinflammation, including IL-1α, IL-2, CCL5, and CXCL1. Our results suggested that DEX alleviated the impaired learning and memory of SD mice potentially by inducing hippocampal neurogenesis via the VEGF-VEGFR2 signaling pathway and by suppressing neuroinflammation, and α2A adrenoceptors are required for the neurogenic effects of DEX after SD. This novel mechanism may add to our knowledge of DEX in the clinical treatment of impaired memory caused by SD.

Reprogramming astrocytic NDRG2/NF-κB/C3 signaling restores the diabetes-associated cognitive dysfunction.

BACKGROUND: Dementia is a serious complication in patients with diabetes-associated cognitive dysfunction (DACD). In this study, we aim to explore the protective effect of exercise on DACD in diabetic mice, and the role of NDRG2 as a potential guarder for reversing the pathological structure of neuronal synapses. METHODS: Seven weeks of standardized exercise at moderate intensity was carried out using an animal treadmill in the vehicle + Run and STZ + Run groups. Based on quantitative transcriptome and tandem mass tag (TMT) proteome sequencing, weighted gene co-expression analysis (WGCNA) and gene set enrichment analysis (GSEA) were used to investigate the activation of complement cascades to injury neuronal synaptic plasticity. Golgi staining, Western blotting, immunofluorescence staining, and electrophysiology were used to verify the reliability of sequencing data. The role of NDRG2 was assessed by overexpressing or inhibiting the NDRG2 gene in vivo. Moreover, we estimated the cognitive function in diabetic or normal patients using DSST scores. FINDINGS: Exercise reversed the injury of neuronal synaptic plasticity and the downregulation of astrocytic NDRG2 in diabetic mice, which succeeded in attenuating DACD. The deficiency of NDRG2 aggravated the activation of complement C3 by accelerating the phosphorylation of NF-κB, ultimately leading to synaptic injury and cognitive dysfunction. Conversely, the overexpression of NDRG2 promoted astrocytic remodeling by inhibiting complement C3, thus attenuating synaptic injury and cognitive dysfunction. Meanwhile, C3aR blockade rescued dendritic spines loss and cognitive deficits in diabetic mice. Moreover, the average DSST score of diabetic patients was significantly lower than that of non-diabetic peers. Levels of complement C3 in human serum were elevated in diabetic patients compared to those in non-diabetic patients. INTERPRETATION: Our findings illustrate the effectiveness and integrative mechanism of NDRG2-induced improvement of cognition from a multi-omics perspective. Additionally, they confirm that the expression of NDRG2 is closely related to cognitive function in diabetic mice and the activation of complement cascades accelerated impairment of neuronal synaptic plasticity. NDRG2 acts as a regulator of astrocytic-neuronal interaction via NF-κB/C3/C3aR signaling to restore synaptic function in diabetic mice. FUNDING: This study was supported by the National Natural Science Foundation of China (No. 81974540, 81801899, 81971290), the Key Research and Development Program of Shaanxi (Program No. 2022ZDLSF02-09) and Fundamental Research Funds for the Central Universities (Grant No. xzy022019020).

Tri-Layered Bicomponent Microfilament Composite Fabric for Highly Efficient Cold Protection.

Functional thin fabric with highly efficient cold protection properties are attracting the great attention of long-term dressing in a cold environment. Herein, a tri-layered bicomponent microfilament composite fabric comprised of a hydrophobic layer of PET/PA@C6 F13 bicomponent microfilament webs, an adhesive layer of LPET/PET fibrous web, and a fluffy-soft layer of PET/Cellulous fibrous web is designed and also successfully been fabricated through a facile process of dipping, combined with thermal belt bonding. The prepared samples exhibit a large resistance to wetting of alcohol, a high hydrostatic pressure of 5530 Pa, and brilliant water slipping properties, owing to the presence of dense micropores ranging from 25.1 to 70.3 µm, as well as to the smooth surface with an arithmetic mean deviation of surface roughness (Sa) ranging from 5.112 to 4.369 µm. Besides, the prepared samples exhibited good water vapor permeability, and a tunable CLO value ranging from 0.569 to 0.920, in addition to the fact that it exhibited a very suitable working temperature range of -5 °C to 15 °C. Additionally, it also showed excellent clothing tailorability including high mechanical strength with a remarkably soft texture and lightweight foldability that suitable for cold outdoor clothing applications.

PirB negatively regulates the inflammatory activation of astrocytes in a mouse model of sleep deprivation.

Reactive astrocytes play a potential regulatory role in sleep deprivation (SD). Paired immunoglobulin-like receptor B (PirB) is expressed in reactive astrocytes, suggesting that PirB may participate in regulating the inflammatory response of astrocytes. We used lentiviral and adeno-associated viral approaches to interfere with the expression of PirB in vivo and in vitro. C57BL/6 mice were sleep deprived for 7 days and neurological function was measured via behavioral tests. We found that overexpressed PirB in SD mice could decrease the number of neurotoxic reactive astrocytes, alleviate cognitive deficits, and promote reactive astrocytes tended to be neuroprotective state. IL-1α, TNFα, and C1q were used to induce neurotoxic reactive astrocytes in vitro. Overexpression of PirB relieved the toxicity of neurotoxic astrocytes. Silencing PirB expression had the opposite effect and exacerbated the transition of reactive astrocytes to a neurotoxic state in vitro. Moreover, PirB-impaired astrocytes demonstrated STAT3 hyperphosphorylation which could be reversed by stattic (p-STAT3 inhibitor). Furthermore, Golgi-Cox staining confirmed that dendrite morphology defects and synapse-related protein were significantly increased in PirB-overexpressed SD mice. Our data demonstrated that SD induced neurotoxic reactive astrocytes and contributed to neuroinflammation and cognitive deficits. PirB performs a negative regulatory role in neurotoxic reactive astrocytes via the STAT3 signaling pathway in SD.

Inhibition of VDAC1 prevents oxidative stress and apoptosis induced by bisphenol A in spermatogonia via AMPK/mTOR signaling pathway.

Bisphenol A (BPA), one of the main components of industrial products, is clinically associated with the increased male infertility rate. However, the underlying molecular mechanism of the BPA-resulted reproductive toxicity is not fully elucidated. Voltage-dependent anion channel 1 (VDAC1) is a pore protein and located at the outer mitochondrial membrane. As a mitochondrial gatekeeper, VDAC1 controls the release of reactive oxygen species (ROS) and the metabolic and energetic functions of mitochondria, and serves as a critical player in mitochondrial-mediated apoptosis. Herein, we explored the role of VDAC1 in BPA-induced apoptosis of spermatogonia. The results showed that BPA increased spermatogonia cell line GC-1 spg cell apoptosis and intracellular ROS level, and suppressed AMPK/mTOR signaling pathway at a dose of 80 µM for 48 hr. Lentivirus-mediated short hairpin RNA targeting VDAC1 (Lv-shVDAC1) silenced VDAC1 expression and enhanced BPA-restricted cell viability. Knockdown of VDAC1 inhibited the apoptosis of BPA-treated GC-1 spg cells determined by with changes of the expressions of pro-apoptotic and anti-apoptotic proteins. Knockdown of VDAC1 also alleviated the BPA-triggered intracellular ROS generation and oxidative stress. Moreover, silence of VDAC1 increased AMPKα1/2 phosphorylation and suppressed mTOR phosphorylation under BPA exposure. Dorsomorphin, an AMPK inhibitor, partially abolished the effects of VDAC1 gene silencing on BPA-stimulated GC-1 spg cells. In conclusion, inhibition of VDAC1 attenuated the BPA-induced oxidative stress and apoptosis and promoted the cell viability in spermatogonia through modulating AMPK/mTOR signaling pathway.

Esketamine ameliorates post-stroke anxiety by modulating microglial HDAC3/NF-κB/COX1 inflammatory signaling in ischemic cortex.

Post-stroke anxiety (PSA) is a kind of affective disorder occurring after a stroke, with anxiety as the primary clinical manifestation. PSA's mechanism is unclear, and there are few prevention and treatment measures. Our previous study found that HDAC3 could activate NF-κB signaling through mediated p65 deacetylation, which further influenced microglia activation. That implies HDAC3 may be the key mediator in ischemic stroke mice and modulates anxiety susceptibility to stress. This study established a PSA model in male C57BL/6 mice through photothrombotic stroke combined with chronic restrain stress. We focused on exploring whether esketamine administration can alleviate anxiety-like behavior and neuroinflammation, which may be associated with inhibiting HDAC3 expression and NF-κB pathway activation. The results showed that esketamine administration alleviated anxiety-like behavior in PSA mice. And the results showed that esketamine alleviated cortical microglial activation, altered microglial number, and kept morphology features. Furthermore, the results showed that the expression of HDAC3, phosphor-p65/p65, and COX1 significantly decreased in esketamine-treated PSA mice. Besides, we also found that esketamine reduced PGE2 expression, one of the primary regulators of negative emotions. Interestingly, our results indicate that esketamine reduced the perineuronal net (PNN) number in the pathological process of PSA. In conclusion, this study suggests esketamine could alleviate microglial activation, reduces inflammatory cytokine, and inhibits the expression of HDAC3 and NF-κB in the cortex of PSA mice to attenuate anxiety-like behavior. Our results provided a new potential therapeutic target for applying esketamine to PSA.

The deconstruction and recombination of endogenous active units of carbon@chitosan@montmorillonite nanosheet microsphere adsorbent caused by cadmium and copper cations benefit for high adsorption performance.

The highly efficient removal of heavy metals is one of the important factors to evaluate adsorbents. In our study, carbon@chitosan@montmorillonite nanosheet (C@CS@MTN) was successfully prepared via layer-by-layer assembly for the removal of Cu2+ and Cd2+ from solution. High-intensity ultrasound peeling technology was used to release Si-O tetrahedron and Al-O octahedron from montmorillonite in order to exert their optimal adsorption potential. Fourier transform infrared spectroscopy, an X-ray diffractometer, BET surface area measurement, and the inductively coupled plasma emission spectrometry were adopted to investigate the morphology, functional groups, and adsorption capacity of C@CS@MTN. Batch experiment results indicated that both Cu2+ and Cd2+ were effectively removed from solution with the range of pH from 2 to 6. The removal ratio of Cu2+ and Cd2+ onto C@CS@MTN increased with the rise of reaction temperature and their maximum adsorption capacities reached 1108.8 mg·g-1 and 237.4 mg·g-1, respectively, under the condition of the reaction temperature 40 °C, the reaction time 4 h, and the pH = 6. The molecular simulation calculation indicated that there was an obvious electron transfer between Si-O tetrahedron and metal cations, but not for Al-O octahedron. In comparison to Al-O octahedron, the bonding of Cu-O and Cd-O caused the Si-O bond to be broken, resulting in the deconstruction of Si-O tetrahedron and their recombination via the junction of O atoms. It was exactly the deconstruction and recombination of endogenous active units that provide more sites for metal ion adsorption.

A novel somatic mutation in POLE exonuclease domain associated with ultra-mutational signature and MMR deficiency in endometrial cancer: a case report.

BACKGROUND: Defect in proofreading exonuclease activity of polymerases epsilon and delta (Pols ε and δ) leads to mutagenesis and genomic instability and has been described in several cancer types. Somatic POLE exonuclease domain mutations (EDMs) have been reported in 7-12% endometrial cancers (ECs) and defined a subgroup of endometrial cancers with ultrahigh somatic mutation frequencies, high tumor infiltrated lymphocytes and favorable outcomes. CASE PRESENTATION: Herein, we presented a novel somatic mutation in POLE exonuclease domain associated with ultra-mutational signature and MMR deficiency in endometrial cancer. A novel POLE EDM (p.T278K) was found by a 11-gene NGS panel. The MSS status detected by the MSI test was inconsistent with the dMMR status by IHC. The loss of MSH6 expression in the tumor could be interpreted by the two nonsense mutations (p.E1234* and p.E1322*) of the MSH6 gene which may lead to truncated proteins. The T278K mutation was pathogenic identified by a 602-gene NGS panel with 27.3% of C > A substitution, 0.6% of indels, 0.6% of C > G substitution and a high TMB of 203.8 mut/Mb. CONCLUSIONS: We report an endometrial cancer patient harbored a novel somatic POLE T278K mutation. This mutation was a novel pathogenic POLE EDM should be considered as "POLE (ultramutated)" in clinical practice for the molecular classification of EC.

CD33/TREM2 Signaling Mediates Sleep Deprivation-Induced Memory Impairment by Regulating Microglial Phagocytosis.

Sleep deprivation causes significant memory impairment in healthy adults. Extensive research has focused on identifying the biological mechanisms underlying memory impairment. Microglia-mediated synaptic elimination plays an indispensable role in sleep deprivation. Here, the potential role of the CD33/TREM2 signaling pathway in modulating memory decline during chronic sleep restriction (CSR) was evaluated. In this study, adult male C57BL/6 mice were sleep-restricted using an automated sleep deprivation apparatus for 20 h per day for 7 days. The Y-maze test revealed that spontaneous alternation was significantly reduced in CSR mice compared with control mice. The percentage of exploratory preference for the novel object in CSR mice was significantly decreased compared with that in control mice. These memory deficits correlated with aberrant microglial activation and increased phagocytic ability. Moreover, in CSR mice, the CD33 protein level in hippocampal tissue was significantly downregulated, but the TREM2 protein level was increased. In BV2 microglial cells, downregulation of CD33 increased TREM2 expression and improved microglial phagocytosis. Then, the sialic ligand monosialo-ganglioside 1 (GM1, 20 mg/kg, i.p.) was administered to mice once a day during CSR. Our results further showed that GM1 activated CD33 and consequently disturbed TREM2-mediated microglial phagocytosis. Finally, GM1 reversed CSR-induced synaptic loss and memory impairment via the CD33/TREM2 signaling pathway in the CA1 region of the hippocampus. This study provides novel evidence that activating CD33 and/or inhibiting TREM2 activity represent potential therapies for sleep loss-induced memory deficits through the modulation of microglial phagocytosis.

Involvement of Paired Immunoglobulin-Like Receptor B in Cognitive Dysfunction Through Hippocampal-Dependent Synaptic Plasticity Impairments in Mice Subjected to Chronic Sleep Restriction.

Sleep loss is often associated with cognitive dysfunction. Alterations in the structure and function of synapses in the hippocampus are thought to underlie memory storage. Paired immunoglobulin-like receptor B (PirB) plays a negative role in various neurological diseases by inhibiting axon regeneration and synaptic plasticity. However, the contributions of PirB to the mechanisms underlying the changes in synaptic plasticity after sleep loss that ultimately promote deficits in cognitive function have not been well elucidated. Here, we showed that chronic sleep restriction (CSR) mice displayed cognitive impairment and synaptic deficits accompanied by upregulation of PirB expression in the hippocampus. Mechanistically, PirB caused the dysregulation of actin through the RhoA/ROCK2/LIMK1/cofilin signalling pathway, leading to abnormal structural and functional plasticity, which in turn resulted in cognitive dysfunction. PirB knockdown alleviated synaptic deficits and cognitive impairment after CSR by inhibiting the RhoA/ROCK2/LIMK1/cofilin signalling pathway. Moreover, we found that fasudil, a widely used ROCK2 inhibitor, could mimic the beneficial effect of PirB knockdown and ameliorate synaptic deficits and cognitive impairment, further demonstrating that PirB induced cognitive dysfunction after CSR via the RhoA/ROCK2/LIMK1/cofilin signalling pathway. Our study sheds new light on the role of PirB as an important mediator in modulating the dysfunction of synaptic plasticity and cognitive function via the RhoA/ROCK2/LIMK1/cofilin signalling pathway, which indicated that hippocampal PirB is a promising therapeutic target for counteracting cognitive impairment after CSR. This illustration depicts the signalling pathway by PirB in mediating cognitive impairment and synaptic deficits in CSR mice. In the hippocampus of CSR mice, the expression level of PirB was significantly increased. In addition, CSR increases RhoA and ROCK2 levels and reduces levels of both LIMK1 and cofilin phosphorylation. PirB knockdown reverses cognitive impairment and synaptic plasticity disorders caused by CSR through the RhoA/ROCK2/LIMK1/cofilin signalling pathway.

Changes in pathogens of neonatal bacterial meningitis over the past 12 years: a single-center retrospective study.

Background: Bacterial meningitis is a serious central nervous system infection associated with high morbidity and mortality during the neonatal period, while the pathogen distribution was rarely reported on a large scale in China. This study aimed to investigate the distribution and change trends of neonatal bacterial meningitis pathogens in Children's Hospital of Fudan University over the past 12 years. Methods: This retrospective study included all cases diagnosed with neonatal bacterial meningitis and admitted to our hospital from 2009 to 2020. Results: Totally 231 cases were enrolled, including 128 (55.4%) for male, 72 (31.2%) for premature infants, 48 (20.8%) for early-onset meningitis. The most common pathogens were Escherichia coli (E. coli) (39.0%) and Group B Streptococcus (GBS) (22.1%). Gram-negative bacteria were more common in preterm infants than in full-term infants (P=0.005). GBS was more common in term infants (P=0.000); Klebsiella pneumoniae (P=0.000) and Enterobacter cloacae (P=0.034) were more common in preterm infants. Gram-positive bacteria were more frequent in early-onset meningitis than in late-onset meningitis (P=0.002). Both E. coli (46.3% vs. 30.9%, P=0.017) and GBS (29.8% vs. 13.6%, P=0.003) increased, and Enterococcus (3.3% vs. 12.7%, P=0.008) decreased significantly in the epoch from 2015 to 2020 compared with the epoch from 2009 to 2014. Conclusions: GBS and E. coli are the most common pathogens of neonatal bacterial meningitis in our hospital, and both have shown an upward trend over the past 12 years.