Although SARS-CoV-2 primarily targets the respiratory system, patients with and survivors of COVID-19 can suffer neurological symptoms
. However, an unbiased understanding of the cellular and ...molecular processes that are affected in the brains of patients with COVID-19 is missing. Here we profile 65,309 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples across 14 control individuals (including 1 patient with terminal influenza) and 8 patients with COVID-19. Although our systematic analysis yields no molecular traces of SARS-CoV-2 in the brain, we observe broad cellular perturbations indicating that barrier cells of the choroid plexus sense and relay peripheral inflammation into the brain and show that peripheral T cells infiltrate the parenchyma. We discover microglia and astrocyte subpopulations associated with COVID-19 that share features with pathological cell states that have previously been reported in human neurodegenerative disease
. Synaptic signalling of upper-layer excitatory neurons-which are evolutionarily expanded in humans
and linked to cognitive function
-is preferentially affected in COVID-19. Across cell types, perturbations associated with COVID-19 overlap with those found in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia and depression. Our findings and public dataset provide a molecular framework to understand current observations of COVID-19-related neurological disease, and any such disease that may emerge at a later date.
In this study, we adopt laser-melting deposition (LMD) technology to fabricate TiB2/7075 aluminum matrix composites (AMCs), and we investigate in detail the effect of the TiB2 content on the ...microstructure, nano-hardness, compressive properties, and wear performance. We prepare experimental samples by using a laser power of 800 W and a velocity of 0.01 m/s, and the results are evaluated. It was observed that the reinforcement particles dispersed irregularly throughout the Al matrix as the TiB2 contents increased. The grain size of the fine-grain zone decreased appreciably by 31.9% from 8.41 µm (LMD sample without TiB2 reinforcement) to 5.73 µm. Furthermore, the AMCs with 4 wt% reinforcement exhibited impressive mechanical properties, i.e., nanohardness of 1.939 Gpa, compressive strength of 734.8 MPa, and a wear rate of 1.889 × 10−4 mm3/Nm. The wear resistance improved and the wear mechanism changed from adhesive wear to debris wear with the addition of TiB2 reinforcement.
Laser welding–brazing of Ti/Al butt joints was performed with coaxial Al–10Si–Mg powders feeding. The experimental results indicated that a sound Ti/Al butt joint could be obtained by an additive ...layer approach. The influence of the laser melting deposition layers on the weld appearance, interfacial microstructure and tensile properties were investigated. High-quality joints were produced when five and seven layers were deposited. The morphology and thickness distributions of the interfacial intermetallic compounds (IMC) at the brazing interface along the thickness direction of the joint varied with the number of deposition layers. Continuous serrated IMC was obtained in joints produced by seven deposition layers, and the IMC layer was distributed homogenously along the thickness direction. The maximum thickness difference of the IMC was only approximately 0.12 μm. The microstructure of the IMC layer was composed of a nanosized granular Ti7Al5Si12 phase and serrated Ti(Al, Si)3 phase. The maximum tensile joint strength reached 240 MPa, 80% of that of the aluminum base metal, and the lower tensile strength of the other joints was caused by insufficient IMC layer or a porosity defect.
Background Inflammation plays an important role in tumor proliferation, metastasis, and resistance to chemotherapy. The systemic inflammation response index (SIRI), has been reported to be closely ...related to prognosis in many tumors, such as breast and gastric cancers. However, the predictive value of pretreatment SIRI on pathological complete response (pCR) rates in patients with breast cancer treated with neoadjuvant chemotherapy (NAC) is unknown. This study examined the correlation between SIRI and pCR in patients with breast cancer receiving NAC and identified convenient and accurate predictive indicators for pCR. Methods We retrospectively analyzed the clinicopathological parameters and pretreatment peripheral blood characteristics of the 241 patients with breast cancer who received NAC between June 2015 and June 2020. Receiver operating characteristic (ROC) curves were used to determine the optimal cutoff of SIRI. ROC curves were also plotted to verify the accuracy of inflammatory markers for pCR prediction. The chi-squared test was used to explore the relationships of SIRI with pCR and other clinicopathological parameters. Multivariate analyses were performed using a logistic regression model. Results Among the 241 patients, 48 (19.92%) achieved pCR. pCR was significantly related to SIRI, the neutrophil-lymphocyte ratio (NLR), the lymphocyte-monocyte ratio (LMR), molecular subtypes and other clinicopathological parameters, such as BMI, clinical T and N staging, and histological grade. Multivariate analyses indicated that the clinical T and N staging, SIRI, and NLR were independent prognostic factors for pCR in patients with breast cancer. The area under the ROC curve for SIRI was larger than that for NLR. Compared to patients with SIRI greater than or equai to0.72, patients with SIRI < 0.72 had a nearly 5-fold higher chance of obtaining pCR (odds ratio = 4.999, 95% confidence interval = 1.510-16.551, p = 0.000). Conclusions Pretreatment SIRI is predictive of pCR in patients with breast cancer receiving NAC, and the index can assist physicians in formulating personalized treatment strategies. Keywords: Breast cancer, Neoadjuvant chemotherapy, Systemic inflammation response index, SIRI, Pathological complete response
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Amyloid precursor protein (APP) is enriched at the synapse, but its synaptic function is still poorly understood. We previously showed that GABAergic short-term plasticity is impaired in
knock-out (
...) animals, but the precise mechanism by which APP regulates GABAergic synaptic transmission has remained elusive. Using electrophysiological, biochemical, moleculobiological, and pharmacological analysis, here we show that APP can physically interact with KCC2, a neuron-specific K
-Cl
cotransporter that is essential for Cl
homeostasis and fast GABAergic inhibition. APP deficiency results in significant reductions in both total and membrane KCC2 levels, leading to a depolarizing shift in the GABA reversal potential (E
). Simultaneous measurement of presynaptic action potentials and inhibitory postsynaptic currents (IPSCs) in hippocampal neurons reveals impaired unitary IPSC amplitudes attributable to a reduction in α1 subunit levels of GABA
R. Importantly, restoration of normal KCC2 expression and function in
mice rescues E
, GABA
R α1 levels and GABA
R mediated phasic inhibition. We show that APP functions to limit tyrosine-phosphorylation and ubiquitination and thus subsequent degradation of KCC2, providing a mechanism by which APP influences KCC2 abundance. Together, these experiments elucidate a novel molecular pathway in which APP regulates, via protein-protein interaction with KCC2, GABA
R mediated inhibition in the hippocampus.
The new generation of Sc and Zr modified Al alloys has been attracted wide concerns in aerospace industry, owing to the excellent mechanical performances and superior thermal stability than other ...normal Al alloys. By microalloying with Sc and Zr, the Al3(Sc, Zr) particle forms as the grain refiner during the solidification, which is extremely beneficial for the laser powder bed fusion (LPBF) processed Al alloys. In this study, a new type Al-14.1Mg-0.47Si-0.31Sc-0.17 Zr alloy was additively manufactured by LPBF, and the microstructure, tensile properties and thermal stability were studied in detail. By using a single melt-67° scanning strategy, the LPBF-processed specimen with a relative density of 99.4 % and tensile strength of 487.7 MPa was obtained at 160 W-200 mm/s. And this AlMgSiScZr alloy can still exhibit an excellent tensile strength of 393.9 MPa at a moderate temperature of 473 K. After the aging treatment, the tensile properties further increased due to the precipitate hardening of Mg2Si and Al3(Sc, Zr), and the maximum value (580 MPa) was reached at an aging time of 10 h. The average crystal size was almost unchanged after aging treated at 325 ℃ and 24 h, indicating this AlMgSiScZr alloy has an improved thermal stability. The AlMgSiScZr alloy is recommended to substitute some particular titanium alloys in aerospace field afterwards.
A one‐pot transition‐metal‐free selective iodoarylation of pyrazoles with aryliodine diacetates has been developed. The reaction proceeds via the generation of NH‐pyrazole‐iodonium salts in situ, ...followed by sequential phen/K2CO3‐mediated intermolecular arylation. When the iodonium ylide was directly used as substrate, the difunctionalization products could be prepared in high yield under base‐ and metal‐free conditions. This transformation provides an efficient route to high‐value multisubstituted pyrazole derivatives from simple and readily available substrates.
A one‐pot transition‐metal‐free selective iodoarylation of pyrazoles with aryliodine diacetates was developed. The reaction proceeds via the generation of NH‐pyrazole‐iodonium salts in situ, followed by sequential phen/K2CO3‐mediated intermolecular arylation. The proposed iodonium ylide intermediate could be isolated and directly affords the difunctionalization products in high yield under base‐ and metal‐free conditions.
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•Crack-free nickel-based single crystal superalloy samples were fabricated via directed energy deposition.•Hot cracking occurred at high-angle grain boundaries and especially at ...low-angle grain boundaries.•The existence conditions of the liquid film for hot cracking in CMSX-10 are calculated with analysis models.•Re-rich precipitations promote cracks initiation by the pinning effect on the liquid feeding.•The hot cracking mechanism is related to the stability of liquid film, stress concentration and Re-rich precipitations.
Hot cracking is a frequent and severe defect that occurs during the directed energy deposition (DED) of single-crystal superalloys. Understanding the cracking behavior and mechanism is key to avoiding these defects. Thus, in this study, a third-generation single-crystal superalloy, CMSX-10, was investigated. Hot cracking occurred at high-angle grain boundaries and especially at low-angle grain boundaries. Cracks were formed beyond a critical misorientation angle of 6.9°. Hot cracking was determined to be caused by a stable liquid film, stress concentration, and Re-rich precipitates. The stability of the liquid film depended on dendrite coalescence undercooling which was related to the misorientation angle. The dendrite coalescence undercooling at low-angle grain boundary (misorientation angle 6.9°) was 178 K, which was far higher than the vulnerable temperature interval 38 K for hot cracking within a single dendrite. Stress concentration provided the driving force for crack initiation and propagation. Re-rich precipitates promoted crack initiation by a pinning effect on the liquid feed. These findings provide technical support for achieving high-quality additive manufacturing and repair of non-weldable Ni-based single-crystal superalloys.
ObjectiveThe neutrophil-to-lymphocyte ratio (NLR) is recognised as a suitable prognostic biomarker in patients with breast cancer. Nevertheless, the efficacy of this biomarker in predicting the ...pathological complete response (pCR) and survival in patients with breast cancer receiving neoadjuvant chemotherapy (NACT) is still controversial. This meta-analysis aimed to identify the association between baseline NLR and the prognosis of patients with breast cancer treated with NACT.DesignMeta-analysis.Data sourcesRelevant literature published before 1 May 2021 was searched using the Cochrane Library, Embase, PubMed and the Web of Science databases.Eligibility criteriaAll studies involving patients with breast cancer treated with NACT and peripheral blood pretreatment NLR recorded as a dichotomous variable were included.Data extraction and synthesisTwo researchers independently extracted and evaluated OR/HR and its 95% CIs of survival outcomes and clinicopathological parameters.ResultsA total of 19 studies were identified. From each study, the impact of NLR on the pCR, OR and HR, with their 95% CIs were extracted and combined using either a random or fixed-effects model. The results indicate that a higher pCR in patients with a low NLR (OR 1.620, 95% CI 1.209 to 2.169, p＜0.001). In addition, an elevated NLR predicted lower disease-free survival (HR 2.269, 95% CI 1.557 to 3.307, p<0.001) and overall survival (HR 1.691, 95% CI 1.365 to 2.096, p<0.001) in patients with breast cancer treated with NACT.ConclusionsNLR is a suitable biomarker for predicting pCR and survival in patients with breast cancer receiving NACT.
Dysfunction of neurovascular pericytes underlies breakdown of the blood-brain barrier, but the molecular mechanisms are largely unknown. In this study, we evaluated the role of the transient receptor ...potential melastatin-related 2 (TRPM2) channel and autophagy during brain pericyte injury both in vitro and in vivo.
A rapid induction in autophagy in human brain vascular pericytes, in the zinc oxide nanoparticles (ZnO-NP)-induced cell stress model, was paralleled with an increase in the expression of the TRPM2-S truncated isoform, which was abolished by treatment with a nitric oxide synthase inhibitor and a peroxynitrite scavenger. Furthermore, Y1485 in the C-terminus of the TRPM2 protein was identified as the tyrosine nitration substrate by mass spectrometry. Overexpression of the Y1485S TRPM2 mutant reduced LC3-II accumulation and pericyte injury induced by ZnO-NP. Consistently, LC3-II accumulation was reduced and pericytes were better preserved in intact brain microvessels of the TRPM2 knockout mice after ZnO-NP-induced vascular injury. Innovation and Conclusions: Our present study has revealed a novel mechanism of autophagy disturbance secondary to nitrosative stress-induced tyrosine nitration of TRPM2 during pericyte injury. Antioxid. Redox Signal. 27, 1297-1316.
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