Preparation of graphene film reinforced CoCrFeNiMn high-entropy alloy matrix composites with strength-plasticity synergy via flake powder metallurgy method

Inspired by the design principle of pearl structure, a bottom-up flake powder self-assembly arrangement strategy, flake powder metallurgy, is used to prepare graphene films (GFs) reinforced CoCrFeNiMn high-entropy alloy (HEA) matrix composites with a pearl laminated structure. Flaky HEA powder was prepared by ball milling method and homogeneously mixed with Ni plated GFs. Vacuum hot-press sintering (VHPS) technique was carried out to solidify the mixed powders to obtain composites with uniform distribution of GFs(Ni) and flaky HEA. The results show that the bottom-up preparation strategy can effectively fabricate bionic laminated HEA matrix composites, and the composites have a distinct pearly laminated structure. The tensile strength of the composites with 5 vol% GFs(Ni) content reached 834.04 MPa, and the elongation reached 26.58 %. The compressive strength in parallel and perpendicular laminar directions reached 2069.66 MPa and 2418.45 MPa at 50 % strain, respectively. The laminated GFs(Ni)/HEA matrix composites possessed excellent strength and maintained good plasticity. In this study, the strengthening and toughening mechanism of the laminated GFs(Ni)/HEA matrix composites is discussed in detail, and the results show that the laminated structure and GFs(Ni) are favorable for the hardening and strengthening of the HEA matrix

Photoelectrochemical and electrochemical ratiometric aptasensing: a case study of streptomycin

There has been much interest in constructing ratiometric sensors using different sensing techniques because of their synergistic effect, although the simultaneous collection of the signals is challenging. Herein, we propose a ratiometric aptasensing strategy based on the dual-detection model with a photoelectrochemical (PEC) “signalon” and an electrochemical (EC) “signal-off”. As a proof-of-concept study, CdTe quantum dots (CdTe QDs) and a methylene blue-labeled aptamer (MB-Apt) were used to generate PEC and EC signals in the sensing system. The target-induced conformational change of MB-Apt pushed MB away from the electrode, thereby decreasing the EC signal; at the same time, the reduced steric hindrance favored the restoration of the PEC signal from the CdTe QDs. Thus, this PEC-EC strategy can achieve the PEC “signal-on” and EC “signal-off” states simultaneously, as well as allowing quantitative analysis of the target based on the ratio of the current intensities. As a model application, an aptasensor fabricated for streptomycin detection showed a wide linear range from 0.03 to 100 μM with a detection limit of 10 nM (S/N = 3). The proposed sensing platform displayed superior analytical properties compared with methods based on PEC or EC alone. Our work provides an efficient dual-detection modelbased ratiometric strategy for advanced analysis, and paves the way to the simultaneous acquisition of signals

The Microsoft System for VoxCeleb Speaker Recognition Challenge 2022

In this report, we describe our submitted system for track 2 of the VoxCeleb Speaker Recognition Challenge 2022 (VoxSRC-22). We fuse a variety of good-performing models ranging from supervised models to self-supervised learning(SSL) pre-trained models. The supervised models, trained using VoxCeleb-2 dev data, consist of ECAPA-TDNN and Res2Net in a very deep structure. The SSL pre-trained models, wav2vec and wavLM, are trained using large scale unlabeled speech data up to million hours. These models are cascaded with ECAPA-TDNN and further fine-tuned in a supervised fashion to extract the speaker representations. All 13 models are applied with score normalization and calibration and then fused into the the submitted system. We also explore the audio quality measures in the calibration stage such as duration, SNR, T60, and MOS. The best submitted system achieves 0.073 in minDCF and 1.436% in EER on the VoxSRC-22 evaluation set.Comment: 3 pages, 3 tables, VoxSRC202

Population genetics and molecular phylogeography of Thamnaconus modestus (Tetraodontiformes, Monachanthidae) in Northwestern Pacific inferred from variation of the mtDNA control region

In order to study the genetic diversity of Thamnaconus modestus, a species of great commercial importance in Southeast Asia, the 5′-end hypervariable regions (423 bp) of the mitochondrial control region of T. modestus in nine geographical populations (248 individuals) were sequenced and analysed in this study. The target sequence fragment contained large numbers of polymorphic sites (87) involved in high levels of haplotype diversity (h = 0.97 ± 0.01) and nucleotide diversity (π = 0.0285 ± 0.0143). The genetic variations within populations (92.71%) were significantly larger than those among populations (7.29%). No significant genetic divergences were detected among the wild populations owing to their gregarious habits, strong moving ability, r-selection strategy. Significant genetic divergences were found between the cultured and wild populations, probably resulting from kin selection and aquacultural environment. Three significant phylogenetic lineages were identified, and the variation among lineages (56.90%) was greater than that among individuals within the lineages (43.10%), with the significant ΦST value (ΦST = 0.57, P = 0.0000). The results showed great and significant genetic differentiations among these three lineages, indicating that they may have independent phylogenetic dynamics. Dominant shared haplotypes that included individuals from each population and the median-joining network of haplotypes presented a star-like structure. Historic demographic analysis of each lineage showed that population expansion occurred after the Pleistocene glacial period. At the last glacial maximum, T. modestus in China seas was scattered across variable refuges, including Central South China Sea and Okinawa Trough

PHLPP Negatively Regulates Cell Motility Through Inhibition of Akt Activity and Integrin Expression in Pancreatic Cancer Cells

Pancreatic adenocarcinoma is currently the fourth leading cause for cancer-related mortality. Malignant progression of pancreatic cancer depends not only on rapid proliferation of tumor cells but also on increased cell motility. In this study, we showed that increased PHLPP expression significantly reduced the rate of migration in pancreatic ductal adenocarcinoma (PDAC) cells whereas knockdown of PHLPP had the opposite effect. In addition, cell motility at the individual cell level was negatively regulated by PHLPP as determined using time-lapse imaging. Interestingly, the expression of β1 and β4 integrin proteins were decreased in PHLPP overexpressing cells and increased in PHLPP knockdown cells whereas the mRNA levels of integrin were not altered by changes in PHLPP expression. In determining the molecular mechanism underlying PHLPP-mediated regulation of integrin expression, we found that inhibition of lysosome activity rescued integrin expression in PHLPP overexpressing cells, thus suggesting that PHLPP negatively controls cell motility by inhibiting Akt activity to promote lysosome-dependent degradation of integrins. Functionally, the increased cell migration observed in PHLPP knockdown cells was effectively blocked by the neutralizing antibodies against β1 or β4 integrin. Taken together, our study identified a tumor suppressor role of PHLPP in suppressing cell motility by negatively regulating integrin expression in pancreatic cancer cells

Neurotensin Regulates Proliferation and Stem Cell Function in the Small Intestine in a Nutrient-Dependent Manner

BACKGROUND & AIMS: Intestinal stem cells (ISCs) are sensitive to dietary alterations and nutrient availability. Neurotensin (NT), a gut peptide localized predominantly to the small bowel and released by fat ingestion, stimulates the growth of intestinal mucosa under basal conditions and during periods of nutrient deprivation, suggesting a possible role for NT on ISC function. METHODS: Leucine-rich repeat-containing G-protein coupled receptor 5-Enhanced Green Fluorescent Protein (Lgr5-EGFP) NT wild type (Nt+/+) and Lgr5-EGFP NT knockout (Nt-/-) mice were fed ad libitum or fasted for 48 hours. Small intestine tissue and crypts were examined by gene expression analyses, fluorescence-activated cell sorting, Western blot, immunohistochemistry, and crypt-derived organoid culture. Drosophila expressing NT in midgut enteroendocrine cells were fed a standard diet or low-energy diet and esg-green fluorescent protein+ ISCs were quantified via immunofluorescence. RESULTS: Loss of NT impaired crypt cell proliferation and ISC function in a manner dependent on nutrient status. Under nutrient-rich conditions, NT stimulated extracellular signal-regulated kinases 1 and 2 signaling and the expression of genes that promote cell-cycle progression, leading to crypt cell proliferation. Under conditions of nutrient depletion, NT stimulated WNT/β-catenin signaling and promoted an ISC gene signature, leading to enhanced ISC function. NT was required for the induction of WNT/β-catenin signaling and ISC-specific gene expression during nutrient depletion, and loss of NT reduced crypt cell proliferation and impaired ISC function and Lgr5 expression in the intestine during fasting. Conversely, the expression of NT in midgut enteroendocrine cells of Drosophila prevented loss of ISCs during nutrient depletion. CONCLUSIONS: Collectively, our findings establish an evolutionarily conserved role for NT in ISC maintenance during nutritional stress. GSE182828

Metagenomic Next-Generation Sequencing in the Diagnosis of HHV-1 Reactivation in a Critically Ill COVID-19 Patient: A Case Report

Background: Secondary infections pose tremendous challenges in Coronavirus disease 2019 (COVID-19) treatment and are associated with higher mortality rates. Clinicians face of the challenge of diagnosing viral infections because of low sensitivity of available laboratory tests. Case Presentation: A 66-year-old woman initially manifested fever and shortness of breath. She was diagnosed as critically ill with COVID-19 using quantitative reverse transcription PCR (RT-qPCR) and treated with antiviral therapy, ventilator and extracorporeal membrane oxygenation (ECMO). However, after the condition was relatively stabled for a few days, the patient deteriorated with fever, frequent cough, increased airway secretions, and increased exudative lesions in the lower right lung on chest X-rays, showing the possibility of a newly acquired infection, though sputum bacterial and fungal cultures and smears showed negative results. Using metagenomic next-generation sequencing (mNGS), we identified a reactivation of latent human herpes virus type 1 (HHV-1) in the respiratory tract, blood and gastrointestinal tract, resulting in a worsened clinical course in a critically ill COVID-19 patient on ECMO. Anti-HHV-1 therapy guided by these sequencing results effectively decreased HHV-1 levels, and improved the patient\u27s clinical condition. After 49 days on ECMO and 67 days on the ventilator, the 66-year-old patient recovered and was discharged. Conclusions: This case report demonstrates the potential value of mNGS for evidence-based treatment, and suggests that potential reactivation of latent viruses should be considered in critically ill COVID-19 patients

Preclinical Evaluation of Novel Fatty Acid Synthase Inhibitors in Primary Colorectal Cancer Cells and a Patient-Derived Xenograft Model of Colorectal Cancer

Fatty Acid Synthase (FASN), a key enzyme of de novo lipogenesis, is upregulated in many cancers including colorectal cancer (CRC); increased FASN expression is associated with poor prognosis. Potent FASN inhibitors (TVBs) developed by 3-V Biosciences demonstrate anti-tumor activity in vitro and in vivo and a favorable tolerability profile in a Phase I clinical trial. However, CRC characteristics associated with responsiveness to FASN inhibition are not fully understood. We evaluated the effect of TVB-3664 on tumor growth in nine CRC patient-derived xenografts (PDXs) and investigated molecular and metabolic changes associated with CRC responsiveness to FASN inhibition. CRC cells and PDXs showed a wide range of sensitivity to FASN inhibition. TVB-3664 treatment showed significant response (reduced tumor volume) in 30% of cases. Anti-tumor effect of TVB-3664 was associated with a significant decrease in a pool of adenine nucleotides and alterations in lipid composition including a significant reduction in fatty acids and phospholipids and an increase in lactosylceramide and sphingomyelin in PDXs sensitive to FASN inhibition. Moreover, Akt, Erk1/2 and AMPK were major oncogenic pathways altered by TVBs. In summary, we demonstrated that novel TVB inhibitors show anti-tumor activity in CRC and this activity is associated with a decrease in activation of Akt and Erk1/2 oncogenic pathways and significant alteration of lipid composition of tumors. Further understanding of genetic and metabolic characteristics of tumors susceptible to FASN inhibition may enable patient selection and personalized medicine approaches in CRC