We characterized intrinsic and extrinsic specification of progenitors in the lateral and medial ganglionic eminences (LGE and MGE). We identified seven genes whose expression is enriched or ...restricted in either the LGE biregional cell adhesion molecule-related/downregulated by oncogenes binding protein (Boc), Frizzled homolog 8 (Fzd8), Ankrd43 (ankyrin repeat domain-containing protein 43), and Ikzf1 (Ikaros family zinc finger 1) or MGE Map3k12 binding inhibitory protein 1 (Mbip); zinc-finger, SWIM domain containing 5 (Zswim5); and Adamts5 a disintegrin-like and metallopeptidase (reprolysin type) with thrombospondin type 1 motif, 5. Boc, Fzd8, Mbip, and Zswim5 are apparently expressed in LGE or MGE progenitors, whereas the remaining three are seen in the postmitotic mantle zone. Relative expression levels are altered and regional distinctions are lost for each gene in LGE or MGE cells propagated as neurospheres, indicating that these newly identified molecular characteristics of LGE or MGE progenitors depend on forebrain signals not available in the neurosphere assay. Analyses of Pax6(Sey/Sey), Shh(-/-), and Gli3(XtJ/XtJ) mutants suggests that LGE and MGE progenitor identity does not rely exclusively on previously established forebrain-intrinsic patterning mechanisms. Among a limited number of additional potential patterning mechanisms, we found that extrinsic signals from the frontonasal mesenchyme are essential for Shh- and Fgf8-dependent regulation of LGE and MGE genes. Thus, extrinsic and intrinsic forebrain patterning mechanisms cooperate to establish LGE and MGE progenitor identity, and presumably their capacities to generate distinct classes of neuronal progeny.
•Miltefosine exhibits good activity against azole-resistant Candida spp.•The fungicidal activity of miltefosine could be weakened by N-acetyl-L-cysteine.•Miltefosine changes the expression and ...cellular localization of Aif1.•Pex8 is involved in reactive oxygen species elimination in sensing miltefosine.•Miltefosine triggers Hog1 phosphorylation.
Invasive candidiasis is the most common and serious fungal disease worldwide, and the development of antifungal drug resistance in Candida spp. is an emerging problem. Miltefosine, approved as an orphan drug for the therapy of invasive candida infections by the US Food and Drug Administration, has broad-spectrum antifungal activity, but its mechanism of action is unclear. This study evaluated the antifungal drug susceptibility of azole-resistant Candida spp. isolates and found that miltefosine showed good activity, with a geometric mean value of 2 µg/mL. Miltefosine was found to increase production of intracellular reactive oxygen species (ROS) and induce apoptosis in Candida albicans. RNA sequencing (RNA-Seq) analysis and iTRAQ-labelling-based quantitative proteomic mass spectrometry analysis were undertaken. Aif1 and the oxidative stress pathway involved in miltefosine-mediated apoptosis were identified using global transcriptomic and proteomic combined screening. Miltefosine increased mRNA and protein expressions of Aif1. The localization of Aif1 was examined using confocal microscopy, and the GFP-Aif1 fusion protein was found to be translocated from the mitochondria to the nucleus when sensing miltefosine. Next, the pex8 Δ/Δ strain was constructed, and the minimum inhibitory concentration of miltefosine was found to decrease four-fold (from 2 to 0.5 µg/mL) and the intracellular ROS increased significantly after knocking out the PEX8 gene. Moreover, miltefosine was found to trigger Hog1 phosphorylation. These findings indicate that Aif1 activation and the Pex8-mediated oxidative stress pathway are the mechanisms of action of miltefosine on C. albicans. The results help to aid understanding of the mechanisms by which miltefosine acts on fungi.
We put forward a multimode slotted nanobeam cavity (MM-SPCNC) supporting both air and dielectric modes through a specific design of band properties. Dual-parameter detection is realized by jointly ...measuring the resonance wavelength shifts of both air and dielectric modes. The proposed sensor is robust against external interference and shows higher sensitivity compared with other dual-parameter sensors. The maximum external interference ranges of the proposed sensor are 4.82×10
−6
and 0.05 for refractive index (RI) and temperature (T), respectively, which indicates that the sensor can effectively resist against external interference. The RI and T sensitivities of the fundamental air mode are 421 nm/RIU and 58 pm/K respectively, whereas those of the fundamental dielectric mode are 706 nm/RIU and 46 pm/K respectively. The proposed sensor thus represents a promising candidate for future multifunctional and lab-on-chip sensing applications.
Cell death from spinal cord injury is mediated in part by apoptotic mechanisms involving downstream caspases (e.g., caspase-3). Upstream mechanisms may involve other caspases such as procaspase-8, a ...55 kDa apical caspase, which we found constitutively expressed within spinal cord neurons along with Fas. As early as 1.5 hr after transient ischemia, activated caspase-8 (p18) and caspase-8 mRNA appeared within neurons in intermediate gray matter and in medial ventral horn. We also detected evidence for an increase in death receptor complex by co-immunoprecipitation using Fas and anti-procaspase-8 after ischemia. At early time points, Fas and p18 were co-expressed within individual neurons, as were activated caspase-8 and caspase-3. Moreover, we detected p18 in cells before procaspase-3 cleavage product (p20), suggesting sequential activation. The appearance of cytosolic cytochrome c and gelsolin cleavage after ischemia was consistent with mitochondrial release and caspase-3 activation, respectively. Numerous terminal deoxynucleotidyl transferase-mediated DNA nick end-labeling-positive neurons contained p18 or p20 (65 and 80%, respectively), thereby supporting the idea that cells undergoing cell death contain both processed caspases. Our data are consistent with the idea that transient spinal cord ischemia induces the formation of a death-inducing signaling complex, which may participate in caspase-8 activation and sequential caspase-3 cleavage. Death receptors as well as downstream caspases may be useful therapeutic targets for limiting the death of cells in spinal cord.
A physics-based SPICE model for dopant segregated tunneling field-effect transistors (DS-TFETs) with gate-to-drain underlap is developed for the design technology co-optimization (DTCO) of TFETs with ...the foundry process. It captures all the current components in full operation regions, including band-to-band tunneling (BTBT), forward p-i-n diode, gate leakage, and also ambipolar conduction. The channel surface potential is formulated first, with which the current expressions are derived and verified with experiments calibrated TCAD simulations. Model predictions of current, conductance, and voltage transfer characteristic (VTC) are in good agreement with measurement data of hardware devices (nTFET and pTFET) as well as circuits. This model has been written in Verilog-A language and employed in the TFET circuits design.
To investigate the characteristics of transmission correlativity regarding subtype B among elderly HIV-1 infected individuals in Yongding district, Zhangjiajie city, Hunan province and to explore a ...method on its traceability.
A total of 43 newly diagnosed elderly HIV-1 Infected individuals in Yongding district were enrolled in this study. Pol area genes were amplified and sequenced by 'In house' method. Methods used to analyze the relationship related to HIV individuals transmission would include Bayesian phylogenetic tree and other epidemiological ones.
A total of 42 valid sequences were successfully obtained, with predominant strain as subtype B (80.95%, 34/42). All the 42 sequences were gathered into eight clusters. In each cluster, the genetic distance was significantly shorter than the average from the 34 subtype B strains (0.058 3). The HIV-1 infected individuals in one cluster had the same high-risk behaviors and the significantly patchy distributions were identified at the sites where the high-risk be
•Optimising the blood culture process can improve the positive detection rate.•Optimising the blood culture process can shorten reporting time.•Optimising the blood culture process can reduce the ...length of hospital stay and costs.
Optimising blood culture processing is important to ensure that bloodstream infections are accurately diagnosed while minimising adverse events caused by antibiotic abuse. This study aimed to evaluate the impact of optimised blood culture processes on antibiotic use, clinical outcomes and economics in intensive care unit (ICU) patients with positive blood cultures.
From March 2020 to October 2021, this microbiology laboratory implemented a series of improvement measures, including the clinical utility of Fastidious Antimicrobial Neutralization (FAN® PLUS) bottles for the BacT/Alert Virtuo blood culture system, optimisation of bottle reception, graded reports and an upgraded laboratory information system. A total of 122 ICU patients were included in the pre-optimisation group from March 2019 to February 2020, while 179 ICU patients were included in the post-optimisation group from November 2021 to October 2022.
Compared with the pre-optimisation group, the average reporting time of identification and antimicrobial sensitivity was reduced by 16.72 hours in the optimised group. The time from admission to targeted antibiotic therapy within 24 hours after receiving both the Gram stain report and the final report were both significantly less in the post-optimisation group compared with the pre-optimisation group. The average hospitalisation time was reduced by 6.49 days, the average antimicrobial drug cost lowered by $1720.85 and the average hospitalisation cost by $9514.17 in the post-optimisation group.
Optimising blood culture processing was associated with a significantly increased positive detection rate, a remarkable reduction in the length of hospital stay and in hospital costs for ICU patients with bloodstream infections.
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