Skin mottling score assesses peripheral tissue hypoperfusion in critically ill patients following cardiac surgery.

BACKGROUND: Skin mottling is a common manifestation of peripheral tissue hypoperfusion, and its severity can be described using the skin mottling score (SMS). This study aims to evaluate the value of the SMS in detecting peripheral tissue hypoperfusion in critically ill patients following cardiac surgery. METHODS: Critically ill patients following cardiac surgery with risk factors for tissue hypoperfusion were enrolled (n = 373). Among these overall patients, we further defined a hypotension population (n = 178) and a shock population (n = 51). Hemodynamic and perfusion parameters were recorded. The primary outcome was peripheral hypoperfusion, defined as significant prolonged capillary refill time (CRT, > 3.0 s). The characteristics and hospital mortality of patients with and without skin mottling were compared. The area under receiver operating characteristic curves (AUROC) were used to assess the accuracy of SMS in detecting peripheral hypoperfusion. Besides, the relationships between SMS and conventional hemodynamic and perfusion parameters were investigated, and the factors most associated with the presence of skin mottling were identified. RESULTS: Of the 373-case overall population, 13 (3.5%) patients exhibited skin mottling, with SMS ranging from 1 to 5 (5, 1, 2, 2, and 3 cases, respectively). Patients with mottling had lower mean arterial pressure, higher vasopressor dose, less urine output (UO), higher CRT, lactate levels and hospital mortality (84.6% vs. 12.2%, p < 0.001). The occurrences of skin mottling were higher in hypotension population and shock population, reaching 5.6% and 15.7%, respectively. The AUROC for SMS to identify peripheral hypoperfusion was 0.64, 0.68, and 0.81 in the overall, hypotension, and shock populations, respectively. The optimal SMS threshold was 1, which corresponded to specificities of 98, 97 and 91 and sensitivities of 29, 38 and 67 in the three populations (overall, hypotension and shock). The correlation of UO, lactate, CRT and vasopressor dose with SMS was significant, among them, UO and CRT were identified as two major factors associated with the presence of skin mottling. CONCLUSION: In critically ill patients following cardiac surgery, SMS is a very specific yet less sensitive parameter for detecting peripheral tissue hypoperfusion.

Effect of early stepwise cardiopulmonary rehabilitation on function and quality of life in sepsis patients.

BACKGROUND: Sepsis, as a non-limiting host infection disease, can be accompanied by serious complications such as organ failure, which seriously threatens patient quality of life. AIM: To investigate the effect of early stepwise cardiopulmonary rehabilitation on cardiopulmonary function and quality of life in patients evacuated from mechanical ventilation with sepsis. METHODS: A total of 80 patients with sepsis who were hospitalized in our hospital from January 2021 to January 2022 were selected and divided into the observation group (n = 40) and the control group (n = 40) according to the random number table method. The observation group was treated with early stepwise cardiopulmonary rehabilitation, and the control group was treated with a conventional treatment regimen. Cardiac function indexes (central venous pressure, cardiac troponin I, B-type brain natriuretic peptide), lung function indicators (diaphragmatic mobility, changes in central venous oxygen saturation, oxygenation index), and quality of life (Quality of Life Evaluation Scale) were compared between the two groups after treatment. RESULTS: After treatment, the central venous pressure, diaphragm mobility, central venous oxygen saturation, oxygenation index, and Quality of Life Evaluation Scale scores in the observation group were higher than those in the control group, and the differences were statistically significant (P < 0.05). The observation group was less than that of the control group for other parameters, and the differences were statistically significant (P < 0.05). CONCLUSION: Early stepwise cardiopulmonary rehabilitation can effectively enhance cardiac and pulmonary function and improve the quality of life in patients evacuated from mechanical ventilation with sepsis.

Graded-Band-Gap Zinc-Tin Oxide Thin-Film Transistors with a Vertically Stacked Structure for Wavelength-Selective Photodetection.

Filter-free wavelength-selective photodetectors have garnered significant attention due to the growing demand for smart sensors, artificial intelligence, the Internet of Everything, and so forth. However, the challenges associated with large-scale preparation and compatibility with complementary metal-oxide-semiconductor (CMOS) technology limit their wide-ranging applications. In this work, we address the challenges by constructing vertically stacked graded-band-gap zinc-tin oxide (ZTO) thin-film transistors (TFTs) specifically designed for wavelength-selective photodetection. The ZTO thin films with various band gaps are fabricated via atomic layer deposition (ALD) by varying the ALD cycle ratios of zinc oxide (ZnO) and SnO2. The ZTO film with a small Sn ratio exhibits a decreased band gap, and the resultant TFT shows a degraded performance, which can be attributed to the Sn4+ dopant introducing a series of deep-state energy levels in the ZnO band gap. As the ratio of Sn increases further, the band gap of the ZTO also increases, and the mobility of the ZTO TFT increases up to 30 cm2/V s, with a positive shift of the threshold voltage. The photodetectors employing ZTO thin films with distinct band gaps show different spectral responsivities. Then, vertically stacked ZTO (S-ZTO) thin films, with gradient band gaps increasing from the bottom to the top, have been successfully deposited using consecutive ALD technology. The S-ZTO TFT shows decent performance with a mobility of 18.4 cm2/V s, a threshold voltage of 0.5 V, an on-off current ratio higher than 107, and excellent stability under ambient conditions. The resultant S-ZTO TFT also exhibits obviously distinct photoresponses to light at different wavelength ranges. Furthermore, a device array of S-ZTO TFTs demonstrates color imaging by precisely reconstructing patterned illuminations with different wavelengths. Therefore, this work provides CMOS-compatible and structure-compact wavelength-selective photodetectors for advanced and integrable optoelectronic applications.

Drp1 regulated PINK1-dependent mitophagy protected duck follicular granulosa cells from acute heat stress injury.

The mitochondrial quality control system is crucial in maintaining cellular homeostasis during environmental stress. Granulosa cells are the main cells secreting steroid hormones, and mitochondria are the key organelles for steroid hormone synthesis. The impact of the mitochondrial quality control system on granulosa cells' steroid hormone synthesis and survival under heat stress is still unclear. Here, we showed that acute heat stress induces mitochondrial damage and significantly increases the number of mitophagy-like vesicles in the cytoplasm of duck ovary granulosa cells at the ultra-structural level. Meanwhile, we also found heat stress significantly increased mitochondrial fission and mitophagy-related protein expression levels both in vivo and in vitro. Furthermore, by confocal fluorescence analysis, we discovered that LC3 was distributed spot-like manner near the nucleus in the heat treatment group, and the LC3 spots and lysosomes were colocalized with Mito-Tracker in the heat treatment group. We further detected the mitophagy-related protein in the cytoplasm and mitochondria, respectively. Results showed that the PINK1 protein was significantly increased both in cytoplasm and mitochondria, while the LC3-Ⅱ/LC3-Ⅰ ratio increase only occurred in mitochondrial. In addition, the autophagy protein induced by acute heat treatment was effectively inhibited by the mitophagy inhibitor CysA. Finally, we demonstrated that the alteration of cellular mitophagy by siRNA interference with Drp1 and PINK1 inhibited the steroid synthesis of granulosa cells and increased cell apoptosis. Study provides strong evidence that the Drp1 regulated PINK1-dependent mitophagy pathway protects follicular granulosa cells from acute heat stress-induced injury.

DNA methylation of promoter region inhibits galectin-1 expression in BMSCs of aged mice.

Senile osteoporosis increases fracture risks. Bone marrow stromal cells (BMSCs) are sensitive to aging. Deep insights into BMSCs aging are vital to elucidate the mechanisms underlying age-related bone loss. Recent advances showed that osteoporosis is associated with aberrant DNA methylation of many susceptible genes. Galectin-1 (Gal-1) has been proposed as a mediator of BMSCs functions. In our previous study, we showed that Gal-1 was downregulated in aged BMSCs and global deletion of Gal-1 in mice caused bone loss via impaired osteogenesis potential of BMSCs. Gal-1 promoter is featured by CpG islands. However, there are no reports concerning the DNA methylation status in Gal-1 promoter during osteoporosis. In the current study, we sought to investigate the role of DNA methylation in Gal-1 downregulation in aged BMSCs. The potential for anti-bone loss therapy based on modulating DNA methylation is explored. Our results showed that Dnmt3b-mediated Gal-1 promoter DNA hypermethylation plays an important role in Gal-1 downregulation in aged BMSCs, which inhibited ß-catenin binding on Gal-1 promoter. Bone loss of aged mice was alleviated in response to in vivo deletion of Dnmt3b from BMSCs. Finally, when bone marrow of young wild-type (WT) mice or young Dnmt3bPrx1-Cre mice was transplanted into aged WT mice, Gal-1 level in serum and trabecular bone mass were elevated in recipient aged WT mice. Our study will benefit for deeper insights into the regulation mechanisms of Gal-1 expression in BMSCs during osteoporosis development, and for the discovery of new therapeutic targets for osteoporosis via modulating DNA methylation status.NEW & NOTEWORTHY There is Dnmt3b-mediated DNA methylation in Gal-1 promoter in aged bone marrow stromal cell (BMSC). DNA methylation causes Gal-1 downregulation and osteogenesis attenuation of aged BMSC. DNA methylation blocks ß-catenin binding on Gal-1 promoter. Bone loss of aged mice is alleviated by in vivo deletion of Dnmt3b from BMSC.

Heat enhances the inhibitory effect of lipopolysaccharide on duck granulosa cell proliferation and steroid biosynthesis in vitro.

Lipopolysaccharide (LPS) reduces the reproductive performance of laying ducks, especially during the hot summer months. To study the underlying mechanisms, we investigated the effects of different LPS concentrations and heat on duck granulosa cell (GC) proliferation and steroid biosynthesis in vitro. We investigated GC proliferation, secretion, and activation of the MAPK pathway. The cell cycle results showed that LPS treatment alone did not significantly affect cell proliferation, whereas the mRNA expression levels of IGF2, IGFBP2, and CyclinD1 were downregulated and p27kip1 was significantly upregulated after 2000 ng/mL LPS treatment when compared to untreated cells. In steroid hormone synthesis, although LPS increased the expression of most steroid biosynthesis genes, it inhibited the expression of CYP11A1 at high LPS concentrations. High temperatures enhanced the inhibitory effect of LPS on the expression of proliferation-promoting genes. Heat significantly reduced CYP11A1 and CYP19A1 expression. In addition, the phosphorylation of P38 was significantly upregulated by high temperatures combined with LPS, whereas the phosphorylation of ERK1/2 and JNK was downregulated. The relative protein expression of Bax/BCL-2 was upregulated at high temperatures in combination with LPS. Heat treatment enhanced the inhibitory effects of LPS on the proliferation and hormone biosynthesis of duck GCs in vitro.

MsNRAMP2 Enhances Tolerance to Iron Excess Stress in Nicotiana tabacum and MsMYB Binds to Its Promoter.

Iron(Fe) is a trace metal element necessary for plant growth, but excess iron is harmful to plants. Natural resistance-associated macrophage proteins (NRAMPs) are important for divalent metal transport in plants. In this study, we isolated the MsNRAMP2 (MN_547960) gene from alfalfa, the perennial legume forage. The expression of MsNRAMP2 is specifically induced by iron excess. Overexpression of MsNRAMP2 conferred transgenic tobacco tolerance to iron excess, while it conferred yeast sensitivity to excess iron. Together with the MsNRAMP2 gene, MsMYB (MN_547959) expression is induced by excess iron. Y1H indicated that the MsMYB protein could bind to the "CTGTTG" cis element of the MsNRAMP2 promoter. The results indicated that MsNRAMP2 has a function in iron transport and its expression might be regulated by MsMYB. The excess iron tolerance ability enhancement of MsNRAMP2 may be involved in iron transport, sequestration, or redistribution.

High Performance On-Chip Energy Storage Capacitors with Plasma-Enhanced Atomic Layer-Deposited Hf0.5Zr0.5O2/Al-Doped Hf0.25Zr0.75O2 Nanofilms as Dielectrics.

Concurrently achieving high energy storage density (ESD) and efficiency has always been a big challenge for electrostatic energy storage capacitors. In this study, we successfully fabricate high-performance energy storage capacitors by using antiferroelectric (AFE) Al-doped Hf0.25Zr0.75O2 (HfZrO:Al) dielectrics together with an ultrathin (1 nm) Hf0.5Zr0.5O2 underlying layer. By optimizing the Al concentration in the AFE layer with the help of accurate controllability of the atomic layer deposition technique, an ultrahigh ESD of 81.4 J cm-3 and a perfect energy storage efficiency (ESE) of 82.9% are simultaneously achieved for the first time in the case of the Al/(Hf + Zr) ratio of 1/16. Meanwhile, both the ESD and ESE exhibit excellent electric field cycling endurance within 109 cycles under 5~5.5 MV cm-1, and robust thermal stability up to 200 °C. Thus, the fabricated capacitor is very promising for on-chip energy storage applications due to favorable integratability with the standard complementary metal-oxide-semiconductor (CMOS) process.

Complete chloroplast genome features and phylogenetic analysis of Abies ernestii var. salouenensis (Bordères and Gaussen) W. C. Cheng and L. K. Fu from southwest China.

Abies ernestii var. salouenensis (Bordères & Gaussen) W. C. Cheng & L. K. Fu is endemic to southwest China, including the southeastern Tibetan Plateau and the northwestern Yunnan Province. The taxonomic relationships between A. ernestii var. salouenensis and two other closely related fir species (A. chensiensis Tiegh. and A. ernestii Rehd.) still need to be determined. Here, we report for the first time the whole chloroplast genome of A. ernestii var. salouenensis. Its genome is 121,759 bp long and is characterized by a circular structure with 68 peptide-encoding genes, 16 tRNAs, six ORFs, and four rRNAs. We also identified 70 microsatellite repeat sequences and 14 tandem repeat sequences in the chloroplast genome of A. ernestii var. salouenensis. Comparative genome analysis indicated considerable variation in ycf1 and ycf2. Phylogenetic analysis supported the monophyly of A. ernestii var. salouenensis, A. chensiensis Tiegh., and A. ernestii Rehd. The relationships among them should be surveyed using more samples at the species level. This study will facilitate taxonomic studies and the development of suitable chloroplast markers for fir species.

The immunomodulation role of Th17 and Treg in renal transplantation.

Kidney transplantation (KT) is an ultimate treatment of end-stage chronic kidney disease, which can meet a lot of complications induced by immune system. With under-controlled immunosuppression, the patient will obtain a good prognosis. Otherwise, allograft disfunction will cause severe organ failure and even immune collapse. Acute or chronic allograft dysfunction after KT is related to Th17, Treg, and Th17/Treg to a certain extent. Elevated Th17 levels may lead to acute rejection or chronic allograft dysfunction. Treg mainly plays a protective role on allografts by regulating immune response. The imbalance of the two may further aggravate the balance of immune response and damage the allograft. Controlling Th17 level, improving Treg function and level, and adjusting Th17/Treg ratio may have positive effects on longer allograft survival and better prognosis of receptors.

Performance improvement of Hf0.45Zr0.55Oxferroelectric field effect transistor memory with ultrathin Al-O bonds-modified InOxchannels.

Ferroelectric field effect transistor (FeFET) memories with hafnium zirconium oxide (HZO) ferroelectric gate dielectric and ultrathin InOxchannel exhibit promising applicability in monolithic three-dimensional (M3D) integrated chips. However, the inferior stability of the devices severely limits their applications. In this work, we studied the effect of single cycle of atomic-layer-deposited Al-O bonds repeatedly embedded into an ultrathin InOxchannel (∼2.8 nm) on the Hf0.45Zr0.55OxFeFET memory performance. Compared to the pure InOxchannel, three cycles of Al-O bonds modified InOxchannel (IAO-3) generates a much larger memory window (i.e. drain current ratio between the programmed and erased devices) under the same program conditions (+5.5 V/500 ns), especially after post-annealing at 325 °C for 180 s in O2(1238 versus 317). Meanwhile, the annealed IAO-3 FeFET memory also shows quite stable data retention up to 104s, and much more robust program/erase stabilities till 105cycles. This is because the modification of strong Al-O bonds stabilizes the oxygen vacancies and reduces the bulk trap density in the channel. Furthermore, it is indicated that the program and erase efficiencies increase gradually with reducing the channel length of the memory device. By demonstrating markedly improved performance of the HZO FeFET memory with the ultrathin IAO-3 channel, this work provides a promising device for M3D integratable logic and memory convergent systems.

Advances in numerical simulation of unit operations for tablet preparation.

Recently, there has been an increase in the use of numerical simulation technology in pharmaceutical preparation processes. Numerical simulation can contribute to a better understanding of processes, reduce experimental costs, optimize preparation processes, and improve product quality. The intermediate material of most dosage forms is powder or granules, especially in the case of solid preparations. The macroscopic behavior of particle materials is controlled by the interactions of individual particles with each other and surrounding fluids. Therefore, it is very important to analyze and control the microscopic details of the preparation process for solid preparations. Since tablets are one of the most widely used oral solid preparations, and the preparation process is relatively complex and involves numerous units of operation, it is especially important to analyze and control the tablet production process. The present paper discusses recent advances in numerical simulation technology for the preparation of tablets, including drying, mixing, granulation, tableting, and coating. It covers computational fluid dynamics (CFD), discrete element method (DEM), population balance model (PBM), finite element method (FEM), Lattice-Boltzmann model (LBM), and Monte Carlo model (MC). The application and deficiencies of these models in tablet preparation unit operations are discussed. Furthermore, the paper provides a systematic reference for the control and analysis of the tablet preparation process and provides insight into the future direction of numerical simulation technology in the pharmaceutical industry.

Flexible Microspectrometers Based on Printed Perovskite Pixels with Graded Bandgaps.

Miniaturized spectrometers have attracted much attention due to their capability to detect spectral information within a small size. However, such technology still faces challenges including large-scale preparation and performance repeatability. In this work, we overcome these challenges by demonstrating a microspectrometer constructed with a series of pixelized graded-bandgap perovskite photodetectors fabricated with inkjet printing. High-quality perovskite films with minimal pinholes and large grains are deposited by optimizing printing conditions including substrate temperature and surface modification. The resulting perovskite photodetectors show decent photosensing performance, and the different photodetectors based on perovskite films with different bandgaps exhibit various spectral responsivities with different cutoff wavelength edges. Microspectrometers are then constructed with the array of the pixelized graded-bandgap perovskite photodetectors, and incident spectra are algorithmically reconstructed by combining their output currents. The reconstruction performance of the miniaturized spectrometer is evaluated by comparing the results to the spectral curve measured with a commercial bulky spectrometer, indicating a reliable spectral reconstruction with a resolution of around 10 nm. More significantly, the miniaturized spectrometers are successfully fabricated on polymer substrates, and they demonstrate excellent mechanical flexibility. Therefore, this work provides a flexible miniaturized spectrometer with large-scale fabricability, which is promising for emerging applications including wearable devices, hyperspectral imaging, and internet of things.

FOXG1 Contributes Adult Hippocampal Neurogenesis in Mice.

Strategies to enhance hippocampal precursor cells efficiently differentiate into neurons could be crucial for structural repair after neurodegenerative damage. FOXG1 has been shown to play an important role in pattern formation, cell proliferation, and cell specification during embryonic and early postnatal neurogenesis. Thus far, the role of FOXG1 in adult hippocampal neurogenesis is largely unknown. Utilizing CAG-loxp-stop-loxp-Foxg1-IRES-EGFP (Foxg1fl/fl), a specific mouse line combined with CreAAV infusion, we successfully forced FOXG1 overexpressed in the hippocampal dentate gyrus (DG) of the genotype mice. Thereafter, we explored the function of FOXG1 on neuronal lineage progression and hippocampal neurogenesis in adult mice. By inhibiting p21cip1 expression, FOXG1-regulated activities enable the expansion of the precursor cell population. Besides, FOXG1 induced quiescent radial-glia like type I neural progenitor, giving rise to intermediate progenitor cells, neuroblasts in the hippocampal DG. Through increasing the length of G1 phase, FOXG1 promoted lineage-committed cells to exit the cell cycle and differentiate into mature neurons. The present results suggest that FOXG1 likely promotes neuronal lineage progression and thereby contributes to adult hippocampal neurogenesis. Elevating FOXG1 levels either pharmacologically or through other means could present a therapeutic strategy for disease related with neuronal loss.

[Detection of Fusion Gene and Prognosis Analysis in Children with Acute Lymphoblastic Leukemia of Different Immunophenotypes].

OBJECTIVE: To observe the detection of fusion gene in children with acute lymphoblastic leukemia (ALL) of different immunophenotypes, and analyze the relationship between fusion gene and prognosis. METHODS: The clinical data of 86 children with ALL treated in the hospital from May 2015 to May 2020 were retrospectively analyzed, the immunophenotypes and the prognosis of children were recorded, the detection of fusion gene in ALL children with different immunophenotypes was compared, the relationship between detection of fusion gene and prognosis was analyzed. RESULTS: The results of bone marrow immunophenotype showed that there were 13 cases of T cell type and 73 cases of B cell type in 86 children with ALL. The detection rate of fusion gene SIL-TAL1 in ALL children with T cell type was significantly higher than that in ALL children with B cell type (P<0.05). The detection rates of fusion genes BCR-ABL1, E2A-PBX1 and TEL-AML1 in ALL children with B cell type were higher than those in ALL children with T cell type, but the differences were not statistically significant (P>0.05). Followed up for 8-12 months, recurrence was taken as the end point, the average follow-up time was (10.14±1.75) months, in 86 children with ALL 15 cases recurred (17.44%). The recurrence curve drawn by Kaplan-Meier method showed that the median recurrence time of 15 children with recurrent ALL was 9 months. The proportions of positive minimal residual disease and extramedullary infiltration in the poor prognosis group were higher than those in the good prognosis group, and the differences were statistically significant (P<0.05). The detection rates of fusion genes BCR-ABL and SIL-TAL1 in the poor prognosis group were higher than those in the good prognosis group, and the differences were statistically significant (all P<0.05). Logistic regression analysis showed that positive minimal residual lesions, extramedullary infiltration, and detection of fusion genes BCR-ABL and SIL-TAL1 were risk factors for poor prognosis in children with ALL (OR>1, P<0.05). The ROC curve analysis showed that the area under the curve (AUC) of combined detection of fusion gene BCR-ABL and SIL-TAL1 for predicting the poor prognosis of ALL children was >0.707, which had a certain predictive value. CONCLUSION: There are differences in fusion genes among ALL children with different immunophenotypes, minimal residual disease, extramedullary infiltration, and fusion gene are associated with prognosis of ALL children. Fusion gene detection can be used as new method to predict the prognosis of children with ALL.

Superhigh energy storage density on-chip capacitors with ferroelectric Hf0.5Zr0.5O2/antiferroelectric Hf0.25Zr0.75O2 bilayer nanofilms fabricated by plasma-enhanced atomic layer deposition.

Thanks to their excellent compatibility with the complementary metal-oxide-semiconductor (CMOS) process, antiferroelectric (AFE) HfO2/ZrO2-based thin films have emerged as potential candidates for high-performance on-chip energy storage capacitors of miniaturized energy-autonomous systems. However, increasing the energy storage density (ESD) of capacitors has been a great challenge. In this work, we propose the fabrication of ferroelectric (FE) Hf0.5Zr0.5O2/AFE Hf0.25Zr0.75O2 bilayer nanofilms by plasma-enhanced atomic layer deposition for high ESD capacitors with TiN electrodes. The effects of the FE/AFE thickness composition and annealing conditions are investigated, revealing that the Hf0.5Zr0.5O2 (1 nm)/Hf0.25Zr0.75O2 (9 nm) bilayer can generate the optimal ESD after optimized annealing at 450 °C for 30 min. This is mainly ascribed to the factor that the introduction of a 1 nm Hf0.5Zr0.5O2 layer enhances the formation of the tetragonal (T) phase with antiferroelectricity in the AFE Hf0.25Zr0.75O2 layer as well as the breakdown electric field of the bilayer while fixing the FE/AFE bilayer thickness at 10 nm. As a result, a ESD as high as 71.95 J cm-3 can be obtained together with an energy storage efficiency (ESE) of 57.8%. Meanwhile, with increasing the measurement temperature from 300 and 425 K, the capacitor also demonstrates excellent stabilities of ESD and ESE. In addition, superior electrical cycling endurance is also demonstrated. Further, by integrating the capacitor into deep silicon trenches, a superhigh ESD of 364.1 J cm-3 is achieved together with an ESE of 56.5%. This work provides an effective way for developing CMOS process-compatible, eco-friendly and superhigh ESD three-dimensional capacitors for on-chip energy storage applications.

Surface Modifiers on Composite Particles for Direct Compaction.

Direct compaction (DC) is considered to be the most effective method of tablet production. However, only a small number of the active pharmaceutical ingredients (APIs) can be successfully manufactured into tablets using DC since most APIs lack adequate functional properties to meet DC requirements. The use of suitable modifiers and appropriate co-processing technologies can provide a promising approach for the preparation of composite particles with high functional properties. The purpose of this review is to provide an overview and classification of different modifiers and their multiple combinations that may improve API tableting properties or prepare composite excipients with appropriate co-processed technology, as well as discuss the corresponding modification mechanism. Moreover, it provides solutions for selecting appropriate modifiers and co-processing technologies to prepare composite particles with improved properties.

A Role for PGC-1a in the Control of Abnormal Mitochondrial Dynamics in Alzheimer's Disease.

Emerging evidence suggests that the proper control of mitochondrial dynamics provides a window for therapeutic intervention for Alzheimer's disease (AD) progression. The transcriptional coactivator peroxisome proliferator activated receptor gamma coactivator 1 (PGC-1a) has been shown to regulate mitochondrial biogenesis in neurons. Thus far, the roles of PGC-1a in Alzheimer's disease and its potential value for restoring mitochondrial dysfunction remain largely unknown. In the present study, we explored the impacts of PGC-1a on AD pathology and neurobehavioral dysfunction and its potential mechanisms with a particular focus on mitochondrial dynamics. Paralleling AD-related pathological deposits, neuronal apoptosis, abnormal mitochondrial dynamics and lowered membrane potential, a remarkable reduction in the expression of PGC-1a was shown in the cortex of APP/PS1 mice at 6 months of age. By infusing AAV-Ppargc1α into the lateral parietal association (LPtA) cortex of the APP/PS1 brain, we found that PGC-1a ameliorated AD-like behavioral abnormalities, such as deficits in spatial reference memory, working memory and sensorimotor gating. Notably, overexpressed PGC-1a in LPtA rescued mitochondrial swelling and damage in neurons, likely through correcting the altered balance in mitochondrial fission-fusion and its abnormal distribution. Our findings support the notion that abnormal mitochondrial dynamics is likely an important mechanism that leading to mitochondrial dysfunction and AD-related pathological and cognitive impairments, and they indicate the potential value of PGC-1a for restoring mitochondrial dynamics as an innovative therapeutic target for AD.

Multiple Mechanistic Models Reveal the Neuroprotective Effects of Diterpene Ginkgolides against Astrocyte-Mediated Demyelination via the PAF-PAFR Pathway.

Currently, therapies for ischemic stroke are limited. Ginkgolides, unique Folium Ginkgo components, have potential benefits for ischemic stroke patients, but there is little evidence that ginkgolides improve neurological function in these patients. Clinical studies have confirmed the neurological improvement efficacy of diterpene ginkgolides meglumine injection (DGMI), an extract of Ginkgo biloba containing ginkgolides A (GA), B (GB), and K (GK), in ischemic stroke patients. In the present study, we performed transcriptome analyses using RNA-seq and explored the potential mechanism of ginkgolides in seven in vitro cell models that mimic pathological stroke processes. Transcriptome analyses revealed that the ginkgolides had potential antiplatelet properties and neuroprotective activities in the nervous system. Specifically, human umbilical vein endothelial cells (HUVEC-T1 cells) showed the strongest response to DGMI and U251 human glioma cells ranked next. The results of pathway enrichment analysis via gene set enrichment analysis (GSEA) showed that the neuroprotective activities of DGMI and its monomers in the U251 cell model were related to their regulation of the sphingolipid and neurotrophin signaling pathways. We next verified these in vitro findings in an in vivo cuprizone (CPZ, bis(cyclohexanone)oxaldihydrazone)-induced model. GB and GK protected against demyelination in the corpus callosum (CC) and promoted oligodendrocyte regeneration in CPZ-fed mice. Moreover, GB and GK antagonized platelet-activating factor (PAF) receptor (PAFR) expression in astrocytes, inhibited PAF-induced inflammatory responses, and promoted brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) secretion, supporting remyelination. These findings are critical for developing therapies that promote remyelination and prevent stroke progression.