Glioblastoma evolution and heterogeneity from a 3D whole-tumor perspective.

Treatment failure for the lethal brain tumor glioblastoma (GBM) is attributed to intratumoral heterogeneity and tumor evolution. We utilized 3D neuronavigation during surgical resection to acquire samples representing the whole tumor mapped by 3D spatial coordinates. Integrative tissue and single-cell analysis revealed sources of genomic, epigenomic, and microenvironmental intratumoral heterogeneity and their spatial patterning. By distinguishing tumor-wide molecular features from those with regional specificity, we inferred GBM evolutionary trajectories from neurodevelopmental lineage origins and initiating events such as chromothripsis to emergence of genetic subclones and spatially restricted activation of differential tumor and microenvironmental programs in the core, periphery, and contrast-enhancing regions. Our work depicts GBM evolution and heterogeneity from a 3D whole-tumor perspective, highlights potential therapeutic targets that might circumvent heterogeneity-related failures, and establishes an interactive platform enabling 360° visualization and analysis of 3D spatial patterns for user-selected genes, programs, and other features across whole GBM tumors.

Interspecies regulatory landscapes and elements revealed by novel joint systematic integration of human and mouse blood cell epigenomes.

Knowledge of locations and activities of cis-regulatory elements (CREs) is needed to decipher basic mechanisms of gene regulation and to understand the impact of genetic variants on complex traits. Previous studies identified candidate CREs (cCREs) using epigenetic features in one species, making comparisons difficult between species. In contrast, we conducted an interspecies study defining epigenetic states and identifying cCREs in blood cell types to generate regulatory maps that are comparable between species, using integrative modeling of eight epigenetic features jointly in human and mouse in our Validated Systematic Integration (VISION) Project. The resulting catalogs of cCREs are useful resources for further studies of gene regulation in blood cells, indicated by high overlap with known functional elements and strong enrichment for human genetic variants associated with blood cell phenotypes. The contribution of each epigenetic state in cCREs to gene regulation, inferred from a multivariate regression, was used to estimate epigenetic state regulatory potential (esRP) scores for each cCRE in each cell type, which were used to categorize dynamic changes in cCREs. Groups of cCREs displaying similar patterns of regulatory activity in human and mouse cell types, obtained by joint clustering on esRP scores, harbor distinctive transcription factor binding motifs that are similar between species. An interspecies comparison of cCREs revealed both conserved and species-specific patterns of epigenetic evolution. Finally, we show that comparisons of the epigenetic landscape between species can reveal elements with similar roles in regulation, even in the absence of genomic sequence alignment.

scENCORE: leveraging single-cell epigenetic data to predict chromatin conformation using graph embedding.

Dynamic compartmentalization of eukaryotic DNA into active and repressed states enables diverse transcriptional programs to arise from a single genetic blueprint, whereas its dysregulation can be strongly linked to a broad spectrum of diseases. While single-cell Hi-C experiments allow for chromosome conformation profiling across many cells, they are still expensive and not widely available for most labs. Here, we propose an alternate approach, scENCORE, to computationally reconstruct chromatin compartments from the more affordable and widely accessible single-cell epigenetic data. First, scENCORE constructs a long-range epigenetic correlation graph to mimic chromatin interaction frequencies, where nodes and edges represent genome bins and their correlations. Then, it learns the node embeddings to cluster genome regions into A/B compartments and aligns different graphs to quantify chromatin conformation changes across conditions. Benchmarking using cell-type-matched Hi-C experiments demonstrates that scENCORE can robustly reconstruct A/B compartments in a cell-type-specific manner. Furthermore, our chromatin confirmation switching studies highlight substantial compartment-switching events that may introduce substantial regulatory and transcriptional changes in psychiatric disease. In summary, scENCORE allows accurate and cost-effective A/B compartment reconstruction to delineate higher-order chromatin structure heterogeneity in complex tissues.

DDX5 inhibits inflammation by modulating m6A levels of TLR2/4 transcripts during bacterial infection.

DExD/H-box helicases are crucial regulators of RNA metabolism and antiviral innate immune responses; however, their role in bacteria-induced inflammation remains unclear. Here, we report that DDX5 interacts with METTL3 and METTL14 to form an m6A writing complex, which adds N6-methyladenosine to transcripts of toll-like receptor (TLR) 2 and TLR4, promoting their decay via YTHDF2-mediated RNA degradation, resulting in reduced expression of TLR2/4. Upon bacterial infection, DDX5 is recruited to Hrd1 at the endoplasmic reticulum in an MyD88-dependent manner and is degraded by the ubiquitin-proteasome pathway. This process disrupts the DDX5 m6A writing complex and halts m6A modification as well as degradation of TLR2/4 mRNAs, thereby promoting the expression of TLR2 and TLR4 and downstream NF-κB activation. The role of DDX5 in regulating inflammation is also validated in vivo, as DDX5- and METTL3-KO mice exhibit enhanced expression of inflammatory cytokines. Our findings show that DDX5 acts as a molecular switch to regulate inflammation during bacterial infection and shed light on mechanisms of quiescent inflammation during homeostasis.

FAM210A: An emerging regulator of mitochondrial homeostasis.

Mitochondrial homeostasis serves as a cornerstone of cellular function, orchestrating a delicate balance between energy production, redox status, and cellular signaling transduction. This equilibrium involves a myriad of interconnected processes, including mitochondrial dynamics, quality control mechanisms, and biogenesis and degradation. Perturbations in mitochondrial homeostasis have been implicated in a wide range of diseases, including neurodegenerative diseases, metabolic syndromes, and aging-related disorders. In the past decades, the discovery of numerous mitochondrial proteins and signaling has led to a more complete understanding of the intricate mechanisms underlying mitochondrial homeostasis. Recent studies have revealed that Family with sequence similarity 210 member A (FAM210A) is a novel nuclear-encoded mitochondrial protein involved in multiple aspects of mitochondrial homeostasis, including mitochondrial quality control, dynamics, cristae remodeling, metabolism, and proteostasis. Here, we review the function and physiological role of FAM210A in cellular and organismal health. This review discusses how FAM210A acts as a regulator on mitochondrial inner membrane to coordinate mitochondrial dynamics and metabolism.

Accurate identification of structural variations from cancer samples.

Structural variations (SVs) are commonly found in cancer genomes. They can cause gene amplification, deletion and fusion, among other functional consequences. With an average read length of hundreds of kilobases, nano-channel-based optical DNA mapping is powerful in detecting large SVs. However, existing SV calling methods are not tailored for cancer samples, which have special properties such as mixed cell types and sub-clones. Here we propose the Cancer Optical Mapping for detecting Structural Variations (COMSV) method that is specifically designed for cancer samples. It shows high sensitivity and specificity in benchmark comparisons. Applying to cancer cell lines and patient samples, COMSV identifies hundreds of novel SVs per sample.

Loss of FoxO1 activates an alternate mechanism of mitochondrial quality control for healthy adipose browning.

Browning of white adipose tissue is hallmarked by increased mitochondrial density and metabolic improvements. However, it remains largely unknown how mitochondrial turnover and quality control are regulated during adipose browning. In the present study, we found that mice lacking adipocyte FoxO1, a transcription factor that regulates autophagy, adopted an alternate mechanism of mitophagy to maintain mitochondrial turnover and quality control during adipose browning. Post-developmental deletion of adipocyte FoxO1 (adO1KO) suppressed Bnip3 but activated Fundc1/Drp1/OPA1 cascade, concurrent with up-regulation of Atg7 and CTSL. In addition, mitochondrial biogenesis was stimulated via the Pgc1α/Tfam pathway in adO1KO mice. These changes were associated with enhanced mitochondrial homeostasis and metabolic health (e.g., improved glucose tolerance and insulin sensitivity). By contrast, silencing Fundc1 or Pgc1α reversed the changes induced by silencing FoxO1, which impaired mitochondrial quality control and function. Ablation of Atg7 suppressed mitochondrial turnover and function, causing metabolic disorder (e.g., impaired glucose tolerance and insulin sensitivity), regardless of elevated markers of adipose browning. Consistently, suppression of autophagy via CTSL by high-fat diet was associated with a reversal of adO1KO-induced benefits. Our data reveal a unique role of FoxO1 in coordinating mitophagy receptors (Bnip3 and Fundc1) for a fine-tuned mitochondrial turnover and quality control, underscoring autophagic clearance of mitochondria as a prerequisite for healthy browning of adipose tissue.

Genetically engineering of Saccharomyces cerevisiae for enhanced oral delivery vaccine vehicle.

As a series of our previous studies reported, recombinant yeast can be the oral vaccines to deliver designed protein and DNA, as well as functional shRNA, into dendritic cells (DCs) in mice for specific immune regulation. Here, we report the further optimization of oral yeast-based vaccine from two aspects (yeast characteristics and recombinant DNA constitution) to improve the effect of immune regulation. After screening four genes in negative regulation of glucan synthesis in yeast (MNN9, GUP1, PBS2 and EXG1), this research combined HDR-based genome editing technology with Cre-loxP technology to acquire 15 gene-knockout strains without drug resistance-gene to exclude biosafety risks; afterward, oral feeding experiments were performed on the mice using 15 oral recombinant yeast-based vaccines constructed by the gene-knockout strains harboring pCMV-MSTN plasmid to screen the target strain with more effective inducing mstn-specific antibody which in turn increasing weight gain effect. And subsequently based on the selected gene-knockout strain, the recombinant DNA in the oral recombinant yeast-based vaccine is optimized via a combination of protein fusion expression (OVA-MSTN) and interfering RNA technology (shRNA-IL21), comparison in terms of both weight gain effect and antibody titer revealed that the selected gene-knockout strain (GUP1ΔEXG1Δ) combined with specific recombinant DNA (pCMV-OVA-MSTN-shIL2) had a better effect of the vaccine. This study provides a useful reference to the subsequent construction of a more efficient oral recombinant yeast-based vaccine in the food and pharmaceutical industry.

Impact of non-emergency surgical timing on postoperative recovery quality in mild or asymptomatic SARS-CoV-2 infected patients: a grouped cohort study.

OBJECTIVE: To explore the relationship between the timing of non-emergency surgery in mild or asymptomatic SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infected individuals and the quality of postoperative recovery from the time of confirmed infection to the day of surgery. METHODS: We retrospectively reviewed the medical records of 300 cases of mild or asymptomatic SARS-CoV-2 infected patients undergoing elective general anaesthesia surgery at Yijishan Hospital between January 9, 2023, and February 17, 2023. Based on the time from confirmed SARS-CoV-2 infection to the day of surgery, patients were divided into four groups: ≤2 weeks (Group A), 2-4 weeks (Group B), 4-6 weeks (Group C), and 6-8 weeks (Group D). The primary outcome measures included the Quality of Recovery-15 (QoR-15) scale scores at 3 days, 3 months, and 6 months postoperatively. Secondary outcome measures included postoperative mortality, ICU admission, pulmonary complications, postoperative length of hospital stay, extubation time, and time to leave the PACU. RESULTS: Concerning the primary outcome measures, the QoR-15 scores at 3 days postoperatively in Group A were significantly lower compared to the other three groups (P < 0.05), while there were no statistically significant differences among the other three groups (P > 0.05). The QoR-15 scores at 3 and 6 months postoperatively showed no statistically significant differences among the four groups (P > 0.05). In terms of secondary outcome measures, Group A had a significantly prolonged hospital stay compared to the other three groups (P < 0.05), while other outcome measures showed no statistically significant differences (P > 0.05). CONCLUSION: The timing of surgery in mild or asymptomatic SARS-CoV-2 infected patients does not affect long-term recovery quality but does impact short-term recovery quality, especially for elective general anaesthesia surgeries within 2 weeks of confirmed infection. Therefore, it is recommended to wait for a surgical timing of at least greater than 2 weeks to improve short-term recovery quality and enhance patient prognosis.

[Research progress in Astragali Radix and its active ingredients in treatment of lung cancer].

Lung cancer is the leading cause of cancer death, and its effective treatment is a difficult medical problem. Lung cancer belongs to the traditional Chinese medicine(TCM) disease categories of lung accumulation, lung amassment, and overstrain cough. Rich theoretical basis and practical experience have been accumulated in the TCM treatment of lung cancer. Astragali Radix is one of the representatives of Qi-tonifying drugs. It mainly treat the lung cancer with the syndrome of Qi deficiency and pathogen stagnation, following the principle of reinforcing healthy Qi and eliminating patgogenic Qi. Astragali Radix exerts a variety of pharmacological activities in the treatment of lung cancer, including inhibiting tumor cell proliferation and promoting tumor cell apoptosis, inhibiting tumor invasion and migration, regulating the tumor microenvironment, suppressing tumor angiogenesis, modulating autophagy, inducing macrophage polarization, enhancing immunity, inhibiting immune escape, and reversing cisplatin resistance. The active ingredients of Astragali Radix in treating lung cancer include polysaccharides, saponins, and flavonoids. This study reviewed the pharmacological activities and active ingredients of Astragali Radix in the treatment of lung cancer, providing a basis for the development and utilization of Astragali Radix resources and active ingredients and the research and development of anti-tumor drugs.

Enabling Stable and Low-Strain Lithium Plating/Stripping with 2D Layered Transition Metal Carbides by Forming Li-Zipped MXenes and a Li Halide-Rich Solid Electrolyte Interphase.

Two-dimensional (2D) layered materials demonstrate prominent advantage in regulating lithium plating/stripping behavior by confining lithium diffusion/plating within interlayer gaps. However, achieving effective interlayer confined lithium diffusion/plating without compromising the stability of bulk-structural and the solid electrolyte interphase (SEI) remains a considerable challenge. This paper presents an electrochemical scissor and lithium zipper-driven protocol for realizing interlayer confined lithium plating with pretty-low strain and volume change. In this protocol, lithium serves as a "zipper" to reunite the adjacent MXene back to MAX-like phase to markedly enhance the structural stability, and a lithium halide-rich SEI is formed by electrochemically removing the terminals of halogenated MXenes to maintain the stability and rapid lithium ions diffusion of SEI. When the Ti3 C2 I2 serves as the host for lithium plating, the average coulomb efficiency exceeds 97.0 % after 320 lithium plating/stripping cycles in conventional ester electrolyte. Furthermore, a full cell comprising of LiNi0.8 Mn0.1 Co0.1 O2 and Ti3 C2 I2 @Li exhibits a capacity retention rate of 73.4 % after 200 cycles even under high cathode mass-loading (20 mg cm-2 ) and a low negative/positive capacity ratio of 1.4. Our findings advance the understanding of interlayer confined lithium plating in 2D layered materials and provide a new direction in regulating lithium and other metal plating/stripping behaviors.

First Report of Erysiphe astragali Causing Powdery Mildew on Astragalus mongholicus in China.

Astragalus mongholicus Bge. [A. membranaceus Bge. var. mongholicus (Bge.) Hsiao] is a highly valuable perennial medicinal plant mainly distributed in China, whose dry roots are known as Huangqi in traditional Chinese medicine for reinforcing vital energy, strengthening superficial resistance, and promoting tissue regeneration (Lin et al. 2000). A. mongholicus roots of high quality are produced in Northwest and North China. Since July 2021, powdery mildew outbreaks happened annually on the leaves of A. mongholicus in a plantation (123° 56' 40'' E, 47° 22' 20'' N) in Qiqihar city, Heilongjiang Province, China. Disease incidence reached 100% by October (Fig. 1A-C), causing severe impairment of growth. Powdery mildew spots of circular or irregular shapes emerged on upper surface of leaf, resulting in plentiful lesion specks. Dense white hyphae appeared chaotically intertwined. Hyphae were hyaline and highly flexuous, 5.3 - 10.7 µm in diameter (n = 20). Chasmothecia were globose or slightly ovoid-shaped and turned dark brown when matured. Chasmothecia (diameter: 135.2 - 222.9 µm, n = 20) existed abundantly on the diseased leaves in the fields. Conidiophores were 89.0 - 129.9 µm in length (n = 20) and composed of one cylindrical, straight foot cell, followed by two cells and one to three conidia. Conidia were slim ellipsoid-shaped, occasionally ovoid-shaped, measuring 14.6 - 24.7 µm by 6.4 to10.4 µm, length/width ratio was 1.8 - 3.0 (n = 30). Hyphal appressoria were nipple-shaped and appeared in singular, occasionally in pairs. Unbranched germ tube emerged reaching out of the germinating conidia while forming an acute angle with the long axis. Comprehensively, the pathogen exhibited micro-morphology of the genus Erysiphe. For molecular identification, pathogen was carefully scraped off diseased leaves for DNA extraction. We used the DNA samples of three biological replicates for the sequencing of the ITS rDNA fragment (primers by (White et al. 1990). All the samples resulted in an identical ITS sequence (deposited in GenBank as OQ390098.1). It displayed 99.83% identity with OP806835.1 of an E. astragali voucher collected in Iran (Fig. 1D-M, O). Hence, our pathogen was identified as an E. astragali stain. Additionally, we amplified the Mcm7 sequence (using primers by (Ellingham et al. 2019), deposited as OQ397582.1). We propagated 40-day-old A. mongholicus plants via germinating seeds in pot soil and performed pathogenicity tests. Firstly, we incubated detached healthy leaves of propagated plants with severely symptomatic leaves collected from the fields in petri dishes under saturated moisture content and room temperature. Powdery mildew symptoms emerged on each healthy leaf (n = 5) after two weeks. Further, we infected healthy plants (n = 5) by gently pressing and rubbing symptomatic leaves on each healthy leaf, and kept them in a greenhouse (24 ℃, 80% humidity, 16/8-hour light/dark cycle). After a month, symptoms emerged on a number of leaves of each infected plant. We performed micromorphology observation (Fig. 1N-P) and ITS sequencing to confirm that the results fulfilled Koch's postulates. Powdery mildew caused by E. astragali on A. strictus in Tibet (Wang and Jiang 2023) and on A. scaberrimus in Inner Mongolia (Sun et al. 2023) have been reported. Here we report powdery mildew caused by E. astragali on Astragalus mongholicus for the first time. These Astragalus spp. are all acknowledged to have medicinal values in China but their usages are quite different.

Hijacked enhancer-promoter and silencer-promoter loops in cancer.

Recent work has shown that besides inducing fusion genes, structural variations (SVs) can also contribute to oncogenesis by disrupting the three-dimensional genome organization and dysregulating gene expression. At the chromatin-loop level, SVs can relocate enhancers or silencers from their original genomic loci to activate oncogenes or repress tumor suppressor genes. On a larger scale, different types of alterations in topologically associating domains (TADs) have been reported in cancer, such as TAD expansion, shuffling, and SV-induced neo-TADs. Furthermore, the transformation from normal cells to cancerous cells is usually coupled with active or repressive compartmental switches, and cancer-specific compartments have been proposed. This review discusses the sites, and the other latest advances in studying how SVs disrupt higher-order genome structure in cancer, which in turn leads to oncogene dysregulation. We also highlight the clinical implications of these changes and the challenges ahead in this field.

Glycemic Response in Nonhuman Primates Fed Gluten-Free Rice Cakes Enriched with Soy, Pea, or Rice Protein and Its Correlation with Nutrient Composition.

Celiac disease (CD) is a chronic disease caused by the consumption of gluten foods and is closely related to type 1 diabetes (T1D). Adherence to a gluten-free (GF) diet is the cornerstone of treating CD, and certain plant proteins added to GF foods affect blood glucose to varying degrees. The aim of this study was to analyze and compare the changes in glycemic index (GI) and incremental area under the postprandial glucose tolerance curve (IAUC) of various foods through consumption of GF foods supplemented with certain plant proteins in non-human primates. The test foods were GF rice cakes with 5%, 10%, and 15% added single plant proteins (rice protein, soy protein, and pea protein) mixed with rice flour, as well as 5%, 10%, and 15% gluten rice cakes, and rice flour alone, for a total of 13 food items, and 12 healthy cynomolgus monkeys were examined for their glucose levels in the blood after fasting and after eating each test food (50 g) for 15, 30, 45, 60, 90, and 120 min after fasting and eating each test food. Fingertip blood glucose levels were measured, and the nutrient content of each food, including protein, fat, starch, ash, and amino acids, was examined. All foods tested had a low GI (<50) when analyzed using one-way ANOVA and nonparametric tests. Postprandial IAUC was significantly lower (p < 0.05) for GF rice cakes with 15% pea protein (499.81 ± 34.46) compared to GF rice cakes with 5% pea protein (542.19 ± 38.78), 15% soy protein (572.94 ± 72.74), and 15% rice protein (530.50 ± 14.65), and GF rice cakes with 15% wheat bran protein (533.19 ± 34.89). A multiple regression analysis showed that glycine was negatively associated with IAUC in GF rice cakes with 5%, 10%, and 15% pea protein added (p = 0.0031 < 0.01). Fat was negatively correlated with IAUC in GF rice cakes supplemented with 5%, 10%, and 15% soy protein (p = 0.0024 < 0.01). In this study, GF rice cakes made with added pea protein were superior to other gluten and GF rice cakes and had a small effect on postprandial glucose.

Health Outcomes of Social Pension Expansion: A Quasi-Experiment Among Older Adults in Hong Kong.

A social pension, regarded as a reliable source of income, has the potential to significantly influence the overall wellbeing of vulnerable older adults. This study aimed to extend the understanding of the effects of social pension expansion beyond its economic impacts to encompass recipients' health status. Using three-wave data from a representative sample of older adults, we employed a quasi-experimental assessment model to evaluate the impact of a recent social pension expansion in Hong Kong on health-related consumption and health outcomes among older adults. The results of the triple difference estimations revealed that an increased social pension significantly enhanced older people's engagement in entertainment activities, utilization of healthcare services, and expenditures on preventive health products. Furthermore, the increased social pension was found to have a significant positive effect on mitigating poor self-rated health and poor sleep quality. However, it did not have a significant impact on the prevalence of depression. These findings suggest that social pension expansion should be coordinated with other policy initiatives to comprehensively improve the physical and mental health of older adults.

Improved Performance and Stability of Quasi-Two-Dimensional Perovskite Solar Cells by Post-treatment with Acetaminophen.

Recently, perovskite solar cells (PSCs) based on quasi-two-dimensional (quasi-2D) perovskites have drawn more attention due to their excellent stability, although their efficiencies are still lower than those of 3D ones. Here we applied post-treatment of 2D perovskite GAMA5Pb5I16 (GA = guanidinium, MA = methylammonium) films with acetaminophen (AMP) to improve their performance. The efficiency of the solar cells with 2 mg/mL AMP post-treatment increased to 18.01% from 16.72% for those without post-treatment. The efficiency improvement results from the enlarged grain size, reduced trap state density, and better energy level matching after AMP post-treatment. In addition, the stability of the solar cells is improved. The solar cells with AMP post-treatment maintain 91% of the original power conversion efficiency value after aging for 30 days in the atmosphere. This work opens a new approach for the efficiency and stability enhancement of quasi-2D PSCs.

Characterization of preclinical Alzheimer's disease model: spontaneous type 2 diabetic cynomolgus monkeys with systemic pro-inflammation, positive biomarkers and developing AD-like pathology.

BACKGROUND: The key to the prevention and treatment of Alzheimer's disease (AD) is to be able to predict and diagnose AD at the preclinical or early stage, but the lack of a preclinical model of AD is the critical factor that causes this problem to remain unresolved. METHODS: We assessed 18 monkeys in vivo evaluation of pro-inflammatory cytokines and AD pathological biomarkers (n = 9 / type 2 diabetic mellitus (T2DM) group, age 20, fasting plasma glucose (FPG) ≥ 100 mg/dL, and n = 9 / negative control (NC) group, age 17, FPG < 100 mg/dL). Levels of pro-inflammatory cytokines and AD pathological biomarkers was measured by ELISA and Simoa Technology, respectively. 9 monkeys evaluated ex vivo for AD-like pathology (n = 6 / T2DM group, age 22.17, FPG ≥ 126 mg/dL, and n = 3 / NC group, age 14.67, FPG < 100 mg/dL). To evaluate the pathological features of AD in the brains of T2DM monkeys, we assessed the levels of Aß, phospho-tau, and neuroinflammation using immunohistochemistry, which further confirmed the deposition of Aß plaques by Bielschowsky's silver, Congo red, and Thioflavin S staining. Synaptic damage and neurodegeneration were assessed by immunofluorescence. RESULTS: We found not only increased levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) in peripheral blood (PB) and brain of T2DM monkeys but also changes in PB of AD pathological biomarkers such as decreased ß-amyloid (Aß) 42 and Aß40 levels. Most notably, we observed AD-like pathological features in the brain of T2DM monkeys, including Aß plaque deposition, p-tau from neuropil thread to pre-neurofibrillary tangles (NFTs), and even the appearance of extracellular NFT. Microglia were activated from a resting state to an amoeboid. Astrocytes showed marked hypertrophy and an increased number of cell bodies and protrusions. Finally, we observed impairment of the postsynaptic membrane but no neurodegeneration or neuronal death. CONCLUSIONS: Overall, T2DM monkeys showed elevated levels of peripheral and intracerebral inflammation, positive AD biomarkers in body fluids, and developing AD-like pathology in the brain, including Aß and tau pathology, glial cell activation, and partial synaptic damage, but no neuronal degeneration or death as compared to the healthy normal group. Hereby, we consider the T2DM monkeys with elevation of the peripheral pro-inflammatory factors and positive AD biomarkers can be potentially regarded as a preclinical AD model.

Single-Cell Oral Delivery Platform for Enhanced Acid Resistance and Intestinal Adhesion.

Oral delivery of cells, such as probiotics and vaccines, has proved to be inefficient since cells are generally damaged in an acidic stomach prior to arrival at the intestine to exert their health benefits. In addition, short retention in the intestine is another obstacle which affects inefficiency. To overcome these obstacles, a cell-in-shell structure was designed with pH-responsive and mucoadhesive properties. The pH-responsive shell consisting of three cationic layers of chitosan and three anionic layers of trans-cinnamic acid (t-CA) was made via layer-by-layer (LbL) assembly. t-CA layers are hydrophobic and impermeable to protons in acid, thus enhancing cell gastric resistance in the stomach, while chitosan layers endow strong interaction between the cell surface and the mucosal wall which facilitates cell mucoadhesion in the intestine. Two model cells, probiotic L. rhamnosus GG and dead Streptococcus iniae, which serve as inactivated whole-cell vaccine were chosen to test the design. Increased survival and retention during oral administration were observed for coated cells as compared with naked cells. Partial removal of the coating (20-60% removal) after acid treatment indicates that the coated vaccine can expose its surface immunogenic protein after passage through the stomach, thus facilitating vaccine immune stimulation in the intestine. As a smart oral delivery platform, this design can be extended to various macromolecules, thus providing a promising strategy to formulate oral macromolecules in the prevention and treatment of diseases at a cellular level.

[Clinical observation of different intramedullary fixation methods for the treatment of intertrochanteric fracture].

OBJECTIVE: To explore clinical efficacy of proximal femoral nail anti-rotation(PFNA),InterTan and proximal femoral bionic intramedullary nail (PFBN) in treating femoral intertrochanteric fracture. METHODS: Clinical data of 120 patients with intertrochanteric fracture who were underwent closed reduction intramedullary nail-internal fixation from January 2020 to January 2021 were retrospectively analyzed. According to methods of internal fixation,patients were divided into 3 groups. There were 25 patients in PFBN group,including 16 females and 9 males,aged from 69 to 79 years old with an average of (73.67±5.16) years old. There were 55 patients in PFNA group,including 38 females and 17 males,aged from 68 to 80 years old with an average of (74.23±5.57) years old. There were 40 patients in InterTan group,including 26 females and 14 males,aged from 68 to 79 years old with an average of (73.45±5.34) years old. Operative time,intraoperative blood loss,incision length,hospital stay,weight-bearing time,fracture healing time and complications among 3 groups were compared,and clinical effect was evaluated by Harris score of hip function before operation,1,6 and 12 months after opertaion,respectively. RESULTS: Patients among 3 groups were successfully completed operation and were followed up for more than 12 months. There were no significant difference in hospital stay,operative time,intraoperative blood loss and incision length among 3 groups (P>0.05). Weight bearing time of PFBN group (7.98±1.34) d and InterTan group (8.22±0.46) d were earlier than that of PFNA group (10.27±0.66) d(P<0.01). Fracture healing time of PFBN group (10.14±2.33) weeks and InterTan group (11.87±2.48) weeks were earlier than that of PFNA group (13.68±2.36) weeks (P<0.01). One month after operation,Harris score in PFBN group (70.52±5.34) and InterTan group (69.81±6.17) was higher than that of PFNA group (51.46±5.36),and there was no significant difference between PFBN group and InterTan group (P>0.05). There were no significant difference in Harris scores among 3 groups before operation,6 and 12 months after opertaion(P>0.05). Cases of complication of InterTan group and PFNA group were lower than that of PFNA group (P<0.05). CONCLUSION: PFBN and InterTan for the treatment of intertrochanteric fracture have advantages of faster fracture healing,earlier weight-bearing time and fewer postoperative complications than traditional PFNA,but three operations could achieve higher effective rates without significant difference in long-term results.

The Co-oligomers of Aß42 and Human Islet Amyloid Polypeptide Exacerbate Neurotoxicity and Alzheimer-like Pathology at Cellular Level.

The Aß hypothesis has long been central to Alzheimer's disease (AD) theory, with a recent surge in attention following drug approvals targeting Aß plaque clearance. Aß42 oligomers (AßO) are key neurotoxins. While ß-amyloid (Aß) buildup is a hallmark of AD, postmortem brain analyses have unveiled human islet amyloid polypeptide (hIAPP) deposition in AD patients, suggesting a potential role in Alzheimer's pathology. This study investigates the neurotoxic effects of co-aggregates of Aß42 and hIAPP, specifically focusing on their impact on cell survival, apoptosis, and AD-like pathology. We analyzed and compared the impact of AßO and Aß42-hIAPP on cell survival in SH-SY5Y cells, apoptosis and inducing AD-like pathology in glutamatergic neurons. Aß42-hIAPP co-oligomers exhibited significantly greater toxicity, causing 2.3-3.5 times higher cell death compared to AßO alone. Furthermore, apoptosis rates were significantly exacerbated in glutamatergic neurons when exposed to Aß42-hIAPP co-oligomers. The study also revealed that Aß42-hIAPP co-oligomers induced typical AD-like pathology in glutamatergic neurons, including the presence of Aß deposits (detected by 6E10 and 4G8 immunofluorescence) and alterations in tau protein (changes in total tau HT7, phosphorylated tau AT8, AT180). Notably, Aß42-hIAPP co-oligomers induced a more severe AD pathology compared to AßO alone. These findings provide compelling evidence for the heightened toxicity of Aß42-hIAPP co-oligomers on neurons and their role in exacerbating AD pathology. The study contributes novel insights into the pathogenesis of Alzheimer's disease, highlighting the potential involvement of hIAPP in AD pathology. Together, these findings offer novel insights into AD pathogenesis and routes for constructing animal models.