CSF biomarkers of immune activation and Alzheimer's disease for predicting cognitive impairment risk in the elderly.

The immune system substantially influences age-related cognitive decline and Alzheimer's disease (AD) progression, affected by genetic and environmental factors. In a Mayo Clinic Study of Aging cohort, we examined how risk factors like APOE genotype, age, and sex affect inflammatory molecules and AD biomarkers in cerebrospinal fluid (CSF). Among cognitively unimpaired individuals over 65 (N = 298), we measured 365 CSF inflammatory molecules, finding age, sex, and diabetes status predominantly influencing their levels. We observed age-related correlations with AD biomarkers such as total tau, phosphorylated tau-181, neurofilament light chain (NfL), and YKL40. APOE4 was associated with lower Aß42 and higher SNAP25 in CSF. We explored baseline variables predicting cognitive decline risk, finding age, CSF Aß42, NfL, and REG4 to be independently correlated. Subjects with older age, lower Aß42, higher NfL, and higher REG4 at baseline had increased cognitive impairment risk during follow-up. This suggests that assessing CSF inflammatory molecules and AD biomarkers could predict cognitive impairment risk in the elderly.

Dual-Responsive MXene-Functionalized Wool Yarn Artificial Muscles.

Fiber-based artificial muscles are promising for smart textiles capable of sensing, interacting, and adapting to environmental stimuli. However, the application of current artificial muscle-based textiles in wearable and engineering fields has largely remained a constraint due to the limited deformation, restrictive stimulation, and uncomfortable. Here, dual-responsive yarn muscles with high contractile actuation force are fabricated by incorporating a very small fraction (<1 wt.%) of Ti3C2Tx MXene/cellulose nanofibers (CNF) composites into self-plied and twisted wool yarns. They can lift and lower a load exceeding 3400 times their own weight when stimulated by moisture and photothermal. Furthermore, the yarn muscles are coiled homochirally or heterochirally to produce spring-like muscles, which generated over 550% elongation or 83% contraction under the photothermal stimulation. The actuation mechanism, involving photothermal/moisture-mechanical energy conversion, is clarified by a combination of experiments and finite element simulations. Specifically, MXene/CNF composites serve as both photothermal and hygroscopic agents to accelerate water evaporation under near-infrared (NIR) light and moisture absorption from ambient air. Due to their low-cost facile fabrication, large scalable dimensions, and robust strength coupled with dual responsiveness, these soft actuators are attractive for intelligent textiles and devices such as self-adaptive textiles, soft robotics, and wearable information encryption.

Urchin-like (NH4)2V10O25·8H2O hierarchical arrays with significantly expanded interlayer spacing for superior aqueous zinc-ion batteries.

The practical application of zinc ion batteries (ZIBs) can be facilitated by designing cathode materials with unique structures that can overcome the critical problems of slow reaction kinetics and large volume expansion associated with the intercalation reaction of divalent zinc ions. In this study, a novel urchin-like (NH4)2V10O25·8H2O assembled from nanorods was synthesized by a simple hydrothermal method, noted as U-NVO. The interlayer organic pillar of cetyltrimethylammonium cation (CTAB) has been intercalated between layers to regulate the interlayer microstructure and expand the interlayer spacing to 1.32 nm, which effectively increased the contact between the electrode and electrolyte interface and shortened the diffusion path of electrolyte ions. The interlayer pillars of structural H2O and NH4+ provide a flexible framework structure and enhance the cohesion of the layered structure, which helps to maintain structural stability during the charging and discharging process, resulting in long-term durability. These unique properties result in the U-NVO cathodes demonstrating high specific capacity (401.7 mA h g-1 at 0.1 A g-1), excellent rate capability (99.6 % retention from 0.1 to 5 A g-1 and back to 0.1 A g-1), and long-term cycling performance (∼87.5 % capacity retention after 2600 cycles). These results offer valuable insights into the design of high-performance vanadium oxide cathode materials.

Clopidogrel Plus Aspirin vs Aspirin Alone in Patients With Acute Mild to Moderate Stroke: The ATAMIS Randomized Clinical Trial.

Importance: Dual antiplatelet therapy has been demonstrated to be superior to single antiplatelet in reducing recurrent stroke among patients with transient ischemic attack or minor stroke, but robust evidence for its effect in patients with mild to moderate ischemic stroke is lacking. Objective: To evaluate whether dual antiplatelet therapy is superior to single antiplatelet among patients with mild to moderate ischemic stroke. Design, Setting, and Participants: This was a multicenter, open-label, blinded end point, randomized clinical trial conducted at 66 hospitals in China from December 20, 2016, through August 9, 2022. The date of final follow-up was October 30, 2022. The analysis was reported on March 12, 2023. Of 3065 patients with ischemic stroke, 3000 patients with acute mild to moderate stroke within 48 hours of symptom onset were enrolled, after excluding 65 patients who did not meet eligibility criteria or had no randomization outcome. Interventions: Within 48 hours after symptom onset, patients were randomly assigned to receive clopidogrel plus aspirin (n = 1541) or aspirin alone (n = 1459) in a 1:1 ratio. Main Outcomes and Measures: The primary end point was early neurologic deterioration at 7 days, defined as an increase of 2 or more points in National Institutes of Health Stroke Scale (NIHSS) score, but not as a result of cerebral hemorrhage, compared with baseline. The superiority of clopidogrel plus aspirin to aspirin alone was assessed based on a modified intention-to-treat population, which included all randomized participants with at least 1 efficacy evaluation regardless of treatment allocation. Bleeding events were safety end points. Results: Of the 3000 randomized patients, 1942 (64.6%) were men, the mean (SD) age was 65.9 (10.6) years, median (IQR) NIHSS score at admission was 5 (4-6), and 1830 (61.0%) had a stroke of undetermined cause. A total of 2915 patients were included in the modified intention-to-treat analysis. Early neurologic deterioration occurred in 72 of 1502 (4.8%) in the dual antiplatelet therapy group vs 95 of 1413 (6.7%) in the aspirin alone group (risk difference -1.9%; 95% CI, -3.6 to -0.2; P = .03). Similar bleeding events were found between 2 groups. Conclusions and Relevance: Among Chinese patients with acute mild to moderate ischemic stroke, clopidogrel plus aspirin was superior to aspirin alone with regard to reducing early neurologic deterioration at 7 days with similar safety profile. These findings indicate that dual antiplatelet therapy may be a superior choice to aspirin alone in treating patients with acute mild to moderate stroke. Trial Registration: ClinicalTrials.gov Identifier: NCT02869009.

Fusobacterium nucleatum induces chemoresistance in colorectal cancer by inhibiting pyroptosis via the Hippo pathway.

Chemotherapy resistance is one of the main reasons for the poor prognosis of colorectal cancer (CRC). Moreover, dysbiosis of gut bacteria was found to be a specific environmental risk factor. In this study, enrichment of F. nucleatum was elucidated to be significantly associated with CRC recurrence after chemotherapy. Functional experiments showed that F. nucleatum could inhibit pyroptosis induced by chemotherapy drugs, thereby inducing chemoresistance. Furthermore, mechanistic investigation demonstrated that F. nucleatum could regulate the Hippo pathway and promote the expression of BCL2, thereby inhibiting the Caspase-3/GSDME pyroptosis-related pathway induced by chemotherapy drugs and mediating CRC cell chemoresistance. Taken together, these results validated the significant roles of F. nucleatum in CRC chemoresistance, which provided an innovative theoretical basis for the clinical diagnosis and therapy of CRC.

KN046, a bispecific antibody against PD-L1 and CTLA-4, plus chemotherapy as first-line treatment for metastatic NSCLC: A multicenter phase 2 trial.

KN046, a bispecific antibody targeting PD-L1 and CTLA-4, presents a promising therapeutic option for metastatic non-small cell lung cancer (NSCLC). In this multicenter phase 2 trial, patients with nonsquamous (non-sq) NSCLC receive pemetrexed, whereas those with sq-NSCLC receive paclitaxel, plus KN046 and carboplatin. Following four cycles, maintenance therapy includes KN046 with pemetrexed for non-sq-NSCLC and KN046 for sq-NSCLC. The objective response rate is 46.0%, and the median duration of response is 8.1 months. The median progression-free and overall survival are 5.8 and 26.6 months, respectively. The common adverse events include anemia (87.4%), loss of appetite (72.4%), and neutropenia (70.1%). The most prevalent immune-related adverse event is pruritus (28.7%). These findings indicate that first-line treatment with KN046 and chemotherapy is effective and tolerable in metastatic NSCLC patients, warranting further investigation in a larger phase 3 trial. The trial is registered at ClinicalTrials.gov (NCT04054531).

From Fluorescence-Transfer-Lightening-Printing-Assisted Conductive Adhesive Nanocomposite Hydrogels toward Wearable Interactive Optical Information-Electronic Strain Sensors.

The interactive flexible device, which monitors the human motion in optical and electrical synergistic modes, has attracted growing attention recently. The incorporation of information attribute within the optical signal is deemed advantageous for improving the interactive efficiency. Therefore, the development of wearable optical information-electronic strain sensors holds substantial promise, but integrating and synergizing various functions and realizing strain-mediated information transformation keep challenging. Herein, an amylopectin (AP) modified nanoclay/polyacrylamide-based nanocomposite (NC) hydrogel and an aggregation-induced-emission-active ink are fabricated. Through the fluorescence-transfer printing of the ink onto the hydrogel film in different strains with nested multiple symbolic information, a wearable interactive fluorescent information-electronic strain sensor is developed. In the sensor, the nanoclay plays a synergistic "one-stone-three-birds" role, contributing to "lightening" fluorescence (≈80 times emission intensity enhancement), ionic conductivity, and excellent stretchability (>1000%). The sensor has high biocompatibility, resilience (elastic recovery ratio: 97.8%), and strain sensitivity (gauge factor (GF): 10.9). Additionally, the AP endows the sensor with skin adhesiveness. The sensor can achieve electrical monitoring of human joint movements while displaying interactive fluorescent information transformation. This research poses an efficient strategy to develop multifunctional materials and provides a general platform for achieving next-generation interactive devices with prospective applications in wearable devices, human-machine interfaces, and artificial intelligence.

Protective effect of Tao Hong Si Wu Decoction against inflammatory injury caused by intestinal flora disorders in an ischemic stroke mouse model.

BACKGROUND AND AIMS: Recent studies have shown that intestinal flora are involved in the pathological process of ischemic stroke (IS). The potential protective effect of the traditional Chinese prescription, Tao Hong Si Wu Decoction (THSWD), against inflammatory injury after IS and its underlying mechanisms of action were investigated in the current study. METHODS: Fifty SPF(Specefic pathogen Free) male C57 mice were randomly assigned to sham operation, model, THSWD low-dose (6.5 g/kg), medium-dose (13 g/kg) and high-dose (26 g/kg) groups (10 mice per group). Mouse models of transient middle cerebral artery occlusion were prepared via thread embolism. Neurological function score, hematoxylin-eosin (HE) staining, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), 16S ribosomal DNA (rDNA) sequencing, quantitative reverse transcription PCR (qRT-PCR) and other methods were employed to elucidate the underlying molecular mechanisms. RESULTS: Notably, THSWD induced a reduction in the neurological function score (P < 0.01) and neuronal injury in brain tissue, increase in protein expression of Claudin-5 and zonula occludens-1 (ZO-1) in brain tissue(P < 0.01), and decrease in serum lipopolysaccharide (LPS)(P < 0.01), diamine oxidase (DAO)(P < 0.01) and D-lactic acid(P < 0.01, P < 0.05) levels to a significant extent. THSWD also inhibited the levels of tumor necrosis factor-α (TNF-α)(P < 0.01) and interleukin - 1ß (IL-1ß)(P < 0.01) in brain tissue, and increased alpha and beta diversity in ischemic stroke mice, along with a certain reversal effect on different microflora. Finally, THSWD inhibited the polarization of microglia cells(P < 0.01) and decreased the protein and gene expression of toll-like receptor-4 (TLR-4)(P < 0.01, P < 0.05) and nuclear factor kappa B (NF-κB)(P < 0.01) in brain tissue. CONCLUSION: Our data indicate that THSWD may interfere with inflammatory response in ischemic stroke by regulating intestinal flora and promoting intestinal barrier repair.

Dysregulation of ferroptosis-related genes in granulosa cells associates with impaired oocyte quality in polycystic ovary syndrome.

Background: Poor oocyte quality remains one of the major challenges for polycystic ovary syndrome (PCOS) patients during in vitro fertilization (IVF) treatment. Granulosa cells (GCs) in PCOS display altered functions and could cause an unfavorable microenvironment for oocyte growth and maturation. Ferroptosis is a new form of programmed cell death, but its role in PCOS has been largely unclarified. Methods: Ferroptosis-related differentially expressed genes (DEGs) of GCs in women with PCOS were identified by bioinformatic analyses of GSE155489 and GSE168404 datasets. Functional enrichment analyses were conducted using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Core ferroptosis-related genes were further screened by random forest, and evaluated for diagnostic value by receiver operating characteristic curve analyses. Gene expression was validated by real-time quantitative polymerase chain reaction of collected GC samples, and analyzed for association with oocyte quality. In addition, gene regulatory network was constructed based on predicted RNA interactions and transcription factors, while potential therapeutic compounds were screened through molecular docking with crystallographic protein structures. Results: A total of 14 ferroptosis-related DEGs were identified. These DEGs were mainly enriched in reactive oxygen species metabolic process, mitochondrial outer membrane, antioxidant activity as well as ferroptosis and adipocytokine signaling pathways. Eight core ferroptosis-related genes (ATF3, BNIP3, DDIT4, LPIN1, NOS2, NQO1, SLC2A1 and SLC2A6) were further selected in random forest model, which showed high diagnostic performance for PCOS. Seven of them were validated in GC samples, and five were found to be significantly and positively correlated with one or more oocyte quality parameters in PCOS patients, including oocyte retrieval rate, mature oocyte rate, normal fertilization rate, and good-quality embryo rate. Gene regulatory network revealed JUN and HMGA1 as two important transcription factors, while dicoumarol and flavin adenine dinucleotide were predicted as small molecules with therapeutic potential. Conclusions: This is the first comprehensive report to study the differential expression of ferroptosis-related genes in GCs of PCOS and their clinical relevance with oocyte quality. Our findings could provide novel insights on the potential role of GC ferroptosis in PCOS pathogenesis, diagnosis, and targeted treatment.

The Transcriptome Analysis of Circular RNAs between the Doxorubicin-Induced Cardiomyocytes and Bone Marrow Mesenchymal Stem Cells-Derived Exosomes Treated Ones.

AIM: To analyze the sequencing results of circular RNAs (circRNAs) in cardiomyocytes between the doxorubicin (DOX)-injured group and exosomes treatment group. Moreover, to offer potential circRNAs possibly secreted by exosomes mediating the therapeutic effect on DOXinduced cardiotoxicity for further study. MATERIALS & METHODS: The DOX-injured group (DOX group) of cardiomyocytes was treated with DOX, while an exosomes-treated group of injured cardiomyocytes were cocultured with bone marrow mesenchymal stem cells (BMSC)-derived exosomes (BEC group). The high-throughput sequencing of circRNAs was conducted after the extraction of RNA from cardiomyocytes. The differential expression of circRNA was analyzed after identifying the number, expression, and conservative of circRNAs. Then, the target genes of differentially expressed circRNAs were predicted based on the targetscan and Miranda database. Next, the GO and KEGG enrichment analyses of target genes of circRNAs were performed. The crucial signaling pathways participating in the therapeutic process were identified. Finally, a real-time quantitative polymerase chain reaction experiment was conducted to verify the results obtained by sequencing. RESULTS: Thirty-two circRNAs are differentially expressed between the two groups, of which twenty-three circRNAs were elevated in the exosomes-treated group (BEC group). The GO analysis shows that target genes of differentially expressed circRNAs are mainly enriched in the intracellular signalactivity, regulation of nucleic acid-templated transcription, Golgi-related activity, and GTPase activator activity. The KEGG analysis displays that they were involved in the autophagy biological process and NOD-like receptor signaling pathway. The verification experiment suggested that mmu_circ_0000425 (ID: 116324210) was both decreased in the DOX group and elevated in BEC group, which was consistent with the result of sequencing. CONCLUSION: mmu_circ_0000425 in exosomes derived from bone marrow mesenchymal stem cells (BMSC) may have a therapeutic role in alleviating doxorubicin-induced cardiotoxicity (DIC).

Aging-Related Rotator Cuff Tears: Molecular Mechanisms and Implications for Clinical Management.

Shoulder pain and disabilities are prevalent issues among the elderly population, with rotator cuff tear (RCT) being one of the leading causes. Although surgical treatment has shown some success, high postoperative retear rates remain a great challenge, particularly in elderly patients. Aging-related degeneration of muscle, tendon, tendon-to-bone enthesis, and bone plays a critical role in the development and prognosis of RCT. Studies have demonstrated that aging worsens muscle atrophy and fatty infiltration, alters tendon structure and biomechanical properties, exacerbates enthesis degeneration, and reduces bone density. Although recent researches have contributed to understanding the pathophysiological mechanisms of aging-related RCT, a comprehensive systematic review of this topic is still lacking. Therefore, this article aims to present a review of the pathophysiological changes and their clinical significance, as well as the molecular mechanisms underlying aging-related RCT, with the goal of shedding light on new therapeutic approaches to reduce the occurrence of aging-related RCT and improve postoperative prognosis in elderly patients.

Clinical evaluation of targeted sedation nursing combined with comprehensive nursing in children with severe pneumonia.

The severity of severe pneumonia in children depends on the degree of local inflammation, spread of lung inflammation and systemic inflammatory response. Appropriate care can effectively reduce the mortality of children with severe pneumonia. This study was designed to explore the nursing effect of targeted sedation nursing and comprehensive nursing intervention in children with severe pneumonia. Eighty children with severe pneumonia who complained of the main complaint were selected, and they were evenly distributed to receive comprehensive care (control group) and targeted sedation care and comprehensive care (observation group). In each group, different degrees of sedation, pain scores, and changes in adverse reactions were evaluated. Before nursing, the sedation and pain scores of the 2 groups of children were not statistically significant; after nursing, the sedation and pain scores of the 2 groups of children improved with time, and the sedation effect of the observation group was significantly lower than that of the control. In the group, the pain score was lower than that of the control group, indicating improvement. The SAS and SDS of the observation group were lower than those of the control group, while the social support score was significantly higher than that of the control group. The difference was statistically significant (P < .05). The accidental extubation, delirium, respiratory depression, and laryngospasm of the 2 groups of children were significantly improved, and the observation group was significantly less than the control group. This difference was statistically significant (P < .05). Targeted sedation nursing and comprehensive nursing intervention can effectively reduce the incidence of adverse reactions in children with severe pneumonia, reduce the pain and discomfort of children with severe pneumonia, and significantly improve the degree of sedation, which has certain reference value for the care of children with severe pneumonia.

Transforming Growth Factor-ß/Smad Signaling Inhibits Melanoma Cancer Stem Cell Self-Renewal, Tumor Formation and Metastasis.

The secreted protein transforming growth factor-beta (TGFß) plays essential roles, ranging from cell growth regulation and cell differentiation in both normal and cancer cells. In melanoma, TGFß acts as a potent tumor suppressor in melanoma by blocking cell cycle progression and inducing apoptosis. In the present study, we found TGFß to regulate cancer stemness in melanoma through the Smad signaling pathway. We discovered that TGFß/Smad signaling inhibits melanosphere formation in multiple melanoma cell lines and reduces expression of the CD133+ cancer stem cell subpopulation in a Smad3-dependent manner. Using preclinical models of melanoma, we further showed that preventing Smad3/4 signaling, by means of CRISPR knockouts, promoted both tumorigenesis and lung metastasis in vivo. Collectively, our results define new functions for the TGFß/Smad signaling axis in melanoma stem-cell maintenance and open avenues for new therapeutic approaches to this disease.

RpUGT344J7 is involved in the reproduction switch of Rhopalosiphum padi with holocyclic life cycle.

Many aphid species exhibit both cyclical parthenogenesis (CP) and the obligate parthenogenesis (OP) life history, which are genetically determined. In CP aphid lineages, the parthenogenetic individuals can switch from asexual to sexual reproduction quickly in response to environmental factors such as changes in photoperiod and temperature. However, the OP aphid lineages do not undergo sexual reproduction under any conditions. So far, mechanisms underlying the reproduction switch in CP aphids have not been fully elucidated. Rhopalosiphum padi, a serious worldwide insect pest of wheat, has both CP and OP lineages. Uridine diphosphate-glycosyltransferases (UGTs) are enzymes that participate in the metabolic detoxification of xenobiotics. Here, we identified 43 RpUGT genes from R. padi genome and transcriptome sequences, and found that: (1) the UGT content of the CP lineage was significantly higher than that in the OP lineage at the key time points when CP lineage mainly produce virginoparae, gynoparae, and males under inducing condition, while there were no significant difference under normal conditions; (2) RpUGT344J7 gene was highly expressed during the time points when CP lineages produce gynopara and males; (3) the critical time points for CP lineages to produce virginoparaee, gynoparae, and males were affected when the CP lineages were injected with dsRpUGT344J7; (4) the knockdown of RpUGT344J7 caused a significant reduction in the total number of virginoparae, gynoparae, and males in the offspring under inducing condition. The findings contribute to our understanding of the molecular mechanisms underlying the quick shift from asexual to sexual reproduction in aphid species.

Plasma Cytokine Expression and Immune Reconstitution in Early and Delayed Anti-HIV 96-Weeks Treatment: A Retrospective Study.

HIV is an immunodeficiency disease with emergence of inadequate corresponding reconstruction therapies. Pyroptosis of CD4+T cell is mainly caused by immune activation and inflammation that cannot be reduced by successful antiretroviral therapy (ART) alone. Coinfections because of CD4+T cell reconstitution failure can occur. Anti-inflammatory treatment determines the success of immune reconstitution. In our experiment, only a few cytokines could recover to normal level following a 2-year antiretroviral treatment in early ART initiation, which is consistent with current findings about adjuvant HIV anti-inflammatory therapy. Early infection is often accompanied by a more severe inflammatory response. Innate immunity cytokines like granulocyte macrophage-colony stimulating factor, IFN-γ induced protein 10 kDa, and tumor necrosis factor-α exhibited the most elevated levels among all kinds of inflammatory cytokines. The correlation analysis showed at least eight cytokines contributing to the changes of CD4/CD8 ratio.

Skin delivery of synthetic benzoyl pterostilbenes suppresses atopic dermatitis-like inflammation through the inhibition of keratinocyte and macrophage activation.

Atopic dermatitis (AD) is one of the most common skin autoimmune diseases needing continuous anti-inflammatory management. Pterostilbene is reported to exhibit anti-inflammatory activity with higher bioavailability and stability than its parent compound, resveratrol. In this study, a series of synthetic pterostilbene analogs were designed by the hybridization of pterostilbene with chalcones or benzoyl chloride. Seventeen analogs derived from pterostilbene were synthesized with differences in the positions of hydroxyl, methoxyl, or fluoro moieties. These compounds were screened by the inhibitory effect on the overexpressed Th2-associated cytokines/chemokines in the activated human keratinocytes (HaCaT). The anti-IL-5 and anti-CCL5 activity of these compounds led to the identification of three effective compounds: 3a ((E)- 4-(3,5-dimethoxystyryl)phenyl benzoate), 3d ((E)- 4-(3,5-dimethoxystyryl)phenyl 2-methoxybenzoate), and 3g ((E)- 4-(3,5-dimethoxystyryl)phenyl 2-fluorobenzoate). These benzoyl pterostilbenes also significantly decreased Th1/Th17-associated proinflammatory mediators in the activated macrophages (differentiated THP-1). The result showed that the conditioned medium of benzoyl pterostilbene-treated macrophages reduced the phosphorylated STAT3 in the keratinocytes, indicating the blockade of crosstalk between resident and immune cells. Compounds 3d and 3g generally showed greater skin absorption than 3a. The flux of 3g across barrier-defective skins mimicking the AD skin was 3-fold higher than that of across intact skin. The dinitrochlorobenzene (DNCB)-induced AD mouse model manifested that topical delivery with 3g improved the pathological signs through inhibiting cytokines/chemokines (IL-5, TNF-α, CCL17, and CCL22) and macrophage recruitment. The epidermal thickness was reduced from 76 to 55 µm after topical 3g delivery. The therapeutic activity of 3g was comparable to that of tacrolimus (TAC) used as a positive control. The benzoyl pterostilbenes attenuated the inflammation via the MAPK and c-Jun signaling. Furthermore, this study provided experimental evidence of benzoyl pterostilbene analogs for therapeutic potential on AD.

Karyotyping of aneuploid and polyploid plants from low coverage whole-genome resequencing.

BACKGROUND: Karyotype, as a basic characteristic of species, provides valuable information for fundamental theoretical research and germplasm resource innovation. However, traditional karyotyping techniques, including fluorescence in situ hybridization (FISH), are challenging and low in efficiency, especially when karyotyping aneuploid and polyploid plants. The use of low coverage whole-genome resequencing (lcWGR) data for karyotyping was explored, but existing methods are complicated and require control samples. RESULTS: In this study, a new protocol for molecular karyotype analysis was provided, which proved to be a simpler, faster, and more accurate method, requiring no control. Notably, our method not only provided the copy number of each chromosome of an individual but also an accurate evaluation of the genomic contribution from its parents. Moreover, we verified the method through FISH and published resequencing data. CONCLUSIONS: This method is of great significance for species evolution analysis, chromosome engineering, crop improvement, and breeding.

ABCA7 deficiency causes neuronal dysregulation by altering mitochondrial lipid metabolism.

ABCA7 loss-of-function variants are associated with increased risk of Alzheimer's disease (AD). Using ABCA7 knockout human iPSC models generated with CRISPR/Cas9, we investigated the impacts of ABCA7 deficiency on neuronal metabolism and function. Lipidomics revealed that mitochondria-related phospholipids, such as phosphatidylglycerol and cardiolipin were reduced in the ABCA7-deficient iPSC-derived cortical organoids. Consistently, ABCA7 deficiency-induced alterations of mitochondrial morphology accompanied by reduced ATP synthase activity and exacerbated oxidative damage in the organoids. Furthermore, ABCA7-deficient iPSC-derived neurons showed compromised mitochondrial respiration and excess ROS generation, as well as enlarged mitochondrial morphology compared to the isogenic controls. ABCA7 deficiency also decreased spontaneous synaptic firing and network formation in iPSC-derived neurons, in which the effects were rescued by supplementation with phosphatidylglycerol or NAD+ precursor, nicotinamide mononucleotide. Importantly, effects of ABCA7 deficiency on mitochondria morphology and synapses were recapitulated in synaptosomes isolated from the brain of neuron-specific Abca7 knockout mice. Together, our results provide evidence that ABCA7 loss-of-function contributes to AD risk by modulating mitochondria lipid metabolism.

Combined in vitro/in vivo genome-wide CRISPR screens in triple negative breast cancer identify cancer stemness regulators in paclitaxel resistance.

Triple negative breast cancer (TNBC) is defined as lacking the expressions of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC patients exhibit relatively poor clinical outcomes due to lack of molecular markers for targeted therapies. As such chemotherapy often remains the only systemic treatment option for these patients. While chemotherapy can initially help shrink TNBC tumor size, patients eventually develop resistance to drug, leading to tumor recurrence. We report a combined in vitro/in vivo genome-wide CRISPR synthetic lethality screening approach in a relevant TNBC cell line model to identify several targets responsible for the chemotherapy drug, paclitaxel resistance. Computational analysis integrating in vitro and in vivo data identified a set of genes, for which specific loss-of-function deletion enhanced paclitaxel resistance in TNBC. We found that several of these genes (ATP8B3, FOXR2, FRG2, HIST1H4A) act as cancer stemness negative regulators. Finally, using in vivo orthotopic transplantation TNBC models we showed that FRG2 gene deletion reduced paclitaxel efficacy and promoted tumor metastasis, while increasing FRG2 expression by means of CRISPR activation efficiently sensitized TNBC tumors to paclitaxel treatment and inhibited their metastatic abilities. In summary, the combined in vitro/in vivo genome-wide CRISPR screening approach proved effective as a tool to identify novel regulators of paclitaxel resistance/sensitivity and highlight the FRG2 gene as a potential therapeutical target overcoming paclitaxel resistance in TNBC.

Association Between Circulating Resistin Level and Preeclampsia: A Meta-Analysis.

Resistin, a diminutive secretory adipokine, has been linked to obesity and its related ailments. A growing body of evidence suggests that resistin may also be related to the pathogenesis preeclampsia. However, results of previous studies were not consistent. We performed a systematic review and meta-analysis to evaluate the level of circulating resistin in women with PE. A systematic search of Medline, Web of Science, and Embase databases from inception to April 28, 2023, was conducted to identify studies that compared blood resistin levels in pregnant women with and without PE. A random-effects model was utilized to pool the results, accounting for heterogeneity. The present study analyzed eighteen datasets from sixteen observational studies. The results of the meta-analysis demonstrated a statistically significant increase in blood resistin levels among women with PE compared to the control group. (standardized mean difference=0.35, 95% confidence interval: 0.16 to 0.54, p<0.001; I2=74%). The findings of the subgroup analysis indicate that various study characteristics, including study design, timing, and methods for measuring resistin, matching of body mass index between cases and controls, and study quality scores did not exert a significant impact on the outcomes. Nonetheless, it is noteworthy that the diagnostic criteria for PE employed in the studies included in the analysis may have influenced the results (p for subgroup difference=0.001). Women with preeclampsia exhibit a greater concentration of resistin in circulation when compared to healthy pregnant controls.