Cerebral amyloidosis and severe tauopathy in the brain are key pathological features of Alzheimer's disease (AD). Despite a strong influence of the intestinal microbiota on AD, the causal ...relationship between the gut microbiota and AD pathophysiology is still elusive.
Using a recently developed AD-like pathology with amyloid and neurofibrillary tangles (ADLP
) transgenic mouse model of AD, which shows amyloid plaques, neurofibrillary tangles and reactive gliosis in their brains along with memory deficits, we examined the impact of the gut microbiota on AD pathogenesis.
Composition of the gut microbiota in ADLP
mice differed from that of healthy wild-type (WT) mice. Besides, ADLP
mice showed a loss of epithelial barrier integrity and chronic intestinal and systemic inflammation. Both frequent transfer and transplantation of the faecal microbiota from WT mice into ADLP
mice ameliorated the formation of amyloid β plaques and neurofibrillary tangles, glial reactivity and cognitive impairment. Additionally, the faecal microbiota transfer reversed abnormalities in the colonic expression of genes related to intestinal macrophage activity and the circulating blood inflammatory monocytes in the ADLP
recipient mice.
These results indicate that microbiota-mediated intestinal and systemic immune aberrations contribute to the pathogenesis of AD in ADLP
mice, providing new insights into the relationship between the gut (colonic gene expression, gut permeability), blood (blood immune cell population) and brain (pathology) axis and AD (memory deficits). Thus, restoring gut microbial homeostasis may have beneficial effects on AD treatment.
ZnO is a potential candidate for photodetection utilizing the pyroelectric effect. Here, a self‐biased and translucent photodetector with the configuration of Cu4O3/ZnO/FTO/Glass is designed and ...fabricated. In addition, the pyroelectric effect is effectively harvested using indium tin oxide (ITO), silver nanowires (AgNWs), and a blend of AgNWs‐coated ITO as the transparent selective contact electrode. The improved rise times are observed from 1400 µs (bare condition; without the selective electrode) to 69, 60, 7 µs, and fall times from 720 µs (bare condition) to 80, 70, 10 µs for corresponding ITO, AgNWs, and AgNWs‐coated ITO contact electrodes, respectively. Similarly, the responsivity and detectivity are enhanced by about 4.39 × 107 and 5.27 × 105%, respectively. An energy band diagram is proposed to explain the underlying working mechanism based on the workfunction of the ITO (4.7 eV) and AgNWs (4.57 eV) as measured by Kelvin probe force microscopy, which confirms the formation of type‐II band alignment resulting in the efficient transport of photogenerated charge carriers. The functional use of the transparent selective contact electrode can effectively harness the pyro‐phototronic effect for next‐generation transparent and flexible optoelectronic applications.
The effective utilization of photovoltaic and pyro‐phototronic effect facilitates an ultrahigh‐performing self‐biased translucent photodetector by introducing transparent AgNWs, ITO, and their blended structure on Cu4O3/ZnO heterojunction. The underlying working mechanism is explored by various material and electrical characterization tools. Specifically, Kelvin probe force microscopy measurement verifies formation of feasible type‐II band alignment due to suitable workfunction of selective electrodes with heterojunction.
The rapid spread of COVID-19 has resulted in the shortage of medical resources, which necessitates accurate prognosis prediction to triage patients effectively. This study used the nationwide cohort ...of South Korea to develop a machine learning model to predict prognosis based on sociodemographic and medical information. Of 10,237 COVID-19 patients, 228 (2.2%) died, 7772 (75.9%) recovered, and 2237 (21.9%) were still in isolation or being treated at the last follow-up (April 16, 2020). The Cox proportional hazards regression analysis revealed that age > 70, male sex, moderate or severe disability, the presence of symptoms, nursing home residence, and comorbidities of diabetes mellitus (DM), chronic lung disease, or asthma were significantly associated with increased risk of mortality (p ≤ 0.047). For machine learning, the least absolute shrinkage and selection operator (LASSO), linear support vector machine (SVM), SVM with radial basis function kernel, random forest (RF), and k-nearest neighbors were tested. In prediction of mortality, LASSO and linear SVM demonstrated high sensitivities (90.7% 95% confidence interval: 83.3, 97.3 and 92.0% 85.9, 98.1, respectively) and specificities (91.4% 90.3, 92.5 and 91.8%, 90.7, 92.9, respectively) while maintaining high specificities > 90%, as well as high area under the receiver operating characteristics curves (0.963 0.946, 0.979 and 0.962 0.945, 0.979, respectively). The most significant predictors for LASSO included old age and preexisting DM or cancer; for RF they were old age, infection route (cluster infection or infection from personal contact), and underlying hypertension. The proposed prediction model may be helpful for the quick triage of patients without having to wait for the results of additional tests such as laboratory or radiologic studies, during a pandemic when limited medical resources must be wisely allocated without hesitation.
Animals display a range of innate social behaviors that play essential roles in survival and reproduction. While the medial amygdala (MeA) has been implicated in prototypic social behaviors such as ...aggression, the circuit-level mechanisms controlling such behaviors are not well understood. Using cell-type-specific functional manipulations, we find that distinct neuronal populations in the MeA control different social and asocial behaviors. A GABAergic subpopulation promotes aggression and two other social behaviors, while neighboring glutamatergic neurons promote repetitive self-grooming, an asocial behavior. Moreover, this glutamatergic subpopulation inhibits social interactions independently of its effect to promote self-grooming, while the GABAergic subpopulation inhibits self-grooming, even in a nonsocial context. These data suggest that social versus repetitive asocial behaviors are controlled in an antagonistic manner by inhibitory versus excitatory amygdala subpopulations, respectively. These findings provide a framework for understanding circuit-level mechanisms underlying opponency between innate behaviors, with implications for their perturbation in psychiatric disorders.
Calf diarrhea is associated with enteric infections, and also provokes the overuse of antibiotics. Therefore, proper treatment of diarrhea represents a therapeutic challenge in livestock production ...and public health concerns. Here, we describe the ability of a fecal microbiota transplantation (FMT), to ameliorate diarrhea and restore gut microbial composition in 57 growing calves. We conduct multi-omics analysis of 450 longitudinally collected fecal samples and find that FMT-induced alterations in the gut microbiota (an increase in the family Porphyromonadaceae) and metabolomic profile (a reduction in fecal amino acid concentration) strongly correlate with the remission of diarrhea. During the continuous follow-up study over 24 months, we find that FMT improves the growth performance of the cattle. This first FMT trial in ruminants suggest that FMT is capable of ameliorating diarrhea in pre-weaning calves with alterations in their gut microbiota, and that FMT may have a potential role in the improvement of growth performance.
Outcomes for patients with chronic myeloid leukemia (CML) have substantially improved due to advances in drug development and rational treatment intervention strategies. Despite these significant ...advances there are still unanswered questions on patient management regarding how to more reliably predict treatment failure at the time of diagnosis and how to select frontline tyrosine kinase inhibitor (TKI) therapy for optimal outcome. The BCR-ABL1 transcript level at diagnosis has no established prognostic impact and cannot guide frontline TKI selection. BCR-ABL1 mutations are detected in ~50% of TKI resistant patients but are rarely responsible for primary resistance. Other resistance mechanisms are largely uncharacterized and there are no other routine molecular testing strategies to facilitate the evaluation and further stratification of TKI resistance. Advances in next-generation sequencing technology has aided the management of a growing number of other malignancies, enabling the incorporation of somatic mutation profiles in diagnosis, classification, and prognostication. A largely unexplored area in CML research is whether expanded genomic analysis at diagnosis, resistance, and disease transformation can enhance patient management decisions, as has occurred for other cancers. The aim of this article is to review publications that reported mutated cancer-associated genes in CML patients at various disease phases. We discuss the frequency and type of such variants at initial diagnosis and at the time of treatment failure and transformation. Current limitations in the evaluation of mutants and recommendations for future reporting are outlined. The collective evaluation of mutational studies over more than a decade suggests a limited set of cancer-associated genes are indeed recurrently mutated in CML and some at a relatively high frequency. Genomic studies have the potential to lay the foundation for improved diagnostic risk classification according to clinical and genomic risk, and to enable more precise early identification of TKI resistance.
A recent study has suggested that fibroblasts can be converted into mouse-induced neural stem cells (miNSCs) through the expression of defined factors. However, successful generation of human iNSCs ...(hiNSCs) has proven challenging to achieve. Here, using microRNA (miRNA) expression profile analyses, we showed that let-7 microRNA has critical roles for the formation of PAX6/NESTIN-positive colonies from human adult fibroblasts and the proliferation and self-renewal of hiNSCs. HMGA2, a let-7-targeting gene, enables induction of hiNSCs that displayed morphological/molecular features and in vitro/in vivo differentiation potential similar to H9-derived NSCs. Interestingly, HMGA2 facilitated the efficient conversion of senescent somatic cells or blood CD34+ cells into hiNSCs through an interaction with SOX2, whereas other combinations or SOX2 alone showed a limited conversion ability. Taken together, these findings suggest that HMGA2/let-7 facilitates direct reprogramming toward hiNSCs in minimal conditions and maintains hiNSC self-renewal, providing a strategy for the clinical treatment of neurological diseases.
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•Inhibition of let-7 promotes direct reprogramming and self-renewal of hiNSCs•HMGA2, a target of let-7, promotes the rapid and efficient generation of hiNSCs•HMGA2 facilitates the direct reprogramming of human senescent cells and blood cells
Efficient generation of induced neural stem cells (iNSCs) from human somatic cells has remained challenging. Here, Yu et al. show that inhibition of the let-7 microRNA, or expression of its target HMGA2, facilitates SOX2-mediated direct reprogramming of human adult fibroblasts, senescent somatic cells, and blood cells into iNSCs. These hiNSCs display tridifferentiation ability and functionality, which could potentially provide therapeutic treatment for diverse neurological diseases.
Patients with chronic myeloid leukemia in chronic phase (CML-CP) resistant/intolerant to ≥2 tyrosine kinase inhibitors (TKIs) are at high risk of experiencing poor outcomes because of disease biology ...and inadequate efficacy and/or safety of current therapies. Asciminib, a first-in-class BCR-ABL1 inhibitor Specifically Targeting the ABL Myristoyl Pocket (STAMP), has the potential to overcome resistance/intolerance to approved TKIs. In this phase 3, open-label study, patients with CML-CP previously treated with ≥2 TKIs were randomized (2:1) to receive asciminib 40 mg twice daily vs bosutinib 500 mg once daily. Randomization was stratified by major cytogenetic response (MCyR) status at baseline. The primary objective was to compare the major molecular response (MMR) rate at week 24 for asciminib vs bosutinib. A total of 233 patients were randomized to asciminib (n = 157) or bosutinib (n = 76). Median follow-up was 14.9 months. The MMR rate at week 24 was 25.5% with asciminib and 13.2% with bosutinib. The difference in MMR rate between treatment arms, after adjusting for MCyR at baseline, was 12.2% (95% confidence interval, 2.19-22.30; 2-sided P = .029). Fewer grade ≥3 adverse events (50.6% vs 60.5%) and adverse events leading to treatment discontinuation (5.8% vs 21.1%) occurred with asciminib than with bosutinib. The study showed a superior efficacy of asciminib compared with that of bosutinib, together with a favorable safety profile. These results support the use of asciminib as a new therapy in patients with CML-CP who are resistant/intolerant to ≥2 prior TKIs. This trial was registered at www.clinicaltrials.gov as #NCT03106779.
Research on cancer theragnosis with gold nanoparticles (AuNPs) has rapidly increased, as AuNPs have many useful characteristics for various biomedical applications, such as biocompatibility, tunable ...optical properties, enhanced permeability and retention (EPR), localized surface plasmon resonance (LSPR), photothermal properties, and surface enhanced Raman scattering (SERS). AuNPs have been widely utilized in cancer theragnosis, including phototherapy and photoimaging, owing to their enhanced solubility, stability, biofunctionality, cancer targetability, and biocompatibility. In this review, specific characteristics and recent modifications of AuNPs over the past decade are discussed, as well as their application in cancer theragnostics and future perspectives. In the future, AuNP-based cancer theragnosis is expected to facilitate the development of innovative and novel strategies for cancer therapy.
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