Hybrid-index-based array configuration optimization for Michelson interferometric imaging.

Array configuration design is a critical issue for a high quality of the snapshot point spread function (PSF) and restored image in Michelson imaging interferometer. In classic design, the optimized configurations usually address the few specifications and single objective, which is unable to balance the requirements of both non-redundancy and sampling distribution. In this paper, we formalize mathematically the composite metric to trade-off the multiple demands of observation, and propose the hybrid-index-based array layout optimization strategy. The simulation results demonstrate that, in comparison with the typical distribution, the optimized array using the proposed optimization framework enables the acquisition of more comprehensive spectrum information while utilizing an equal number of apertures, providing superior imaging quality in different observation situations. Furthermore, the designed optimized array masks and the compared conventional array masks were fabricated and used for our experimental validation, further verifying the feasibility of this strategy. This array configuration optimization framework may not only find applications to Michelson interferometric imaging, but also provide a positive impact on all u-v sampling-based imaging modes, including radio interferometry, magnetic resonance imaging, and photonic integrated interferometric imaging.

Sequential in vivo labeling of insulin secretory granule pools in INS-SNAP transgenic pigs.

ß cells produce, store, and secrete insulin upon elevated blood glucose levels. Insulin secretion is a highly regulated process. The probability for insulin secretory granules to undergo fusion with the plasma membrane or being degraded is correlated with their age. However, the molecular features and stimuli connected to this behavior have not yet been fully understood. Furthermore, our understanding of ß cell function is mostly derived from studies of ex vivo isolated islets in rodent models. To overcome this translational gap and study insulin secretory granule turnover in vivo, we have generated a transgenic pig model with the SNAP-tag fused to insulin. We demonstrate the correct targeting and processing of the tagged insulin and normal glycemic control of the pig model. Furthermore, we show specific single- and dual-color granular labeling of in vivo-labeled pig pancreas. This model may provide unprecedented insights into the in vivo insulin secretory granule behavior in an animal close to humans.

Multimodal-based machine learning strategy for accurate and non-invasive prediction of intramedullary glioma grade and mutation status of molecular markers: a retrospective study.

BACKGROUND: Determining the grade and molecular marker status of intramedullary gliomas is important for assessing treatment outcomes and prognosis. Invasive biopsy for pathology usually carries a high risk of tissue damage, especially to the spinal cord, and there are currently no non-invasive strategies to identify the pathological type of intramedullary gliomas. Therefore, this study aimed to develop a non-invasive machine learning model to assist doctors in identifying the intramedullary glioma grade and mutation status of molecular markers. METHODS: A total of 461 patients from two institutions were included, and their sagittal (SAG) and transverse (TRA) T2-weighted magnetic resonance imaging scans and clinical data were acquired preoperatively. We employed a transformer-based deep learning model to automatically segment lesions in the SAG and TRA phases and extract their radiomics features. Different feature representations were fed into the proposed neural networks and compared with those of other mainstream models. RESULTS: The dice similarity coefficients of the Swin transformer in the SAG and TRA phases were 0.8697 and 0.8738, respectively. The results demonstrated that the best performance was obtained in our proposed neural networks based on multimodal fusion (SAG-TRA-clinical) features. In the external validation cohort, the areas under the receiver operating characteristic curve for graded (WHO I-II or WHO III-IV), alpha thalassemia/mental retardation syndrome X-linked (ATRX) status, and tumor protein p53 (P53) status prediction tasks were 0.8431, 0.7622, and 0.7954, respectively. CONCLUSIONS: This study reports a novel machine learning strategy that, for the first time, is based on multimodal features to predict the ATRX and P53 mutation status and grades of intramedullary gliomas. The generalized application of these models could non-invasively provide more tumor-specific pathological information for determining the treatment and prognosis of intramedullary gliomas.

Vibration rejection of phased array telescope systems via disturbance-propagation-characteristics-based feedforward control.

Vibration rejection is one of the key techniques to stabilize the line of sight (LOS) for phased array telescope systems. Conventionally, feedback control based on image sensors is mainly used to correct the tip/tilt errors caused by disturbances and to keep the LOS stable. However, it is restricted by the sampling rate and time delay of image sensors, leading to a limited closed-loop bandwidth. Disturbances in the middle and high frequencies are hard to suppress. In this paper, disturbance-propagation-characteristics-based feedforward control is proposed to overcome these problems. A theoretical imaging model of the phased array telescope is developed to analyze the LOS disruption caused by disturbance. In addition, to improve the disturbance suppression bandwidth and correction accuracy of the system, the disturbance propagation characteristics of the phased array telescope system are analyzed. Combined with the disturbance feedforward, targeted compensation is achieved for the sub-apertures. Finally, a comparative experiment is carried out based on the self-developed Fizeau phased array telescope system to verify the superiority of the proposed method.

Rh(II)-catalyzed Doyle-Kirmse reaction: access to unprotected 3-allyl/3-allenyl-3-(thio)oxindoles.

The construction of the 3-allyl/3-allenyl-3-(thio)oxindole core remains a challenge in organic synthesis. Herein, we report a novel Rh2(esp)2 catalytic Doyle-Kirmse reaction to furnish the oxindole core, bearing unbiased NH as well as a quaternary stereogenic center at the 3-position, in good to excellent yields under mild conditions. These reactions are concise, practical, atom-economic, and highly efficient, and feature a TON of up to 3700. Moreover, a non-radical pathway was observed in this approach.

Magnetoelectric Bio-Implants Powered and Programmed by a Single Transmitter for Coordinated Multisite Stimulation.

This paper presents a hardware platform including stimulating implants wirelessly powered and controlled by a shared transmitter for coordinated leadless multisite stimulation. The adopted novel single-transmitter, multiple-implant structure can flexibly deploy stimuli, improve system efficiency, easily scale stimulating channel quantity and relieve efforts in device synchronization. In the proposed system, a wireless link leveraging magnetoelectric effects is co-designed with a robust and efficient system-on-chip to enable reliable operation and individual programming of every implant. Each implant integrates a 0.8-mm2 chip, a 6-mm2 magnetoelectric film, and an energy storage capacitor within a 6.2-mm3 size. Magnetoelectric power transfer is capable of safely transmitting milliwatt power to devices placed several centimeters away from the transmitter coil, maintaining good efficiency with size constraints and tolerating 60-degree, 1.5-cm misalignment in angular and lateral movement. The SoC robustly operates with 2-V source amplitude variations that spans a 40-mm transmitter-implant distance change, realizes individual addressability through physical unclonable function IDs, and achieves 90% efficiency for 1.5-to-3.5-V stimulation with fully programmable stimulation parameters.

Synergetic integrations of bone marrow stem cells and transforming growth factor-ß1 loaded chitosan nanoparticles blended silk fibroin injectable hydrogel to enhance repair and regeneration potential in articular cartilage tissue.

The cartilage repair and regeneration show inadequate self-healing capability and have some complications, which are inordinate challenges in clinical therapy. Biopolymeric injectable hydrogels, a prominent type of cell-carrier as well tissue engineering scaffolding materials, establish promising therapeutic potential of stem cell-based cartilage-regeneration treatment. In addition, injectable scaffolding biomaterial should have rapid gelation properties with adequate rheological and mechanical properties. In the present investigation, we developed and fabricated the macromolecular silk fibroin blended with polylysine modified chitosan polymer (SF/PCS) using thermal-sensitive glycerophosphate (GP), which contains effective gelation ability, morphology, porosity and also has enhanced mechanical properties to induce physical applicability, cell proliferation and nutrient exchange in the cell-based treatment. The developed and optimised injectable hydrogel group has good biocompatibility with human fibroblast (L929) cells and bone marrow-derived mesenchymal stem cells (BMSCs). Additionally, it was found that SF/PCS hydrogel group could sustainably release TGF-ß1 and efficiently regulate cartilage-specific and inflammatory-related gene expressions. Finally, the cartilage-regeneration potential of the hydrogel groups embedded with and without BMSCs were evaluated in SD rat models under histopathological analysis, which showed promising cartilage repair. Overall, we conclude that the TGF-ß1-SF/PCS injectable hydrogel demonstrates enhanced in vitro and in vivo tissue regeneration properties, which lead to efficacious therapeutic potential in cartilage regeneration.

Deep Learning Model for Automated Detection and Classification of Central Canal, Lateral Recess, and Neural Foraminal Stenosis at Lumbar Spine MRI.

Background Assessment of lumbar spinal stenosis at MRI is repetitive and time consuming. Deep learning (DL) could improve -productivity and the consistency of reporting. Purpose To develop a DL model for automated detection and classification of lumbar central canal, lateral recess, and neural -foraminal stenosis. Materials and Methods In this retrospective study, lumbar spine MRI scans obtained from September 2015 to September 2018 were included. Studies of patients with spinal instrumentation or studies with suboptimal image quality, as well as postgadolinium studies and studies of patients with scoliosis, were excluded. Axial T2-weighted and sagittal T1-weighted images were used. Studies were split into an internal training set (80%), validation set (9%), and test set (11%). Training data were labeled by four radiologists using predefined gradings (normal, mild, moderate, and severe). A two-component DL model was developed. First, a convolutional neural network (CNN) was trained to detect the region of interest (ROI), with a second CNN for classification. An internal test set was labeled by a musculoskeletal radiologist with 31 years of experience (reference standard) and two subspecialist radiologists (radiologist 1: A.M., 5 years of experience; radiologist 2: J.T.P.D.H., 9 years of experience). DL model performance on an external test set was evaluated. Detection recall (in percentage), interrater agreement (Gwet κ), sensitivity, and specificity were calculated. Results Overall, 446 MRI lumbar spine studies were analyzed (446 patients; mean age ± standard deviation, 52 years ± 19; 240 women), with 396 patients in the training (80%) and validation (9%) sets and 50 (11%) in the internal test set. For internal testing, DL model and radiologist central canal recall were greater than 99%, with reduced neural foramina recall for the DL model (84.5%) and radiologist 1 (83.9%) compared with radiologist 2 (97.1%) (P < .001). For internal testing, dichotomous classification (normal or mild vs moderate or severe) showed almost-perfect agreement for both radiologists and the DL model, with respective κ values of 0.98, 0.98, and 0.96 for the central canal; 0.92, 0.95, and 0.92 for lateral recesses; and 0.94, 0.95, and 0.89 for neural foramina (P < .001). External testing with 100 MRI scans of lumbar spines showed almost perfect agreement for the DL model for dichotomous classification of all ROIs (κ, 0.95-0.96; P < .001). Conclusion A deep learning model showed comparable agreement with subspecialist radiologists for detection and classification of central canal and lateral recess stenosis, with slightly lower agreement for neural foraminal stenosis at lumbar spine MRI. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Hayashi in this issue.

Transient antibiotic-induced changes in the neonatal swine intestinal microbiota impact islet expression profiles reducing subsequent function.

Neonatal antibiotics administered to human infants initiate gut microbiota dysbiosis that may have long-term effects on body weight and metabolism. We examined antibiotic-induced adaptations in pancreatic islets of the piglet, a well-accepted model of human infant microbiota and pancreas development. Neonatal piglets randomized to amoxicillin [30 mg/kg body wt/day; n = 7, antibiotic (ANTI)] or placebo [vehicle control; n = 7, control (CON)] from postnatal day (PND)0-13 were euthanized at PND7, 14, and 49. The metabolic phenotype along with functional, immunohistological, and transcriptional phenotypes of the pancreatic islets were studied. The gut microbiome was characterized by 16S rRNA gene sequencing, and microbial metabolites and microbiome-sensitive host molecules were measured. Compared with CON, ANTI PND7 piglets had elevated transcripts of genes involved in glucagon-like peptide 1 ((GLP-1) synthesis or signaling in islets (P < 0.05) coinciding with higher plasma GLP-1 (P = 0.11), along with increased tumor necrosis factor α (Tnf) (P < 0.05) and protegrin 1 (Npg1) (P < 0.05). Antibiotic-induced relative increases in Escherichia, Coprococcus, Ruminococcus, Dehalobacterium, and Oscillospira of the ileal microbiome at PND7 normalized after antibiotic withdrawal. In ANTI islets at PND14, the expression of key regulators pancreatic and duodenal homeobox 1 (Pdx1), insulin-like growth factor-2 (Igf2), and transcription factor 7-like 2 (Tcf7l2) was downregulated, preceding a 40% reduction of ß-cell area (P < 0.01) and islet insulin content at PND49 (P < 0.05). At PND49, a twofold elevated plasma insulin concentration (P = 0.07) was observed in ANTI compared with CON. We conclude that antibiotic treatment of neonatal piglets elicited gut microbial changes accompanied by phasic alterations in key regulatory genes in pancreatic islets at PND7 and 14. By PND49, reduced ß-cell area and islet insulin content were accompanied by elevated nonfasted insulin despite normoglycemia, indicative of islet stress.

Enhanced neural differentiation of neural stem cells by sustained release of Shh from TG2 gene-modified EMSC co-culture in vitro.

As a promising cell therapy, neural crest-derived ectoderm mesenchymal stem cells (EMSCs) secrete high amounts of extracellular matrix (ECM) and neurotrophic factors, promoting neural stem cell (NSC) differentiation into neuronal lineages and aiding tissue regeneration. Additionally, the forced overexpression of secreted proteins can increase the therapeutic efficacy of the secretome. Tissue transglutaminase (TG2) is a ubiquitously expressed member of the transglutaminase family of calcium-dependent crosslinking enzymes, which can stabilize the ECM, inducing smart or living biomaterial to stimulate differentiation and enhance the neurogenesis of NSCs. In this study, we examined the neuronal differentiation of NSCs induced by TG2 gene-modified EMSCs (TG2-EMSCs) in a co-culture model directly. Two weeks after initiating differentiation, levels of the neuronal markers, tubulin beta 3 class III and growth-associated protein 43, were higher in NSCs in the TG2-EMSC co-culture group and those of the astrocytic marker glial fibrillary acidic protein were lower, compared with the control group. These results were confirmed by immunofluorescence, and laminin, fibronectin and sonic hedgehog (Shh) contributed to this effect. The results of western blot analysis and the enzyme-linked immunoassay showed that after TG2-EMSCs were co-cultured for 2 weeks, they expressed much higher levels of Shh than the control group. Moreover, the sustained release of Shh was observed in the TG2-EMSC co-culture group. Overall, our findings indicate that EMSCs can induce the differentiation of NSCs, of which TG2-EMSCs can promote the differentiation of NSCs compared with EMSCs.

Glycosyltransferase Jhp0106 (PseE) contributes to flagellin maturation in Helicobacter pylori.

BACKGROUND: Flagella-mediated motility is both a crucial virulence determinant of Helicobacter pylori and a factor associated with gastrointestinal diseases. Flagellar formation requires flagellins to be glycosylated with pseudaminic acid (Pse), a process that has been extensively studied. However, the transfer of Pse to flagellins remains poorly understood. Therefore, the aim of this study is to characterize a putative glycosyltransferase jhp0106 in flagellar formation. MATERIALS AND METHODS: Western blotting and chemical deglycosylation were performed to examine FlaA glycosylation. Protein structural analyses were executed to identify the active site residues of Jhp0106, while the Jhp0106-FlaA interaction was examined using a bacterial two-hybrid assay. Lastly, site-directed mutants with mutated active site residues in the jhp0106 gene were generated and investigated using a motility assay, Western blotting, cDNA-qPCR analysis, and electron microscopic examination. RESULTS: Loss of flagellar formation in the Δjhp0106 mutant was confirmed to be associated with non-glycosylated FlaA. Furthermore, three active site residues of Jhp0106 (S350, F376, and E415) were identified within a potential substrate-binding region. The interaction between FlaA and Jhp0106, Jhp0106::S350A, Jhp0106::F376A, or Jhp0106::E415A was determined to be significant. As well, the substitution of S350A, F376A, or E415A in the site-directed Δjhp0106 mutants resulted in impaired motility, deficient FlaA glycosylation, and lacking flagella. However, these phenotypic changes were regardless of flaA expression, implying an indefinite proteolytic degradation of FlaA occurred. CONCLUSIONS: This study demonstrated that Jhp0106 (PseE) binds to FlaA mediating FlaA glycosylation and flagellar formation. Our discovery of PseE has revealed a new glycosyltransferase family responsible for flagellin glycosylation in pathogens.

Piston error correction of sparse aperture systems using the metaheuristic stochastic parallel gradient descent algorithm.

The next generation of optical telescopes will provide high-resolution imaging of celestial objects by using the aperture synthesis technique. To preserve the quality of the image, fast corrections of the pistons among subapertures have to be applied, namely, the co-phasing of the array. The image-based co-phasing method via an optimization procedure has been newly developed. Despite simplicity and strong commonality, when dealing with large piston errors, this correction method is also faced with a problem in which the metric function easily falls into the local convergence, especially in the case of broadband imaging with many subapertures. In this study, an improved stochastic parallel gradient descent (SPGD) algorithm based on heuristic search is proposed for co-phasing, termed the metaheuristic SPGD algorithm. The heuristic research scheme assists the original SPGD algorithm in getting rid of local extrema. By iterations of this algorithm, the synthetic system can be co-phased without any additional instruments and operations. The effectiveness of the proposed algorithm is verified by means of simulation. Given the efficiency and superiority, it is expected that the method proposed in this study may find wide applications in multi-aperture imaging.

Supratentorial high-grade astrocytoma with leptomeningeal spread to the fourth ventricle: a lethal dissemination with dismal prognosis.

PURPOSE: Leptomeningeal spread to the fourth ventricle (LSFV) from supratentorial high-grade astrocytoma (HGA) is rarely investigated. The incidence and prognostic merit of LSFV were analyzed in this study. METHODS: A consecutive cohort of 175 patients with pathologically diagnosed HGA according to the 2016 WHO classification of brain tumors was enrolled. LSFV was defined as radiological occupation in the fourth ventricle at the moment of initial progression. Clinical, radiological, and pathological data were analyzed to explore the difference between HGA patients with and without LSFV. RESULTS: There were 18 of 175 (10.3%) HGAs confirmed with LSFV. The difference of survival rate between patients with LSFV or not was significant in both overall survival (OS) (14.5 vs. 24 months, P = 0.0007) and post progression survival (PPS) (6.0 vs. 11.5 months, P = 0.0004), while no significant difference was observed in time to progression (TTP) (8.5 months vs. 9.5 months P = 0.6795). In the Cox multivariate analysis, LSFV was confirmed as an independent prognostic risk factor for OS (HR 2.06, P = 0.010). LSFV was correlated with younger age (P = 0.044), ventricle infringement of primary tumor (P < 0.001) and higher Ki-67 index (P = 0.013) in further analysis, and the latter two have been validated in the Logistic regression analysis (OR 18.16, P = 0.006; OR 4.04, P = 0.012, respectively). CONCLUSION: LSFV was indicative of end-stage for supratentorial HGA patients, which shortened patients' PPS and OS instead of TTP. It's never too cautious to alert this lethal event when tumor harbored ventricle infringement and higher Ki-67 index in routine clinical course.

Super-early initiation of temozolomide prolongs the survival of glioblastoma patients without gross-total resection: a retrospective cohort study.

OBJECTIVE: The optimal timing of chemoradiotherapy in patients with newly diagnosed glioblastoma (GBM) remains unclear. In this study, we explored the clinical efficacy of super-early initiation of temozolomide (TMZ) in the treatment interval from surgery to radiotherapy. METHODS: We retrospectively reviewed the clinical data of 375 patients with GBM in our institution from 2012 to 2018. One hundred and sixty-three patients received super-early TMZ within 7 days after craniotomy based on standard Stupp protocol (super-early group, SEG), while two hundred and twelve patients underwent standard Stupp protocol alone (control group, CG). We performed propensity score matching (PSM) to reduce patient selection bias between the two groups. RESULTS: Before PSM, both median progression-free survival (PFS) and overall survival (OS) of patients in SEG were longer than those in CG (PFS 11.5 vs. 9.0 months, P = 0.0384 and OS 23.0 vs. 17.0 months, P = 0.0014). After PSM, the clinical efficacy of super-early initiation of TMZ only remained significant in term of OS, which was further validated in Cox hazard proportional model (HR = 0.583, 95% CI 0.384-0.884, P = 0.011). In the subgroup analysis, patients without gross total resection (GTR) or with O6-methylguanine DNA methyltransferase promoter methylation could benefit from super-early initiation of TMZ in both PFS and OS (P < 0.05). No significant difference of treatment emerging adverse events was observed between the two groups (P > 0.05). CONCLUSIONS: This retrospective study highlights that super-early initiation of TMZ in newly diagnosed GBM may confer to survival benefit, especially for those without GTR.

Prognostic implications of epidermal growth factor receptor variant III expression and nuclear translocation in Chinese human gliomas.

OBJECTIVE: To determine the prognostic implications and clinical significance of epidermal growth factor receptor variant III (EGFRvIII) expression and EGFRvIII nuclear translocation in Chinese human gliomas. METHODS: We retrospectively examined EGFRvIII expression and EGFRvIII nuclear translocation using immunohistochemistry in specimens of 240 Chinese patients with glioma, including 84 World Health Organization (WHO) II gliomas, 84 WHO III gliomas and 72 glioblastomas (WHO IV). Factors that correlated with EGFRvIII and EGFRvIII nuclear translocation expression were analyzed by the Chi-square test. Kaplan-Meier methodology and Cox regression were used for the survival analysis. RESULTS: Log-rank tests showed that patient age, Karnofsky performance scale (KPS) score, tumor grade, EGFRvIII expression, EGFRvIII nuclear translocation, 1p/19q codeletion, isocitrate dehydrogenase (IDH) mutation, Ki-67 labeling index and O6-methylguanine-DNA methyltransferase (MGMT) status (P<0.05) were significantly correlated with overall survival (OS) time. Multivariate Cox regression analysis revealed that patient age, tumor grade, EGFRvIII nuclear translocation, 1p/19q codeletion, and IDH mutation (P<0.05) were significantly correlated with OS. Patients with a high level of EGFRvIII nuclear translocation (≥7%) had both significantly shorter OS [hazard ratio (HR): 1.920, 95% confidence interval (95% CI): 1.228-3.003, P=0.004] and progression-free survival (PFS) times (HR: 1.661, 95% CI: 1.116-2.471, P=0.012) than those with a low level of EGFRvIII nuclear translocation (<7%). CONCLUSIONS: A high level of EGFRvIII nuclear translocation in glioma is an independent factor indicating a poor prognosis, but EGFRvIII expression is not an independent clinical prognostic factor. The level of EGFRvIII nuclear translocation maybe a novel and crucial prognostic biomarker in glioma.

Epicatechin potentiation of glucose-stimulated insulin secretion in INS-1 cells is not dependent on its antioxidant activity.

Epicatechin (EC) is a monomeric flavan-3-ol. We have previously demonstrated that glucose-intolerant rats fed flavan-3-ols exhibit improved pancreatic islet function corresponding with an increase in circulating EC-derived metabolites. Thus, we speculate that EC may act as a cellular signaling molecule in vivo to modulate insulin secretion. In this study we further examined the effects of different concentrations of EC on H2O2 or hyperglycemia-induced ROS production, as well as on saturated fatty acid (SFA)-impaired glucose-stimulated insulin secretion (GSIS) in INS-1 cell line in vitro. We showed that EC at a high concentration (30 µmol/L), but not a low concentration (0.3 µmol/L), significantly decreased H2O2 or hyperglycemia-induced ROS production in INS-1 cells. However, EC (0.3 µmol/L) significantly enhanced SFA-impaired GSIS in INS-1 cells. Addition of KN-93, a CaMKII inhibitor, blocked the effect of EC on insulin secretion and decreased CaMKII phosphorylation. Addition of GW1100, a GPR40 antagonist, significantly attenuated EC-enhanced GSIS, but only marginally affected CaMKII phosphorylation. These results demonstrate that EC at a physiological concentration promotes GSIS in SFA-impaired ß-cells via activation of the CaMKII pathway and is consistent with its function as a GPR40 ligand. The findings support a role for EC as a cellular signaling molecule in vivo and further delineate the signaling pathways of EC in ß-cells.

Initial Gut Microbial Composition as a Key Factor Driving Host Response to Antibiotic Treatment, as Exemplified by the Presence or Absence of Commensal Escherichia coli.

Antibiotics are important for treating bacterial infection; however, efficacies and side effects of antibiotics vary in medicine and experimental models. A few studies have correlated microbiota composition variations with health outcomes in response to antibiotics; however, no study has demonstrated causality. We had noted variation in colonic expression of C-type lectins, regenerating islet-derived protein 3ß (Reg3ß) and Reg3γ, after metronidazole treatment in a mouse model. To investigate the effects of specific variations in the preexisting microbiome on host response to antibiotics, mice harboring a normal microbiota were allocated to 4 treatments in a 2-by-2 factorial arrangement with or without commensal Escherichia coli and with or without metronidazole in drinking water. E. coli colonized readily without causing a notable shift in the microbiota or host response. Metronidazole administration reduced microbiota biodiversity, indicated by decreased Chao1 and Shannon index values, and altered microbiota composition. However, the presence of E. coli strongly affected metronidazole-induced microbiota shifts. Remarkably, this single commensal bacterium in the context of a complex population led to variations in host responses to metronidazole treatment, including increased expression of antimicrobial peptides Reg3ß and Reg3γ and intestinal inflammation indicated by tumor necrosis factor alpha levels. Similar results were obtained from 2-week antibiotic exposure and with additional E. coli isolates. The results of this proof-of-concept study indicate that even minor variations in initial commensal microbiota can drive shifts in microbial composition and host response after antibiotic administration. As well as providing an explanation for variability in animal models using antibiotics, the findings encourage the development of personalized medication in antibiotic therapies.IMPORTANCE This work provides an understanding of variability in studies where antibiotics are used to alter the gut microbiota to generate a host response. Furthermore, although providing evidence only for the one antibiotic, the study demonstrated that initial gut microbial composition is a key factor driving host response to antibiotic administration, creating a compelling argument for considering personalized medication based on individual variations in gut microbiota.

CircHIPK2 Contributes Cell Growth in Intestinal Epithelial of Colitis and Colorectal Cancer through Promoting TAZ Translation.

Colorectal cancer (CRC) and inflammatory bowel disease (IBD) are escalating global health concerns. Despite their distinct clinical presentations, both disorders share intricate genetic and molecular interactions. The Hippo signaling pathway plays a crucial role in regulating cell processes and is implicated in the pathogenesis of IBD and CRC. Circular RNAs (circRNAs) have gained attention for their roles in various diseases, including IBD and CRC. However, a comprehensive understanding of specific circRNAs involved in both IBD and CRC, and their functional roles is lacking. Here, it is found that circHIPK2 (hsa_circRNA_104507) is a bona fide circRNA consistently upregulated in both IBD and CRC suggesting its potential as a biomarker. Furthermore, silencing of circHIPK2 suppressed the growth of CRC cells in vitro and in vivo. Interestingly, decreased circHipk2 potentiated dextran sulfate sodium (DSS)-induced colitis but alleviated colitis-associated tumorigenesis. Most significantly, mechanistic investigations further unveil that circHIPK2, mediated by FUS, interacting with EIF4A3 to promote the translation of TAZ, ultimately increasing the transcription of downstream target genes CCN1 and CCN2. Taken together, circHIPK2 emerges as a key player in the shared mechanisms of IBD and CRC, modulating the Hippo signaling pathway. CircHIPK2-EIF4A3 axis contributes to cell growth in intestinal epithelial of colitis and CRC by enhancing TAZ translation.

Acinar to ß-like cell conversion through inhibition of focal adhesion kinase.

Insufficient functional ß-cell mass causes diabetes; however, an effective cell replacement therapy for curing diabetes is currently not available. Reprogramming of acinar cells toward functional insulin-producing cells would offer an abundant and autologous source of insulin-producing cells. Our lineage tracing studies along with transcriptomic characterization demonstrate that treatment of adult mice with a small molecule that specifically inhibits kinase activity of focal adhesion kinase results in trans-differentiation of a subset of peri-islet acinar cells into insulin producing ß-like cells. The acinar-derived insulin-producing cells infiltrate the pre-existing endocrine islets, partially restore ß-cell mass, and significantly improve glucose homeostasis in diabetic mice. These findings provide evidence that inhibition of the kinase activity of focal adhesion kinase can convert acinar cells into insulin-producing cells and could offer a promising strategy for treating diabetes.

Extracellular vesicles-based point-of-care testing for the diagnosis and monitoring of Alzheimer's disease.

Alzheimer's disease (AD) is a debilitating condition that affects millions of people worldwide. One promising strategy for detecting and monitoring AD early on is using extracellular vesicles (EVs)-based point-of-care testing; however, diagnosing AD using EVs poses a challenge due to the low abundance of EV-biomarkers. Here, we present a fully integrated organic electrochemical transistor (OECT) that enables high accuracy, speed, and convenience in the detection of EVs from AD patients. We incorporated self-aligned acoustoelectric enhancement of EVs on a chip that rapidly propels, enriches, and specifically binds EVs to the OECT detection area. With our enhancement of pre-concentration, we increased the sensitivity to a limit of detection of 500 EV particles/µL and reduced the required detection time to just two minutes. We also tested the sensor on an AD mouse model to monitor AD progression, examined mouse Aß EVs at different time courses, and compared them with intraneuronal Aß cumulation using MRI. This innovative technology has the potential to diagnose Alzheimer's and other neurodegenerative diseases accurately and quickly, enabling monitoring of disease progression and treatment response.