Oncogenic KRAS, Mucin 4, and Activin A-Mediated Fibroblast Activation Cooperate for PanIN Initiation.

Over 90% of patients with pancreatic ductal adenocarcinoma (PDAC) have oncogenic KRAS mutations. Nevertheless, mutated KRAS alone is insufficient to initiate pancreatic intraepithelial neoplasia (PanIN), the precursor of PDAC. The identities of the other factors/events required to drive PanIN formation remain elusive. Here, optic-clear 3D histology is used to analyze entire pancreases of 2-week-old Pdx1-Cre; LSL-KrasG12D/+ (KC) mice to detect the earliest emergence of PanIN and observed that the occurrence is independent of physical location. Instead, it is found that the earliest PanINs overexpress Muc4 and associate with αSMA+ fibroblasts in both transgenic mice and human specimens. Mechanistically, KrasG12D/+ pancreatic cells upregulate Muc4 through genetic alterations to increase proliferation and fibroblast recruitments via Activin A secretion and consequently enhance cell transformation for PanIN formation. Inhibition of Activin A signaling using Follistatin (FST) diminishes early PanIN-associated fibroblast recruitment, effectively curtailing PanIN initiation and growth in KC mice. These findings emphasize the vital role of interactions between oncogenic KrasG12D/+ -driven genetic alterations and induced microenvironmental changes in PanIN initiation, suggesting potential avenues for early PDAC diagnostic and management approaches.

Electrically tunable graphene-based multi-band terahertz metamaterial filters.

In this study, we have designed an electrically tunable multi-band terahertz (THz) metamaterial filter based on graphene and multiple-square-loop structures. The structure contains multiple metal square loops, and these loops with different sizes correspond to different THz frequencies, achieving our expected efficacy of a multiband wave filter. Furthermore, by sweeping external voltages, we could change graphene's Fermi levels, and thus the high-sensitivity THz filter's capability from single-band to multi-band filtering can be modulated. We expect that this study of a hybrid THz wave filter would be promising for the development of selecting channels in THz and 6 G communications.

Differential effects of glucose and N-acetylglucosamine on genome instability.

Aberrant sugar metabolism is linked to an increased risk of pancreatic cancer. Previously, we found that high glucose induces genome instability and de novo oncogenic KRAS mutation preferentially in pancreatic cells through dysregulation of O-GlcNAcylation. Increasing O-GlcNAcylation by extrinsically supplying N-acetyl-D-glucosamine (GlcNAc) causes genome instability in all kinds of cell types regardless of pancreatic origin. Since many people consume excessive amount of sugar (glucose, fructose, and sucrose) in daily life, whether high sugar consumption directly causes genome instability in animals remains to be elucidated. In this communication, we show that excess sugar in the daily drink increases DNA damage and protein O-GlcNAcylation preferentially in pancreatic tissue but not in other kinds of tissue of mice. The effect of high sugar on the pancreatic tissue may be attributed to the intrinsic ratio of GFAT and PFK activity, a limiting factor that dictates UDP-GlcNAc levels. On the other hand, GlcNAc universally induces DNA damage in all six organs examined. Either inhibiting O-GlcNAcylation or supplementing dNTP pool diminishes the induced DNA damage in these organs, indicating that the mechanism of action is similar to that of high glucose treatment in pancreatic cells. Taken together, these results suggest the potential hazards of high sugar drinks and high glucosamine intake to genomic instability and possibly cancer initiation.

Disruption of DNA Repair and Survival Pathways through Heat Shock Protein Inhibition by Onalespib to Sensitize Malignant Gliomas to Chemoradiation Therapy.

PURPOSE: Proficient DNA repair by homologous recombination (HR) facilitates resistance to chemoradiation in glioma stem cells (GSC). We evaluated whether compromising HR by targeting HSP90, a molecular chaperone required for the function of key HR proteins, using onalespib, a long-acting, brain-penetrant HSP90 inhibitor, would sensitize high-grade gliomas to chemoradiation in vitro and in vivo. EXPERIMENTAL DESIGN: The ability of onalespib to deplete HR client proteins, impair HR repair capacity, and sensitize glioblastoma (GBM) to chemoradiation was evaluated in vitro in GSCs, and in vivo using zebrafish and mouse intracranial glioma xenograft models. The effects of HSP90 inhibition on the transcriptome and cytoplasmic proteins was assessed in GSCs and in ex vivo organotypic human glioma slice cultures. RESULTS: Treatment with onalespib depleted CHK1 and RAD51, two key proteins of the HR pathway, and attenuated HR repair, sensitizing GSCs to the combination of radiation and temozolomide (TMZ). HSP90 inhibition reprogrammed the transcriptome of GSCs and broadly altered expression of cytoplasmic proteins including known and novel client proteins relevant to GSCs. The combination of onalespib with radiation and TMZ extended survival in a zebrafish and a mouse xenograft model of GBM compared with the standard of care (radiation and TMZ) or onalespib with radiation. CONCLUSIONS: The results of this study demonstrate that targeting HR by HSP90 inhibition sensitizes GSCs to radiation and chemotherapy and extends survival in zebrafish and mouse intracranial models of GBM. These results provide a preclinical rationale for assessment of HSP90 inhibitors in combination with chemoradiation in patients with GBM.

Changes in Humans' Autonomic Nervous System under Dynamic Lighting Environment During A Short Rest.

Overloaded work and life stress often result in excessive fatigue and stresses in people, further leading to psychological burden and physiological disease. In this case, good rest is important in busy life. Good rest could result in good quality of life and work efficiency. In order to assist people in getting into deep rest to obtain a restorative state after fatigue, a dynamic lighting system with low-frequency change for assisting users in effective relaxation is proposed in this study. Heart rate variability analysis is used for discussing the change in the autonomic nervous system of the subjects under dynamic lighting environment, and a self-report questionnaire is applied to understand the subjects' psychological feeling. The research results indicate that the subjects significantly showed enhancement in the activities of parasympathetic nervous system within 25 minutes in the dynamic lighting process, in comparison with the steady lighting system. The questionnaire survey results also reveal that the subjects receive higher quality of rest, after the dynamic and low-illuminance lighting stimuli, with good feeling.

Reducing the discomfort in viewing 3D video with a prism device modified eye convergence.

A prism device is utilized in this study for modifying the eye convergence to reduce eye accommodation and enhance the comfort in viewing 3D video. Without changing the contents of 3D films, it aims to apply the myosis, convergence, and accommodation visual triad of eyeballs viewing near distance to not change the eyeball pupillary distance when viewing 3D films. Without convergence, the discomfort caused by intraocular muscle contraction when viewing near distance is reduced. Such an effect of a small prism lens is also proven in this study. When viewing 3D films with 1.0△ lenses, the physiological accommodation reaction of eyes would reduce (the right eye decreases 65% and the left eye decreases 70%), revealing the decreasing tension of intraocular muscle. The subjective psychological evaluation result also shows that viewing 3D images with small prism lenses could enhance the comfort. The evaluation of optical simulation, physiological reaction, and mental fatigue proves that the small prism lens proposed in this study could actually improve the comfort in viewing 3D films.

Adhesive stem cell coatings for enhanced retention in the heart tissue.

Injection into the heart tissue is a direct route for optimally placing mesenchymal stem cells (MSC) to regulate local inflammation following a heart attack. The retention of MSCs at the injection site is severely limited by the fluid flows that rapidly wash cells away and minimize their capacity to modulate cardiac inflammation. To prevent this loss of MSCs and their function, antibody coatings were designed for the surface of MSCs to enhance their adhesion to the inflamed tissue. MSCs were biotinylated, and biotinylated antibodies against intercellular cell adhesion molecules were conjugated to the cell surface through an intermediate layer of streptavidin. MSC surfaces were modified with ~7,000 biotin/µm2 and ~23 antibodies/µm2. The heart tissue injection of antibody-coated MSCs offered a 3-fold increase of cell retention in an infarcted heart over the injection of uncoated MSCs. We supported the mechanism of adhesion through analysis of MSC adhesion to inflamed endothelial cells and also surfaces of purified adhesion molecules on glass under microfluidic shear flow.

Hydrolyzed Chicken Extract (ProBeptigen®) on Cognitive Function in Healthy Middle-Aged People: A Randomized Double-Blind Trial.

Cognitive decline is an important issue of global public health. Cognitive aging might begin at middle adulthood, the period particularly vulnerable to stress in lifespan. Essence of chicken (EOC) has consistently demonstrated its beneficial effects on various cognitive domains as nutritional supplementation. This study primarily aimed to examine the cognitive enhancement effects of ProBeptigen® (previously named CMI-168), hydrolyzed peptides extracted from EOC, in healthy middle-aged people under mild stress. Ninety healthy subjects were randomly assigned into the ProBeptigen® or placebo group for eight weeks. Neurocognitive assessment, event-related potentials (ERPs), and blood tests were conducted before, during, and after the treatment. The ProBeptigen® group outperformed placebo group on Logical Memory subtests of Wechsler Memory Scale-third edition (WMS-III) and Spatial Working Memory task in the Cambridge Neuropsychological Test Automated Battery (CANTAB). The anti-inflammatory effects of ProBeptigen® in humans were also confirmed, with progressively declining high-sensitivity C-reactive protein (hs-CRP) levels. Regular dietary supplementation of ProBeptigen® is suggested to improve verbal short- and long-term memory as well as spatial working memory, and reduce inflammation in middle-aged healthy individuals with stress. The effects of ProBeptigen® on cognition warrant further investigation. (NCT03612752).

Impaired neuronal sodium channels cause intranodal conduction failure and reentrant arrhythmias in human sinoatrial node.

Mechanisms for human sinoatrial node (SAN) dysfunction are poorly understood and whether human SAN excitability requires voltage-gated sodium channels (Nav) remains controversial. Here, we report that neuronal (n)Nav blockade and selective nNav1.6 blockade during high-resolution optical mapping in explanted human hearts depress intranodal SAN conduction, which worsens during autonomic stimulation and overdrive suppression to conduction failure. Partial cardiac (c)Nav blockade further impairs automaticity and intranodal conduction, leading to beat-to-beat variability and reentry. Multiple nNav transcripts are higher in SAN vs atria; heterogeneous alterations of several isoforms, specifically nNav1.6, are associated with heart failure and chronic alcohol consumption. In silico simulations of Nav distributions suggest that INa is essential for SAN conduction, especially in fibrotic failing hearts. Our results reveal that not only cNav but nNav are also integral for preventing disease-induced failure in human SAN intranodal conduction. Disease-impaired nNav may underlie patient-specific SAN dysfunctions and should be considered to treat arrhythmias.

Detection of proteoglycan loss from articular cartilage using Brillouin microscopy, with applications to osteoarthritis.

The degeneration of articular cartilage (AC) occurs in osteoarthritis (OA), which is a leading cause of pain and disability in middle-aged and older people. The early disease-related changes in cartilage extra-cellular matrix (ECM) start with depletion of proteoglycan (PG), leading to an increase in tissue hydration and permeability. These early compositional changes are small (<10%) and hence difficult to register with conventional non-invasive imaging technologies (magnetic resonance and ultrasound imaging). Here we apply Brillouin microscopy for detecting changes in the mechanical properties and composition of porcine AC. OA-like degradation is mimicked by enzymatic tissue digestion, and we compare Brillouin microscopy measurements against histological staining of PG depletion over varying digestion times and enzyme concentrations. The non-destructive nature of Brillouin imaging technology opens new avenues for creating minimally invasive arthroscopic devices for OA diagnostics and therapeutic monitoring.

Coatings on mammalian cells: interfacing cells with their environment.

The research community is intent on harnessing increasingly complex biological building blocks. At present, cells represent a highly functional component for integration into higher order systems. In this review, we discuss the current application space for cellular coating technologies and emphasize the relationship between the target application and coating design. We also discuss how the cell and the coating interact in common analytical techniques, and where caution must be exercised in the interpretation of results. Finally, we look ahead at emerging application areas that are ideal for innovation in cellular coatings. In all, cellular coatings leverage the machinery unique to specific cell types, and the opportunities derived from these hybrid assemblies have yet to be fully realized.

2D/3D-Display Auto-Adjustment Switch System.

Recently, 2-D/3-D switchable displays have become the mainstream in 3-D display technologies, and people can now watch 3-D movies with a naked 2-D/3-D switchable display at home. However, some studies have indicated that people might encounter visual fatigue after enjoying a 3-D film in the theater. Although 2-D/3-D switchable technologies have been widely developed, 3-D display technologies are still lacking in ergonomic and human-care factors such as reducing visual fatigue. This study proposes a novel 2-D/3-D display autoadjustment switch system to provide biofeedback functions to reduce users' visual fatigue. In addition, the relationship between the blink rate and the visual fatigue state while watching 3-D films was investigated and quantified. In this study, liquid crystal barrier technology was used to develop a 2-D/3-D switchable display, and a wearable EOG acquisition device was also designed to monitor electro-oculography signals to estimate the blink rate. Here, the 2-D/3-D display autoadjustment criterion of the proposed system was designed according to the change in the visual fatigue state as estimated from the blink rate. Finally, the experimental results show that the proposed system could effectively reduce users' visual fatigue while watching 3-D films.

Deletion of the Inflammasome Sensor Aim2 Mitigates Aß Deposition and Microglial Activation but Increases Inflammatory Cytokine Expression in an Alzheimer Disease Mouse Model.

OBJECTIVE: Inflammation is clearly associated with Alzheimer disease (AD). Knockout of Nlrp3, a gene encoding an inflammasome sensor, has been shown to ameliorate AD pathology in a mouse model. Because AIM2 is the most dominant inflammasome sensor expressed in mouse brains, here we investigate whether Aim2 deletion also influences the phenotype of a 5XFAD AD mouse model. METHODS: Quantitative RT-PCR, immunostaining, immunoblotting, and behavioral analyses were applied to compare wild-type, Aim2-/-, 5XFAD, and Aim2-/-;5XFAD mice. RESULTS: We found that Aim2 knockout mitigates Aß deposition in the cerebral cortex and hippocampus of 5XFAD mice. The activation of microglial cells is also reduced in Aim2-/-;5XFAD brains compared with 5XFAD brains. However, Aim2 knockout does not improve memory and anxiety phenotypes of 5XFAD mice in an open field, cued Y-maze, or Barnes maze. Compared with 5XFAD mice, Il-1 expression levels are not reduced in Aim2-/-;5XFAD mice. Unexpectedly, Il-6 and Il-18 expression levels in 5XFAD brains were further increased when Aim2 was deleted. Thus, inflammatory cytokine expression in 5XFAD brains is upregulated by Aim2 deletion through an unknown mechanism. CONCLUSION: Although Aim2 knockout mitigates Aß deposition and microglial activation, Aim2 deletion does not have a beneficial effect on the spatial memory or cytokine expression of 5XFAD mice. Our findings suggest that Aß aggregation and microglial activation may not always be correlated with the expression of inflammatory cytokines or cognitive function of 5XFAD mice. Our study also implies that different inflammasomes likely perform distinct roles in different physiological and/or pathological events.

Hydrogel Patches on Live Cells through Surface-Mediated Polymerization.

Many naturally occurring cells possess an intrinsic ability to cross biological barriers that block conventional drug delivery, and these cells offer a possible mode of active transport across the blood-brain barrier or into the core of tumor masses. While many technologies for the formation of complete, nanoparticle-loaded coatings on cells exist, a complete coating on the cell surface would disrupt the interaction of cells with their environments. To address this issue, cell surface patches that partially cover cell surfaces might provide a superior approach for cell-mediated therapeutic delivery. The goal of this study is to establish a simplified approach to producing polymeric patches of arbitrary shapes on a live cell via surface-mediated photopolymerization. Cell surfaces were nonspecifically labeled with eosin, and polyethylene (glycol) diacrylate (PEGDA) coatings were directed to specific sites using 530 nm irradiation through a chrome-coated photomask. These coatings may entrap drug-loaded or imaging particles. The extent of nonspecific formation of PEGDA hydrogel coatings increased with irradiation time, light intensity, and initiating species; 40 mW/cm2 irradiation for 5 min delivered high-resolution patterns on the surface of A549 cells, and these cells remained viable for 48 h postpatterning with fluorescent nanoparticle-loaded coatings. This work first demonstrated the feasibility of photopatterning polymer patches directly on the surface of cells.

AIM 2 inflammasomes regulate neuronal morphology and influence anxiety and memory in mice.

Inflammasomes are the protein assemblies that consist of inflammasome sensors, adaptor apoptosis-associated speck-like proteins containing a CARD (ASC) and inflammasome caspase. Inflammasomes sense multiple danger signals via various inflammasome sensors and consequently use caspase to trigger proteolytic processing and secretion of IL-1ß cytokines. Recent studies have suggested that neurons use their own innate immune system to detect danger signals and regulate neuronal morphology. Here, we investigate whether inflammasomes, the critical components of innate immunity, participate in regulation of neuronal morphology and function. Among various sensors, Absent in melanoma 2 (Aim2) expression in neurons is most prominent. Adding synthetic double-stranded DNA (dsDNA) to cultured neurons induces IL-1ß secretion in an AIM2-dependent manner and consequently downregulates dendritic growth but enhances axon extension. The results of Aim2 knockout and knockdown show that AIM2 acts cell-autonomously to regulate neuronal morphology. Behavioral analyses further reveal that Aim2-/- mice exhibit lower locomotor activity, increased anxious behaviors and reduced auditory fear memory. In conclusion, our study suggests that AIM2 inflammasomes regulate neuronal morphology and influence mouse behaviors.

Effectiveness of Essence of Chicken in Improving Cognitive Function in Young People Under Work-Related Stress: A Randomized Double-Blind Trial.

Work-related stress (WS) can result in considerable and extensive changes in physiological and psychological performance. WS beyond the optimal levels induces anxiety, confusion, exhaustion, and burnout. Chronic WS affects neurocognitive performance, particularly attention and visuospatial memory. Essence of chicken (EC) has been reported to improve neurocognitive function after mental stress.To investigate the beneficial effects of EC in improving neurocognitive performance under WS, we conducted a randomized, double blind trial. Total 102 young workers in New Taipei City with high WS, evaluated using the Individual Subjective Perception Job Stress Scale scores (>36 for job leaders and 33 for nonleaders) were recruited. Fifty-one participants received 70 mL of EC and 51 received a placebo daily for 2 weeks. Blood tests and neurocognitive assessment were performed before treatment, at the end of treatment, and 2 weeks after treatment.EC improved the performance of participants with high depression scores in the form-color associative memory test, used for assessing short-term memory. Although creatinine and glutamic-pyruvic transaminase (GPT) levels increased in week 2, but the levels returned to the baseline in week 4. Blood urea nitrogen (BUN) levels decreased in week 4.EC significantly improved short-term memory in participants with high WS and concomitant depressive mood, although it slightly increased GPT and creatinine levels and reduced BUN levels. The long-term treatment effects of EC warrant further investigation.

Access site complications following transfemoral coronary procedures: comparison between traditional compression and angioseal vascular closure devices for haemostasis.

BACKGROUND: Vascular closure devices such as angioseal are used as alternatives to traditional compression haemostasis. Although the safety and efficacy of angioseal are confirmed, their use remains controversial because of the potential complications of these devices compared with those of traditional compression haemostasis. The aim of this study was to compare the access site complication rate, the predictive factors for these complications, and patient comfort levels after coronary procedures with traditional compression or angioseal haemostasis. METHODS: Data were collected from a cardiac unit in a medical center in northern Taiwan. A total of 130 adult patients were recruited and equally divided into two groups according to the method of haemostasis used after the coronary procedure: a traditional compression group and an angioseal group. We observed the incidence of access site complications, including bleeding, oozing, haematoma formation, and arteriovenous fistula formation. In addition, we used a 0-10 numeric rating scale to assess soreness, numbness, and back and groin access site pain after 1 h of catheter removal and immediately before getting out of bed. RESULTS: The overall incidence of complications was 3.8 % (n = 5), which was not significantly different between the two groups (p = .06). The propensity score--adjusted multivariate analyses revealed that the only independent predictor for access site complications was an age of >70 years (OR, 10.44; 95 % CI, 1.81-60.06; p = .009). Comfort levels were higher in the angioseal group than in the traditional compression group. CONCLUSIONS: Angioseal used after coronary procedures did not increase the incidence of complications relative to that associated with traditional compression haemostasis; however, it increased patient comfort levels. Health personnel should pay special attention to the predictive factor for access site complications after coronary procedures, such as age >70 years.

A reusable magnetic graphene oxide-modified biosensor for vascular endothelial growth factor detection in cancer diagnosis.

Early cancer diagnosis is critical for the prevention of metastasis. However, simple and efficient methods are needed to improve the diagnosis and evaluation of cancer. Here, we propose a reusable biosensor based on a magnetic graphene oxide (MGO)-modified Au electrode to detect vascular endothelial growth factor (VEGF) in human plasma for cancer diagnosis. In this biosensor, Avastin is used as the specific biorecognition element, and MGO is used as the carrier for Avastin loading. The use of MGO enables rapid purification due to its magnetic properties, which prevents the loss of bioactivity. Moreover, the biosensor can be constructed quickly, without requiring a drying process, which is convenient for proceeding to detection. Our reusable biosensor provides the appropriate sensitivity for clinical diagnostics and has a wide range of linear detection, from 31.25-2000 pg mL(-1), compared to ELISA analysis. In addition, in experiments with 100% serum from clinical samples, readouts from the sensor and an ELISA for VEGF showed good correlation within the limits of the ELISA kit. The relative standard deviation (RSD) of the change in current (ΔC) for reproducibility of the Au biosensor was 2.36% (n=50), indicating that it can be reused with high reproducibility. Furthermore, the advantages of the Avastin-MGO-modified biosensor for VEGF detection are that it provides an efficient detection strategy that not only improves the detection ability but also reduces the cost and decreases the response time by 10-fold, indicating its potential as a diagnosis product.