Microglial Reactivity Correlates with Presynaptic Loss Independent of ß-Amyloid and Tau.

OBJECTIVE: Triggering receptor expressed on myeloid cells-2 (TREM2) and progranulin (PGRN) are critical regulators of microglia activation and can be detected in cerebrospinal fluid (CSF). However, whether microglial reactivity is detrimental or neuroprotective for Alzheimer disease (AD) is still debatable. METHODS: We identified 663 participants with baseline ß-amyloid (Aß) positron emission tomography (PET) and CSF biomarker data, including phosphorylated tau181 (p-Tau181), soluble TREM2 (sTREM2), PGRN, and growth-associated protein-43 (GAP-43). Among them, 254 participants had concurrent longitudinal CSF biomarkers. We used multivariate regression analysis to study the associations of CSF microglial biomarkers with Aß PET, CSF p-Tau181, and CSF GAP-43 cross-sectionally and longitudinally. A Chinese aging cohort's independent CSF samples (n = 65) were analyzed as a validation. RESULTS: Higher baseline levels of CSF microglial biomarkers were related to faster rates of CSF sTREM2 increase and CSF PGRN decrease. Elevated CSF p-Tau181 was associated with higher levels of CSF microglial biomarkers and faster rates of CSF sTREM2 increase and CSF PGRN decrease. In both cohorts, higher Aß burden was associated with attenuated CSF p-Tau181 effects on CSF microglial biomarker increases. Independent of Aß PET and CSF p-Tau181 pathologies, higher levels of CSF sTREM2 but not CSF PGRN were related to elevated CSF GAP-43 levels and faster rates of CSF GAP-43 increase. INTERPRETATION: These findings suggest that higher Aß burden may attenuate the p-Tau-associated microglial responses, and TREM2-related microglial reactivity may independently correlate with GAP-43-related presynaptic loss. This study highlights the two-edged role of microglial reactivity in AD and other neurodegenerative diseases. ANN NEUROL 2024;95:917-928.

Tau pathology is associated with synaptic density and longitudinal synaptic loss in Alzheimer's disease.

The associations of synaptic loss with amyloid-ß (Aß) and tau pathology measured by positron emission tomography (PET) and plasma analysis in Alzheimer's disease (AD) patients are unknown. Seventy-five participants, including 26 AD patients, 19 mild cognitive impairment (MCI) patients, and 30 normal controls (NCs), underwent [18F]SynVesT-1 PET/MR scans to assess synaptic density and [18F]florbetapir and [18F]MK6240 PET/CT scans to evaluate Aß plaques and tau tangles. Among them, 19 AD patients, 12 MCI patients, and 29 NCs had plasma Aß42/40 and p-tau181 levels measured by the Simoa platform. Twenty-three individuals, 6 AD patients, 4 MCI patients, and 13 NCs, underwent [18F]SynVesT-1 PET/MRI and [18F]MK6240 PET/CT scans during a one-year follow-up assessment. The associations of Aß and tau pathology with cross-sectional and longitudinal synaptic loss were investigated using Pearson correlation analyses, generalized linear models and mediation analyses. AD patients exhibited lower synaptic density than NCs and MCI patients. In the whole cohort, global Aß deposition was associated with synaptic loss in the medial (r = -0.431, p < 0.001) and lateral (r = -0.406, p < 0.001) temporal lobes. Synaptic density in almost all regions was related to the corresponding regional tau tangles independent of global Aß deposition in the whole cohort and stratified groups. Synaptic density in the medial and lateral temporal lobes was correlated with plasma Aß42/40 (r = 0.300, p = 0.020/r = 0.289, p = 0.025) and plasma p-tau 181 (r = -0.412, p = 0.001/r = -0.529, p < 0.001) levels in the whole cohort. Mediation analyses revealed that tau tangles mediated the relationship between Aß plaques and synaptic density in the whole cohort. Baseline tau pathology was positively associated with longitudinal synaptic loss. This study suggested that tau burden is strongly linked to synaptic density independent of Aß plaques, and also can predict longitudinal synaptic loss.

Relationship between topological efficiency of white matter structural connectome and plasma biomarkers across the Alzheimer's disease continuum.

Both plasma biomarkers and brain network topology have shown great potential in the early diagnosis of Alzheimer's disease (AD). However, the specific associations between plasma AD biomarkers, structural network topology, and cognition across the AD continuum have yet to be fully elucidated. This retrospective study evaluated participants from the Sino Longitudinal Study of Cognitive Decline cohort between September 2009 and October 2022 with available blood samples or 3.0-T MRI brain scans. Plasma biomarker levels were measured using the Single Molecule Array platform, including ß-amyloid (Aß), phosphorylated tau181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). The topological structure of brain white matter was assessed using network efficiency. Trend analyses were carried out to evaluate the alterations of the plasma markers and network efficiency with AD progression. Correlation and mediation analyses were conducted to further explore the relationships among plasma markers, network efficiency, and cognitive performance across the AD continuum. Among the plasma markers, GFAP emerged as the most sensitive marker (linear trend: t = 11.164, p = 3.59 × 10-24 ; quadratic trend: t = 7.708, p = 2.25 × 10-13 ; adjusted R2 = 0.475), followed by NfL (linear trend: t = 6.542, p = 2.9 × 10-10 ; quadratic trend: t = 3.896, p = 1.22 × 10-4 ; adjusted R2 = 0.330), p-tau181 (linear trend: t = 8.452, p = 1.61 × 10-15 ; quadratic trend: t = 6.316, p = 1.05 × 10-9 ; adjusted R2 = 0.346) and Aß42/Aß40 (linear trend: t = -3.257, p = 1.27 × 10-3 ; quadratic trend: t = -1.662, p = 9.76 × 10-2 ; adjusted R2 = 0.101). Local efficiency decreased in brain regions across the frontal and temporal cortex and striatum. The principal component of local efficiency within these regions was correlated with GFAP (Pearson's R = -0.61, p = 6.3 × 10-7 ), NfL (R = -0.57, p = 6.4 × 10-6 ), and p-tau181 (R = -0.48, p = 2.0 × 10-4 ). Moreover, network efficiency mediated the relationship between general cognition and GFAP (ab = -0.224, 95% confidence interval [CI] = [-0.417 to -0.029], p = .0196 for MMSE; ab = -0.198, 95% CI = [-0.42 to -0.003], p = .0438 for MOCA) or NfL (ab = -0.224, 95% CI = [-0.417 to -0.029], p = .0196 for MMSE; ab = -0.198, 95% CI = [-0.42 to -0.003], p = .0438 for MOCA). Our findings suggest that network efficiency mediates the association between plasma biomarkers, specifically GFAP and NfL, and cognitive performance in the context of AD progression, thus highlighting the potential utility of network-plasma approaches for early detection, monitoring, and intervention strategies in the management of AD.

Regional differences of Mycobacterium tuberculosis complex infection and multidrug resistance epidemic in Luoyang.

BACKGROUND: Tuberculosis (TB) remains a global public health event of great concern, however epidemic data on TB covering entire areas during the special period of the COVID-19 epidemic have rarely been reported. We compared the dissemination and multidrug-resistance patterns of Mycobacterium tuberculosis complex (MTBC) in the main urban area of Luoyang City, China (including six municipal jurisdictions) and nine county and township areas under its jurisdiction, aimed to establish the epidemiology of TB in this region and to provide reference for precision anti-TB in places with similar settings. METHODS: From 2020 to 2022, sputum samples were collected from 18,504 patients with confirmed, suspected and unexcluded TB in 10 designated TB medical institutions. Insertion sequence 6110 was amplified by PCR (rpoB gene detection if necessary) to confirm the presence of MTBC. PCR-positive specimens were analyzed by multicolor melting curve analysis to detect multidrug resistance. RESULTS: Among the 18,504 specimens, 2675 (14.5%) were MTBC positive. The positive rate was higher in the main urban area than in the county and township areas (29.8% vs. 10.9%, p < 0.001). Male, re-treated and smear-positive groups were high-burden carriers of MTBC. Individuals aged > 60 years were the largest group infected with MTBC in the main urban area, compared with individuals aged < 61 years in the county and township areas. The detection of multidrug-resistant TB (MDR-TB) was higher in the main urban area than in the county and township areas (13.9% vs. 7.8%, p < 0.001). In all areas, MDR-TB groups were dominated by males, patients with a history of TB treatment, and patients aged < 61 years. Stratified analysis of MDR-TB epidemiology showed that MDR4 (INH þ RIF þ EMB þ SM) was predominant in the main urban area, while MDR3 (INH þ RIF þ SM) was predominant in the county and township areas. MDR-TB detection rate and epidemiology differed among the county and township areas. CONCLUSIONS: For local TB control, it is necessary to plan more appropriate and accurate prevention and control strategies according to the regional distribution of MTBC infection.

Presynaptic density determined by SV2A PET is closely associated with postsynaptic metabotropic glutamate receptor 5 availability and independent of amyloid pathology in early cognitive impairment.

INTRODUCTION: Metabotropic glutamate receptor 5 (mGluR5) is involved in regulating integrative brain function and synaptic transmission. Aberrant mGluR5 signaling and relevant synaptic failure play a key role in the pathophysiological mechanism of Alzheimer's disease (AD). METHODS: Ten cognitively impaired (CI) individuals and 10 healthy controls (HCs) underwent [18F]SynVesT-1 and [18F]PSS232 positron emission tomography (PET)/magnetic resonance to assess synaptic density and mGluR5 availability. The associations between mGluR5 availability and synaptic density were examined. A mediation analysis was performed to investigate the possible mediating effects of mGluR5 availability and synaptic loss on the relationship between amyloid deposition and cognition. RESULTS: CI patients exhibited lower mGluR5 availability and synaptic density in the medial temporal lobe than HCs. Regional synaptic density was closely associated with regional mGluR5 availability. mGluR5 availability and synaptic loss partially mediated the relationship between amyloid deposition and cognition. CONCLUSIONS: Reductions in mGluR5 availability and synaptic density exhibit similar spatial patterns in AD and are closely linked. HIGHLIGHTS: Cognitively impaired patients exhibited lower mGluR5 availability and synaptic density in the medial temporal lobe than HCs. Reductions in mGluR5 availability and synaptic density exhibit similar spatial patterns in AD. Regional synaptic density was closely associated with regional mGluR5 availability. mGluR5 availability and synaptic loss partially mediated the relationship between amyloid deposition and global cognition. With further research, modulating mGluR5 availability might be a potential therapeutic strategy for improving synaptic function in AD.

How are early-career dementia researchers considered and supported on a national level by dementia plans and organizations? An overview of global policy approaches.

INTRODUCTION: Despite representing an essential workforce, it is unclear how global policy efforts target early-career dementia researchers (ECDRs). Thus, this study aimed to provide an overview of policies through which ECDRs are considered and supported by dementia plans and organizations. METHODS: G20 member states were evaluated for their national dementia plan alongside policies of leading dementia organizations. Data targeting support for ECDRs were extracted and subject to content analysis using inductive coding. Findings were categorized and narratively synthesized. RESULTS: Only China, Denmark, England, Greece, Northern Ireland, Scotland, Spain, and the United States mentioned ECDRs in their national plan. Additionally, 17 countries formalized ECDR support via dementia organizations. Support efforts included research funding, dissemination and networking, career development, and research advice. DISCUSSION: Few nations formally recognized ECDRs in dementia plans or through dementia organizations. To facilitate equal prospects for ECDRs, top-down approaches are urged to enhance and align their efforts. HIGHLIGHTS: Few G20 countries (8/46) had national dementia plans for early-career researchers. Targeted support comes from government and nongovernmental dementia organizations. Support includes funding, training, advice, research dissemination, and networking. Inconsistent definitions and eligibility criteria are barriers to accessing support. Global coordination and top-down policy will aid early-career dementia researchers.

Association of Presynaptic Loss with Alzheimer's Disease and Cognitive Decline.

OBJECTIVE: Increased presynaptic dysfunction measured by cerebrospinal fluid (CSF) growth-associated protein-43 (GAP43) may be observed in Alzheimer's disease (AD), but how CSF GAP43 increases relate to AD-core pathologies, neurodegeneration, and cognitive decline in AD requires further investigation. METHODS: We analyzed 731 older adults with baseline ß-amyloid (Aß) positron emission tomography (PET), CSF GAP43, CSF phosphorylated tau181 (p-Tau181 ), and 18 F-fluorodeoxyglucose PET, and longitudinal residual hippocampal volume and cognitive assessments. Among them, 377 individuals had longitudinal 18 F-fluorodeoxyglucose PET, and 326 individuals had simultaneous longitudinal CSF GAP43, Aß PET, and CSF p-Tau181 data. We compared baseline and slopes of CSF GAP43 among different stages of AD, as well as their associations with Aß PET, CSF p-Tau181 , residual hippocampal volume, 18 F-fluorodeoxyglucose PET, and cognition cross-sectionally and longitudinally. RESULTS: Regardless of Aß positivity and clinical diagnosis, CSF p-Tau181 -positive individuals showed higher CSF GAP43 concentrations (p < 0.001) and faster rates of CSF GAP43 increases (p < 0.001) compared with the CSF p-Tau181 -negative individuals. Moreover, higher CSF GAP43 concentrations and faster rates of CSF GAP43 increases were strongly related to CSF p-Tau181 independent of Aß PET. They were related to more rapid hippocampal atrophy, hypometabolism, and cognitive decline (p < 0.001), and predicted the progression from MCI to dementia (area under the curve for baseline 0.704; area under the curve for slope 0.717) over a median 4 years of follow up. INTERPRETATION: Tau aggregations rather than Aß plaques primarily drive presynaptic dysfunction measured by CSF GAP43, which may lead to sequential neurodegeneration and cognitive impairment in AD or neurodegenerative diseases. ANN NEUROL 2022;92:1001-1015.

Presynaptic membrane protein dysfunction occurs prior to neurodegeneration and predicts faster cognitive decline.

INTRODUCTION: Although presynaptic loss measured by cerebrospinal fluid (CSF) growth-associated protein-43 (GAP-43) is significantly involved in Alzheimer's disease (AD), the sequential association between CSF GAP-43 and AD-typical neurodegeneration is poorly understood. METHODS: We compared baseline CSF GAP-43 levels (n = 730) and longitudinal CSF GAP-43 changes (n = 327) in various biological stages of AD, and investigated their relationships with cross-sectional and longitudinal measures of residual hippocampal volume, 18 F-fluorodeoxyglucose PET, regional gray matter volume and cortical thickness, and cognition. RESULTS: Elevated CSF GAP43 levels were significantly associated with faster rates of hippocampal atrophy, AD-signature hypometabolism and cortical thinning, and middle temporal gray matter atrophy-related and AD-signature hypometabolism-related cognitive decline. In contrast, baseline levels of all these neurodegeneration biomarkers did not predict longitudinal CSF GAP-43 increases. DISCUSSION: These findings suggest that presynaptic loss may occur prior to neurodegeneration, highlighting the importance of lowing tau aggregation and tau-related synaptic dysfunction in elderly adults and AD patients.

Review on treatment and utilization of barium slag in China.

Barium slag (BS) is generated as a by-product waste during the production of barium salts from barite. A large amount of BS is discharged annually threating the ecological environment and restricting the development of the barium salts industry. In China, BS is classified as hazardous waste due to its corrosivity, and more importantly because of its extraction toxicity of barium. Soluble barium is toxic and can result in barium poisoning for environment and human beings. The current review presents a detailed summary on general characteristics, discharge and disposal status, harmless treatment pathways and comprehensive utilization of BS in China. BaO, SiO2, CaO, and SO3 occur as main chemical compositions in BS, especially BaO accounting approximately for 35-40%. The mineral compositions include unreacted barite, quartz, clay minerals, newly-formed phases from the side reactions such as BaCO3, BaSiO3 and BaSO3, and residual carbon. A special attention is given to the assessment of the harmless treatment methods for BS from hazardous waste to general waste, which will decrease its management costs. Precipitation and solidification of soluble barium is the common pathway for harmless treatment of BS, and the using of other industrial waste can realize cost-saving. Methods for comprehensive utilization of BS include recovery of barium and carbon, application in building materials, and using as adsorbents for wastewater treatment. In particular, we analyzed and discussed the advantages and disadvantages of these existing process routes, intending to promote potentials for comprehensive utilization of BS in the future.

Regional distribution of Mycobacterium tuberculosis infection and resistance to rifampicin and isoniazid as determined by high-resolution melt analysis.

BACKGROUND: Identifying the transmission mode and resistance mechanism of Mycobacterium tuberculosis (MTB) is key to prevent disease transmission. However, there is a lack of regional data. Therefore, the aim of this study was to identify risk factors associated with the transmission of MTB and regional patterns of resistance to isoniazid (INH) and rifampicin (RFP), as well as the prevalence of multidrug-resistant tuberculosis (MDR-TB). METHODS: High-resolution melt (HRM) analysis was conducted using sputum, alveolar lavage fluid, and pleural fluid samples collected from 17,515 patients with suspected or confirmed MTB infection in the downtown area and nine counties of Luoyang City from 2019 to 2021. RESULTS: Of the 17,515 patients, 82.6% resided in rural areas, and 96.0% appeared for an initial screening. The HRM positivity rate was 16.8%, with a higher rate in males than females (18.0% vs. 14.1%, p < 0.001). As expected, a positive sputum smear was correlated with a positive result for HRM analysis. By age, the highest rates of MTB infection occurred in males (22.9%) aged 26-30 years and females (28.1%) aged 21-25. The rates of resistance to RFP and INH and the incidence of MDR were higher in males than females (20.5% vs. 16.1%, p < 0.001, 15.9% vs. 12.0%, p < 0.001 and 12.9% vs. 10.2%, p < 0.001, respectively). The HRM positivity rate was much higher in previously treated patients than those newly diagnosed for MTB infection. Notably, males at the initial screening had significantly higher rates of HRM positive, INH resistance, RFP resistance, and MDR-TB than females (all, p < 0.05), but not those previously treated for MTB infection. The HRM positivity and drug resistance rates were much higher in the urban vs. rural population. By multivariate analyses, previous treatment, age < 51 years, residing in an urban area, and male sex were significantly and positively associated with drug resistance after adjusting for smear results and year of testing. CONCLUSION: Males were at higher risks for MTB infection and drug resistance, while a younger age was associated with MTB infection, resistance to INH and RFP, and MDR-TB. Further comprehensive monitoring of resistance patterns is needed to control the spread of MTB infection and manage drug resistance locally.

Repression of Death Receptor-Mediated Apoptosis of Hepatocytes by Hepatitis B Virus e Antigen.

Hepatitis B virus (HBV) e antigen (HBeAg) is associated with viral persistence and pathogenesis. Resistance of HBV-infected hepatocytes to apoptosis is seen as one of the primary promotors for HBV chronicity and malignancy. Fas receptor/ligand (Fas/FasL) and the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) system plays a key role in hepatic death during HBV infection. We found that HBeAg mediates resistance of hepatocytes to FasL or TRAIL-induced apoptosis. Introduction of HBeAg into human hepatocytes rendered resistance to FasL or TRAIL cytotoxicity in a p53-dependent manner. HBeAg further inhibited the expression of p53, total Fas, membrane-bound Fas, TNF receptor superfamily member 10a, and TNF receptor superfamily member 10b at both mRNA and protein levels. In contrast, HBeAg enhanced the expression of soluble forms of Fas through facilitation of Fas alternative mRNA splicing. In a mouse model, expression of HBeAg in mice injected with recombinant adenovirus-associated virus 8 inhibited agonistic anti-Fas antibody-induced hepatic apoptosis. Xenograft tumorigenicity assay also found that HBeAg-induced carcinogenesis was resistant to the proapoptotic effect of TRAIL and chemotherapeutic drugs. These results indicate that HBeAg may prevent hepatocytes from FasL and TRAIL-induced apoptosis by regulating the expression of the proapoptotic and antiapoptotic forms of death receptors, which may contribute to the survival and persistence of infected hepatocytes during HBV infection.

Increasing phosphate sorption on barium slag by adding phosphogypsum for non-hazardous treatment.

Barium slag (BS) is a waste residue in the barium salt industrial procedure. Due to its high leaching concentration of Ba2+, BS is classified as a kind of hazardous waste. Industrial waste phosphogypsum (PG) is effective to immobilize barium ion in BS owing to the slightly soluble sulfate included. In this study, two different proportions of PG were selected for mixing with BS to solidify soluble barium ion. The non-hazardous BS samples treated with the proportions of PG (BS-PG1, BS-PG3) were then functionally used for phosphate removal in solution. Batch experiments for removal of phosphate were performed to evaluate the adsorption efficiency of BS-PG1 and BS-PG3. The effect of various factors such as contact time, initial pH, and reaction temperature on sorption performance was investigated. BS-PG1 and BS-PG3 reached adsorption equilibrium in approximately 3h at the initial concentration of 15 mg/L, and BS-PG1 exhibited adsorption capacity of 12.47 mg P/g, higher than that of BS (11.49 mg P/g) under the condition of solid:liquid, 1g:1L, 25 °C, natural pH. The results show that the adsorption processes of phosphates ions onto both BS-PG1 and BS-PG3 fitted well with the pseudo-second-order kinetic model. The Langmuir isothermal model was considered as the appropriate equation for experimental data, showing a maximum adsorption capacity for phosphate up to 13.67 mg P/g and 11.59 mg P/g for BS-PG1 and BS-PG3. In comparison with other adsorbents, BS-PG1 and BS-PG3 could be considered as efficient materials for the removal of phosphate.

Hepatitis B virus core protein promotes hepatocarcinogenesis by enhancing Src expression and activating the Src/PI3K/Akt pathway.

Hepatitis B virus core protein (HBc) is expressed preferentially in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). HBc can function as an oncogene arising from its gene regulatory properties, but how it contributes functionally to hepatocarcinogenesis remains unclear. In this study, we determined the molecular and functional roles of HBc during HBV-associated hepatocellular tumorigenesis. HBc increased tumor formation of hepatoma cells. Moreover, expression of HBc specifically promoted proliferation of hepatoma cells in vitro. Mechanistic investigations revealed that these effects were caused by activation of the Src/PI3K/Akt pathway through proximal switch from inactive Src to the active form of the kinase by HBc. HBc-mediated sarcoma (Src) kinase activation was associated with down-regulation of C-terminal Src kinase (Csk). In addition, HBc enhances Src expression by activation of alternative Src 1A promoter in an Sp1 transcription factor-dependent manner. Proliferation induced by stable HBc expression was associated with increased G1-S cell cycle progression mediated by Src kinase activation. HBc-induced cellular proliferation and tumor formation were reversed by administration of the Src inhibitor saracatinib. Together, our findings suggest that HBc promotes tumorigenesis of hepatoma cells by enhancing the expression of total Src and the active form of the kinase and subsequently activates Src/PI3K/Akt signaling pathway, revealing novel insights into the underlying mechanisms of HBV-associated hepatocarcinogenesis.-Liu, W., Guo, T.-F., Jing, Z.-T., Yang, Z., Liu, L., Yang, Y.-P., Lin, X., Tong, Q.-Y. Hepatitis B virus core protein promotes hepatocarcinogenesis by enhancing Src expression and activating the Src/PI3K/Akt pathway.

Effect of Oxidization Temperatures and Aging on Performance of Carbonate Melt Oxidized Iridium Oxide pH Electrode.

Iridium oxide pH electrodes employing the carbonate melt oxidation method were fabricated with oxidation temperatures of 750 °C, 800 °C and 850 °C, respectively. Scanning electron microscope (SEM) and atomic force microscope (AFM) images showed that the oxide film regularized with the increase in oxidation temperatures. The pH response, response time and long-term stability of the electrodes indicated that the electrodes made at 850 °C had the best performance. X-ray photoelectron spectra (XPS) surveys investigated the change in the electrodes' chemical composition and element oxidation states at 850 °C, and the results showed that the relative content of Ir3+ had increased by 23.9%, and the Ir4+ and Ir6+ had decreased by 10.9% and 13%, respectively, in the surface oxide layer after one month of aging. However, the relative contents of Ir3+, Ir4+ and Ir6+ were almost constant for the inner oxide layer. Meanwhile, the XPS result also indicated that the outer oxide layer of the electrode had a higher hydration degree than the inner oxide layer.

Tape-Assisted Photolithographic-Free Microfluidic Chip Cell Patterning for Tumor Metastasis Study.

Cancer metastatic dissemination is a complex event during tumor progression which involves cell-cell and cell-matrix interactions. Micropatterning is one of the most efficient ways to study tumor development because it can tune the distribution of cells with spatial and temporal control. Extensive studies have shown that microfluidics can provide a feasible method for cell patterning. However, the current technique requires a microfabrication laboratory to manufacture the chip, which results in inaccessibility to researchers, especially biologists who focus on disclosing biological mechanisms rather than the methods. In this work, we developed a new methodology (tape-assisted photolithographic-free microfluidic chip, TAPMiC) that can realize homogeneous and heterogeneous micropatterning (45 features, 300 µm diameter of each) on a culture dish without the photolithographic procedure. We have applied this method to study critical biological problems, such as tumor cell migration under different conditions, including antitumor pharmaceutics and candidate gene RNAi assay that was relevant to tumor translocation and invasion. Moreover, this platform can achieve copatterning to recapitulate the tumor invasion scenario with single-cell trackable analysis. To decode regulation during metastasis, we conducted in situ recovering for quantitative polymerase chain reaction (qPCR) analysis from each cell type from tumor-fibroblast copairing. Regulation of several essential genes has unveiled that matrix degradation gene MMP2 and angiogenesis associated gene VEGFA were up-regulated in tumor cells in the fibroblast-enriched niche compared with homogeneous cultivation. Therefore, this approach constitutes a novel tool for investigating metastasis with quantitative measurements both on phenotype and genetical information.

Mice Deficient in Cyp4a14 Have An Increased Number of Goblet Cells and Attenuated Dextran Sulfate Sodium-Induced Colitis.

BACKGROUND/AIMS: Cyp4a14 is a member of cytochrome P450 (Cyp450) enzyme superfamily that possesses NADPH monooxygenase activity, which catalyzes omega-hydroxylation of medium-chain fatty acids and arachidonic acid. Study suggests that down-regulation of Cyp4a14 has an anti-inflammatory response in intestine. The present study was to test the function of Cyp4a14 in dextran sulfate sodium (DSS)-induced colitis. METHODS: Female Cyp4a14-knockout (KO) and wild-type (WT) mice were treated with DSS for 6 days to induce colitis. The colon of mice was histologically observed by hematoxylin and eosin (H&E) and periodic acid Schiff (PAS) staining. The serum malondialdehyde (MDA), an endogenous indicator of oxidative stress, was chemically measured. Proinflammatory and NADPH oxidase genes were examined by quantitative polymerase chain reaction (qPCR). RESULTS: Cyp4a14-KO mice had a significantly higher number of goblet cells in the colon and were more resistant to DSS-induced colitis compared with the WT mice. The DSS-treated KO mice had lower levels of MDA. Consistent with the milder inflammatory pathological changes, DSS-treated KO mice had lower levels of IL-1ß, IL-6 and TNF-α mRNA in the liver and the colon. Moreover, the colon of DSS-treated Cyp4a14-KO and WT mice had higher mRNA levels of two members of NADPH oxidases, Nox2 and Nox4, suggesting that both Nox2 and Nox4 are inflammatory markers. By contrast, DSS-treated WT and KO mice had drastically decreased epithelium-localized Nox1 and dual oxidase (Duox) 2 mRNA levels, coinciding with the erosion of the mucosa induced by DSS. CONCLUSION: These results suggests a hypothesis that the increased goblet cell in the colon of Cyp4a14-KO mice provides protection from mucosal injury and Cyp4a14-increased oxidative stress exacerbates DSS-induced colitis. Therefore, Cyp4a14 may represent a potential target for treating colitis.

Flatbands and Emergent Ferromagnetic Ordering in Fe_{3}Sn_{2} Kagome Lattices.

A flatband representing a highly degenerate and dispersionless manifold state of electrons may offer unique opportunities for the emergence of exotic quantum phases. To date, definitive experimental demonstrations of flatbands remain to be accomplished in realistic materials. Here, we present the first experimental observation of a striking flatband near the Fermi level in the layered Fe_{3}Sn_{2} crystal consisting of two Fe kagome lattices separated by a Sn spacing layer. The band flatness is attributed to the local destructive interferences of Bloch wave functions within the kagome lattices, as confirmed through theoretical calculations and modelings. We also establish high-temperature ferromagnetic ordering in the system and interpret the observed collective phenomenon as a consequence of the synergetic effect of electron correlation and the peculiar lattice geometry. Specifically, local spin moments formed by intramolecular exchange interaction are ferromagnetically coupled through a unique network of the hexagonal units in the kagome lattice. Our findings have important implications to exploit emergent flat-band physics in special lattice geometries.

Differential roles for ArcA and ArcB homologues in swarming motility in Serratia marcescens FS14.

ArcAB is a two-component regulatory system that can help bacteria respond to and survive in a changing environment. To identify the function of ArcAB homologues in Serratia marcescens FS14, in-frame deletion mutants of the arcA, arcB and arcAB genes were constructed. Surprisingly, ArcB affects the motility of FS14, but ArcA does not. These results are the reverse of those found in Escherichia coli. Further studies demonstrated that ArcB could promote bacterial motility by activating the synthesis of flagella and particularly by activating the expression of the biosurfactant serrawettin W1. Our results suggest that ArcB may regulate FS14 motility by interacting with an unidentified response regulator other than ArcA. The regulation of ArcAB may be bacterial strain-specific, and the same regulatory system may participate in different mechanisms to adapt to different environments.

Rate of ß-amyloid accumulation varies with baseline amyloid burden: Implications for anti-amyloid drug trials.

INTRODUCTION: This study examined a longitudinal trajectory of ß-amyloid (Aß) accumulation at the predementia stage of Alzheimer's disease in the context of clinical trials. METHODS: Analyzed were baseline (BL) and 2 years' follow-up 18F-florbetapir positron emission tomography data of 246 Aß-positive subjects with normal cognition and mild cognitive impairment. We studied the relationship between annual accumulation rates of 18F-florbetapir and BL standard uptake value ratios in whole gray matter (SUVRGM). RESULTS: Subjects with BL SUVRGM of 0.56 to 0.92 (n = 134) appeared to accumulate Aß approximately 1.5 times faster than remaining subjects. In subjects with SUVRGM above 0.95, most regions with the highest annual accumulation rate were outside the established set of Alzheimer's disease typical regions. CONCLUSION: There are global and regional variations in annual accumulation rate at the predementia stage of Alzheimer's disease. When taken into account, the sample size in anti-amyloid trials can be substantially reduced. Critically, treated and placebo groups should be matched for BL SUVRGM.