Real-time label-free detection of dynamic aptamer-small molecule interactions using a nanopore nucleic acid conformational sensor.

Nucleic acids can undergo conformational changes upon binding small molecules. These conformational changes can be exploited to develop new therapeutic strategies through control of gene expression or triggering of cellular responses and can also be used to develop sensors for small molecules such as neurotransmitters. Many analytical approaches can detect dynamic conformational change of nucleic acids, but they need labeling, are expensive, and have limited time resolution. The nanopore approach can provide a conformational snapshot for each nucleic acid molecule detected, but has not been reported to detect dynamic nucleic acid conformational change in response to small -molecule binding. Here we demonstrate a modular, label-free, nucleic acid-docked nanopore capable of revealing time-resolved, small molecule-induced, single nucleic acid molecule conformational transitions with millisecond resolution. By using the dopamine-, serotonin-, and theophylline-binding aptamers as testbeds, we found that these nucleic acids scaffolds can be noncovalently docked inside the MspA protein pore by a cluster of site-specific charged residues. This docking mechanism enables the ion current through the pore to characteristically vary as the aptamer undergoes conformational changes, resulting in a sequence of current fluctuations that report binding and release of single ligand molecules from the aptamer. This nanopore tool can quantify specific ligands such as neurotransmitters, elucidate nucleic acid-ligand interactions, and pinpoint the nucleic acid motifs for ligand binding, showing the potential for small molecule biosensing, drug discovery assayed via RNA and DNA conformational changes, and the design of artificial riboswitch effectors in synthetic biology.

High-throughput droplet-based analysis of influenza A virus genetic reassortment by single-virus RNA sequencing.

The segmented RNA genome of influenza A viruses (IAVs) enables viral evolution through genetic reassortment after multiple IAVs coinfect the same cell, leading to viruses harboring combinations of eight genomic segments from distinct parental viruses. Existing data indicate that reassortant genotypes are not equiprobable; however, the low throughput of available virology techniques does not allow quantitative analysis. Here, we have developed a high-throughput single-cell droplet microfluidic system allowing encapsulation of IAV-infected cells, each cell being infected by a single progeny virion resulting from a coinfection process. Customized barcoded primers for targeted viral RNA sequencing enabled the analysis of 18,422 viral genotypes resulting from coinfection with two circulating human H1N1pdm09 and H3N2 IAVs. Results were highly reproducible, confirmed that genetic reassortment is far from random, and allowed accurate quantification of reassortants including rare events. In total, 159 out of the 254 possible reassortant genotypes were observed but with widely varied prevalence (from 0.038 to 8.45%). In cells where eight segments were detected, all 112 possible pairwise combinations of segments were observed. The inclusion of data from single cells where less than eight segments were detected allowed analysis of pairwise cosegregation between segments with very high confidence. Direct coupling analysis accurately predicted the fraction of pairwise segments and full genotypes. Overall, our results indicate that a large proportion of reassortant genotypes can emerge upon coinfection and be detected over a wide range of frequencies, highlighting the power of our tool for systematic and exhaustive monitoring of the reassortment potential of IAVs.

Spike substitution T813S increases Sarbecovirus fusogenicity by enhancing the usage of TMPRSS2.

SARS-CoV Spike (S) protein shares considerable homology with SARS-CoV-2 S, especially in the conserved S2 subunit (S2). S protein mediates coronavirus receptor binding and membrane fusion, and the latter activity can greatly influence coronavirus infection. We observed that SARS-CoV S is less effective in inducing membrane fusion compared with SARS-CoV-2 S. We identify that S813T mutation is sufficient in S2 interfering with the cleavage of SARS-CoV-2 S by TMPRSS2, reducing spike fusogenicity and pseudoparticle entry. Conversely, the mutation of T813S in SARS-CoV S increased fusion ability and viral replication. Our data suggested that residue 813 in the S was critical for the proteolytic activation, and the change from threonine to serine at 813 position might be an evolutionary feature adopted by SARS-2-related viruses. This finding deepened the understanding of Spike fusogenicity and could provide a new perspective for exploring Sarbecovirus' evolution.

Long Noncoding RNA HAFML Promotes Migration and Invasion of Rheumatoid Fibroblast-like Synoviocytes.

The aggressive phenotype exhibited by fibroblast-like synoviocytes (FLSs) is critical for the progression of joint destruction in rheumatoid arthritis (RA). Long noncoding RNAs (lncRNAs) have crucial roles in the pathogenesis of diverse disorders; however, few have been identified that might be able to control the joint damage in RA. In this study, we identified an lncRNA, ENST00000509194, which was expressed at abnormally high levels in FLSs and synovial tissues from patients with RA. ENST00000509194 positively modulates the migration and invasion of FLSs by interacting with human Ag R (HuR, also called ELAVL1), an RNA-binding protein that mainly stabilizes mRNAs. ENST00000509194 binds directly to HuR in the cytoplasm to form a complex that promotes the expression of the endocytic adaptor protein APPL2 by stabilizing APPL2 mRNA. Knockdown of HuR or APPL2 impaired the migration and invasion of RA FLSs. Given its close association with HuR and FLS migration, we named ENST00000509194 as HAFML (HuR-associated fibroblast migratory lncRNA). Our findings suggest that an increase in synovial HAFML might contribute to FLS-mediated rheumatoid synovial aggression and joint destruction, and that the lncRNA HAFML might be a potential therapeutic target for dysregulated fibroblasts in a wide range of diseases.

NAT10 promotes synovial aggression by increasing the stability and translation of N4-acetylated PTX3 mRNA in rheumatoid arthritis.

OBJECTIVE: Recent studies indicate that N-acetyltransferase 10 (NAT10)-mediated ac4C modification plays unique roles in tumour metastasis and immune infiltration. This study aimed to uncover the role of NAT10-mediated ac4C in fibroblast-like synoviocytes (FLSs) functions and synovial immune cell infiltration in rheumatoid arthritis (RA). METHODS: FLSs were obtained from active established patients with RA. Protein expression was determined by western blotting or immunohistochemistry or multiplexed immunohistochemistry. Cell migration was measured using a Boyden chamber. ac4C-RIP-seq combined with RNA-seq was performed to identify potential targets of NAT10. RNA immunoprecipitation was used to validate the interaction between protein and mRNA. NAT10 haploinsufficiency, inhibitor remodelin or intra-articular Adv-NAT10 was used to suppress arthritis in mice with delayed-type hypersensitivity arthritis (DYHA) and collagen II-induced arthritis (CIA) and rats with CIA. RESULTS: We found elevated levels of NAT10 and ac4C in FLSs and synovium from patients with RA. NAT10 knockdown or specific inhibitor treatment reduced the migration and invasion of RA FLSs. Increased NAT10 level in the synovium was positively correlated with synovial infiltration of multiple types of immune cells. NAT10 inhibition in vivo attenuated the severity of arthritis in mice with CIA and DTHA, and rats with CIA. Mechanistically, we explored that NAT10 regulated RA FLS functions by promoting stability and translation efficiency of N4-acetylated PTX3 mRNA. PTX3 also regulated RA FLS aggression and is associated with synovial immune cell infiltration. CONCLUSION: Our findings uncover the important roles of NAT10-mediated ac4C modification in promoting rheumatoid synovial aggression and inflammation, indicating that NAT10 may be a potential target for the treatment of RA, even other dysregulated FLSs-associated disorders.

lncRNA BANCR promotes the colorectal cancer metastasis through accelerating exosomes-mediated M2 macrophage polarization via regulating RhoA/ROCK signaling.

Cancer cells-derived exosomal lncRNAs could modulate the tumorigenesis of colorectal cancer (CRC) via modulating macrophage M2 polarization. However, the clarified mechanism and function of lncRNA BANCR in CRC remains unclear. Exosomes were identified by TEM, NTA, western blot and fluorescent staining. M2 macrophages were identified by CD206 and CD163 expressions using by flow cytometry and RT-qPCR. In addition, the relation between IGF2BP2 and BANCR or RhoA were explored by RIP assay. The malignant behaviors of CRC cells were examined by CCK-8, EdU and transwell assays. Histopathological changes in mice were observed by H&E staining. Silencing of BANCR notably inhibited the proliferation, migration and invasion of CRC cells. SW620 and HCT-15 cells-derived exosomal BANCR positively regulated the macrophage M2 polarization. In addition, exosomal BANCR remarkably enhanced the promoting roles mediated by M2 macrophages on proliferation and invasion in CRC cells. Meanwhile, exosomal BANCR promoted the M2 macrophage polarization via activation of RhoA/Rock pathway by recruiting IGF2BP2. Inhibition of RhoA/Rock pathway reversed exosomal BANCR-mediated macrophages M2 polarization and CRC malignant behaviors in SW620 and HCT-15 cells. Exosomal lncRNA BANCR derived from SW620 and HCT-15 cells promoted the metastasis of CRC via inducing the polarization of M2 macrophages. Thus, BANCR might be a new target for the treatment of CRC.

Calcineurin inhibitor effects on kidney electrolyte handling and blood pressure: tacrolimus versus voclosporin.

BACKGROUND AND HYPOTHESIS: Calcineurin inhibitors affect kidney electrolyte handling and blood pressure through an effect on the distal tubule. The second generation calcineurin inhibitor voclosporin causes hypomagnesemia and hypercalciuria less often than tacrolimus. This suggests different effects on the distal tubule, but this has not yet been investigated experimentally. METHODS: Rats were treated with voclosporin, tacrolimus or vehicle for 28 days. Dosing was based on a pilot experiment to achieve clinically therapeutic concentrations. Drug effects were assessed by electrolyte handling at day 18 and 28, thiazide testing at day 20, telemetric blood pressure recordings, and analysis of mRNA and protein levels of distal tubular transporters at day 28. RESULTS: Compared to vehicle, tacrolimus but not voclosporin significantly increased the fractional excretions of calcium (>4-fold), magnesium and chloride (both 1.5-fold) and caused hypomagnesemia. Tacrolimus but not voclosporin significantly reduced distal tubular transporters at mRNA and/or protein level, including the sodium-chloride cotransporter, transient receptor melastatin 6, transient receptor potential vanilloid 5, cyclin M2, sodium-calcium exchanger and calbindin-D28K. Tacrolimus but not voclosporin reduced the mRNA level and urinary excretion of epidermal growth factor. The saluretic response to hydrochlorothiazide at day 20 was similar in the voclosporin and vehicle groups, whereas it was lower in the tacrolimus group. The phosphorylated form of the sodium-chloride cotransporter was significantly higher at day 28 in rats treated with voclosporin than in those treated with tacrolimus. Tacrolimus transiently increased blood pressure, whereas voclosporin caused a gradual but persistent increase in blood pressure which was further characterized by high renin, normal aldosterone, and low endothelin-1. CONCLUSIONS: In contrast to tacrolimus, voclosporin does not cause hypercalciuria and hypomagnesemia, but similarly causes hypertension. Our data reveal differences between the distal tubular effects of tacrolimus and voclosporin and provide a pathophysiological basis for the clinically observed differences between the two calcineurin inhibitors.

Bclaf1 regulates c-FLIP expression and protects cells from TNF-induced apoptosis and tissue injury.

TNF stimulation generates pro-survival signals through activation of NF-κB that restrict the build-in death signaling triggered by TNF. The competition between TNF-induced survival and death signals ultimately determines the fate of a cell. Here, we report the identification of Bclaf1 as a novel component of the anti-apoptotic program of TNF. Bclaf1 depletion in multiple cells sensitizes cells to TNF-induced apoptosis but not to necroptosis. Bclaf1 exerts its anti-apoptotic function by promoting the transcription of CFLAR, a caspase 8 antagonist, downstream of NF-κB activation. Bclaf1 binds to the p50 subunit of NF-κB, which is required for Bclaf1 to stimulate CFLAR transcription. Finally, in Bclaf1 siRNA administered mice, TNF-induced small intestine injury is much more severe than in control mice with aggravated signs of apoptosis and pyroptosis. These results suggest Bclaf1 is a key regulator in TNF-induced apoptosis, both in vitro and in vivo.

Cellular mechanisms underlying extraordinary sulfide tolerance in a crustacean holobiont from hydrothermal vents.

The shallow-water hydrothermal vent system of Kueishan Island has been described as one of the world's most acidic and sulfide-rich marine habitats. The only recorded metazoan species living in the direct vicinity of the vents is Xenograpsus testudinatus, a brachyuran crab endemic to marine sulfide-rich vent systems. Despite the toxicity of hydrogen sulfide, X. testudinatus occupies an ecological niche in a sulfide-rich habitat, with the underlying detoxification mechanism remaining unknown. Using laboratory and field-based experiments, we characterized the gills of X. testudinatus that are the major site of sulfide detoxification. Here sulfide is oxidized to thiosulfate or bound to hypotaurine to generate the less toxic thiotaurine. Biochemical and molecular analyses demonstrated that the accumulation of thiosulfate and hypotaurine is mediated by the sodium-independent sulfate anion transporter (SLC26A11) and taurine transporter (Taut), which are expressed in gill epithelia. Histological and metagenomic analyses of gill tissues demonstrated a distinct bacterial signature dominated by Epsilonproteobacteria. Our results suggest that thiotaurine synthesized in gills is used by sulfide-oxidizing endo-symbiotic bacteria, creating an effective sulfide-buffering system. This work identified physiological mechanisms involving host-microbe interactions that support life of a metazoan in one of the most extreme environments on our planet.

Comparison of the Diagnostic Accuracies of Monocyte Distribution Width, Procalcitonin, and C-Reactive Protein for Sepsis: A Systematic Review and Meta-Analysis.

OBJECTIVES: We performed a systemic review and meta-analysis to evaluate the diagnostic accuracy of monocyte distribution width (MDW) and to compare with procalcitonin and C-reactive protein (CRP), in adult patients with sepsis. DATA SOURCES: A systematic literature search was performed in PubMed, Embase, and the Cochrane Library to identify all relevant diagnostic accuracy studies published before October 1, 2022. STUDY SELECTION: Original articles reporting the diagnostic accuracy of MDW for sepsis detection with the Sepsis-2 or Sepsis-3 criteria were included. DATA EXTRACTION: Study data were abstracted by two independent reviewers using a standardized data extraction form. DATA SYNTHESIS: Eighteen studies were included in the meta-analysis. The pooled sensitivity and specificity of MDW were 84% (95% CI [79-88%]) and 68% (95% CI [60-75%]). The estimated diagnostic odds ratio and the area under the summary receiver operating characteristic curve (SROC) were 11.11 (95% CI [7.36-16.77]) and 0.85 (95% CI [0.81-0.89]). Significant heterogeneity was observed among the included studies. Eight studies compared the diagnostic accuracies of MDW and procalcitonin, and five studies compared the diagnostic accuracies of MDW and CRP. For MDW versus procalcitonin, the area under the SROC was similar (0.88, CI = 0.84-0.93 vs 0.82, CI = 0.76-0.88). For MDW versus CRP, the area under the SROC was similar (0.88, CI = 0.83-0.93 vs 0.86, CI = 0.78-0.95). CONCLUSIONS: The results of the meta-analysis indicate that MDW is a reliable diagnostic biomarker for sepsis as procalcitonin and CRP. Further studies investigating the combination of MDW and other biomarkers are advisable to increase the accuracy in sepsis detection.

Impaired retinal microcirculation in patients with non-obstructive coronary artery disease.

PURPOSE: To quantitatively investigate alterations of retinal microcirculation in patients with non-obstructive coronary artery disease (NOCAD) using optical coherence tomography angiography (OCTA), and to identify the ability of retinal microcirculation parameters in differentiating coronary artery disease (CAD) subtypes. METHODS: All participants with angina pectoris underwent coronary computed tomography angiography. Patients with lumen diameter reduction of 20-50 % in all major coronary arteries were defined as NOCAD, while patients with at least one major coronary artery lumen diameter reduction ≥ 50 % were recruited as obstructive coronary artery disease (OCAD). Participants without a history of ophthalmic or systemic vascular disease were recruited as healthy controls. Retinal neural-vasculature was measured quantitatively by OCTA, including peripapillary retinal nerve fiber layer (RNFL) thickness and vessel density (VD) of the optic disc, superficial vessel plexus (SVP), deep vessel plexus (DVP), and foveal density (FD 300). p < 0.017 is considered significant in multiple comparisons. RESULTS: A total of 185 participants (65 NOCAD, 62 OCAD, and 58 controls) were enrolled. Except for the DVP fovea (p = 0.069), significantly reduced VD in all other regions of SVP and DVP was detected in both the NOCAD and OCAD groups compared to control group (all p < 0.017), while a more significant decrease was found in OCAD compared to NOCAD. Multivariate regression analysis showed that lower VD in superior hemi part of whole SVP (OR: 0.582, 95 % CI: 0.451-0.752) was an independent risk factor for NOCAD compared to controls, while lower VD in the whole SVP (OR: 0.550, 95 % CI: 0.421-0.719) was an independent risk factor for OCAD compared to NOCAD. Using the integration of retinal microvascular parameters, the area under the receiver operating characteristic curve (AUC) for NOCAD versus control and OCAD versus NOCAD were 0.840 and 0.830, respectively. CONCLUSION: Significant retinal microcirculation impairment, while milder than that in OCAD was observed in NOCAD patients, indicating retinal microvasculature assessment might provide a new systemic microcirculation observation window for NOCAD. Furthermore, retinal microvasculature may serve as a new indicator to assess the severity of CAD with good performance of retinal microvascular parameters in identifying different CAD subtypes.

Modeled production, oxidation, and transport processes of wetland methane emissions in temperate, boreal, and Arctic regions.

Wetlands are the largest natural source of methane (CH4 ) to the atmosphere. The eddy covariance method provides robust measurements of net ecosystem exchange of CH4 , but interpreting its spatiotemporal variations is challenging due to the co-occurrence of CH4 production, oxidation, and transport dynamics. Here, we estimate these three processes using a data-model fusion approach across 25 wetlands in temperate, boreal, and Arctic regions. Our data-constrained model-iPEACE-reasonably reproduced CH4 emissions at 19 of the 25 sites with normalized root mean square error of 0.59, correlation coefficient of 0.82, and normalized standard deviation of 0.87. Among the three processes, CH4 production appeared to be the most important process, followed by oxidation in explaining inter-site variations in CH4 emissions. Based on a sensitivity analysis, CH4 emissions were generally more sensitive to decreased water table than to increased gross primary productivity or soil temperature. For periods with leaf area index (LAI) of ≥20% of its annual peak, plant-mediated transport appeared to be the major pathway for CH4 transport. Contributions from ebullition and diffusion were relatively high during low LAI (<20%) periods. The lag time between CH4 production and CH4 emissions tended to be short in fen sites (3 ± 2 days) and long in bog sites (13 ± 10 days). Based on a principal component analysis, we found that parameters for CH4 production, plant-mediated transport, and diffusion through water explained 77% of the variance in the parameters across the 19 sites, highlighting the importance of these parameters for predicting wetland CH4 emissions across biomes. These processes and associated parameters for CH4 emissions among and within the wetlands provide useful insights for interpreting observed net CH4 fluxes, estimating sensitivities to biophysical variables, and modeling global CH4 fluxes.

Observational constraints reduce model spread but not uncertainty in global wetland methane emission estimates.

The recent rise in atmospheric methane (CH4 ) concentrations accelerates climate change and offsets mitigation efforts. Although wetlands are the largest natural CH4 source, estimates of global wetland CH4 emissions vary widely among approaches taken by bottom-up (BU) process-based biogeochemical models and top-down (TD) atmospheric inversion methods. Here, we integrate in situ measurements, multi-model ensembles, and a machine learning upscaling product into the International Land Model Benchmarking system to examine the relationship between wetland CH4 emission estimates and model performance. We find that using better-performing models identified by observational constraints reduces the spread of wetland CH4 emission estimates by 62% and 39% for BU- and TD-based approaches, respectively. However, global BU and TD CH4 emission estimate discrepancies increased by about 15% (from 31 to 36 TgCH4 year-1 ) when the top 20% models were used, although we consider this result moderately uncertain given the unevenly distributed global observations. Our analyses demonstrate that model performance ranking is subject to benchmark selection due to large inter-site variability, highlighting the importance of expanding coverage of benchmark sites to diverse environmental conditions. We encourage future development of wetland CH4 models to move beyond static benchmarking and focus on evaluating site-specific and ecosystem-specific variabilities inferred from observations.

Chronic kidney disease increases the susceptibility to negative effects of low and high potassium intake.

BACKGROUND AND HYPOTHESIS: Dietary potassium (K+) has emerged as a modifiable factor for cardiovascular and kidney health in the general population, but its role in people with chronic kidney disease (CKD) is unclear. Here, we hypothesize that CKD increases the susceptibility to negative effects of low and high K+ diets. METHODS: We compared the effects of low, normal, or high KChloride (KCl) diets and a high KCitrate diet for four weeks in male rats with normal kidney function and in male rats with CKD using the 5/6th nephrectomy model (5/6Nx). RESULTS: Compared to rats with normal kidney function, 5/6Nx rats on the low KCl diet developed more severe extracellular and intracellular hypokalemia and more severe kidney injury, characterized by nephromegaly, infiltration of T-cells and macrophages, decreased eGFR and increased albuminuria. The high KCl diet caused hyperkalemia, hyperaldosteronism, hyperchloremic metabolic acidosis and severe hypertension in 5/6Nx but not in sham rats. The high KCitrate diet caused hypochloremic metabolic alkalosis but attenuated hypertension despite higher abundance of the phosphorylated sodium chloride cotransporter (pNCC) and similar levels of plasma aldosterone and epithelial sodium channel (ENaC) abundance. All 5/6Nx groups had more collagen deposition than the sham groups and this effect was most pronounced in the high KCitrate group. Plasma aldosterone correlated strongly with kidney collagen deposition. CONCLUSIONS: CKD increases the susceptibility to negative effects of low and high K+ diets in male rats, although the injury patterns are different. The low K+ diet caused inflammation, nephromegaly and kidney function decline, whereas the high K+ diet caused hypertension, hyperaldosteronism and kidney fibrosis. High KCitrate attenuated the hypertensive but not the pro-fibrotic effect of high KCl, which may be attributable to K+-induced aldosterone secretion. Our data suggest that especially in people with CKD it is important to identify the optimal threshold of dietary K+ intake.

Molecular Composition of Beijing PM2.5 Brown Carbon Revealed by an Untargeted Approach Based on Gas Chromatography and Time-of-Flight Mass Spectrometry.

The knowledge of the chemical composition of brown carbon (BrC) is limited to the categories of components or parts of specific organic components. In this paper, the light-absorbing properties and molecular compositions of lipid-soluble organic components in fine particulate matter of Beijing from 2016 to 2018, characterized by an ultraviolet-visible spectrometer and gas chromatography coupled with time-of-flight mass spectrometry, respectively, were combined to untargetedly screen the key BrC molecules by a partial least squares regression model for the first time. A total of 421 molecules were obtained, where 61 molecules were identified qualitatively and 22 molecules quantitatively. To the best of our knowledge, 11 molecules were newly identified BrC species. These qualitative molecules included polycyclic aromatic hydrocarbons with higher ambient concentrations and mass absorbing efficiencies (MAEs), as well as oxygen- and nitrogen-containing aromatic components with relatively lower concentrations and MAEs. The absorption contribution at 365 nm of quantified BrC species to lipid-soluble BrC during heating seasons was 39.1 ± 17.0%, which was about 5 times as high as previous studies. These results help establish a complete BrC molecular database and provide data support for better evaluating the climate effect of atmospheric carbonaceous aerosols and formulating air pollution control strategies.

Vertical Hydrologic Exchange Flows Control Methane Emissions from Riverbed Sediments.

CH4 emissions from inland waters are highly uncertain in the current global CH4 budget, especially for streams, rivers, and other lotic systems. Previous studies have attributed the strong spatiotemporal heterogeneity of riverine CH4 to environmental factors such as sediment type, water level, temperature, or particulate organic carbon abundance through correlation analysis. However, a mechanistic understanding of the basis for such heterogeneity is lacking. Here, we combine sediment CH4 data from the Hanford reach of the Columbia River with a biogeochemical-transport model to show that vertical hydrologic exchange flows (VHEFs), driven by the difference between river stage and groundwater level, determine CH4 flux at the sediment-water interface. CH4 fluxes show a nonlinear relationship with the magnitude of VHEFs, where high VHEFs introduce O2 into riverbed sediments, which inhibit CH4 production and induce CH4 oxidation, and low VHEFs cause transient reduction in CH4 flux (relative to production) due to reduced advective CH4 transport. In addition, VHEFs lead to the hysteresis of temperature rise and CH4 emissions because high river discharge caused by snowmelt in spring leads to strong downwelling flow that offsets increasing CH4 production with temperature rise. Our findings reveal how the interplay between in-stream hydrologic flux besides fluvial-wetland connectivity and microbial metabolic pathways that compete with methanogenic pathways can produce complex patterns in CH4 production and emission in riverbed alluvial sediments.

HSF1, Aging, and Neurodegeneration.

Heat shock factor 1 (HSF1) is a master transcription regulator that mediates the induction of heat shock protein chaperones for quality control (QC) of the proteome and maintenance of proteostasis as a protective mechanism in response to stress. Research in this particular area has accelerated dramatically over the past three decades following successful isolation, cloning, and characterization of HSF1. The intricate multi-protein complexes and transcriptional activation orchestrated by HSF1 are fundamental processes within the cellular QC machinery. Our primary focus is on the regulation and function of HSF1 in aging and neurodegenerative diseases (ND) which represent physiological and pathological states of dysfunction in protein QC. This chapter presents an overview of HSF1 structural, functional, and energetic properties in healthy cells while addressing the deterioration of HSF1 function viz-à-viz age-dependent and neuron-specific vulnerability to ND. We discuss the structural domains of HSF1 with emphasis on the intrinsically disordered regions and note that disease proteins associated with ND are often structurally disordered and exquisitely sensitive to changes in cellular environment as may occur during aging. We propose a hypothesis that age-dependent changes of the intrinsically disordered proteome likely hold answers to understand many of the functional, structural, and organizational changes of proteins and signaling pathways in aging - dysfunction of HSF1 and accumulation of disease protein aggregates in ND included.Structured AbstractsIntroduction: Heat shock factor 1 (HSF1) is a master transcription regulator that mediates the induction of heat shock protein chaperones for quality control (QC) of the proteome as a cyto-protective mechanism in response to stress. There is cumulative evidence of age-related deterioration of this QC mechanism that contributes to disease vulnerability. OBJECTIVES: Herein we discuss the regulation and function of HSF1 as they relate to the pathophysiological changes of protein quality control in aging and neurodegenerative diseases (ND). METHODS: We present an overview of HSF1 structural, functional, and energetic properties in healthy cells while addressing the deterioration of HSF1 function vis-à-vis age-dependent and neuron-specific vulnerability to neurodegenerative diseases. RESULTS: We examine the impact of intrinsically disordered regions on the function of HSF1 and note that proteins associated with neurodegeneration are natively unstructured and exquisitely sensitive to changes in cellular environment as may occur during aging. CONCLUSIONS: We put forth a hypothesis that age-dependent changes of the intrinsically disordered proteome hold answers to understanding many of the functional, structural, and organizational changes of proteins - dysfunction of HSF1 in aging and appearance of disease protein aggregates in neurodegenerative diseases included.

SARS-CoV-2 rapid antigen testing positive rate in community testing stations as an indicator for COVID-19 epidemic trend, Taipei, Taiwan, May to August 2021.

BACKGROUND: Real-time surveillance of COVID-19 in large-scale community outbreaks presents challenges. Simple counts of the daily confirmed cases can be misleading due to constraints from bottlenecks in access to care or laboratory testing. This study aimed to investigate the role of the SARS-CoV-2 antigen rapid diagnostic test (Ag-RDT) in addressing these challenges for real-time COVID-19 surveillance. METHODS: This study included the results of 86,994 SARS-CoV-2 Ag-RDT and real-time reverse transcription polymerase chain reaction (RT-PCR) tests. These were conducted at four community testing stations within the Taipei metropolitan area during a community COVID-19 outbreak spanning from May 17, 2021, to August 9, 2021. We examined the correlation between the positive rates of Ag-RDT tests and the epidemic curve of laboratory-confirmed COVID-19 cases by onset date to examine its role in real-time surveillance. RESULTS: During the 85-day study period, the trend of Ag-RDT test positive rates paralleled that of the epidemic curve. The correlation between the Ag-RDT positive rate and the number of cases (Pearson correlation coefficient: 0.968) is comparable to that of the RT-PCR positive rate (Pearson correlation coefficient: 0.964). The Ag-RDT positive rate exhibited a more advanced leading trend, with Ag-RDT leading by 3 days in comparison to the 2-day lead for RT-PCR. CONCLUSION: The positive rate of SARS-CoV-2 Ag-RDT tests at community testing stations serves as a good surrogate for assessing virus activity within the community and a useful tool for real-time COVID-19 surveillance. It is a robust indicator of the outbreak trend and near-term numbers of cases. This finding may facilitate the management of subsequent outbreaks of emerging infectious diseases.

[Association Between Dietary Knowledge and Food Preferences in Residents Aged 18 and Over in China Based on Latent Class Analysis].

Objective To investigate the food preferences and explore the potential association between dietary knowledge and food preferences in residents aged 18 and over in China,so as to provide a basis for promoting healthy diets.Methods The latent class analysis was carried out with the 2015 cross-sectional data of China health and nutrition survey to categorize the food preferences among 8 783 residents aged 18 and over.Multinomial Logistic regression was adopted to assess the association between and dietary knowledge and food preferences.Results The food preferences of the residents aged 18 and over in China were classified into preference for less vegetable(3.28%),lack of preference(11.20%),diverse preferences(4.19%),and preference for healthy diets(81.33%).The proportion of the adults with dietary knowledge was 36.87%(3 238/8 783).The dietary knowledge varied in the adults with different food preferences(all P<0.001).After adjusting for gender,age,urban and rural distribution,education background,and annual household income,for each point increase in the dietary knowledge score,there was an estimated reduction of 22% in the probability of preferring less vegetables(OR=0.78,95%CI=0.76-0.80, P<0.001),13% in the probability of lacking preference(OR=0.87,95%CI=0.86-0.89, P<0.001),and 3% in the probability of having diverse preferences(OR=0.97,95%CI=0.94-1.00, P=0.030).Compared with those lacking dietary knowledge,the individuals with dietary knowledge had a 77% less probability of preferring less vegetables(OR=0.23,95%CI=0.16-0.32, P<0.001),a 55% less probability of lacking preference(OR=0.45,95%CI=0.39-0.53, P<0.001),and a 23% less probability of having diverse preferences(OR=0.77,95%CI=0.61-0.96, P=0.023).Conclusions The residents aged 18 and over in China presented four food preferences,including preference for less vegetables,lack of preference,diverse preferences,and preference for healthy diets,the last of which had the highest proportion.The individuals with lower levels of dietary knowledge have higher probability of preferring unhealthy food.

[Comparison on Performance of Quantitative Ultrasound and Dual-Energy X-ray Absorptiometry in Evaluating Bone Health of Adults Aged 18-40 Years].

Objective To compare the consistency of quantitative ultrasound(QUS)and dual-energy X-ray absorptiometry(DXA)in measuring bone mineral density(BMD)of adults aged 18-40 years in Guangzhou and evaluate the diagnostic value of QUS for identifying low bone mass.Methods DXA was employed to measure the BMD and QUS to measure the speed of sound(SOS)in 731 participants.The Bland-Altman analysis was performed to evaluate the consistency of Z scores between SOS and BMD.With the BMD Z ≤-2.00 as the diagnostic criterion for low bone mass,the receiver operating characteristics curve of QUS was established,and the area under the curve(AUC)and the sensitivity,specificity,and correct diagnostic index for the optimal cut-off of SOS Z score were calculated.Results The results of Bland-Altman analysis showed that the mean differences in the Z scores of SOS and BMD in males and females were 1.27(-0.94 to 3.47)and 0.93(-1.33 to 3.18),respectively.The AUC of SOS Z score in the diagnosis of low bone mass in males and females was 0.734(95%CI=0.380-0.788)and 0.679(95%CI=0.625-0.732),respectively.In males,the optimal cut-off of SOS Z score for low bone mass was -0.35,with the sensitivity,specificity,and correct diagnostic index of 64.1%,68.6%,and 0.327,respectively.In females,the optimal cut-off value of SOS Z scores for low bone mass was -1.14,with the sensitivity,specificity,and correct index of 73.9%,54.8%,and 0.285,respectively.Conclusion QUS and DXA show poor consistency in the diagnosis of BMD in the adults aged 18-40 years in Guangzhou,while QUS demonstrates an acceptable value in identifying low bone mass.